Allogeneic Stem Cell Transplant Curative for Many Cancers

Stem Cell Transplant Allogeneic Cancer Gov CDR765030Allogeneic Stem Cell Transplant Curative for Many Cancers

by Jeffrey Dach MD

One of the secrets of mainstream oncology is they actually have a cure for Cancer.  I was somewhat surprised and astonished to discover mainstream oncology has been using allogeneic stem cell transplant to cure many hematologic cancers for many years now.   This is not widely known. Above image: Stem Cell Transplant Procedure Explained Courtesy of National Cancer Institute.

Part of the reason for secrecy is the early transplant procedures were associated with a high mortality rate from the procedure itself, mostly from fulminating infection caused by immunosuppressive drugs, or from graft vs. host disease.

However lately, studies from Weil Cornell in New York and University of Washington in Seattle show the techniques have evolved to the point that, at least in younger patients, mortality from the procedure has been minimized enough to make transplant a reasonable option.  Those patients who survive past the one year mark after the transplant are likely to be cured.

What is Allogeneic Bone Marrow Transplantation ?

In a procedure called Autologous bone marrow transplant, the patient’s own stem cells are harvested before chemotherapy.  The patient is then given back their own cells after high dose chemotherapy which obliterates the bone marrow.  To rescue the patient and restore the bone marrow, the patient’s pre-harvested stem cells are re-infused, restoring bone marrow function.  This is a relatively safe procedure compared to Allogeneic transplant which uses donor cells.

Allogeneic transplant differs from Autologous transplant.  In this case, the patients own cells cannot be used for clinical reasons.  So the transplanted bone marrow cells must come from a donor patient, either a matched sibling, or matched unrelated donor.  Newer techniques developed in China use umbilical cord stem cells as the donor source.  A Halplo-Identical transplant from a sibling is used as a bridge allowing time for the umbilical cord stem cells to engraft.(30)  (Link to more Articles on Google Scholar).

Excellent Results for Haplo-Cord Allogeneic Transplantation for Lymphoma

Allogeneic Transplant Weil Cornell Koen van Besien F1

The above chart comes from a 2016 report in Blood from Weil Cornell in New York, and the University of Chicago.(1)  Over an 8 year period, 45 patients with aggressive Lymphoma refractory to conventional chemotherapy were treated with Haplo-Cord  Allogeneic Transplant with excellent results.(1)  The two charts above show virtually all the mortality occurs in the first year, with a flat line extending to the right of the charts, indicating those patients who survived past one year are cured.  The authors state:

“HaploCord Transplantation offers an excellent treatment alternative for patients with recurrent and refractory lymphoid malignancies who lack matching donors. Count recovery is rapid, non relapse mortality is limited, excellent disease control can be achieved and the incidence of chronic GVHD is limited.”

Allogeneic Transplant for Mantle Cell Lymphoma Long term Follow Up

Vaugn Seattle Allogeneic Transplantation Mantle cell Lymphoma

Left Chart Figure 1 (A) Cumulative incidences of non-relapse mortality and progression/relapse, courtesy of Jennifer Vaugn University of Washington, Seattle.(3)

In a 2015 report by Jennifer Vaugn MD, at the Fred Hutchinson Cancer Center, 33 Mantle Cell Lymphoma patients were given Allogeneic stem cell transplant and followed for 10 years.  The chart at the left shows most of the disease relapse occurred with the first 6-12 months after transplant (Red Arrow).   Except for one patient who relapsed at the 4 year mark, the remaining patients remained cancer free over the 10 years of follow up indicating they were “Cured” (Green Arrows point to flat horizontal line indicating cure).  The “Cure” is attributed to the Graft vs. Tumor effect.(2)  The new immune system attacks and kills the cancer cells.  The authors state:

“Despite recent progress in conventional treatment,(1,2) allogeneic hematopoietic cell transplantation (HCT) remains the only potentially curative treatment option in patients with mantle cell lymphoma (MCL).”

Relapse After Allogeneic Transplantation

Seven years ago in 2011 , Dr Koen van Besien reported on “Current status of allogeneic transplantation for aggressive non-Hodgkin lymphoma.”    Dr Koen van Besien writes in 2011 that allogeneic transplantation can cure some patients, and he observes that relapse often occurs in the first 6 months after transplant as demonstrated on the above charts.  Unfortunately, as of 2011, prognosis for these relapsed patients was dismal with few achieving durable response after relapse.(35)  In 2011 Dr Van Biesen wrote:

“A large number of reports show that allogeneic transplantation can be curative in a fraction of patients with otherwise refractory disease. ….When relapse occurs in patients with aggressive lymphoma it often happens within the first six months after transplant and the prognosis for such early relapsing patients is poor. …Few if any such patients obtain durable remissions to further chemotherapeutic or immunologic intervention.”(35)

The reason for the cancer relapse within the first 6 months after allogeneic transplantation could be explained by a combination of rapidly proliferating cancer cell type, and a delay of 6-10 months in maturation of the new immune system represented by the allogeneic transplant.  For the slower, less aggressive cell types, the new graft has plenty of time to mature and start attacking cancer cells.  However, the rapidly proliferating highly aggressive cell types relapse early before graft maturation.

New Path-Way Inhibitor Drugs

One might wonder if the new drugs available for hematologic malignancies since 2011 have changed the outlook for relapse after Allogeneic transplant.   For example, Dr Mauricette Michallet reported in Blood 2016 on their experience using path-way inhibitors such as Ibrutinib, Idealsib and venetoclax in the relapse post allogeneic transplant setting. reporting Ibrutinib effective after relapse. (55)  One possible approach to relapse after transplant is to slow the proliferation rate of the aggressive cancers with pathway inhibitors such as Bruton’s Tyrosine Kinase Inhibitor, (Ibrutinib) and the Bcl2 inhibitor, (Venetoclax).(31) In 24 patients with Mantle Cell Lymphoma, this combination provided a 71% complete response at 16 weeks by PET scan as reported in 2018 by Constantine Tam in the New England Journal .(31)

Another benefit of Ibrutinib in the post allogenic transplant setting is augmentation of Graft vs. Tumor Effect.(62-63)

If the cancer cell proliferation rate can be slowed with path-way inhibitor drugs, this may buy time to allow the new immune system to mature and kick in the Graft vs. Tumor effect.  In addition to FDA approved drugs, off label use of old repurposed drugs might prove helpful.  Off label use of old drugs such as itraconazole, Doxycycline, Clarithromycin, Fenofibrate etc. have been explored.  There are many others that can serve as a monkey wrench in the cancer cell machinery.

The Graft vs. Tumor Effect

Once the new immune system matures, a robust Graft vs. Tumor Effect can be observed as reported by Dr Frédéric Baron from Fred Hutchinson Cancer Research Center, Seattle, in 2005 JCO. (2)  Dr Baron observed that almost two thirds of cancer patients who had  measurable cancer masses at the time of transplant still achieved complete remission after a delay of 176 days, presumably allowing time for graft maturation.

“Fifty-seven percent of patients with measurable disease at HCT (Hematopoetic Stem cell Transplant) responded. The delayed time to achieve complete remissions (median, 176 days) and the fact that none of the patients with graft rejection achieved sustained complete remissions were consistent with the notion that responses were a result of GVT effects (Graft vs Tumor Effects).(2)

Others have commented on the curative effect of Allogeneic transplant. Dr Kobrinski in 2017 JCO says.(4):

“Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only potential curative treatment option for patients with MCL (Mantle Cell Lymphoma) due to its potent graft-versus-lymphoma (GVL) effect“(4)

Dr Jose Sandoval-Sus from Moffitt Cancer Center in Tampa says in July 2018, (17)

”Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for mantle cell lymphoma (MCL). “(17)

Dr Atilla writes in the International Journal of Hematology,  referring to treatment of Mantle cell lymphoma:(5)

Allogeneic hematopoietic stem cell transplantation is the only curative option,”(5)

Dr Timothy Fenske at the University of Milwaukee (with Brad Kahl) is in agreement commenting Allogeneic Transplant is curative therapy and should be expanded to older patients.(6)(32)  Dr Fenske  says in 2016 :

“Allogeneic hematopoietic cell transplantation is curative therapy for patients with non-Hodgkin lymphoma: increasingly successful application to older patients.”(6)

Reduced Intensity Conditioning Preferable to High Intensity Conditioning

In 2013, Dr Mehdi Hamadani reported his analysis of chemotherapy resistant mantle cell lymphoma treated with Allogeneic Stem Cell Transplant, finding that about 25% of the patients were alive and in remission at the three year mark, meaning they were “cured”.(61)  Dr Mehdi Hamadani’s second observation was this:

“the intensity of the pretransplantation conditioning regimen used apparently had no significant affect on rates of (Non-Relapse Mortality) NRM, relapse/progression, Progression Free Survival PFS, and Over-All Survival OS.”(61)

This report by Dr Hamadani and others suggests that Reduced Intensity Conditioning is preferable to high intensity (myeloablative)  conditioning since it is associated with similar outcomes with less toxicity .(65-66)

Other Hematologic Cancers

Dr Frank Heinzelmann from Germany says transplant offers cure for transformed Follicular Lymphoma, a highly aggressive variant with otherwise poor prognosis.(7)

Mark-Alexander Schwarzbich, MD in 2016 Oncology shares his thought on the subject.(8)  Dr Schwarzbic says that recent improvements and refinements in stem cell transplant techniques makes it a more reasonable option for CLL (chronic leukemia patients).” (8)

“Hematopoietic stem cell transplantation (HSCT) is the only established potentially curative treatment option for chronic lymphocytic leukemia (CLL) to date. However, this approach is associated with high toxicity and significant treatment-related morbidity and mortality;…….In the wake of novel treatment approaches that offer high efficacy and highly durable responses with little toxicity, our approach to HSCT in CLL needs to be re-evaluated.”(8)

Allogeneic Stem Cell Transplant Curative for Other Cancers

If the Graft vs. Tumor Effect is curative in hematologic malignancies, then one might expect  it should work for other cancers.  Blastic plasmacytoid dendritic cell neoplasm (BPDCN), incurable with conventional therapies, can be cured with Allogeneic tranplantation. (9-11)  AML (acute myelogenous leukemia) and Cutaneous T cell leukemia can be cured with Allogeneic Transplant.(12-14)  Multiple Myeloma can be cured with Allogeneic Transplant (15-16)

Allogeneic Transplant for Solid Tumors –  A Disappointment

In spite of the success for Allogeneic transplant for hematologic cancers, use for sold cancers has been a disappointment.(20)  Dr Yshay Ofran writes in 2008. (20),

“In contrast to hematologic malignancies, where GVL (Graft vs Lymphoma) frequently results in complete remission, clinical outcomes after allogeneic HSCT for solid tumors have been disappointing. A recent review of allogeneic HSCT in patients with meta-static breast cancer, melanoma, and renal cell cancer revealed evidence of significant graft versus tumor activity, but few complete responses were documented and patients seldom maintain partial responses for prolonged periods.  If the results of allogeneic HSCT for solid tumors can be improved, this may introduce an entirely new therapeutic modality in our armamentarium against these cancers”.(20).

