Post-Transplantation High Dose Cyclophosphamide (Cy) Is Effective Single Agent for Prevention of Acute and Chronic Graft Versus Host Disease after Myeloablative HLA Matched Related and Unrelated Bone Marrow Transplantation (BMT)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 56-56 ◽  
Author(s):  
Leo Luznik ◽  
Javier Bolanos-Meade ◽  
Robert Brodsky ◽  
B. Douglas Smith ◽  
Carol A. Huff ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
De Novo ◽  
Chronic Gvhd ◽  
Immunosuppressive Treatment ◽  
High Dose ◽  
Post Transplantation ◽  
Gvhd Prophylaxis ◽  
History Of ◽  
Grade Ii ◽  
Low Incidence

Abstract Based on our results in animal models and promising results in HLA-haploidentical setting (L. Luznik, Blood 2002 and BBMT 2008), we studied whether high dose Cy alone is sufficient as GVHD prophylaxis after myeloablative HLA-matched related or unrelated BMT in patients with advanced, poor risk, hematologic malignancies. One hundred and seventeen consecutive patients (median age 48, range 23–65; 36 de novo AML, 23 2° AML (arising from previous MDS/MPD or therapy-related), 13 high-risk MDS, 9 ALL, 8 CML, 3 CLL, 5 MM, 9 NHL and 11 HL), of whom the majority (57%) were not in remission, received HLA-matched related (n=78) or unrelated (n=39) BMT. Conditioning consisted of oral or IV busulfan (pharmacokinetically adjusted) on days −7 to −3 and Cy (50 mg/kg/day) on days −2 and −1. Cy (50 mg/kg/day) was also given on days +3, and +4 as a sole agent for GVHD prophylaxis. All patients received bone marrow allografts without growth factor support. Three patients failed to engraft, but two were successfully rescued with a second allograft. The cumulative incidence of non-relapse mortality (NRM) at day 100 and 1 year after transplantation was 8.5% and 16%, respectively. Of the 18 patients dying of NRM, 2 were from VOD, 3 from non infectious pneumonia, 3 were from GVHD, 3 from sepsis/bacterial infections, 4 from MOF, and 3 of CNS/organ hemorrhage. The incidences of acute grade II–IV and grade III–IV GVHD were 43% and 11%, respectively. With a median follow-up of 19 months, 66 (56.4%) patients are alive, of whom 52 (44.4%) are in complete remission. Only 7/66 related and 4/32 unrelated patients developed chronic GVHD (classic limited in 7, overlap syndrome limited in 1, and classic extensive in 3 patients). Since in a competing risk model (relapse and death as competing risks) the cumulative incidence of chronic GVHD remained low, we analyzed the impact of the preceding history of acute GVHD and systemic immunosuppressive treatment given beyond the originally prescribed prophylaxis with high dose Cy on the incidence of chronic GVHD. Only one patient without a preceding history of acute GVHD developed de novo chronic GVHD. Overall, 3 patients with grade II–IV acute GVHD were untreated, 10 patients received steroids alone, 31 received steroids + a calcineurin inhibitor (CNI), and 7 received steroids + non CNI-based agents. The use of CNI for the treatment of acute GVHD did not appear to influence the development of chronic GVHD: 6/31 (19%) patients who received CNI-based immunosuppressive treatment developed chronic GVHD compared to 3/20 (15%) patients who did not. These results suggest that highdose of post-transplantation Cy is effective as the sole prophylaxis for acute and chronic GVHD after HLA-matched related or unrelated BMT. This approach is associated with rapid immunologic recovery as indicated by the low incidence of opportunistic infections, as well as a low incidence of acute and especially chronic GVHD. Further clinical and correlative studies are needed to elucidate the mechanisms behind the unique effectiveness of post-transplantation Cy on the prevention of acute and chronic GVHD.

Greater HLA Disparity Is Associated with Reduced Risk of Relapse and Improved Event-Free Survival after Nonmyeloablative, HLA-Haploidentical BMT with Post-Transplantation High-Dose Cyclophosphamide

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 150-150 ◽  
Author(s):  
Yvette L. Kasamon ◽  
Mary S. Leffell ◽  
Jeanne Kowalski ◽  
Hua-Ling Tsai ◽  
Nancy Rossiter ◽  
...  
Keyword(s):  
Cumulative Incidence ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Class I ◽  
High Dose ◽  
Post Transplantation ◽  
Free Survival ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
One Year

