Protected: Mantle Cell Lymphoma Stepping Up to the Plate

Mantle Cell Lymphoma, Stepping Up to the Plate by Jeffrey Dach MD..... Regular readers of my blog will know that I am not a great fan of chemotherapy as a cancer treatment. However, for certain types of cancer, conventional chemotherapy can be curative. These include lymphomas, testicular cancer and childhood leukemias. One must realize, of course, that chemotherapy drugs kill normal cells as well as cancer cells. This explains why chemotherapy is highly toxic even when curative. In those fortunate to be cured of their disease, there is a price to pay. The harsh chemotherapy may damage the nervous system, leaving the patient with permanent neurological and cognitive dysfunction. peripheral neuropathy and "chemo brain". Chemotherapy induced bone marrow suppression with neutropenia leaves the patient at greater risk for infection, which may be devastating. Left image: Micky Mantle courtesy of wikimedia commons. Searching For the Targeted Cancer Drug- Rituximab Dr. Sapna Parmar in a July 2014 article explains why Targeted Therapy is preferred over chemotherapy.(18): Unlike cytotoxic chemotherapy, which attacks all rapidly dividing cells, targeted therapy is directed toward precise pathways thought to contribute to the growth of cancer cells. This modality of treating cancer allows for more specific antitumor activity while avoiding normal cells and thus decreases traditional toxicity seen with chemotherapy, such as alopecia, gastrointestinal distress, and myelosuppression.(18) This is the reason a search is underway for newer more selective drug treatments which target cancer cells, while leaving normal cells unharmed. First Mono-Clonal Antibody for Cancer A new drug which revolutionized lymphoma treatment is Rituximab. from Genentech, (10-11) Rituxan was the first monoclonal antibody approved for cancer treatment in 1997, dramatically improving survival rates for lymphoma patients. The Rituximab antibody is directed at the CD-20 protein expressed on the surface of B-Cells (lymphoma cells). Although not a curative drug, addition of Rituximab to a standard chemotherapy protocols, CHOP (Cyclophosphamide, Hydroxy-Doxorubicin, Oncovin and Prednisone), has improved progression free survival. This new regimen has been dubbed R-CHOP. (the R stands for Rituxan). Mantle Cell Lymphoma Lymphoma is actually a heterogeneous group of hematological malignancies which can vary considerably in presentation, clinical course and prognosis. They range from indolent chronic forms which require no immediate treatment with a good prognosis to the more aggressive, highly proliferative forms with poor outcomes. T(11:14) Translocation One of the more aggressive types of lymphoma is called "Mantle Cell", relatively rare, 5% of all lymphomas and has a characteristic acquired genetic alteration, translocation between the chromosomes 11 and 14, (T11:14), resulting in up-regularion of Cyclin D1, a protein growth factor causing the rapid proliferation rate. Cyclin D1 is normally not present in lymphocytes. Biopsy samples of Mantle cell lymphoma reveal tell-tale staining for Cyclin-D1 a growth factor that induces rapid cell proliferation.(13) FISH stains performed on lymphocytes from biopsy material can reveal the chormosomal translocation (see image below). Above Left Image . (A) Normal lymphoid nucleus containing two chromosome 11 (red) and two chromosome 14 signals (green). Above Right Image (B) Mantle-cell lymphoma t(11;14) nucleus containing one red, one green and two red/green fusion signals, indicated by arrows (1000times original magnification). FISH) Fluorescent in situ hybridization of peripheral blood imprints for t(11;14) translocation. Images Courtesy of Tran, Huy, et al. "Methotrexate-associated mantle-cell lymphoma in an elderly man with myasthenia gravis." Nature Clinical Practice Oncology 5.4 (2008): 234-238. Cancer Clusters - Environmental Carcinogens Exposure to environmental chemical carcinogens is thought to be the cause for the genetic mutation in the lymphocyte, and a search for an Environmental Cancer Cluster is warranted. Cytosine Arabinoside For Mantle Cell Left image: the normal deoxycytosine triphosphate , forms DNA , courtesy of wikimedia. The standard chemotherapy regimen R-CHOP, (R-Rituximab C-Cylophosphamide H-hydroxy-doxorubicin O-Oncovin P-Prednisone) is frequently used for Lymphomas. However because of Mantle Cell Lymphoma's high proliferation rate, it is treated with a chemotherapy drug commonly used for childhood leukemia, cytosine arabinosise, a DNA nucleotide analog which blocks DNA replication by virtue of replacement of ribose with arabinose. The Ara-C analog is incorporated into DNA instead of the usual deoxycytosine triphosphate (see image) and this places a "monkey wrench" into the machinery of DNA replication, preventing cell replication. The drug preferentially affects rapidly dividing malignant cells, although normal cells undergoing cell division will also be affected.(12)) Left image Cytarabin courtesy of wikimedia commons. D-Ribose Compared to Arabinose The difference between D-ribose and L-Arabiniose is subtle as one can deduce form the chemical structure image below. The positions of the hydrogen and hydroxyl groups at the bottom of the sugar ring are "flipped" . This is called stereo-isomerism. However, this slight difference is enough to inhibit or block the enzymes involved in DNA replication, namely DNA polymerase and topoisomerase I. (12) Above image courtesy of tutorhelpdesk. New Drug Approved for Mantle Cell - ibrutinib - Imbruvica In the search for targeted therapies, a new drug has been developed. The drug, ibrutinib - Imbruvica, developed by Pharmacyclics, Inc and Johnson & Johnson's Janssen Pharmaceutical division, (14-20) Taken as a daily pill, ibrutinib - Imbruvica, blocks the Tyrosine Kinase pathway in malignant B- Cells. In a 2014 article in Hematology, Dr Aalipor sums up the benefits of the ibrutinib - Imbruvica drug with a description of the molecular pathways involved.:(16) "In mantle cell lymphoma (MCL), inhibition of BTK (Tyrosine Kinase) induces apoptosis and decreases levels of the antiapoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 . siRNA-mediated knockdown of BTK in MCL cells significantly reduces phospho-STAT3 and inhibits the NFκB pathway, which are necessary for MCL growth and cellular migration." (16) New Targeted Drugs on the Horizon Drugs This article by Dr Marc Weniger describes a large number of new targeted drugs still under development, Molecular Targeted Approaches in Mantle Cell.(21) One of these is Vorinostat (Zolinza) is a HDAC (histone deactelyase inhibitor) FDA approved for cutaneous T cell Lymphoma in 2006. ( 28-30 ) Another new drug mentioned in Bortezomib (Velcade). proteosome inhibitor FDA approved in 2003 and 2006 for Multiple Myeloma. Non-Toxic Therapies for Mantle Cell Lymphoma Curcumin My previous article, Cancer as a metabolic disease outlined a number of promising non-toxic cancer therapies. One of these is Curcumin available as a nutritional supplement, A number of publications deal with Curcumin as an ideal anti-cancer agent selectively killing Mantle Cell Lymphoma cells while leaving normal cells unharmed.(22-27) Curcumin Down Regulates Cyclin D1 Down regulation of Cyclin D1 is very advantageous in mantle cell lymphoma. Dr. Elliot Epner from Penn State reports in 2012, "Curcumin...has been shown in vitro to downregulate cyclins D1 and D3 at both the transcriptional and post-transcriptional levels in Mantle Cell Lymphoma and Multiple Myeloma. " (22) Curcumin Induces Apoptosis in Mantle Cells Dr Shishodia et al. in 2005 found that Curcumin inhibits Nuclear Factor Kappa Beta (NF-κB) activation, induces G1/S cell cycle arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma.(23) The authors state: "Overall, our results indicate that curcumin results in the suppression of proliferation, cell cycle arrest, and induction of apoptosis in Mantle Cell Lymphoma."(23) Mantle Cell Induction of apoptosis by curcumin was confirmed by others, as well.(23-27) Cannabis Medicine for Mantle Cell Lymphoma It may surprise you that a number of studies have been carried out dealing with cannabinoid receptors and ligands in mantle cell lymphoma showing striking benefits.(1-9) Left image: Fig C - shows intense red stain for CB1 receptors on mantle cells, while normal lymphocytes (Fig D) show no red staining. From Leukemia (2003) 17, 1880–1890. T C Islam, B Sander et al.(4) In a 2002 report in Leukemia, Dr Sander from the Karolinska Inst. in Sweden described features of mantle cells from biopsy samples obtained from 9 patients, (4) CB1 cannabinoid receptors are found in the brain and are usually not found in lympocytes. However, Dr Sander reported CB1 receptors are over-expressed in mantle cells samples obtained from biopsy materials. ( 4 ) The authors state: "These results clearly demonstrate that high expression of CB1 (Cannabinoid Receptor 1) is a characteristic feature of MCL (Mantle Cell Lymhoma)."(4) "All MCL cases were positive for Cyclin D1 protein and exhibited a characteristic nuclear staining." "These reports suggest that CB receptors have biologically important roles during B-cell differentiation and activation and together with our findings of an upregulation of CB1 receptor in MCL indicates that modulation of CB1 might be a candidate for tumour therapy." (4) Left Image: Fig E hows granular intra-cellular staining (green) for CB1 receptors in Mantle Cell Lymphoma case. (4) Later studies revealed that Cannabinoids are potent inducers of apoptosis in Mantle Cell lymphoma, while completely sparing normal lymphocytes..(5) In 2005, Dr Flygare states: "Our data suggest that cannabinoid receptors may be considered as potential therapeutic targets in MCL."(5) From 2004 to 2009, Dr Kristin Gustaffson from The Karolinska Inst. in Stockholm published a series of studies on the effect of cannabinoid ligands on mantle cells. (6-8) The author reports cannabinoids induce apoptosis in mantle cells via ceramide accumulation and P38 activation.(6-8) Dr Wasik in a 2011 report found that both CB1 and CB2 receptors are over-expressed in mantle cells.(9) The authors state: "Agonists to CB1 and CB2 promote ceramide de novo synthesis, p38–mitogen-activated protein kinase-dependent activation of caspase-3 and apoptotic cell death in most MCLs."(9) Artemisinin - Sulfasalazine Artemisisin and its derivatives are effective anticancer agents due to the high iron content of cancer cells compared to normal cells. The endoperoxide bridge in Artemisinin reacts with the Iron molecules in cancer cells, the Fenton Reaction, thus liberating ROS (reactive oxygen species) which induces apoptosis. See my article on this topic. Mantle cell lymphoma cells are resistant to oxidative chemotherapy by virtue of mutations which upregulate Glutathione transferase. This renders the Mantle cell relatively protected from oxidative damage.(53) Targeting Glutathione in the Mantle Cell Non-toxic targeted agents which deplete glutathione might render mantle cell lymphoma more sensitive to oxidative chemotherapy, as well as synergize with cell killing effect of Artemisinin. Sulfasalazine, a commonly used rheumatology drug, blocks the transport for cellular uptake of cystine, required for glutathione production, and the drug depletes the cancer cell of glutathione. Normal cells can manufacture cystine and are unaffected. Thus sulfasalazine has been found effective in selectively killing lymphoma cells in xenograft mouse models by reducing intracellular glutathione which triggers ferroptosis. A 2003 report by Dr Bebb showed sulfasalazine inhibits growth of Mantle Cell Lymphoma via cystine starvation in vitro as well as in vivo animal xenogradft studies.(54) As an added bonus, sullfasalazine also down regulates Nuclear Factor Kappa Beta as a separate mechanism.(54) Parthenolide Another non-toxic targeted agent found to target glutathione metabolism in cancer cells parthenolide which depletes intracellular glutathione. Parthenolide, the active molecule in , Feverfew, also is downregulates Nuclear Kappa Beta. A more active derivative, di-methyl-aminno-parthenolide (DMAPT) is currently undergoing clinical trials at Cardiff University. Anti-Platelet Activity- Targets Cancer Stem Cells Feverfew extracts are available as herbal supplements. Caution is advised because platelet inhibition may lead to bleeding expecially when used other agents with anti-platelet activity such as ibrutinib or aspirin. Another advantage of parthenolide is that it is one of the few agents known to selectively target and kill leukemia cancer stem cells and progenitor cells. Vitamin A Derivatives Effective Against Mantle Cell Lymphoma Novel Treatments on the Horizon - CAT Chimeric T Cells This new technology modifies the patients own T-cells, usually by adding an tumor associated antibody to the membrane surface of the T cells which binds to receptors on the tumor cell, the activated T cell then kills the tumor cell. (35-37) For more information see this Patients Against Lymphoma Page. The technique, although successful in some cases, is not harmless, as deaths from adverse effects have been reported related to T-cell attack on normal tissues which share the tumor associated antigen (TAA). A 2014 report from Dr Wang at MD Anderson describes favorable results for CAT treatement of 15 patients with chemotherapy refractory lymphoma. (38) As mentioned above, ibrutinib, a monoclonal antibody directed against CD-20, has shown favorable results in clinical trials and has received FDA approval for relapsed mantle cell lymphoma. The drug is also been (off-label) incorporated into first line treatment for newly diagnosed Mantle Cell cases. The main adverse effect is anti-platelet activity with bleeding events. The second problem is development of ibrutinib resistance through mutation of the cancer cells. CAT chimeric T cells work in combination with ibrutinib to increase the tumor cell killing effect.(34) A new technology under development, the chimeric antigen T cell (CAT), has been studied in combination with ibrutinib.(34) ( See image left) Top row showing Day 6 after MCL cells injected into mice (colored patches in mice). Left column shows control mice with extensive disease Day 60 (Red color in mouse). Second from left column shows ibutinib treated mice with less disease at day 60 (red color in mouse). Thrid column from left shows CAT19 treated mouse with disease progresion day 110 (red mouse) . Far right column combination treatment show best results. Courtesy of Fig 2 from (34) showing Mantle Cell- RL xenografts in mice treated with combination of CART19 (Chimeric Antigen Receptor T Cell) and ibrutinib resulting in 80% of mice achieving long-term disease-free survival. Markers and PCR Testing In the best case scenario, a combination of the above non-toxic targeted therapies along with cytotoxic chemotherapy will be successful. A Follow up PET/CAT scan will show clearing of tumor activity noted pre-treatment. A complete remission is defined as a normal PET/CAT scan, and return to normal of all tumor markers such as LDH, hs-CRP and Beta2 Microglobulin. PCR for MRD Another useful marker is the quantitative PCR for MRD (minimal residual disease) based on detecting in lymphocytes or plasma DNA containing the typical mantle cell translocation at t(11:14) bcl-1. This test is offered by Quest Labs (Nichols Institute in California). Serial Quantitative PCR is a powerful tool and now widely accepted technique for following Mantle Cell patient disease activity and risk for relapse.(39-49) Preventing Relapse in Mantle Cell Lymphoma Once complete remission is obtained, Allogeneic stem cell transplant may be offered at some institutions for the young patient with aggressive blastoid variant high KI-67 mantle cell lymphoma. A difficulty in attempting to evaluate Allogeneic stem cell transplant for Mantle Cell Lymphoma is there are no prospective randomized trials comparing it with other therapies.(52) Although there are some anecdotal reports of patients achieving durable remission after Allogeneic transplant, in my opinion, this procedure carries an unacceptable risk for mortality and morbidity, which is why most experts in the field do not recommend it for first remission. Graft vs. Lymphoma is considered the benefit of Allogeneic transplant, however, graft vs. host disease can lead to significant morbidity and mortality. .(50-52) Although newer targeted therapies are now coming into use, conventional oncology offers the Mantle Cell patient cytotoxic chemotherapy followed by autologous or allogeneic stem cell transplant. This is useful for the newly diagnoses patient symptomatic from organ infiltration by tumor masses. Remissions can be obtained. However relapse in inevitable. The reality is that in the world of conventional oncology there is no really curative treatment for Mantle Cell Lymphoma. This is openly stated as a fact in many hematology/oncology publications.(50-52) Vitamin A Derivatives for Prevention of Relapse in Mantle Cell (55-82) It has been known for 20 years now that the vitamin A derivative, All-trans-retinoic acid (ATRA) exhibits striking inhibition of aggressive B cell lymphoma cells (60) The Vitamin A derivative all-trans-retinoic acid (ATRA) induces complete remission in most patients with AML (acute Promyelocytic Leukemia), a remarkable fact considering the disease was previously 100% fatal. Working in collaboration with Leo Gordon MD at Northwestern University, the company Lypo Bioscience has a development pipeline which includes a nanodisk delivery system using combined Curcumin and ATRA. Preliminary cell culture studies show remarkable effectiveness against Mantel Cell Lymphoma at pharmacologically achievable doses with little or no toxicity.