- Email: [email protected]
How to treat patients with CMML?
Leukemia Research 37 (2013) 605–606
Contents lists available at SciVerse ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
How to treat patients with CMML? In this issue of Leukemia Research a French-American group reports on results of hypomethylating treatment in patients with CMML. The authors add important knowledge to the hematologic community, as they come up with predictive parameters that seem to be feasible in clinical day to day practice, namely elevated blasts, splenomegaly and to less extend high WBC and potentially influence our treatment decisions. Since the WHO proposals of 2001, the entity of chronic myelomonocytic leukemia (CMML) got lost in classification and has a shadowy existence between other types of myeloid malignancies. Although at least about half of the patients, those with leukocytes of than 13,000/l, called “dysplastic CMML” present with clinical and prognostic features that are very similar to classical MDS. An analysis of data of the Düsseldorf MDS registry showed that dysplastic CMML with less than 5% medullary blasts (CMML 0) are very similar to RCMD, CMMLI are similar to RAEB I and CMMLI are similar to RAEB II with regard to prognosis, as well hemoglobin and platelet counts, whereas the WBC is a little bit higher in CMML types (median survival CMML 0 33 months, RCMD 36 months, CMML 1 22 months, RAEB I 19 months, CMML II 15 months and RAEB II 13 months, all p-values n.s.) Nevertheless, dysplastic CMML usually are not included into clinical trials for patients with RCMD, RAEB I, or RAEB II. In many cases, the presence of a little bit more than 1000/l monocytes leads to exclusion of the patients from a clinical trial, although all other parameters are very similar. The major problem of these patients with dysplastic CMML is hematopoietic insufficiency. Even worse is the situation for patients with a proliferative CMML who present with leukocytes of more than 13,000/l, as they also do not fit into the majority of clinical trials. These subtypes have a worse prognosis (17 months vs. 15 months vs. 11 months) as compared to RCMD, RAEB I and RAEB II. Their major problem is primarily related to high WBC and progression and not to hematopoietic insufficiency. The separation of the CMML in a dysplastic and a proliferative type as proposed by the FAB group reflects these characteristics. In addition, we screened the clinical trials that we run at our site for patients with MDS and the percentage of CMML patients that fit into one of our trials is very low. But even in times of the FAB classification of 1982, where the CMML belonged to the classical MDS family, it obviously was not easy to perform clinical trials for these patients. The only phase III trial, performed by the Group Francais de Myelodysplasie is more than 15 years ago and demonstrated that hydroxyurea is superior to etoposid [1]. Only smaller phase II trials were performed later on, not leading to promising results with the exception of
DOI of original article: http://dx.doi.org/10.1016/j.leukres.2013.01.004. 0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.02.017
decitabine and 5-azazytidine. The majority of these trials included some CMML patients together with other MDS types and AML, and therefore the conclusions that could be drawn for CMML patients were vague. A nice overview on these data with 5-azazytidine was summed up by Breccia and colleagues and some decitabine data came out as well [2,3]. What is known for sure is that there are patients with CMML responding to treatment with hypomethylating agents. Another limitation of the smaller studies and reports is the fact that the CMML patients often were stratified according to the IPSS, which is not an adequate tool for assessment of prognosis at least in proliferative CMML. In addition, our knowledge on predictive marker for hypomethylating agents in general and especially in CMML agents is poor. About 50% of patients with MDS achieve some kind of response. In other words, about half of the patients are treated in vain. The only potentially predictive parameter for the assessment of treatment outcome after decitabine is the presence of TET2 mutation, but this marker is not available in many places. Having this scenario in mind, the authors of the FrenchAmerican study [4] should be congratulated to present data on the treatment of patients with CMML with 5-azazytidine. The study population is described properly and covers both dysplastic as well as proliferative patients and on each group those with less and those with more than 10% medullary blasts. This composition of the study population allows meaningful analyses and identifies predictive markers that are associated with a poor response. Unfortunately, these factors, especially a high percentage of medullary blasts and high WBC are poor prognostic factors for untreated CMML patients as well and therefore were included into the CMML prognostic scoring system (CPSS) [5] which recently was published by a Spanish-Italian-German collaborating group. This means that those parameters that define a high risk CMML are predicting negative outcome after treatment with Vidaza. Those with the highest need to be treated do not respond well. Nevertheless, hypomethylation in CMML is promising. The data should prompt the MDS community to perform further trials at least including CMML, better concentrating on the different types of CMML, either dysplastic or proliferative. The CPSS perhaps could provide a meaningful separation of risk groups taking into account proliferation, blast expansion, hematopoietic insufficiency and chromosomal findings, in order to define homogenous patient groups. As CMML is rare, covering about 10–15% of all MDS, studies should be performed in a multicentric way. Conflict of interest statement U.G. received speakers honoraria and research support from Celgene.
