Cladribine As Single Agent And in Combination for Treatment of CLL

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Blood First Edition Paper, prepublished online March 21, 2006

Submitted December 6, 2005

Accepted March 10, 2006

Cladribine alone and in combination with cyclophosphamide or

cyclophosphamide plus mitoxantrone in the treatment of progressive

chronic lymphocytic leukemia: report of prospective, multicenter,

randomized trial of the Polish Adult Leukemia Group (PALG CLL2)

Tadeusz Robak*, Jerzy Z Blonski, Joanna Gora-Tybor, Krzysztof

Jamroziak, Jadwiga Dwilewicz-Trojaczek, Agnieszka Tomaszewska, Lech

Konopka, Bernadetta Ceglarek, Dmoszynska, Malgorzata Kowal,

Janusz Kloczko, Beata Stella-Holowiecka, Kazimierz Sulek, Malgorzata

Calbecka, Krystyna Zawilska, Kazimierz Kuliczkowski, Aleksander B

Skotnicki, Krzysztof Warzocha, and Marek Kasznicki

Department of Hematology, Medical University of Lodz, Lodz, Poland

Department of Hematology and Oncology, Medical University of Warsaw,

Warsaw, Poland

Institute of Hematology and Transfusiology, Warsaw, Poland

Department of Hematology and Bone Marrow Transplantation, Medical

University of Lublin, Lublin, Poland

Department of Hematology, Medical Uiversity, Bialystok, Poland

Department of Hematology and Bone Marrow Transplantation, Medical

University of Katowice, Katowice, Poland

Department of Internal Medicine, Military Institute of Medicine,

Warsaw, Poland

City Hospital, Torun, Poland

Department of Hematology, Medical University of Poznan, Poznan, Poland

Department of Hematology, Medical University, Wroclaw, Poland

Department of Hematology, Jagiellonian University, Krakow, Poland

In this prospective randomized trial we compared the efficacy and

toxicity of cladribine (2-CdA) alone to 2-CdA combined with

cyclophosphamide (CC) or cyclophosphamide and mitoxantrone (CMC) in

untreated progressive CLL. Study end points were complete response

(CR), overall response, minimal residual disease (MRD), progression-

free survival, overall survival and toxicity.

From January 1st 1998 to December 31st 2003, 508 patients from 15

hematology departments were randomized. Compared to 2-CdA, CMC

induced higher CR rate (36% vs. 21%, p=0.004), whilst only trend for

higher CR rate with CC was observed (29% vs. 21%, p=0.08).

Furthermore, percentage of patients in CR and MRD negative were

higher in CMC compared to 2-CdA (23% vs 14% p=0.042). There were no

differences in overall response, progression-free survival and

overall survival among treatment groups.

Grade 3/4 neutropenia occurred more frequently in CC (32%) and CMC

(38%) than in 2-CdA (20%) (p=0.01 and p=0.004, respectively).

Infections were more frequent in CMC compared to 2-CdA (40% vs. 27%,

p=0.02).

In conclusion, CMC used in first-line treatment of CLL gives higher

CR rate and suppresses MRD more efficiently than 2-CdA monotherapy,

although associates with increased toxicity. No important differences

in efficacy and toxicity were found between CC and 2-CdA regimens.