One exception is renal cell carcinoma where disappearance of lung mets was reported by Dr Richard Childs in the New England Journal Sept 2000 after treatment with Allogeneic transplant.(23)   It seems that renal cell carcinoma may be responsive to the immunotherapy effects of Allogeneic Transplant.

Conclusion: Allogeneic transplantion has been reported as curative for hematologic malignancy as early as 2012 in Cancer Journal by Dr Issa Khouri at MD Anderson.(56)  In the past, Allogeneic Transplant was associated with high non-relapse mortality mostly due to Graft vs. Host disease, and and disseminated infection related to immunosuppression.   However recent refinements in technique have reduced the procedural related mortality to the point where its curative potential can now be offered to a larger subset of patients. Previously dismal prognosis for those patients who relapse within 6 months of transplant has been improved by the use of pathway inhibitors that slow proliferation rate and buy time for graft maturation.

Articles with related Interest: Link to this article

The Mouse that Was Immune to Cancer

Stevn Rosenberg and Cancer Immunotherapy

Anti-Cancer Vaccine with Embryonic Stem Cells

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie Florida 33314
954 792-4663

Links and References

Nice charts showing most relapse and most mortality is in first year. Dr VB Weil Cornell Data.

Allogeneic transplantation mantle cell

!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! excellent Fred Hutch

2) Baron, Frédéric, et al. “Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning.” Journal of Clinical Oncology 23.9 (2005): 1993-2003. Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation Baron Frederic J Clin Onc 2005

Fifty-seven percent of patients with measurable disease at HCT responded. The delayed time to achieve complete remissions (median, 176 days) and the fact that none of the patients with graft rejection achieved sustained complete remissions were consistent with the notion that responses were a result of GVT effects.

The persistence of host antigen-presenting cells, including dendritic cells, during the first months after HCT with nonmyeloablative condi-tioning might, in part, be responsible for efficient donor T-cell immunization against host hematopoietic cells re-sulting in GVT effects.41

Strong antitumor responses were seen in some patients in the absence of clinical GVHD,
suggesting that those responses were directed against anti-gens preferentially expressed on hematopoietic cells.36

Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D1-100, PO Box 19024, Seattle, WA 98109-1024, USA.

PURPOSE:

We have used a nonmyeloablative conditioning regimen consisting of total-body irradiation (2 Gy) with or without fludarabine (30 mg/m(2)/d for 3 days) for related and unrelated hematopoietic cell transplantation (HCT) in patients with hematologic malignancies who were not candidates for conventional HCT because of age, medical comorbidities, or preceding high-dose HCT. This approach relied on graft-versus-tumor (GVT) effects for control of malignancy.
PATIENTS AND METHODS: We analyzed GVT effects in 322 patients given grafts from HLA-matched related (n = 192) or unrelated donors (n = 130).
RESULTS:  Of the 221 patients with measurable disease at HCT, 126 (57%) achieved complete (n = 98) or partial (n = 28) remissions. In multivariate analysis, there was a higher probability trend of achieving complete remissions in patients with chronic extensive graft-versus-host disease (GVHD; P = .07). One hundred eight patients (34%) relapsed or progressed. In multivariate analysis, achievement of full donor chimerism was associated with a decreased risk of relapse or progression (P = .002). Grade 2 to 4 acute GVHD had no significant impact on the risk of relapse or progression but was associated with increased risk of nonrelapse mortality and decreased probability of progression-free survival (PFS). Conversely, extensive chronic GVHD was associated with decreased risk of relapse or progression (P = .006) and increased probability of PFS (P = .003).
CONCLUSION:  New approaches aimed at reducing the incidence of grade 2 to 4 acute GVHD might improve survival after allogeneic HCT after nonmyeloablative conditioning.

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Nice charts showing most of relapse occurs within first 6 months.

3) Vaughn, Jennifer E., et al. “Long-term sustained disease control in patients with mantle cell lymphoma with or without active disease after treatment with allogeneic hematopoietic cell transplantation after nonmyeloablative conditioning.” Cancer 121.20 (2015): 3709-3716.

see Figure 1A (below)

26% Relapse Rate within first 5 years ???? ….

However if you look at the chart, almost all the relapse cases occur within 6 months of the transplant.

the chart is almost a straight horizontal line after that…indicating very little further relapse.

The MCL patients are relapsing early after transplant (within 6 months) because they all had residual disease at the time of transplant which the chemotherapy could not eradicate.

After one year there is almost no further relapse….the Graft has matured by one year…this is graft vs lymphoma effect….which is why this is a curable treatment.

Notice the blip in the chart at 4 years: of 33 patients, one patient relapsed at 4 years, an outlier.

By definition, if you are disease free after 1.5 years, the graft has matured and is able to prevent disease relapse.

Quote from this article: “Despite recent progress in conventional treatment,(1,2) allogeneic hematopoietic cell transplantation (HCT) remains the only potentially curative treatment option in patients with mantle cell lymphoma (MCL).”

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Allogeneic hematopoietic stem cell transplantation for mantle cell lymphoma

4) Kobrinski, Daniel Allen, et al. ” Allogeneic hematopoietic stem cell transplantation for mantle cell lymphoma in a heavily pretreated patient population.” (2017): 7558-7558.Journal of Clinical Oncology 35, no. 15_suppl (May 20 2017) 7558-7558. Loyola University Medical Center, Maywood, IL;

Background: Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only potential curative treatment option for patients with MCL due to its potent graft-versus-lymphoma (GVL) effect. Survival following allo-SCT for MCL is variable due to high rates of non-relapse mortality (NRM). Methods: We retrospectively identified all patients who were treated with an allo-SCT for MCL at Loyola University Medical Center between January 1, 1999 and January 1, 2016. Probability estimates for overall survival (OS) and non-relapse mortality (NRM) at 5 years were calculated from the date of allo-SCT to the date of patient death or last known follow-up. Significance was determined using a cox proportional hazard (CPH) model. Rates of acute graft-versus-host disease (aGVHD) and relapse were also reported. Results: Patient characteristics (n = 29) are listed in Table. Median follow-up in surviving patients is 10 years (range 5-14 years). A majority of patients (n = 23, 79%) had 3 or more lines of treatment prior to allo-SCT. The 5 year rates of OS and NRM for all patients are 42% and 53%, respectively. Univariate analysis showed a lower risk of death in patients who received TBI-based conditioning (HR: 0.19, 95 CI: 0.04 – 0.81, p = 0.03), and those who had HLA-matched related donor (MRD) transplants (HR: 0.29, 95 CI: 0.11 – 0.79, p = 0.02). Patients who received more than 3 lines of prior treatment had a higher risk of death (HR: 2.77, 95% CI: 1.05-7.34, p = 0.04). Low rates of grade III/IV aGVHD (n = 4) and relapse (n = 4) occurred in our patient population. Two patient deaths were attributable to aGVHD, and the majority of other deaths were due to treatment-related toxicities. Conclusions: In an era of numerous effective non-curative salvage therapies, the optimal timing of allo-SCT for MCL needs further clarification. Our data supports early opposed to delayed allo-SCT for select high-risk patients with MCL who have a MRD.

5) Atilla, Erden, Pinar Ataca Atilla, and Taner Demirer. “Current treatment strategies in relapsed/refractory mantle cell lymphoma: where are we now?.” International journal of hematology 105.3 (2017): 257-264.

The management of relapsed/refractory mantle cell lymphoma remains challenging. Patients with relapsed mantle cell lymphoma have been treated with multi-agent salvage chemotherapies; however, outcomes are poor. Although there have been studies in the relapse/refractory setting, current data indicate that autologous hematopoietic stem cell transplantation may be an especially useful approach in the front line setting in patients in first complete or partial remission following induction chemotherapy. Allogeneic hematopoietic stem cell transplantation is the only curative option, although reduced intensity conditioning in chemo-sensitive relapse or refractory mantle cell lymphoma provides better survival rates. In addition, bortezomib, lenalidomide, temsirolimus, and ibrutinib have opened a new therapeutic era. More randomized trials should be conducted to evaluate the appropriate use of these new molecules. In this review, I discuss autologous and allo-transplant options as well as the data regarding recently approved novel agents in the relapse/refractory setting in patients with MCL.

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6) Fenske, Timothy S., et al. “Allogeneic hematopoietic cell transplantation as curative therapy for patients with non-Hodgkin lymphoma: increasingly successful application to older patients.” Biology of Blood and Marrow Transplantation 22.9 (2016): 1543-1551.
Non-Hodgkin lymphoma (NHL) constitutes a collection of lymphoproliferative disorders with widely varying biologic, histologic and clinical features. For the B-cell NHLs, great progress has been made due to the addition of monoclonal antibodies and, more recently, other novel agents such as B-cell receptor signaling inhibitors, immunomodulatory agents, and proteasome inhibitors. Autologous hematopoietic cell transplantation (auto-HCT) offers the promise of cure or prolonged remission in some NHL patients. For some patients, however, auto-HCT may never be a viable option, while in others their disease may progress despite auto-HCT. In those settings, allogeneic HCT (allo-HCT) offers the potential for cure. Over the past 10–15 years, considerable progress has been made in the implementation of allo-HCT, such that this approach now is a highly effective therapy for patients up to (and even beyond) age 75. Recent advances in conventional lymphoma therapy, peri-transplant supportive care, patient selection, and donor selection (including the use of alternative hematopoietic cell donors), has allowed broader application of allo-HCT to NHL patients. As a result, an ever-increasing number of NHL patients over age 60–65 years stand to benefit from allo-HCT. In this review, we present data in support of the use of allo-HCT for patients with diffuse large B-cell lymphoma, follicular lymphoma, and mantle cell lymphoma. These histologies account for a large majority of allo-HCT performed for patients over 60 in the U.S. Where possible, we highlight available data in older patients. This body of literature strongly supports the concept that allo-HCT should be offered to fit patients well beyond age 65 and, accordingly, that this treatment should therefore be covered by their insurance carriers.