(55-58) ATRA may also be an effective treatment for other cancers such as breast cancer, lung cancer etc. (59-82) Articles with related interest Cannabis Oil for Leukemia Jeffrey Dach MD Links and References Medical Cannabis in Mantle Cell Lymphoma 1) Semin Cancer Biol. 2011 Nov;21(5):313-21. The role of cannabinoid receptors and the endocannabinoid system in mantle cell lymphoma and other non-Hodgkin lymphomas. Wasik AM1, Christensson B, Sander B. The initiating oncogenic event in mantle cell lymphoma (MCL) is the translocation of cyclin D1, t(11;14)(q13;q32). However, other genetic aberrations are necessary for an overt lymphoma to arise. Like other B cell lymphomas, MCL at some points during the oncogenesis is dependent on interactions with other cells and factors in the microenvironment. The G protein coupled receptors cannabinoid receptors 1 and 2 (CB1 and CB2) are expressed at low levels on non-malignant lymphocytes and at higher levels in MCL and other lymphoma subtypes. In this review we give an overview of what is known on the role of the cannabinoid receptors and their ligands in lymphoma as compared to non-malignant T and B lymphocytes. In MCL cannabinoids mainly reduce cell proliferation and induce cell death. Importantly, our recent findings demonstrate that cannabinoids may induce either apoptosis or another type of programmed cell death, cytoplasmic vacuolation/paraptosis in MCL. The signalling to death has been partly characterized. Even though cannabinoid receptors seem to be expressed in many other types of B cell lymphoma, the functional role of cannabinoid receptor targeting is yet largely unknown. In non-malignant B and T lymphocytes, cannabinoid receptors are up-regulated in response to antigen receptor signalling or CD40. For T lymphocytes IL-4 has also a crucial role in transcriptional regulation of CB1. In lymphocytes, cannabinoid act in several ways - by affecting cell migration, cytokine response, at high doses inhibit cell proliferation and inducing cell death. The possible role for the endocannabinoid system in the immune microenvironment of lymphoma is discussed. 2) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4278325/ Wasik AM, Nygren L, Almestrand S, et al. Perturbations of the endocannabinoid system in mantle cell lymphoma: correlations to clinical and pathological features. Oncoscience. 2014;1(8):550-557. 3) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4171598/ Chakravarti B, Ravi J, Ganju RK. Cannabinoids as therapeutic agents in cancer: current status and future implications. Oncotarget. 2014;5(15):5852-5872. >>>>>>>>>>>>>>>>>>>>>>>>> NICE IMAGE OF GREEN STAIN FOR CB1 RECEPTOR 4) http://www.nature.com/leu/journal/v17/n9/full/2403057a.html Leukemia (2003) 17, 1880–1890. doi:10.1038/sj.leu.2403057 High level of cannabinoid receptor 1, absence of regulator of G protein signalling 13 and differential expression of Cyclin D1 in mantle cell lymphoma T C Islam1, A C Asplund1, J M Lindvall1, L Nygren2, J Liden3, E Kimby4, B Christensson2, C I E Smith1 and B Sander2 5) Flygare, Jenny, et al. "Cannabinoid receptor ligands mediate growth inhibition and cell death in mantle cell lymphoma." FEBS letters 579.30 (2005): 6885-6889. We have earlier reported overexpression of the central and peripheral cannabinoid receptors CB1 and CB2 in mantle cell lymphoma (MCL), a B cell non-Hodgkin lymphoma. In this study, treatment with cannabinoid receptor ligands caused a decrease in viability of MCL cells, while control cells lacking CB1 were not affected. Interestingly, equipotent doses of the CB1 antagonist SR141716A and the CB1/CB2 agonist anandamide inflicted additive negative effects on viability. Moreover, treatment with the CB1/CB2 agonist Win-55,212-2 caused a decrease in long-term growth of MCL cells in culture. Induction of apoptosis, as measured by FACS/Annexin V–FITC, contributed to the growth suppressive effect of Win-55,212-2. Our data suggest that cannabinoid receptors may be considered as potential therapeutic targets in MCL. 6) http://molpharm.aspetjournals.org/content/70/5/1612.long Gustafsson, Kristin, et al. "Cannabinoid receptor-mediated apoptosis induced by R (+)-methanandamide and Win55, 212-2 is associated with ceramide accumulation and p38 activation in mantle cell lymphoma." Molecular pharmacology 70.5 (2006): 1612-1620. 7) Int J Cancer. 2008 Sep 1;123(5):1025-33. Expression of cannabinoid receptors type 1 and type 2 in non-Hodgkin lymphoma: growth inhibition by receptor activation. Gustafsson K1, Wang X, Severa D, Eriksson M, Kimby E, Merup M, Christensson B, Flygare J, Sander B. Endogenous and synthetic cannabinoids exert antiproliferative and proapoptotic effects in various types of cancer and in mantle cell lymphoma (MCL). In this study, we evaluated the expression of cannabinoid receptors type 1 and type 2 (CB1 and CB2) in non-Hodgkin lymphomas of B cell type (n 62). A majority of the lymphomas expressed higher mRNA levels of CB1 and/or CB2 as compared to reactive lymphoid tissue. With the exception of MCL, which uniformly overexpresses both CB1 and CB2, the levels of cannabinoid receptors within other lymphoma entities were highly variable, ranging from 0.1 to 224 times the expression in reactive lymph nodes. Low levels of the splice variant CB1a, previously shown to have a different affinity for cannabinoids than CB1, were detected in 44% of the lymphomas, while CB1b expression was not detected. In functional studies using MCL, Burkitt lymphoma (BL), chronic lymphatic leukemia (CLL) and plasma cell leukemia cell lines, the stable anandamide analog R(+)-methanandamide (R(+)-MA) induced cell death only in MCL and CLL cells, which overexpressed both cannabinoid receptors, but not in BL. In vivo treatment with R(+)-MA caused a significant reduction of tumor size and mitotic index in mice xenografted with human MCL. Together, our results suggest that therapies using cannabinoid receptor ligands will have efficiency in reducing tumor burden in malignant lymphoma overexpressing CB1 and CB2. 8) Gustafsson, Kristin, et al. "Potentiation of cannabinoid-induced cytotoxicity in mantle cell lymphoma through modulation of ceramide metabolism." Molecular Cancer Research 7.7 (2009): 1086-1098. Cannabinoid induced cytotoxicity mantle cell lymphoma ceramide metabolism Gustafsson Kristin 2009 Ceramide levels are elevated in mantle cell lymphoma (MCL) cells following treatment with cannabinoids. Here, we investigated the pathways of ceramide accumulation in the MCL cell line Rec-1 using the stable endocannabinoid analogue R(+)-methanandamide (R-MA). We further interfered with the conversion of ceramide into sphingolipids that promote cell growth. Treatment with R-MA led to increased levels of ceramide species C16, C18, C24, and C24:1 and transcriptional induction of ceramide synthases (CerS) 3 and 6. The effects were attenuated using SR141716A, which has high affinity to cannabinoid receptor 1 (CB1). The CB1-mediated induction of CerS3 and CerS6 mRNA was confirmed using Win-55,212-2. Simultaneous silencing of CerS3 and CerS6 using small interfering RNA abrogated the R-MA-induced accumulation of C16 and C24. Inhibition of either of the enzymes serine palmitoyl transferase, CerS, and dihydroceramide desaturase within the de novo ceramide pathway reversed ceramide accumulation and cell death induced by R-MA treatment. To enhance the cytotoxic effect R-MA, sphingosine kinase-1 and glucosylceramide synthase, enzymes that convert ceramide to the pro-proliferative sphingolipids sphingosine-1-phospate and glucosylceramide, respectively, were inhibited. Suppression of either enzyme using inhibitors or small interfering RNA potentiated the decreased viability, induction of cell death, and ceramide accumulation induced by R-MA treatment. Our findings suggest that R-MA induces cell death in MCL via CB1-mediated up-regulation of the de novo ceramide synthesis pathway. Furthermore, this is the first study were the cytotoxic effect of a cannabinoid is enhanced by modulation of ceramide metabolism. (Mol Cancer Res 2009;7(7):1086–98) 9) Wasik, A. M., et al. "WIN55, 212-2 induces cytoplasmic vacuolation in apoptosis-resistant MCL cells." Cell death & disease 2.11 (2011): e225. Cannabinoid receptors 1 (CB1) and/or 2 (CB2) are overexpressed in many types of human malignancies including mantle cell lymphoma (MCL). Agonists to CB1 and CB2 promote ceramide de novo synthesis, p38–mitogen-activated protein kinase-dependent activation of caspase-3 and apoptotic cell death in most MCLs. However, in this report we describe that in some MCLs the response to treatment with cannabinoids decreased cell viability as assessed by metabolic activity but did not involve the caspase-3 cascade or loss of plasma membrane integrity. Both primary cells from one MCL patient and the MCL cell line Granta519 responded to treatment with cannabinoids by formation of cycloheximide-sensitive cytoplasmic vacuoles, but did not enter apoptosis. The persistent expression of mammalian homolog of Atg8 with microtubule-associated protein-1 light chain-3 II (LC3 II) and p62, as well as the lack of protection from chloroquine, indicates that lysosomal degradation is not involved in this cytoplasmic vacuolation process, distinguishing from classical autophagy. Transmission electron microscopy images and immunofluorescence staining of endoplasmic reticulum (ER) chaperone calreticulin showed that the vacuoles were of ER origin and that chromatin remained normal. These features resemble paraptosis-like cell death—a third type of a programmed cell death not previously described in response to cannabinoids. ------------------------------------------------------------------------ Rituximab 10) Coiffier, Bertrand. "Treatment of non-Hodgkin's lymphoma: a look over the past decade." Clinical Lymphoma and Myeloma 7 (2006): S7-S13. The past decade has seen enormous changes in our understanding of lymphomas with a better classification (World Heath Organization) and identification of better prognostic factors; however, important genetic prognostic factors have not been completely analyzed. The appearance of rituximab and other monoclonal antibodies has completely revolutionized the treatment of this disease. If monoclonal antibodies have activity when used alone, most patients experienced relapse after such a treatment, even after maintenance therapy. The combination of rituximab with chemotherapy has now been shown in several randomized studies to increase the response rate, decrease the relapse rate, and prolong progression-free survival and overall survival. Rituximab plus CHOP (cyclophosphamide/doxorubicin/prednisone/vincristine; R-CHOP) has become the standard for patients with diffuse large B-cell lymphoma. Rituximab chemotherapy, probably with the CHOP regimen, is slowly gaining importance as the standard for patients with follicular lymphoma. Although little is known for other indolent lymphomas and mantle cell lymphoma, progress has been made there, too. Several questions remain for future randomized studies to continue our search toward cure. 11) Bello, Celeste, and Eduardo M. Sotomayor. "Monoclonal antibodies for B-cell lymphomas: rituximab and beyond." ASH Education Program Book 2007.1 (2007): 233-242. 12) Zhang, Ximbo, and Frederick L. Kiechle. "Cytosine arabinoside substitution decreases transcription factor-DNA binding element complex formation." Archives of pathology & laboratory medicine 128.12 (2004): 1364. The pyrimidine nucleoside analog, cytosine arabinoside (Ara-C), is an effective therapeutic agent for acute leukemia. The phosphorylated triphosphate, cytosine arabinoside triphosphate, competes with deoxycytosine triphosphate as a substrate for incorporation into DNA. Once incorporated into DNA, it inhibits DNA polymerase and topoisomerase I and modifies the tertiary structure of DNA. OBJECTIVE:To determine if the substitution of Ara-C for cytosine in double-stranded oligonucleotides that contain 4 specific transcription factor binding sites (TATA, GATA, C/EBP, and AP-2alpha) alters transcription factor binding to their respective DNA binding elements. DESIGN:Transcription factors were obtained from nuclear extracts from human promyelocytic leukemia HL-60 cells. -end-labeled double-stranded oligonucleotides that contained 1 or 2 specific transcription factor binding sites with or without Ara-C substitution for cytosine were used to assess transcription factor binding by electrophoretic mobility shift assay. RESULTS:The substitution of Ara-C for cytosine within and outside the transcription factor binding element (AP-2alpha, C/EBP), outside the binding element only (GATA, TATA), or within the binding element only (AP-2alpha) all result in a reduction in transcription factor binding to their respective DNA binding element. CONCLUSION:The reduction of the binding capacity of transcription factors with their respective DNA binding elements may depend on structural changes within oligonucleotides induced by Ara-C incorporation. This altered binding capacity of transcription factors to their DNA binding elements may represent one mechanism for Ara-C cytotoxicity secondary to inhibition of transcription of new messenger RNAs and, subsequently, translation of new proteins. ------------- 13) Hasanali, Zainul, Kamal Sharma, and Elliot Epner. "Flipping the cyclin D1 switch in mantle cell lymphoma." Best Practice & Research Clinical Haematology 25.2 (2012): 143-152. --------------------------------- ibrutinib - Imbruvica 14) FDA NEWS RELEASE : Nov. 13, 2013 - FDA approves Imbruvica for rare blood cancer (Mantle Cell) Second drug with breakthrough therapy designation to receive FDA approval. Imbruvica’s accelerated approval for MCL is based on a study where 111 participants were given Imbruvica daily until their disease progressed or side effects became intolerable. Results showed nearly 66 percent of participants had their cancer shrink or disappear after treatment (overall response rate). An improvement in survival or disease-related symptoms has not been established. 15) IMBRUVICA® (ibrutinib) Long-term Follow-up Data in Patients Living with Relapsed/Refractory Mantle Cell Lymphoma Show Almost Half Alive at Two Years Follow-up data from the Phase 2 PCYC-1104 trial presented at the American Society of Hematology Annual Meeting show sustained efficacy and safety over time ·Note: This press release corresponds to ASH abstracts 78, 4453 and 4471 16) Aalipour, Amin, and Ranjana H. Advani. "Bruton’s tyrosine kinase inhibitors and their clinical potential in the treatment of B-cell malignancies: focus on ibrutinib." Therapeutic advances in hematology 5.4 (2014): 121-133. 17) Shah, Nimish, Claire Hutchinson, and Simon Rule.Ibrutinib for the treatment of mantle cell lymphoma Shah Nimish hematology 2014. "Ibrutinib for the treatment of mantle cell lymphoma." Expert review of hematology 7.5 (2014): 521-531. 18) Parmar, Sapna, Khilna Patel, and Javier Pinilla-Ibarz. "Ibrutinib (imbruvica): a novel targeted therapy for chronic lymphocytic leukemia." Pharmacy and Therapeutics 39.7 (2014): 483. 19) Pharmacotherapy. 2014 Mar;34(3):303-14. The promising impact of ibrutinib, a Bruton's tyrosine kinase inhibitor, for the management of lymphoid malignancies. Bhatt V1, Alejandro L, Michael A, Ganetsky A. Lymphoid malignancies comprise a heterogeneous group of disorders originating from clonal proliferation of B or T lymphocytes. Treatment of lymphoid neoplasms has traditionally been pursued with cytotoxic chemotherapy. To improve efficacy and ameliorate the adverse effects associated with classic chemotherapy, molecularly targeted therapy has been developed. At the forefront of clinical development is ibrutinib, an inhibitor of Bruton's tyrosine kinase (Btk). Btk is a protein tyrosine kinase that plays an important role in regulating B-cell signaling. Dysregulated Btk results in uncontrolled B-lymphocyte proliferation, differentiation, and survival. Ibrutinib is currently being studied in numerous malignancies of lymphoid origin including chronic lymphocytic leukemia, mantle cell lymphoma, non-Hodgkin lymphoma, follicular lymphoma, and multiple myeloma. Thus far, ibrutinib has demonstrated very promising results in treatment-naive patients as well as those with relapsed or refractory disease with an acceptable safety profile. In this article, we describe the pharmacology, efficacy, and toxicity profile of ibrutinib and depict the potential role that ibrutinib will play in the treatment paradigm of lymphoid neoplasms. 