Abstract Background: Although a lower relapse risk has been reported after allogeneic BMT with increasing HLA disparity, this potential benefit has been offset by higher rates of acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM). However, it is possible that the type of GVHD prophylaxis could influence the balance between GVHD toxicity and relapse. Patients and methods: We retrospectively analyzed the outcomes of 185 patients with poor-risk hematologic malignancies enrolled on three similar clinical trials of related-donor, haploidentical BMT incorporating high-dose post-transplantation cyclophosphamide (Cy) for GVHD and graft rejection prophylaxis (as published in BBMT2008;14:641–50). Molecular typing was at an allele level for HLA-A, -B, -Cw, and -DRB1 and at an allele group level for -DQB1. All received Cy (14.5 mg/kg IV on days −6, −5), fludarabine (30 mg/m2 IV on days −6 to −2), total body irradiation (200 cGy on day −1), and non-T-cell depleted bone marrow infusion. GVHD prophylaxis consisted of Cy (50 mg/kg IV) either once (on day 3; n = 48) or twice (on days 3, 4; n = 137), mycophenolate mofetil for 35 days, and tacrolimus for up to 6 months, with filgrastim begun after the last dose of Cy. Most patients (median age 50, range 1–71) had advanced disease and 49 (26%) had failed autologous BMT. Diagnoses were MDS (22), CMML (3), acute leukemia or lymphoblastic lymphoma (58), CML (11), CLL (15), multiple myeloma (9), non-Hodgkin lymphoma (42), and Hodgkin lymphoma (25). Results: Median follow-up after BMT is 20 months (range, 2–71 months) in those without events. Nonengraftment attributed to primary graft failure or to residual bone marrow malignancy occurred in 29 of 177 evaluable patients (16%). Cumulative incidences of grade II–IV acute GVHD and chronic GVHD were 31% and 15%, respectively. Cumulative incidences of NRM and relapse or progression at one year were 15% and 50%, respectively. Actuarial event-free survival (EFS) at one year was 35%, with grade II–IV acute GVHD by day 100 associated with a trend toward lower cumulative incidence of relapse (p = 0.08) but a significantly higher cumulative incidence of NRM (p = 0.002) on subgroup analysis. Notably, increasing degrees of HLA mismatch at either class I or class II loci had no significant effect on cumulative incidence of acute or chronic GVHD or NRM. In contrast, the presence of a DRB1 antigen mismatch in the GVH, but not host-versus-graft (HVG), direction was associated with a significantly lower cumulative incidence of relapse (Figure a; p = 0.04) and improved EFS (Figure c; p = 0.009), whereas DQB1 antigen and class II allele mismatch status had no effect. Additionally, the presence of two or more class I allele mismatches (composite of A, B, and Cw) in either direction was associated with a significantly lower cumulative incidence of relapse (Figure b; p = 0.045 for GVH direction, p = 0.01 for HVG direction) and improved EFS (Figure d; p = 0.07 for GVH direction, p = 0.001 for HVG direction). Conclusion: Greater HLA disparity appears to be beneficial after nonmyeloablative, HLA-haploidentical BMT that incorporates high-dose post-transplantation Cy. These results suggest an anti-tumor effect of partially HLA-mismatched BMT that is irrespective of clinically significant GVHD. Potential effectors of anti-tumor immunity include HLA-DRB1 reactive CD4+ T-cells, class I reactive CD8+ T-cells, and/or natural killer cells recognizing missing self. Since most patients have several potential HLA-haploidentical related donors, the results support a strategy of choosing a donor who is incompatible for both HLA-DRB1 antigen and multiple HLA class I alleles. Figure Figure

Post-Transplantation High-Dose Cyclophosphamide (Cy) Is Effective Single Agent GVHD Prophylaxis That Permits Prompt Immune Reconstitution after Myeloablative HLA Matched Related and Unrelated Bone Marrow Transplantation (BMT).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2891-2891 ◽  
Author(s):  
Luznik Leo ◽  
Chen R. Allen ◽  
Kaup Michele ◽  
Bright C. Emilie ◽  
Bolanos-Meade Javier ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Gvhd ◽  
Single Agent ◽  
High Dose ◽  
Post Transplantation ◽  
Cell Counts ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
The Impact

Abstract Prolonged pharmacologic immunosuppression is a major obstacle to early immunologic recovery after allogeneic BMT. Based on our results in animal models, we studied whether properly timed high-dose Cy post-HLA matched related and unrelated BMT is an effective strategy for limiting GVHD; we hypothesized that avoiding prolonged immunosuppression would speed immune recovery and reconstitution of regulatory T cells (T regs) thereby decreasing post-transplant complications. We are reporting results on 46 consecutive patients (median age 41, range 1–64) with high-risk hematologic malignancies (20 AML, 12 ALL, 6 NHL, 3 HD, 2 MM, 2 CML, 1 CMMoL); 28 received related and 18 unrelated unmanipulated HLA-matched BM (median of 2.2 x 108 MNC per kg) after conditioning with busulfan on days -7 to -3 and Cy (50 mg/kg/day) on days -2 and -1, and followed by Cy (50 mg/kg/day) on days +3 and +4 as the sole GVHD prophylaxis. All the patients had advanced disease (20 in advanced remission with the rest having refractory disease), and the median follow-up is 13 (range 6–24) months. All but two patients had sustained engraftment. The cumulative incidence of acute grades II–IV and grades III–IV GVHD were 41% and 9%, respectively. All patients with GVHD responded fully to standard therapy (steroids ± tacrolimus) or therapy per BMT CTN0302, and all except 2 patients were rapidly weaned from all immunosuppressive agents. Of the thirty-six patients alive after day 100, only 1 of the 23 patients that received HLA-matched related, and 3 of 13 patients that received unrelated allografts, developed chronic GVHD. Twenty-six (56%) patients are alive, of whom 21 (45%) are in complete remission. There were no deaths secondary to infection or GVHD. CMV reactivation was detected in 11 of 36 (31%) patients, of whom 9 had GVHD. There was no CMV infection. Median (± SEM) CD4+ T cell counts were 99 ± 16/mL and 209 ± 49/mL on days 60 (n = 23) and 180 (n= 8), respectively. Corresponding values for CD8+ T cells were 248 ± 132/mL and 228 ± 161/mL on days 60 and 180, respectively. Patients with grade II–IV GVHD had significantly fewer peripheral blood (PB) CD4+Foxp3+ T cells compared to patients with grade 0–I GVHD (p<0.05). Development of grade II–IV GVHD negatively correlated with the expression of the Foxp3 (p<0.05) and was associated with relatively higher expression of interferon-γ mRNA (p=0.08) in PB, suggesting higher effector function in the absence of Tregs in patients with grade II–IV GVHD. No differences in IL-10 mRNA expression between patients with or without GVHD were found, while significantly higher expression of interleukin-2 mRNA was detected in patients with grade II–IV GVHD (p<0.025). These results indicate that high-dose post-transplantation Cy is effective as a single agent strategy for limiting acute and chronic GVHD after myeloablative HLA-matched related and unrelated allografting; this approach also limits the need for prolonged immunosuppression, resulting in favorable immunoreconstitution with few opportunistic infections in this unfavorable group of patients. Longer follow-up and larger numbers of patients are needed to assess the impact of this strategy on survival.

