Cladribine in a weekly versus daily schedule for untreated active hairy cell leukemia: final report from the Polish Adult Leukemia Group (PALG) of a prospective, randomized, multicenter trial

Abstract

Cladribine (2-chlorodeoxyadenosine, 2-CdA) treatment-associated infections may shorten potentially long-term survival in hairy cell leukemia (HCL). In search of the optimal mode of 2-CdA administration, 132 patients with untreated HCL were randomized to receive either standard 5-day 2-CdA protocol or a novel schedule of 6 weekly 2-CdA infusions suggested to be less toxic. Analysis of treatment response confirmed similar complete remission rates, overall response rates, progressionfree survival, and overall survival in both 2-CdA protocols. However, we did not observe lower toxicity in the weekly schedule. Of special interest, no significant differences were found in the rate of grade 3/4 infections (18% for daily and 26% for weekly protocol, difference ؊8.2%; 95% confidence interval [CI] ؊23.2% to 6.9%; P ‫؍‬ .28) and the rate of septic deaths (3% for daily and 2% for weekly protocol, difference 1.4%; 95% CI ؊4.3% to 7.0%; P ‫؍‬ .64). In conclusion, HCL treatment with weekly 2-CdA infusions is equally effective but no safer than the standard 5-day 2-CdA protocol. IntroductionCladribine (2-chlorodeoxyadenosine, 2-CdA) belongs to standard therapeutic options for hairy cell leukemia (HCL). In chemotherapy-naive HCL, one course of 2-CdA induces complete response (CR) and long-term survival in the vast majority of patients. [1][2][3][4][5] Given this considerable clinical efficacy, the major challenge regarding 2-CdA therapy is reduction of side effects, especially severe infections that may lead to septic death. Lauria et al 6 suggested that a novel schedule based on 6 weekly 2-hour 2-CdA infusions could be as effective as the standard 7-day and 5-day protocols but associated with less neutropenia and fewer life-threatening infections. To test the potential clinical benefit of the weekly schedule, in 1998 the Polish Adult Leukemia Group (PALG) initiated a prospective multicenter, randomized comparison with 5-day 2-CdA infusion that is the standard treatment of active HCL in Poland. Patients, materials, and methodsThe study was carried out at 14 hematology centers, with central randomization and data management performed in the Department of Hematology at the Medical University of Lodz. The study was approved by the ethics committee of the Medical University of Lodz, and all patients gave informed consent in accordance with the Declaration of Helsinki. Eligibility criteriaPatients with untreated, active HCL, World Health Organization (WHO) scale performance status better than grade 4, normal liver and renal function, without secondary neoplasm, and age 18 years or older were considered eligible. The diagnosis of HCL and the criteria of activity of disease were defined as previously reported. Preliminary results of this study were presented at 46th annual meeting of the American Society of Hematology, San Diego, CA, December 4-7, 2004, 17 and at the 48th annual meeting of the American Society of Hematology, Orlando, FL, December 9-12, 2006. 18 The publication costs of this article were defrayed in part by page...

How I treat hairy cell leukemia

“…They found no significant difference in the number of serious infections or septic deaths between these 2 arms, and concluded that the interrupted schedule was equally effective but no safer than the daily administration. 54 A recent Swiss study reached the same conclusion that subcutaneously administered cladribine daily for 5 days versus weekly had similar outcomes and no difference in toxicity. 59 Unfortunately, the long-term follow-up studies with cladribine administered by these alternative doses and schedules are not as uniformly mature as the extensive data reported by investigators at Scripps Clinic.…”

“…[53][54][55][56] There is, however, general agreement that the goal should be to achieve a complete remission. The National Cancer Institute's PDQ published Treatment Summaries (www.cancer.gov/cancertopics/pdq/ treatment/hairy-cell-leukemia/) provide some guidance, but there are no concise and specific recommendations regarding selection of dose or schedule of drug administration for patients with severely compromised bone marrow reserves.…”

“…12, 57,58 The weekly intravenous schedule reportedly had less myelosuppression. 12,58 However, Robak et al 54 recently reported a prospective randomized study with 132 patients who received either daily doses for 5 days or 6 weekly doses. They found no significant difference in the number of serious infections or septic deaths between these 2 arms, and concluded that the interrupted schedule was equally effective but no safer than the daily administration.…”

My Treatment Approach to Hairy Cell Leukemia

“…The Polish Adult Leukemia Group reported results from a randomization of 132 untreated HCL patients at 14 centers to receive 5 daily doses of cladribine at 0.12 mg/kg or 6 weekly doses. 22 No differences were found in PR, ORR, OS, or progression-free survival (PFS) rates between the 2 arms. The CR rates were 76% and 72% in the daily and weekly arms, respectively, a finding that was also not statistically significant.…”

Orphan drugs for the treatment of hairy cell leukemia

“…weekly/ 6weeks, 3.4 mg/m 2 /day s.c. per 7 days and 0.14 mg/Kg/day s.c. per 5 days. A prospective randomized study on 132 HCL patients who received CDA daily for 5 days versus once a week for 6 weeks have not shown differences in toxicity between the two arms [62]. However, data is not available on the duration of response using these two different schedules to deliver the drug.…”