20) http://onlinelibrary.wiley.com/doi/10.1111/bjh.13149/full Combination of ibrutinib with ABT-199: synergistic effects on proliferation inhibition and apoptosis in mantle cell lymphoma cells through perturbation of BTK, AKT and BCL2 pathways Xiaoxian Zhao1,Juraj Bodo1,Danyu Sun2,Lisa Durkin1,Jeffrey Lin1,Mitchell R. Smith2 and Eric D. Hsi1 Article first published online: 4 OCT 2014 21) Weniger, Marc A., and Adrian Wiestner. "Molecular targeted approaches in mantle cell lymphoma." Seminars in hematology. Vol. 48. No. 3. WB Saunders, 2011. curcumin and mantle cell 22) Hasanali, Zainul, Kamal Sharma, and Elliot Epner. "Flipping the cyclin D1 switch in mantle cell lymphoma." Best Practice & Research Clinical Haematology 25.2 (2012): 143-152. Curcumin, a plant flavonoid that is available naturally in turmeric and as an herbal supplement, has been shown in vitro to downregulate cyclins D1 and D3 at both the transcriptional and post-transcriptional levels in MCL and MM cell lines . Curcumin is known to inhibit the COP9 signalosome, a multiprotein complex similar to the proteasome , , and . Our laboratory has demonstrated that curcumin and bortezomib synergize in downregulating protein levels of cyclins D1 and D3 in MM and MCL cells . Clinical trials of this agent in combination in lymphoid malignancies alone or in combination with bortezomib are ongoing. Curcumin against Four MCL cell lines 23) Shishodia, Shishir, et al. "Curcumin (diferuloylmethane) inhibits constitutive NF-κB activation, induces G1/S arrest, suppresses proliferation, and induces apoptosis in mantle cell lymphoma." Biochemical pharmacology 70.5 (2005): 700-713. Biochem Pharmacol. 2005 Sep 1;70(5):700-13. Shishodia S1, Amin HM, Lai R, Aggarwal BB. Human mantle cell lymphoma (MCL), an aggressive B cell non-Hodgkin's lymphoma, is characterized by the overexpression of cyclin D1 which plays an essential role in the survival and proliferation of MCL. Because of MCL's resistance to current chemotherapy, novel approaches are needed. Since MCL cells are known to overexpress NF-kappaB regulated gene products (including cyclin D1), we used curcumin, a pharmacologically safe agent, to target NF-kappaB in a variety of MCL cell lines. All four MCL cell lines examined had overexpression of cyclin D1, constitutive active NF-kappaB and IkappaB kinase and phosphorylated forms of IkappaBalpha and p65. This correlated with expression of TNF, IkappaBalpha, Bcl-2, Bcl-xl, COX-2 and IL-6, all regulated by NF-kappaB. On treatment of cells with curcumin, however, downregulated constitutive active NF-kappaB and inhibited the consitutively active IkappaBalpha kinase (IKK), and phosphorylation of IkappaBalpha and p65. Curcumin also inhibited constitutive activation of Akt, needed for IKK activation. Consequently, the expression of all NF-kappaB-regulated gene products, were downregulated by the polyphenol leading to the suppression of proliferation, cell cycle arrest at the G1/S phase of the cell cycle and induction of apoptosis as indicated by caspase activation, PARP cleavage, and annexin V staining. That NF-kappaB activation is directly linked to the proliferation of cells, is also indicated by the observation that peptide derived from the IKK/NEMO-binding domain and p65 suppressed the constitutive active NF-kappaB complex and inhibited the proliferation of MCL cells. Constitutive NF-kappaB activation was found to be due to TNF, as anti-TNF antibodies inhibited both NF-kappaB activation and proliferation of cells. Overall, our results indicate that curcumin inhibits the constitutive NF-kappaB and IKK leading to suppression of expression of NF-kappaB-regulated gene products that results in the suppression of proliferation, cell cycle arrest, and induction of apoptosis in MCL. 24) Choudhuri, Tathagata, et al. "Curcumin selectively induces apoptosis in deregulated cyclin D1-expressed cells at G2 phase of cell cycle in a p53-dependent manner." Journal of Biological Chemistry 280.20 (2005): 20059-20068. All of these data suggest that curcumin can exert its apoptogenic effect in those cells whose cyclin D1 expression is deregulated due to genetic manipulations. 25) Singh, Amareshwar TK, et al. "Curcumin nanodisk-induced apoptosis in mantle cell lymphoma." Leukemia & lymphoma 52.8 (2011): 1537-1543. 26) Tadmor, Tamar, and Aaron Polliack. "Mantle cell lymphoma: curcumin nanodisks and possible new concepts on drug delivery for an incurable lymphoma." Leukemia & lymphoma 52.8 (2011): 1418. 27) Yallapu, Murali M., Meena Jaggi, and Subhash C. Chauhan. "Curcumin nanomedicine: a road to cancer therapeutics." Current pharmaceutical design 19.11 (2013): 1994. ------------------------------------------------- vorinostat 28) Chen, Robert, et al. "A phase II study of vorinostat and rituximab for treatment of newly diagnosed and relapsed/refractory indolent non-Hodgkin lymphoma." haematologica 100.3 (2015): 357-362. 29) Xargay-Torrent, Sílvia, et al. "Vorinostat-induced apoptosis in mantle cell lymphoma is mediated by acetylation of proapoptotic BH3-only gene promoters." Clinical Cancer Research 17.12 (2011): 3956-3968. 30) Richon, V. M. "Cancer biology: mechanism of antitumour action of vorinostat (suberoylanilide hydroxamic acid), a novel histone deacetylase inhibitor." British journal of cancer 95 (2006): S2-S6. -------------------------------------------------------- 31) Leuk Lymphoma. 2011 Aug;52(8):1488-94. doi: 10.3109/10428194.2011.575489. Epub 2011 May 31. Cladribine plus rituximab is an effective therapy for newly diagnosed mantle cell lymphoma.Spurgeon SE1, Pindyck T, Okada C, Chen Y, Chen Z, Mater E, Abbi K, Epner EM.1Knight Cancer Institute at Oregon Health and Science University, Portland, OR 97239-3098, USA. Mantle cell lymphoma (MCL) is a non-Hodgkin lymphoma that is incurable with standard chemotherapy. There is no consensus on the best initial therapy, especially for elderly patients, who are not candidates for aggressive treatment approaches. Current National Comprehensive Cancer Network (NCCN) treatment guidelines include rituximab (R) plus cladribine for the initial treatment of MCL. However, few data are available to substantiate this recommendation. Therefore, to further define the role of R-cladribine for the initial treatment of MCL, we performed a retrospective chart review of 31 patients with MCL (median age, 67) treated with R-cladribine. The majority of responding patients also received R maintenance. The overall response rate was 87%, with 61% of patients achieving a complete remission (CR/CRu). The estimated median follow-up was 32.5 months, median PFS was 37.5 months, and median OS was 85.2 months. One of 19 (5.3%) subjects in CR/CRu relapsed (median follow-up of 23 months). CR/CRu was associated with improved survival (p < 0.0001), while a high mantle cell international prognostic index (MIPI) was associated with worse survival (p 0.05). There was one toxic death (neutropenic pseudomonal sepsis) related to treatment. R-cladribine is an effective therapy for previously untreated MCL, and these results validate the use of R-cladribine for the initial treatment of MCL. Nordic Group 2008 32) Geisler, Christian H., et al. "Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo–purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group." Blood 112.7 (2008): 2687-2693.Mantle cell lymphoma stem cell rescue Nordic Lymphoma Group Christian Geisler Blood 2008 Cannabinoids 2016 33) Velasco, Guillermo, et al. "The use of cannabinoids as anticancer agents." Progress in Neuro-Psychopharmacology and Biological Psychiatry 64 (2016): 259-266.(full free) --------------------------------------------------------------- Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) 34) 704 The Addition of the BTK Inhibitor Ibrutinib to Anti-CD19 Chimeric Antigen Receptor T Cells (CART19) Improves Engraftment and Antitumor Responses Against Mantle Cell Lymphoma Lymphoma: Pre-Clinical – Chemotherapy and Biologic Agents Program: Oral and Poster Abstracts Type: Oral Session: 625. Lymphoma: Pre-Clinical – Chemotherapy and Biologic Agents: B-cell Receptor Signaling and Resistance in Lymphoma Monday, December 7, 2015: 3:00 PM Hall E2, Level 2 (Orange County Convention Center) Marco Ruella, MD1, Saad S Kenderian, MD1, Olga Shestova, PhD1*, Joseph A. Fraietta, PhD1*, Sohail Qayyum, MD2*, Qian Zhang, MD, PhD2*, Marcela V. Maus, MD, PhD1, Xiaobin Liu, PhD2*, Selene Nunez-Cruz, PhD1*, Michael Klichinsky, PharmD1*, Omkar Uday Kawalekar, MS, BS1, Michael C. Milone, MD, PhD1*, Simon F. Lacey, PhD, BSc1*, Anthony Mato, MD3*, Stephen J. Schuster, MD4, Michael Kalos, PhD2, Carl H. June, MD1, Saar I Gill, MBBS, PhD1 and Mariusz A. Wasik, MD5* 1Center for Cellular Immunotherapies, University of Pennsylvania, Philadelphia, PA 2Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 3Center for Chronic Lymphocytic Leukemia, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA 4Division of Hematology-Oncology, University of Pennsylvania, Philadelphia, PA 5Pathology and Laboratory Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA Introduction: The bruton tyrosine kinase (BTK) inhibitor ibrutinib demonstrates considerable activity in mantle cell lymphoma (MCL). However, approximately 30% of patients do not respond to this treatment and the therapy invariably leads to drug resistance with a median response of 17.5 months. Infusion of autologous T cells transduced with chimeric antigen receptors (CAR) against the B-cell specific CD19 antigen (CART19) leads to dramatic clinical responses in the majority of patients with acute lymphoblastic leukemia and the activity in B cell lymphoma is currently being evaluated in clinical trials. Bulky disease, as sometimes seen in MCL, may impair T cell infiltration. The features of ibrutinib that make it an interesting addition to CART19 include its efficacy in reducing tumor masses and its ability to mobilize neoplastic B cells into the peripheral blood, thereby potentially exposing them to the killing activity of CART19. Therefore, we sought to investigate the combination of the two novel targeted therapies, ibrutinib and CART19 in MCL. Results: In vitro studies with established MCL cell lines and with a novel cell line (MCL-RL) showed a range of responses to ibrutinib with an IC50 ranging from 10 nM to 10 µM; MCL-RL was the most sensitive cell line evaluated with an IC50 of 10nM, similar to primary MCL. Both ibrutinib-sensitive and ibrutinib-resistant cell lines strongly activated CART19 in an antigen-specific manner as detected by CD107a degranulation, cytokine production and CFSE proliferation assays. Importantly, in vitro assays with MCL cell lines co-cultured with increasing doses of CART19 (E:T 2:1, 1:1, 0.5:1, 0.25:1) combined with increasing concentrations of ibrutinib (0, 10, 100, 1000 nM) demonstrated strong additive tumor killing (Figure 1). Notably, supra-therapeutic doses of Ibrutinib (>/1 uM) impaired cytokine production and T cell proliferation in vitro. In order to test this combination in vivo we established a novel MCL model, injecting i.v. luciferase-positive MCL-RL cells into NSG mice. This resulted in 100% MCL engraftment in liver and spleen, with eventual dissemination into lymph nodes and bone marrow. Treatment with three different doses of CART19 (0.5, 1 and 2 million cells/mouse) led to a dose dependent anti-tumor effect. A similar dose response to CART19 was also observed in the ibrutinib-resistant Jeko-1 cell line. We also treated MCL-RL xenografts with different doses (0, 25 and 125 mg/Kg/day) of ibrutinib, with a median overall survival respectively of 70, 81 and 100 days (p<0.001). Importantly, a direct in vivo comparison of the highest ibrutinib dose (125 mg/kg) and CART19 showed a significantly improved tumor control for mice treated with CART19. However, treatment with either CART19 or ibrutinib as single agents invariably led to late relapse. Therefore we sought to treat MCL-RL xenografts with the combination of CART19 and ibrutinib and compare it to the single agent activity. The combination resulted in significant improvement in tumor control compared to mice treated with the single agents with 80% of mice achieving long-term disease-free survival (p0.007 at day 110, representative mice shown in Figure 2A). Intriguingly, we found that mice treated with ibrutinib had higher numbers of circulating CART19 cells (Figure 2B). Conclusions: Combining CART19 with ibrutinib represents a rational way to incorporate two of the most recent therapies in MCL. Our findings pave the way to a two-pronged therapeutic strategy in patients with MCL and other types of B-cell lymphoma. 35) Ramos CA, Dotti G. Chimeric Antigen Receptor (CAR)-Engineered Lymphocytes for Cancer Therapy. Expert opinion on biological therapy. 2011;11(7):855-873. 36) J Immunol. 2015 Aug 1;195(3):755-61. Chimeric Antigen Receptor- and TCR-Modified T Cells Enter Main Street and Wall Street. Barrett DM1, Grupp SA2, June CH3. The field of adoptive cell transfer (ACT) is currently comprised of chimeric Ag receptor (CAR)- and TCR-engineered T cells and has emerged from principles of basic immunology to paradigm-shifting clinical immunotherapy. ACT of T cells engineered to express artificial receptors that target cells of choice is an exciting new approach for cancer, and it holds equal promise for chronic infection and autoimmunity. Using principles of synthetic biology, advances in immunology, and genetic engineering have made it possible to generate human T cells that display desired specificities and enhanced functionalities. Clinical trials in patients with advanced B cell leukemias and lymphomas treated with CD19-specific CAR T cells have induced durable remissions in adults and children. The prospects for the widespread availability of engineered T cells have changed dramatically given the recent entry of the pharmaceutical industry to this arena. In this overview, we discuss some of the challenges and opportunities that face the field of ACT. 37) Power Point Slide Presentation: Chimeric_Antigen_Receptor_T-cell_Power_Point 38) Kochenderfer, James N., et al. "Chemotherapy-refractory diffuse large B-cell lymphoma and indolent B-cell malignancies can be effectively treated with autologous T cells expressing an anti-CD19 chimeric antigen receptor." Journal of Clinical Oncology 33.6 (2015): 540-549. Lymphoma Can Be Effectively Treated With Anti-CD19 Chimeric Antigen ReceptorJames Kochenderfer PCR Testing 39) video of dr Pott discussing her study findings' http://www.cancertherapyadvisor.com/ash-2014/mantle-cell-lymphoma-minimal-residual-disease-prognosis/article/387224/ December 08, 2014 Christiane Pott, MD, PhD, MD, Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany Christiane Pott, MD. Senior Consultant, Department of. Hemotology, University Hospital Schleswig-. Holstein, Campus Kiel, Germany. Minimal Residual Disease Negativity Predicts Prognosis in Mantle Cell Lymphoma. “Achievement and preservation of MRD response is a strong independent predictor of prognosis in mantle cell lymphoma and correlates significantly with long-term survival,” Christiane Pott, MD, PhD, from the University Hospital Schleswig-Holstein in Kiel, Germany, said while presenting at the meeting. “MRD response should be integrated into current response criteria as it more precisely defines prognosis than clinical response alone. Treatment strategies focusing on MRD eradication should be part of future clinical trials,” Dr. Pott concluded. 40) 147 MRD Eradication Should be the Therapeutic Goal in Mantle Cell Lymphoma and May Enable Tailored Treatment Approaches: Results of the Intergroup Trials of the European MCL Network Lymphoma: Chemotherapy, excluding Pre-Clinical Models: Indolent Lymphoma and Mantle Cell Lymphoma. Sunday, December 7, 2014: 5:00 PM North Building, Hall D (Moscone Center) Christiane Pott, MD, PhD1*, Elizabeth Macintyre, MD, PhD2, Marie-Helene Delfau-Larue, MD, PhD3*, Vincent Ribrag, MD4, Michael Unterhalt, MD5*, Michael Kneba, MD, PhD6, Wolfgang Hiddemann, MD7, Martin Dreyling, MD, PhD8, Olivier Hermine, MD, PhD9 and Eva Hoster, PhD5* 1Second Medical Department, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany Background: Minimal residual disease (MRD) measurement is an increasingly recognized tool for response assessment in B-cell malignancies and represents a useful surrogate marker for prognosis, allowing prediction of the clinical course prior to clinical study endpoints. Based on the randomized intergroup trials of the European MCL Network for patients with stage II-IV mantle cell lymphoma (MCL) investigating immuno-chemotherapy followed by autologous stem cell transplantation (ASCT) for patients 65 yrs, we prospectively monitored MRD. Methods: According to the protocols MRD analyses were performed after completed induction and subsequently in 3-monthly intervals after ASCT or 2-monthly during maintenance until progression. MRD results were evaluated according to ESG criteria (van der Velden, Leukemia 2007) and compared with clinical outcome. RQ-PCR was designed to reach a sensitivity of 10E-5, MRD negativity was defined as a negative RQ-PCR result with a sensitivity of at least 10E-4. Patients in complete or partial remission 6 months after ASCT/end of induction (MCL Younger/MCL Elderly) were included in this analysis. During follow-up MRD status in peripheral blood (PB) was assessed and defined as negative, if there were only negative MRD values, or positive in case of at least one positive MRD value during a 6-months period. Landmark analyses were performed for progression-free survival (PFS) according to MRD status for each 6-months period until 4 years of follow-up and PFS was compared between PB positive and PB negative patients. Results: Among patients in remission 6 months after ASCT/end of induction, MRD results during follow-up were available in 406 patients (255 MCL Younger,151 MCL Elderly). The distribution into low, intermediate, and high risk MIPI of 44%, 34% and 22%, respectively, was similar to the total study population. During follow-up period, percentage of patients with evaluable MRD status dropped from about 50%-55% during the first two years to 40%-45% during years 3-4, and less than 40% afterwards. The rate of MRD positive samples was about 20-25% during the first 3 years, and less than 20% in the subsequent follow-up. In each landmark analysis, a positive MRD status in PB was highly associated with a shorter PFS. This association was independent of baseline MIPI score, treatment arm or protocol (Figure 1). Thus, the prognostic value of MRD positivity was maintained in both trials MCL Younger and MCL Elderly. Remarkably, landmark analyses at all time points indicated a strong association also of low-level MRD with a shortened PFS. Finally, MRD analyses in 76 patients at relapse confirmed the close association of clinical relapse to MRD positivity, with only 10 patients (13%) being PB-negative. Conclusion: Our data demonstrate that achievement and preservation of MRD negativity is the strongest independent predictor of prognosis in patients with MCL. Applying MRD status as tool for tailored treatment, therapeutic approaches should focus on a maximum MRD response to improve long term outcome. Fig. 1: Landmark analyses for PFS in remission after ASCT (MCL Younger) or end of induction (MCL Elderly). For each landmark time point only patients in follow-up at the landmark are included and stratified according to MRD status in PB in the 6 months period preceding the landmark. 