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© 2001 American Society for Clinical Oncology
Classifying Chronic Myelomonocytic LeukemiaThe Brooklyn Hospital Center, Brooklyn, NY, New York University Medical Center, New York, NY To the Editor:We read with interest the discussion of "Problematic WHO Reclassification of Myelodysplastic Syndromes" that appeared in the October 1, 2000, issue of the Journal.1 Of particular interest is the World Health Organization (WHO) committee’s proposal to remove chronic myelomonocytic leukemia (CMML) from the category of myelodysplastic syndromes (MDSs) for reclassification as a subgroup of MDS/myeloproliferative diseases (MPDs). The International Myelodysplastic Syndrome Study Group (IMDSSG) does not concur, noting that "although cellular dysplasia may be present, CMML is predominantly an MPD with dominant clinical characteristics of excessive myeloproliferation,"1 and adds that the "MDS patients with relatively low WBCs with monocytosis seem to be best categorized as an MDS subgroup rather than as standard CMML." The WHO committee has stated that "subdividing CMML arbitrarily into two subtypes would not help to understand it any better."2 A recent work by Germing et al3 suggests that "division of CMML into MPD and MDS types according to the leukocyte count is likely not sufficient to recognize subgroups of CMML with major biologic or prognostic differences." Thus, in contention is optimal categorization of the CMML. The major aspects of this dilemma, in our opinion, are (1) diversity of CMML, (2) inconsistent application of pathogenic concept to all MDS subtypes, and (3) semantics. Diversity of CMML. CMML classification is confounded by the diversity of clinical behavior and morphology, as has long been apparent.4-6 CMML has been variously described as a preleukemic condition with predominant dysplasia,4 a myeloproliferative disease,7,8 and a mixed proliferative and dysplastic process.5,6 CMML discussion has been hampered by casual definitions of fundamental terminology, including "myeloproliferative" and "myelomonocytic." "Myeloproliferation" has been considered variously to mean marrow hypercellularity or any process involving myeloid leukocytosis and splenomegaly. "Myelomonocytic" has also been variously used to describe bilineage proliferation limited to granulocytes and monocytes5 and a multilineage marrow proliferation.4 The inclusion of CMML by the French-American-British (FAB) group in MDS classification9 increased appreciation of the dysplastic features of CMML but not its diversity. The recent WHO proposal to include CMML (along with atypical chronic myeloid leukemia and juvenile myelomonocytic leukemia) in a new category reflects the mixed nature of CMML. Since this proposed category comprises diseases with mixed features, it could potentially quench arguments regarding whether CMML is more MDS or MPD but it will not resolve whether CMML is a single entity with mixed features or a mixture of similar but distinct diseases. The concept of the CMML as a single disease with multiple patterns seems suspect. Pathogenic concept. The pathogenic concept of MDS as a process of ineffective myelopoiesis is inadequate for CMML in general because many patients display exceedingly effective myelopoiesis. Additionally, cellular dysplasia is recognized to be a secondary event in the context of frank leukemia, where it has been referred to as a leukemic "chaperon" and likewise occurs in myeloproliferative disorders. In contrast to dysplasia, the number of WBCs distinguishes between two pathogenically different processes: myeloproliferation, an overly effective myelopoiesis, and myelodysplasia, an ineffective myelopoiesis. However, two CMML subtypes proposed by the FAB group—myelodysplastic CMML (MDS-CMML) and myeloproliferative CMML (MPD-CMML), based on WBC count in blood10—had similar major clinical or laboratory findings.3,11,12 