ALBERT

Description: 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.

Description: Background AlloBMT is a potentially curative treatment for multiple myeloma (MM). However, its effectiveness has been compromised by high transplant related mortality (TRM) and acute and/or chronic graft-versus host disease (GvHD). Our development of PTCy has reduced the incidence of GvHD allowing safe and effective related haploidentical alloBMT. PTCy promotes tolerance in both alloreactive host and donor T cells, leading to suppression of both graft rejection and GVHD after alloBMT. Patients and Methods As part of an IRB-approved study we performed a retrospective analysis on all patients with MM who underwent alloBMT followed by PTCy. A total of 39 patients who were transplanted between 2003 and 2011 were identified. All patients received 2 doses of PTCy 50mg/kg on days 3 and 4 after alloBMT. High risk MM was defined as having any one of the following: del(13q) by cytogenetics or t(4;14), t(14;16), t(14;20), -17p ,+1q21 on FISH/cytogenetics. International Staging System (ISS) stage was based on beta2 microglobulin and albumin at diagnosis of symptomatic MM. The definitions of progression, stable disease and response were as per the International Myeloma Working Group criteria. Survival probability was determined using Kaplan-Meier method and differences assessed with the log-rank test. Cox regression was used to model prognostic factors with respect to progression-free (PFS) and overall survival (OS) rates. Results The median follow-up for living patients was 80 months (22-115). The minimum follow up was 23 months. The median age at BMT was 54 (range 37-70). 30 patients (77%) received a transplant from a matched sibling donor. Of the remaining 9 patients, 7 (18%) received a transplant from a haploidentical donor and 2 (5%) from a matched unrelated donor. 28 patients (72%) were in 〉 PR at the time of alloBMT. Only 1 patient (3%) was in a CR prior to alloBMT. Thirty patients (77%) received reduced intensity conditioning and the remaining 9 patients (23%) received myeloablative conditioning. 28 patients (72%) received unmanipulated bone marrow, while remaining 11 patients (28%) received mobilized peripheral blood cells. The median time between diagnosis and alloBMT was 10.6 months (4.1-178.7). Cytogenetics and FISH for evaluating high risk MM were available for 26 patients (66.6%) and of those 15 patients (58%) had high risk features. 28 patients (72%) were evaluable for ISS at diagnosis and of those 13 patients (46%) had ISS III at diagnosis. 36 patients (92%) had been treated with either bortezomib based or immunomodulatory (Imid) based therapy prior to alloBMT. 7 patients (18%) had received an autologous transplant prior to alloBMT. 20 patients (51%) are alive after a median follow up of 〉 6 years after alloBMT. Only 1 (2.5%) patient died from complications related to alloBMT. At last follow up, 6 patients (15%) are in sustained first complete remission after alloBMT. Of the 9 patients who received myeloablative prep, 6 are alive and 3 are in sustained CR. At 6 months following alloBMT, 12 patients (31%) were in a deeper response compared to their pre-transplant status. 15 patients (38%) developed 〉 grade 2 acute GvHD at a median of 1.5 (range 0.6-4.5) months. Only 3 patients (8%) developed grade 3 acute GvHD and there was no grade 4 acute GVHD. 14 (36%) patients received systemic treatment for acute GvHD. 5 (13%) patients developed chronic GvHD. The median OS was 96 months, and the median PFS was 14 months (95% CI 6.2-32.8). Chronic GvHD was significantly associated with PFS, with a median PFS of 90 months in patients who developed cGvHD compared to 11 months in patients who did not (hazard ratio = 0.3, 95% CI 0.07-1.25). The major cause of death was disease progression. Conclusion The use of PTCy led to a very low TRM in MM, including with related haploidentical donors. Although only a minority of patients maintained long-term PFS, the prolonged OS allows incorporation of novel post-alloBMT strategies to improve disease control. Disclosures: Off Label Use: Outcomes of Allogeneic Blood Or Marrow Transplantation (AlloBMT) In Multiple Myeloma With Post-Transplantation Cyclophosphamide (PTCy).

