Two hundred and sixty-one patients with WHO-defined CMML were included in the current international study: 105 (40%) were from the GFM cohort, 86 (33%) from Mayo Clinic Minnesota, 47 (18%) from the Moffitt Cancer Center Florida and 23 (9%) from the University of Milan. There were no statistically significant demographic, clinical or laboratory differences between patients from the four participating centers. Two hundred and nineteen (84%) patients had CMML-1 and 42 (16%) had CMML-2, with median OS of 59 months and 24 months, respectively. The median age of the cohort was 59 years (range, 18–65 years) and 73% (n=192) were males. Table 1 outlines the presenting clinical and laboratory features and subsequent events in the 261 study patients with CMML, stratified by their AHSCT status. At a median follow-up of 26 months, 126 (48%) deaths and 72 (28%) LTs were documented. Of 220 evaluable patients, 53 (24%) did undergo AHSCT and in this group at last follow-up 8 (19%) deaths were documented.
Cytogenetic information was available in 246 (94%) patients; 60 (23%) displayed an abnormal karyotype and the Mayo-French cytogenetic risk designations included 200 (81%) low, 39 (16%) intermediate and 7 (3%) high risk. The common cytogenetic abnormalities included: −7(18%), +8 (16%), −Y (14%), der(3q) (13%) and 20q-(9%). Forty-five (80%) of the 60 patients had a sole abnormality, while 4 (7%) had two, 7 (13%) had a complex karyotype and 6 (11%) had a monosomal karyotype.
Mutational frequencies were 45% (72/161) for SRSF2, 33% (58/174) for ASXL1, 8% (9/113) for SF3B1, 4% (7/164) for SETBP1 and 4% (5/111) for U2AF1. The most common ASXL1 mutation was the c.1934dupG; p.G646WfsX12 variant (40%), followed by the 1900_1922_ del (11%). The most common SRSF2 mutations were P95H (33%) and P95L (33%), while K700E (90%) was the most common SF3B1 mutation. In the French CMML cohort, of the 53 evaluable patients 29(53%) had TET2 mutations, while of the 59 evaluable patients 13 (22%) had RAS mutations (NRAS-10 and KRAS-3). The distribution according to the four studied risk stratification algorithms is shown in Figure 1. For example, the distribution according to the MMM was: 20 (12%) low, 46 (26%) intermediate-1, 61 (36%) intermediate-2 and 44 (26%) high risk.
Figure 2a demonstrates the OS of 261 ‘young’ adults with CMML. With a median follow-up of 54.5 months, overall survival was 84% at 1 year, 45% at 5 years, and 26% at 10 years, with a median survival of 55 months. The median OS for CMML-1 and CMML-2 were 59 months and 24 months, respectively (Figure 2b). In an univariate OS analysis, after censoring for AHSCT lower HB (P<0.0001), higher WBC (P=0.0002), higher absolute neutrophil count (P=0.001), higher AMC (P=0.0004), higher circulating blast % (P<0.0001), higher BM blast % (P=0.02), presence of circulating IMC (P<0.0001), ASXL1 mutations (P=0.003), SRSF2 mutations (P=0.04), the Mayo-French cytogenetic risk stratification (P<0.0001) and the Spanish cytogenetic risk stratification system (P=0.0002) predicted shortened survival (Table 2). In multivariable analysis, lower HB (P=0.01), higher circulating blast % (P=0.002), ASXL1 mutations (P=0.0007), SRSF2 mutations (P=0.008) and the Mayo-French cytogenetic risk stratification system (P=0.04) retained their negative prognostic impact. Interestingly, without censoring for AHSCT, on a multivariable analysis OS was independently affected by lower HB (P=0.01), lower platelets (P=0.03), higher circulating blast % (P=0.001), SRSF2 mutations (P=0.04) and the high risk stratification of the Mayo-French cytogenetic stratification (P=0.02; Table 2). SETBP1 mutations had no impact on OS.
Similarly, in a univariate analysis for LFS lower HB (P<0.0001), higher AMC (P=0.01), higher circulating blast% (P<0.0001), higher BM blast % (P<0.0001), presence of circulating IMC (P<0.0001), the Mayo-French cytogenetic risk stratification (P<0.0001) and the Spanish cytogenetic risk stratification (P<0.0001) predicted shortened survival (Table 2). In multivariable analysis, LFS was independently affected by higher circulating blast % (P<0.0001), higher BM blast % (P=0.0007) and the presence of circulating IMC (P=0.0002). Karyotype risk designation, ASXL1, SETBP1 and SRSF2 mutations had no impact on LFS.
Response to HMAs
Seventy-five (29%) patients received HMA, of which, 45 (60%) received 5-AZA, 30 (40%) received DAC and 7 (9%) received both. Table 3 outlines the treatment characteristics and outcomes of ‘young’ CMML patients that received HMA. In the 5-AZA group, the median age was 56 years and 78% (n=35) were male. Thirty-five (78%) had CMML-1, while 10 (22%) had CMML-2. Of 20 evaluable patients, 9 (45%) had ASXL1 mutations. The risk designations according to the MMM were: 3 (16%) high, 7 (37%) intermediate-2, 8 (42%) intermediate-1 and 1 (5%) low risk (evaluable n=19). The median number of cycles was 5 (range, 1–44), median duration of therapy 4.6 months (range, 0.1–32.2), with 5 (11%) receiving DAC on progression and 20 (39%) proceeding with AHSCT. The over-all response rate was 40% (n=18/45) and included complete response (CR) in 3 (7%), partial response in 10 (25%) and hematological improvement (HI) in 5 (12%). Of 30 evaluable patients, reasons for 5-AZA discontinuation included patient choice-1 (3%), 5-AZA intolerance-3 (10%), disease progression-14 (47%), death-4 (13%) and bridge to AHSCT-8 (27%).
