This study focuses on patients with high risk hematologic malignancies, i.e. those with leukemia not in remission, lymphoma not achieving at least a partial response undergoing allo-SCT. The primary objective of the clinical trial is to assess progression-free survival (PFS) at 2 years after SCT for high-risk hematologic malignancies receiving T-cell depleted (TCD) grafts followed by an escalating dose regimen (EDR) of prophylactic DLI compared to historical controls not receiving DLI.

Aim 1: To determine if prophylactic DLI will prevent disease relapse in high risk patients with hematologic malignancies after RIC TCD SCT with acceptable GVHD in a single arm Phase II clinical trial. A single arm Phase II trial will be conducted to determine whether the prophylactic DLI after TCD SCT will improve the 2 year DFS with tolerable incidence of GVHD.

Aim 2: To determine whether prophylactic DLI will accelerate the donor-derived immune reconstitution and eliminate MRD in high risk patients with hematologic malignancies after RIC TCD SCT. We hypothesize that prophylactic DLI will enhance the donor-derived immune reconstitution to prevent opportunistic infections; will help to eliminate MRD to prevent relapse.

During the support period of the grant, 17 patients were enrolled on the study since it received IRB approval on 3/26/13 (three patients with matched unrelated donors were enrolled before the NMDP IRB approval of the study, and thus were later removed from the study). One patient died early from complication of SCT, 2 patients had early GVHD before early immunosuppression; and one patient developed GVHD with early immunosuppression withdrawal. 6 patients tolerated early immunosuppression withdrawal and 4 patients received first dose of DLI, 2 patients were scheduled to receive first pDLI in 2 weeks; So far, only one patients developed GVHD after second dose prophylactic dose DLI (the donor is 9/10 matched related donor). Another three patients are still in their early phase of transplantation. Four more patients have been scheduled to have transplant on this study.

The enrollment on the study is very fast, since it is the only study we have for high risk patients with hematologic malignancies undergoing stem cell transplant in our center at this time. We will have interim analysis after 10^th patient on the study finished all the planned DLI. We are optimistic that at least 50% of participant will get at least one dose prophylactic DLI. Correlative study samples were collected during the treatment course, which will be analyzed during the second year period of the grant.

In order to have better historical data for this prophylactic DLI study, we performed a retrospective analysis to examine pre-HCT variables for patients with high risk AML or MDS who underwent reduced intensity conditioning (RIC) for T-cell depleted HCT from 2002-2012. Our primary objective was to critically assess which variables may serve as prognostic factors that predispose patients to better or worse clinical outcomes. Inclusion criteria for our study included adult patients: (a) who received RIC; (b) undergoing first allogeneic HCT without previous HCT; (c) with high risk disease status; and, (d) who are not in remission at time of HCT. Based on previous studies, pre-HCT variables considered for analysis include: C-reactive protein, number of courses of induction chemotherapy, number of previous relapses, time of relapse after induction therapy, age at relapse post induction therapy, presence of molecular FLT-ITD mutations, bone marrow blast percentage at HCT, neutrophil nadir, cytogenetic profiles, and ECOG performance status. Using univariate and multivariate analysis, we aim to show how different pre-HCT variables correlate with post-HCT outcomes: namely, incidence of graft versus host disease, progression free survival, and overall survival.

127 patients were evaluable based on inclusion criteria; 96 AML (disease status: 60 PIF/Refractory, 36 relapse); 31 MDS (disease status: 12 RAEB-1, 10 RAEB-2, 5 CMML, 4 active disease/progressing); median age was 56 years (range 18-71); sex: 78 M, 49 F. 18 patients had low risk, 52 had intermediate risk, and 49 had high risk cytogenetic profiles at diagnosis. 8 patients had an inadequate sample or did not have cytogenetic analysis. Of the 36 patients who relapsed prior to HCT, only 3 patients relapsed after > 12mo of induction and 14 patients relapsed between 6 and 12 months, but 19 patients relapsed after < 6mo of induction; median age at first relapse was 53 years (range 25-68); 31 patients had only 1 relapse while 5 patients had multiple relapses. 9 of 60 patients evaluated showed a FLT3 ITD mutation. 32 of 45 evaluable patients had high C-reactive protein levels at study entry (>5mg/L). Nearly all patients had ECOG performance status of 0 to 1.

2 patients did not have pre-HCT induction chemotherapy, 46 patients had one, 47 patients had two, and 32 patients had three or more courses; 79 patients had pre-HCT BM blast percentage < 10%, 16 had between 10-20%, 31 had > 20%; 70 patients had pre-HCT BM cellularity < 20%, 56 had > 20%; One patient’s pre-HCT BM was inadequate for analysis. Graft sources included: 108 PBSC (64 matched related, 44 matched unrelated), and 19 haploidentical PBSC plus a cord blood unit.

Right now, all the data fields have been filled, and we expect that with further statistical analysis of our results, we can identify which variables predict favorable or unfavorable clinical outcomes prior to HCT. This provides us with the potential to optimize therapeutic strategies and identify subgroups of high-risk patients with AML or MDS who are more likely to benefit from HCT. By detecting the prognostic factors that correlate with post-HCT outcomes, we advance our understanding of how patients with hematologic malignancies vary in their response to HCT.

The statistics analysis is in progress, and we hope we could present the results soon at a national meeting, such as ASCO next year. Many of these patients had research study samples available; we are also in the process of obtaining samples to check WT1 PCR level before and after allo-SCT to see if WT1 MRD before and after SCT will predict relapse and survival.