Description: Because of its potent immunosuppressive yet stem cell–sparing activity, high-dose cyclophosphamide was tested as sole prophylaxis of graft-versus-host disease (GVHD) after myeloablative allogeneic bone marrow transplantation (alloBMT). We treated 117 patients (median age, 50 years; range, 21-66 years) with advanced hematologic malignancies; 78 had human leukocyte antigen (HLA)–matched related donors and 39 had HLA-matched unrelated donors. All patients received conventional myeloablation with busulfan/cyclophosphamide (BuCy) and T cell–replete bone marrow followed by 50 mg/kg/d of cyclophosphamide on days 3 and 4 after transplantation. The incidences of acute grades II through IV and grades III through IV GVHD for all patients were 43% and 10%, respectively. The nonrelapse mortality at day 100 and 2 years after transplantation were 9% and 17%, respectively. The actuarial overall survival and event-free survivals at 2 years after transplantation were 55% and 39%, respectively, for all patients and 63% and 54%, respectively, for patients who underwent transplantation while in remission. With a median follow-up of 26.3 months among surviving patients, the cumulative incidence of chronic GVHD is 10%. These results suggest that high-dose posttransplantation cyclophosphamide is an effective single-agent prophylaxis of acute and chronic GVHD after BuCy conditioning and HLA-matched BMT (clinicaltrials.gov no. NCT00134017).

Description: Key Points Posttransplantation cyclophosphamide is effective as sole GVHD prophylaxis for myeloablative HLA-matched–related or –unrelated BMT. Despite low chronic GVHD with PTCy, relapse and survival are comparable with outcomes reported using other GVHD prophylactic approaches.

