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© 2000 American Society for Clinical Oncology
Problematic WHO Reclassification of Myelodysplastic Syndromes
To the Editor:A World Health Organization (WHO) panel recently issued a report in the Journal of Clinical Oncology with proposals for reclassifying myelodysplastic syndromes (MDS).1 In this report, suggestions were made to modify the French-American-British (FAB) definitions2 of MDS. An important goal for characterizing patients with MDS is to further improve methods that enhance our ability to better risk-stratify patients according to their morphologic and biologic features. Such approaches could improve prognostication and treatment for these individuals, but any changes should be evidence-based. Many of the proposals of the WHO panel are controversial, lack supportive data, and should not be adopted without much wider discussion. 1. The WHO panel proposed excluding refractory anemia with excess blasts in transformation (RAEBT) patients from MDS, proposing acute myeloid leukemia (AML) to now include patients with 20% marrow blasts rather than the previously used 30% value.3 We recognize that the blast percentage alone is an arbitrary feature. However, MDS is distinguished from de novo AML not merely by marrow blast count, but by a more indolent pace of disease associated with distinctive biologic features.4,5 For a number of reasons, we believe that RAEBT is not AML, and its inclusion as AML would be problematic. In contrast to AML, the differing features of RAEBT include the following: (a) the pace of disease is more indolent (thus requiring MDS to have clinical stability for 1 to 2 months, in contrast to the relatively acute course of AML)4; (b) some early MDS patients evolve into RAEBT, generally with an indolent course; (c) morphologic dysplasia is evident in RAEBT, not in all AML patients; (d) the biology of RAEBT stem cells differs from that of standard AML, with an increase in the former entity of complex/poor-risk cytogenetics, early stem-cell phenotype, and multidrug resistance overexpression5,6; and (e) RAEBT patients (diagnosed with characteristics excluding true de novo AML) have poorer response to standard chemotherapy.7,8 This feature is associated with the inherent biology of the MDS-related neoplastic clone rather than solely with the blast percentage per se. Given these disparate features, we are concerned that the WHO proposal merging RAEBT and AML risks losing these fundamental distinctions. Such approaches have implications for patient management as well as for accurate design and interpretation of clinical trials. 2. The WHO panel also proposed that refractory anemia (RA, or refractory anemia with ringed sideroblasts [RARS] have abnormalities solely involving the erythroid line. However, as clinically characterized by most MDS investigators, MDS requires dysplasia in at least two hematopoietic cell lines.4 It is well recognized that RARS (a subgroup of MDS) differs clinically from unilineage erythroid dysplasia, such as is present in pure sideroblastic anemia (also termed idiopathic sideroblastic ineffective erythropoiesis).9 The latter has a much improved natural history, essentially lacking evolution to AML. These unilineage erythroid dysplastic changes may also occur in a number of reactive nonneoplastic conditions. Merging these distinctive entities would problematically blur relevant clinical distinctions. 3. The WHO panel added a new category of "refractory cytopenia with multilineage dysplasia (RCMD)". Although many patients with these findings have poorer prognoses than those lacking extensive dysplasia,10 data have not demonstrated independent prognostic value of these abnormalities (ie, independent of marrow cytogenetic abnormalities and blasts, degree and number of cytopenias). Such weighting of clinical and biologic variables has been shown by the International MDS Risk Analysis Workshop to be important for classifying MDS, generating the International Prognostic Scoring System (IPSS).4 In addition, RARS patients with multilineage dysplasia would be merged with other RCMDs, despite data indicating differences for RARS regarding certain therapeutic responses.11 These features highlight two important issues not addressed by the WHO proposals: (a) the lack of minimum essential criteria for defining MDS, and (b) the lack of morphologic criteria for defining dysplastic involvement of a particular hematopoietic cell line (as needed for the diagnosis of RCMD and RA). 4. The WHO group proposed another new category: "MDS, unclassifiable." This entity is not further defined. Such a category is confusing and would include a miscellany of poorly characterized cases. It would not add clarity to communication about diagnostic classification. In contrast, the use of FAB criteria has permitted nearly all MDS cases to be classified, with relative consistency of definitions worldwide.