A limitation of these studies is violation of the same MDS pathogenic concept. Indeed, splenomegaly as a marker of myeloproliferation is not recognized by most CMML studies,3,11,12 which has resulted in significant overlap between these different groups of patients. In addition, the absolute neutrophil count rather than total WBC count is a better indicator of myeloproliferation, particularly in patients with normal or nearly normal WBCs. Therefore, multiple criteria13,14 rather than a sole variable, such as WBCs, is needed to discriminate myeloproliferative and myelodysplastic categories. Semantics. Discussion of CMML categorization is limited by the reality that the term CMML includes patients with widely different manifestations. The disease is too diverse to be meaningfully defined by a single term. In addition, the descriptive terms "myeloproliferative" and "myelomonocytic," as mentioned above, require uniform definition. Thus, we agree with the IMDSSG recommendation that CMML be subcategorized. We previously proposed that splitting FAB-CMML into several subcategories helpfully describes its heterogeneity,13-15 and similar to the current IMDSSG proposal, we categorized patients with normal or low neutrophil count without splenomegaly as having MDS. The proposed groups included refractory anemia and refractory anemia with excess of blasts with associated monocytosis. Myelomonocytic dysplasia was proposed as an indolent entity within the MDS category. The recognition of these MDS subtypes as distinct entities provides a basis for their uniform identification, diagnosis, and comparative therapeutic trials. The term "CMML," however limited, is unsurpassed in delineating patients with apparent myeloproliferative features, such as neutrophilia and splenomegaly. Diagnostic criteria for this relatively indolent type of leukemia were reported in older literature.7,8 Our findings suggest at least two distinct subtypes of this chronic myeloid leukemia–like disease, differing in WBC count, monocyte count, degree of dysplasia, and, perhaps, survival, can be identified.14 Pronounced dysplasia associated with one of these subtypes may have created confusion between MDS and CMML. Given these vagaries, any statement that "CMML is predominantly an MPD"1 clearly is not our intent; rather we believe that the CMML patients diagnosed according to the FAB criteria can be interpreted as having either MPD or MDS but not as having predominantly one of the diseases or, more confusing, a mixture of the diseases. If one disregards FAB criteria, CMML becomes truly and exclusively an MPD. In summary, the WHO’s opinion that a less restrictive view of CMML will resolve arguments of classification may not be correct. We strongly believe that lack of due restrictions caused the situation that for years CMML cannot be agreed on. We concur with the WHO’s opinion, however, that CMML should not be subdivided arbitrarily. On the contrary, strict and rational criteria can do a trick. Through separating distinct entities covered presently by the FAB-CMML umbrella term, it should become possible to report these entities uniformly and thus to better understand and predict their natural course. Furthermore, more scrupulous analysis of these patients, which is a prerequisite for CMML subcategorization, can be of enormous help in distinguishing conditions that may seem like CMML but in fact are different diseases. The most typical scenario is an early stage of acute leukemia (prodrome) developing from underlying MDS with increased monocytes, which are frequently unrecognized monoblasts. In conclusion, the subcategorization of the FAB-CMML that we have been using for almost 20 years proved to be effective and practical, and the whole concept of the FAB-CMML as a cluster of diseases that should be viewed apart, entirely satisfying. Beyond a doubt, these diseases must have their own name. REFERENCES
1.
