Treatment of MDS, AML and CMML Relapse after Allogeneic Blood Stem Cell Transplantation with Azacitidine, Lenalidomide and Donor Lymphocyte Infusions - Final Results of the Prospective Azalena-Trial (NCT02472691)

Background Azacitidine (Aza) in combination with donor lymphocyte infusions (DLI) is an established treatment option for pts with relapse of myeloid malignancies after allo-SCT. Accounting for its immunomodulatory and anti-leukemic properties, we considered Lenalidomide (Len) to be a synergistic partner for Aza and DLI that may further improve response rate and outcome. To investigate the tolerability and efficacy of the combination of Aza, Len and DLI as first salvage therapy for relapsed MDS, AML and CMML after allo-SCT we performed a prospective, multicenter, single-arm phase-II trial. Results from two safety interim analyses have previously been reported. Here, we report the final results from this investigator-initiated trial. Design/Methods: Patients with relapse of MDS, AML and CMML after first allo-SCT were eligible. Envisaged treatment according to the protocol consisted of up to 8 cycles Aza (75 mg/m 2/d d1-7, every 28 days) and up to 3 DLI with increasing T cell dosages (0.5×10 6 - 1.5×10 7 cells/kg). Len was administered concomitantly for 21 days of a 28-day cycle. Following a positive first interim safety analysis in 10 patients the daily dose of Len was increased from 2.5 to 5mg. The primary endpoint of the study was safety, while secondary efficacy endpoints included response type and rates, time to and duration of response and overall survival. Results: Overall, 50 pts with molecular (n=29, 58%) or hematological (n=21, 42%) relapse of MDS (n=24, 48%), AML (n=23, 46%) or CMML (n=3, 6%) detected after median of 233 days (range, 98 to 2659) after allo-SCT were included. Fourteen patients (28%) received Len at a daily dosage of 2.5 mg and 36 patients (72%) at a daily dosage of 5 mg with no DLTs observed in the interim analyses. Median number of Len cycles per patient was 7 (range, 1 to 8) with no differences between the two dose levels. Concomitantly, 34 pts (68%) received at least one DLI (median: 3, range: 1-11). Overall response rate (ORR) during treatment was 56% (CR n=25, 50%, PR n=3, 6%). ORR and CR rates did not differ between Len dose levels. Of interest, CR rate did not differ between pts treated at the stage of molecular relapse and those initiated at hematological relapse (52% vs. 48%). Median time to CR was 112 days (range 1-286) corresponding to 4 cycles (range 1 to 8). At the time of data lock, 20 patients (80%) were still in CR without additional therapy for a median of 15 months, while 5 patients (20%) had relapsed again after a median of 8 months. With a median follow-up of 20 months median OS was 21 months and 1-year OS rate 65%. While therapy-related CTC grade III/IV neutropenia (92%), thrombopenia (80%) or anemia (36%) occurred frequently, drug-related non-hematological adverse events (AE) >grade II were rare and mainly consisted of gastrointestinal toxicity (6%), laboratory findings (28%) and infections (22%). Twenty-three pts (46%) developed acute GvHD including 5 patients (10%) with grade III/IV aGvHD, and 26 pts (52%) chronic GvHD (mild n=10; moderate n=11; severe n=5). During the study period, 3 secondary malignancies (squamous cell, basal cell and vulvar carcinoma) occurred. There were no therapy related deaths. Conclusion: Len up to a dosage to 5 mg/day can be safely added to the combination of AZA and DLI without excess of GvHD and toxicity. Furthermore, these data suggest that the combination of Aza, Len and DLI has promising clinical activity for relapse of myeloid malignancies after allo-SCT and is able to induce durable responses and survival in a substantial proportion of pts. Disclosures Schroeder: Celgene: Honoraria, Other: Travel support, Research Funding. Stelljes: Kite/Gilead: Consultancy, Speakers Bureau; MSD: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene/BMS: Consultancy, Speakers Bureau; Medac: Speakers Bureau; Amgen: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Holtick: Celgene: Honoraria; Sanofi: Honoraria. Germing: Janssen: Honoraria; Bristol-Myers Squibb: Honoraria, Other: advisory activity, Research Funding; Jazz Pharmaceuticals: Honoraria; Celgene: Honoraria; Novartis: Honoraria, Research Funding. Kröger: AOP Pharma: Honoraria; Celgene: Honoraria, Research Funding; Gilead/Kite: Honoraria; Jazz: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Novartis: Honoraria; Riemser: Honoraria, Research Funding; Sanofi: Honoraria. Kobbe: Celgene: Research Funding. OffLabel Disclosure: Lenalidomide is not licensed for AML, CMML and advanced MDS except for MDS with isolated del5q

Donor lymphocyte infusions after first allogeneic hematopoietic stem-cell transplantation in adults with acute myeloid leukemia: a single-center landmark analysis