Thirty (40%) patients received DAC; with the median age being 58 years (range, 33–65), with a male predilection (60%) (Table 3). Twenty-one (70%) had CMML-1, while 9 (30%) had CMML-2. Of 21 evaluable patients, 6 (28%) had ASXL1 mutations and the risk designations according to the MMM were: 4 (21%) high risk, 7 (37%) intermediate-2, 6 (32%) intermediate-1 and 2 (10%) low risk. The median number of cycles was 6 (range, 1–30), median duration of therapy 5 months (range, 0.1–49), with two (7%) receiving DAC on progression and nine (31%) proceeding with AHSCT. The over-all response rate was 30% (n=9/30) and included CR in 6 (32%), partial response in one (5%) and HI in two (10%). Of 15 evaluable patients, reasons for DAC discontinuation included disease progression-9 (60%), death-3(20%) and bridge to AHSCT-3 (20%). Neither did ASXL1 (P=0.4) and SRSF2 (P=0.7) mutational status, nor karyotype (P=0.3 for Mayo-French cytogenetic stratification and 0.5 for the Spanish stratification) correlate with response to HMA. In 53 evaluable patients in the French cohort, TET2 mutations demonstrated a trend toward predicting HMA response (P=0.5), but this did not reach statistical significance.
Outcomes of AHSCT
Fifty-three patients (20%) underwent AHSCT. Conditioning regimen was reported in 42 patients and included MA in 14 (33%) and reduced intensity in 28 (67%) (Table 4). Donor source was documented in 40 patients and included: matched related donor in 20 (50%; MA-7 and RIC-13), MUD in 13 (32%; MA-4, RIC-9), 9/10 mismatched unrelated donor in 4 (10%; MA-1, RIC-3), double umbilical cord blood units in 1 (3%; MA-1) and RIC haploidentical transplants in 2 (8%). In the MA group, the median age was 51 years (range, 27–62), 32 (60%) were males and 36 (68%) had CMML-1, while the remaining 17 (32%) had CMML-2. In the RIC group, the median age was 48 years (range, 18–65), 8 (57%) were males, 21 (75%) had CMML-1, while the remaining 7 (25%) had CMML-2. Of 25 evaluable patients, 7 (28%) had ASXL1 mutations (MA-3, RIC-4) and the risk designation according to the MMM was: high-11 (44%), intermediate-2-5 (20%), intermediate-1-8 (32%) and low risk-1 (4%). Nineteen patients (47%) developed grade II–IV acute GVHD, 7 (54%) with a MA regimen and 12 (46%) with RIC, while 29 (67%) developed chronic GVHD, 8 (57%) with a MA regimen and 21 (75%) with RIC. Of 43 evaluable patients, 1 (2%) had primary engraftment failure, 8 died secondary to treatment related causes (NRM-19%), 10 (25%) had disease relapse and 24 (56%) achieved a CR. Neither did ASXL1 (P=0.9) and SRSF2 (P=0.5) mutational status, nor karyotype (P=0.3 for Mayo-French cytogenetic stratification and 0.2 for the Spanish stratification) correlate with response to AHSCT.
The 2008 World Health Organization (WHO) classification of myeloid neoplasms defines chronic myelomonocytic leukemia (CMML) as a clonal hematopoietic stem cell disorder that is characterized by the presence of an absolute monocytosis (>1 × 109 L−1) in the peripheral blood and the presence of myelodysplastic and myeloproliferative features in the bone marrow .
CMML was included in the myelodysplastic syndromes (MDS) category in the original French-American-British classification of 1982 . However, there was considerable controversy as to whether it truly represented MDS or a myeloproliferative neoplasm (MPN) [3, 4]. Indeed, patients with CMML were divided into two separate categories depending on the degree of leukocytosis—CMML, MDS-type (leukocyte count ≤13 × 109 L−1) and CMML, MPN-type (leukocyte count > 13 × 109 L−1). Clinical studies with such a classification failed to provide any meaningful biologic or prognostic differences, and this classification was therefore discarded [5, 6].
In 2001, the WHO classification assigned CMML to a new category of myeloid neoplasms—the myelodysplastic/myeloproliferative (MDS/MPN) disorders . Other disorders included in this category are juvenile myelomonocytic leukemia, atypical chronic myeloid leukemia (aCML), BCR-ABL1-negative, and MDS/MPN, unclassifiable. Because the percentage of blast count was perceived to affect prognosis in patients with CMML, WHO created two separate categories among patients with CMML: (a) CMML-1 (<5% peripheral blasts including promonocytes and <10% bone marrow blasts) and (b) CMML-2 (5–19% peripheral blasts including promonocytes or 10–19% bone marrow blasts including promonocytes or presence of Auer rods). The 2008 WHO revision changed the name of the general category of the MDS/MPN disorders to MDS/MPN “neoplasms” to reflect the neoplastic nature of these diseases . The distinction of CMML into CMML-1 and CMML-2 was shown to have prognostic significance in the interim [8, 9], and hence this classification schema was retained.