Secondary Graft-Versus-Host Disease (GVHD) Prophylaxis with Oral Proteasome Inhibitor Ixazomib Is Associated with Low Incidence of Recurrent, Late Acute and Chronic GVHD and Facilitated Calcineurin Inhibitor Taper within the First Year Post Allogeneic Stem Cell Transplantation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 41-42
Author(s):  
Natasia Rodriguez ◽  
Jasme Lee ◽  
Lisa Flynn ◽  
Fiona Murray ◽  
Sean Devlin ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Calcineurin Inhibitor ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Overlap Syndrome ◽  
Advisory Committees ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Low Incidence

Background. GVHD is a frequent complication within the 1st year after allogeneic stem cell transplantation (allo-HCT). Recipients of reduced intensity (RI) and non-myeloablative (NMA) conditioning combined with calcineurin inhibitor (CNI)-based GVHD prophylaxis, frequently develop GVHD in the context of immunosuppression taper. Ixazomib is an oral proteasome inhibitor (PI) that has demonstrated immunomodulatory properties, inhibition of pro-inflammatory cytokines, anti-tumor activity, and has a wide safety profile. We hypothesized that secondary GVHD prophylaxis using ixazomib, will facilitate CNI taper without increase in GVHD frequency and severity, maintaining graft-versus-tumor (GVT) effect, and a safety profile. Methods. We conducted an open label, prospective, single-center pilot study between 11/16 and 03/19. Eligible patients were &gt; 18 yrs old, had a hematologic malignancy treated with RI or NMA conditioning allo-HCT, received CNI-based GVHD prophylaxis, and were within day 100 to 150 post-HCT. Patients with active acute and/or chronic GVHD were excluded. Patients were treated with ixazomib 4 mg orally once weekly, each cycle consisting of 3 weeks on and 1 week off therapy, until completion of taper from prophylactic CNI or 1-year post-HCT was reached, whichever occurred first. Patients who developed grade II-IV acute GVHD, chronic GVHD, or died of transplant-related mortality (TRM) were deemed treatment failure. The primary endpoint was the efficacy of ixazomib for the prevention of recurrent or late grade II-IV acute GVHD or chronic GVHD at 1-year post-HCT. Additional endpoints included TRM, relapse rate, survival analysis, safety evaluation, and immune reconstitution. Results. A total of 18 patients (median age of 58 yrs) were accrued in the study. The majority were male, had a diagnosis of NHL, and received RI conditioning (Table 1). All patients had a PBSC graft, and 16 (89%) were 10/10 HLA-matched. The median time for initiation of ixazomib was 141.5 days post-HCT. Fourteen patients had no GVHD during the study period. The 4 patients who developed GVHD had severe overlap syndrome (n = 2), mild de novo chronic GVHD (n = 1), and recurrent grade II acute GVHD (n = 1). Notably, patients with severe overlap syndrome had limited chronic GVHD involvement affecting the mouth and/or eyes, and the severity score was driven by acute manifestations affecting the skin and GI tract. Six patients successfully discontinued CNI and 4 patients were tapering immunosuppression close to the end of study at 1-year post-HCT. The cumulative incidence (CI) of grade II-IV acute and chronic GVHD at 1-year post-HCT was 25% (95%CI: 7.2-48.1) (Fig. 1A). No patients died during the study and therefore, the CI of TRM at 1-year was 0%, and only 1 patient had malignant relapse (NHL). The CI of PFS and the composite endpoint GVHD-free/relapse-free survival (GRFS) at 1-year were 83% (95%CI: 58-100) and 73% (95%CI: 49-100, Fig 1B), respectively. All patients experienced at least 1 TEAE of any grade. Most AEs were grade 1 or 2, with the most common being cytopenia and elevation in ALT/AST. Drug-related SAEs were reported in 9 patients and included neutrophil and decreased WBC. Seven patients required ixazomib dose reduction due to side effects, and 5 patients were removed from the study due to toxicity (1 neutropenia, 3 GI, 1 skin rash). Of those, 1 had subsequent GVHD by day 365 post-HCT. Immune recovery at 3, 6 and 12 months post-HCT was evaluated. There was a rapid and sustained recovery in T-cell subpopulations and B cell reconstitution Fig 2. Conclusions. Secondary GVHD prophylaxis with ixazomib was associated with low incidence of recurrent and late acute and chronic GVHD within the 1st year post-HCT. This approach allowed CNI taper while preserving GVT effect without aggravating GVHD. No deaths occurred during the study period and the 1-year GRFS was high. Ixazomib was overall well tolerated and favored immune reconstitution post-HCT. Our findings support further development of this approach and provide a proof-of-concept for secondary GVHD prophylaxis. Disclosures Dahi: Kite: Consultancy. Giralt:TAKEDA: Research Funding; JAZZ: Consultancy, Honoraria; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; MILTENYI: Consultancy, Research Funding; KITE: Consultancy; NOVARTIS: Consultancy, Honoraria, Research Funding; OMEROS: Consultancy, Honoraria; ACTINUUM: Consultancy, Research Funding. Sauter:Bristol-Myers Squibb: Research Funding; GSK: Consultancy; Gamida Cell: Consultancy; Celgene: Consultancy, Research Funding; Kite - a Gilead Company: Consultancy; Precision Biosciences: Consultancy, Research Funding; Genmab: Consultancy; Novartis: Consultancy; Spectrum Pharamaceuticals: Consultancy; Sanofi-Genzyme: Consultancy, Research Funding; Juno Therapeutics: Consultancy, Research Funding. Perales:Omeros: Honoraria, Membership on an entity's Board of Directors or advisory committees; Medigene: Membership on an entity's Board of Directors or advisory committees, Other; NexImmune: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees, Other; Cidara Therapeutics: Other; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Nektar Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Honoraria; Miltenyi Biotec: Research Funding; Kite/Gilead: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; MolMed: Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Bellicum: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ponce:Ceramedix: Membership on an entity's Board of Directors or advisory committees; Generon: Membership on an entity's Board of Directors or advisory committees; Kadmon: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding.

