Interest of the Association Azacitidine-Lenalidomide As Front Line Therapy in High-Risk Myelodysplasia (MDS) or Acute Myeloid Leukemia (AML) with Complex Karyotype

Results of intensive chemotherapy (ICT) in myelodysplasia (MDS) or secondary acute myeloid leukaemia (sAML) are poor, particularly in the presence of complex cytogenetic. Allogeneic haematopoietic stem cell transplantation (HSCT) remains the only curative treatment but only a minority of patients is eligible for HSCT notably because of difficulties to assess disease control underlining the need for novel strategies. Although, the use of hypomethylating agents has improved the overall survival (OS) of MDS with excess of blasts and might be interesting in AML (Fenaux, Lancet Oncol 2009), the prognosis of high risk MDS and AML remains poor (Itzykson, Blood 2011). Lenalidomide has demonstrated its efficiency in MDS with del5q and, has also been tested in patients with high-risk MDS or AML (Ades, Blood 2009).

We report our experience of the association of azacitidine and lenalidomide in patients presenting with high risk MDS or sAML and who were unfit for ICT.

Eight consecutive patients were referred to our haematological department from August 2008 to March 2010 with a diagnosis of high-risk MDS or sAML because of the presence of a complex karyotype including in all cases abnormalities of the 5q chromosome. At diagnosis, median age of patients was 66.5 years (range, 23–76); median WBC was 2×10.9/L (range, 0.11–7.1) and median marrow blast was 23% (range, 11%-37%). Four patients had secondary therapy-related AML and four patients had type-2 refractory anemia with excess of blasts (RAEB). None of them was eligible for an intensive chemotherapy because of age and/or poor performans status and/or comorbidities. They received cycles of 28 days of azacitidine (75 mg/m2 Day 1 to 5 or 7 SC) and lenalidomide (10 mg per day, day 1 to 14 or 21, oral) as first line treatment for a median of 4.5 cycles (range, 1–13 cycles).

Main side effects were cytopenias: 7 patients on the 8 developed grade 4 thrombocytopenia. Five patients, 4 with baseline ANC more than 1000/mm3 developed grade 4 neutropenia. Severe infections occurred in neutropenic patients: 6 sepsis (4 fevers of unknown origin, 1 facial cellulitis, 1 fungal infection and 1 CMV reactivation.) including 2 septic shock. However, no death was related to the toxicity of the treatment.

Of the eight patients, 6 achieved a haematological response (3 complete response (CR), 3 partial response (PR)) and 2 progressed under treatment. Among the 6 responding patients, initial responses occurred at a median of 10 weeks (range, 6–28 weeks) from the beginning of therapy. Two patients were allografted, one with a reduced intensity conditioning in haematological and cytogenetic CR at transplant, and the other one with a sequential type reduced intensity conditioning in complete haematological but partial cytogenetic remission at HSCT. With a median follow-up of 60 weeks for the responding patients, (range, 0–72), the 4 responding patients who were not allografted because of age did experience relapse at a median of 12 weeks (range, 8–36 weeks) from initial response while the two patients who were allografted are still alive in CR at 15 and 14 months after HSCT, respectively. Considering the whole population, with a median follow up of 18 months, the median OS was 15 months (range, 1–18 months), and median progression-free survival (PFS) was 9.5 months (range, 0–18 months).

The association of azacitidine and lenalidomide in the context of high risk MDS and sAML might offer a significant probability of remission with tolerable toxicity. For patients considered for an allogeneic HSCT, the use in first line therapy of such novel combination strategy rather than intensive chemotherapy represents an interesting option particularly in the case of complex cytogenetic.

Off Label Use: Interest of the association Azacitidine-Lenalidomide as front line therapy in high-risk myelodysplasia (MDS) or acute myeloid leukemia (AML) with complex karyotype.