5. The WHO proposals retain refractory anemia with excess blasts (RAEB) as a category. It is reasonable to retain this category. However, although this category was initially used by FAB, it has become well recognized that RAEB patients with 6. The WHO proposals include 5q- syndrome as a separate entity. Although a classical syndrome with 5q- alone has been described,13 many patients with the 5q- abnormality lack consistent clinical features, particularly if they have additional cytogenetic abnormalities or higher marrow blast percentages (including AML patients with 5q-).4,14,15 Multivariate analyses have failed to show 5q- cytogenetic features in MDS to have independent prognostic significance. Similarly, although other cytogenetic subgroups may have somewhat specific clinical features (chromosome 7, 17p abnormalities), they also have not been shown to be distinctive in multivariate analysis. Rather, incorporating MDS patients’ specific cytogenetic abnormalities with other clinical features (eg, blasts, cytopenias), as in IPSS categorization,4 more usefully defines the natural history of their disease. 7. The WHO proposals suggest that all patients with chronic myelomonocytic leukemia (CMML) be placed into another new subgroup, that of "MDS/myeloproliferative diseases (MPD)." Although cellular dysplasia may be present, CMML is predominantly an MPD, with dominant clinical characteristics of excessive myeloproliferation.16-18 Despite marrow blast percentage having major influence on clinical outcomes, it seems confusing to consider (for example) leukopenic RAEB patients possessing monocytosis as having CMML and to merge such patients with atypical chronic myeloid leukemia (as included in the MDS/MPD category by the WHO proposal). MDS patients with relatively low WBCs who have monocytosis seem to be best categorized as an MDS subgroup defined by their marrow blast percentage using FAB (or as nonproliferative CMML4,19), rather than as standard CMML. Even this is not an entirely satisfactory characterization, as some patients with nonproliferative CMML become proliferative in the course of time. 8. The WHO proposals suggest excluding from MDS the "low blast count" leukemias with "AML-type" cytogenetic abnormalities, eg, t(8;21), inv(16), t(15;17).20 We concur with this suggestion. In fact, a problem with some prior studies of MDS patients that suggested that RAEBT and AML were similar was their inclusion of a number of patients with these cytogenetic findings within the RAEBT subgroup.21 Thus although further morphologic advances (eg, degree of dysplasia, fibrosis, cellularity) could provide additive information for characterizing MDS, we believe that such proposals should be evidence-based and built upon well-established forms of MDS categorization (eg, FAB, IPSS)2,4 unless clear data indicate otherwise. Such an approach should demonstrate the independent nature of new criteria by multivariate statistical analysis. Regarding biologic advances, as new understanding of critical molecular, immunologic, and cytogenetic features of MDS emerge, addition of these parameters to currently accepted methods of characterization will likely further improve prognostication methods for MDS. For the reasons given above, we do not believe the WHO proposals for reclassifying MDS provide useful new information for either prognostic or morphologic assessment of these patients. REFERENCES
1.
Harris N, Jaffe E, Diebold J, et al: World Health Organization 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 2. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 51: 189-199, 1982[Medline] 3. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the acute leukemias. Br J Haematol 33: 451-458, 1976[Medline]
4.