41) Pott, Christiane. "Minimal residual disease detection in mantle cell lymphoma: technical aspects and clinical relevance." Seminars in hematology. Vol. 48. No. 3. WB Saunders, 2011. 42) Pott, Christiane, et al. "MRD detection in B-cell non-Hodgkin lymphomas using Ig gene rearrangements and chromosomal translocations as targets for real-time quantitative PCR." Lymphoma. Humana Press, 2013. 175-200. Methods Mol Biol. 2013;971:175-200. doi: 10.1007/978-1-62703-269-8_10. MRD detection in B-cell non-Hodgkin lymphomas using Ig gene rearrangements and chromosomal translocations as targets for real-time quantitative PCR. Pott C1, Brüggemann M, Ritgen M, van der Velden VH, van Dongen JJ, Kneba M. Minimal residual disease (MRD) diagnostics is of high clinical relevance in patients with indolent B-cell Non-Hodgkin lymphomas (B-NHL) and serves as a surrogate parameter to evaluate treatment effectiveness and long-term prognosis. MRD diagnostics performed by real-time quantitative PCR (RQ-PCR) is the gold-standard and currently the most sensitive and the most broadly applied method in follicular lymphoma (FL) and mantle cell lymphoma (MCL). RQ-PCR analysis of the junctional regions of the rearranged immunoglobulin heavy-chain gene (IgH) serves as the most broadly applicable MRD target in B-NHL (∼80%). Chromosomal translocations as t(14;18) translocation in FL and t(11;14) translocation in MCL can be used in selected lymphoma subtypes. In patients with B-cell chronic lymphocytic leukemia, both flow-cytometry as well as RQ-PCR are equally suitable for MRD assessment as long as a sensitivity of ≤10(-4) shall be achieved.MRD diagnostics targeting the IgH gene is complex and requires extensive knowledge and experience because the junctional regions of each lymphoma have to be identified before the patient-specific RQ-PCR assays can be designed for MRD monitoring. Furthermore, somatic mutations of the IgH region occurring during B-cell development of germinal center and post-germinal center lymphomas may hamper appropriate primer binding leading to false negative results. The translocations mentioned above have the advantage that consensus forward primers and probes, both placed in the breakpoint regions of chromosome 18 in FL and chromosome 11 in MCL, can be used in combination with a reverse primer placed in the IgH joining region of chromosome 14. RQ-PCR-based methods can reach a good sensitivity (≤10(-4)). This chapter provides all relevant background information and technical aspects for the complete laboratory process from detection of the clonal IgH gene rearrangement and the chromosomal translocations at diagnosis to the actual MRD measurements in clinical follow-up samples of B-NHL. However, it should be noted that MRD diagnostics for clinical treatment protocols has to be accompanied by regular international quality control rounds to ensure the reproducibility and reliability of the MRD results. 43) Minimal residual disease detection in mantle cell lymphoma: methods and significance of four-color flow cytometry compared to consensus IGH-polymerase chain reaction at initial staging and for follow-up examinations. Sebastian Böttcher, Matthias Ritgen, Sebastian Buske, Stefan Gesk, Wolfram Klapper, Eva Hoster, Wolfgang Hiddemann, Michael Unterhalt, Martin Dreyling, Reiner Siebert, Michael Kneba, Christiane Pott. Haematologica April 2008 93: 551-559; 44) Pott, Christiane, et al. "Molecular remission is an independent predictor of clinical outcome in patients with mantle cell lymphoma after combined immunochemotherapy: a European MCL intergroup study." Blood 115.16 (2010): 3215-3223. Sequential MRD monitoring is a powerful predictor for treatment outcome in MCL. Clonal IGH VH-JH rearrangements as well as the t(11;14) translocation are suitable targets for molecular MRD assessment in MCL. Four-color flow cytometry (4C-FC) was performed to assess the proportion of MCL cells in diagnostic blood and BM samples. DNA from PB, peripheral blood mononuclear cells or BM was extracted with a standard proteinase K digestion and a phenol-chloroform extraction or the QIAGEN Blood Mini Kit (QIAGEN). Samples were analyzed by t(11;14) (BCL1-IGH) PCR and IGH multiplex PCR as published to assess the clonal rearrangement However, the postinduction MRD status has the advantage of providing the prognostic information more timely, thereby allowing for better planning of potential postconsolidation treatment intensification or maintenance treatment. The present study demonstrates, for the first time, that prospective longitudinal monitoring of MRD after combined immunochemotherapy can be a powerful predictor of treatment outcome in patients with MCL, allowing an early individual risk assessment already during treatment. Accordingly, MRD assessment should be integrated into future clinical trial concepts to evaluate new treatment strategies and to serve as an early surrogate marker that can be used for risk-adapted treatment. 45) Gimenez, Estelle, et al. "Cloned IGH VDJ targets as tools for personalized minimal residual disease monitoring in mature lymphoid malignancies; a feasibility study in mantle cell lymphoma by the Groupe Ouest Est d'Etude des Leucemies et Autres Maladies du Sang." British journal of haematology 158.2 (2012): 186-197. 46) Pharmacol Sci. 2015 Dec;19(24):4801-10. Quantitative PCR detection of t(11;14) bcl-1/JH in mantle cell lymphoma patients: comparison of peripheral blood and bone marrow aspirate samples. Di Martino S1, Catapano O, Siesto SR, Di Paolo M, Pugliese S, Morelli CD, Fiorica F, Varriale E, Di Francia R, Abbadessa A. Pathology Unit, A.O. Sant'Anna e San Sebastiano, Caserta, Italy. PCR t(11_14) bcl_1_JH mantle cell lymphoma Di Martino Pharmacol Sci 2015 47) Press Release Quest Diagnostics Launches the First Tests to Help Doctors Assess Status of Leukemia and Lymphoma in Patients Using Blood Plasma Instead of Bone Marrow - LEUMETA Cancer Tests Are Less Invasive Than Bone Marrow Biopsies, Providing Doctors With New Tools to More Frequently Assess Disease Progress and Help the Physician Tailor Cancer Therapy to Individual Needs - LYNDHURST, N.J., March 28 /PRNewswire-FirstCall/ -- Nearly 1 million Americans who are battling or recovering from leukemia and lymphoma have a powerful new diagnostic tool available as Quest Diagnostics Incorporated (NYSE: DGX) today launches the first of its LEUMETA(TM) cancer testing assays, a new family of laboratory-developed tests that may, in the future, provide an alternative to painful bone marrow biopsies. As the nation's leading provider of diagnostic testing, information and services, Quest Diagnostics developed LEUMETA to identify and analyze genetic components of leukemia and lymphoma tumors using blood plasma instead of bone marrow. The assays are designed to measure "tumor load," or the amount of cancer in a patient; detect certain blood cancer markers; and assist the physician in monitoring the impact of treatment. They are the first diagnostic assays available to doctors that directly measure tumor load and identify markers in blood plasma. "LEUMETA assays have the potential to help doctors personalize the way they practice medicine by providing information about the status of leukemia and lymphoma in blood plasma to help the physician determine the drug and dosage that works best for each patient, based on the specifics of that patient's cancer and other clinical information available to the physician," said Surya N. Mohapatra, Ph.D., Chairman and Chief Executive Officer of Quest Diagnostics. "More prospective studies are needed, but in the meantime, sample collection for these blood plasma assays developed from this technology will be less painful than for bone marrow tests, while offering doctors a new tool to assess the status of these cancers." While conventional tests look for cancer cells in bone marrow or, in certain cases, peripheral blood, LEUMETA cancer assays track genetic components of leukemia and lymphoma tumors, including messenger RNA, DNA and protein in blood plasma -- the liquid portion of the blood. Studies performed at Quest Diagnostics and The University of Texas M. D. Anderson Cancer Center and presented at the American Society of Hematology (ASH) meeting in December 2005 showed that information about tumor load and blood cancer markers of leukemia and lymphoma tumors is contained in blood plasma. Sample collection for these LEUMETA assays does not require the painful extraction of bone marrow cells with a large-bore needle through the hipbone. "Using these tests, doctors can get a more frequent indication of a patient's disease status and decide whether to alter their treatment," explained Francis Giles, M.D., Professor of Medicine and Chief of Developmental Therapeutics within the Department of Leukemia at the M.D. Anderson Cancer Center, Houston. "In an era of increasing focus on targeted therapies, the ability to sequentially obtain so much data from blood plasma specimens is a major help in optimally using the available therapies, and in assessing the efficacy of novel agents. To obtain this data without the need for bone marrow tissue is a major advance." Developed by a team of researchers at Quest Diagnostics using licensed technology discovered by one of the researchers while previously at M.D. Anderson Cancer Center, LEUMETA cancer assays are available to physicians and oncology programs nationwide through Quest Diagnostics. For more information about the full range of currently available LEUMETA cancer tests, please visit www.questdiagnostics.com. LEUMETA cancer assays look for a variety of clinical disease markers in blood plasma to assist the physician in diagnosing and monitoring major types of leukemia and lymphoma. For example, as one study indicates, one of the tests identifies a protein tumor marker called the bcr-abl fusion protein that signals how well Chronic Myeloid Leukemia (CML) patients are responding to treatment. Another assay in the family, called ABL Kinase Domain Mutation, Plasma-based, LEUMETA, reveals genetic mutations of the ABL gene that suggest a more aggressive form of leukemia or may be indicative of resistance to therapy. "Some of these new assays provide physicians with a direct measure of tumor load, or the amount of cancer within a patient's body. Others provide a more convenient way to detect the presence or absence of tumor markers. As a result, they provide a new tool to assess disease status," said Maher Albitar, M.D., Medical Director for Hematopathology at Quest Diagnostics, and lead developer of the LEUMETA assays. "Oncologists may now use LEUMETA cancer tests to assess patients more frequently, permitting closer monitoring of the patient's progress on therapy, allowing the oncologist to interpret the results more frequently and to tailor treatment accordingly." Some current cancer treatment drugs work by inhibiting phosphorylation of oncoproteins. By measuring phosphorylated proteins in plasma, LEUMETA may in the future help doctors predict how well these drugs are binding and fighting cancer. As a result, doctors may one day be able to tailor therapy to the specific profiles and requirements of each patient. ------------------------------------------------ 48) Mantle Cell Lymphoma, bcl-1/JH t(11;14), Real-Time PCR, Leumeta® Test Code 17679 CPT Code(s) 81401 Preferred Specimen(s) 3 mL whole blood collected in an EDTA (lavender-top) tube Minimum Volume 2 mL Collection Instructions Follow standard whole blood collection procedure. Collect 3-5 mL whole blood samples in an EDTA tube. Blood samples are shipped at room temperature or 4° C. Do not freeze whole blood. Record the draw time and date on the tube. Ship immediately to maintain sample stability. Transport Container EDTA (lavender-top) tube Transport Temperature Refrigerated (cold packs) Real-Time Polymerase Chain Reaction (RT-PCR) Performing Laboratory Quest Diagnostics Nichols Institute-San Juan Capistrano, CA 33608 Ortega Highway San Juan Capistrano, CA 92675-2042 The plasma based molecular assay is based on the concept that in hematological diseases, tumor cells pour their DNA and RNA into the circulation. These components can be detected in plasma, and can replace the routine painful bone marrow aspiration or biopsy procedure. Bcl-1/JH, t(11;14) is highly specific for mantle cell lymphoma (MCL). The real-time quantitative PCR can be used to monitor minimal residual disease in non-Hodgkin’s Lymphoma. ----------------------------------------------- 49) Mantle Cell Lymphoma, bcl-1/JH t(11;14), Cell-Based Test Code 14991 CPT Code(s) 81401 5 mL bone marrow or whole blood collected in an EDTA (lavender-top) tube Minimum Volume 1 mL ) Collection Instructions Whole blood or bone marrow (preferred): Collect in an EDTA (lavender-top tube ship refrigerated or room temperature. Do not ship frozen. Transport Container EDTA (lavender-top) tube Real-Time Polymerase Chain Reaction (RT-PCR) Bcl-1/JH t(11;14) is highly specific for mantle cell lymphoma (MCL). The t(11;14) can be found in approximately 70% to 95% cases of MCL. Half of these translocations fall within the BCL-1 major translocation cluster (MTC). The t(11;14) Real-Time PCR assay can be used to monitor minimal residual disease in NHL. Ideally, recent patient samples should be tested side by side with the previous sample to better illustrate the quantitative changes. 50) Rajabi B, Sweetenham JW. Mantle cell lymphoma: observation to transplantation. Therapeutic Advances in Hematology. 2015;6(1):37-48. doi:10.1177/2040620714561579. 51) Dreyling, Martin, and Simone Ferrero. "The role of targeted treatment in mantle cell lymphoma: is transplant dead or alive?." Haematologica 101.2 (2016): 104-114. 52) Cassaday RD, Gopal AK. Allogeneic hematopoietic cell transplantation in mantle cell lymphoma. Best practice & research Clinical haematology. 2012;25(2):165-174. Mantle cells have high levels glutathione transferase confers protection from oxidative chemotherapy. 53) Bennaceur-Griscelli, Annelise, et al. "High level of glutathione-S-transferase π expression in mantle cell lymphomas." Clinical cancer research 10.9 (2004): 3029-3034. The GST-π gene in located at 11q13 and is coamplified with the cyclin D1 gene (in the same amplicon) in some human solid tumors (breast carcinoma, squamous cell lung carcinoma, bladder carcinomas, and esophageal carcinoma; Ref. 19 ). The unusual resistance to chemotherapy in MCL compared with other lymphoma entities. GST-π overexpression has been associated with resistance to alkylating agents and anthracyclines A high GST-π expression (>50% cells stained) was observed in the 24 cases of MCL MCL is one of the most chemotherapy-drug-resistant lymphomas. The 10 patients who received sequential CHOP and cytarabine-based chemotherapy at diagnosis did not reach complete remission after CHOP alone but entered into complete remission after high-dose cytarabine (38) . The modest role of the glutathione system in cytarabine resistance compared with alkylating and anthracyclin resistance could be an explanation for the high complete remission rate observed after high-dose cytarabine therapy in MCL (7 , 39) 54) Bebb, G., et al. "Sulfasalazine, inhibits growth of mantle cell lymphoma (MCL) cell cultures via cyst (e) ine starvation and delays tumour growth in a newly developed murine MCL model." BLOOD. Vol. 102. No. 11. 