Epidemiology and clinical manifestations
The incidence and prevalence of CMML are unknown. Large population-based studies estimate that CMML constitutes ∼10% of all cases of MDS [6, 10, 11]. Median age at diagnosis varies between 65 and 75 years, and there is a 2:1 male predominance [10, 12]. The most common symptoms of CMML are a reflection of the underlying cytopenias. Patients with MDS-type CMML present with fatigue and dyspnea due to anemia, susceptibility to infections, and rarely bleeding. Patients with MPN-type CMML present with symptoms of an underlying hypercatabolic state. Some patients may have significant weight loss, drenching night sweats, and left upper quadrant pain from significant splenomegaly. With an increasingly laboratory-oriented management of patients in general, a few are diagnosed very early in the disease stage where they only have monocytosis as the manifestation of their disease. Occasionally, skin infiltration with abnormal monocytes (leukemia cutis) has been reported as the initial manifestation [13, 14]. Some patients may directly present in the blastic phase of CMML as acute myeloid leukemia (AML). CMML may be associated with other malignancies. D816VKIT mutation is observed in >90% patients with systemic mastocytosis . In a recent report, D816V KIT mutation was found in “associated clonal hematological nonmast cell lineage disease” cells in the vast majority of patients with systemic mastocytosis and concomitant CMML . The high frequency of D816VKIT mutation in neoplastic mast cells and leukemic myelomonocytic cells may point to a common precursor in these patients. Therapy-related CMML has been reported to arise following cytotoxic chemotherapy for solid organ tumors [17, 18].
An approach to patients with monocytosis is shown in Fig. 1. It is important to exclude reactive causes of monocytosis before embarking upon a workup of myeloid neoplasm. Monocytosis could be attributable to a number of nonmalignant causes—infectious etiologies such as tuberculosis, chronic fungal infections, infective endocarditis, and viral and protozoal infections; connective tissue disorders such as systemic lupus erythematosus and sarcoidosis, and lipid storage disorders. The recovery phase of an acute infectious illness or the bone marrow regeneration postchemotherapy is generally associated with monocytosis.
Once these etiologies have been ruled out, clonal hematopoietic disorders need to be considered. First, chronic myeloid leukemia (CML) with its distinctive signature of the Philadelphia chromosome or the BCR-ABL1 fusion gene should be tested. Rearrangement of the platelet-derived growth factor A (PDGFRA) and B (PDGFRB) should then be excluded—most of these patients present with concomitant eosinophilia in the peripheral smear. The formation of an ETV6-PDGFRB or other PDGFRB fusion genes due to rearrangement of PDGFRB at 5q31-33, as a distinctive subtype of myeloid neoplasm, is responsive to imatinib . Finally, presence of dysplasia in at least one hematopoietic lineage should be established with a bone marrow biopsy. If myelodysplasia is absent or minimal, a diagnosis of CMML can still be made if criteria in Table I are met. By definition, monocytes are >1 × 109 L−1 in patients with CMML; however, more commonly they range from 2 to 5 × 109 L−1 and at times may exceed 80 × 109 L−1 . In contrast to aCML, BCR-ABL1-negative monocytes constitute >10% of the total leukocyte count in most patients with CMML.
|1. Peripheral blood monocytosis of >1 × 109 L−1|
|2. No Philadelphia chromosome or BCR-ABL1 fusion gene|
|3. No rearrangement of the PDGFRAa or PDGFRBa|
|4. Less than 20% blastsb in the peripheral blood and bone marrow|
|5. Dysplasia present in one or more myeloid lineages. If myelodysplasia is minimal or absent, CMML can still be diagnosed if: an acquired, clonal cytogenetic or molecular cytogenetic abnormality is demonstrated in the hematopoietic stem cell or monocytosis has persisted for greater than 3 months, and all other causes have been excluded|
Histopathology and immuohistochemistry
There is no single finding pathognomonic of the diagnosis of CMML. Instead, CMML is established by a combination of histopathologic features and immunophenotypic characteristics. In patients with CMML, peripheral blood monocytes are generally mature with an unremarkable morphology, but they can sometimes have an unusual chromatin pattern . As stated above, patients with CMML are classified into CMML-1 and CMML-2 depending on the number of peripheral blood and bone marrow blasts. It is important to recognize that in addition to myeloblasts and monoblasts, promonocytes are counted toward the total percent of blasts . It is therefore critical to differentiate promonocytes from unusual looking monocytes in the peripheral smear and the bone marrow. Promonocytes typically have a light-gray cytoplasm with a few lilac-colored granules and a stippled nuclear chromatin.
