Phase II Study of Azacitidine (Vidaza®, Aza) and Donor Lymphocyte Infusions (DLI) As First Salvage Therapy in Patients with Acute Myeloid Leukemia (AML) or Myelodysplastic Syndromes (MDS) Relapsing After Allogeneic Hematopoietic Stem Cell Transplantation (allo-SCT): Final Results From the AZARELA-Trial (NCT-00795548)

Relapse after allo-SCT is a major cause of treatment failure in patients (pts) with myeloid malignancies and is associated with a poor prognosis. As therapeutic options are limited, treatment of these pts is challenging. Indeed, there is a need for novel strategies which ideally target the leukemic clone and direct the immune system towards an enhanced GvL effect without aggravating GvHD. The hypomethylating agent Aza might provide these properties, and results from retrospective studies investigating Aza+/−DLI in pts with AML/MDS relapsing after allo-SCT were encouraging.

We here report the final results from a prospective single-arm EBMT multicenter phase II trial which aimed to investigate the efficacy and safety of a combination of Aza and DLI as 1^st salvage therapy in pts with AML or MDS with hematological relapse after allo-SCT. Treatment schedule contained up to 8 cycles Aza (100 mg/m²/d d1-5, every 28 d) followed by DLI with increasing dosages (1-5×10⁶–1-5×10⁸cells/kg) after every 2^ndAza cycle.

A total of 30 pts (19 f/11 m, median age 56 years, range 29–71) from 6 German transplant centres were included between January 2009 and May 2010. The majority of pts (n=28, 93%) suffered from AML, while 2 pts (8%) had MDS or MDS/MPN, respectively. At transplant, 16 pts (53%) had active disease (6 induction failure, 7 relapse I/II, 3 untreated) and 14 pts (47%) were in remission (12 CR1, 2 CR2). Following standard-dose (n=4, 13%) or dose-reduced conditioning (n=26, 87%), 10 pts (33%) received a graft from MSD and 20 pts (67%) from MUD. PBSC were used in 29 pts (97%), while 1 pt (3%) received BM. Acute GvHD occurred in 13 pts (46%) and 4 pts (13%) had chronic GvHD prior inclusion. None of the pts had active GvHD at the time of relapse, but 6 pts were still on immunosuppressive therapy. All pts had hematological relapse (median BM blasts: 34%, median chimerism: 67%) at a median time of 160 days (range 19–1699) following allo-SCT. A median of 3 courses Aza (range 1–8) were administered, and 22 of 30 pts (73%) received DLI (median: 1, range: 1–4, median CD3 dose 5×10⁶/kg/DLI, range: 1–100×10⁶). Overall response rate was 47%. Seven pts (23%) achieved CR or CRi, 2 pts (7%) PR, and 5 pts (17%) had stable disease (SD). Median time and median number of Aza cycles to best response were 79 days (range 28–299) and 3 cycles (range 1–8) respectively. Of the 7 pts who achieved a CR, 5 pts continue in CR for a median of 605 days (range 307–763) without any additional treatment, while 1 pt relapsed after 490 days and 1 pt died from GvHD. By July 2011 median follow-up of surviving pts is 645 days (range 564–857) and 5 of 30 pts (17%) are currently alive. Twelve pts have died due to progressive disease (PD), while 7 pts died during (n=3, 2 infection, 1 bleeding) or after the end of therapy (n= 4, 1 GvHD, 2 infection, 1 bleeding). All 5 pts who underwent 2nd allo-SCT died. Median overall survival (OS) of all pts is 117 days (95% CI 66–168 days). Patients with CR/CRi had a significant longer OS than pts not reaching CR/CRi (not reached vs. 83 days, p<.001). Eleven pts (37%) developed aGvHD, while cGvHD was observed in 5 pts (17%). Any type of GvHD was seen in 78% of pts with CR/PR as opposed to 33% in pts with SD/PD (p=.03). Cytopenias grade III/IV occurred in all pts, but were considered to be drug-related in only 11 pts (37%). The most common drug-related grade III/IV non-hematological toxicities were infection and bleeding.

Aza and DLI as first salvage therapy is a safe and active approach for pts with AML or MDS who relapse after allo-SCT, and induces durable remissions in a subgroup of pts. Further research to better define target patient groups and combination partners for AZA+DLI is needed.

Schroeder:Celgene: Financial travel support. Bug:Celgene: Lecture fees, Membership on an entity's Board of Directors or advisory committees. Luft:Celgene: Research Funding. Kobbe:Celgene: Financial travel support, Research Funding.