scholarly journals TLI and ATG conditioning with low risk of graft-versus-host disease retains antitumor reactions after allogeneic hematopoietic cell transplantation from related and unrelated donors

Blood ◽  
2009 ◽  
Vol 114 (5) ◽  
pp. 1099-1109 ◽  
Author(s):  
Holbrook E. Kohrt ◽  
Brit B. Turnbull ◽  
Kartoosh Heydari ◽  
Judith A. Shizuru ◽  
Ginna G. Laport ◽  
...  

A hematopoietic cell transplantation regimen was adapted from a preclinical model that used reduced-intensity conditioning (RIC) and protected against graft-versus-host disease (GVHD) by skewing residual host T-cell subsets to favor regulatory natural killer T cells. One hundred eleven patients with lymphoid (64) and myeloid (47) malignancies received RIC using total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) followed by the infusion of granulocyte colony-stimulating factor-mobilized grafts. Included were 34 patients at least 60 years of age, 32 patients at high risk of lymphoma relapse after disease recurrence following prior autologous transplantation, and 51 patients at high risk of developing GVHD due to lack of a fully human leukocyte antigen (HLA)–matched related donor. Durable chimerism was achieved in 97% of patients. Cumulative probabilities of acute GVHD (grades II-IV) were 2 and 10% of patients receiving related and unrelated donor grafts. Nonrelapse mortality (NRM) at 1 year was less than 4%. Cumulative incidence of chronic GVHD was 27%. The 36-month probability of overall and event-free survival was 60% and 40%, respectively. Disease status at start of conditioning and the level of chimerism achieved after transplantation significantly impacted clinical outcome. The high incidence of sustained remission among patients with active disease at time of transplantation suggests retained graft-versus-tumor reactions. Active trial registration currently at clinicaltrials.gov under IDs of NCT00185640 and NCT00186615.

2022 ◽  
pp. 106002802110681
Author(s):  
Rémi Tilmont ◽  
Ibrahim Yakoub-Agha ◽  
Nassima Ramdane ◽  
Micha Srour ◽  
Valérie Coiteux ◽  
...  

Background Defibrotide is indicated for patients who develop severe sinusoidal obstructive syndrome following allogeneic hematopoietic cell transplantation (allo-HCT). Preclinical data suggested that defibrotide carries a prophylactic effect against acute graft-versus-host disease (aGVHD). Objective The purpose of this study was to investigate the effect of defibrotide on the incidence and severity of aGVHD. Methods This single-center retrospective study included all consecutive transplanted patients between January 2014 and December 2018. A propensity score based on 10 predefined confounders was used to estimate the effect of defibrotide on aGVHD via inverse probability of treatment weighting (IPTW). Results Of the 482 included patients, 64 received defibrotide (defibrotide group) and 418 did not (control group). Regarding main patient characteristics and transplantation modalities, the two groups were comparable, except for a predominance of men in the defibrotide group. The median age was 55 years (interquartile range [IQR]: 40-62). Patients received allo-HCT from HLA-matched related donor (28.6%), HLA-matched unrelated donor (50.8%), haplo-identical donor (13.4%), or mismatched unrelated donor (7.0%). Stem cell source was either bone marrow (49.6%) or peripheral blood (50.4%). After using IPTW, exposure to defibrotide was not significantly associated with occurrence of aGVHD (HR = 0.97; 95% CI 0.62-1.52; P = .9) or occurrence of severe aGVHD (HR = 1.89, 95% CI: 0.98-3.66; P = .058). Conclusion and Relevance Defibrotide does not seem to have a protective effect on aGVHD in patients undergoing allo-HCT. Based on what has been reported to date and on these results, defibrotide should not be considered for the prevention of aGVHD outside clinical trials.


Author(s):  
Marie Bleakley ◽  
Alison Sehgal ◽  
Stuart Seropian ◽  
Melinda A. Biernacki ◽  
Elizabeth F. Krakow ◽  
...  

PURPOSE Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (TN) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of TN-depletion of peripheral blood stem-cell (PBSC) grafts. METHODS One hundred thirty-eight patients with acute leukemia received TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of TN. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD. RESULTS cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years. CONCLUSION Depletion of TN from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1907-1907 ◽  
Author(s):  
Attaphol Pawarode ◽  
Steven Goldstein ◽  
Daniel R. Couriel ◽  
Thomas Braun ◽  
John M. Magenau ◽  
...  