Hypercellularity of the bone marrow is the most common finding in patients with CMML. There is generally a predominance of the granulocytic lineage, with dysgranulopoiesis being a defining feature of the disease. There is also an increase in the number of monocytes. However, it may be difficult to identify monocytic proliferation in the bone marrow aspirate and biopsy specimen. Staining with naphthyl butyrate esterase may help identify monocytes and differentiate CMML from CML and aCML . Eosinophilia is not as striking in patients with CMML as it is in CML. However, the presence of eosinophilia in the absence of BCR-ABL1 transcripts should alert the pathologist for a possible rearrangement of PDGFRA,PDGFRB, or fibroblast growth factor receptor-1 (FGFR1) overexpression. Aberrant expression of CD25 and CD2 may also be useful to exclude the presence of concomitant mast cell neoplasms. Erythropoiesis is generally decreased and there may be accompanying abnormal nuclear contours, ring sideroblasts, and megaloblastoid changes in red cell precursors. Megakaryocytes are generally small and may have hypolobulated nuclei. Bone marrow fibrosis may be present in up to 30% of patients with CMML . It is generally focal; however, more extensive fibrosis has also been reported . Patients with CMML may also have myeloblasts and monoblasts (which stain for CD34), diffusely or focally, and the percentage of which will determine whether it is CMML-1 (<10%), CMML-2 (11–19%), or AML (≥20%).
The peripheral blood and bone marrow monocytes usually express CD33 and CD13, the typical antigens on myelocytes. There may be variable expression of CD68, CD14, and CD64 . Occasionally, overexpression of CD56, aberrant expression of CD2, and decreased expression of HLA-DR, CD13, CD15, and CD36 may be observed .
Chromosomal and molecular abnormalities
No specific cytogenetic alterations have been identified in chromosome banding analysis of patients with CMML. Some of the more frequently reported recurring abnormalities include: monosomy 7 (3.9–8.5%), trisomy 8 (4.1–7.8%), complex karyotype involving ≥3 abnormalities (4.4–6.3%), trisomy 21 (1–2%), isochromosome 17 (1–2%), deletion 5q (1.5%), and deletion 20q (0.7–1%) [6, 24–26]. Sophisticated methods such as single-nucleotide polymorphism arrays (SNP-A) and comparative genomic hybridization (CGH) have been able to detect microdeletions and microduplications that are missed by conventional metaphase cytogenetic analysis. In patients with CMML, copy number abnormalities have been identified in 49% of patients (with recurrent losses described most commonly at 7q22.1, 4q24, and 11q23.3) . Loss of heterozygosity due to uniparental disomy (seen on chromosomes 1p, 4q, 7q, and 11q) has been described in about 50% of patients with CMML .
Numerous molecular abnormalities have been identified in patients with CMML recently. The earliest molecular aberration reported in patients with CMML was the presence of RAS mutation in up to 40% of patients . Since that publication, others have variably confirmed the incidence to be about 10–26% [29–32]. The discovery of the JAK2V617F mutation in patients with BCR-ABL1-negative MPN [33–36] led investigators to assess for its presence in CMML. Its incidence in patients with CMML has been reported to range anywhere from 8 to 10%, thereby implying that the JAK-STAT pathway is not constitutively activated in the vast majority of these patients [25, 36, 37]. Numerous other gene mutations such as the Casitas B-cell lymphoma (CBL) [26, 28, 38, 39], Runt-related transcription factor 1 (RUNX1) [26, 39, 40], additional sex-comb like 1 (ASXL1) [39, 41, 42], nucleophosphmin 1 (NPM1) , tet oncogene family member 2 (TET2) [26, 44, 45], isocitrate dehydrogenase 1 and 2 (IDH1 and IDH2) [39, 42], and histone methyltransferase (EZH2) [41–43] have been identified with different frequencies in patients with CMML, as shown in Table II. Although the use of techniques such as CGH, SNP-A, and high-throughput sequencing have led to the discovery of a number of molecular abnormalities, the prognostic impact of each of these mutations in the management of patients with CMML remains to be defined. The simultaneous presence of more than one abnormality [26, 39] in patients with CMML indicates that these are likely secondary events and are not the primary drivers of the disease process.
|I. Genes associated with signaling pathways and proliferation|
|RAS (exons 1, 2)||25/65 (38%)||6|
|JAK2 (V617F)||9/116 (8%)||36|
|CBL (exons 8, 9)||10/78 (13%)||28|
|II. Putative tumor suppressor genes|
|RUNX1 (exons 1–8)||12/53 (21%)||39|
|ASXL1 (exon 12)||25/53 (49%)||39|
|NPM1 (exon 12)||6/97 (6%)||43|
|TET2 (exons 3–12)||3/15 (20%)||44|
|III. Epigenetic regulators/others|
|IDH1 (exon 4)||1/81 (1%)||42|
|IDH2 (exon 4)||5/48 (10%)||39|
The International Prognostic Scoring System (IPSS) for survival in MDS was originally proposed in 1997 . This study classified 816 previously untreated patients with MDS into four distinct risk categories (low, intermediate-1, intermediate-2, and high) based on the following: number of cytopenias, karyotype, and percentage of blasts. One hundred and twenty-six patients with CMML were also included in this analysis. However, patients with “proliferative-type CMML” (WBC > 12 × 109 L−1) were excluded from this analysis, because these individuals were believed to predominantly represent MPN rather than MDS. The IPSS classification scheme therefore cannot be used for patients with CMML.