Description: Abstract 840 Significance of Missing Inhibitory KIR Ligands in Nonmyeloablative, HLA-Haploidentical (Haplo) BMT with Posttransplantation High-Dose Cyclophosphamide (PT/Cy). Yvette L. Kasamon 1, Leo Luznik1, Mary S. Leffell1, Hua-Ling Tsai1, Heather J. Symons1, Javier Bolaños-Meade1, Gary Rosner1, Lawrence E. Morris2, Pamela A. Crilley3, Richard J. Jones1 and Ephraim J. Fuchs1, (1)Johns Hopkins University, Baltimore, MD, (2)Northside Blood and Marrow Transplant Program, Atlanta, GA, (3)Hahnemann University Hospital, Philadelphia, PA Introduction: NK cells can influence haplo BMT outcomes including risks of relapse and GVHD. Our group previously reported that, in allogeneic BMT for hematologic malignancies that incorporates PT/Cy, donor-recipient iKIR (inhibitory killer-cell immunoglobulin-like receptor) gene mismatches and having a KIR haplotype B donor were associated with improved outcomes (BBMT 2010;16:533). Because the reported impact of NK cell alloreactivity models in haplo BMT has been variable and some models are relevant to donor selection, we expanded our analysis of iKIR ligand status in this transplantation platform. Patients and methods: Outcomes of 212 uniformly treated patients (pts) enrolled on two similar clinical trials of related-donor, haplo BMT were retrospectively analyzed. Planned treatment consisted of fludarabine (30 mg/m2 IV on days −6 to −2), Cy (14.5 mg/kg IV on days −6 and −5), total body irradiation (200 cGy on day −1), and non-T-cell depleted bone marrow infusion. GVHD prophylaxis consisted of high-dose Cy (50 mg/kg IV on days 3 and 4), mycophenolate mofetil on days 5–35, and tacrolimus on days 5–180 without taper, with filgrastim begun on day 5. All pts (median age 51, range 1–73) had poor-risk hematologic malignancies; 60 (28%) had prior BMT. Diagnoses were Hodgkin lymphoma (31 pts), NHL (69), CLL (21), multiple myeloma (6), acute leukemia or lymphoblastic lymphoma (62), MDS (9), CML (9), CMML (4), PV (1). Missing ligands (ML; defined as absence in the recipient of one or more HLA ligands for iKIRs) and donor/recipient iKIR ligand incompatibility (LI; defined as presence of an iKIR ligand in the donor that is absent in the recipient) were determined using high-resolution HLA typing of class I alleles. For study purposes, HLA-A*2301, A*2402, and A*3201 were included in the Bw4 serologic group and effects attributable to HLA-A3 and A11 ligand groups were excluded. Results: With a median 2.9 year follow-up (range, 0.3–7 years) in pts without events, the actuarial 2-year progression-free survival (PFS) was 34%. On competing-risk analysis, cumulative incidences of grade II–IV acute GVHD and chronic GVHD were 28% and 14%, respectively; 1-year cumulative incidences of relapse and nonrelapse mortality (NRM) were 42% and 14%. Baseline characteristics in pts with ML (157 pts, of whom 76 had LI) and without ML were similar. On univariate analysis, pts with LI had no significant difference in PFS (figure A), grade II–IV acute GVHD, relapse or NRM compared to those without LI. In contrast, as compared to no ML, the presence of ML was associated with a statistically significantly improved PFS on univariate analysis (hazard ratio [HR] = 0.68, p = 0.03; figure B). This association was not identified in our previous analysis, potentially due to underpowering or inclusion of pts receiving one dose of PT/Cy. No statistically significant difference was detected according to the presence or absence of ML in the cumulative incidences of acute GVHD, relapse, or NRM, although presence of ML was associated with a tendency toward lower NRM risk (HR = 0.61, p = 0.17). On multivariate analysis, the presence of ML was found to be independently associated with a significant improvement in PFS (HR = 0.66, p = 0.03). This multivariate