Cladribine, Cytarabine and Mitoxantrone As Treatment Intensification for Patients with Acute Myeloid Leukemia with the Excess of Bone Marrow Blasts on Day 14 of the First Induction. Prospective, Multicenter Study By the Polish Adult Leukemia Group (PALG)
Authors: Pluta Agnieszka , Brzozowski Kamil , Stepka Konrad , Wawrzyniak Ewa , Krawczynska Anna , Szmigielska-Kaplon Anna , Grzybowska-Izydorczyk Olga , Czemerska Magdalena , Gromek Tomasz , Hus Marek , Helbig Grzegorz , Bodzenta Ewa , Grosicki Sebastian , Razny Malgorzata , Bolkun Lukasz , Kloczko Janusz , Knopinska-Posluszny Wanda , Piekarska Agnieszka , Hellmann Andrzej , Sobas Marta , Wrobel Tomasz , Patkowska Elzbieta , Lech-Maranda Ewa , Warzocha Krzysztof , Holowiecki Jerzy , Giebel Sebastian , Robak Tadeusz , Wierzbowska Agnieszka 
Published: October 2019

Abstract
Objectives
The treatment results of acute myeloid leukemia (AML) patients (pts) younger than 60yo are still unsatisfactory. The strategy of double induction in AMLis based on two courses of chemotherapy depends on percentage of bone marrow (BM) blast at 7-14 days of treatment. This therapy intensification may induce higher response rate but toxicity appeared as early death (ED) rates still a medical dilemma. The advantage from addition of cladribine (2CdA) to standard induction and reinduction treatment was previously confirmed in PALG's trials.
Aim
The aim of this study was an estimation of efficacy and toxicity of treatment intensification based on BM blast at 14 day (D14) by second early induction, CLAM (2CdA + cytarabine + mitoxantron)
Methods
We performed multicenter, prospective, non-randomized trial where pts received DAC induction treatment with subsequent second early induction according as D14 BM biopsy results. When BM examination revealed >10% of blast without hypocellular marrowand pts met all criteria to intensive chemotherapy, second intensive induction with CLAM protocol (2CdA 5mg/m2 iv days 1-5, Cytarabine 2g/m2 iv days 1-5, Mitoxantron 10mg/m2 iv days 1-3) from day 16 was applied. The pts were allocated to risk-adjusted postremission treatment with high-dose cytarabine (HD-AraC) for low-risk group according to European Leukemia Net (ELN) classification and allogeneic stem cell transplantation (allo-SCT) recommended for intermediate and high-risk group.
Results
One hundred seventy one newly diagnosed AML pts from 8 PALG's centers were enrolled to the study. The median age was 47 yo (range19-60). According to WHO 2008 classification, our group consisted of 9% AML with recurrent genetic abnormalities, 19% AML related to myelodysplasia, 3% therapy-related AML and 69% AML not otherwise classified. Analysis of cytogenetic-molecular risk factors based on ELN classification revealed favorable, intermediate-1, intermediate-2, poor-risk groups in 17%, 44%, 18% and 21% AML pts, respectively. Twenty-six (15%) out of 171 pts had elevated BM infiltration of blasts at D14, with the median 44% (range 11-100%). Overall, 22 of 26 pts were judged as eligible to receive second induction, reasons for exclusion being in all cases active infection.
Response evaluation was available in 150 pts, 21 pts were still ongoing in the protocol. Complete remission (CR) rate after single DAC induction course was 71% (n=106), partial remission (PR), non-remission (NR) and ED was 8% (n=12), 18% (n=28) and 3% (n=4), respectively. Response after double induction was evaluated in 21 out of 22 cases; one patient still has not reached time of measurement. CR was observed in 14/21 pts (67%), NR in 5% (n=1), ED 28% (n=6). The CR rate after inductiontreatment applied to first hospitalization (DAC or DAC+ CLAM) was 81% (n=120). Twelve pts who had <10% of blasts at day 14 and achieved PR after first induction were allocated to second DAC induction. Six out of them achieved CR leading to the overall CR rate 85%.In 27 pts who achieved CR allo-SCT was performed till June 2016, however there are pts who are still awaiting allo-SCT.
The median duration of hospital stay was 31 (11-73) and 66 (52-76) days respectively for the DAC and the DAC + CLAM induction. During the single DAC induction the median number of days with neutropenia <0.5 G/l was 24 (12-101), and with thrombocytopenia <20 G/l was 12 (0-51). The median number of transfused packed red blood cell (PRBC) was 9 (0-32) and the number of platelet concentrate units was 15 (2-124). During DAC+CLAM double induction the median number of days of the neutropenia <0.5 G/l was 53 (17-73) and thrombocytopenia <20 G/l was 19 (4-57). The median number of PRBC was 18 (10-44) and the number of platelet concentrate units was 30 (5-153).
With the median time of follow-up 16 months the median overall survival (OS) was not reached. The probability of 1-year OS was 59% and the probability of 1-year disease free survival was 83% (Figure 1, Panel A and B).
Conclusion
The preliminary results of our study suggest that early second induction CLAM is a feasible and effective treatment option in younger AML patients which further improves the CR rate and do not compromise the feasibility of allo-SCT.

Disclosures
Grzybowska-Izydorczyk: BMS: Honoraria; Novartis: Honoraria. Warzocha:BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Robak:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Wierzbowska:Novartis: Consultancy, Honoraria; Janssen Cilag: Consultancy.