Members of the International MDS Study Group: Problematic WHO reclassification of myelodysplastic syndromes. J Clin Oncol 18: 3447-3449, 2000 (letter) 2. Members of the WHO Myeloid Disease Writing Committees and the WHO Clinical Advisory Committee: Problematic WHO reclassification of myelodysplastic syndromes, Reply 1. J Clin Oncol 18: 3449-3451, 2000 (letter) 3. Germing U, Gatterman N, Minning H, et al: Problems in the classification of CMML: Dysplastic versus proliferative type. Leukemia Res 22: 871-878, 1998[Medline] 4. Saarni MI, Linman JW: Myelomonocytic leukemia: Disorderly proliferation of all marrow cells. Cancer 27: 1221-1230, 1970 5. Miescher P, Farquet J: Chronic myelomonocytic leukemia in adults. Semin Hematol 11: 129-139, 1974[Medline] 6. Geary C, Catovsky D, Witlshaw E, et al: Chronic myelomonocytic leukemia. Br J Haematol 30: 289-302, 1975[Medline] 7. Gingrich R, Burns P: Disseminated coagulopathy in chronic myelomonocytic leukemia. Cancer 44: 2249-2253, 1979[Medline] 8. Iavorkovskii LI, Solovei DY, Press BO, et al: Chronic myelomonocytic leukemia. Problemi Gematologii 1: 40-45, 1974 9. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndrome. Br J Haematol 51: 189-199, 1982[Medline] 10. Bennett JM, Catovsky D, Daniel MT, et al: The chronic myeloid leukemias: Guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukemia—Proposals by the French-American-British Cooperative Leukemia Group. Br J Haematol 87: 746-754, 1994[Medline] 11. Noesslinger T, Pfeilstoecker M, Tuechler H, et al: Dysplastic vs. proliferative CMML: Retrospective analysis of 92 patients from a single institution. Blood 92: 628a, 1998 (suppl 1, abstr) 12. Oscier D, Chapmena R: The classification of chronic myelomonocytic leukemia. Leuk Res 22: 779-880, 1998 (commentary)[Medline] 13. Yavorkovsky LL, Solovey DY, Ryauzova LY, et al: FAB-classification of chronic myelomonocytic leukemia: Heterogeneity revealed on the basis of bone marrow findings. Neoplasma 35: 565-569, 1988[Medline] 14. Yavorkovsky LL, Ryauzova LY, Solovey DY, et al: Diversity of bone marrow findings in CMML, in Fleischer J (ed): Leukemias. Berlin, Germany, Springer-Verlag, 1993, pp 11-13 15. Iavorkovskii LL, Solovei DY, Ryauzova LY, et al: Significance of the bone marrow biopsy in differentiation of chronic myelomonocytic leukemia. Gematol Transfuziol 33: 23-28, 1988
Response
Stanford University Medical Center, Stanford, CA In Reply:Drs Yavorkovsky and Cook comment on difficulties inherent in the term "chronic myelomonocytic leukemia" (CMML), one of the issues we raised in our discussion of concerns1 about the recent proposals by the World Health Organization’s panel for reclassifying myelodysplastic syndromes (MDSs).2 Although CMML was initially included within the MDSs by the French-American-British group,3 its clinical and biologic heterogeneity is well recognized. The proliferative form of CMML (ie, with high WBC counts, hepatosplenomegaly, and constitutional symptoms) is more characteristic of a myeloproliferative disorder (MPD) that of an MDS.4-8 The disorder differs in its management issues (ie, control of hyperleukocytosis, organomegaly, and their consequences) and major clinical features from the nonproliferative subtype of CMML (ie, MDS accompanied by monocytosis but relatively low WBC counts); patients with the latter subtype previously were likely considered to have monocystosis as a component of their refractory anemia or refractory anemia with excess blasts. Clinical outcomes in CMML are more closely related to their proportion of marrow blasts than to their peripheral monocyte numbers.5,6,9 For these reasons, the International MDS Risk Analysis Workshop (IMRAW)10 and others7 attempted to diminish the heterogeneity present within MDS by excluding from this entity the proliferative type of CMML, including only those with WBC counts less than 12,000/mm3. Although the recent World Health Organization panel initially placed all CMML patients in a separate category (MDS/MPD),2 this proposal has subsequently been revised such that the same leukocyte count as used by the Workshop was utilized to separate MDS from MDS/MPD (the latter including proliferative CMML).11 Despite this segregation, we agree with Yavorkovsky and Cook that clinical heterogeneity remains; some MDS patients with monocytosis and dysplasia may develop a proliferative phase akin to CMML. Biologic as well as clinical features also segregate the two types of CMML. Molecular lesions that result in a "gain of function," including activating ras and c-fms oncogene mutations, which are capable of altering cell proliferation patterns, are common features of hemopoietic cells in proliferative-type CMML and in patients with undifferentiated MPD, but less so for MDS.12-14 In addition, cytogenetic changes, such as the t(5;12) translocation, which results in a fusion protein between the platelet-derived growth factor receptor beta and the transcription factor tel, are present in a subset of CMML patients.15 Related to these findings, biologic features of hemopoietic precursors from juvenile myelomonocytic leukemia (a disease similar to proliferative CMML) demonstrate in vitro hyperresponsiveness to myeloid growth factors arising from inactivating mutations of the GTPase, NF1, and unrestrained ras activation.16,17 Thus, important focus is needed to extend the debate regarding these patients. Studies are required to evaluate clinical outcomes in the two types of CMML and to analyze of their biologic, cytogenetic, and molecular parameters. Combining such analyses with a study of their morphologic features should permit a more rational and therapeutically useful approach for categorizing these patients. REFERENCES 1. Greenberg P, Anderson J, De Witte T, et al: Problematic WHO re-classification of myelodysplastic syndromes. J Clin Oncol 18: 3447-3449, 2000
2.
