Feasibility and efficacy of addition of individualized-dose lenalidomide to chlorambucil and rituximab as first-line treatment in elderly and FCR-unfit patients with advanced chronic lymphocytic leukemia

HOVON CLL study group, Arnon P. Kater, Marinus H. J. van Oers, Yvette van Norden, Lina van der Straten, Julia Driessen, Ward F. M. Posthuma, Martin Schipperus, Martine E. D. Chamuleau, Marcel Nijland, Jeanette K. Doorduijn, Michel van Gelder, Mels Hoogendoorn, Francien de Croon, Shulamiet Wittebol, J. Martijn Kerst, Erik W. A. Marijt, Reinier A. P. Raymakers, Martijn R. Schaafsma, Johan A. Dobber & 2 others Sabina Kersting, Mark-David Levin

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Lenalidomide has been proven to be effective but with a distinct and difficult to manage toxicity profile in the context of chronic lymphocytic leukemia, potentially hampering combination treatment with this drug. We conducted a phase 1-2 study to evaluate the efficacy and safety of six cycles of chlorambucil (7 mg/m2 daily), rituximab (375 mg/m2 cycle 1 and 500 mg/m2 cycles 2-6) and individually-dosed lenalidomide (escalated from 2.5 mg to 10 mg) (induction-I) in first-line treatment of patients with chronic lymphocytic leukemia unfit for treatment with fludarabine, cyclophosphamide and rituximab. This was followed by 6 months of 10 mg lenalidomide monotherapy (induction-II). Of 53 evaluable patients in phase 2 of the study, 47 (89%) completed induction-I and 36 (68%) completed induction-II. In an intention-to-treat analysis, the overall response rate was 83%. The median progression-free survival was 49 months, after a median follow-up time of 27 months. The 2- and 3-year progression-free survival rates were 58% and 54%, respectively. The corresponding rates for overall survival were 98% and 95%. No tumor lysis syndrome was observed, while tumor flair reaction occurred in five patients (9%, 1 grade 3). The most common hematologic toxicity was grade 3-4 neutropenia, which occurred in 73% of the patients. In conclusion, addition of lenalidomide to a chemotherapy backbone followed by a fixed duration of lenalidomide monotherapy resulted in high remission rates and progression-free survival rates, which seem comparable to those observed with novel drug combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile. EuraCT number: 2010-022294-34.
LanguageEnglish
Pages147-154
JournalHaematologica
Volume104
Issue number1
DOIs
Publication statusPublished - 2019

Cite this

@article{e4dfeaaf64454840a0e51411c2576fad,
title = "Feasibility and efficacy of addition of individualized-dose lenalidomide to chlorambucil and rituximab as first-line treatment in elderly and FCR-unfit patients with advanced chronic lymphocytic leukemia",
abstract = "Lenalidomide has been proven to be effective but with a distinct and difficult to manage toxicity profile in the context of chronic lymphocytic leukemia, potentially hampering combination treatment with this drug. We conducted a phase 1-2 study to evaluate the efficacy and safety of six cycles of chlorambucil (7 mg/m2 daily), rituximab (375 mg/m2 cycle 1 and 500 mg/m2 cycles 2-6) and individually-dosed lenalidomide (escalated from 2.5 mg to 10 mg) (induction-I) in first-line treatment of patients with chronic lymphocytic leukemia unfit for treatment with fludarabine, cyclophosphamide and rituximab. This was followed by 6 months of 10 mg lenalidomide monotherapy (induction-II). Of 53 evaluable patients in phase 2 of the study, 47 (89{\%}) completed induction-I and 36 (68{\%}) completed induction-II. In an intention-to-treat analysis, the overall response rate was 83{\%}. The median progression-free survival was 49 months, after a median follow-up time of 27 months. The 2- and 3-year progression-free survival rates were 58{\%} and 54{\%}, respectively. The corresponding rates for overall survival were 98{\%} and 95{\%}. No tumor lysis syndrome was observed, while tumor flair reaction occurred in five patients (9{\%}, 1 grade 3). The most common hematologic toxicity was grade 3-4 neutropenia, which occurred in 73{\%} of the patients. In conclusion, addition of lenalidomide to a chemotherapy backbone followed by a fixed duration of lenalidomide monotherapy resulted in high remission rates and progression-free survival rates, which seem comparable to those observed with novel drug combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile. EuraCT number: 2010-022294-34.",
author = "{HOVON CLL study group} and Kater, {Arnon P.} and {van Oers}, {Marinus H. J.} and {van Norden}, Yvette and {van der Straten}, Lina and Julia Driessen and Posthuma, {Ward F. M.} and Martin Schipperus and Chamuleau, {Martine E. D.} and Marcel Nijland and Doorduijn, {Jeanette K.} and {van Gelder}, Michel and Mels Hoogendoorn and {de Croon}, Francien and Shulamiet Wittebol and Kerst, {J. Martijn} and Marijt, {Erik W. A.} and Raymakers, {Reinier A. P.} and Schaafsma, {Martijn R.} and Dobber, {Johan A.} and Sabina Kersting and Mark-David Levin",
year = "2019",
doi = "10.3324/haematol.2018.193854",
language = "English",
volume = "104",
pages = "147--154",
journal = "Haematologica",
issn = "0390-6078",
publisher = "Ferrata Storti Foundation",
number = "1",

}

Feasibility and efficacy of addition of individualized-dose lenalidomide to chlorambucil and rituximab as first-line treatment in elderly and FCR-unfit patients with advanced chronic lymphocytic leukemia. / HOVON CLL study group.

