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)

Abstract

Acute myeloid leukemia (AML) in older unfit patients is a therapeutic challenge for clinical hematologists. We evaluated the efficacy and safety of a novel low-intensity regimen consisting of low-dose cytarabine and cladribine (LD-AC+cladribine) in first-line treatment of elderly (≥60 years) AML patients not eligible for intensive chemotherapy (IC) who had either the Eastern Cooperative Oncology Group performance status (ECOG PS) ≥2 or the hematopoietic cell transplantation comorbidity index (HCT-CI) score ≥3. The induction phase included two cycles of LD-AC+cladribine. Patients who achieved at least partial remission (PR) received maintenance treatment with LD-AC alone. Overall, 117 patients with a median age of 70 years were enrolled. Adverse cytogenetics, ECOG PS ≥2 and HCT-CI score ≥3 was observed in 43.5%, 60%, and 58% of patients, respectively. The response rate (≥PR) was 54% (complete remission [CR], 32%; CR with incomplete hematologic recovery [CRi], 5%). A median overall survival (OS) was 21 and 8.8 months in CR/CRi and PR group, respectively. Advanced age (≥75 years) and adverse cytogenetics had a negative impact on OS. The 56-day mortality rate was 20.5%. In conclusion, LD-AC+cladribine is a beneficial therapeutic option with a predictable safety profile in elderly AML patients not eligible for IC.

Prognosis of older patients with newly diagnosed AML undergoing antileukemic therapy: A systematic review

“…Twenty-seven studies, reporting on 18,309 patients, provided a HR to quantify the prognostic value of age [ 15 , 16 , 25 – 27 , 29 , 32 , 33 , 42 , 43 , 49 , 50 , 56 , 59 , 75 , 82 , 87 , 90 , 91 , 99 – 101 , 103 , 105 – 107 , 109 ]. Meta-analyses showed that an age increase of 5 year-increments was associated with increased long-term mortality (HR 1.16; 95% CI 1.11 to 1.21, high-quality evidence, Table 1 , S4 Appendix ).…”

“…Three studies, including 614 patients, reported a HR for a Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score of 3 or more compared to less than 3 in predicting long-term mortality [ 41 , 62 , 105 ]. Meta-analyses showed that a higher HCT-CI score increased the risk for long-term mortality (HR 1.60; 95% CI 1.31 to 1.95, high-quality evidence, Table 1 , S5 Appendix ).…”

“…Twenty-one studies, including 5,349 patients, reported the HR for performance status measured using ECOG/WHO (score 2 or more compared with less than 2) in predicting long-term mortality [ 25 , 34 , 35 , 40 , 42 , 48 , 53 , 63 , 67 , 78 , 79 , 81 , 84 , 87 , 88 , 96 , 101 , 103 , 105 , 108 ]. One study separately reported the results of two cohort studies (defined by patients 55 to 65 years and over 65 years) [ 67 ].…”

“…Of the 90 eligible studies, 17 (18.9%) had low risk of bias [16,22,23,25,35,43,49,53,62,69,70,75,79,81,83,87,103], 55 (61.1%) had moderate risk of bias [15, 26-28, 30-33, 36-42, 45, 46, 48, 50-52, 54, 56, 58-61, 63, 65-68, 71, 72, 76, 77, 80, 82, 85, 86, 88-90, 92, 94, 96, 98-101, 104, 106-109], 8 (8.9%) had high risk of bias [24,34,47,78,91,95,97,102] for all predictors and outcomes. The other ten studies had different risk of bias among reported predictors and outcomes: four studies had high risk of bias [55, 57,73,84,93] and one study had moderate risk of bias for age as a predictor of outcomes [44], five studies had high risk of bias for performance status as a predictor of outcomes [29, 73,74,93,105], and one study had high risk of bias for comorbidities as a predictor of outcomes [64]. Most bias was due to study confounding, statistical analysis, and/or reporting issues.…”

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.…”