Post-Transplantation High Dose Cyclophosphamide As Gvhd Prophylaxis in 9/10 HLA-Matched Unrelated Donors Hematopoietic Stem Cell Transplantation

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3135-3135 ◽  
Author(s):  
Rohtesh S. Mehta ◽  
Rima M Saliba ◽  
Julianne Chen ◽  
Gabriela Rondon ◽  
Aimee E Hammerstrom ◽  
...  
Keyword(s):  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Hla Class I ◽  
Conventional Group ◽  
Unrelated Donor ◽  
Post Transplantation ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Grade Iii

Abstract Background: Post-transplantation cyclophosphamide (PTCy) is an effective strategy to prevent GVHD after haploidentical or HLA-matched related or unrelated donor hematopoietic stem cell transplantation (HSCT). Our study aim was to determine its efficacy in HLA-mismatched unrelated donor (MMUD) HSCT. Methods: We included 113 consecutive adult patients with high risk hematological malignancies who underwent one-antigen MMUD (9/10-matched) bone marrow (BM) or peripheral blood (PB) HSCT after myeloablative or reduced-intensity conditioning at our institution from 2009-2013. Outcomes were compared between (a) conventional GVHD group (n=71) that received in-vivo T-cell depletion with ATG, tacrolimus and methotrexate and (b) PTCy group (n=41) that received PTCy (50 mg/kg/day IV on days 3 and 4) with tacrolimus and MMF. After exclusion of 29 patients with isolated HLA-DQ mismatches, a separate analysis was performed in 84 patients with 7/8 HLA-MUD HSCT; 38 patients received PTCy while 46 patients received conventional prophylaxis. Results: Patients in the conventional group were marginally older (median 54 years; range 19-74) than those in the PTCy group (median 50 years; range 20-64). PB was used more frequently as a graft source in the conventional group (38% vs 17%, p=0.02). PTCy group included more patients with HLA class-I mismatches (87.8%) compared to conventional group (56.9%). There were no other differences between the groups. Incidence of grade II-IV (37% vs 36%, p=0.8) or grade III-IV (17% vs 12%, p=0.5) acute GVHD at day 100 post-transplant was not different between the groups. [Figure 1] Incidence of grade II-IV acute GVHD at day 30 was significantly lower after PTCy compared with conventional prophylaxis (0% vs 15%, p <0.001). Correspondingly, incidence of grade III-IV GVHD at day 30 was 0% in the PTCy group and 8% in the conventional group (p=0.08). Cumulative incidence of chronic GVHD was similar between the two groups at 6 months (20% vs 15%), 1-year (30% vs 31%) or 2-years (30% vs 42%). Risk factors analysis showed that use of PTCy was the sole independent predictor of lower risk of grade II-IV acute GVHD at day 30 (p=0.01). None of the risk factors evaluated, including PTCy use, were shown to predict the rate of grade II-IV acute GVHD within day 100. Two-year cumulative incidences of NRM (35% vs 25%), disease progression (20% vs 31%), DFS (42% vs 38%) and OS (52% vs 40%) were similar in the PTCy and the conventional groups, respectively. [Figure 1] Median times to neutrophil (18 vs. 12 days, p<0.001) and platelet (25.5 vs. 18 days, p=0.05) engraftment were prolonged in PTCy group. Disease recurrence/persistence was the leading cause of death in both groups, accounting for about 46% of all deaths. Subgroup analysis restricting to patients with BM grafts produced similar findings. In patients with HLA class-I mismatch, PTCy was associated with significantly reduced risk of grade II-IV, but not grade III-IV, acute GVHD at day 30 (p=0.01). However, there were no differences in acute grade II-IV GVHD (HR 1.1, 95% C.I. 0.5-2.5, p=0.7) or acute grade III-IV GVHD (HR 1.5, 95% C.I. 0.4-5.4, p=0.5) by day 100 between the groups. Comparing patients with 7/8-HLA-MUD HSCT, no patient in PTCy group developed acute GVHD at day 30 compared with 8 patients in conventional group (p=0.005). There were no differences in incidence of grade II-IV (HR 1, 95% C.I. 0.5-2.1, p=0.9) or grade III-IV (HR 1.1, 95% C.I. 0.3-3.3, p=0.9) acute GVHD at day 100, chronic GVHD at 6 months (HR 0.8, 95% C.I. 0.2-2.9, p=0.7), 1-year (HR 0.8, 95% C.I. 0.3-2.2, p=0.6) or 2-years (HR 0.7, 95% C.I. 0.2-1.9, p=0.5) between the groups. Conclusion: Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA-MMUD HSCT. Disclosures Alousi: Therakos, Inc: Research Funding.