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7) Heinzelmann, Frank, et al. “Allogeneic haematopoietic cell transplantation offers the chance of cure for patients with transformed follicular lymphoma.Journal of cancer research and clinical oncology 144.6 (2018): 1173-1183.

In patients with follicular lymphoma, secondary transformation to aggressive lymphoma (tFL) implies a poor prognosis. In principle, allogeneic haematopoietic cell transplantation (allo-HCT) offers a chance of cure for tFL but is rarely practiced. Aim of this retrospective multicenter study was to define the actual significance of allo-HCT in treatment of tFL.
Methods  The database of the German Registry for Stem Cell Transplantation (DRST) was screened for patients who underwent allo-HCT for tFL 1998–2008. Confirmation of tFL-diagnosis by local and/or pathologists of the National NHL Board was mandatory for enrolment. Gaps in reported EBMT Minimum Essential Data datasets (MED-A) were filled by local DRST data managers. Relevant HCT outcome variables were evaluated by uni- and multivariate statistical analysis.
Results  Median age of enrolled 33 patients was 51 years with a post allo-HCT median follow-up of 7.1 years of surviving patients. At time of HCT 24/33 patients had chemosensitive disease. In 24/33 patients reduced intensity conditioning (RIC) was used. Estimated 1, 2, 5-year overall survival (OS) and event-free survival rates were 49/39/33, and 33/30/24%. Cumulative 100 days non-relapse mortality was 25%. Chemosensitive disease, RIC, and limited chronic GvHD were identified as independent prognostic factors for OS.
Conclusions:  Allo-HCT offers the chance of cure for tFL.

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8) Schwarzbich, M. A., F. McClanahan, and J. Gribben. “Allogeneic Transplantation for Chronic Lymphocytic Leukemia in the Age of Novel Treatment Strategies.” Oncology (Williston Park, NY) 30.6 (2016): 526.

Hematopoietic stem cell transplantation (HSCT) is the only established potentially curative treatment option for chronic lymphocytic leukemia (CLL) to date. However, this approach is associated with high toxicity and significant treatment-related morbidity and mortality; thus, it is suitable for only a minority of high-risk patients, given that most persons with CLL have comorbidities and are of advanced age. Until very recently, international guidelines recommended HSCT for physically fit patients who displayed poor-risk features or had only a short response to immunochemotherapy. In the wake of novel treatment approaches that offer high efficacy and highly durable responses with little toxicity, our approach to HSCT in CLL needs to be re-evaluated. While we wait for data on the long-term efficacy of novel therapies to inform the choice of HSCT or alternative treatment, strategies must be assessed individually for every patient, and treatment must be conducted in the setting of randomized clinical trials whenever possible.

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Other neoplasms

9) Deotare, Uday, et al. “Allogeneic hematopoietic stem cell transplantions in blastic plasmacytoid dendritic cell neoplasm in first complete remission: an effective therapy for a rare disease.Leukemia & lymphoma 57.8 (2016): 1942-1944.

10)   Kharfan‐Dabaja, Mohamed A., et al. “Haematopoietic cell transplantation for blastic plasmacytoid dendritic cell neoplasm: a North American multicentre collaborative study.” British journal of haematology 179.5 (2017): 781-789.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is incurable with conventional therapies. Limited retrospective data have shown durable remissions after haematopoietic cell transplantation (HCT) [allogeneic (allo) or autologous (auto)]. We conducted a multicentre retrospective study in BPDCN patients treated with allo-HCT and auto-HCT at 8 centres in the United States and Canada. Primary endpoint was overall survival (OS). The population consisted of 45 consecutive patients who received an allo-HCT (n = 37) or an auto-HCT (n = 8) regardless of age, pre-transplant therapies, or remission status at transplantation. Allo-HCT recipients were younger (50 (14-74) vs. 67 (45-72) years, P = 0·01) and had 1-year and 3-year OS of 68% [95% confidence interval (CI) = 49-81%] and 58% (95% CI = 38-75%), respectively. Allo-HCT in first complete remission (CR1) yielded superior 3-year OS (versus not in CR1) [74% (95% CI = 48-89%) vs. 0, P < 0·0001]. Allo-HCT outcomes were not impacted by regimen intensity [3-year OS for myeloablative conditioning = 61% (95% CI = 28-83%) vs. reduced-intensity conditioning = 55% (95% CI = 28-76%)]. One-year OS for auto-HCT recipients was 11% (95% CI = 8-50%). These results demonstrate efficacy of allo-HCT in BPDCN, especially in patients in CR1. Pertaining to auto-HCT, our results suggest lack of efficacy against BPDCN, but this observation is limited by the small sample size. Larger prospective studies are needed to better define the role of HCT in BPDCN.

11) Kharfan-Dabaja, M. A., et al. “Allogeneic Hematopoietic Cell Transplantation Is an Effective Treatment for Blastic Plasmacytoid Dendritic Cell Neoplasm in First Complete Remission: Systematic Review and Meta-analysis.” Clinical lymphoma, myeloma & leukemia (2018).

It is common practice to refer patients to transplantation centers for allogeneic hematopoietic cell transplantation (allo-HCT) for blastic plasmacytoid dendritic-cell neoplasm (BPDCN) despite lack of randomized controlled trials. We performed a systematic review to assess the totality of evidence pertaining to the efficacy of allo-HCT in BPDCN.
METHODS:We searched the Cochrane, PubMed, and Embase databases through January 5, 2018, for studies on allo-HCT for BPDCN. Two authors independently reviewed all references for inclusion and extracted data related to benefits (overall [OS] and progression-free/disease-free [PFS/DFS] survival) and harms (relapse and nonrelapse mortality) from included studies. When appropriate, data were pooled using random-effects model.
RESULTS:Four studies (128 patients) were included in analysis. Pooled OS rate was 50% (95% confidence interval [CI], 41-59) for all patients. Among patients who underwent allografting whose disease was in first complete remission (CR1), pooled OS and PFS/DFS rates were 67% (95% CI, 52-80) and 53% (95% CI, 29-76), respectively. For patients who underwent allografting in > CR1, pooled OS and PFS/DFS rates were 7% (95% CI, 0-32) for both outcomes. Relapse rates were higher when reduced-intensity regimens were used (40% [95% CI, 25-56] vs. 18% [95% CI, 7-31]).
CONCLUSION:This systematic review represents the best available evidence supporting allo-HCT in BPDCN, especially when offered in CR1. Use of myeloablative allo-HCT results in lower pooled relapse rates (18% vs. 40%). A prospective comparative study will be needed to determine the impact of intensity of the conditioning regimen on postallograft relapse.

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AML

12) Rashidi, Armin, et al. “Outcomes of allogeneic stem cell transplantation in elderly patients with acute myeloid leukemia: a systematic review and meta-analysis.” Biology of blood and marrow transplantation 22.4 (2016): 651-657.

A large number of elderly patients with acute myeloid leukemia (AML) are not offered curative intent treatments such as allogeneic stem cell transplantation (SCT) due to fears of toxicity and perceived futility of intensive treatment.

Our results suggest that reduced-intensity SCT is a viable treatment option for elderly AML patients with a 3-year RFS relapse-free survival of 35% for those over the age of 60.

13) Lipof, Jodi J., et al. “Allogeneic hematopoietic cell transplantation for older adults with acute myeloid leukemia.” Cancers 10.6 (2018).
Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative therapy for these patients but is underutilized due to frequent comorbidities and perceived higher risk of treatment-related mortality and non-relapse mortality.

14) Guitart, Joan, et al. “Long-term remission after allogeneic hematopoietic stem cell transplantation for refractory cutaneous T-cell lymphoma.” Archives of dermatology 138.10 (2002): 1359-1365.

Allogeneic hematopoietic stem cell transplantation has proved to be an effective therapeutic option in various hematologic neoplastic disorders. Because patients with advanced cutaneous T-cell lymphoma have a poor prognosis, with minimal possibilities of sustained remission, we studied the therapeutic potential of hematopoietic stem cell transplantation.
OBSERVATIONS:  Three young patients with refractory tumor stage mycosis fungoides underwent allogeneic HLA-matched sibling transplantation with combined marrow and CD34-enriched peripheral blood stem cell transplantation after cytoreductive chemotherapy and total-body irradiation. Complete and sustained clinical and histologic remission was achieved in 2 patients, and both remain disease free 4(1/2) years and 15 months later. One patient was in complete remission for 9 months, followed by limited cutaneous recurrence. Mild graft-vs-host disease and graft-vs-tumor effect have contained the recurring disease as a low-grade process.
CONCLUSIONS:  Allogeneic hematopoietic stem cell transplantation has the potential for sustained remission and the possibility of cure for young patients with advanced and recalcitrant cutaneous T-cell lymphoma. !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!! Even in the absence of complete remission, an allogeneic graft-vs-tumor effect may provide an immune mechanism to control the malignant T-cell process and alter the natural history of disease.

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Myeloma

15) Allogeneic Transplant for Young, High-Risk Myeloma Patients with Dr. Cristina Gasparetto, MD, Duke Medical Center  Interview Date: February 17, 2017

We have different types of transplant, but for many years and we know even now that it’s very difficult to tell a patient that we can cure myeloma, but maybe with allogeneic transplant we have done that.

Because the bottom line is the allogeneic approach, the allogeneic transplant is to replace the immune system of the patient. The immune system of the patient clearly is not working, and so we are giving the patient a new immune system to control the myeloma from coming back.  The key is to have a myeloma well controlled until the new graft, the new immune system, is able to repopulate and control the disease from coming back.  You are replacing the immuno system. That is the concept. You are giving a patient a new immune system.