1900 M STREET. NW SUITE 200, WASHINGTON, DC 20036 USA: AMER SOC HEMATOLOGY, 2003. Introduction: Cyst(e)ine deficiency within lymphoid cells leads to a rapid decline in their levels of glutathione (a major free radical scavenger), loss of defense against oxidative stress, and subsequently apoptosis. Lymphoid cells cannot synthesize the amino acid and depend for growth and viability on its uptake from their micro-environment. Since lymphomas have been shown to retain the inability to synthesize cyst(e)ine they are potentially susceptible to cyst(e)ine starvation-based therapy. We have previously demonstrated that sulfasalazine (SASP), a drug used for treatment of severe inflammatory bowel disease and rheumatoid arthritis, is a potent inhibitor of the cystine/glutamate antiporter, xc-, a major plasma membrane cystine transporter. SASP abrogated growth of T and B lymphoma cell cultures via cystine starvation; SASP, administered intraperitoneally, markedly inhibited growth of rat Nb2-U17 lymphoma transplants in Nb rats without major toxicity to the hosts (Anti-Cancer Drugs 14:21, 2003). In the present study we investigated the usefulness of SASP in our newly developed model of MCL, a B-cell non-Hodgkin lymphoma (NHL), characterized by cyclin D1 and BCL2 over-expression. Results: Growth of human MCL cultures in Fischer's medium, supplemented with 10% fetal bovine serum and antibiotics, was markedly inhibited by SASP at therapeutic concentrations, showing IC50s of 0.13 and 0.30 for Z138C and Granta MCL cultures, respectively. Culture growth arrest could be largely prevented by enhancing cellular cystine uptake using 66 uM 2-mercaptoethanol (reported to promote cystine uptake via the leucine transporter), indicating that the SASP-induced inhibition resulted from cyst(e)ine starvation. A study into the efficacy of SASP in vivo was initiated using SCID/Rag2-M mice injected subcutaneously with Z138C cells (5 million cells/mouse); such a procedure leads to consistent development of tumours within 28 days. When tumours had reached a weight of about 0.1 gr, groups of six mice were treated for 10 consecutive days with saline (controls) or SASP (250 mg/kg body weight i.p., b.i.d.), a dosage well below the maximally tolerated dosage (300 mg/kg every 8 hr). It was found that treatment with SASP inhibited tumour growth, showing a delay in growth of at least 7 days, without major toxicity. Conclusions: SASP has a marked inhibitory effect on growth of MCL cell lines in vitro, an effect also seen in vivo in our murine SC MCL model. SASP may represent a novel approach for MCL treatment. The precise molecular consequences of SASP treatment on MCL cells warrant further investigation. Additional studies on the effect of SASP at higher dosages and in combination with cyclophosphamide and targeted therapies, eg. ASO and monoclonal antibodies against bcl-2, are in progress. Vitamin A Derivatives Lypro Biosciences Product Pipeline Targeted NanoDisk for Mantle Cell Lymphoma 55) NanoDisk targeted to the CD20 cell surface antigens and loaded with ATRA (ATRA-tND) In collaboration with Dr. Leo I. Gordon, M.D., a renowned lymphoma clinician and Professor of Oncology Research at the Feinberg School of Medicine at Northwestern University, we have demonstrated that NanoDisk targeted to the CD20 cell surface antigens and loaded with ATRA (ATRA-tND) confers specificity and increases potency. Looking first at cell viability, ATRA-tND at concentrations as low as 5 uM, induces cell death and outperforms free drug and untargeted ATRA-ND (Figure 1). The addition of a CD20 targeting moiety results in specific binding to CD20 expressing cells (Figure 2, Pagel B). Microscopy studies demonstrate that the bioactive agent is internalized into the cell (Figure 2, Panel C & D). Since ATRA is not intrinsically fluorescent, the water-insoluble, naturally fluorescent hydrophobic bioactive polyphenol, curcumin, was used. Remarkably, Targeted curcumin-ND binding to cultured MCL cells facilitates bioactive agent off-loading, transit across the cell membrane and access to the cell interior. It is expected that other, nonfluorescent hydrophobic bioactive agents, including ATRA, will behave in a similar manner such that Targeted ATRA-ND binding to CD20 on the surface of MCL cells will facilitate ATRA transit to the cell interior. 56) Lypro Biosciences Product Pipeline: targeted NanoDisk program for treatment of mantle cell lymphoma. Leo I. Gordon, M.D.: is our collaborator for our targeted NanoDisk program for treatment of mantle cell lymphoma. Dr. Gordon is the Abby and John Friend Professor of Oncology Research at the Feinberg School of Medicine at Northwestern University where his laboratory focuses on translational research in lymphoma. His laboratory research interest include the biology of reactive oxygen species signaling pathways. Dr. Gordon has served on committees of several national organizations and foundations related to cancer. He has served as co-chairman of the Eastern Cooperative Oncology Group Lymphoma Committee and as chair of the Oncological Sciences Clinical Oncology Study Section at the National Cancer Institute. Dec 2015 - combination of Curcumin and ATRA 57) STAUFFER, RICHARD G., MANAR MOHAMMAD, and AMARESHWAR TK SINGH. "Novel Nanoscale Delivery Particles Encapsulated with Anticancer Drugs, All-trans Retinoic Acid or Curcumin, Enhance Apoptosis in Lymphoma Cells Predominantly Expressing CD20 Antigen." Anticancer research 35.12 (2015): 6425-6429. Background: Mantle cell lymphoma (MCL), a B-cell lymphoma, pursues a relatively aggressive course, is resistant to long-term remission, and is associated with a poor prognosis. There is a pressing need for innovative treatment approaches against MCL. One such approach is targeted delivery of cytotoxic drugs to MCL cells. Materials and Methods: In the current investigation, we pursued a strategy to employ retinoid-based or curcumin-based nanoscale delivery particles, called nanodisks (NDs), for targeted drug delivery to MCL cells (Granta), and human follicular lymphoma (HF-1) cells. The cells were incubated with NDs made of CD20 single-chain variable antibody fragment (scFv)/apolipoprotein A-1 fusion protein, and loaded with either all- trans retinoic acid (ATRA) or curcumin, and cell apoptosis was measured using flow cytometry. Results and Conclusion: At 10 μM, curcumin-ND induced cell death more effectively than ATRA-ND. Combination of curcumin-ND and ATRA-ND significantly enhanced the biological activity of these drugs against lymphoma cells compared to individual treatments. ATRA-ND in Mantle Cell Lymphoma 58) Singh, Amareshwar TK, et al. "All trans retinoic acid nanodisks enhance retinoic acid receptor mediated apoptosis and cell cycle arrest in mantle cell lymphoma." British journal of haematology 150.2 (2010): 158-169. The antioxidant, N-acetylcysteine, inhibited ATRA-ND induced apoptosis. Compared to naked ATRA, ATRA-ND enhanced G1 growth arrest, up-regulated p21and p27, and down regulated cyclin D1 Retinoic Acid Effective Mantle Cell Lymphoma 59) Guidoboni, Massimo, et al. "Retinoic Acid Inhibits the Proliferative Response Induced by CD40 Activation and Interleukin-4 in Mantle Cell Lymphoma." Cancer research 65.2 (2005): 587-595. Retinoic acid inhibits mantle cell lymphoma Guidoboni Massimo Cancer research 2005 Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin's lymphoma with poor response to therapy and unfavorable prognosis. Here, we show that retinoic acid (RA) isomers significantly inhibit the proliferation of both primary MCL cultures (n 7) and established cell lines (Granta 519 and SP-53) as shown by thymidine uptake and carboxyfluorescein diacetate succinimidyl ester labeling coupled with cyclin D1 staining. RA induces cell accumulation in G0-G1 together with a marked up-regulation of p27Kip1 by inhibiting ubiquitination and proteasome-dependent degradation of the protein. The p21Cip1 inhibitor was also up-regulated by RA in Granta 519 cells, whereas the expression of cyclin D1 is unaffected. Most of RA-induced p27Kip1 was bound to cyclin D1/cyclin-dependent kinase 4 complexes, probably contributing to the decreased cyclin-dependent kinase 4 kinase activity and pRb hypophosphorylation observed in RA-treated cells. Experiments with receptor-selective ligands indicate that RA receptor α cooperates with retinoid X receptors in mediating RA-dependent MCL cell growth inhibition. Notably, RA isomers, and particularly 9-cis-RA, also inhibited the growth-promoting effect induced in primary MCL cells by CD40 activation alone or in combination with interleukin-4. Immunohistochemical analysis showed that significant numbers of CD40L-expressing lymphoid cells are present in lymph node biopsies of MCL patients. These results therefore further strengthen the possibility that triggering of CD40 by infiltrating CD40L+ cells may continuously promote the growth of MCL cells in vivo. On these grounds, our findings that RA inhibits basal MCL proliferation as well as MCL growth-promoting effects exerted by microenvironmental factors make these compounds highly attractive in terms of potential clinical efficacy in this setting. 1997 full pdf nice images of lymphoma cells before and after ATRA 60) Sundaresan, Alamelu, et al. "Retinoid-mediated inhibition of cell growth with stimulation of apoptosis in aggressive B-cell lymphomas." Cell Growth and Differentiation-Publication American Association for Cancer Research 8.10 (1997): 1071-1082. Retinoid inhibition and apoptosis in aggressive B-cell lymphomas Sundaresan 1997 The key differences found between L-ATRA-sensitive cells like McA, RV (and other NHL-B cells which we analyzed), and refractory cells like MS in our system is that bax, one of the possible target genes of L-ATRA, is not present or is present at very low levels. The L-ATRA doses used (0.006-1 .0 ı.LM) are within nontoxic pharmacological dosage limits achievable in patients, making L-ATRA a potential inhibitor of tumor growth and inducer of apoptosis in aggressive NHL-B. ---------------------------- liposomal-all- trans -retinoic acid (Atragen) following intravenous and oral ATRA (Vesanoid) All- trans -retinoic acid (ATRA), a physiologic derivative of vitamin A (retinol), induces complete clinical remissions (CR) in majority of patients with acute promyelocytic leukemia (APL) 61) J Pharm Pharm Sci. 2003 May-Aug;6(2):292-301. Pharmacokinetics of intravenously administered liposomal all-trans-retinoic acid (ATRA) and orally administered ATRA in healthy volunteers. Ozpolat B1, Lopez-Berestein G, Adamson P, Fu CJ, Williams AH. Author information 1Department of Bioimmunotherapy, Section of Immunobiology and Drug Carriers, The University of Texas M. D. Anderson Cancer Center, Houston 77030, USA. To determine single-and multiple-dose pharmacokinetics of liposomal-all- trans -retinoic acid (Atragen) following intravenous and oral ATRA (Vesanoid) administration in healthy volunteers. METHODS:This was a randomized, prospective, open-label, parallel pharmacokinetic study in which 29 subjects were given 90 mg/m (2) i.v. liposomal (L)-ATRA (16 subjects) every other day or 45 mg/m (2) oral ATRA (13 subjects) daily over 15 days. Pharmacokinetic parameters were assessed on days 1, 9, and 15. RESULTS:Twenty-two subjects (11 in each group) completed the study and were evaluated. Area under the plasma concentration-time curve and maximum plasma concentration (C(max) ) of ATRA did not decrease during the 15 days of L-ATRA treatment. However, the oral ATRA regimen resulted in a significant decrease in the AUC(0, infinity) and C(max) of 45.3% and 31.8%, respectively, on day 9 as compared with that to day 1 (p< 0.05). In addition, the mean AUC(0, infinity) was 13- and 22-fold greater for L-ATRA than for oral ATRA on days 1 and 9, respectively. Despite the significantly higher plasma concentrations after L-ATRA treatment, the side effects of each formulation were similar, except for dermal exfoliation, which was seen in 31% of the subjects after L-ATRA dosing, and abnormal liver function tests that were seen in 23% of the subjects after oral ATRA administration. CONCLUSIONS:These findings suggest that i.v. administration of L-ATRA maintains higher and stable plasma ATRA concentrations than oral ATRA in healthy subjects after repetitive administration. L-ATRA with a favorable pharmacokinetic profile may have potential advantages over oral ATRA and may be more efficacious in the treatment of acute promyelocytic leukemia or other retinoid-responsive cancers. ----------------------------- full pdf Bexarotene 62) Functions therapeutic applications synthesis of retinoids and carotenoids Álvarez 2013 Álvarez, Rosana, et al. "Functions, therapeutic applications, and synthesis of retinoids and carotenoids." Chemical Reviews 114.1 (2013): 1-125. Tamibarotene (benzanilide Am80, 107),245 a potent inducer of cell-differentiation,274 is approved in Japan for the treatment of refractory acute promyelocytic leukemia (APL). The use of alltrans- retinoic acid (3) and As2O3 in combination (together with chemotherapy protocols primarily for postremission consolidation and maintenance therapy) for the therapy of acute promyelocytic leukemia (APL), in the past one of the most fatal acute leukemias, results today in the cure of more than 90% of patients.28 Bexarotene (LGD1069, 110)277 is a therapeutic option for refractory cutaneous T-cell lymphoma (CTCL) and is undergoing clinical trials for the treatment of breast, lung, and colon cancer and other diseases caused by uncontrolled cell proliferation.278 It is generally believed that the anticancer activity of retinoids is due to their ability to induce stem cell differentiation, as in the case of APL. However, other activities, such as postdifferentiation apoptosis involving activation of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) ignaling,281 contribute to therapeutic effects, at least in cell models and ex vivo experiments with leukemic blasts. 7.2.2. Rexinoids can induce cell death through an entirely distinct signaling paradigm, a phenomenon referred to as “rexinoid apoptosis. Retinoid toxicity associated with retinoid supplementation can be manifested in drying, ulceration, and desquamation of the skin, anorexia, anemia, and bone loss. Hypervitaminosis also damages the liver through fibrosis and hepatic stellate cell activation, leading to cirrhosis. Bone loss in the elderly can lead to osteopenia and osteoporosis.222 Experience from therapy with acute promyelocytic leukemia (APL) patients showed that the so-called “retinoic acid syndrome” (also referred to as “differentiation syndrome”) occurs in approximately 25% of patients treated with all-transretinoic acid or As2O3 (as induction therapy for APL). ------------------------------------- !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! 63) Bushue, Nathan, and Yu-Jui Yvonne Wan. "Retinoid pathway and cancer therapeutics." Advanced drug delivery reviews 62.13 (2010): 1285-1298. All-trans RA is the most abundant natural retinoid and has been widely studied for many years. It is currently in clinical trials for the treatment of lymphoma, leukemia, melanoma, lung cancer, cervical cancer, kidney cancer, neuroblastoma, and glioblastoma. Tretinoin (Vesanoid®, All-Trans-Retinoic Acid, ATRA) -------------------- 64) Baranowitz, Steven A. "Treatment of cutaneous T-cell lymphoma with beta carotene." New England Journal of Medicine 330.25 (1994): 1830-1830. The patient began taking high-dose oral beta carotene, 300 mg per day, in May 1993. Beta carotene has many biologic effects apart from its pro-vitamin A function4. It is well tolerated, and there is substantial medical experience in its use in high doses3. It is thought to be impossible to induce hypervitaminosis A with beta carotene3. The upper level of safety in humans is unknown, but beta carotene has been used in doses of 300 mg per day for erythropoietic protoporphyria for many years, with no side effects except orange skin3. bexarotene Non Small Cell Lung CA 65) Rigas, James R., and Konstantin H. Dragnev. "Emerging role of rexinoids in non-small cell lung cancer: focus on bexarotene." The Oncologist 10.1 (2005): 22-33. 66) Kaur S. Retinoids as chemopreventive agents. Indian J Dermatol Venereol Leprol 2016 ;82:59-64. Available from: 66) Orthomolecular Medicine News Service, August 20, 2008 VITAMIN A : Cancer Cure or Cancer Cause? Vitamin A fights cancer by inhibiting the production of DNA in cancerous cells. It slows down tumor growth in established cancers and may keep leukemia cells from dividing." (11) A derivative of the vitamin has been shown to kill CEM-C7 human T lymphoblastoid leukemia cells and P1798-C7 murine T lymphoma cells. (12) 67) Chan LN, Zhang S, Shao J, Waikel R, Thompson EA, Chan TS. N-(4-hydroxyphenyl)retinamide induces apoptosis in T lymphoma and T lymphoblastoid leukemia cells. Leuk Lymphoma. 1997 Apr;25(3-4):271-80. We demonstrate that N-(4-hydroxyphenyl)-all-trans-retinamide (4-HPR), a synthetic retinoic acid (RA) derivative, is a potent and selective inducer of apoptosis in malignant T lymphoid cells, but has little effect on normal lymphoid cells of the thymus or spleen. 4-HPR and its stereoisomer, 9-cis-4-HPR, are 50 to > 150 times more potent than 7 other retinoids in killing CEM-C7 human T lymphoblastoid leukemia cells and P1798-C7 murine T lymphoma cells. 