scholarly journals Shortened Immunosuppression Following Peripheral Blood (PB) Haploidentical (haplo) Transplantation with Post-Transplant Cyclophosphamide (PTCy) Is Associated with Tolerable Rates of Graft-Vs-Host Disease (GVHD)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3320-3320
Author(s):  
Amy E. DeZern ◽  
Marianna Zahurak ◽  
Javier Bolanos-Meade ◽  
Richard J. Jones
Keyword(s):  
Graft Failure ◽  
Acute Gvhd ◽  
Risk Index ◽  
Chronic Gvhd ◽  
Prospective Trial ◽  
Stopping Rules ◽  
High Dose ◽  
Gvhd Prophylaxis ◽  
Grade 3

With PTCy as GVHD prophylaxis, nonmyeloablative (NMA) HLA- haplo and HLA-matched blood or marrow (BMT) have comparable outcomes. Previous reports showed that discontinuation of immunosuppression (IST) as early as day 60 after infusion of bone marrow (BM) haplo allograft with PTCy is feasible. However, there are certain diseases in which PB may be favored over BM grafts to augment engraftment rates; however, given the higher rates of GVHD with PB, excessive GVHD becomes a concern with early discontinuation of IST. We present a completed, prospective single-center trial of stopping IST at days 90 and 60 after NMA haplo PB. (NCT02556931) From 12/2015-7/2018, 117 evaluable patients (pts) with hematologic malignancies associated with higher rates of graft failure with PTCy (MDS, MPN, overlap syndromes, 2o AML, AML with MRD, MM, and CLL) received NMA PB allografts on trial. Haplo donors were preferred, but in patients lacking suitable haplo relatives, unrelated donors were employed with 6 in each IST cohort. The primary objective was to evaluate the safety and feasibility of reduced‐duration IST (from Day 5 through Day 90 in cohort 1 and through Day 60 in cohort 2.) Transplant inclusion criteria were standard and the conditioning included Cy (14.5 mg/kg IV D -6 and -5), fludarabine (D -6 to -2), TBI (200 cGy D -1) and T-cell replete PB. GVHD prophylaxis consisted of high-dose PTCy (50 mg/kg IV D 3 and 4), mycophenolate mofetil (D 5-35) and IST (tacrolimus/sirolimus) from D 5 forward. Priot to transplantation, pts were assigned to stop IST early if eligible, as defined by having ≥ 5% donor T cells at ~D 56 onward, no relapse, and no grade 2-4 acute or significant chronic GVHD. If ineligible to discontinue IST early, it continued through D 180. Monitoring rules declared reduced IST feasible if ≥ 33% of pts stopped IST early as planned. Safety stopping rules for early IST cessation were based on ≥ 5% graft failure, ≥ 5% NRM, ≥ 50% relapse, and ≥ 10% combined grade 3-4 acute GVHD and severe chronic GVHD, measured from the IST stop date to ~D 180. Historical data from 55 haplo transplants for MDS, CLL, and MPNs at our center using the same regimen and PB grafts informed safety calculations. Of the 117 pts (median age 64 years, range 24-78), the most common diagnoses were MDS (33%), AML (with MRD or arising from antecedent disorder) (31%), MPNs (21%) myeloma (10%), and CLL (6%). By refined Disease Risk Index, 13% were low risk, 69% intermediate and 18% high. Shortened IST was feasible in 75 pts (64%) overall. Ineligibility for shortened IST was due most commonly to GVHD (17 pts), followed by early relapse (11 pts), NRM (7 pts), patient/ physician preference (4 pts) or graft failure (3 pts). Of the 57 patients in the D90 cohort (median follow up 35 mos), 33 (58%) stopped IST early as planned. Of the 60 patients in the D60 cohort (median follow up 20 mos), 42 (70%) stopped IST early as planned. The graft failure rate was 2.6%. NRM was very similar in the two arms, 12% at both 12 and 18 months in the D90 cohort and 10% and 13% at 12 and 18 months in the D60 cohort. Relapse in D90 cohort is 40% at 18 months compared to 33% at 18 months in the D60 cohort. Figure 1 shows cumulative incidence (CI) of acute grade 2-4 and grade 3-4 GVHD. Although the CI of grade 1-2 GVHD may be slightly higher in day 60 cohort, it is only 40% at D180. Severe chronic GVHD was 12% (D90) and 11% (D60) at 540 days. One year OS is 75% and 78% for the D90 and D60 cohorts, respectively. At 12 months PFS is 54% in the D90 group and 67% in the D60. At 12 months, the GRFS is 33% in the D90 group, and 38% in the D60 group. (Figure 2) These data suggest that reduced-duration IST in pts receiving NMA haplo PB with PTCy is feasible and carries an acceptable safety profile. Risks of acute GVHD, chronic GVHD, graft failure and NRM appear similar to historical outcomes with IST until D180 and between the two cohorts. When comparing the D90 and D60 arms, grade 3-4, severe chronic GVHD, GRFS, OS and PFS were similar. Although a larger, prospective trial would be needed to uncover potential small differences in outcomes based on IST duration, these data show that similar to our findings with BM, many PB pts (64% in this trial) can discontinue IST as early as D60 without undue toxicity. The favorable toxicity profile of the PTCy platform, coupled with the feasibility and safety of early IST cessation, provides an ideal setting to incorporate novel post-transplantation approaches for relapse reduction. Figure 1 Disclosures DeZern: Astex Pharmaceuticals, Inc.: Consultancy; Celgene: Consultancy. Bolanos-Meade:Incyte Corporation: Other: DSMB fees.