In a retrospective analysis of 213 patients, Onida et al. proposed the “MD Anderson prognostic score (MDAPS)” using four variables: hemoglobin < 12 g/dL, circulating immature myeloid cells, absolute lymphocyte count > 2.5 × 109 L−1, and bone marrow blasts > 10% . Each of these variables was independently associated with a worse survival. This prognostic model identified four groups of patients with median overall survival (OS) of 24, 15, 8, and 5 months. The investigators could not identify a difference in survival when CMML was classified into “dysplastic” and “proliferative” categories based on an arbitrary WBC cutoff value of 13 × 109 L−1. Germing et al. applied the MDAPS to the large MDS registry of Dusseldorf, which consists of 212 patients with CMML . The authors were able to confirm all the adverse prognostic markers of the MDAPS; in addition, they identified an elevated LDH and male sex as also independently associated with worse survival. The Dusseldorf score was developed, which classified patients into three risk categories with median OS of 93, 26, and 11 months. In another single-center study, Breccia et al. identified 83 patients with CMML and divided them according to their baseline WBC count (dividing patients into CMML, MDS-type and CMML, MPN-type) . CMML, MPN-type was associated with shorter median survival and higher disease progression rate when compared with CMML, MDS-type. The MDAPS was not able to segregate patients in this registry. In a more recent study, Such et al. published their experience in 414 CMML patients from the Spanish MDS database . This was the first study that took karyotype into account to determine a survival model. Factors associated with a worse survival on multivariable analysis included: bone marrow blasts ≥10%, leukocyte count ≥ 13 × 109 L−1, hemoglobin < 10 g/dL, platelet count < 100 × 109 L−1, and CMML-specific cytogenetics. This CMML-specific cytogenetics model included three cytogenetic risk categories: low risk (normal karyotype or loss of Y chromosome as a single anomaly), high risk (presence of trisomy 8 or abnormalities of chromosome 7, or complex karyotype), and intermediate risk (all other abnormalities). OS at 5 years for patients in the low-, intermediate-, and high-risk cytogenetic categories was 35, 26, and 4%, respectively.
Rates of transformation into AML vary among different series of patients with CMML reported in the literature. However, most studies quote an incidence of 15–52%, with a higher incidence (albeit statistically nonsignificant) in the CMML, MPN-type when compared with CMML, MDS-type [5, 48, 50]. Development of leukemia cutis has been shown to predict a faster progression to AML .
General principles of treatment
Since the first description of this disease in the 1980s, treatment options were predominantly confined to best supportive care and a “wait and watch” approach until recently . If patients progressed to develop AML, standard induction therapy with cytarabine and an anthracycline was pursued. However, with refinement in the definition, and an improved understanding of the natural history of the disease as being sufficiently distinct from MDS, various treatment strategies have been used. These include cytotoxic agents, hypomethylating agents, histone deacetylase inhibitors, and farnesyltransferase inhibitors (Table III). With the introduction of reduced intensity conditioning (RIC), allogeneic stem cell transplantation (SCT) has also become an attractive option for the treatment of a subset of patients with CMML. Definitions of complete remission (CR), partial remission (PR), and hematologic improvement (HI) in most of the studies listed below are based on the 2000 report of an International Working Group for MDS .
|I. Cytotoxic chemotherapy|
|51||105||71 (38–91)||III||1–4 g/day of hydroxyurea versus 150–600 mg/week of oral etoposide||60% in the hydroyurea arm versus 36% in etoposide arm||Higher incidence of alopecia in etoposide arm||20 months in hydroxyurea arm versus 9 months in the etoposide arm||27% in hydroxyurea arm versus 38% in etoposide arm|
|52||30||66 (39–84)||II||Topotecan 2 mg/m2 continuous infusion daily for 5 days, courses repeated every 4–8 weeks||CR: 27%, HI: 12%||Mucositis, diarrhea, neuropathy. Induction mortality: 20%||10.5 months||NR|
|53||27||64 (21–80)||II||Topotecan 1.25 mg/m2 continuous infusion and cytarabine 1.0 g/m2 over 2 hr for 5 days; courses repeated every 4–8 weeks||CR: 44%, HI: NR||Mucositis, diarrhea, rash. Induction mortality: 7%||9.4 months||NR|
|54||32||68 (29–81)||II||9-Nitro-camptothecin 2 mg/m2 orally daily for 5 days a week, every 4–6 weeks||CR: 11%, PR: 16%, HI: 16%||Nausea, vomiting, and diarrhea||14 months||NR|
|II. Hypomethylating agents|
|55||191 (14 with CMML)||68 (31–92)||III||Azacitidine (75 mg/m2/day subcutaneously for 7 days every 28 days) versus supportive care||CR: 7%, PR: 16%, HI: 37% in azacitidine arm versus 5% in the supportive care arm||Infectious complications: 20%, treatment-related mortality: 1%||20 months for azacitidine versus 14 months for supportive care||15% for azacitidine versus 38% for supportive care|
|56||170 (14 with CMML)||70 (65–76)||III||Decitabine at a dose of 15 mg/m2 given intravenously was administered over 3 hr every 8 hr for 3 days versus supportive care||CR: 8%, PR: 7%, HI: 13% in decitabine arm versus 6% in supportive arm||Infectious complications: 18%||14.0 months for decitabine versus 14.9 months for supportive care||12.1 months for decitabine versus 7.8 months for supportive care|
|57||19||66 (44–82)||II||Decitabine 100 mg/m2 per course in three different schedules, repeated every 4 weeks||CR: 58%, HI: 11%||Myelosuppression-associated complications: 8%||19 months||NR|
|58||31||71 (53–81)||II||Decitabine 15 mg/m2 over 4 hr IV three times per day on 3 consecutive days with a total dose of 135 mg/m2 per course every 6 weeks||CR: 10%, PR: 16%, HI: 19%||Nausea, vomiting, and pneumonia. Mortality due to sepsis: 3%||15 months||NR|