Greenberg P, Cox C, Le Beau MM, et al: International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 89: 2079-2088, 1997 5. Head DR: Revised classification of acute myeloid leukemia. Leukemia 10: 1826-1831, 1996[Medline] 6. Willman CL: Molecular genetic features of myelodysplastic syndromes. Leukemia 12: S2-6, 1998 (suppl 1) 7. Wattel E, De Botton S, Luc Lai J, et al: Long-term follow-up of de novo myelodysplastic syndromes treated with intensive chemotherapy: Incidence of long-term survivors and outcome of partial responders. B J Haematol, 98: 983-991, 1997[Medline] 8. De Witte T, Sucio S, Peetermans M, et al: Intensive chemotherapy for poor prognosis myelodysplasia (MDS) and secondary acute myeloid leukemia following MDS of more than 6 months duration: A pilot study by the Leukemia Cooperative Group of the European Organization for Research and Treatment in Cancer. Leukemia 9: 1805-1811, 1995[Medline] 9. Germing U, Gatterman N, Aivado M, et al: Two types of acquired idiopathic sideroblastic anaemia (AISA): A time-tested distinction. Br J Haematol 108: 724-728, 2000[Medline] 10. Rosati S, Mick R, Xu F, et al: Refractory cytopenia with multilineage dysplasia: Further characterization of an ’unclassifiable’ myelodysplastic syndrome. Leukemia 10: 20-26, 1996[Medline] 11. Hellstrom-Lindberg E: Efficacy of erythropoietin in the myelodysplastic syndromes: A meta-analysis of 205 patients from 17 studies. Br J Haematol 89: 67-71, 1995[Medline]
12.
Sanz GF, Sanz MA, Vallespi T, et al: Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: A multivariate analysis of prognostic factors in 370 patients. Blood 74: 395-408, 1989 13. Van den Berghe H, Vermaelen K, Mecucci C, et al: The 5q- anomaly. Cancer Genet Cytogenet 17: 189-255, 1985[Medline] 14. Kantarjian H, Keating M, Walters R, et al: Therapy-related leukemia and myelodysplastic syndrome: Clinical, cytogenetic and prognostic features. J Clin Oncol 4: 1748-1757, 1986[Abstract] 15. Keating M, Smith T, Kantarjian H, et al: Cytogenetic pattern in acute myelogenous leukemia: A major reproducible determinant of outcome. Leukemia 2: 403-412, 1988[Medline]
16.
Fenaux P, Benscart R, Lai J, et al: Prognostic factors in adult chronic myelomonocytic leukemia: Analysis of 107 cases. J Clin Oncol 6: 1417-1424, 1988 17. Storniolo AM, Moloney WC, Rosenthal DS, et al: Chronic myelomonocytic leukemia. Leukemia 4: 766-770, 1990[Medline] 18. Bennett JM, Catovsky D, Daniel MT, et al: The chronic myeloid leukaemias: Guidelines for distinguishing chronic granulocytic, atypical chronic myeloid, and chronic myelomonocytic leukaemia. Br J Haematol 87: 746-754, 1994[Medline] 19. Worsley A, Oscier D, Stevens J, et al: Prognostic features of chronic myelomonocytic leukemia. Br J Haematol 68: 17-21, 1988[Medline] 20. Taj A, Ross F, Vickers M, et al: t(8;21) myelodysplasia, an early presentation of M2 AML. Br J Haematol 89: 890-892, 1995[Medline]
21.
Estey E, Thall P, Beran M, et al: Effect of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 90: 2969-2977, 1997
Response
Reply 1:We appreciate the comments of Dr Greenberg et al regarding the classification of the myelodysplastic syndromes (MDS) proposed by the World Health Organization (WHO) Committees.1 The letter is timely, because it has engendered a re-evaluation of the proposals before their final publication, and because our response allows an opportunity to provide the rationale for some of the suggested modifications to the French-American-British (FAB) scheme. It is important to note that the WHO proposals were not instigated by a small number of individuals. Rather, they represent the consensus opinion of an international panel of nearly 100 clinicians, pathologists, and scientists who met at Airlie House, VA, in 1997, where many of the same issues raised in the letter from Greenberg et al were debated at length. Although complete unanimity was not achieved on every issue, it was the majority view that there are sufficient data in the literature to indicate that changes to the FAB classification for MDS2 and acute myeloid leukemia (AML)3 should be made to permit better identification of biologically distinct subgroups of patients. The following paragraphs address the major concerns of the International MDS Study Group (IMDSSG) and reflect the discussions of the Airlie House Conference participants.