Sirolimus, Tacrolimus and Reduced-Dose Methotrexate as Graft Versus Host Disease (GVHD)Prophylaxis after Non-Myeloablative Stem Cell Transplantation: Low Incidence of Acute GVHD Compared with Tacrolimus/Methotrexate or Cyclosporine/Prednisone.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 730-730 ◽  
Author(s):  
Edwin P. Alyea ◽  
Shuli Li ◽  
Haesook Kim ◽  
Corey Cutler ◽  
Vincent Ho ◽  
...  
Keyword(s):  
Serum Level ◽  
Low Dose ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Unrelated Donor ◽  
Peripheral Blood Stem Cells ◽  
Dose Methotrexate ◽  
Gvhd Prophylaxis ◽  
Low Incidence

Abstract Sirolimus (rapamycin) is a macrocyclic lactone similar in structure to tacrolimus and cyclosporine (CSA) but with a distinct mechanism of action. Sirolimus binds to both FKBP12 and mTOR and inhibits signal transduction and cell cycle progression. The drug is synergistic with tacrolimus but has a distinct toxicity profile, thereby allowing their use in combination. We report results of a phase II trial combining sirolimus with tacrolimus and low-dose methotrexate (MTX) as GVHD prophylaxis in matched related and unrelated donor NST. Results of this trial were compared with patients who had previously undergone NST receiving tacrolimus/MTX alone or CSA/prednisone(pred). All patients received fludarabine (30 mg/m2/d x 4days) and intravenous busulfan (0.8mg/kg/d x 4 days) as conditioning. All patients received G-CSF mobilized peripheral blood stem cells with a targeted cell dose of 1 x 107 CD34+ cells/kg. G-CSF 5 mcg/kg was started on day 1. Sirolimus containing GVHD prophylaxis included sirolimus 12 mg loading dose on day −3 and then 4 mg po qd targeting a serum level of 3–12 ng/ml. Tacrolimus was initiated at 0.05 mg/kg po b. i.d. beginning day −3 with a targeted serum level of 5–10 ng/ml. MTX (5 mg/m2) was given days, 1, 3 and 6. Planned taper of the GVHD medications was ~30% at days 60, and 120 with discontinuation by day 180. The median follow up is 14 months for patients receiving sirolimus and all evaluable patients have been followed for >100 days. 40 patients have been transplanted, 20 from related and 20 from unrelated donors. The median age was 57 years (range 20–69). Diseases included: NHL (9), MDS (7), Hodgkin’s disease (6), CLL (6), AML(5), CML (5), MM (1) and CMML(1). 18 patients (45%) had received prior myeloablative transplantation. 31 patients (78 %) had advanced disease at the time of transplantation. Patients receiving tacrolimus/MTX (n=36) and CSA/pred (n=49)had similar characteristics. Sirolimus was well tolerated and no severe adverse events related to the drug were noted. Acute grade 2–4 GVHD was significantly reduced in patients receiving sirolimus/tacrolimus/MTX, 8% vs 18% in patients receiving tacrolimus/MTX and 37% in those receiving CSA/Pred (p=0.003). Time to neutrophil engraftment was slower in methotrexate containing regimens (13 days vs 9 days, p=0.01), but there was no difference between sirolimus/tacrolimus/MTX and tacrolimus/MTX alone. Median donor derived hematopoiesis, measured 1–2 months after transplant, was high in all groups (sirolimus/tacrolimus/MTX 91%, tacrolimus/MTX 95% and CSA/pred 90%, p=0.91). The 1 year overall survival was sirolimus/tacrolimus/MTX 71%, tacrolimus/MTX 48% and CSA/pred 45% (p=0.17). 1-year progression free survival was 49%, 27% and 37%, respectively (p=0.11). The addition of sirolimus to tacrolimus and low dose MTX is well tolerated and is associated with a low incidence of acute GVHD. The addition of sirolimus does not delay engraftment compared with tacrolimus/MTX and results in a similar high level of donor derived hematopoiesis. Further patient accrual and longer follow-up is needed to yield information on the incidence of chronic GVHD and overall outcome.

Reduced-Intensity Conditioning Followed by Allogeneic Stem Cell Transplantation (allo-SCT) Is an Effective Salvage Treatment for Peripheral T-Cell Non-Hodgkin’s Lymphoma (PTCL).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1128-1128 ◽  
Author(s):  
Paolo Corradini ◽  
Anna Dodero ◽  
Marco Bregni ◽  
Francesco Zallio ◽  
Lucia Farina ◽  
...  
Keyword(s):  
De Novo ◽  
Present Report ◽  
Chronic Gvhd ◽  
High Dose Chemotherapy ◽  
High Dose ◽  
Unrelated Donor ◽  
Not Otherwise Specified ◽  
Short Course ◽  
Gvhd Prophylaxis

