5-Azacytidine (AZA) in Combination with Ruxolitinib (RUX) As Therapy for Patients (pts) with Myelodysplastic/Myeloproliferative Neoplasms (MDS/MPNs)

Background: Clinical trials exclusively focusing on pts with MDS/MPN are lacking. AZA is a DNA methyltransferase (DNMT) inhibitor approved for the therapy of MDS while RUX is a JAK inhibitor approved as therapy for primary myelofibrosis and polycythemia vera. RUX and AZA may target distinct clinical and pathological manifestations of MDS/MPNs.

Aim: To determine the efficacy and safety of RUX + AZA in pts with MDS/MPN requiring therapy including chronic myelomonocytic leukemia (CMML), atypical chronic myeloid leukemia BCR-ABL1 negative (aCML), and myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS/MPN-U)(ClinicalTrials.gov Identifier: NCT01787487).

Methods: A sequential approach with single-agent RUX 15 mg orally twice daily (if platelets 100-200) or 20 mg twice daily (if platelets >200) continuously (pts with platelets below 50 were not eligible) in 28-day cycles for the first 3 cycles followed by the addition of AZA 25 mg/m² on days 1-5 of each 28-day cycle starting cycle 4 was adopted. The AZA dosage could be gradually increased to a maximum of 75 mg/m². The AZA could be started earlier than cycle 4 and/or at a higher dose in pts with proliferative disease or elevated blasts.

Results: 24 pts were enrolled between March 1, 2013 and April 1, 2015. Baseline characteristics are summarized in table 1. 17 pts remain alive after a median (med) follow-up of 6.0 (3.7 - 21.3+) months. Responses were evaluated by the MDS/MPN IWG response criteria (Savona et al., Blood 2015, 125(12):1857-65). Responses were noted in 12 (50%) pts. Details of responses are shown in table 2. Med time to responses was 1.8 mos (0.7 - 5.5+) and the med duration of response is 7.0 mos (1.8 - 17.6+). Additionally, 9 pts had >5% pretreatment BM blasts: 6 of these pts had follow-up BM evaluations and 3 achieved a reduction in blasts to <5% with a med time to blast reduction of 5.5 mos (5.5 - 11.2+). Serial evaluation of bone marrow biopsies documented reduction in EUMNET fibrosis score in 3 of 11 (27%) evaluable pts after a med of 5.5 mos (2.1 - 5.6+) on therapy. The reduction was by one grade in all 3 pts (MF-2 to MF-1 in 2 pts, MF-1 to MF-0 in 1 pt) and was confirmed on a subsequent BM biopsy in 2 pts.

No pts experienced grade 3/4 non-hematological toxicity. New onset grade 3/4 anemia and thrombocytopenia were seen in 12 (50%; of which 5 had a 2+ grade change) and 8 (31%) pts, respectively. The med overall survival is 15.1+ mos. 7 pts have died: pneumonia (n=3), sepsis (n=2), progression to AML (n=1), and transition to hospice (n=1).

The AZA was started in cycle 4 in 12 pts (50%). The AZA was started earlier due to leukocytosis or increased blasts in 11 pts (46%), in cycle 1 (n=6), cycle 2 (n=4), and cycle 3 (n=1). 13 pts have discontinued protocol therapy due to leukocytosis (n=6), progression to AML (n=1), lack of response (n=3), pneumothorax (n=1), stem cell transplant (n=1), and loss of insurance (n=1), respectively.

Conclusion: Concomitant administration of RUX with AZA was feasible and effective in pts with MDS/MPNs, with expected myelosuppression as the only significant toxicity. This combination warrants further evaluation.