Clofarabine Salvage Therapy Prior To Allogeneic Hematopoietic Stem Cell Transplantation (HCT) In Patients With Relapsed Or Refractory Acute Leukemia
Authors: Serrano Josefina , Buenasmañanas Diana , Herrera P , Amigo Mari Luz , Calabuig Marisa , Martin Eusebio , Vidriales Maria-Belén , Fuente Adolfo de la , Santero M , Negri Silvia , Gonzalez-Campos Jose , Albo Carmen , Gonzalez Sonia , Rifon Jose J. , Viguria M Cruz , Garcia-Gutierrez V , Martin Carmen , Sanchez-Garcia Joaquin 
Published: October 2019

HCT is the only potentially curative approach that may provide long-term disease control for patients con relapsed and/or refractory acute leukemia (Re/Ref AL). However, active disease burden at HCT is associated with high relapse rates and dismal outcomes. Recently, promising results in this way have been reported using sequential treatment schedules. We performed a retrospective multicentre analysis to investigate the safety and efficacy of clofarabine (CLO) cytoreduction prior to HCT for Re/Ref AL. Spanish Agency Qualification was obtained (AAH-CLO-2013-01/EPA-OD).

A total of 50 patients from 14 Spanish centres (AML 33; ALL 17) who received CLO and had an HLA-matched donor were included. Median age was 37 years (18-64); sex: 26 M, 24 F. High risk cytogenetic/molecular profile in 31.4%, Intermediate 54%, and low risk 14.6%. Patients received first-line chemotherapy (ct) regimens based on cooperative national groups (PETHEMA, CETLAM and SHOP) and 2nd lines with fludarabine-based regimens in 85%. Prior to CLO, 56.3% of patients had received 2 CT lines and 35.5% ≥ 3 lines including 6 auto-HCT and 12 allogeneic HCT. Disease status at CLO administration was primary refractoriness (29.2%) secondary refractoriness (33.3%), first relapse (10%) and ≥2nd relapse (27%). CLO was administered at 20-40 mg/m2/day for 5 consecutive days combined with ARA-C in AML cases and Citoxan-Etoposide in ALL cases. Response was assessed by IWG-2006 criteria and toxicity evaluated according to CTCAE v3.

Out of 50 included patients, 16 did not underwent allogeneic HCT due to early toxic deaths (N=6) or due to lack of disease control (N=10)

1.- Response was valuable in 44 cases, achieving 11 CR and 7 PR. Effective Cytoreduction (defined as <20% of marrow cellularity and/or <10% of marrow blast count) was achieved in 59% of cases.

2.- Most frequent toxicity was haematological gr.4 in 100% of cases, mucositis gr.≥ 3 in 15%, liver toxicity with bilirrubin and/or SGOT elevation gr.≥3 in 23%, infections gr.≥3 in 50% and skin toxicity gr.2 in 4%

3.- Eventually, HCT was performed in 34 patients (22 AML and 12 ALL); 19 form HLA-matched sibling donor, 7 HLA-matched unrelated donor, 4 HLA-matched umbilical cord and 4 HLA-haploidentical donor. Conditioning regimen was fludarabine-based reduced-intensity in 19 patients and myeloablative in 15 patients. Median elapsed time from CLO administration and HCT was 37 days (range: 6-105).

4.-Transplant-related mortality (TRM)at day +100 and +365 was 20.6% and 41% respectively. Acute GVHD was developed in 16 patients (grades III-IV in 6 cases) and chronic GVHD was observed in 6 patients. With a median follow-up of 14.3 months after HCT, Overall Survival was 28.5% for the global series, 39.6% for AML patients and 15% for ALL patients. Patients achieving effective cytoreduction with CLO had a significantly superior Relapse Free Survival (48% vs. 0%, P=.002). Similarly, patients receiving CLO at earlier disease status (first relapse or primary refractoriness) had a significantly better OS than those treated at more advanced disease (48% vs. 5%). Elapsed time from CLO administration and HCT shorter than 50 days was also associated to a better OS (40.2% vs. 12.2%, P =.14) ) although no statistical difference was reached.

Salvage CLO-based regimens as bridge to HCT in patients with Re/Ref AL can be administered with an acceptable toxicity profile and are followed by an acceptable TRM. Achievement of effective cytoreduction and no delayed HCT procedure could identify patients with less leukemic burden capable to achieve long-lasting sustained disease control.

Disclosures:

No relevant conflicts of interest to declare.