16) Allogeneic hematopoietic cell transplantation in multiple myeloma S Vincent Rajkumar, MD Section Editor: Robert A Kyle, MD Deputy Editor: Rebecca F Connor, MD

INTRODUCTION  Allogeneic hematopoietic cell transplantation (HCT) may be the only treatment for patients with multiple myeloma (MM) that has a chance of producing cure. Its use, however, is limited since even ideal candidates who undergo allogeneic HCT have a high rate of treatment-related mortality, and because its efficacy compared with autologous HCT is not fully established.

Bryant Furlow April 19, 2016 Q&A With Dr Muhammad A. Mir: Allogeneic Stem Cell Transplantation for Multiple Myeloma

Dr Mir: Allo-transplant, as with many other malignancies, remains the only curative therapy in myeloma.

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Ibrutinib as bridge to Allogeneic transplant

16) Epperla, Narendranath, et al. “Predictive factors and outcomes for ibrutinib therapy in relapsed/refractory mantle cell lymphoma—a “real world” study.” Hematological oncology 35.4 (2017): 528-535.

Our results confirm the high ORR and DOR of ibrutinib in MCL and that prior hematopoietic cell transplantation does not negatively influence ibrutinib outcomes. Survival following ibrutinib failure is poor with no specific subsequent therapy showing superior activity in this setting. As a result, for select (transplant eligible) patients, allogeneic transplant should be strongly considered soon after ibrutinib response is documented to provide durable responses.

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Mantle Cell Lymphoma

/Moffitt Cancer Center , Tampa July 2018 article:”Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for mantle cell lymphoma (MCL). “

Abstract: Allogeneic hematopoietic cell transplantation (allo-HCT) is the only curative treatment for mantle cell lymphoma (MCL).

We retrospectively analyzed outcomes of 36 patients, median age of 54 (41-68) years, who underwent allo-HCT, mostly (66%) receiving a myeloablative (MAC) regimen. Median overall survival (OS) was 86 months and 5-year OS was 54%. Median progression-free survival (PFS) was 54 months and 5-year PFS was 49%. Cumulative incidence (CI) of non-relapse mortality (NRM) and 2-year progression were 20.1 and 22.1%, respectively. Day +100?CI of grade II-IV acute graft-versus-host disease (GVHD) was 38.1%; 2-year CI of moderate/severe chronic GVHD was 31.7%. Seven patients received allo-HCT as frontline consolidation and had better OS (median?=?not reached versus 54 months, p?=?.045). Notwithstanding the small sample size and retrospective study design, our findings suggest a role for allo-HCT in selected MCL patients. Future prospective studies would be needed to better define the role of allo-HCT in this disease.

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Evidence of Graft vs. Lymphoma Effect

18) McCulloch, Rory, and Simon Rule. “What is the optimal initial management of the younger mantle cell lymphoma patient?.” Best Practice & Research Clinical Haematology (2017).

“The outcomes appeared the same whether the transplant was performed up front or at relapse, and the remission status bore no relationship to outcome. ”

“the remission status before transplant did not affect outcome. ”

Note from me: this means the Graft vs. Lymphoma effect is working. Patients had active disease which was cleared once the graft matured.

Patients under 56 had particularly good outcome

A reduced intensity conditioning (RIC) allogeneic procedure has shown efficacy at relapse, including some high-risk patients and offers a potential for cure. However, data on upfront allogeneic haematopoietic cell transplant (allo-HCT) is sparse and there is insufficient data to comment specifically on this high-risk group.

The largest experience comes from an analysis of 519 patients on the Centre for International Blood and Marrow Research database who received either an autologous or RIC allogeneic transplant as first consolidation for chemosensitive MCL [28]. Patients were analysed by time of transplantation into early (in first partial response/CR after no more than 2 lines of prior therapy) or late (all other patients). The study concluded that early transplantation was superior to late for both ASCT and RIC allo-HCT. For early transplantation after 5 years, relapse was significantly lower in favour of RIC allo-HCT (15% vs 32%), but OS was identical (~60%) due to higher non–relapse related mortality in the patients receiving a RIC allo.

There have been 2 prospective studies using allogeneic transplants as part of frontline therapy. The final report of the East German Study Group of Haematology and Oncology [29] combined data on 2 studies, one frontline and the other in relapsed patients. 21 of 24 frontline patients proceeded to an allogeneic procedure following either R-CHOP or R-CHOP/R-DHAP therapy. At transplant, only 43% were in a complete remission, but at 5 years the OS was 73%. The outcomes appeared the same whether the transplant was performed up front or at relapse, and the remission status bore no relationship to outcome. Patients under 56 had particularly good outcome, but only a small number of high risk patients were included.

The other prospective trial is the recently presented UK study that performed a RIC allo-HCT using the BCNU, etoposide, cytarabine, melphalan, Campath regimen in 25 patients with untreated MCL [30]. Fewer than 50% of patients were in CR at the time of transplant following a variety of induction regimens. The 2-year treatment-related mortality was only 8.6%, with 2-year PFS and OS of 68% and 80%, respectively, but with a 50% incidence of chronic graft-versus-host disease. In keeping with the German study, the remission status before transplant did not affect outcome. Although immature, the results are encouraging and provide data to support frontline allogeneic transplant for some patients.

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19) Magnusson, Erik, et al. “Hematopoietic cell transplantation for mantle cell lymphoma: predictive value of pretransplant positron emission tomography/computed tomography and bone marrow evaluations for outcomes.Clinical Lymphoma Myeloma and Leukemia 14.2 (2014): 114-121.

We examined the predictive value of pretransplant positron emission tomography/computed tomography and marrow involvement evaluation on outcomes of 66 patients with mantle cell lymphoma treated with hematopoietic cell transplantation (HCT).

Residual disease detected by either method prior to autograft was associated with increased relapse rates at 2 years and worse 5-year disease-free survival.

“Allograft recipients had favorable long-term outcomes despite the presence of residual disease pre-HCT.”

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20) Ofran, Yishay, and Jerome Ritz. “Targets of tumor immunity after allogeneic hematopoietic stem cell transplantation.” Clinical Cancer Research 14.16 (2008): 4997-4999. Targets of tumor immunity after allogeneic hematopoietic stem cell transplantation Ofran Yishay Jerome Ritz Clin Ca Res 2008

Allogeneic hematopoietic stem cell transplantation (HSCT) currently provides effective and potentially curative therapy for a variety of hematologic malignancies.

the clinical effectiveness of this approach is due primarily to immunologic recognition and the
elimination of recipient leukemia cells by donor T cells.

In contrast to hematologic malignancies, where GVL frequently results in complete remission, clinical outcomes after allogeneic HSCT for solid tumors have been disappoint-
ing. A recent review of allogeneic HSCT in patients with meta-static breast cancer, melanoma, and renal cell cancer revealed evidence of significant graft versus tumor activity, but few complete responses were documented and patients seldom maintain partial responses for prolonged periods (11, 12).

If the results of allogeneic HSCT for solid tumors can be improved, this may introduce an entirely new therapeutic modality in our armamentarium against these cancers.
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Allogeniec Transplantation also curative for other types of cancers:

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5175225/

21) Karadurmus, Nuri, et al. “Review of allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning in solid tumors excluding breast cancer.” World journal of transplantation 6.4 (2016): 675.

Solid tumors in adults constitute a heterogeneous group of malignancy originating from various organ systems. Solid tumors are not completely curable by chemotherapy, even though some subgroups are very chemo-sensitive. Recently, oncologists have focused on the use of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with reduced intensity conditioning (RIC) for the treatment of some refractory solid tumors. After the demonstration of allogeneic graft-versus-leukemia effect in patients with hematological malignancies who received allo-HSCT, investigators evaluated this effect in patients with refractory metastatic solid tumors. According to data from experimental animal models and preliminary clinical trials, a graft-versus-tumor (GvT) effect may also be observed in the treatment of some solid tumors (e.g., renal cell cancer, colorectal cancer, etc.) after allo-HSCT with RIC. The use of RIC regimens offers an opportunity of achieving full-donor engraftment with GvT effect, as well as, a reduced transplant-related mortality. Current literature suggests that allo-HSCT with RIC might become a choice for elderly and medically fragile patients with refractory metastatic solid tumors.

22) free pdf
Karadurmus, Nuri, et al. “A Review of Allogeneic Hematopoietic Stem Cell Transplantation in Metastatic Breast Cancer.” International Journal of Hematology-Oncology and Stem Cell Research 12.2 (2018): 111-116.

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Nice images CAT Lung resolving lung mets

Subject: Regression of metastatic renal-cell carcinoma after allogeneic transplantation.

23) Childs, Richard, et al.”Regression of metastatic renal-cell carcinoma after nonmyeloablative allogeneic peripheral-blood stem-cell transplantation.” New England Journal of Medicine 343.11 (2000): 750-758.    Regression metastatic renal-cell carcinoma after allogeneic stem-cell transplantation New Eng J Med 2000

Renal Cancer with Lung Nodules (metastatic disease) before (upper) and after allogeneic transplant (lower).  Inline image 1
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24) Valcárcel, David, et al.  “Sustained remissions of high-risk acute myeloid leukemia and myelodysplastic syndrome after reduced-intensity conditioning allogeneic hematopoietic transplantation: chronic graft-versus-host disease is the strongest factor improving survival.” Journal of Clinical Oncology 26.4 (2008): 577-584.
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25) INDUCTION OF COMPLETE REMISSION OF ADVANCED STAGE MYCOSIS FUNGOIDES BY ALLOGENEIC HEMATOPOIETIC STEM CELL TRANSPLANTATION: A CASE REPORT.

26) Ben-Yosef, R., et al. “Graft-versus-tumour and graft-versus-leukaemia effect in patient with concurrent breast cancer and acute myelocytic leukaemia.” The Lancet 348.9036 (1996): 1242-1243.  Graft-versus-leukaemia (GVL) effects induced by allogeneic peripheral blood stem-cell transplantation (PBSCT) with or without post-transplant donor-derived blood lymphocyte infusion (allogeneic cell therapy [allo-CT]) has been reported in patients with various haematological cancers 1, 2 and in some solid cancers. 3 We report a patient who developed concurrent recurrent breast cancer and acute myelocytic leukaemic (AML) who is in complete response after allogeneic PBSCT and allo-CT.

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solid tumors
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27) Blaise, Didier, et al. “Reduced-intensity preparative regimen and allogeneic stem cell transplantation for advanced solid tumors.” Blood 103.2 (2004): 435-441.