Harris N, Jaffe E, Diebold J, et al: WHO classification of neoplastic diseases of the hematopoietic and lymphoid tissues: Report of the Clinical Advisory Committee meeting—Airlie House, Virginia, November 1997. J Clin Oncol 17: 3835-3849, 1999 3. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51: 189-199, 1982 4. Worsley A, Oscier D, Stevens J, et al: Prognostic features of chronic myelomonocytic leukemia. Br J Haematol 68: 17-21, 1988[Medline]
5.
Fenaux P, Beuscart R, Lai JL, et al: Prognostic factors in adult chronic myelomonocytic leukemia: An analysis of 107 cases. J Clin Oncol 6: 1417-1424, 1988 6. Storniolo AM, Moloney WC, Rosenthal DS, et al: Chronic myelomonocytic leukemia. Leukemia 4: 766-770, 1990[Medline] 7. Bennett JM, Catovsky D, Daniel MT, et al: The chronic myeloid leukaemias: Guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia: Proposals by the French-American-British Cooperative Leukaemia Group. Br J Haematol 87: 746-754, 1994 8. Germing U, Gattermann N, Minning H, et al: Problems in the classification of CMML-dysplastic versus proliferative type. Leuk Res 22: 871-878, 1998 9. Oscier D, Chapman R: The classification of chronic myelomonocytic leukaemia. Leuk Res 22: 879-880, 1988
10.
Greenberg P, Cox C, Le Beau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89: 2079-2088, 1997 11. Bennett J: WHO classification of the acute leukemias and myelodysplastic syndrome. Int J Hematol 72: 131-133, 2000[Medline]
12.
Hirsch-Ginsberg C, LeMaistre AC, Kantarjian H, et al: Ras mutations are rare events in Philadelphia chromosome-negative/bcr gene rearrangement-negative chronic myelogenous leukemia, but are prevalent in chronic myelomonocytic leukemia. Blood 76: 1214-1219, 1990
13.
Beaupre DM, Kurzrock R: Ras and leukemia: From basic mechanisms to gene-directed therapy. J Clin Oncol 17: 1071-1079, 1999 14. Carter G, Ridge S, Padua RA: Genetic lesions in preleukemia. Crit Rev Oncog 3: 339364, 1992 15. Golub TR, Barker GF, Lovett M, et al: Fusion of PDGF receptor beta to a novel ets-like gene, tel, in chronic myelomonocytic leukemia with t(5;12) chromosomal translocation. Cell 77: 307-316, 1994[Medline] 16. Emmanuel PD, Bates LJ, Castleberry RP, et al: Selective hypersensitivity to granulocyte-macrophage colony-stimulating factor by juvenile chronic myeloid leukemia hematopoietic progenitors. Blood 77: 925929, 1991
17.
Shannon KM, O’Connell P, Martin GA, et al: Loss of the normal NF1 allele from the bone marrow of children with type 1 neurofibromatosis and malignant myeloid disorders. N Engl J Med 330: 597-601, 1994
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Copyright © 2001 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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