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is potentially curative for acute myeloid leukemia (AML). The inherent graft-versus-leukemia activity (GvL) may be optimized by donor lymphocyte infusions (DLI). Here we present our single-center experience of DLI use patterns and effectiveness, based on 342 consecutive adult patients receiving a first allo-HSCT for AML between 2009 and 2017. The median age at transplantation was 57 years (range 19–79), and the pre-transplant status was active disease in 58% and complete remission (CR) in 42% of cases. In a combined landmark analysis, patients in CR on day +30 and alive on day +100 were included. In this cohort (n=292), 93 patients received cryopreserved aliquots of peripheral blood-derived grafts for DLI (32%) and median survival was 55.7 months (2-year/5-year probability: 62%/49%). Median survival for patients receiving a first dose of DLI “preemptively,” in the absence of relapse and guided by risk marker monitoring (preDLI; n=42), or only after hematological relapse (relDLI; n=51) was 40.9 months (2-year/5-year: 64%/43%) vs 10.4 months (2-year/5-year: 26%/10%), respectively. Survival was inferior when preDLI was initiated at a time of genetic risk marker detection vs mixed chimerism or clinical risk only. Time to first-dose preDLI vs time to first-dose relDLI was similar, suggesting that early warning and intrinsically lower dynamics of AML recurrence may contribute to effectiveness of preDLI-modified GvL activity. Future refinements of the preemptive DLI concept will benefit from collaborative efforts to diagnose measurable residual disease more reliably across the heterogeneous genomic spectrum of AML.

Comparison of Outcomes of Donor Lymphocyte Infusions with or without Lenalidomide in Patients with Hematological Malignancies Post Allogeneic Transplant

Introduction Outcomes of patients (pts) with relapsed hematological malignancies post allogeneic stem cell transplant (ASCT) are dismal. Donor lymphocyte infusion (DLI) is one of the treatment options; however outcomes with DLI are also poor especially in acute leukemias. Addition of immunomodulatory drugs to DLI may augment graft-versus-leukemia effect and may improve outcomes. Lenalidomide (len) is an immunomodulatory drug and has several effects on the immune system. Addition of len to DLI has been variably practiced at our centre. In this study, we retrospectively compare the outcomes of DLI with or without len. Methods All pts who received DLI from January 2010 to January 2020 were included in this retrospective analysis. No immunosuppressant prophylaxis was administered and ongoing immunosuppression (if any) was stopped prior to DLI. DLI was defined as therapeutic if it was given for hematological relapse (with or without cytoreductive chemotherapy); pre-emptive if there was cytogenetic / flow cytometric / molecular relapse or slipping chimerism. DLI was prophylactic if it was given to prevent a relapse in the absence of any of the above features. Len was given on a continuous schedule at a starting dose of 2.5-25 mg/day. Len was started along with 1st or subsequent DLI as per discretion of treating clinician. For the purpose of this study, pts were divided into two groups - those who received DLI alone (no len group) versus those who received DLI with len (len group). In both groups, cytoreductive chemotherapy was given for some pts with hematological relapse at discretion of treating physician. Event free and overall survival were calculated from the date of 1st DLI. Event was defined as hematological relapse / progression or death. Complete response (CR) was defined as attainment of full donor chimerism in those with chimerism slippage; attainment of cytogenetic/ flow/molecular negativity in those with any of these positive at time of DLI; attainment of morphological remission in those with hematologic relapse. The primary objective was to compare the overall survival (OS) in no len group versus len group. Secondary endpoints were event free survival (EFS), CR rates, grade II-IV acute GVHD, len related toxicities and therapy related mortality. Patient and donor age, gender, diagnosis, type of ASCT, disease risk index (DRI), time to relapse (or slipping chimerism), type of DLI, pre-DLI morphological disease status, and HLA-A*24 or B*40 in pts were evaluated as factors affecting outcomes with or without len. (HLA-A*24 and B*40 were selected because of prior data from our institute showing benefit of len in pts with AML who had these alleles.) Statistical analysis was done using standard methods. Survival was assessed by Kaplan Meier method. All p values were 2 sided; p value of <0.05 was considered significant. Results Total 61 pts received DLI. Table 1 shows the baseline characteristics, transplant details, & details of DLI & len. The 2 groups were comparable in all aspects except for younger age in len group. Median OS (Fig 1a) and EFS (Fig 1b) were not different in len vs no len group (11 vs 8 months, p=0.66 and 6 vs 2 months, p=0.42). Len was not associated with improvement in OS in pts with myeloid malignancies (n=47, median OS 8 vs 3 months, p=0.80) or in AML pts (n=25, median OS 9 months vs 2 months, p=0.47). Among pts with HLA-A*24 or B*40 (n=26), there was an improvement in OS (median not reached vs 8 months, 4 year OS 62% vs 32%, p=0.1) (Fig 1c) and EFS (median 9 vs 1 month, 4 year EFS 50% vs 22%, p=0.1) (Fig 1d) with len. In this subgroup, hazard ratio for both OS and EFS was 0.47 (Fig 1e and 1f respectively). 49 pts had measurable disease / slipped chimerism at DLI. Among these, CR rate was not different between the 2 groups (41% vs 40% with len, p=0.9). Median time to CR was similar (31 vs 38 days, p= 0.36). Post DLI acute grade II-IV GVHD developed in 8 (19%) in no len group vs 4 (22%) in len group respectively, p=0.75. Median duration of len was 36 days. In the len group, 17 discontinued len; 8 (44%) due to disease progression, 5 (28%) due to GVHD, 3 (17%) due to cytopenias and 1 due to unrelated cause. Death due to DLI related GVHD was seen in 1 (6%) and 4 (9%) in len and no len group respectively, p=0.6. Conclusions There was no difference in outcomes in patients who received DLI with or without len. However, in subset of patients who had HLA*24 or B*40, an improvement in OS and EFS was seen. The relation of above HLA alleles with len needs further exploration. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: This abstract discusses the use of lenalidomide as an immunomodulatory drug to enhance the graft versus leukemia effect of donor lymphocyte infusions for hematological malignancies post allogeneic transplant.