28) Demirer, Taner, et al. “Transplantation of allogeneic hematopoietic stem cells: an emerging treatment modality for solid tumors.” Nature Reviews Clinical Oncology 5.5 (2008): 256.

Allogeneic transplantation of hematopoietic cells from an HLA-compatible donor has been used to treat hematologic malignancies. Allogeneic transplantation not only replaces the marrow affected by the disease, but exerts an immune graft-versus-tumor (GVT) effect mediated by donor lymphocytes. The development of nonmyeloablative conditioning regimens before allogeneic transplantation has allowed this therapy to be used in elderly and disabled patients. An allogeneic GVT effect is observed in a proportion of patients with renal, breast, colorectal, ovarian, and pancreatic cancer treated with allogeneic transplantation. In general, the tumor response is associated with the development of acute and chronic graft-versus-host disease. Further improvements will depend on the identification of the antigen targets of GVT, and on reduction of the toxicity of the procedure. Targeted therapies may complement the immune effect of allogeneic transplantation. We present updated results from the literature and data recently placed on file at the European Bone Marrow Transplantation Solid Tumors Working Party.

29) Aglietta, Massimo, et al. “Reduced-intensity allogeneic hematopoietic stem cell transplantation in metastatic colorectal cancer as a novel adoptive cell therapy approach. The European group for blood and marrow transplantation experience.” Biology of Blood and Marrow Transplantation 15.3 (2009): 326-335.
Reduced-intensity conditioning (RIC) regimens for allogeneic hematopoietic stem cell transplantation (HCT) allowed the existence of an allogeneic cell-mediated antitumor effect in metastatic colorectal cancer (mCRC) to be explored. We report on 39 patients with progressing mCRC treated with different RIC regimens in a multicenter clinical trial of the European Bone Marrow Transplantation Group. Disease status at transplant was progressive disease (PD) in 31 patients (80%), stable disease (SD) in 6 (15%), and partial response (PR) in 2 (5%). All patients engrafted (median donor T cell chimerism of 90% at day +60). Transplant-related morbidities were limited. Grades II-IV acute graft-versus-host disease (aGVHD) occurred in 14 patients (35%) and chronic GVHD (cGVHD) in 9 patients (23%). Transplant-related mortality occurred in 4 patients (10%). The best tumor responses were: 1 complete response (CR) (2%), 7 PR (18 %), and 10 SD (26%), giving an overall disease control in 18 of 39 patients (46%). Allogeneic HCT after RIC is feasible; the collected results compared favorably in terms of tumor response with those observed using conventional approaches beyond second-line therapies. The study of an allogeneic cell based therapy in less advanced patients is warranted.

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30) Hsu, J., et al. “Combined Haploidentical and Umbilical Cord Blood Allogeneic Stem Cell Transplantation for High-Risk Lymphoma and Chronic Lymphoblastic Leukemia.” Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 24.2 (2018): 359.

Limited studies have reported on outcomes for lymphoid malignancy patients receiving alternative donor allogeneic stem cell transplants. We have previously described combining CD34-selected haploidentical grafts with umbilical cord blood (haplo-cord) to accelerate neutrophil and platelet engraftment. Here, we examine the outcome of patients with lymphoid malignancies undergoing haplo-cord transplantation at the University of Chicago and Weill Cornell Medical College. We analyzed 42 lymphoma and chronic lymphoblastic leukemia (CLL) patients who underwent haplo-cord allogeneic stem cell transplantation. Patients underwent transplant for Hodgkin lymphoma (n = 9, 21%), CLL (n = 5, 12%) and non-Hodgkin lymphomas (n = 28, 67%), including 13 T cell lymphomas. Twenty-four patients (52%) had 3 or more lines of therapies. Six (14%) and 1 (2%) patients had prior autologous and allogeneic stem cell transplant, respectively. At the time of transplant 12 patients (29%) were in complete remission, 18 had chemotherapy-sensitive disease, and 12 patients had chemotherapy-resistant disease. Seven (17%), 11 (26%), and 24 (57%) patients had low, intermediate, and high disease risk index before transplant. Comorbidity index was evenly distributed among 3 groups, with 13 (31%), 14 (33%), and 15 (36%) patients scoring 0, 1 to 2, and ≥3. Median age for the cohort was 49 years (range, 23 to 71). All patients received fludarabine/melphalan/antithymocyte globulin conditioning regimen and post-transplant graft-versus-host disease (GVHD) prophylaxis with tacrolimus and mycophenolate mofetil. The median time to neutrophil engraftment was 11 days (range, 9 to 60) and to platelet engraftment 19.5 days (range, 11 to 88). Cumulative incidence of nonrelapse mortality was 11.6% at 100 days and 19 % at one year. Cumulative incidence of relapse was 9.3% at 100 days and 19% at one year. With a median follow-up of survivors of 42 months, the 3-year rates of GVHD relapse free survival, progression-free survival, and overall survival were 53%, 62%, and 65%, respectively, for these patients. Only 8% of the survivors had chronic GVHD. In conclusion, haplo-cord transplantation offers a transplant alternative for patients with recurrent or refractory lymphoid malignancies who lack matching donors. Both neutrophil and platelet count recovery is rapid, nonrelapse mortality is limited, excellent disease control can be achieved, and the incidence of chronic GVHD is limited. Thus, haplo-cord achieves high rates of engraftment and encouraging results.

31)  Tam, Constantine S., et al. “Ibrutinib plus venetoclax for the treatment of mantle-cell lymphoma.” New England Journal of Medicine 378.13 (2018): 1211-1223.
N Engl J Med. 2018 Mar 29;378(13):1211-1223.

Both the BTK inhibitor ibrutinib and the BCL2 inhibitor venetoclax are active as monotherapy in the treatment of mantle-cell lymphoma. Complete response rates of 21% have been observed for each agent when administered as long-term continuous therapy. Preclinical models predict synergy in combination.
METHODS: We conducted a single-group, phase 2 study of daily oral ibrutinib and venetoclax in patients, as compared with historical controls. Patients commenced ibrutinib monotherapy at a dose of 560 mg per day. After 4 weeks, venetoclax was added in stepwise, weekly increasing doses to 400 mg per day. Both drugs were continued until progression or an unacceptable level of adverse events. The primary end point was the rate of complete response at week 16. Minimal residual disease (MRD) was assessed by flow cytometry in bone marrow and by allele-specific oligonucleotide-polymerase chain reaction (ASO-PCR) in blood.
RESULTS:  The study included 24 patients with relapsed or refractory mantle-cell lymphoma (23 patients) or previously untreated mantle-cell lymphoma (1 patient). Patients were 47 to 81 years of age, and the number of previous treatments ranged from none to six. Half the patients had aberrations of TP53, and 75% had a high-risk prognostic score. The complete response rate according to computed tomography at week 16 was 42%, which was higher than the historical result of 9% at this time point with ibrutinib monotherapy (P<0.001). The rate of complete response as assessed by positron-emission tomography was 62% at week 16 and 71% overall. MRD clearance was confirmed by flow cytometry in 67% of the patients and by ASO-PCR in 38%. In a time-to-event analysis, 78% of the patients with a response were estimated to have an ongoing response at 15 months. The tumor lysis syndrome occurred in 2 patients. Common side effects were generally low grade and included diarrhea (in 83% of the patients), fatigue (in 75%), and nausea or vomiting (in 71%).
CONCLUSIONS:   In this study involving historical controls, dual targeting of BTK and BCL2 with ibrutinib and venetoclax was consistent with improved outcomes in patients with mantle-cell lymphoma who had been predicted to have poor outcomes with current therapy. (Funded by Janssen and others; AIM ClinicalTrials.gov number, NCT02471391 .).

32) Fenske, Timothy S., et al. “Allogeneic transplantation provides durable remission in a subset of DLBCL patients relapsing after autologous transplantation.” British journal of haematology 174.2 (2016): 235-248.

In conclusion, the CIBMTR prognostic model identifies a subgroup of DLBCL patients experiencing long-term survival with alloHCT after a failed prior autoHCT.

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33)  Bone Marrow Transplant. 2000 Mar;25(6):681-2. Potential allogeneic graft-versus-tumor effect in a patient with ovarian cancer. Bay JO1, Choufi B, Pomel C, Dauplat J, Durando X, Tournilhac O, Travade P, Plagne R, Blaise D. Unité de Transplantation Médullaire, Marseille, France.

A 33-year-old woman developed progressive ovarian cancer resistant to classical chemotherapy agents. We performed a bone marrow allograft after a myeloablative regimen. During hematological recovery, she developed acute graft-versus-host disease (GVHD). From this time her tumor diminished progressively. One year post transplant she has limited chronic liver GVHD and is still free of disease. The complete remission of advanced ovarian cancer was probably related to the GVHD which might therefore provide a new treatment option for this disease.

34) Bay, J. O., et al. “Allogeneic hematopoietic stem cell transplantation in ovarian carcinoma: results of five patients.” Bone marrow transplantation 30.2 (2002): 95.

Allogeneic hematopoietic stem cell transplantation is often used to treat hematologic malignancies. The efficacy of this procedure is due to both myeloablative conditioning and graft-versus-leukemia (GVL). However, the disadvantages of allogeneic transplantation include graft-versus-host disease (GVHD), relapse from the original tumor, and patient susceptibility to opportunistic infections. Lately, allogeneic transplantation has been developed to treat solid tumors, with the expectation that graft-versus-tumor (GVT), like GVL, will have a significant anti-tumor effect. This effect has been demonstrated in renal carcinomas, and with less evidence in breast cancers. Five patients with malignant ovarian tumors resistant to chemotherapy underwent allogeneic transplantation, four from bone marrow, and one from peripheral blood stem cells. All donors were HLA-identical siblings. One patient received a myeloablative conditioning regimen, while the other four received a non-myeloablative regimen. Two patients received donor lymphocyte infusions (DLI). Four of the patients presented with acute or chronic GVHD associated with tumor regression of at least 50%. These tumor regressions were measured by CA-125 levels and CT scans. The fifth patient died of rapid progression just after transplantation. Of the four transplantation survivors, three received a non-myeloablative regimen which did not seem to reduce treatment effectiveness. While it did reduce toxicity, one of these patients died of GVHD after 127 days. DLI was administered to two patients. These infusions seemed to promote GVHD which was able to control disease progression for one patient and had no apparent effect on the other. Allograft of hematopoietic stem cells might be of interest in ovarian cancer. The results in one patient also suggest that DLI may be an effective immunotherapy, although doses and timing need to be determined. The number of cases presented is small, however, and clinical experience on a larger scale will be required to determine the real clinical efficacy of graft versus cancerous ovarian cells.