Abstract Patients with relapsed PTCL have a poor prognosis. We had previously shown the existence of a graft-versus-lymphoma effect against PTCL (J Clin Oncol, 2004). In the present report, we extended our previous observations to 26 patients (pts) receving allo-SCT. All patients received several courses of debulkying chemotherapy (usually 3 DHAP and/or high-dose chemotherapy) followed by the same RIC regimen containing thiotepa (10 mg/kg), fludarabine (60 mg/ms) and cyclophosphamide (60 mg/kg). GVHD prophylaxis consisted of cyclosporine A and short-course methotrexate. Patients’ median age was 45 years (range, 15–64). Histologic PTCL subtypes included: PTCL not otherwise specified (n=12), ALCL (n=7), angioimmunoblastic (n=3), others subtypes (n=4). Twenty-two pts (84%) received transplant from HLA-identical sibling, 3 from haploidentical sibling and one from unrelated donor. The median time from diagnosis to transplantation was 17 months. Thirteen patients (50%) had failed a previous auto and the majority received at least 2 lines of chemotherapy before allo-SCT. Seven (27%) and 13 pts (50%) were in CR and PR at the time of allo-SCT, respectively. At median follow-up of 27 months (range, 8–73), 17 (65%) were alive (n=14 in CR) and 9 died (n=6 disease, n=3 toxicity). The estimated 3-year TRM was 13%. The estimated 5 year OS and PFS projections were 61% (95% CI, 41–81%) and 51% (95% CI, 30–72%), respectively. Relapses occurred in the first 6 months after allo-SCT and we did not observe differences in PFS between specified and unspecified variants. De-novo acute GVHD (II/IV) and chronic GVHD incidence were 28% and 24%, respectively. Eight patients received DLI, 6 for relapse, 1 pre-emptive, 1 for infection: 3 responded (n=1 CR, n=2 PR). Following DLIs, 4 patients developed GVHD with associated a clinical response. In conclusion, our data indicate: 1) long-term disease control was achieved in patients with an aggressive subtype of NHL; 2) although optimal therapeutic strategies for relapsed PTCL are yet to be defined, further prospective evaluation of allo-SCT is required.

Reduced Intensity Conditioning (RIC) with Cladribine, Busulfan and 4 Gy Total Body Irradiation (TBI) for Bone Marrow Transplantation (BMT) from an HLA-Matched Unrelated Donor (URD): A Prospective Multi-Institutional Clinical Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 5397-5397 ◽  
Author(s):  
Sung-Won Kim ◽  
Masayuki Hino ◽  
Kazuo Hatanaka ◽  
Yasunori Ueda ◽  
Ryuji Tanosaki ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Acute Gvhd ◽  
Chronic Gvhd ◽  
Survival Rates ◽  
Conditioning Regimen ◽  
High Response Rate ◽  
High Dose ◽  
Unrelated Donor ◽  
Grade Ii ◽  
Neutrophil Engraftment

Abstract [Background] We report the results of a prospective multi-institutional clinical trial of BMT from an HLA-matched URD following RIC. [Patients and Methods] The conditioning regimen included cladribine 0.11 mg/kg on day -8 to day -3, busulfan 4 mg/kg po on day -6 and day -5, and 4 Gy TBI on day -1. GVHD prophylaxis included cyclosporine and short-term methotrexate. Patients with hematologic diseases were eligible for this study if they were either older than 50 years or had significant medical contraindications to undergo conventional transplantation. Primary endpoints were neutrophil engraftment and achievement of complete donor-type chimerism (CD3+ cells >90%) on day 90. Regimen-related toxicities (RRT) between day -8 and day 28 were assessed by the NCI-CTC v2.0. A total of 27 patients were registered, but one patient was removed before transplant because of severe fungal infection. [Results] The median follow-up time was 722 days (range, 324–996) among survivors. The median age of patients was 56.5 years (36–64). Nine of the 26 patients (36%) had advanced-stage diseases and 3 (11%) had failed previous high-dose autologous or allogeneic transplantation. The diagnoses included AML (n=9), MDS/MPD (n=7), NHL (n=3), ALL (n=2), CML, ATLL, PCL, biphenotypic acute leukemia, and severe aplastic anemia (n=1). The median number of infused nucleated cells was 2.2 × 108/kg. After transplant, while one patient experienced engraftment failure and subsequent sepsis, and died on day 34, the remaining 25 patients achieved neutrophil engraftment (median, 17th day). Another patient was censored from the study due to grade 4 liver dysfunction, which developed on day 19, which left 24 patients for the chimerism analysis. The percentage of donor chimerism in CD3+ cells on days 28, 56 and 90 was, respectively, 88% (21/24), 100% (24/24) and 100% (24/24). Grade 3 RRT included arrhythmia (n=1), hypoxia (n=3), hyperbilirubinemia or hypertransaminasemia (n=7), stomatitis (n=18) and diarrhea (n=4), and grade 4 RRT included hypoxia (n=1) and hyperbilirubinemia (n=1). Acute GVHD of grade II, III and IV occurred in 27%, 27% and 4%, respectively. Ten of 15 evaluable patients (67%) had extensive chronic GVHD. CMV reactivation occurred in 23 patients (89%); 4 had histologically confirmed CMV colitis, 1 had CMV pneumonitis and 1 had CMV hepatitis, while the remaining patients had asymptomatic viremia. Of the 16 patients with measurable disease at the time of BMT, 15 achieved complete remission. The 100-day and 1-year cumulative incidences of non-relapse mortality (NRM) estimated by the Kaplan-Meier method were 20% and 54%, respectively. The cause of death that contributed to NRM was infection, with grade 0–I acute GVHD in 29% and grade II–IV acute GVHD in 71%. The 100-day and 1-year cumulative incidences of relapse were 8% and 35%, respectively, and the 1-year overall and progression-free survival rates were 42% and 30%, respectively. [Conclusions] The results support the feasibility of this procedure with a high response rate, but there is still a problem with the high NRM due to uncontrollable infections primarily associated with GVHD.