4-HPR's apoptotic action requires the intact molecule bearing both the retinoid moiety and the hydroxyphenol ring; 4-HPR remains unmetabolized after uptake into CEM-C7 and P1798-C7 cells for up to 24 hours. We also show that glucocorticoid (GC)-resistant variants are equally susceptible to 4-HPR as are GC-sensitive cells. Thus, 4-HPR may be potentially important as a new chemotherapeutic drug for use as alternative to, or in combination with, conventional drugs for treating lymphoid malignancies. HDAC Inhibitors in Mantel Cell - Sodium Butyrate 68) Heider, Ulrike, et al. "Histone deacetylase inhibitors reduce VEGF production and induce growth suppression and apoptosis in human mantle cell lymphoma." European journal of haematology 76.1 (2006): 42-50. Three MCL cell lines (JeKo-1, Hbl-2 and Granta-519) were exposed to different concentrations of the HDAC inhibitors sodium butyrate (NaB) and suberoylanilide hydroxamic acid vorinostat (SAHA) for 8-72 h. Mantle cell lymphoma (MCL) is an incurable disease with an aggressive course and novel treatment strategies are urgently needed. The purpose of this study was to evaluate the effects of histone deacetylase (HDAC) inhibitors, a new group of antiproliferative agents, on human MCL cells. METHODS: Three MCL cell lines (JeKo-1, Hbl-2 and Granta-519) were exposed to different concentrations of the HDAC inhibitors sodium butyrate (NaB) and suberoylanilide hydroxamic acid (SAHA) for 8-72 h. Their effects on cell viability, apoptosis induction and cell cycle proliferation were studied. Moreover, the influence of SAHA on the expression of cyclin D1, the cell cycle regulators p21 and p27 and the production of vascular endothelial growth factor (VEGF) were analyzed. RESULTS: The HDAC inhibitors induced accumulation of acetylated histones in MCL cells. MTT assays and Annexin-V staining showed that they potently inhibited viability in a dose-dependent manner and induced apoptosis in all cell lines tested. Cell cycle analysis indicated that their exposure to SAHA or NaB decreased the proportion of cells in S phase and increased the proportion of cells in the G0/G1 and/or G2/M phases. Incubation with the two HDAC inhibitors resulted in downregulation of cyclin D1. SAHA lead to an upregulation of p21 in all cell lines and an upregulation of p27 in JeKo-1 and Granta-519 cells, while expression of p27 in Hbl-2 was not altered. In addition, SAHA inhibited the production of the angiogenic cytokine VEGF. Treatment with NaB increased the expression of p21 in JeKo-1 and Hbl-2 cells, while in Granta 519 cells no effect was noted. The expression of p27 remained constant in all three cell lines after exposure to NaB. CONCLUSION: Based on these findings, we provide evidence that HDAC inhibitors have antiproliferative effects in MCL and may represent a promising therapeutic approach. ATRA Lithium - Inhibition of the GSK3 enzyme with lithium sensitizes AML cells to the differentiating effects of all-trans-retinoic acid (ATRA) 69) Caimi, Paolo, et al. "All-Trans-Retinoic Acid (ATRA) Combined with Lithium As Treatment of Relapsed Non-Progranulocytic AML: Therapeutic Targeting Inhibition of the Glycogen Synthase Kinase 3-Beta (GSK3) Enzyme." Blood 124.21 (2014): 5299-5299. Introduction: Targeting the maturation arrest in acute myeloid leukemia (AML) to induce differentiation instead of killing rapidly dividing cells can lead to more efficacious and less toxic therapies for AML. Inhibition of the GSK3 enzyme with lithium sensitizes AML cells to the differentiating effects of all-trans-retinoic acid (ATRA), resulting in differentiation and inhibition of proliferation (Gupta K, et al. and Wald DN. Leukemia. 2012;26:1277-85.). In vitro and animal studies suggest the combination of ATRA and lithium has therapeutic activity against AML. We are conducting a phase I study of ATRA and lithium for the treatment of relapsed, non-progranulocytic AML Retinoic acid vitamin A 70) di Masi, Alessandra, et al. "Retinoic acid receptors: From molecular mechanisms to cancer therapy." Molecular aspects of medicine 41 (2015): 1-115.Retinoic acid receptors From molecular mechanisms to cancer therapy di Masi Alessandra 2015 80) Doldo, Elena, et al. "Vitamin A, Cancer Treatment and Prevention: The New Role of Cellular Retinol Binding Proteins." BioMed research international 2015 (2015). It is noteworthy that natural retinoids act as chemotherapeutic agents for the treatment of acute promyelocytic leukemia (APL). APL is a subset of acute myeloid leukaemia characterized by uncontrolled expansion of leukemia blast cells, blocked at promyelocytic stage of hematopoiesis in the bone marrow . It is characterized by a reciprocal translocation between the long arms of chromosomes 15 and 17 . This aberration leads to the fusion between the promyelocytic leukemia (PML) gene located on chromosome 15q21, normally responsible for the formation of the nuclear bodies and regulation of the stem cells self-renewal and the (RAR-α) gene from the chromosome 17q21, with the formation of a chimeric oncoprotein PML-RARA . The fusion transcript is detectable in more than 95% of APL patients with and acts as an oncogene, causing an enhanced DNA hypermethylation, proliferation, and inhibition of terminal differentiation of hematopoietic cells . ATRA-induced degradation of the fusion product is a basic therapeutic mechanism in APL cells . Recent results reveal several mechanisms leading to the destruction of the fusion oncogene, such as ubiquitination , sumoylation , or autophagy High concentrations of ATRA induce postmaturation apoptosis of APL-blasts through the induction of the tumour-selective death ligand TNF-related apoptosis-inducing ligand . Effectiveness of ATRA in the treatment of APL observed in more than 90% of the patients leading to the complete remission 81) Connolly, Roisin M., Nguyen K. Nguyen, and Saraswati Sukumar. "Molecular pathways: current role and future directions of the retinoic acid pathway in cancer prevention and treatment." Clinical Cancer Research 19.7 (2013): 1651-1659. 82) full pdf Retinoids and breast cancer from basic studies to the clinic Garattini Enrico 2014 Garattini, Enrico, et al. "Retinoids and breast cancer: from basic studies to the clinic and back again." Cancer treatment reviews 40.6 (2014): 739-749. ATRA is the first clinically useful cytodifferentiating agent, being employed in the treatment of acute promyelocytic leukemia (APL) Neurotoxicity of Chemotherapy ) http://neuro-oncology.oxfordjournals.org/content/16/4/476.full Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms Dias, Gisele Pereira, et al. "Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms." Neuro-oncology (2014): not321. The human brain is capable of generating new functional neurons throughout life, a phenomenon known as adult neurogenesis. The generation of new neurons is sustained throughout adulthood due to the proliferation and differentiation of adult neural stem cells. This process in humans is uniquely located in the subgranular zone of the dentate gyrus in the hippocampus. Adult hippocampal neurogenesis (AHN) is thought to play a major role in hippocampus-dependent functions, such as spatial awareness, long-term memory, emotionality, and mood. The overall aim of current treatments for cancer (such as radiotherapy and chemotherapy) is to prevent aberrant cell division of cell populations associated with malignancy. However, the treatments in question are absolutist in nature and hence inhibit all cell division. An unintended consequence of this cessation of cell division is the impairment of adult neural stem cell proliferation and AHN. Patients undergoing treatment for cancerous malignancies often display specific forms of memory deficits, as well as depressive symptoms. This review aims to discuss the effects of cancer treatments on AHN and propose a link between the inhibition of the neurogenetic process in the hippocampus and the advent of the cognitive and mood-based deficits observed in patients and animal models undergoing cancer therapies. Possible evidence for coadjuvant interventions aiming to protect neural cells, and subsequently the mood and cognitive functions they regulate, from the ablative effects of cancer treatment are discussed as potential clinical tools to improve mental health among cancer patients. Brain Toxicity - Regeneration ) http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4660740/ Yang, Miyoung, and Changjong Moon. "Effects of cancer therapy on hippocampus-related function." Neural regeneration research 10.10 (2015): 1572. ) http://www.ncbi.nlm.nih.gov/pubmed/25529185 Winocur, G., J. M. Wojtowicz, and I. F. Tannock. "Memory loss in chemotherapy-treated rats is exacerbated in high-interference conditions and related to suppression of hippocampal neurogenesis." Behavioural brain research 281 (2014): 239. Kleinberg, Lawrence. "Neurocognitive challenges in brain tumor survivors: is there anything we can do?." Journal of Clinical Oncology 33.15 (2015): 1633-1636. Drugs used to treat cancer have neurotoxic effects that often produce memory loss and related cognitive deficits. In a test of the hypothesis that chemotherapy-induced cognitive impairment is related to a loss of inhibitory control, rats injected with a combination of methotrexate+5-fluouracil or equal volumes of saline, were administered a retroactive interference task in which memory for a learned discrimination problem was tested under conditions of high- and low-interference. The drugs had no effect on original learning or on re-learning the discrimination response when there was little interference, but the chemotherapy group was severely impaired in the hippocampus-sensitive, high-interference memory test. The impaired performance correlated significantly with reduced neurogenesis in the hippocampus. The failure to suppress interfering influences is consistent with a breakdown in pattern separation, a process that distinguishes and separates overlapping neural representations of experiences that have a high degree of similarity. >>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>>> http://www.ncbi.nlm.nih.gov/pubmed/24343419 Psychopharmacology (Berl). 2014 Jun;231(11):2311-20. doi: 10.1007/s00213-013-3394-0. Epub 2013 Dec 17. Physical exercise prevents suppression of hippocampal neurogenesis and reduces cognitive impairment in chemotherapy-treated rats. Winocur G1, Wojtowicz JM, Huang J, Tannock IF. Chemotherapy, used for the treatment of cancer, often produces cognitive impairment that has been related to suppression of neurogenesis. Physical exercise, which promotes neurogenesis, is known to improve cognitive function in neurologically challenged animals and humans. It is unknown whether exercise similarly protects against chemotherapy-induced cognitive impairment and whether recovery of neurogenesis is a critical factor. OBJECIVE: The present study investigated the relationship between hippocampal neurogenesis and cognitive performance in chemotherapy-treated rats that engaged in different amounts of physical activity. METHODS: Groups of rats, housed individually in standard cages or in specially designed cages that allowed unlimited access to a running wheel, received three injections of the chemotherapeutic drugs methotrexate and 5-fluorouracil, or equal volumes of saline. They were then administered the following cognitive tests in a water maze: (1) spatial memory (SM), (2) cued memory, (3) non-matching to sample (NMTS) rule learning; (4) delayed NMTS (DNMTS). Hippocampal neurogenesis was quantified by counting doublecortin-expressing cells in the dentate gyrus. RESULTS: Chemotherapy administered to rats in standard cages resulted in a significant reduction in hippocampal neurogenesis and impaired performance on the SM, NMTS, and DNMTS tasks. In rats receiving chemotherapy and housed in exercise cages, neurogenesis was not suppressed and cognitive performance was similar to controls. CONCLUSIONS: Physical exercise can reduce cognitive deficits that result from chemotherapy and this effect is mediated, at least in part, by preventing suppression of drug-induced hippocampal neurogenesis. The results suggest benefits of exercise in preventing or treating cognitive impairment associated with chemotherapy. 12) http://www.sciencedirect.com/science/article/pii/S0166432815302692 Seigers, R., et al. "Neurobiological changes by cytotoxic agents in mice." Behavioural brain research 299 (2016): 19-26. Abstract Cognitive deficit is a frequently reported side-effect of adjuvant chemotherapy. A large number of animal studies has been performed to examine the neurobiological mechanisms underlying this phenomenon, however, definite conclusions from these studies are restricted due to differences in experimental set-up. We systematically investigated the effects of 6 cytotoxic agents on various neurobiological parameters. C57Bl/6J mice were treated with cyclophosphamide, docetaxel, doxorubicin, 5-fluorouracil, methotrexate, or topotecan. The animals were sacrificed 3 or 15 weeks after treatment and the effect on neurogenesis, blood vessel density, and neuroinflammation was analyzed using immunohistochemistry. None of the cytostatic agents tested affected neurogenesis (cell survival or cell proliferation). Blood vessel density was increased in the hippocampus and prefrontal cortex 3 weeks after treatment with docetaxel and doxorubicin compared with control animals. A decrease in the number of microglial cells was observed in the prefrontal cortex after treatment with cyclophosphamide, docetaxel, 5-FU, and topotecan compared with control mice. The observed decrease in microglia cells is indicative of inflammation that occurred after treatment. Overall, the magnitude of the effects was relatively modest. Therefore, we conducted a similar study with topotecan in Abcg2;Abcb1a/b knock out and wildtype FVB mice. Animals were sacrificed 3 weeks after treatment and no notable effect was seen in hippocampal cell differentiation (DCX), microglia activation, or blood vessel density. Perhaps the FVB strain is more resistant to the neurotoxic effects of topotecan which makes this not the correct model to study the mechanism of chemotherapy-induced cognitive impairment ................................................. Cannabinoids as Anticancer agents http://www.sciencedirect.com/science/article/pii/S0278584615001190 Progress in Neuro-Psychopharmacology and Biological Psychiatry Volume 64, 4 January 2016, Pages 259–266 The use of cannabinoids as anticancer agents Guillermo Velasco, , Sonia Hernández-Tiedra1, David Dávila1, Mar Lorente1 Department of Biochemistry and Molecular Biology I, School of Biology, Complutense University of Madrid, Spain Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Spain --------------------------- http://www.ncbi.nlm.nih.gov/pubmed/16000986 PET SCAN Lymphoma Even-Sapir, Einat, et al. "Fluorine-18 Fluorodeoxyglucose PET/CT Patterns of Extranodal Involvement in Patients with Non-Hodgkin Lymphoma and Hodgkin’s Disease." CNS Involvement Central nervous system involvement following diagnosis of non-Hodgkin’s lymphoma: a risk model. A. Hollender1+, S. Kvaloy1, O. Nome1, E. Skovlund12, K. Lote1 and H. Holte1 1Department of Medical Oncology and Radiotherapy, The Norwegian Radium Hospital, Oslo; 2Norwegian Medicines Agency, Oslo, Norway To determine the incidence and risk factors for central nervous system (CNS) relapse in patients with non-Hodgkin’s lymphoma (NHL). Patients and methods: Patient records were registered prospectively in successive patients with NHL admitted to the Norwegian Radium Hospital from 1980 to 1996. A total of 2514 patients had no CNS involvement at diagnosis and were treated according to standard protocols. The incidence and risk factors for CNS progression or relapse were examined retrospectively. Results: In low-grade (L)-NHL, the risk of CNS involvement was low (2.8%). In high-grade (H)-NHL, lymphoblastic and Burkitt’s NHL patients had a high risk of CNS recurrence (24.4%) at 5 years, and prophylaxis seemed to reduce this risk. For the other patients with H-NHL, the proportion with CNS involvement at 5 years was 5.2%. Multivariate analysis identified five independent risk factors, each present in >5% of patients: elevated serum lactate dehydrogenase, serum albumin <35 g/l, <60 years of age, retroperitoneal lymph node involvement and involvement of more than one extranodal site. If four or five of these risk factors were present, the risk of CNS recurrence was in excess of 25% at 5 years. Conclusions: The risk of CNS involvement in this study is comparable with the results from other large series. CNS prophylaxis is not recommended in any subgroup of L-NHL. The risk of CNS involvement among patients with either Burkitt’s or lymphoblastic lymphomas is considerable and these patients should therefore receive intensive chemotherapy including systemic and intrathecal methotrexate. Patients with other types of H-NHL should receive adequate CNS prophylaxis if at least four of the five risk factors identified are present. http://www.bloodjournal.org/content/114/26/5402?sso-checkedtrue Central nervous system prophylaxis in mantle cell lymphoma. Moshe E. Gatt and Sigal Grisaro Hadassah Hebrew University Medical Center, Jerusalem, Israel In their thorough review of mantle cell lymphoma (MCL),1 Ghielmini and Zucca describe that central nervous system (CNS) disease involvement, albeit rare at presentation, has an incidence of 4% to 22% in relapsed patients. Nevertheless, they do not state their recommendations regarding prophylaxis to MCL patients. The National Comprehensive Cancer Network (www.nccn.org) guidelines for diffuse large B-cell (DLBCL) lymphoma recommend CNS prophylaxis with 4 to 8 doses of intrathecal methotrexate (MTX) and/or cytarabine for patients with aggressive lymphomas who have paranasal sinus, testicular, epidural, bone marrow, 2 extranodal site involvement, or HIV lymphomas. The guidelines for MCL patients further suggest lumbar puncture at diagnosis for patients with blastic variants or with neurologic symptoms, but do not state any recommendations for prophylactic treatment at either diagnosis or relapse. Because there are no definite guidelines, and most patients are not treated