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35) van Besien, Koen. “Current status of allogeneic transplantation for aggressive non-Hodgkin lymphoma.” Current opinion in oncology 23.6 (2011): 681.

A large number of reports show that allogeneic transplantation can be curative in a fraction of patients with otherwise refractory disease

When relapse occurs in patients with aggressive lymphoma it often happens within the first six months after transplant and the prognosis for such early relapsing patients is poor.

Few if any such patients obtain durable remissions to further chemotherapeutic or immunologic intervention

free pdf
36) Ofran, Yishay, and Jerome Ritz. “Targets of tumor immunity after allogeneic hematopoietic stem cell transplantation.” Clinical Cancer Research 14.16 (2008): 4997-4999.

free pdf
37) Dzopalic, T. “Dendritic cell-cancer vaccines–a promising antitumor strategy.” Vaccine Immunol Open Access J 1.1 (2018): 00001.

38) Negrin, Robert S. “Biology of the graft-versus tumor effect following hematopoietic cell transplantation.” UpToDate, Waltham, MA. Accessed on October 19 (2016).

40) Godfrey, James, et al. “PD-1 blockade induces remissions in relapsed classical Hodgkin lymphoma following allogeneic hematopoietic stem cell transplantation.” Journal for immunotherapy of cancer 5.1 (2017): 11.

41) Zilberberg, Jenny, Rena Feinman, and Robert Korngold. “Strategies for the identification of T cell–recognized tumor antigens in hematological malignancies for improved graft-versus-tumor responses after allogeneic blood and marrow transplantation.” Biology of Blood and Marrow Transplantation 21.6 (2015): 1000-1007.

42)  Weber, G., et al. “Generation of multi-leukemia antigen-specific T cells to enhance the graft-versus-leukemia effect after allogeneic stem cell transplant.” Leukemia 27.7 (2013): 1538.

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Stem Cell VAccines

43) Autologous iPSC-Based Vaccines Elicit Anti-tumor Responses In Vivo Kooreman, Nigel G. et al. Cell Stem Cell , Volume 0 , Issue 0 ,
our data show the feasibility of creating broad tumor immunity against multiple cancer types using an iPSC-based vaccine that presents the immune system with large quantities of tumor antigens. Compared to current immunotherapy strategies, our iPSC vaccine is capable of reactivating the immune system to target cancers without therapy-associated adverse effects and can be created within a few weeks after diagnosis. These beneficial properties make this iPSC vaccine a potential option for personalized adjuvant immunotherapy shortly after conventional primary treatment of cancer.

44) Int J Cancer. 2018 Apr 1;142(7):1453-1466. doi: 10.1002/ijc.31159. Epub 2017 Nov 28.
Vaccination with human amniotic epithelial cells confer effective protection in a murine model of Colon adenocarcinoma.
Tabatabaei M1, Mosaffa N1, Ghods R2,3, Nikoo S4, Kazemnejad S5, Khanmohammadi M5, Mirzadeghan E5, Mahmoudi AR4, Bolouri MR4, Falak R4, Keshavarzi B1, Ramezani M6, Zarnani AH4,7.

As a prophylactic cancer vaccine, human amniotic membrane epithelial cells (hAECs) conferred effective protection in a murine model of colon cancer. The immunized mice mounted strong cross-protective CTL and antibody responses. Tumor burden was significantly reduced in tumor-bearing mice after immunization with hAECs. Placental cancer immunotherapy could be a promising approach for primary prevention of cancer. In spite of being the star of therapeutic strategies for cancer treatment, the results of immunotherapeutic approaches are still far from expectations. In this regard, primary prevention of cancer using prophylactic cancer vaccines has gained considerable attention. The immunologic similarities between cancer development and placentation have helped researchers to unravel molecular mechanisms responsible for carcinogenesis and to take advantage of stem cells from reproductive organs to elicit robust anti-cancer immune responses. Here, we showed that vaccination of mice with human amniotic membrane epithelial cells (hAECs) conferred effective protection against colon cancer and led to expansion of systemic and splenic cytotoxic T cell population and induction of cross-protective cytotoxic responses against tumor cells. Vaccinated mice mounted tumor-specific Th1 responses and produced cross-reactive antibodies against cell surface markers of cancer cells. Tumor burden was also significantly reduced in tumor-bearing mice immunized with hAECs. Our findings pave the way for potential future application of hAECs as an effective prophylactic cancer vaccine.

45) https://pdfs.semanticscholar.org/4557/c04b33cb42cb29312209461942f6f96eb1c7.pdf

Asian Pac J Cancer Prev. 2012;13(9):4295-300.
Human embryonic stem cells–a potential vaccine for ovarian cancer.
Zhang ZJ1, Chen XH, Chang XH, Ye X, Li Y, Cui H.

To investigate the therapeutic potential of human embryonic stem cells (hESCs) as a vaccine to induce an immune response and provide antitumor protection in a rat model.
METHODS:Cross-reactivity of antigens between hESCs and tumour cells was screened by immunohistochemistry. Fischer 344 rats were divided into 7 groups, with 6 rats in each, immunized with: Group 1, hESC; Group 2, pre-inactivated mitotic NuTu-19; Group 3 PBS; Group 4, hESC; Group 5, pre-inactivated mitotic NuTu-19; Group 6, PBS; Group 7, hESC only. At 1 (Groups 1-3) or 4 weeks (Groups 4-6) after the last vaccination, each rat was challenged intraperitoneally with NuTu-19. Tumor growth and animal survival were closely monitored. Rats immunized with H9 and NuTu- 19 were tested by Western blot analysis of rat orbital venous blood for cytokines produced by Th1 and Th2 cells.
RESULTS:hESCs presented tumour antigens, markers, and genes related to tumour growth, metastasis, and signal pathway interactions. The vaccine administered to rats in Group 1 led to significant antitumor responses and enhanced tumor rejection in rats with intraperitoneal inoculation of NuTu-19 cells compared to control groups. In contrast, rats in Group 4 did not display any elevation of antitumour responses. Western blot analysis found cross-reactivity among antibodies generated between H9 and NuTu-19. However, the cytokines did not show significant differences, and no side effects were detected.
CONCLUSION:hESC-based vaccination is a promising modality for immunotherapy of ovarian cancer.

46) Kwiatkowska-Borowczyk, Eliza P., et al. “Immunotargeting of cancer stem cells.” Contemporary Oncology 19.1A (2015): A52.
Cancer stem cells (CSCs) represent a distinctive population of tumour cells that control tumour initiation, progression, and maintenance. Their influence is great enough to risk the statement that successful therapeutic strategy must target CSCs in order to eradicate the disease. Because cancer stem cells are highly resistant to chemo- and radiotherapy, new tools to fight against cancer have to be developed. Expression of antigens such as ALDH, CD44, EpCAM, or CD133, which distinguish CSCs from normal cells, together with CSC immunogenicity and relatively low toxicity of immunotherapies, makes immune targeting of CSCs a promising approach for cancer treatment. This review will present immunotherapeutic approaches using dendritic cells, T cells, pluripotent stem cells, and monoclonal antibodies to target and eliminate CSCs.

47) Exp Mol Pathol. 2009 Jun;86(3):192-7. doi: 10.1016/j.yexmp.2008.12.002. Epub 2009 Jan 6.  Embryonic vaccines against cancer: an early history.
Brewer BG1, Mitchell RA, Harandi A, Eaton JW.
Almost 100 years have passed since the seminal observations of Schöne showing that vaccination of animals with fetal tissue would prevent the growth of transplantable tumors. Many subsequent reports have affirmed the general idea that immunologic rejection of transplantable tumors, as well as prevention of carcinogenesis, may be affected by vaccination with embryonic/fetal material. Following a decade of intense research on this phenomenon during approximately 1964-1974, interest appears to have waned. This earlier experimental work may be particularly pertinent in view of the rising interest in so-called cancer stem cells. We believe that further work – perhaps involving the use of embryonic stem cells as immunogens – is warranted and that the results reviewed herein support the concept that vaccination against the appearance of cancers of all kinds is a real possibility.

48) The development of a malignant tumor is due to a desperate asexual self-cloning process in which cancer stem cells develop the ability to mimic the genetic program of germline cells  Vladimir Vinnitsky

Immunization against cancer using embryonic material has a history of more than 100 years. Oncodevelopmental antigens were reported to have been identified by transplantation as early as 1906 when Schone148 SchöneG. Untersuchungen uber Kakzinomimmunitat bei Mausen. Munch Med Wochenschr1906; 53:2517 – 9 [Google Scholar] found that tumor transplants that would kill normal mice would be rejected by mice that had previously been immunized with fetal tissue; immunization with adult tissue was ineffective.149 SellS, BeckerFF, LeffertHL, WatabeL. Expression of an oncodevelopmental gene product (alpha-fetoprotein) during fetal development and adult oncogenesis. Cancer Res1976; 36:4239 – 49; PMID: 61804 [PubMed], [Web of Science ®], [Google Scholar] In the following decades, many reports affirmed the general idea that immunization of an individual with fetal tissue, including placental tissue, can result in immunologic rejection of transplantable tumors, as well as prevention of the development of chemically-induced tumors.150

We consider the development of effective cancer vaccines using tumor-embryo cross-reacting antigens for early-life immunization as a new research strategy aimed at creation of life-long immunity against cancer.

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49) Induced pluripotent stem cells could serve as cancer vaccine
Date: February 15, 2018 Source: Stanford Medicine
Summary: Induced pluripotent stem cells, or iPS cells, are a keystone of regenerative medicine. Outside the body, they can be coaxed to become many different types of cells and tissues that can help repair damage due to trauma or disease. Now, a study in mice suggests another use for iPS cells: training the immune system to attack or even prevent tumors.

Induced pluripotent stem cells could serve as cancer vaccine

Priming the immune system with induced pluripotent stem cells prevented or slowed the development of cancer in mice, Stanford researchers found.