|59||38||70 (36–83)||II||Azacitidine 75 mg/m2/day for 7 days or 100 mg/m2/day for 5 days every 4 weeks||CR: 11%, PR: 3%, HI: 25%||Pneumonia. Mortality due to sepsis: 3%||12 months||NR|
|60||41 (4 with CMML)||70 (31–91)||I||One cycle of subcutaneous azacitidine 75 mg/m2 on the first 7 days of cycle 1, followed by oral azacitidine daily,120–600 mg, on the first 7 days of each additional 28-day cycle||ORR: 35% in previously treated patients and 73% in previously untreated patients||diarrhea, nausea, vomiting, febrile neutropenia, and fatigue||NR||NR|
|61||39||71 (54–88)||II||Decitabine 20 mg/m2 per day intravenously for 5 days every 28 days||CR: 10%, PR: 20%, HI: 8%, ORR: 38%||Neutropenia and thrombocytopenia (36%), severe infection (20%)||18 months||NR|
|III. Histone deacetylase inhibitors|
|62||19 (4 with CMML)||73 (59–84)||II||Oral valproic acid to achieve serum concentration of 500–700 μmol/L and 13-cis-retinoid acid 10 mg twice a day and Vitamin D3 once a day||CR: 0%, HI: 16%||Fatigue, transaminitis, pneumonia, and hypertriglyceridemia||NR||NR|
|IV. Farnesyltransferase inhibitors|
|63||67 (35 with CMML)||75 (44–86)||II||Lonafarnib 200 mg orally twice daily continuously||CR: 2% (6% in CMML), PR: 1% (3% in CMML), HI: 19%||Diarrhea, nausea/vomiting, fatigue, and anorexia||NR||NR|
In one of the earliest reported randomized trials for CMML, Wattel et al. compared 1,000 mg/day of oral hydroxyurea to 150 mg/week of oral etoposide in 105 patients . After a median follow-up of 11 months, 60% of patients in the hydroxyurea arm responded compared with 36% in the etoposide arm. Median OS was statistically superior in the hydroxyurea arm (20 versus 9 months). Although this study established superiority of hydroxyurea over etoposide, it was regarded to be a nonspecific treatment for such patients. Low-dose cytarabine with or without the use of all-trans retinoic acid has also been used [65–67]. The extremely small number of patients in these studies with varying schedules of treatment precludes a definitive assessment of the merit of this combination in the treatment of patients with CMML.
Investigators from M.D. Anderson Cancer Center studied other topoisomerase inhibitors for the treatment of CMML. Beran et al. reported the use of topotecan at a dose of 2 mg/m2 as a continuous infusion for 5 days . These courses were repeated every 4–8 weeks. Twenty-seven percent of patients achieved CR and 12% experienced HI. Their median OS was 10.5 months, and most common toxicities were mucositis, diarrhea, and neuropathy. However, the induction mortality was 20%. To reduce toxicity and improve response rate (RR), Beran et al. subsequently administered topotecan at a dose of 1.25 mg/m2 as a continuous infusion and cytarabine 1,000 mg/m2 over 2 hr, both for 5 days, to 27 patients with CMML . A CR of 44% was achieved, and the median OS was 9.4 months. Induction mortality was 7%. Another study studied a novel topoisomerase inhibitor, 9-nitro-campothecin, at a dose of 2 mg/m2 orally daily for 5 days a week in 32 patients with CMML . Although the median OS in this series was 14 months, the CR was 11%, PR was 16%, and HI was achieved in 16% patients. This regimen was well tolerated, with nausea and vomiting being the most common toxicities.
The United States Food and Drug Administration (FDA) approved two hypomethylating agents, azacitidine and decitabine, for treatment of patients with MDS. Two pivotal randomized studies that established the efficacy and safety of these drugs included a combined total of 361 patients with MDS [55, 56]. However, these studies only had 14 patients with CMML each. Although the RRs for patients with CMML are not reported separately in these trials, Silverman et al. reported that among patients treated with azacitidine, there were no significant differences in RRs among patients with refractory anemia and refractory anemia with ringed sideroblasts when compared with those with refractory anemia with excess blasts and CMML . Only one out of the seven CMML patients (17%) randomized to the decitabine arm in the second study reported by Kantarjian et al. had a response .
Several Phase II studies have now been completed using hypomethylating agents specifically in patients with CMML. In a study of 19 patients treated with decitabine at a dose of 100 mg/m2 per course in different schedules, Aribi et al. reported a CR of 58% and HI in 11% . The median OS of the cohort was 19 months, and 8% patients experienced myelosuppression-associated complications. Wijermans et al. studied decitabine (total dose of 135 mg/m2 per course, administered as 15 mg/m2 over 4 hr IV three times a day) in 31 patients with CMML . The CR was 10%, PR was 16%, and 19% patients experienced HI for an overall RR (ORR) of 45%. The median OS was 15 months, and mortality was 3% due to sepsis. Costa et al. studied azacitidine in 38 patients with CMML in two different schedules (azacitidine 75 mg/m2/day for 7 days or 100 mg/m2/day for 5 days, every 4 weeks) and reported a CR of 11%, PR in 3%, and HI in 25% . The median OS was 12 months and mortality due to sepsis was seen in 3% patients. In a recently reported study, Garcia-Manero et al. studied the efficacy and toxicity of oral azacitidine in 41 patients with high-risk MDS, CMML, and AML . There were only four patients with CMML in the study. The ORR in patients with MDS and CMML was 35% in previously treated patients and 73% in newly diagnosed patients. To study the impact of molecular factors that might predict response to therapy, Braun et al. administered decitabine at standard doses and schedule to 39 patients with CMML . The ORR was 38% with 10% CR, 21% PR, and 8% patients experiencing HI. With a median follow-up of 23 months, OS was 48% at 2 years. Mutations in ASXL1, TET2, NRAS, KRAS, CBL, FLT3, and JAK2 genes, and hypermethylation of the promoter of the tumor suppressor gene, transcription-intermediary factor-1 gene (TIF1γ), did not predict response or survival. Lower CJUN and CMYB gene expression levels independently predicted improved OS.
