Diagnostik und Therapie der CMML

CMML is the most frequent entity among myelodysplastic/myeloproliferative syndromes according to the WHO classification [1]. CMML is a clonal disease. CMML is a rare (˜1.5 cases/100,000 per year) clonal disorder of the elderly (mean age ˜70 years) characterized by persistent monocytosis. Symptoms, when present, are the consequences of cytopenias (notably anemia, which is invalidating in a third of patients), and/or of extramedullary hematopoiesis, notably splenomegaly but also hepatomegaly, skin infiltration and serous (notably pleural) effusions. Autoimmune manifestations can be associated to CMML.

Patient survival ranges from a few months to several years with a median of 2 to 3 years in most series [2]. Several prognostic scores have been proposed (see [2] for a review). They rely on peripheral blood counts, serum lactate deshydrogenase (LDH) values, percentage of bone marrow blast cells and cytogenetic abnormalities (for which dedicated classifications have been proposed [3]). Allogeneic stem cell transplantation (ASCT) remains to date the only therapeutic option with curative potential in CMML [4]. However, even with the extended use of reduced intensity conditionings (RIC), this approach is rarely feasible in CMML patients, most of whom are older than 70. Furthermore, relapse rates remain high in CMML. In non-transplant patients, coping with chronic anemia requires transfusion support and erythropoiesis stimulating agents as for lower-risk MDS patients. In more advanced CMML, there is a concomitant need to mitigate myeloproliferation, including splenomegaly and extramedullary disease and to delay AML transformation in order to prolong survival. The mainstay of treatment for myeloproliferative CMML remains hydroxyurea. The only randomized trial performed so far in CMML has demonstrated that hydroxyurea gave higher response rates and better survival than etoposide in advanced CMML [5]. Hypomethylating agents (HMA) seem active in all forms of CMML. Azacitidine (AZA) has been approved in Europe for CMML cases with WBC <13 G/L and bone marrow blasts between 10 and 29%, on the basis of the AZA-001 trial where only 16 CMML patients were included. Thus, data on AZA in CMML largely rely on retrospective series [6,7].

The Groupe Francophone des Myelodysplasies has conducted a phase II trial of decitabine (DAC, 20mg/m² 1x/d IV d1–5/cycle) in 39 patients with advanced CMML (defined as in [5]). The overall response rate was 38%, including 10% CR. The median OS was 18.1 months [8]. Other reports of outcome with DAC are retrospective, and have included all types of CMML, reporting an ORR of 45–69% [9,10].

References:

[1] Vardiman JW, Thiele J, Arber DA, et al. The 2008 revision of the World Health Organization (WHO) classification of myeloid neoplasms and acute leukemia: rationale and important changes. Blood 2009;114(5):937–951

[2] Germing U, Kundgen A, Gattermann N. Risk assessment in chronic myelomonocytic leukemia (CMML). Leuk Lymphoma 2004;45(7):1311–1318

[3] Such E, Cervera J, Costa D, et al. Cytogenetic risk stratification in chronic myelomonocytic leukemia. Haematologica 2011;96(3):375–383

[4] Cheng H, Kirtani VG, Gergis U. Current status of allogeneic HST for chronic myelomonocytic leukemia. Bone Marrow Transplant 2012;47(4):535–541

[5] Wattel E, Guerci A, Hecquet B, et al. A randomized trial of hydroxyurea versus VP16 in adult chronic myelomonocytic leukemia. Groupe Francais des Myelodysplasies and European CMML Group. Blood 1996;88(7):2480–2487

[6] Costa R, Abdulhaq H, Haq B, et al. Activity of azacitidine in chronic myelomonocytic leukemia. Cancer 2011;117(12):2690–2696

[7] Ades L, Sekeres MA, Wolfromm A, et al. Prognostic Factors of Response and Survival in CMML Patients Treated with Azacitidine (AZA). ASH Annual Meeting Abstracts 2011;118(21):1726-

[8] Braun T, Itzykson R, Renneville A, et al. Molecular predictors of response to decitabine in advanced chronic myelomonocytic leukemia: a phase 2 trial. Blood 2011;118(14):3824–3831

[9] Aribi A, Borthakur G, Ravandi F, et al. Activity of decitabine, a hypomethylating agent, in chronic myelomonocytic leukemia. Cancer 2007;109(4):713–717

[10] Wijermans PW, Ruter B, Baer MR, et al. Efficacy of decitabine in the treatment of patients with chronic myelomonocytic leukemia (CMML). Leuk Res 2008;32(4):587–591