50)  Induced pluripotent stem cells could serve as cancer vaccine  By Krista Conger Stanford Medical News.  Priming the immune system with induced pluripotent stem cells prevented or slowed the development of cancer in mice, Stanford researchers found.

51)  Dong, Wei, et al. “Administration of embryonic stem cells generates effective antitumor immunity in mice with minor and heavy tumor load.” Cancer immunology, immunotherapy 59.11 (2010): 1697-1705.
The history of immunizing animals with fetal tissues to generate an antitumor response dates back a century ago. Subsequent reports supported the idea that vaccination with embryonic materials could generate cancer-specific immunity and protect animals from transplantable and chemically induced tumors. In our study, we found C57 BL/6 mice vaccinated with embryonic stem cells (ESCs) received obvious antitumor immunity, which protected them from the formation and development of lung cancer. Furthermore, we investigated the antitumor effects of administration of ESCs in mice with minor and/or heavy tumor load. The tumor growth was monitored, the proliferation of lymphocytes and secretion of cytokines were examined, and finally the tissue sections were approached by immunohistochemical and apoptosis staining. The results suggested that mice injected with ESCs received obvious tumor inhibition and retardation due to significant lymphocyte proliferation and cytokine secretion, which help to rebuild the host’s immunity against cancer to some extent and comprise the main part of antitumor immunity. Moreover, mice with minor tumor load received stronger antitumor effect compared with mice with heavy tumor load, may be due to relatively intact immune system. Thus, besides their function as prophylactic vaccines, administration of ESCs could be a potential treatment for cancer, which obviously prevent and control the proliferation and development of malignant tumors.

52) Yaddanapudi, Kavitha, et al. “Vaccination with embryonic stem cells protects against lung cancer: is a broad-spectrum prophylactic vaccine against cancer possible?.” PloS one 7.7 (2012): e42289.

The antigenic similarity between tumors and embryos has been appreciated for many years and reflects the expression of embryonic gene products by cancer cells and/or cancer-initiating stem cells. Taking advantage of this similarity, we have tested a prophylactic lung cancer vaccine composed of allogeneic murine embryonic stem cells (ESC). Naïve C57BL/6 mice were vaccinated with ESC along with a source of granulocyte macrophage-colony stimulating factor (GM-CSF) in order to provide immunostimulatory adjuvant activity. Vaccinated mice were protected against subsequent challenge with implantable Lewis lung carcinoma (LLC). ESC-induced anti-tumor immunity was not due to a non-specific “allo-response” as vaccination with allogeneic murine embryonic fibroblasts did not protect against tumor outgrowth. Vaccine efficacy was associated with robust tumor-reactive primary and memory CD8(+) T effector responses, Th1 cytokine response, higher intratumoral CD8(+) T effector/CD4(+)CD25(+)Foxp3(+) T regulatory cell ratio, and reduced myeloid derived suppressor cells in the spleen. Prevention of tumorigenesis was found to require a CD8-mediated cytotoxic T lymphocyte (CTL) response because in vivo depletion of CD8(+) T lymphocytes completely abrogated the protective effect of vaccination. Importantly, this vaccination strategy also suppressed the development of lung cancer induced by the combination of carcinogen administration and chronic pulmonary inflammation. Further refinement of this novel vaccine strategy and identification of shared ESC/tumor antigens may lead to immunotherapeutic options for lung cancer patients and, perhaps more importantly, could represent a first step toward the development of prophylactic cancer vaccines.

53) Ferretti, C., et al. “Molecular circuits shared by placental and cancer cells, and their implications in the proliferative, invasive and migratory capacities of trophoblasts.” Human reproduction update 13.2 (2007): 121-141.Molecular circuits shared by placental and cancer cells implications in proliferative invasive migratory trophoblasts Ferretti C Human repro upd 2007

54) Erenpreisa, Jekaterina, et al. “The “virgin birth”, polyploidy, and the origin of cancer.” Oncoscience 2.1 (2015): 3.
Recently, it has become clear that the complexity of cancer biology cannot fully be explained by somatic mutation and clonal selection. Meanwhile, data have accumulated on how cancer stem cells or stemloids bestow immortality on tumour cells and how reversible polyploidy is involved. Most recently, single polyploid tumour cells were shown capable of forming spheroids, releasing EMT-like descendents and inducing tumours in vivo. These data refocus attention on the centuries-old embryological theory of cancer. This review attempts to reconcile seemingly conflicting data by viewing cancer as a pre-programmed phylogenetic life-cycle-like process. This cycle is apparently initiated by a meiosis-like process and driven as an alternative to accelerated senescence at the DNA damage checkpoint, followed by an asexual syngamy event and endopolyploid-type embryonal cleavage to provide germ-cell-like (EMT) cells. This cycle is augmented by genotoxic treatments, explaining why chemotherapy is rarely curative and drives resistance. The logical outcome of this viewpoint is that alternative treatments may be more efficacious – either those that suppress the endopolyploidy-associated ‘life cycle’ or, those that cause reversion of embryonal malignant cells into benign counterparts. Targets for these opposing strategies are components of the same molecular pathways and interact with regulators of accelerated senescence.

This cycle is augmented by genotoxic treatments, explaining why chemotherapy is rarely curative and drives resistance.


Ibrutinib after Relpase after Allogeneic Transplant

Ibrutinib after ALLO Relapse in Mantle Cell and CLL

Salvage Use of Ibrutinib after Allogeneic Hematopoietic Stem Cell Transplantation (allo-HSCT) for B Cell Malignancies:

55) Michallet, Mauricette, et al. “Salvage use of ibrutinib after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for B cell malignancies: a study of the French Cooperative Group for CLL, the French Soceity for Blood and Marrow Transplantation (SFGM-TC), and the European Society for Blood and Marrow Transplantation (EBMT) Chronic Malignancy and Lymphoma Working Parties.” (2016): 4659-4659.

BACKGROUND: Allo-HSCT is an accepted treatment option for patients with relapsed and refractory B cell lymphomas or high-risk chronic lymphocytic leukemia (CLL). This treatment option is currently reshaped by the introduction of pathway inhibitors (PWI) as ibrutinib, idelalisib, and venetoclax. However, the mid- and long-term efficacy and toxicity of these drugs are not yet fully defined and most patients need to discontinue their treatment over time because of disease progression or intolerance. Allo-HSCT could induce long-term disease control with curative potential especially in poor prognosis patients. In case of disease relapse after transplantation, patient’s outcome is a major concern and the prognosis is dismal. In this context, PWI could be very promising in the context of lowering the bulky leukemic cells before proceeding to allo-HSCT but also when used after transplantation to treat or prevent disease relapse.

The purpose of the present study is to provide information on the safety and efficacy of ibrutinib when administered after allo-HSCT for mantle cell lymphoma (MCL) or CLL.

DESIGN: We included in this study adult patients who had been registered with the EBMT for an allo-HSCT for CLL or MCL and who received ibrutinib for treating disease recurrence or persistence at any time after transplant. Baseline patient, disease, and transplant data were collected from MED-A forms. Centers were requested to provide additional post-allo-HSCT treatment and follow-up information.

RESULTS: A total of 30 patients, 22 (73%) males, who had undergone allo-HSCT between September 2002 and December 2015 were included in this study. Diagnosis was CLL in 27 (90%) patients and MCL in 3 patients. The median age at transplantation was 55 (range: 38-66) years and the median number of treatment lines prior to transplantation was 3 (1-8). Before transplantation, in CLL patients, del17p was present in 10/27 (37%) of cases and del11q was present in 4/27 (15%) other cases. Prior to allo-HSCT, 4 patients (2 CLL and 2 MCL) had received an auto-HSCT and 4 other CLL patients had been exposed to ibrutinib for a median of 261 (205-376) days. Disease response at allo-HSCT was sensitive in 20/27 (74%) of the CLL patients, and in 1/3 of the MCL patients. Conditioning was reduced-intensity in 20/30 (67%) of the transplants and included in-vivo T cell depletion in the majority of cases (17/20). Donors were identical siblings in 23% with PBSC being the predominant stem cell source (28/30). Acute GVHD grade II-IV was observed in 5/30 (16.6%) patients (3 grade II, 2 grade III), while chronic GVHD had occurred in 15/29 patients but had resolved in 11/15 patients prior to ibrutinib. Patients received ibrutinib for relapse after allo-HSCT (n=27, median time from allo-HSCT to progression: 22 (0.5-53) months), 1 for stable disease and 2 after positive MRD. Donor lymphocyte infusions (DLI) were administered concomitantly with ibrutinib in 3/30 patients. Ibrutinib was generally well tolerated; major toxicities observed after ibrutinib commencement were secondary cancers in 3 patients and toxic epidermiolysis in 1 patient. De novo chronic GVHD occurred in 2 patients, in one of them in the context of DLI. Overall, 23/30 (77%) patients had responsive disease after ibrutinib (33% reached CR), 21/27 with CLL (8 CR) and 2/3 with MCL (2CR). At the last follow-up, 20 (67%) patients are still on ibrutinib after a median exposure of 395 (17-703) days, 19 of them with ongoing response (8 in CR) and one too early for response assessment. Ten patients had discontinued ibrutinib, 4 because of toxicity (2 secondary cancers, 2 skin toxicity), and 6 because of disease progression. In total, 4 deaths (all CLL) were observed and were due only to progression. With altogether 8 progression events, the median PFS after start of ibrutinib of all 30 patients was 23 months, the one year OS and PFS probabilities were 92%. There was no effect of del17p or time from allo-HSCT to ibrutinib start on PFS.

CONCLUSION: Ibrutinib can be safely administered for CLL/MCL relapse after allo-HSCT, with an efficacy at least similar to non-transplanted patients with high-risk disease.

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56)  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.

The results of these 2 series suggest that a significant proportion of patients with relapsed MCL will be cured with NMA allogeneic SCT.

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2017

57) Wudhikarn, Kitsada, et al. ” Relapse of lymphoma after allogeneic hematopoietic cell transplantation: Management strategies and outcomeBiology of Blood and Marrow Transplantation 17.10 (2011): 1497-1504.