model also confirmed our previous observation (BBMT 2010;16:482) that greater donor-recipient HLA disparity was not detrimental to PFS (HR = 0.57, p = 0.04 for 3–4 antigen mismatches versus fewer at HLA-A, B, C, and DRB1 combined). We are currently investigating the impact of KIR haplotypes in this setting with the goal of optimizing donor selection. Conclusion: The presence of ML may be beneficial in haplo BMT with postgrafting immunosuppression that includes high-dose Cy. Further studies are needed to confirm and define the mechanisms of this effect. Our findings do not support selection of donors on the basis of LI in this transplantation platform. Disclosures: No relevant conflicts of interest to declare.

Description: Pentostatin, one of the purine nucleoside analogues, is known to decrease lymphocyte number and function. It has been successfully used to treat steroid refractory acute graft-versus-host disease (GVHD). We are currently investigating pentostatin for refractory chronic GVHD (cGVHD). Fifty-two patients were enrolled and 42 are assessable for response. All patients presented here failed at least two immunosuppressive regimens including steroids at a dose equivalent to at least 1 mg/kg/day prednisone for one month. The treatment protocol consists of giving pentostatin 4 mg/m2/dose IV every 2 weeks for 6 months. Patients with improving disease were permitted to continue pentostatin therapy at a 3 to 4 week interval. To reduce the risk of infection, steroids are tapered early in all patients and they received prophylactic antibiotics (antibiotics, fluconazole, sulfamethoxazole/trimethoprim and valcyclovir). At the end of 3 months, patients with stable or improving cGVHD are weaned off their other medications but maintained on a calcineurin inhibitor. Pentostatin is stopped at 6 months if complete response (CR) is achieved or continued if partial response (PR). Patients are followed for improvement in the skin/fascia, mouth, and liver. The severity of GVHD is scored for each system on a scale from 0 to 4. Complete response is resolution of symptoms (irreversible changes [such as long standing contractures] due to cGVHD were not required to improve to score a CR if all other changes improved); partial response is at least a 1 point improvement in this score system. Mixed response is improvement in 1 system but worsening in another. Fifty-two patients have received a median of 8.5 doses (range 1–34). Median age of the cohort is 40.5 years (range 5 to 67). Diagnoses include AML/MDS (6), ALL (7), hemoglobinopathy (2), aplastic anemia (3), CML (16), myelofibrosis (1), NHL (8), myeloma (4), paroxysmal nocturnal hemoglobinuria (3), CLL (1), and lymphohistiocytosis (1). Graft source included 20 patients: 6/6 sibling BMT; 10 patients: 6/6 sibling PBSCT; 10 patients: MUD BMT; 6 patients 5/6 MUD BMT; 2 patients: 6/6 MUD PBSCT; 1 patient 5/6 sibling BMT; 1 patient: 6/6 sibling BMT followed by DLI; 1 patient 5/6 BMT from a child; and 1 patient, unknown. Most patients were on calcineurin inhibitor, eleven on prednisone, seven on MMF, one on rapamycin, and one was receiving ECP at entry on the study. In the 42 assessable patients, 5 patients attained a CR, 16 a PR, 5 a mixed response (improvement in one organ with deterioration in another one), and 16 patients have progressed. The overall response rate is 50%. Therapy has been well-tolerated with infections being the main concern. Mucormycosis, pneumonia, disseminated fungal infection, fungal pneumonia, progressive disease were the causes of death of the 15 patients who have died and only infections could be related to the study drug. The results suggest that pentostatin has activity in the treatment of cGVHD and may be especially beneficial in children and adolescents as the 5 CR were in this group.