1. Elimination of the category of refractory anemia with excess blasts in transformation (RAEBT) by lowering the blast requirement for a diagnosis of AML from 30% to 20% risks losing the fundamental difference between AML and RAEBT. In their letter, the members of the IMDSSG argue that RAEBT is biologically different from AML, and that it has a more indolent pace. In part, we agree. But the comparison that must be made is whether there are significant biologic and clinical differences between RAEBT and the proposed WHO category into which such cases would be reclassified, ie, "AML with multilineage dysplasia (with or without a preceding history of MDS)." The literature indicates that RAEBT and cases of AML that arise from a previous MDS or that have a background of multilineage dysplasia share important biologic and clinical features, including poor-risk cytogenetic abnormalities, increased expression of MDR-1, and poor response to chemotherapy.4-6 Some investigators have also reported that when matched for similar disease features, patients with RAEBT and AML who are treated with identical therapy have nearly identical outcome and survival times.7-9 Furthermore, our interpretation of the data generated by the International MDS Risk Analysis Workshop is that RAEBT is not necessarily more indolent than AML; 25% of patients with We agree with Greenberg et al that MDS and AML cannot be separated by an arbitrary blast count, and we urge that treatment decisions, in particular, be made in the context of the clinical findings, knowledge of the cytogenetic and molecular genetic data, and the rate of disease progression, regardless of whether the marrow blast count is 20% or 30%. But we believe that the WHO proposal to eliminate RAEBT as a disease category and to classify such patients as AML with multilineage dysplasia does not diminish any fundamental differences between AML and MDS, but instead emphasizes the continuity of the MDS disease process with a unique subtype of AML. Perhaps just as importantly, however, is that elimination of RAEBT will also eliminate a common practice that is a disservice to some patients: that of classifying a patient with true AML de novo, ie, a patient with no myelodysplastic features who has good-risk cytogenetic findings, as RAEBT only because there were less than 30% blasts on a single determination. The IMDSSG does accept this latter group as AML when blasts are less than 30% in the marrow, and thus they evidently suggest that two different thresholds of blast percentages be used to establish the diagnosis of AML. The WHO committee proposes that there is a rationale for one threshold. In summary, the WHO committee believes that the blast count is a useful but inexact marker for distinguishing one disease process from another. In this case, we believe there is evidence that the current distinction between RAEBT and the AML with myelodysplastic features is indeed arbitrary. 2. All MDS categories require dysplasia in at least two hematopoietic cell lineages, and the WHO proposals for refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), and refractory cytopenia with multilineage dysplasia (RCMD) "would problematically blur relevant clinical distinctions." We acknowledge, as asserted by the IMDSSG, that some investigators require dysplasia in at least two cell lineages to make a diagnosis of MDS, including RA or RARS. Although the FAB guidelines for RA and RARS do state that "morphological abnormalities in the granulocytic and megakaryocytic series identical to those present in the other subtypes of MDS may occasionally be found in varying degrees," they also indicate that the erythroid series is mainly affected, and that "the granulocytic and megakaryocytic series almost always appear normal."2 However narrowly or loosely one interprets these criteria, in practice RA and RARS include a heterogeneous population of patients, ranging from those with only erythroid dysplasia to those with significant dysplasia in the other lineages as well. We believe there are data that indicate patients with RA and RARS can be further assigned to clinically relevant groups based on whether the erythroid series is principally involved or whether there is prominent dysplasia (more than 10% dysplastic cells) in the granulocytic and megakaryocytic series as well. As noted by Greenberg et al, numerous investigators (see review in Germing et al11) have shown that patients with pure sideroblastic anemia (PSA) in whom there is unilineage dysplasia in only the erythroid series enjoy a longer survival and have a much lower incidence of transformation to AML than those who have RARS with multilineage dysplasia. The WHO proposal (admittedly not made clear in the initially published outline) does recognize these two types of sideroblastic anemia, ie, RARS with unilineage dysplasia (or PSA) and RARS with multilineage dysplasia. The WHO committee believes that RA as defined by the FAB guidelines is similarly heterogeneous and