Long‐term results of low‐intensity chemotherapy with clofarabine or cladribine combined with low‐dose cytarabine alternating with decitabine in older patients with newly diagnosed acute myeloid leukemia

Abstract

The treatment of older patients with newly diagnosed acute myeloid leukemia (AML) using intensive chemotherapy is associated with treatment intolerance and poor survival. We evaluated two new lower-intensity regimens with clofarabine (n = 119) or cladribine (n = 129) combined with low-dose cytarabine (LDAC) alternating with decitabine. We reviewed response rates by subgroup and long term outcomes of 248 patients with newly diagnosed non core-binding-factor AML treated on two clinical trials investigating double nucleoside-analogue therapy (DNT) alternating with HMA from October, 2008 to April, 2018. Of 248 patients with a median age of 69 years (range, 49-85 years), 102 patients (41%) were ≥ 70 years, and 108 (44%) had adverse karyotype. Overall, 164 patients (66%) responded: 147 (59%) complete remission (CR) and 17 (7%) CR with incomplete count recovery (CRi). With a median follow up of 60 months, median relapse-free and overall survival (OS) were 10.8 and 12.5 months, respectively. The 2-year OS was 29%. Among patients with normal karyotype, the CR/CRi rate was 79% and the median OS 19.9 months. High response rates and OS were observed in patients with mutations in NPM1, FLT3, IDH2, and RUNX1. The 4-and 8-week mortality rates were 2% and 11%, respectively. The backbone of clofarabine or cladribine and LDAC alternating with decitabine was effective and safe for the treatment of older patients with newly diagnosed AML. Incorporating targeted therapies could extend the efficacy of this approach and provide more curative therapeutic options in this AML population.

A retrospective study of cladribine and low‐dose cytarabine–based regimens for the treatment of chronic myelomonocytic leukemia and secondary acute myeloid leukemia

“…3 11 The results that we obtained with the CLAD/LDAC/HMA regimens in HMA-naive sAML arising from CMML also compared favorably with those obtained in two phase 2 studies exploring similar regimens (including either CLAD or clofarabine) in patients with newly diagnosed AML, where the CR/CRi rate was 66% and the median OS was 12.5 months. 7 These results suggest a potentially increased sensitivity to CLAD in disease with a bias toward monocytic differentiation, as has been observed in studies using monocytic cell lines. 5,6 Unfortunately, for the patients with sAML after HMA failure, outcomes with CLAD/LDAC/HMA were dismal with a median OS of only 2.9 months.…”

“…Furthermore, CLAD exhibits synergy with cytarabine by increasing the intracellular concentration of its active metabolite ara‐cytosine triphosphate. The combination of CLAD and low‐dose cytarabine (LDAC) alternating with HMA is a highly effective low‐intensity therapy for acute myeloid leukemia (AML) 7 . The efficacy of CLAD/LDAC/HMA in patients with CMML, including after transformation to secondary acute myeloid leukemia (sAML), has not been established.…”

Cladribine Combined with Low-Dose Cytarabine as Frontline Treatment for Unfit Elderly Acute Myeloid Leukemia Patients: Results from a Prospective Multicenter Study of Polish Adult Leukemia Group (PALG)

“…The low-intensity regimens had significant anti-leukemic activity with CR/CRi rate of 66%. The median relapse-free survival and OS was 10.8 and 12.5 months, respectively [40]. These data suggest significant clinical benefits of combining low-dose chemotherapy with HMA and address the evolutionary nature of AML.…”

“…These differences may explain a difference in CR/CRi rates and median OS for the entire cohorts between our and the MDACC study in favor of the latter. The long-term results of combinations of purine analogues (cladribine or clofarabine) with LD-AC administered alternately with decitabine in the frontline treatment of elderly unfit AML patients were recently evaluated by Kadia et al [40]. Of the 248 patients included in the analysis, 41% were over 70 years of age (the median age was 69 years) and 44% had high-risk cytogenetics (patients with core-binding factor AML were excluded).…”

Combination strategies to promote sensitivity to cytarabine-induced replication stress in acute myeloid leukemia with and without DNMT3A mutations

“…Although dose-dense anthracyclines can overcome resistance and improve outcomes in younger patients (<65 years of age), the survival advantage is lost in older patients due to unacceptable treatment-related mortality (3)(4)(5). This prompted exploration of lower-intensity approaches that often combine multiple nucleoside analogs such as cytarabine and cladribine (7,19,20), which work by inducing unrestrained replication stress while overwhelming DNA damage repair mechanisms.…”