Abstract Allogeneic hematopoietic cell transplant (HCT) remains the primary curative option for patients (pts) with poor-risk hematologic malignancies, but graft-versus-host disease (GVHD) and relapse remain major obstacles. Of note, GVHD therapy with systemic steroid and more potent immunosuppression abrogates graft-versus-tumor effect and further increases relapse. The NF-κB signaling pathway has a pivotal role in maintaining malignant cell survival and in mediating inflammatory and immune response by promoting activated T and dendritic cell function and survival. Inhibition of proteasome function results in down-regulation of the NF-κB signaling pathway, thus selective apoptosis of malignant cells, in which this pathway is up-regulated, and of allo-reactive T and dendritic cells. The reversible proteasome inhibitor bortezomib may abrogate GVHD and relapse based on pre-clinical studies and a phase 1/2 clinical trial when added to high-risk mismatched unrelated donor HCTs for pts with hematologic malignancies. (Koreth J, et al. J Clin Oncol 2012;30(26):3202-8.) Carfilzomib is a second-generation irreversible immunoproteasome inhibitor, with potentially increased efficacy and specificity to the immune and hematologic malignancy cells. It has a less off-target toxicity profile, especially myelosuppression, neuropathy and diarrhea. We are exploring the addition of carfilzomib to fludarabine-based conditioning regimens and GVHD prophylaxis with tacrolimus and methotrexate. Primary Objective: To identify the maximal tolerated dose (MTD) of carfilzomib when administered on day +1, +2, +6, +7. Methods: The phase 1 design is standard 3+3. Eligible conditioning regimens include fludarabine/busulfan and fludarabine/melphalan. Tacrolimus is started on day -3 and tapered off by day +180 if ≥grade II acute GVHD do not occur. Methotrexate 5 mg/m2 is given IV on day +1, +3, +6, +11. Carfilzomib is administered IV on days +1, +2 at 20 mg/m2/day fixed dose and on day +6, +7 at 4 dose levels: 20, 27, 36, 45 mg/m2/day. Premedication with 4 mg dexamethasone IV is administered prior to each dose of carfilzomib 20 and 27 mg/m2 and with 8 mg prior to each dose of 36 and 45 mg/m2, respectively. Carfilzomib is given after IV methotrexate on day +1 and +6. Subcutaneous filgrastim 5 μg/kg/day is started on day +1 until engraftment. Dose-limiting toxicities (DLTs) are defined as any ≥grade 3 non-hematologic National Cancer Institute Common Terminology Criteria for Adverse Events version 4 toxicities which occur within 28 days of carfilzomib treatment (day +35) and are directly attributed to carfilzomib. Results: Since October 2014, 10 pts (Male: Female, 5:5) have been enrolled. Nine pts received all planned 4 doses and 1 female received 3 doses only before being removed due to unrelated infectious adverse events. Among 9 evaluable pts, the median age was 55 (range, 29-61) years; all donors were 8/8 matched (7 sibling, 2 unrelated). Stem cell sources were peripheral blood in 8 and bone marrow in 1 unrelated donor. Primary diseases included FLT3-ITD+ acute myeloid leukemia in 2, acute bi-phenotypic leukemia in 1, BCR/ABL+ acute lymphoblastic leukemia in 1, myelodysplastic syndrome in 2, lymphoma in 2, and multiple myeloma in 1. All pts received the myeloablative reduced-toxicity fludarabine and busulfan x 4 (FluBu4), with busulfan kinetics targeting the concentration at steady state at 600-900 ng/mL. One pt with diffuse large B cell lymphoma received rituximab-FluBu4. All 9 pts engrafted neutrophil and platelet at a median time of 10 (range, 10-15) and 12 (9-14) days, respectively. A pt of dose level 2 (20/27 mg/m2) who received a bone marrow stem cell dose of 1.3 x 106 CD34+ cells/kg unexpectedly engrafted as early as day +15. Expected common toxicities related to the FluBu4 treatment was oral mucositis. Median CD33+ and CD3+ donor chimerisms were 100% and 88% at day 30, respectively, and were 100% and 91% at day 100, respectively. As of 8/4/15, no DLTs occurred in the 8 pts who had passed day +35, with the median transplant day of day +172 (range, 65-292). The 9th pt of dose level 3 (20/36 mg/m2) is day +14 and has engrafted. Conclusion: Adding the irreversible immunoproteasome inhibitor carfilzomib to fludarabine-based conditioning HCT appears safe and feasible. Dose escalation to level 4 (20/45 mg/m2) is ongoing and the results will be updated at the meeting. Disclosures Pawarode: Onyx Pharmaceuticals: Research Funding. Off Label Use: Carfilzomib is an irreversible proteasome inhibitor and is FDA approved for treament of relapsed refractory multiple myeloma. It is here being investigated for its immunomodulatory and anti-tumor properties in the prevention of graft-versus-host disease (GVHD) and disease relapse when incorporated into fludarabine based conditioning and GVHD prophylaxis regimens for allogeneic hematopoietic cell transplantation in patients with high-risk hematologic malignancy.. Levine:Novartis: Consultancy.


2018 ◽  
pp. 1-13 ◽  
Author(s):  
Mehreen A. Khan ◽  
Qaiser Bashir ◽  
Qamar-un-Nisa Chaudhry ◽  
Parvez Ahmed ◽  
Tariq M. Satti ◽  
...  

Use of haploidentical (haplo) donors for hematopoietic cell transplantation (HCT) has significantly increased in the last decade. The major advantage with this strategy is universal availability and faster acquisition of the donor, along with affordability and provision of immunotherapy in post-transplantation period. Historically, haplo-HCT was associated with compromised outcomes because of high rates of graft-versus-host disease and graft failure, but after the development of a post-transplantation high-dose cyclophosphamide strategy, which results in selective T-cell depletion, these issues have been addressed to a large extent. Nevertheless, graft failure, high treatment-related mortality due to graft-versus-host disease, infections, delayed immune reconstitution, and disease relapse remain significant concerns. As the experience with haplo-HCTs grows, the clinical outcomes are becoming more at par with those seen with fully matched unrelated donor allogeneic HCTs.


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