has proposed that patients who demonstrate mainly unilineage erythroid dysplasia be designated as RA, whereas those with prominent multilineage dysplasia be classified as RCMD. There are data from four recent studies to support this view.12-15 Patients with RCMD have been reported to have a higher incidence of pancytopenia and of cytogenetic abnormalities, more frequent progression to AML, and a worse survival than patients with RA in whom only the erythroid series is affected. Whether there are major clinical or biologic differences between RCMD and RARS with multilineage dysplasia is not yet clear, although preliminary data from Germing et al,15 in a study of 284 patients with RCMD, show no significant difference in survival or progression to AML between RCMD and RARS with multilineage dysplasia. We concur with Greenberg et al that minimum essential criteria should be established for defining MDS. This is particularly true for RA, because as defined in the FAB classification, there is considerable leeway for inclusion of cases, including some that may not be myelodysplastic in nature. In the WHO proposal, the definition of RA is sufficiently restrictive to exclude most nonclonal cases of refractory anemia, thus further reducing the heterogeneity of the RA group and allowing for more appropriate patient management. Overall, it is the aim of the WHO committee to refine the definition of the low-grade myelodysplastic disorders so that the subgroups are more homogeneous. This should permit clinicians and investigators to more accurately compare the results of future biologic and clinical studies. 3. "Chronic myelomonocytic leukemia (CMML) is predominantly a myeloproliferative disorder." Although we respect the opinion of the IMDSSG that CMML is primarily a myeloproliferative disorder, there is considerable controversy among a number of other investigators regarding whether CMML is mainly myeloproliferative or myelodysplastic in nature, or both.16-18 Recent studies that divide CMML into MPD and MDS types according to the leukocyte count have concluded that this parameter alone is likely not sufficient to recognize subgroups of CMML with major biologic or prognostic differences,19 and to our knowledge, there are no specific cytogenetic or molecular differences between CMML with myelodysplastic features and CMML with myeloproliferative features. The WHO committee understands the rationale for including CMML with the chronic myeloproliferative disorders and discussed raising the threshold for the monocyte count required for defining CMML so that it could be considered in that group of diseases. Cases with lower monocyte counts might then be assigned to the appropriate myelodysplastic categories, as suggested by the IMDSSG. However, there are no studies that provide another value that has been proven to be more clinically or biologically relevant, so any change in the monocyte requirement would be arbitrary. Furthermore, Greenberg et al correctly acknowledge that some patients who start out as having nonproliferative CMML may eventually have quite proliferative CMML. It may be that, at present, there is no satisfactory definition for this disease, but it was the overwhelming consensus of the Airlie House Conference participants that arbitrarily subdividing CMML into two subtypes would not help to understand it any better. The WHO proposal does not make any significant changes in the criteria for the diagnosis of CMML. We have merely placed it in a category that acknowledges its multifaceted features. This category provides a less restrictive view of CMML than does the FAB classification, and permits clinicians, if they wish, to view the condition of those patients with low or normal leukocyte counts and monocytosis as being more like MDS, and those with higher counts as myeloproliferative in nature, and to manage them accordingly. We believe that atypical chronic myeloid leukemia also fits into this category, as it too has both myeloproliferative and myelodysplastic features, and may at times be difficult if not impossible to separate from CMML on the basis of morphologic and clinical features.16-18 If future studies provide more definitive evidence that CMML or atypical chronic myeloid leukemia are more accurately classified as myelodysplastic or myeloproliferative processes, then appropriate changes in their classification will be warranted. In our opinion, such evidence is not available at the present time. We believe that most of the other concerns raised in the letter of Greenberg et al are addressed in the details of the classification, which will be published shortly. In particular, refractory anemia with excess blasts (RAEB) is divided into two subgroups, RAEB-1 and RAEB-2, based mainly on the finding of less than or more than 10% marrow blasts, respectively. A similar subdivision is proposed for CMML. The 5q- syndrome is defined narrowly and includes only those patients with a de novo, isolated del(5q) abnormality, refractory