The outcome and management of relapsed lymphoma after allogeneic hematopoietic cell transplantation (HCT) is difficult. Therapeutic options may include donor lymphocyte infusion (DLI), reduction of immunosuppression (RIS), chemotherapy, radiation, immunotherapy, second HCT and experimental treatments, but reported data contrasting the response and efficacy of these salvage treatments is limited. We describe the treatments, response, prognosis and long-term survival of 72 patients with relapse of lymphoma after allogeneic HCT.
Between 1991 and 2007, 227 lymphoma patients underwent allogeneic HCT. Of these, 72 (32%) developed relapse/progression after their HCT at a median of 99 days (0–1898 days); 37 had early (<100 days) post-HCT relapse. Forty-four had non-Hodgkin’s lymphoma (7 mantle cell, 5 indolent, 15 diffuse large B cell, 4 Burkitt’s and 13 T/Natural Killer cell) and 28 patients had Hodgkin’s lymphoma. At the time of HCT, 62 patients were in remission (22 in complete [CR] and 40 in partial [PR]), one had stable while 9 had progressive disease. Seventeen cases received myeloablative and 55 received a reduced intensity conditioning regimen. At relapse, most patients had generalized lymphadenopathy, extranodal organ involvement and advanced disease. Five patients received no intervention for the post-HCT relapse. Immunosuppressive treatment was reduced or withdrawn as the first line therapy in 58 patients (80.5%); 47 were treated using combinations of conventional chemotherapy (n=22), rituximab (n=27), interferon (IFN) (n=1), DLI (n=7), second HCT (n=2), local radiation (n=23) and other therapy (n=6). Thirty-eight patients had an objective response (CR in 30, PR in 8) and 2 had stable disease (SD). At the post-HCT relapse, favorable prognostic factors for survival after HCT included good ECOG performance status (0–2), normal lactate dehydrogenase (LDH), early stage disease (stage I–III), isolated extranodal organ involvement and later relapse (>100 days) post-HCT. Three year survival after HCT was significantly better in late than early relapse (53% (95% confidence interval (CI) [34–69%] vs. 36%, [20–52%], p=0.02). Of 72 relapsed patients, 29 (40%) survive at a median of 34 (3–148) months post transplant. The most common cause of death was underlying lymphoma (79%).

Conclusion  The overall prognosis of relapsed/progressive lymphoma after allogeneic HCT is disappointing, yet half of patients respond to withdrawal of immunosuppression and additional therapies. Novel treatments can control lymphoma with acceptable morbidity. Particularly for patients with later relapse, ongoing treatment after relapse can yield meaningful benefit and prolonged survival.

58)  W.H. Krüger, C. Hirt, N. Basara, H.G. Sayer, G. Behre, T. Fischer, et al.
Allogeneic stem cell transplantation for mantle cell lymphoma–-final report from the prospective trials of the East German Study Group Haematology/Oncology (OSHO)
Ann Hematol, 93 (9) (2014), pp. 1587-1597

59) Tucker, D. L., et al. “Reduced intensity conditioned allogeneic stem cell transplantation (RIC-Allo) as front-line therapy for mantle cell lymphoma (MCL): results from the UK Phase II Mini Allo Study (CRUK: C7627/A9080): 19.” British Journal of Haematology 173 (2016): 15.

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60) Robinson, Stephen P., et al. “Long-term outcome analysis of reduced-intensity allogeneic stem cell transplantation in patients with mantle cell lymphoma: a retrospective study from the EBMT Lymphoma Working Party.” Bone marrow transplantation (2018): 1.

Reduced-intensity allogeneic stem cell transplantation (RIST) is usually reserved for patients with mantle cell lymphoma who relapse after an autoSCT. However, the long-term efficacy of RIST and its curative potential have not been clearly demonstrated. We studied the long-term outcome of patients receiving a RIST for MCL as reported to the EBMT. A total of 324 patients, median age 57 years (range 31–70), underwent a RIST between 2000 and 2008; 43% of the patients had received >3 lines of prior therapy, including an autoSCT in 46%. Non-relapse mortality (NRM) was 10% at 100 days and 24% at 1 year and was lower for patients receiving anti-thymocyte globulin (ATG)/ALG (RR 0.59, p?=?0.046). After a median follow-up of 72 months (range 3–159), 118 patients relapsed at a median of 8 months post RIST (range 1–117). The cumulative incidence of relapse was 25% and 40% at 1 and 5 years, respectively, and was associated with chemorefractory disease (HR 0.49, p?=?0.01) and the use of CAMPATH (HR 2.59, p?=?0.0002). The 4-year progression-free survival rate and overall survival rate was 31 and 40%, respectively. RIST results in long-term disease-free survival in about 30% of the patients, including those patients relapsing after a prior autoSCT.

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61) Hamadani, Mehdi, et al. “Allogeneic hematopoietic cell transplantation for chemotherapy-unresponsive mantle cell lymphoma: a cohort analysis from the center for international blood and marrow transplant research.” Biology of Blood and Marrow Transplantation 19.4 (2013): 625-631.

First, despite refractory disease at baseline, approximately 25% of the patients with MCL were alive and in remission at 3 years after allo-HCT. Second, in this uniquely chemotherapy-refractory group, the intensity of the pretransplantation conditioning regimen used apparently had no significant affect on rates of NRM, relapse/progression, PFS, and OS.

Ibrutinib after ALLO transplant improves Graft vs. Lymphoma Effect

62) Sahaf, Bita, et al. “Immune Characterization of Ibrutinib Therapy Following Allo-hct That Provides GVL Benefit without Gvhd.” Biology of Blood and Marrow Transplantation 22.3 (2016): S412.

63) Ryan, Christine E., et al. “Ibrutinib efficacy and tolerability in patients with relapsed chronic lymphocytic leukemia following allogeneic HCT.” Blood (2016): blood-2016.

We postulate that ibrutinib augments the graft-versus-leukemia (GVL) benefit through a T-cell–mediated effect, most likely due to ITK inhibition.
lymphocytic leukemia following allogeneic HCT.    Our results provide evidence that ibrutinib effectively augments GVL without causing GVHD.

64)  Link, C. S., et al. “Durable responses to ibrutinib in patients with relapsed CLL after allogeneic stem cell transplantation.” Bone Marrow Transplantation 51.6 (2016): 793.
Ibrutinib, a recently approved inhibitor of Bruton’s tyrosine kinase (BTK), has shown great efficacy in patients with high-risk CLL. Nevertheless, there are few data regarding its use in patients who relapsed after allogeneic stem cell transplantation (alloSCT). We report clinical data from five CLL patients treated with ibrutinib for relapse after first or even second allogeneic transplantation. Additionally, we performed analyses on cytokine levels and direct measuring of CD4 Th1 and CD4 Th2 cells to evaluate possible clinically relevant immunomodulatory effects of ibrutinib. All patients achieved partial responses including one minimal residual disease (MRD)-negative remission. Within 1 year of follow-up, no relapse was observed. One patient died of severe pneumonia while on ibrutinib treatment. Beside this, no unexpected adverse events were observed. Flow cytometry and analyses of T cell-mediated cytokine levels (IL10 and TNFα) did not reveal substantial changes in T-cell distribution in favor of a CD4 Th1 T-cell shift in our patients. No acute exacerbation of GvHD was reported. In conclusion, these results support further evaluation of ibrutinib in CLL patients relapsing after alloSCT.

65) Kharfan-Dabaja, Mohamed A., et al. “Reduced intensity is preferred over myeloablative conditioning allogeneic HCT in chronic lymphocytic leukemia whenever indicated: A systematic review/meta-analysis.” Hematology/oncology and stem cell therapy 11.2 (2018): 63-74.

Despite availability of new and more effective therapies for chronic lymphocytic leukemia, presently this disease remains incurable unless eligible patients are offered an allogeneic hematopoietic cell transplant. Recent published clinical practice recommendations on behalf of the American Society for Blood and Marrow Transplantation relegated the role of for allogeneic hematopoietic cell transplantation to later stages of the disease. To our knowledge, no randomized controlled trial has been performed to date comparing myeloablative versus reduced intensity conditioning regimens in chronic lymphocytic leukemia patients eligible for the procedure. We performed a systematic review/meta-analysis to assess the efficacy of allogeneic hematopoietic cell transplantation when using myeloablative or reduced intensity conditioning regimens. We report the results in accordance to the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines. Based on lower non-relapse mortality and slightly better overall survival rates, reduced intensity conditioning regimens appear to be the most desirable choice whenever the procedure is indicated for this disease. It appears highly unlikely that a RCT will be ever performed comparing reduced intensity vs. myeloablative allogeneic hematopoietic cell transplantation in chronic lymphocytic leukemia. In the absence of such a study, results of this systematic review/meta-analysis represent the best available evidence supporting this recommendation whenever indicated in patients with chronic lymphocytic leukemia.

66) Bacher, Ulrike, et al. “Conditioning regimens for allotransplants for diffuse large B-cell lymphoma: myeloablative or reduced intensity?.” Blood (2012): blood-2012.
The best conditioning regimen before allogeneic transplantation for high-risk diffuse large B-cell lymphoma (DLBCL) remains to be clarified. We analyzed data from 396 recipients of allotransplants for DLBCL receiving myeloablative (MAC; n = 165), reduced intensity (RIC; n = 143), or nonmyeloablative conditioning (NMAC; n = 88) regimens. Acute and chronic GVHD rates were similar across the groups. Five-year nonrelapse mortality (NRM) was higher in MAC than RIC and NMAC (56% vs 47% vs 36%; P = .007). Five-year relapse/progression was lower in MAC than in RIC/NMAC (26% vs 38% vs 40%; P = .031). Five-year progression-free survival (15%-25%) and overall survival (18%-26%) did not differ significantly between the cohorts. In multivariate analysis, NMAC and more recent transplant year were associated with lower NRM, whereas a lower Karnofsky performance score (< 90), prior relapse resistant to therapy, and use of unrelated donors were associated with higher NRM. NMAC transplants, no prior use of rituximab, and prior relapse resistant to therapy were associated with a greater risk of relapse/progression. In conclusion, allotransplantation with RIC or NMAC induces long-term progression-free survival in selected DLBCL patients with a lower risk of NRM but with higher risk of lymphoma progression or relapse.

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Allogeneic Stem Cell Transplant Curative for Many Cancers
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Allogeneic Stem Cell Transplant Curative for Many Cancers
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Allogeneic Transplant is Curative for Many Cancers such as Lymphoma, Leukemia, and Renal Cell Carcinoma .
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Jeffrey Dach MD
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