In: Haematologica, Vol. 104, No. 1, 2019, p. 147-154.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Feasibility and efficacy of addition of individualized-dose lenalidomide to chlorambucil and rituximab as first-line treatment in elderly and FCR-unfit patients with advanced chronic lymphocytic leukemia

AU - HOVON CLL study group

AU - Kater, Arnon P.

AU - van Oers, Marinus H. J.

AU - van Norden, Yvette

AU - van der Straten, Lina

AU - Driessen, Julia

AU - Posthuma, Ward F. M.

AU - Schipperus, Martin

AU - Chamuleau, Martine E. D.

AU - Nijland, Marcel

AU - Doorduijn, Jeanette K.

AU - van Gelder, Michel

AU - Hoogendoorn, Mels

AU - de Croon, Francien

AU - Wittebol, Shulamiet

AU - Kerst, J. Martijn

AU - Marijt, Erik W. A.

AU - Raymakers, Reinier A. P.

AU - Schaafsma, Martijn R.

AU - Dobber, Johan A.

AU - Kersting, Sabina

AU - Levin, Mark-David

PY - 2019

Y1 - 2019

N2 - Lenalidomide has been proven to be effective but with a distinct and difficult to manage toxicity profile in the context of chronic lymphocytic leukemia, potentially hampering combination treatment with this drug. We conducted a phase 1-2 study to evaluate the efficacy and safety of six cycles of chlorambucil (7 mg/m2 daily), rituximab (375 mg/m2 cycle 1 and 500 mg/m2 cycles 2-6) and individually-dosed lenalidomide (escalated from 2.5 mg to 10 mg) (induction-I) in first-line treatment of patients with chronic lymphocytic leukemia unfit for treatment with fludarabine, cyclophosphamide and rituximab. This was followed by 6 months of 10 mg lenalidomide monotherapy (induction-II). Of 53 evaluable patients in phase 2 of the study, 47 (89%) completed induction-I and 36 (68%) completed induction-II. In an intention-to-treat analysis, the overall response rate was 83%. The median progression-free survival was 49 months, after a median follow-up time of 27 months. The 2- and 3-year progression-free survival rates were 58% and 54%, respectively. The corresponding rates for overall survival were 98% and 95%. No tumor lysis syndrome was observed, while tumor flair reaction occurred in five patients (9%, 1 grade 3). The most common hematologic toxicity was grade 3-4 neutropenia, which occurred in 73% of the patients. In conclusion, addition of lenalidomide to a chemotherapy backbone followed by a fixed duration of lenalidomide monotherapy resulted in high remission rates and progression-free survival rates, which seem comparable to those observed with novel drug combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile. EuraCT number: 2010-022294-34.

AB - Lenalidomide has been proven to be effective but with a distinct and difficult to manage toxicity profile in the context of chronic lymphocytic leukemia, potentially hampering combination treatment with this drug. We conducted a phase 1-2 study to evaluate the efficacy and safety of six cycles of chlorambucil (7 mg/m2 daily), rituximab (375 mg/m2 cycle 1 and 500 mg/m2 cycles 2-6) and individually-dosed lenalidomide (escalated from 2.5 mg to 10 mg) (induction-I) in first-line treatment of patients with chronic lymphocytic leukemia unfit for treatment with fludarabine, cyclophosphamide and rituximab. This was followed by 6 months of 10 mg lenalidomide monotherapy (induction-II). Of 53 evaluable patients in phase 2 of the study, 47 (89%) completed induction-I and 36 (68%) completed induction-II. In an intention-to-treat analysis, the overall response rate was 83%. The median progression-free survival was 49 months, after a median follow-up time of 27 months. The 2- and 3-year progression-free survival rates were 58% and 54%, respectively. The corresponding rates for overall survival were 98% and 95%. No tumor lysis syndrome was observed, while tumor flair reaction occurred in five patients (9%, 1 grade 3). The most common hematologic toxicity was grade 3-4 neutropenia, which occurred in 73% of the patients. In conclusion, addition of lenalidomide to a chemotherapy backbone followed by a fixed duration of lenalidomide monotherapy resulted in high remission rates and progression-free survival rates, which seem comparable to those observed with novel drug combinations including novel CD20 monoclonal antibodies or kinase inhibitors. Although lenalidomide-specific toxicity remains a concern, an individualized dose-escalation schedule is feasible and results in an acceptable toxicity profile. EuraCT number: 2010-022294-34.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30115656

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DO - 10.3324/haematol.2018.193854

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