There has been limited experience with the use of other agents such as histone deacetylase inhibitors and farnesyltransferase inhibitors in patients with CMML. Overall, the results for both these classes of drugs have been disappointing with CR seen in up to 6% and HI in 16–19% of patients [62, 63].
There appears to be a limited role of cytotoxic chemotherapy in the contemporary management of patients with CMML. Hydroxyurea remains the cornerstone of therapy for patients with an elevated leukocyte count. Guidelines for supportive care measures such as the use of erythropoietin analogs for the treatment of anemia, prophylactic antibiotics for isolated neutropenia, and iron chelators for patients with heavy transfusion burdens are generally similar to patients with MDS , and data for their use specifically in patients with CMML do not exist.
Hypomethylating agents are the most commonly prescribed medications in the community for patients with CMML. Unfortunately, there are no Phase III randomized trials sufficiently powered for CMML alone to guide therapy. ORRs vary from 40 to 70% in selected groups of patients. At the present time, a distinction into CMML-1 or CMML-2 and risk stratification with any of the several survival models reported [6, 47–49] do not dictate therapy. According to the Spanish CMML-cytogenetics model, low-risk patients have a 5-year survival of 35%, which suggests that all patients with CMML need to be considered for active treatment at the time of diagnosis. Clinical trials are the best option for patients who are willing to participate. A search on www.clinicaltrials.gov identified 97 studies actively recruiting patients for treatment of CMML . Novel agents such as oral clofarabine (nucleoside analog), lenalidomide (immunomodulatory agent), and vorinostat and panabinostat (histone deacetylase inhibitors) either alone or in combination with hypomethylating agents are being actively investigated.
Allogeneic stem cell transplantation
An allogeneic SCT is the only treatment option for patients with CMML that can maintain a long-term remission and offer a cure to some patients. With the advent of RIC regimens, high-resolution human leukocyte antigen (HLA) typing, and with improvements in management options for graft-versus-host disease (GVHD) and immunosuppression; RRs, and nonrelapse mortality (NRM), has improved for patients undergoing SCT. Unfortunately, there have been no randomized trials to adequately study the impact of SCT in patients with CMML. Frequently, these patients have been combined with patients with MDS or MDS transformed into AML, precluding an adequate analysis. The vast majority of data available are from retrospective registry from large transplant centers.
In one of the largest series reported to date (abstract form only) from the European Group for Blood and Marrow Transplantation, 283 patients with CMML who underwent SCT were retrospectively analyzed . Eighty-seven patients (31%) underwent RIC and 175 patients (62%) received peripheral blood stem cells (PBSCs). Two hundred and forty-five patients (93%) successfully engrafted. Grade III/IV acute GVHD occurred in 85 of 258 evaluable patients (30%), and chronic GVHD occurred in 58 of 102 evaluable patients (57%). NRM was 37% and was lower in patients with PBSC recipients and those that were transplanted after 2002. None of the baseline factors including the conditioning regimen, age, disease status at transplant, cytogenetics, donor–recipient gender match, HLA type of donor, stem cell source, T-cell depletion, or the development of GVHD affected the relapse-free survival (RFS) or the OS.
In another large retrospective analysis from the Fred Hutchinson Cancer Center, Eissa et al. reported the outcomes of 85 patients with CMML who underwent SCT between 1986 and 2008 at their institution . Children were also included in this analysis. Twenty-seven patients (32%) underwent RIC and 53 patients (62%) received PBSC. Seventy-seven patients (91%) achieved sustained engraftment. Acute GVHD of Grades III/IV developed in 21 of 81 patients (26%) and chronic GVHD occurred in 37 patients (44%). After a median follow-up of 5.2 years, 49 patients had died, 20 with progression of CMML and 29 from nonrelapse causes. Ten-year RFS was 40%. A multivariable model identified increasing age, higher SCT comorbidity index, and poor-risk cytogenetics associated with increased mortality and reduced RFS.