with CNS-penetrating agents such as high dose MTX/cytarabine regimens,1 it is left to the physician's discretion whether to administer CNS prophylaxis or not. For instance, in the United Kingdom, one-third of hematologists administer prophylaxis to MCL patients and only in specific circumstances.2 Among the many reports of MCL in the literature, 4 concentrated their efforts on direct assessment of CNS involvement in MCL,3–6 and all are retrospective (Table 1); therefore, the true incidence is unknown. Interestingly, although most patients with CNS involvement develop symptoms at or after first relapse, not only the blastoid variant MCL had this propensity while having a higher risk. It might be argued that since most patients will succumb to their disease, which is rarely curable, and because CNS disease is only one part of a systemic relapse,3 there is limited application for primary prophylaxis. Nevertheless, in all reports, CNS disease was associated with worse overall survival. In addition, with the advent of newer agents and curative treatment attempts, patients may achieve more prolonged survival. It is controversial whether CNS prophylaxis for NHL can prevent CNS disease.7 In most MCL cohorts only a minority of patients received prophylaxis. Gill et al describe 10 patients who received prophylaxis with CNS-penetrating agents or intrathecal injections; none had developed CNS disease, compared with 4 of 52 not receiving such treatment.4 In contrast, Ferrer et al found no prophylactic advantage in patients receiving systemic high-dose MTX.3 It is the policy at our institution to provide CNS prophylaxis to those MCL patients with high-risk features, according to the NCCN guidelines for DLBCL. We use the addition of 2 high-dose MTX (> 3 gr/m2) courses if not included in the original chemotherapy protocol and 4 injections of intrathecal MTX. Given that the rate of CNS involvement at relapse may exceed one-quarter of patients, and more in those with blastoid variants, and the prospect of obtaining prolonged remissions with curative treatment attempts, we believe that CNS prophylaxis is warranted until further recommendations are prospectively investigated in clinical trials. http://annonc.oxfordjournals.org/content/early/2007/10/24/annonc.mdm447.full central nervous system involvement in mantle cell lymphoma A. Ferrer1,†, F. Bosch1, N. Villamor3, M. Rozman3, F. Graus2, G. Gutiérrez1, S. Mercadal1, E. Campo3, C. Rozman1, A. López-Guillermo1,* and E. Montserrat1 1Department of Hematology Department of Neurology and 3Hematopathology Unit, Hospital Clínic, Postgraduate School of Hematology ‘Farreras Valentí’, Institut d'Investigacio Biomedica ‘August Pi i Sunyer’, Barcelona, Spain ------------------------------------------------------------- Ann Oncol. 2007 Mar;18(3):541-5. Epub 2006 Dec 12. The role of intrathecal chemotherapy prophylaxis in patients with diffuse large B-cell lymphoma. Arkenau HT1, Chong G, Cunningham D, Watkins D, Agarwal R, Sirohi B, Trumper M, Norman A, Wotherspoon A, Horwich A. 1Department of Medical Oncology, Royal Marsden Hospital, London and Sutton, UK. Relapse in the central nervous system (CNS) following initial treatment of diffuse large B-cell lymphoma (DLBCL) is an uncommon but serious complication. This single centre retrospective study investigated the rate of CNS relapse in patients with DLBCL who received standardised intrathecal (IT) chemoprophylaxis. PATIENTS AND METHODS:A total of 259 patients were newly diagnosed and treated for DLBCL from October 1996 to May 2005 and retrospectively analysed for incidence of CNS relapse. Our institutional policy for patients at risk for CNS relapse was for IT chemoprophylaxis to be administered concurrently with systemic treatment. Defined at-risk patients were those with lymphoma involvement at the following sites: bone marrow, testis, nasal/paranasal sinuses, orbits, bone/vertebrae and peripheral blood. RESULTS: Of 259 patients with DLBCL, a total of 51 patients (19.7%) received IT chemoprophylaxis. Forty-four patients received single agent IT methotrexate (MTX) 12.5 mg (median 3 doses, range 1-7); 27 patients (53%) received 1-3 doses and 17 patients (33.3%) 4-7 doses of MTX. Seven patients (13.7%) received a combination of IT MTX plus cytarabine. Three patients (1.1%) subsequently developed CNS relapse. One of these patients had IT chemoprophylaxis, the other two did not meet the Royal Marsden Hospital (RMH) criteria for IT chemoprophylaxis. The median time from diagnosis of DLBCL to CNS relapse was 31.8 months (range 27.3-34.1 months). CONCLUSION: The CNS relapse rate in this cohort of patients with primary DLBCL was low at 1.1%. This retrospective analysis demonstrates in a homogeneous group of DLBCL patients that a relatively low-intensity IT chemoprophylaxis regimen given according to site-based risk can be associated with a low risk of CNS relapse. JULIE VOSE Mantle cell lymphoma: 2012 update on diagnosis, risk-stratification, and clinical management Vose, Julie M. "Mantle cell lymphoma: 2012 update on diagnosis, risk‐stratification, and clinical management." American journal of hematology 87.6 (2012): 604-609. Ibrutinib UNMC study to test 'breakthrough' drug in mantle cell lymphoma patients by Vicky Cerino July 29, 2013 Blood. 2012 Mar 1;119(9):2093-9. Comparative outcome of initial therapy for younger patients with mantle cell lymphoma: an analysis from the NCCN NHL Database. LaCasce AS1, Vandergrift JL, Rodriguez MA, Abel GA, Crosby AL, Czuczman MS, Nademanee AP, Blayney DW, Gordon LI, Millenson M, Vanderplas A, Lepisto EM, Zelenetz AD, Niland J, Friedberg JW. 1Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Ave., Boston, MA 02115, USA. --------------------------------------------------------- acyclovir anti-lymphoma http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3742590/ Yao, Jing, et al. "Turning an antiviral into an anticancer drug: Nanoparticle delivery of acyclovir monophosphate." Journal of Controlled Release 170.3 (2013): 414-420. http://onlinelibrary.wiley.com/doi/10.1111/jvim.12050/full Disease Remission in a Horse with EHV-5-Associated Lymphoma K. Vander Werf1,* and E. Davis2 Article first published online: 4 MAR 2013 http://jama.jamanetwork.com/article.aspx?articleid392068 Resnick, Lionel, et al. "Remission of tumor-stage mycosis fungoides following intravenously administered acyclovir." Jama 251.12 (1984): 1571-1573. MYCOSIS fungoides is a T-cell lymphoma that begins in the skin, frequently involves internal organs, and is usually fatal. Chronic dermatitis may be the initial manifestation of the disease, with plaques, tumors, and ulcerations developing later. Altered immunity is common in the late stages of the disease, and death is frequently caused by infection. After the formation of cutaneous tumors, the median survival time is less than three years despite various forms of treatment.1 The cause of mycosis fungoides is not known, but chronic stimulation of the immune system by viral antigens has been postulated to be important in the pathogenesis of lymphomas, including mycosis fungoides.2 We report a case of complete clearing of extensive ulcerated tumors in a patient with mycosis fungoides following therapy with intravenously (IV) administered acyclovir. http://www.infectagentscancer.com/content/7/1/33 Using antimicrobial adjuvant therapy in cancer treatment: a review Kenneth Alibek12, Aliya Bekmurzayeva3, Assel Mussabekova3* and Bolat Sultankulov3 Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana 010000, Kazakhstan Republican Scientific Center for Emergency Care, 3 Kerey and Zhanibek Khanov Street, Astana 010000, Kazakhstan “Nazarbayev University Research and Innovation System” private institution, Nazarbayev University, 53 Kabanbay Batyr Avenue, Astana 010000, Kazakhstan +++++++++++++++++++++++++++++++++++ MD Anderson Report December 2008 Mantle_Cell_Lymphoma_MD_Anderson_Issa_Khouri_Jorge_RomaGuera Khouri MD Anderson http://onlinelibrary.wiley.com/doi/10.1002/cncr.11838/full KHOURI, Issa F., et al. "Long-term follow-up of autologous stem cell transplantation in patients with diffuse mantle cell Lymphoma in first disease remission: The prognostic value of β2-Microglobulin and the Tumor Score." Cancer 98.12 (2003): 2630-2635. A β2-microglobulin (β2m)level ≤ 3 mg/L at the time of diagnosis or transplantation was also found to be strongly predictive of longer survival (5-year survival rate of 100% vs. 22% in patients with a β2m level > 3 mg/L) (P 0.0001). image Figure 1. Overall survival after autologous stem cell transplantation in patients with mantle cell lymphoma in first disease remission. Those whose β2-microglobulin (β2m) level was ≤ 3 mg/L at the time of diagnosis were reported to have a 5-year survival rate of 100%, but those whose β2m level was > 3 mg/L at the time of diagnosis were reported to have a 5-year survival rate of 22%. Khouri MD Anderson http://onlinelibrary.wiley.com/doi/10.1002/cncr.28219/full Chakhachiro, Zaher I., et al. "Cytarabine, Ki‐67, and SOX11 in patients with mantle cell lymphoma receiving rituximab‐containing autologous stem cell transplantation during first remission." Cancer 119.18 (2013): 3318-3325. RESULTS The estimated 4-year overall survival and progression-free survival rates were 82% and 59%, respectively. Twelve patients experienced disease recurrence. Fifteen of 16 patients who were alive and in complete remission at 36 months remained so at a median follow-up of 69 months (range, 38 months-145 months). The only determinant of recurrence risk found was a Ki-67 level of > 30%. Seven of 11 patients with a Ki-67 level > 30% experienced disease recurrence within the first 3 years versus only 3 of 16 patients with a Ki-67 level ≤ 30% (P .02). Patients who received high-dose cytarabine did not have a significantly different risk of developing disease recurrence compared with other patients (P .7). CONCLUSIONS Administering ASCT with rituximab during stem cell collection and immediately after transplantation may induce a continuous long-term disease remission in patients with MCL with a Ki-67 level of ≤ 30%. In conclusion, ASCT with rituximab given during stem cell collection and immediately after transplantation may induce continuous long-term remissions in a substantial subset of patients with MCL who responded to induction chemotherapy, with improved results compared with historical controls not receiving rituximab. The dose and schedule of rituximab in patients treated with ASCT need to be studied in randomized trials. An elevated Ki-67 level appears to be the most significant determinant of disease recurrence. Innovative strategies are needed to treat these patients. At the study institution, we offer allogeneic stem cell transplantation to patients with MCL with a high Ki-67 index. !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! Issa F. Khouri, MD, Department of Stem Cell Transplantation and Cellular Therapy, Unit 423, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; Fax:(713) 794-4902; ikhouri@mdanderson.org allogeneic stem cell transplantation to patients with MCL with a high Ki-67 index Issa F. Khouri, MD, Department of Stem Cell Transplantation and Cellular Therapy, Unit 423, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; Romaguerra MD Anderson (full free) Romaguera, J. E., et al. "Ten-year follow-up after intense chemoimmunotherapy with Rituximab-HyperCVAD alternating with Rituximab-high dose methotrexate/cytarabine (R-MA) and without stem cell transplantation in patients with untreated aggressive mantle cell lymphoma." British journal of haematology 150.2 (2010): 200-208. We conclude that intense chemoimmunotherapy without stem cell transplantation is effective for untreated aggressive MCL. Both intensive chemoimmunotherapy with or without consolidation stem cell transplantation remain acceptable options for initial management of aggressive MCL at this time. Only a randomized prospective trial can address the question of whether consolidation stem cell transplantation improves outcome after intense chemoimmunotherapy. -------------------------------------------------------------------------------------------------------------------------------- 2015 review Skarbnik, Alan P., and Andre H. Goy. "Mantle cell lymphoma: state of the art." Clinical advances in hematology & oncology: H&O 13.1 (2015): 44-55. Mantle Cell Lymphoma State of the Art Andre Goy Jan 2015 --------- Pterostilbene Tolomeo, Manlio, et al. "Pterostilbene and 3′-hydroxypterostilbene are effective apoptosis-inducing agents in MDR and BCR-ABL-expressing leukemia cells." The international journal of biochemistry & cell biology 37.8 (2005): 1709-1726.Pterostilbene apoptosis in MDR leukemia cells Tolomeo 2005 Diclofenac Pantziarka, Pan, et al. "Repurposing Drugs in Oncology (ReDO)—diclofenac as an anti-cancer agent." ecancermedicalscience 10 (2016). Abstract 2632:The COX inhibitor, diclofenac induces mantle cell lymphoma apoptosis independent of p53 status Hesham M. Hassan1, Michelle L. Varney2, Aalia M. Aly3, Shantaram S. Joshi2, Rakesh K. Singh2, and Bhavana J. Dave2Author Affiliations 1Assiut University, Assiut, Egypt;2university of Nebraska Medical Center, Omaha, NE;3South Egypt Cancer institute, Assiut, Egypt.Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Abstract Mantle cell lymphoma (MCL) is characterized by a clinically aggressive course with frequent relapses and poor survival. The p53 pathway is frequently dysregulated and p53 status predicts clinical outcome in MCL. Diclofenac has been reported to increase p53 pathway activity, upregulates p73 expression and inhibit cell growth; hence we investigated the ability of diclofenac to induce apoptosis and/or cell cycle arrest in MCL, and its dependence on p53 status. To investigate the response of MCL to diclofenac, wild-type p53 and mutant p53 expressing cells, therapy resistant cell lines and primary human cells isolated from MCL patients were used. Cell proliferation, apopotosis, and expression of down-stream signaling p53 targets were analyzed. Nontoxic concentrations of diclofenac induced concentration- and duration-dependent inhibition of MCL cell growth independent of p53 status. Diclofenac treatment also resulted in cell cycle arrest and cell death. Molecularly, diclofenac treatment was associated with increased activity of caspases 3, 7, and 8. Increased p53 pathway activity was demonstrated by duration-dependent induction of p53 transcriptional target genes, including the cell cycle regulatory molecule p21 and pro-apoptotic molecules including, PUMA, NOXA, BIM, and CD95. Most importantly, diclofenac treatment was associated with enhanced expression of the pro-apoptotic isoforms of the p53 homologue TAp73. Our data demonstrates that diclofenac treatment results in decreased cell cycle progression, and increased apoptosis that is associated with increased p53 pathway activity, independent of p53 status, and increased activity of its family member p73. Artesenuate Eur J Haematol. 