Randomized Phase II Trial Comparing Cyclosporine (CSP) and Tacrolimus (TAC) for Methotrexate (MTX)-Free Graft-Versus-Host Disease (GVHD) Prophylaxis after Allogeneic Transplantation from a Matched Related Donor (MRD) with a Reduced-Intensity Regimen Containing Cladribine and Busulfan

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1170-1170 ◽  
Author(s):  
Sung-Won Kim ◽  
Takahiro Fukuda ◽  
Shotaro Hagiwara ◽  
Tsunehiko Komatsu ◽  
Tetsuya Goto ◽  
...  
Keyword(s):  
Whole Blood ◽  
Acute Gvhd ◽  
Trough Level ◽  
Chronic Gvhd ◽  
Gvhd Prophylaxis ◽  
Starting Dose ◽  
Grade Ii ◽  
Reduced Intensity ◽  
Grade Iii ◽  
Neutrophil Engraftment

Abstract Background: Although GVHD prophylaxis without MTX might enhance a graft-versus-leukemia effect, no randomized controlled trial (RCT) of GVHD prophylaxis has investigated this possibility in a reduced-intensity stem cell transplantation (RIST) setting. Therefore, we conducted a prospective randomized trial to compare CSP and TAC without MTX as GVHD prophylaxis in RIST from a MRD. Methods: Patients with hematological malignancies in complete remission or with a chemosensitive status were eligible for this study if they were either older than 50 years or had significant medical contraindications for conventional transplantation. The primary endpoint was the incidence of grade II-IV acute GVHD on day 100. Regimen-related toxicities (RRT) between day −8 and day 28 were assessed by NCI-CTC ver 2.0. The conditioning regimen consisted of cladribine (0.11 mg/kg × 6 days) and oral busulfan (4 mg/kg × 2 days). All patients received unmanipulated G-CSF-mobilized peripheral blood stem cells from a MRD. CSP (starting dose 3 mg/kg/day, target whole blood conc. 250–350 ng/mL, target trough level 150–250 ng/mL) or TAC (starting dose 0.03 mg/kg/day, target whole blood conc. 10–20 ng/mL, target trough level 5–10 ng/mL) was given as GVHD prophylaxis from day −1. G-CSF was administered from day +6 until neutrophil engraftment. Results: Sixty-eight patients were enrolled between 2/2003 and 2/2008, but 3 were removed before transplant because of disease progression or infection. The diagnoses included lymphoma (n=27; 10 FL, 6 DLBCL, 6 PTCL and 5 HL), AML (n=14), MDS (n=12), MM (n=5), MPD (n=4) and ALL (n=3). The median age of the patients (56 y vs. 55 y) and the median number of CD34+ cells infused (3.7 ×106/kg vs. 3.1 ×106/kg) were similar in the CSP and TAC arms. The median day of neutrophil engraftment in both arms was day 11. The proportion of patients in the CSP or TAC arm who achieved complete chimerism in CD3+ cell fraction on days 28, 56 and 90 was, respectively, 61% vs. 48%, 80% vs. 76% and 80% vs. 97%. Grade 4 RRT was hepatic disease (n=1, CSP arm), and grade 3 RRT included cardiac (n=1, CSP), renal (n=1, CSP), hepatic (n=2, CSP), oral mucosal (n=1, TAC) and gastrointestinal disease (n=4, CSP vs. n=3, TAC). The incidence of grade II–IV acute GVHD in the TAC arm was significantly lower than that in the CSP arm (Table & Figure). The incidences of grade III–IV acute GVHD and extensive chronic GVHD were not significantly different between the two arms. The non-relapse mortality (NRM) in the TAC arm was significantly lower than that in the CSP arm. The causes of death that contributed to NRM were infection in 6 (CSP arm), GVHD in one (CSP), ARDS in one (TAC) and lung cancer in one (CSP). The relapse rate and relapse-related mortality were not significantly different between the two arms. The median follow-up for surviving patients was 1295 days (169–1954). The overall survival (OS) and progression-free survival (PFS) rates in the TAC arm tended to be higher than those in the CSP arm. Figure Figure Conclusions: A regimen with TAC alone without MTX as GVHD prophylaxis was associated with significantly lower rates of grade II–IV acute GVHD and NRM compared to a regimen with CSP alone after RIST from a MRD. OS and PFS with TAC alone tended to be higher than those with CSP alone. Nevertheless, these results must be considered with care due to the small number of patients, and the optimal use of both drugs is still under investigation. A large-scale RCT to identify suitable GVHD prophylaxis in the RIST setting is warranted. Table: Study Outcomes CSP arm (n=33) TAC arm (n=32) P P value was evaluated with logrank test or Wilcoxon test*. Grade II–IV acute GVHD 64% 39% 0.040 Grade III–IV acute GVHD 30% 23% N.S Extensive chronic GVHD 63% 61% N.S 1-year/3-year NRM 26%/38% 0%/5% 0.008 1-year/3-year relapse 35%/43% 25%/49% N.S 1-year/3-year relapse mortality 27%/33% 10%/42% N.S 1-year/3-year OS 57%/45% 90%/56% 0.135 (0.039*) 1-year/3-year PFS 48%/35% 75%/48% 0.120 (0.047*)

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