High Activity of Cladribine (2-CdA) Combined with Low-Dose Cytarabine in Patients with Acute Myeloid Leukemia or Myelodysplastic Syndrome after Azacitidine Failure
Authors: Wisniewski Kamil , Madry Krzysztof , Grosicki Sebastian , Małecki Piotr , Pula Bartosz , Watek Marzena , Lech-Maranda Ewa , Gora Tybor Joanna 
Published: November 2019

Background:
Azacitidine (AZA) therapy is the standard of care for higher-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) patients not eligible for intensive treatment. Although nearly 50% of patients respond to AZA treatment, most of them experience disease progression within 2 years of remission. The prognosis of patients after AZA failure is dismal with a median overall survival (OS) reaching 3-6 months. Interestingly, recent studies have demonstrated clinical efficacy of cladribine combined with cytarabine in newly diagnosed AML patients. In view of epigenetic properties of cladribine and known synergy with cytarabine, it may be speculated that combination of cladribine and low-dose cytarabine (LD-AraC) exerts some clinical activity also in the setting of relapsed/refractory AML/MDS.
Aim: The aim our study was to assess activity and toxicity of combination of cladribine and LD-AraC in patients with MDS/AML after AZA failure.
Methods:
This retrospective analysis included patients with AML with 20% to 30% blasts, high and intermediate-2 risk MDS and CMML patients with AZA failure who were treated with combination of cladribine and LD-AraC in centers of the Polish Adult Leukemia Group (PALG). Therapy started with induction phase consisting of 2 cycles of cladribine 5 mg/m2 iv on days 1-5 (cycle 1) and on days 1-3 (cycle 2) in combination with LD-AraC 40 mg/m2 sc (days 1-10). Patients who achieved remission moved on to maintenance therapy with LD-AraC 40 mg/m2 sc, days 1-10), every 4 weeks. The treatment was continued for as long as tolerated and there was a clinical benefit. Treatment response was determined in accordance with the 2017 European Leukemia Net (ELN) and the 2006 International Working Group (IWG) criteria after each cycle.
Results:
Overall, 16 patients (8 patients with diagnosis of AML, 7 with diagnosis of MDS, and 1 with diagnosis of CMML myelodysplastic subtype at AZA therapy initiation) who had been treated with combination of cladribine and LD-AraC at AZA failure in 3 centers of PALG between 2014 and 2019 were identified. There were 9 males and 7 females, with median age of 72 years (range 64 - 78). The patients had previously received a median of 15 cycles of AZA (range 4 - 33). At the initiation of cladribine and LD-AraC therapy the median number of blasts was 27,5% (range 15,5 - 77) with 13 patients fulfilling the criteria of AML. At the data cut-off the median of administered chemotherapy cycles reached 4 (range 1-14), with 4 patients continuing treatment. The regimen was relatively well tolerated with no treatment related deaths and the most common non-hematological adverse events of grade 3 or worse being neutropenic fever and pneumonia. Response assessment revealed that nine patients (56%) achieved a remission, including 6 complete remissions (CR) and 3 complete remissions with incomplete recovery (CRi). The median time to response was 1 cycle. Median progression-free survival was 8 months, and the median OS reached 10.6 months. The estimated 6-months and 12-months OS probability were 79.3% and 44.6%, respectively.
Conclusions:
The combination of cladribine and LD-AraC appears to be an attractive option in the therapy of AML/MDS patients after AZA failure. Although prospective studies are needed to confirm these findings such treatment seems to be associated with an improvement in OS compared to the historical data.

Disclosures
Gora Tybor: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.