As shown in Table IV, there are a number of other retrospective series of CMML patients at varying stages of disease who underwent SCT [72–76]. In these studies, RRs have ranged from 17 to 50% and treatment-related mortality from 12 to 52%. Most of these studies report a combination of patients receiving RIC and myeloablative conditioning, and patients received bone marrow stem cells and PBSCs (with a higher proportion receiving RIC and PBSC in recent series).
|72||50||44 (19–61)||CMML-1: 28||Diploid: 18||MRD: 43||MAC: 50||RR: 28%||5-year OS: 21%|
|CMML-2: 17||Abnormal: 11||MUD: 7||RIC: 0||TRM: 52%||5-year DFS: 18%|
|Unknown: 5||Unknown: 21||BM: 40|
|73||8||51 (20–64)||NR||Diploid: 3||MRD: 6||MAC: 4||RR: 50%||18-month OS: 35%|
|Abnormal: 4||MUD: 2||RIC: 4||TRM: 12%||18-month DFS: 31%|
|Unknown: 1||BM: 4|
|74||17||50 (20–60)||NR||Diploid: 9||MRD:14||MAC: 16||RR: 41%||3-year OS: 18%|
|Abnormal: 8||MUD:3||RIC: 1||TRM: 41%||3-year RFS: 18%|
|75||12||56 (38–67)||CMML-1: 7||Diploid: 7||MUD: 11||MAC: 7||RR: 17%||2-year OS: 75%|
|CMML-2: 3||Abnormal: 4||MRD: 1||RIC: 6||TRM: 25%||2-year DFS: 67%|
|Unknown: 2||Unknown: 1||BM: 0|
|76||18||54 (38–66)||CMML-1: 8||Diploid: 7||MRD: 10||MAC: 1||RR: 44%||3-year OS: 31%|
|CMML-2: 10||Abnormal: 11||MUD: 8||RIC: 17||TRM: 31%||3-year DFS: 47% (<5% blasts)|
|BM: 6||3-year DFS: 20% (>5% blasts)|
|70||283||50 (median not reported)||CMML-MDS: 45||NR||MRD: 160||MAC: 152||RR: 25%||OS: 42%|
|CMML-MPN: 60||MUD: 85||RIC: 87||TRM: 37%||DFS: 38% (time interval not specified)|
|Unknown: 178||Unknown: 38|
|71||85||51 (1–69)||CMML-1: 57||Good: 45||MRD: 38||MAC: 58||RR (10 years): 27%||10-year OS: 40%|
|CMML-2: 26||Intermediate: 14||MUD: 47||RIC: 27||TRM (10 years): 35%|
|Poor: 22||BM: 32||10-year DFS: 40%|
Although the results with SCT are promising and will most likely improve over time, the precise indication for SCT in CMML is still debated. Certainly, young patients with poor-risk cytogenetics who have a matched donor available should be considered for SCT. Older patients with a high SCT comorbidity index would not benefit from SCT and are best suited for clinical trials with novel agents. From the studies published thus far, it appears that the use of hypomethylating agents before transplantation is well tolerated and does not appear to adversely impact posttransplantation outcomes. The source of stem cells (BM versus PB) and the type of donor (matched related versus matched unrelated) do not adversely impact outcomes. Reduced intensity conditioning has been shown to improve NRM, OS, and RFS .
The cumulative experience of the scientific literature thus far shows that CMML remains a difficult malignancy to treat, with median survival ranging from 12 to 18 months. Despite the approval of two drugs by the FDA and decent RRs, the natural history of CMML has not changed. With the introduction of newer molecular techniques and the identification of genetic instability in patients with CMML, it is hoped that targeted therapies will become available. Unfortunately, thus far, no single genetic abnormality has been a characteristic of CMML. A smattering of multiple such genetic findings indicates that these findings all represent a noise, rather than a true driving force in the pathogenesis of CMML. Investigators, both bench and clinical, need to work together in close concert in order to be able to identify truly effective novel therapies for these patients.
Disease Overview: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder that is classified as a myelodysplastic/myeloproliferative neoplasm by the 2008 World Health Organization classification of hematopoietic tumors. It is characterized by absolute monocytosis (>1 × 109 L−1) in the peripheral blood that persists for at least 3 months. Patients may present with symptoms related to cytopenias and/or an underlying hypercatabolic state with drenching night sweats, splenomegaly, and weight loss.
Diagnosis: The diagnosis of CMML rests on a combination of morphologic, histopathologic, and chromosomal abnormalities in the bone marrow, after careful exclusion of other conditions (both malignant and nonmalignant) that can cause monocytosis. Numerous molecular abnormalities have been recently recognized in patients with CMML—unfortunately, no single pathognomonic finding specific to CMML has been identified thus far.
Risk stratification: The International Prognostic Scoring System for myelodysplastic syndrome (MDS) cannot be used to risk stratify patients with CMML because this model excluded patients with a leukocyte count >12 × 109 L−1. Other risk stratification models such as the MD Anderson prognostic score and Dusseldorf score have been published. In the only model that took karyotype into account, bone marrow blasts ≥ 10%, leukocyte count ≥ 13 × 109 L−1, hemoglobin < 10 g/dL, platelet count < 100 × 109 L−1, and presence of trisomy 8, abnormalities of chromosome 7, or complex karyotype were found to be independent predictors of adverse survival.
Risk-adapted therapy: The Food and Drug Administration has approved azacitidine and decitabine for the treatment of patients with CMML based on two pivotal trials in MDS. Novel classes of agents including immunomodulatory drugs, nucleoside analogs, and small-molecule tyrosine kinase inhibitors are being investigated in the treatment of CMML. With the advent of reduced intensity conditioning, an allogeneic stem cell transplant has also become a viable option for a subset of patients. Am. J. Hematol. 87:610–619, 2012. © 2012 Wiley Periodicals, Inc.