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

Background

During the last years Azacitidine (Aza) in combination with donor lymphocyte infusions (DLI), has proven to be a valuable treatment option for pts with relapse of MDS or AML after allo-SCT. Reasoning that Lenalidomide (Len) may further improve response rate and outcome due to its immunomodulatory and antileukemic properties, we initiated a prospective, multicenter, single-arm phase-II trial evaluating the combination of Aza, Len and DLI in patients with MDS, AML or CMML who had relapsed after allo-SCT. To acknowledge the risk of triggering GvHD with Len this study comprises two safety interim analyses. Results from the interim analysis I on the first 10 pts did not reveal a dose limiting toxicity (DLT) enabling an increase in the daily Len dosage from 2.5 mg to 5 mg in next cohort.

Design/Methods:

This planned second interim safety analysis (data lock March 2018) was performed in the next 10 pts who were treated with a daily dose of 5 mg Len for 21 days of a 28-day cycle in combination with up to 8 cycles Aza (75 mg/m²/d d1-7, every 28 days) and 3 DLI with increasing T cell dosages (0.5×10⁶ - 1.5×10⁷ cells/kg). In addition, we here present efficacy and safety results of all 24 pts included in this trial so far. The protocol demands a dose reduction of Len to 2.5 mg/day for the remaining 30 patients in case of DLT defined as steroid refractory aGvHD grade III/IV, cGvHD NHI score severe or any unexpected hematologic and non-hematological toxicity grade ≥III in more than 3 pts. In the absence of DLT in more than 3 pts the study will be continued with 5 mg/day.

Results:

Overall, 24 pts, who had suffered from molecular (54%) or hematological (46%) relapse of MDS (58%), AML (38%) or CMML (4%) after median of 260 days (range, 61-2659) following allo-SCT, were treated with a median of 5.5 cycles of Len per patient (range, 1 to 8; total no. of cycles 121; 83 cycles 2.5 mg/day, 38 cycles 5 mg/day). Concomitantly, pts received a median of 7 courses Aza (range 2-8) and 17 pts (71%) received at least one DLI (median: 2, range: 1-12).

No DLT was seen in the cohort of 10 pts treated with a Len dosage of 5mg/day. Furthermore, the increased Len dose did neither result in a higher frequency of dose reductions and treatment interruptions in this cohort, nor to a higher number of AE per cycle (2.5 mg/day: 5.45 AE vs. 5 mg/day: 3.15 AE).

We observed an overall response rate of 68% (CR 58%, PR 10%). CR rate was by trend higher in pts with molecular than in those with hematological relapse (67% vs. 43%) and all pts with CR remained in remission for a median of 183 days (range, 113-513) so far. Four pts (17%) developed acute GvHD (overall grade II, II, III, III) and 5 pts (21%) chronic GvHD (mild n=2; moderate n=2; severe n=1). While therapy-related CTC grade III/IV neutropenia (90%), thrombopenia (71%) or anemia (29%) occurred frequently, non-hematological adverse events (AE) >grade II were rare and mainly consisted of gastrointestinal toxicity, laboratory findings and infections.

Conclusion:

This 2^nd interim-analysis of the AZALena-trial shows, that an increase in the Len dosage to 5 mg/day is feasible, safe and not associated with excess GvHD and toxicity. Consequently, 5 mg/day Len will be used in the remaining pts who will be included in this trial (total no. of pts planned, n=50). Furthermore, results from all 24 pts suggest that the combination of Aza, Len and DLI has promising clinical activity and can induce durable responses in a substantial proportion of pts with MDS and AML who relapse after allo-SCT.