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Editorial / Leukemia Research 37 (2013) 605–606
Acknowledgements UG and JN analyzed data on CMML in the Düsseldorf Registry and wrote the manuscript. References [1] Wattel E, Guerci A, Hecquet B, Economopoulos T, Copplestone A, Mahé B, et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Franc¸ais des Myélodysplasies and European CMML Group. Blood 1996;88:2480–7. [2] Breccia M, Voso MT, Alimena G. Chronic myelomonocytic leukemia treatment: what have we learned to far? Leuk Res 2013;37:204–5. [3] Braun T, Itzykson R, Renneville A, de Renzis B, Dreyfus F, Laribi K, et al. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood 2011;118(14):3824–31. [4] Ades L, Sekers MA, Wolfromm A, Teichmann ML, Tiu RV, Itzykson R, et al. Predictive factors for response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res 2013;37:609–13. [5] Such E, Germing U, Malcovati L, Cervera J, Kuendgen A, Della Porta MG, et al. Development and validation of a prognostic scoring system for patients
with chronic myelomonocytic leukemia. Blood 2013;(January) [Epub ahead of print].
Ulrich Germing ∗ Judith Neukirchen Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany ∗ Corresponding author at: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany. Tel.: +49 211 8117720; fax: +49 211 8118853. E-mail address: [email protected] (U. Germing)
8 February 2013 Available online 17 April 2013
Contents lists available at SciVerse ScienceDirect
Leukemia Research journal homepage: www.elsevier.com/locate/leukres
Editorial
How to treat patients with CMML? In this issue of Leukemia Research a French-American group reports on results of hypomethylating treatment in patients with CMML. The authors add important knowledge to the hematologic community, as they come up with predictive parameters that seem to be feasible in clinical day to day practice, namely elevated blasts, splenomegaly and to less extend high WBC and potentially influence our treatment decisions. Since the WHO proposals of 2001, the entity of chronic myelomonocytic leukemia (CMML) got lost in classification and has a shadowy existence between other types of myeloid malignancies. Although at least about half of the patients, those with leukocytes of than 13,000/l, called “dysplastic CMML” present with clinical and prognostic features that are very similar to classical MDS. An analysis of data of the Düsseldorf MDS registry showed that dysplastic CMML with less than 5% medullary blasts (CMML 0) are very similar to RCMD, CMMLI are similar to RAEB I and CMMLI are similar to RAEB II with regard to prognosis, as well hemoglobin and platelet counts, whereas the WBC is a little bit higher in CMML types (median survival CMML 0 33 months, RCMD 36 months, CMML 1 22 months, RAEB I 19 months, CMML II 15 months and RAEB II 13 months, all p-values n.s.) Nevertheless, dysplastic CMML usually are not included into clinical trials for patients with RCMD, RAEB I, or RAEB II. In many cases, the presence of a little bit more than 1000/l monocytes leads to exclusion of the patients from a clinical trial, although all other parameters are very similar. The major problem of these patients with dysplastic CMML is hematopoietic insufficiency. Even worse is the situation for patients with a proliferative CMML who present with leukocytes of more than 13,000/l, as they also do not fit into the majority of clinical trials. These subtypes have a worse prognosis (17 months vs. 15 months vs. 11 months) as compared to RCMD, RAEB I and RAEB II. Their major problem is primarily related to high WBC and progression and not to hematopoietic insufficiency. The separation of the CMML in a dysplastic and a proliferative type as proposed by the FAB group reflects these characteristics. In addition, we screened the clinical trials that we run at our site for patients with MDS and the percentage of CMML patients that fit into one of our trials is very low. But even in times of the FAB classification of 1982, where the CMML belonged to the classical MDS family, it obviously was not easy to perform clinical trials for these patients. The only phase III trial, performed by the Group Francais de Myelodysplasie is more than 15 years ago and demonstrated that hydroxyurea is superior to etoposid [1]. Only smaller phase II trials were performed later on, not leading to promising results with the exception of