Description: Bcl-2 acts as an important regulator of the mitochondrial pathway of apoptosis and promotes resistance of MM cells to chemotherapy. The Bcl-2 antisense oligonucleotide G3139 specifically targets Bcl-2 and may enhance the anti-tumor efficacy of Dex and Thal. In this trial G3139 was administered at 5 mg to the first 3 Pts and then 7 mg/kg/d by IVCI for 7d of 21d cycle. On day 4, Pts started Dex 40 mg daily for 4 d and Thal 100-400 mg as tolerated. After 3 cycles, responding Pts continued G3139 on a 5-week cycle with Dex 20 mg x 4d and Thal at the tolerated daily dose for up to 1 yr with an optional second yr for responding Pts. Thirty-three Pts treated to date had the following characteristics: median age 60 yrs (range: 28- 76), 22 males; 16 Pts had complex karyotypes; 14 Pts had B2M 〉 2.5 g/dl; LDH 〉1.5 normal in 7 Pts; Cr 〉1.5 mg/dl in 6 Pts; platelets

Description: 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.

Description: 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

Description: On behalf of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) GVHD remains a major limitation of allogeneic hematopoietic cell transplantation (HCT). Steroids are the standard initial therapy yet prior data suggested only 35% complete response (CR) at day 28. We report the results of a randomized, four-arm, phase II trial designed to identify the most promising agent(s) for combination with steroids as initial therapy for aGVHD. Between August, 2005 and March, 2008, 180 pts with newly diagnosed aGVHD were randomized to receive steroids (2 mg/kg/day methylprednisolone) plus either: Etanercept, MMF, Denileukin Diftitox or Pentostatin. Pts who received MMF as GVHD prophylaxis in the preceding 7 days were randomized between the 3 non-MMF arms. The primary objective was to estimate the CR rate at day 28 for each of the four agents and evaluate secondary outcomes pertinent to the best agent for testing in a planned followup phase III trial vs steroids alone. PATIENTS AND RESULTS: Median age was 50 yrs (range, 7.5–69.9) with 96% 〉18 yrs; 39% had AML and 63% were male. The graft was peripheral blood (PB) in 61%, bone marrow (BM) in 25% and cord blood (CB) in 14% of pts. HCT was performed with myeloablative conditioning and/or unrelated donor grafts in 66% and 53%, respectively. Forty-four pts (24%) received MMF as aGVHD prophylaxis and were randomized to a non-MMF arm. At enrollment, 68% of patients had grade I-II aGVHD; 32% had grade III/IV. 53% of pts had visceral organ involvement at the time of enrollment. The treatment arms were balanced except CB grafts were more common in the Denileukin Diftitox arm (26%, p=0.006); PB were more common in the Etanercept arm (78%, p=0.006); and the MMF arm had more myeloablative HCT (82%, p=0.04). The proportion of CR at day 28 were: Etanercept (26%), MMF (60%), Denileukin Diftitox (53%) and Pentostatin (38%), and day 56 CR+PR rates were 59%, 78%, 68%, and 71%, respectively. 6 month chronic GVHD (cGVHD) incidence was: Etanercept (21%), MMF (25%), Denileukin Diftititox (29%), and Pentostatin (24%). Overall survival (OS) at 6 months was Etanercept (59%), MMF (71%), Denileukin Diftitox (63%), and Pentostatin (55%), respectively. After excluding pts who received MMF prophylaxis, the MMF arm still had the highest day 28 CR rate and OS. Overall toxicities and post-randomization infections were less frequent in pts randomized to MMF and Etanercept. CONCLUSIONS: These efficacy and toxicity data, particularly response, survival, cGVHD, and infections, suggest MMF + steroids to be the most promising regimen to compare against steroids alone in a randomized Phase III trial. Treatment Arm Outcome Etanercept (N=46) MMF (N=45) Denileukin Diftitox (N=47) Pentostatin (N=42) Day 28 CR 12 (26%) Skin: 12/36 (33%) 27 (60%) Skin: 21/35 (60%) 25 (53%) Skin: 17/35 (49%) 16 (38%) Skin: 14/34 (41%) L.G.I.: 4/12 (33%) L.G.I.: 12/18 (67%) L.G.I.: 5/14 (36%) L.G.I.: 7/17 (41%) U.G.I.: 5/10 (50%) U.G.I.: 11/12 (92%) U.G.I.:10/14 (71%) U.G.I.: 8/13 (62%) Liver: 2/6 (33%) Liver: 5/7 (71%) Liver: 3/7 (43%) Liver: 2/5 (40%) Day 28 CR (excl. prior MMF ) 9 (28%) 27 (60%) 15 (48%) 11 (39%) Day 28 CR/PR 22 (48%) 35 (78%) 28 (60%) 26 (62%) Day 56 CR/PR 27 (59%) 35 (78%) 32 (68%) 30 (71%) Day 56Treatment Failures 12 (26%) 4 (9%) 12 (26%) 13 (31%) OS Post-Randomization at 6 months 59% (95% CI: 43%–72%) 71% (95% CI: 54%–82%) 63% (95% CI: 47%–76%) 55% (95% CI: 38%–69%) OS Post-Randomization at 6 months (excl. prior MMF) 70% (95% CI: 51%–83%) 71% (95% CI: 54%–82%) 61% (95% CI: 40%–76%) 54% (95% CI: 33%–71%) Cum Incidence of Initial D/C of steroids at 9 months 34% (95 % CI: 20%–48%) 31% (95% CI: 17%–45%) 20% (95% CI: 8%–32%) 20% (95% CI: 8%–33%) Cum Incidence Day 56 Grade 3–5 Toxicity (%) 76% (95% CI: 63%–88%) 80% (95% CI: 67%–92%) 76% 95% CI: 64%–89%) 67% (95% CI: 52%–81%) Cum Incidence Severe/ Life Threatening/Fatal Infections at Day 270 47% (95% CI: 32%–62%) 44% (95% CI: 29%–59%) 58% (95% CI: 43%–72%) 56% (95% CI: 40%–71%) Cum Incidence of acute GVHD Flare after CR at Day 90 36% (95% CI: 21%–50%) 28% (95% CI: 14%–41%) 35% (95% CI: 21%–49%) 36% (95% CI: 21%–51%) Cum Incidence of cGVHD at Day 180 21% (95% CI: 9%–33%) 25% (95% CI: 11%–39%) 29% (95% CI: 15%–43%) 24% (95% CI: 10%–38%) Cum Incidence of Relapse at Day 180 14% (95% CI: 3%–24%) 10% (95% CI: 1%–19%) 9% (95% CI: 1%–19%) 13% (95% CI: 2%–24%)