Efficacy of a 3-Day, Low-Dose Treatment with 5-Azacytidine Followed by Donor Lymphocyte Infusions (DLI ) in Older AML/MDS Patients Relapsed after Allografting.
Authors: Lübbert Michael , Waesch Ralph M. , Marks Reinhard , Rüter Björn , Bertz Hartmut , Finke Juergen 
Published: October 2019

Background: DNA demethylating azanucleoside drugs are known to upregulate HLA molecules and germline/Cancer Testis antigens on malignant cells. Thus these drugs may be considered a rational treatment option also for patients relapsed after allografting. Until now for these patients DLI is standard treatment, with only limited activity of additional low-dose cytarabine (LD-AraC). It has thus been hypothesized that azanucleosides, when given at low doses, may not act solely by cytotoxic effects like LD-AraC, but also via their ability to modulate the aberrant epigenotype of leukemic cells and thus reactivate silenced genes. We have piloted a 3-day schedule of 5-azacytidine (aza) at a total dose (TD) of 300 mg per course (thus substantially lower than the schedule established for treatment of MDS), followed by DLI, in pts with relapse of AML/MDS after allografting.

Patients and Methods: Between 10/2006 und 4/2008, 22 patients (20 with AML, 2 with CMML) relapsed after allografting received a 3-day course of aza at 100 mg/day s. c., where feasible followed by DLI 1–2 weeks later. Median age at time of allografting was 62 years (range 28 – 75). 16/22 pts were male, 12 had de novo, 8 secondary (s)AML. 9/22 (41 %) had poor-risk cytogenetics. 20 pts had received Fludarabine-based reduced-toxicity conditioning regimens, 2 conventional myeloablative conditioning. At start of aza, 16, 4 and 1 pt were in 1st, 2nd or 3rd relapse, respectively, 1 pt had refractory sAML. Median number of days from transplant to first aza was 257 (range, 76 to 1492). Median % blasts in bone marrow and peripheral blood before aza was 57 and 5, respectively (ranges, <5– >95, 0–91), one patient had extramedullary relapse.

Results: 22 pts received a total of 55 courses of aza (43 courses: 300 mg TD, 10 courses: 375 mg TD, 2 courses: 450 mg TD, 1 course: 540 mg TD), with a median of 2 courses (range, 1–10). In 16/22 pts (73 %), aza was followed by DLI, with a total of 42 courses of aza/DLI given. Treatment was repeated every 4 weeks. Only 1 pt. experienced Grade III aGvHD 2 mths after DLI, clinically relevant neutropenia was observed in 3 pts. 5 patients had disease control and stable mixed chimerism but no objective hematologic response. In 2 pts a stable conversion to complete donor chimerism occurred. 15 pts did not respond to this treatment. 9/22 pts proceeded to second allogeneic transplantation. 7/22 pts are alive at time of analysis. The median time from start of aza to death or last follow-up was 131 days (range 23–625).

Conclusions: This low-dose outpatient regimen of aza followed by DLI is feasible, with a very low aGvHD rate. Objective responses including complete donor chimerism (10%) occurred also in pts with poor-risk cytogenetics, and notably also in pts having already received previous DLI monotherapy (suggesting that DLI activity might be enhanced by preceding aza treatment). A dose escalation based on this schedule appears warranted, incorporating translational studies aimed at dissecting whether the effect of aza is via a cytotoxic effect or modulation of gene expression in the malignant cells.