DOI of original article: http://dx.doi.org/10.1016/j.leukres.2013.01.004. 0145-2126/$ – see front matter © 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.leukres.2013.02.017
decitabine and 5-azazytidine. The majority of these trials included some CMML patients together with other MDS types and AML, and therefore the conclusions that could be drawn for CMML patients were vague. A nice overview on these data with 5-azazytidine was summed up by Breccia and colleagues and some decitabine data came out as well [2,3]. What is known for sure is that there are patients with CMML responding to treatment with hypomethylating agents. Another limitation of the smaller studies and reports is the fact that the CMML patients often were stratified according to the IPSS, which is not an adequate tool for assessment of prognosis at least in proliferative CMML. In addition, our knowledge on predictive marker for hypomethylating agents in general and especially in CMML agents is poor. About 50% of patients with MDS achieve some kind of response. In other words, about half of the patients are treated in vain. The only potentially predictive parameter for the assessment of treatment outcome after decitabine is the presence of TET2 mutation, but this marker is not available in many places. Having this scenario in mind, the authors of the FrenchAmerican study [4] should be congratulated to present data on the treatment of patients with CMML with 5-azazytidine. The study population is described properly and covers both dysplastic as well as proliferative patients and on each group those with less and those with more than 10% medullary blasts. This composition of the study population allows meaningful analyses and identifies predictive markers that are associated with a poor response. Unfortunately, these factors, especially a high percentage of medullary blasts and high WBC are poor prognostic factors for untreated CMML patients as well and therefore were included into the CMML prognostic scoring system (CPSS) [5] which recently was published by a Spanish-Italian-German collaborating group. This means that those parameters that define a high risk CMML are predicting negative outcome after treatment with Vidaza. Those with the highest need to be treated do not respond well. Nevertheless, hypomethylation in CMML is promising. The data should prompt the MDS community to perform further trials at least including CMML, better concentrating on the different types of CMML, either dysplastic or proliferative. The CPSS perhaps could provide a meaningful separation of risk groups taking into account proliferation, blast expansion, hematopoietic insufficiency and chromosomal findings, in order to define homogenous patient groups. As CMML is rare, covering about 10–15% of all MDS, studies should be performed in a multicentric way. Conflict of interest statement U.G. received speakers honoraria and research support from Celgene.
606
Editorial / Leukemia Research 37 (2013) 605–606
Acknowledgements UG and JN analyzed data on CMML in the Düsseldorf Registry and wrote the manuscript. References [1] Wattel E, Guerci A, Hecquet B, Economopoulos T, Copplestone A, Mahé B, et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Franc¸ais des Myélodysplasies and European CMML Group. Blood 1996;88:2480–7. [2] Breccia M, Voso MT, Alimena G. Chronic myelomonocytic leukemia treatment: what have we learned to far? Leuk Res 2013;37:204–5. [3] Braun T, Itzykson R, Renneville A, de Renzis B, Dreyfus F, Laribi K, et al. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood 2011;118(14):3824–31. [4] Ades L, Sekers MA, Wolfromm A, Teichmann ML, Tiu RV, Itzykson R, et al. Predictive factors for response and survival among chronic myelomonocytic leukemia patients treated with azacitidine. Leuk Res 2013;37:609–13. [5] Such E, Germing U, Malcovati L, Cervera J, Kuendgen A, Della Porta MG, et al. Development and validation of a prognostic scoring system for patients
with chronic myelomonocytic leukemia. Blood 2013;(January) [Epub ahead of print].
Ulrich Germing ∗ Judith Neukirchen Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany ∗ Corresponding author at: Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Moorenstr. 5, 40225 Düsseldorf, Germany. Tel.: +49 211 8117720; fax: +49 211 8118853. E-mail address: [email protected] (U. Germing)
8 February 2013 Available online 17 April 2013