2013 Oct;91(4):339-46.Lymphoma and myeloma cells are highly sensitive to growth arrest and apoptosis induced by artesunate. Holien T1, Olsen OE, Misund K, Hella H, Waage A, Rø TB, Sundan A. The use of new drugs has improved the treatment of multiple myeloma and diffuse large B-cell lymphoma (DLBCL). Nevertheless, over time many patients relapse and develop resistance to treatment, and efforts are needed to overcome drug resistance. The widely used malaria drug artesunate has been reported to have antitumor activity, and we aimed to test the effects of artesunate on a panel of myeloma and lymphoma cells. METHODS:Myeloma and DLBCL cell lines were treated with artesunate in vitro. The effects of artesunate treatment were evaluated using ATP content measurements for proliferation and annexin V/propidium iodide labeling for apoptosis. Western blotting was used to look for artesunate-induced protein changes. In addition, we measured artesunate effects on patient myeloma cells in the presence of bone marrow stromal cells. RESULTS:Artesunate treatment efficiently inhibited cell growth and induced apoptosis in cell lines. Apoptosis was induced concomitantly with downregulation of MYC and anti-apoptotic Bcl-2 family proteins, as well as with cleavage of caspase-3. The IC50 values of artesunate in cell lines varied between 0.3 and 16.6 μm. Furthermore, some primary myeloma cells were also sensitive to artesunate at doses around 10 μm. Concentrations of this order are pharmacologically relevant as they can be obtained in plasma after intravenous administration of artesunate for malaria treatment. CONCLUSION:Our findings indicate that artesunate is a potential drug for treatment of multiple myeloma and DLBCL at doses of the same order as currently in use for treatment of malaria without serious adverse effects. (BEAM)–Campath Allogeneic Stem Cell Transplantation for Aggressive Non-Hodgkin Lymphoma: An Analysis of Outcomes Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM)–Campath Allogeneic Stem Cell Transplantation for Aggressive Non-Hodgkin Lymphoma: An Analysis of Outcomes from the British Society of Blood and Marrow Transplantation edward Truelove , Christopher Fox , Stephen Robinson , Rachael Pearce, Julia Perry, Keiren Kirkland on behalf of the British Society for Blood and Marrow Transplantation (BSBMT). wE report the United Kingdom experience of Carmustine, Etoposide, Cytarabine, and Melphalan (BEAM)–Campath allogeneic stem cell transplantation in aggressive non-Hodgkin lymphoma • Nonrelapse mortality was 11% at 5 years • Progression-free survival was 36% at 5 years • Overall survival was 42% at 5 years • The regimen can provide durable disease control for a subset of patients Abstract The role of allogeneic stem cell transplantation (SCT) in the management of aggressive non-Hodgkin lymphoma (NHL) remains to be defined, but the number of procedures performed continues to increase. We report here the outcomes of allogeneic SCT using carmustine, etoposide, cytarabine, and melphalan (BEAM)-Campath (Genzyme Corporation, Cambridge, MA) conditioning for aggressive NHL as reported to the British Society of Blood and Marrow Transplantation (BSBMT). This retrospective study identified 46 patients who reported to the BSBMT registry as having undergone BEAM-Campath conditioned allogeneic SCT for aggressive NHL between 1999 and 2010. Disease histology was diffuse large B cell lymphoma (DLBCL, n 25), DLBCL/Burkitt lymphoma (n 5), and T cell lymphoma (n 16). At diagnosis, the median age was 42.5 (range, 17 to 59), 37 had advanced stage disease (Ann Arbor III/IV), 28 had 2 or more extra-nodal sites of disease, and 23 had elevated lactate dehydrogenase. International prognostic index was high or high/intermediate in 58%. The median number of prior therapies was 3 (range, 1 to 5) and 5 patients had previously undergone transplantation (4 autologous, 1 allogeneic). The median age at transplantation was 44.8 (range, 18 to 59), with 34 patients demonstrating chemo-sensitive disease and 22 undergoing transplantation in first response. Performance score was good in 40 patients and all engrafted with a median of 14 days (range, 11 to 27) to neutrophil recovery. At latest follow-up, 20 patients were alive with 17 in complete remission. Acute graft-versus-host disease (GVHD) developed in 7 patients and chronic GVHD developed in 13 (7 limited, 6 extensive). Five patients died from nonrelapse causes, with a cumulative incidence of nonrelapse mortality of 7% at 100 days and 11% at 3 and 5 years. Twenty-one patients died after lymphoma relapse, with a cumulative incidence of relapse/progression of 51% at 1 year and 53% at 5 years. Disease status at transplantation had no impact on relapse rate. Progression-free survival was 41% at 1 year and 36% at 5 years. Overall survival was 54% at 1 year and 42% at 5 years. Overall, BEAM-Campath–conditioned allogeneic SCT is well tolerated and able to deliver durable disease-free survival to a subset of patients with aggressive NHL. However, the high relapse rates indicate further investigation is needed to identify those patients most likely to benefit. Introduction Aggressive histology non-Hodgkin lymphoma (NHL) includes high-grade B cell lymphomas and peripheral T cell lymphomas (PTCL), which have the potential to be cured with combination chemotherapy. Although outcomes for patients with diffuse large B cell lymphoma (DLBCL) have improved with the addition of rituximab to initial chemotherapy , a significant minority of patients still experience relapse . The role of high-dose therapy (HDT) followed by autologous stem cell transplantation (ASCT) in relapsed disease was established in the pre-rituximab era [5. However, those relapsing after or refractory to immuno-chemotherapy have a poor outcome with conventional salvage followed by HDT/ASCT [6. PTCL comprise a heterogeneous group of NHL that tend to have more aggressive disease characteristics at presentation than their B cell counterparts. With the exception of anaplastic lymphoma kinase–positive anaplastic large cell lymphoma, the outcomes with anthracycline-based chemotherapy are worse than those for B NHL and the gold standard front-line combination chemotherapy remains to be defined . The overall poor prognosis for patients with PTCL has led to use of HDT/ASCT to consolidate first responses , with more promising results. The role of HDT/ASCT in the management of patients with aggressive NHL is clearly changing and alternative strategies are required in the management of some patients with high-risk features and those with relapsed disease. Although the optimal role for allogeneic stem cell transplantation (SCT) remains to be established in aggressive NHL, the number of procedures performed has significantly increased in recent years . The less-intensive RIC regimens rely on the potential GVL effect for long-term disease control, but the evidence to support such an effect is less compelling in aggressive NHL than in low-grade disease . We report here the outcome of patients with aggressive NHL conditioned with BEAM-Campath before allogeneic SCT as reported to the British Society of Blood and Marrow Transplantation (BSBMT). ----- ---- Mantle Cell Experience after 17 years at MD anderson Tam, Constantine S., et al. "Mature results of the MD Anderson Cancer Center risk-adapted transplantation strategy in mantle cell lymphoma." Blood 113.18 (2009): 4144-4152. . Interestingly, the efficacy of NST (allogeneic transplant) was most marked in patients who had received a (peripheral blood stem cell) PBSC graft and who achieved a donor chimerism of 95% or better, with none of 24 patients with these characteristics relapsing after a median follow-up of 5 years. The results of the current study support the ongoing exploration of stem cell transplantation as a potentially curative method in the treatment of patients with MCL. In particular, our findings and that of the Nordic Lymphoma Group suggest that the window of opportunity for long-term disease control with autologous transplantation may only be available in the frontline setting, giving substantial impetus to a renewal of interest in studies of early transplantation in younger patients. https://www.ncbi.nlm.nih.gov/pubmed/10631455 Ann Oncol. 1999 Nov;10(11):1293-9. Allogeneic hematopoietic transplantation for mantle-cell lymphoma: molecular remissions and evidence of graft-versus-malignancy. Khouri IF1, Lee MS, Romaguera J, Mirza N, Kantarjian H, Korbling M, Albitar M, Giralt S, Samuels B, Anderlini P, Rodriguez J, von Wolff B, Gajewski J, Cabanillas F, Champlin R. The presence of a graft-versus-tumor effect has been well established for various hematological malignancies but not for mantle-cell lymphoma (MCL). We report preliminary results suggestive of a graft-versus-lymphoma effect in such patients post allogeneic hematopoietic transplantation. PATIENTS AND METHODS: Sixteen patients with the diffuse type of MCL received allogeneic transplantation. Three had blastic features. Fifteen had an HLA-identical and one, a one HLA antigen mismatched sibling donor. Fifteen had stage IV disease. Eleven patients were previously treated, including one who failed prior autologous transplantation. Five patients were newly diagnosed and received transplantation after cytoreduction with three to eight courses of HYPER-CVAD (fractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone) alternating with high-dose methotrexate and cytarabine. RESULTS: Eleven patients received high-dose cyclophosphamide 120 mg/kg and total body irradiation (TBI) (12 Gy given in four daily fractions). Three patients were not eligible for TBI and received the BEAM regimen. Twelve (85.7%) achieved complete and two (14.3%) partial response. Two additional patients received a nonablative preparative regimen consisting of cisplatin, cytarabine and fludarabine. One failed to engraft and later relapsed. The other patient had progressive disease one month post transplant but later achieved complete remission now durable for 14+ months after developing graft-versus-host disease (GVHD). Residual lymphoma was assessed in seven patients by polymerase chain reaction assay (PCR) for bcl-1 or immunoglobulin gene rearrangement. All had detectable disease at the time of transplant. When tested within four months post transplant, four of these patients attained molecular remission. One of the three molecular non-responders converted to a negative PCR status seven months later and one fluctuates between positive and negative PCR fourteen months post transplant. Overall survival (OS) and failure-from-progression (FFP) at three years were both 55% (95% confidence interval (95% CI): 28%-83%). For patients with chemosensitive disease, FFP and OS at one year were both 90% (95% CI: 71%-100%) compared with 44% (95% CI: 1%-88%) (P 0.04) for those who were refractory to conventional chemotherapy at the time of transplantation. There were six deaths. These were related to GVHD (three cases), infection (one case), multiorgan failure (one case), and graft failure (one case). CONCLUSIONS: This report demonstrates the potential efficacy of allogeneic hematopoietic transplantation for MCL and provides the first evidence suggestive of graft-versus-malignancy in MCL. Data supportive of this concept include 1) achievement of remission concomitant with GVHD, 2) the conversion from a positive PCR status early after transplant to negative PCR status over time and 3) that the only relapse was in a patient who failed to engraft. Br J Haematol. 1996 Aug;94(2):376-8. Clinical and molecular remission after allogeneic blood cell transplantation in a patient with mantle-cell lymphoma. Corradini P1, Ladetto M, Astolfi M, Voena C, Tarella C, Bacigalupo A, Pileri A. Author information Abstract Mantle-cell lymphoma (MCL) is a B-cell tumour with a usually poor prognosis, characterized by the proliferation of small cleaved lymphocytes with a diffuse growth pattern. We report a polymerase chain reaction-based analysis of minimal residual disease in a patient who achieved complete remission after allogeneic blood cell transplantation (BCT). Rearrangement of the immunoglobulin heavy-chain genes was used to generate a lymphoma-specific molecular marker. Lymphoma cells were not detectable in a bone marrow sample collected 12 months after BCT. Our findings suggest that allogeneic BCT may offer a curative approach to MCL. Curr Oncol Rep. 2000 Mar;2(2):182-91. Allogeneic hematopoietic transplantation for chronic lymphocytic leukemia and lymphoma: potential for nonablative preparative regimens. Champlin R1, van Besien K, Giralt S, Khouri I. Author information 1Department of Blood and Marrow Transplantation,University of Texas MD Anderson Cancer Center,1515 Holcombe Blvd., Box 24, Houston, TX 77030, Abstract There is increasing interest in the use of allogeneic blood and marrow transplants for chronic lymphocytic leukemia (CLL) and lymphomas. Numerous studies indicate efficacy in patients with advanced disease and demonstrate existence of a potent graft-versus-malignancy effect against these disorders. Allogeneic transplantation is most effective in CLL and low-grade lymphomas, but precise indications and timing of allogeneic transplants in these indolent disorders are not well defined. Allotransplantation is an effective, potentially curative approach, albeit with substantial risks; it is indicated in selected categories of patients. Allogeneic transplants are also promising for mantle cell lymphoma. In large-cell lymphoma, relapses are reduced in allogeneic compared with autologous transplants, but the benefit of allotransplantation has been offset by increased risk of treatment-related complications, and its indications are controversial. A promising new strategy is the use of less toxic, nonmyeloablative preparative regimens to achieve engraftment and allow development of graft-versus-malignancy effects that can produce durable remission in selected categories of lymphoid malignancies. 2012 Khouri, Issa F., and Richard E. Champlin. "Non-myeloablative Allogeneic Stem Cell Transplantation for Non-Hodgkin Lymphoma." Cancer journal (Sudbury, Mass.) 18.5 (2012): 457. Non-Hodgkin's lymphomas constitute a heterogeneous group of hematologic malignancies with varying aggressiveness and many therapeutic options. Non-myeloablative conditioning has been the cornerstone of allogeneic adoptive immunotherapy for these diseases. To optimize this therapeutic approach, we must determine its association with disease characteristics (histologic disease type, new prognostic factors, and conventional chemotherapy response), patient characteristics, and transplantation characteristics (conditioning type, donor source, graft-versus-host disease prophylaxis, donor lymphocyte infusion, and relapse prevention methods). In this review, we discuss the current status of non-myeloablative allogeneic transplantation in the major lymphoma subgroups. Cancer. 2013 Sep 15;119(18):3318-25. doi: 10.1002/cncr.28219. Epub 2013 Jun 17. Cytarabine, Ki-67, and SOX11 in patients with mantle cell lymphoma receiving rituximab-containing autologous stem cell transplantation during first remission. Chakhachiro ZI1, Saliba RM, Okoroji GJ, Korbling M, Alousi AM, Betul O, Anderlini P, Ciurea SO, Popat U, Champlin R, Samuels BI, Medeiros LJ, Bueso-Ramos C, Khouri IF. Author information Abstract BACKGROUND: In the current study, the authors report the results of 39 patients with mantle cell lymphoma (MCL) who were treated with chemotherapy and high-dose rituximab-containing autologous stem cell transplantation (ASCT) during their first disease remission. METHODS: The median age of the patients was 54 years. At the time of diagnosis, 87% of patients had Ann Arbor stage IV disease, and 77% had bone marrow involvement. A Ki-67 level of > 30% was found in 11 of 27 patients (40%), and SOX11 (SRY expression was found to be positive in 17 of 18 patients (94%). Twenty-seven patients (69%) underwent induction therapy with high-dose cytarabine-containing chemotherapy. Rituximab was administered during stem cell collection at a dose of 1000 mg/m2 on days +1 and +8 after ASCT. RESULTS: The estimated 4-year overall survival and progression-free survival rates were 82% and 59%, respectively. Twelve patients experienced disease recurrence. Fifteen of 16 patients who were alive and in complete remission at 36 months remained so at a median follow-up of 69 months (range, 38 months-145 months). The only determinant of recurrence risk found was a Ki-67 level of > 30%. Seven of 11 patients with a Ki-67 level > 30% experienced disease recurrence within the first 3 years versus only 3 of 16 patients with a Ki-67 level ≤ 30% (P .02). Patients who received high-dose cytarabine did not have a significantly different risk of developing disease recurrence compared with other patients (P .7). CONCLUSIONS: Administering ASCT with rituximab during stem cell collection and immediately after transplantation may induce a continuous long-term disease remission in patients with MCL with a Ki-67 level of ≤ 30%. !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! An elevated Ki-67 level appears to be the most significant determinant of disease recurrence. Innovative strategies are needed to treat these patients. At the study institution, we offer allogeneic stem cell transplantation to patients with MCL with a high Ki-67 index. Kevin Berry Kevin Berry is a 10-year mantle cell lymphoma survivor and recently underwent his second bone marrow transplant. He works on Human Spaceflight programs, is a freelance writer and editor, serves as a patient advocate, and supports newly diagnosed patients through his ministry, Taking Vienna (www.takingvienna.blogspot.com). He lives in Central Florida with his wife and adult children. Did Your Cancer Transplant Fail? It’s Time To Learn Another Acronym: DLI - See more at: http://www.curetoday.com/community/kevin-berry/2016/11/did-your-cancer-transplant-fail-its-time-to-learn-another-acronym-dli#sthash.sowyIE8k.dpuf allogeneic transplant "Of note, it should be emphasized that the 5-year OS for the 14 patients younger than 60 years reaches 100% " OS overall survival from this paper: tps://www.ncbi.nlm.nih.gov/pmc/articles/PMC3573392/ Ther Adv Hematol. 2011 Feb; 2(1): 5–10. Long-Term Results of Fludarabine/Melphalan as a Reduced-Intensity Conditioning Regimen in Mantle Cell Lymphoma: The GELTAMO Experience Jorge Gayoso Cruz, PhD,10 Rodrigo Martino, PhD,1 Pascual Balsalobre, RN,2 Inmaculada Heras, PhD,3 José Luis Piñana, PhD,4 David Serrano, PhD,5 Javier de la Serna, PhD,6 José Francisco Tomás, PhD,7 Joséa Luis Díez-Martíin, PhD,8 and Dolores Caballero, PhD9 Early toxicity included mild/moderate mucositis (43%), febrile neutropenia (33%) and bacterial infections (19%). With a median follow up of 48 months, four deaths were reported, all due to infections and/or graft-versus-host disease (GVHD), yielding a 3-year cumulative incidence of nonrelapse mortality of 19.5%. Grade III—IV acute GVHD occurred in 15% and chronic GVHD in 78%, being extensive in 39%. The 5-year progression-free survival (PFS) and overall survival (OS) were both 80% (95% CI: 63-97%). Age was the only possible prognostic factor for OS, which was 43% for those aged more than 60 years and 100% for those younger (p < 0.001). Conclusions: Our data confirm that allo-RIC offers a low toxicity profile and a chance for prolonged long-term disease-free survival in MCL, particularly in younger patients. SlidesShow Mantle Cell Lymphoma: from bench to clinic Michael Wang, MD Associate Professor Co-Director, Clinical Trials in Lymphoma Director, Myeloma Tissue Bank Director, Mantle Cell Lymphoma Program of Excellence Departments of Lymphoma/Myeloma , Stem Cell Transplantation MD Anderson Published on Aug 23, 2013 http://www.slideshare.net/spa718/mantle-cell-lymphoma-from-bench-to-clinic

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