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

Background:

Azacitidine (Aza) and donor lymphocyte infusions have become a standard treatment of myeloid malignancies relapsing after allo-SCT. Studies so far showed response rates ranging from 10% to 75% following treatment with Aza with or without donor lymphocyte infusions (DLI) and particularly patients (pts) with MDS and AML with low disease burden seem to benefit most. Lenalidomide (Len), due to its immunomodulatory and antileukemic properties, may act synergistically with Aza and DLI.

Design/Methods:

We initiated a prospective, multicenter, single-arm phase-II trial combining Aza, Len and DLI in patients with MDS, AML or CMML as first salvage treatment for relapse after allo-SCT. Pts were envisaged to receive up to 8 cycles Aza (75 mg/m²/d d1-7, every 28 days) and 3 DLI with increasing dosages (0.5×10⁶ - 1.5×10⁷ cells/kg) after cycles 4, 6 and 8. Concomitantly, eight cycles of Len were administered with a daily dose of 2.5 mg for the first 21 days of a 28 day-cycle each.

To cope with the potential risk of GvHD induction by Len after allo-SCT the primary endpoint is safety and the study incorporates two interim analyses scheduled after the first 10 and 20 patients respectively. If no dose limiting toxicity (DLT) defined as steroid refractory acute GvHD grade III/IV, chronic GvHD NIH score severe or any unexpected hematologic and non-hematological toxicity grade ≥ III is observed in more than 3 patients in the first interim analysis, the dose of Len will be increased to 5 mg/day for the next 10 patients. Otherwise the study will be stopped.

Results:

Here we present the results of the first interim analysis (data lock February 20^th 2017), which includes 10 patients (median age: 64 years, range 43 to 73) who experienced molecular (70%) or hematological (30%) relapse of MDS (70%), AML (20%) or CMML (10%) after median of 275 days (range: 91 to 937) following allo-SCT. So far, these 10 patients have received a total of 54 cycles of Len corresponding to median of 7 cycles per patient (range: 1 to 8). In addition, patients received a median of 7 courses of Aza (range 1-8) and 7 of 10 pts (70%) received at least one DLI (median: 1, range: 0-5).

No DLT was observed. Two patients either developed acute GvHD (20%, overall grade I and III) and chronic GvHD (20%, NIH score mild and moderate). Treatment-associated neutropenia, thrombocytopenia or anemia CTC grade III/IV occurred in 75%, 50% and 0% of the patients, respectively. Common adverse events were gastrointestinal side effects, elevation of liver enzymes as well as infections. Nevertheless, during the treatment period only 2 patients needed to be hospitalized. Although efficacy was not the major scope of this first interim analysis, of 7 evaluable patients (early drop-out of 3 patients) 4 (57%) achieved complete remission and 1 patient (14%) achieved partial remission resulting in overall response rate of 71%.

Conclusion:

This interim-analysis shows that the combination of Aza, Len (21x2.5 mg/cycle) and DLI as first salvage therapy for relapse after allo-SCT is safe and feasible and not associated with excess GvHD. According to the protocol, the dose of Lena will now be increased to 21x5 mg/cycle for the next 10 patients. Furthermore, due to the label extension of Aza, the inclusion criteria will also be amended to AML patients with >30% BM blasts.