anemia, hypolobated megakaryocytes, and less than 5% medullary blasts.20,21 We do believe, however, that the category of "MDS, unclassifiable" should remain. The frequency with which this category is used will vary with the experience of the morphologist and clinician, but all members of the WHO committee have encountered cases that defy accurate classification into one of the FAB categories, and we acknowledge that will also be the case with the WHO classification. Finally, we agree with Greenberg et al that the best prognostic classification scheme will incorporate a number of genetic, immunologic, and biologic markers. But one must first accurately classify the patient into homogeneous groups in order to accurately interpret the results of studies using these techniques, and we believe that the WHO classification system does provide a useful framework for achieving this latter goal. Recently, Germing et al15 applied the WHO proposals to 1,600 MDS patients for whom long-term follow-up was available. In their study, multivariate analysis of the data demonstrated that the WHO proposals provided more homogeneous categories, fewer unclassifiable cases, and more precise prognostic information than did the FAB classification. We hope that the members of the IMDSSG will consider evaluating the WHO modifications in their studies of patients with MDS. Thank you for giving us the opportunity to respond. REFERENCES 1. Harris N, Jaffe E, Diebold J, et al: World Health Organization 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 2. Bennett JM, Catovsky D, Daniel MT, et al: Proposals for the classification of the myelodysplastic syndrome. Br J Haematol 51: 189-199, 1982 3. Bennett JM, Catovsky D, Daniel MT, et al: Proposed revised criteria for the classification of acute myeloid leukemia: A report of the French-American-British Cooperative Group. Ann Intern Med 103: 620-625, 1985 4. Head DR: Revised classification of acute myeloid leukemia. Leukemia 10: 1826-1831, 1996 5. Sonneveld P, van Dongen JJM, Hagemeijer A, et al: High expression of the multidrug resistance P-glycoprotein in high-risk myelodysplasia is associated with immature phenotype. Leukemia 7: 963-969, 1993[Medline]
6.
Leith CP, Kopecky KJ, Godwin J, et al: Acute myeloid leukemia in the elderly: Assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic subgroups with remarkable distinct responses to standard chemotherapy—A Soutwest Oncology Group study. Blood 89: 3323-3329, 1997 7. Estey E, Pierce S, Kantarjian H, et al: Treatment of myelodysplastic syndromes with AML-type chemotherapy. Leuk Lymphoma 11: 59-63, 1993 (suppl 2) 8. Estey E, Thall P, Beran M, et al: Effects of diagnosis (refractory anemia with excess blasts, refractory anemia with excess blasts in transformation or acute myeloid leukemia [AML]) on outcome of AML-type chemotherapy. Blood 90: 2969-2977, 1997 9. Berstein SH, Brunetto VL, Davey FR: Acute myeloid leukemia-type chemotherapy for newly diagnosed patients without antecedent cytopenias having myelodysplastic syndromes as defined by French-American-British criteria: A Cancer and Leukemia Group B study. J Clin Oncol 14: 2486-2494, 1996[Abstract] 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. Germing U, Gatterman N, Aivado M, et al: Two types of acquired sideroblastic anaemia (AISA): A time-tested distinction. Br J Haematol 108: 724-728, 2000 12. Michels S, Chan W, Jakubowski D, et al: Unclassifiable myelodysplastic syndrome: A study of sixteen cases with a proposal for a new subtype. Lab Invest 62: 67, 1990 (abstr) 13. Rosati S, Mick R, Xu F, et al: Refractory cytopenia with multilineage dysplasia: Further characterization of an "unclassifiable" myelodysplastic syndrome. Leukemia 10: 20-26, 1996 14. Balduini CL, Guarnone R, Pecci A, et al: Multilineage dysplasia without increased blasts identifies a poor prognosis subset of myelodysplastic syndrome. Leukemia 12: 1655-1656, 1998 (letter)[Medline] 15. Germing U, Gatterman N, Strupp C, et al: Validation of the WHO proposals for a new classification of primary myelodysplastic syndromes: A retrospective analysis of 1600 patients. Leukemia Res 24: 983-992, 2000[Medline] 16. Michaux JL, Martiat P: Chronic myelomonocytic leuaemia (CMML): A myelodysplastic or myeloproliferative syndrome? Leuk Lymphoma 9: 35-41, 1993[Medline] 17. Groupe Francais de Cytogenetique Hamatologique: Chronic myelomonocytic leukemia: Single entity or heterogeneous disorder? A prospective multicenter study of 100 patients. Cancer Genet Cytogenet 55: 57-65, 1991[Medline] 18. Bennett JM, Catovsky D, Daniel MT, et al: The chronic myeloid leukaemias: Guidelines for distinguishing the chronic granulocytic, atypical chronic myeloid and chronic myelomonocytic leukaemicas. Br J Haematol 87: 746-754, 1994 19. 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] 20. Van Den Berghe H, Cassiman JJ, David G, et al: Distinct haematological disorder with deletion of long arm of No. 5 chromosome. Nature 251: 437-438, 1974[Medline]
21.
