Azacitidine, lenalidomide and donor lymphocyte infusions for relapse of myelodysplastic syndrome, acute myeloid leukemia and chronic myelomonocytic leukemia after allogeneic transplant: the Azalena-Trial

Abstract

Azacitidine combined with donor lymphocyte infusions (DLI) is an established treatment for relapse of myeloid malignancies after allogeneic transplantation. Based on its immunomodulatory and anti-leukemic properties we considered Lenalidomide to act synergistically with Azacitidine/DLI to improve outcome. We therefore prospectively investigated tolerability and efficacy of this combination as first salvage therapy for adults with post-transplant relapse of AML, MDS and CMML. Patients were scheduled for 8 cycles Azacitidine (75 mg/m2 day 1-7), Lenalidomide (2.5 or 5mg, day 1-21) and up to 3 DLI with increasing T cell dosages (0.5×106-1.5×107 cells/kg). Primary endpoint was safety, while secondary endpoints included response, graft-versus-host disease (GvHD) and overall survival (OS). Fifty patients with molecular (52%) or hematological (48%) relapse of MDS (n=24), AML (n=23) or CMML (n=3) received a median of 7 (range, 1 to 8) cycles including 14 patients with 2.5mg and 36 with 5mg Lenalidomide daily dosage. Concomitantly, 34 patients (68%) received at least one DLI. Overall response rate was 56% and 25 patients (50%) achieved complete remission being durable in 80%. Median OS was 21 months and 1-year OS rate 65% with no impact of type of or time to relapse and Lenalidomide dosages. Treatment was well tolerated indicated by febrile neutropenia being the only grade ≥3 non-hematologic adverse event in >10% of patients and modest acute (grade II-IV 24%) and chronic (moderate/severe 28%) GvHD incidences. In summary, Lenalidomide can be safely added to Azacitidine/DLI without excess of GvHD and toxicity. Its significant anti-leukemic activity suggests that this combination is a novel salvage option for post-transplant relapse. (NCT02472691)

Novel Approaches to Treatment of Acute Myeloid Leukemia Relapse Post Allogeneic Stem Cell Transplantation

“…Notably, both studies analyzed the circulating lymphocytes of patients before and after treatment, demonstrating impaired CD8+ T cells activity and a high incidence of CD4+ FOXP3+ regulatory T cells at baseline. These features were consistent with T cells exhaustion and an immunosuppressed microenvironment, and neither was reversed during treatment [55,56].…”

“…After a median follow-up of 20 months, the median OS was 21 months, whereas the median OS was not reached in those patients who achieved CR. Treatment was well tolerated without an excess of GvHD or toxicity (Table 2) [56]. Notably, both studies analyzed the circulating lymphocytes of patients before and after treatment, demonstrating impaired CD8+ T cells activity and a high incidence of CD4+ FOXP3+ regulatory T cells at baseline.…”

Flow cytometry of DNMT1 as a biomarker of hypomethylating therapies

“…High doses/concentrations of either drug can produce off‐target anti‐metabolite effects and cytotoxicity (Christman, 2002; Estey, 2013). DEC and AZA are routinely used to treat and maintain patients with myelodysplastic syndromes (MDS) (Gangat et al, 2016) and acute myeloid leukemias (AML) (Lancet, 2018), and are also being explored as maintenance therapies after allogeneic hematopoietic stem cell transplantation (SCT) (Abou Dalle et al, 2022; Bewersdorf et al, 2019; de Lima et al, 2018; Guillaume et al, 2021; Keruakous et al, 2023; Najima et al, 2022; Pasvolsky et al, 2021; Rahmat et al, 2018; Schroeder et al, 2015; Schroeder et al, 2016; Schroeder et al, 2018; Schroeder et al, 2023; Wei et al, 2021). There is additional interest in these drugs for other hematopoietic malignancies and solid tumors (Linnekamp et al, 2017; Nie et al, 2014) and to treat hemoglobinapathies (Molokie et al, 2017; Saunthararajah et al, 2008).…”