Long-Term Survival of Patients with Relapsed/Refractory Acute Leukemia Receiving Clofarabine/Cyclophosphamide Prior to Hematopoietic Stem Cell Transplantation
Authors: Graf Irene , Wohlfarth Philipp , Mitterbauer Margit , Schulenburg Axel , Hauswirth Alexander , Gleixner Karoline V. , Rabitsch Werner , Valent Peter , Sperr Wolfgang R. 
Published: December 2024

Background: Acute myeloid leukemia (AML) and acute lymphoblastic leukemia (ALL) are stem cell-derived hematologic malignancies. Patients who do not achieve complete remission after one or more cycles of induction chemotherapy or develop a refractory relapse have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT) is the only potentially curative rescue therapy for these patients. Recently, several new therapeutic approaches have been developed to bridge patients with refractory (R) or relapsed refractory (RR) acute leukemia to HSCT.
Patients and Methods: We retrospectively analyzed 82 patients (median age: 47.5 years, range 19-69; f:m ratio 1:1.28) diagnosed with R or RR acute leukemias (AML, n=44; ALL, n=16; chronic myeloid leukemia blast phase, CML-BP, n=1; mast cell leukemia, MCL, n=1) treated at the Medical University of Vienna from 2008 to 2023. All patients received debulking with ClofCy (clofarabine, 10 mg/m2, days 1-4; cyclophosphamide, 200 mg/m2, days 1-4) as a bridging therapy to HSCT.
Results: A median number of 2 cycles (range 1-5) of ClofCy were administered. Therapy resulted in a significant decrease in blood leukocytes and blast cells in most patients (95 %). Treatment was well tolerated as assessed by the common terminology criteria for adverse events (CTCAE). Only a few patients showed moderate liver toxicity i.e. increase in aspartate aminotransferase (CTCAE grade 1: n=6; grade 2: n=2, grade 3: n=1), alanine aminotransferase (CTCAE grade 1: n=8; grade 4: n=1), and alkaline phosphatase (CTCAE grade 1: n=2; grade 4: n=2). No substantial kidney toxicity was observed during therapy with ClofCy (CTCAE grade 1: n=13). HSCT was performed in 51/82 patients (63%). In 31 patients HSCT was withheld because of infections (n=18), clinical deterioration (n=4), blast cell persistence (n=4), or cerebral bleeding (n=3). The median number of chemotherapies for R or RR leukemia prior to ClofCy was 2 (IQR 1-3) in patients eligible for HSCT and 3 (IQR 2-3) in those not eligible for HSCT. We found that a higher proportion of patients (69 %) with 0-2 chemotherapies administered prior to ClofCy received HSCT compared to those with 3 or more chemotherapies prior to ClofCy (50 %). Uni- and multivariate analysis confirmed that multiple chemotherapy before ClofCy is an adverse prognostic factor for reaching HSCT (p&lt;0.05). The median overall survival (OS) of all 82 patients receiving ClofCy was 0.31 years (IQR 0.12-3.02) with 5- and 10-years survival rates of 24% and 20%, respectively. Of the HSCT patients 39 (77%) received high dose conditioning and 12 (23%) dose-reduced conditioning. For prophylaxis of graft versus host disease (GVHD) cyclosporine with methotrexate or mycophenolate mofetil was used. The median OS was 1.23 years with an IQR of 0.22-not reached (nr) and a 5- and 10-years survival of 38.4% and 31%. In those without HSCT the median survival was 0.11 years (IQR 0.06-0.17) and the 5-year survival 0%. In the HSCT-patients the median OS and relapse-free survival (RFS) were 1.04 years (IQR 0.22-nr) and 0.9 years (IQR 0.19-nr), respectively. Their OS and RFS at 5 years were 38.0% and 37.3%, respectively, and at 10 years, OS and RFS were 31% and 31%, respectively. Patients with chronic graft versus host disease (cGVHD) had the best OS and RFS compared to non-GvHD patients (median OS: nr versus 0.54 years, p=0.011; median RFS: nr versus 0.44 years, p=0.034, respectively). Those with acute GVHD (aGVHD) had a poor OS and RFS compared to those without aGHD (median OS: 0.46 versus 1.59 years, p=0.013; median RFS: OS 0.27 versus 1.84 years, p=0.009, respectively). This was also confirmed in multivariate analysis were acute aGVHD (OS, p=0.016; RFS, p=0.016) and cGVHD (OS, p=0.023; RFS, p=0.036) were the only independent prognostic variables whereas age, type of disease, duration of therapy with ClofCy and type of refractory disease (R versus RR) were not found to be independent prognostic variables.
Conclusion: ClofCy is a new promising debulking strategy for patients with R/RR acute leukemias prior to HSCT although the relatively low number of patients and the retrospective character of our study were limiting factors. According to our results, ClofCy should be introduced early in such cases and cGVHD seems to be a good prognostic factor regarding OS and RFS.