Boultwood J, Lewis S, Wainscoat JS: The 5q- syndrome. Blood 84: 3253-3260, 1994
ResponseVanderbilt University Medical Center Nashville, TN Reply 2:The letter from the International MDS Study Group (IMDSSG) and the World Health Organization (WHO) committee response raise thoughtful issues. An analysis of differences persisting between the two groups follows: 1. Separation of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML). Both groups agree that a marrow blast percentage threshold is irrelevant in one subset of AML, true de novo AML with recurring cytogenetic translocations. This AML subset should be eliminated from discussion. The other major subset, myelodysplasia-related or MDR-AML (WHO classification: AML with multilineage dysplasia), is clearly related to MDS. Both the WHO and IMDSSG groups agree that any marrow blast percentage is imprecise for separating MDS and MDR-AML; when possible, serial marrows and clinical parameters should be used. They further agree that the blast threshold is a surrogate for poorly understood changes that result in transformation of stem cells in MDS and progression to AML. The remaining difference between the groups is which arbitrary blast percentage threshold should be used in making this distinction in the absence of serial marrows or more definitive criteria. A low blast percentage threshold will misclassify as AML more cases that will continue to behave as MDS, whereas a high threshold risks the opposite result. Neither is satisfactory, and we must strive to find a better means to recognize transformation to AML in this setting. 2. Definitions and minimal diagnostic criteria for low-grade MDS. Disagreement here is philosophical. Should we still consider MDS a syndrome, as it was historically and as still implied by its name, or rather should we now consider it a specific set of diseases sharing common biologic and clinical parameters, genetics, and pathogenesis and requiring common treatments? The WHO group has retained the syndrome approach, with more inclusive but less specific diagnostic criteria (unilineage dysplasia) for low-grade MDS. With this approach low-grade MDS will be heterogeneous, including diseases with no acquired genetic abnormality or risk for progression to high-grade MDS or MDR-AML. The IMDSSG has adopted the disease approach, attempting to restrict MDS to a specific set of diseases united at least by involvement of a multipotential hematopoietic progenitor, hence the requirement for bilineage dysplasia. Neither approach is inherently incorrect. However, for clinical protocols and for studies of the biology and pathogenesis of the specific disease group MDS, the disease approach seems preferable, with its more stringent diagnostic criteria (bilineage dysplasia). 3. Definition and placement of chronic myelomonocytic leukemia (CMML). CMML comprises a heterogeneous spectrum of disease, on one end predominantly hypoproductive with minor monocytosis, on the other predominantly hyperproductive and sharing features with myeloproliferative diseases, with a continuous spectrum between. The entire spectrum shares cytogenetic and dysplastic features with MDS. Current data do not indicate how to subdivide CMML, although intuitively the hypoproductive end of the spectrum belongs in MDS and the hyperproductive end in a separate group with a major proliferative component. Placing the entire group in MDS (French-American-British classification) seems to err in placement of the hyperproductive high end, whereas removing all CMML from MDS (WHO classification) may err in removing the hypoproductive end from MDS. Although available data are not helpful, a compromise is obviously possible for use in clinical trials to allow study of hypoproductive CMML cases in common protocols with other cases of MDS, pending clarification of this issue.
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Copyright © 2000 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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10% blasts had poorer prognoses than those with less than 10% blasts.
