Leukemia Research Vol. 16, No. 1, pp. 117-121, 1992. Printed in Great Britain.
0145-2126/92 $5.00 + .00 Pergamon Press plc
COMPLICATIONS AND TREATMENT OF THE MYELODYSPLASTIC SYNDROMES GUIDO J. TRICOT Division of Hematology/Oncology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, U.S.A. Abstract--The major complications of the myelodysplastic syndromes (MDS) are related to cytopenia and evolution to acute myeloid leukemia (AML). Hematopoietic growth factors are only of limited benefit to alleviate the cytopenia. Therapy in MDS patients over the age of 50 should aim at prolonging survival while limiting the risk of toxicity. Those with stable disease should only receive supportive care; those with progressive cytopenia should have a trial with low-dose chemotherapy. Aggressive chemotherapy should only be reserved for those failing low-dose therapy. Therapy in MDS patients under the age of 50 should aim at cure of the disease. Although aggressive chemotherapy can induce complete remission in the majority of these patients, remission is usually short. Allogeneic bone marrow transplantation is probably the only curative option in these patients and should be the treatment of choice. Key words: Myelodysplastic syndromes, cytopenia, acute myeloid leukemia, hematopoietic growth factors, chemotherapy, bone marrow transplantation.
INTRODUCTION
fusions and consequent iron overload should be avoided. A substantial percentage of patients with refractory anemia (RA), but especially with R A with ring sideroblasts (RAS) will require transfusions for a prolonged period of time and may die from organ failure secondary to hemochromatosis. Younger patients with RA and RAS will benefit from iron chelation therapy with subcutaneous desferoxamine and vitamin C [1]. Recombinant human erythropoietin has been studied in patients with MDS [2--4]. The results are listed in Table 1. Twenty-six patients were treated for >4 weeks with different doses of erythropoietin. A response was observed in 6 patients, but only 3 became transfusion-independent. Hellstrom et al. used the highest dose of erythropoietin and had the best results [4]. It is interesting to note that a positive response was seen in 4/6 patients without ring sideroblasts in the bone marrow, while in 0/4 patients with ring sideroblasts. Serum erythropoietin levels prior to therapy were above normal range [3]. There seems to be little correlation between response in clonogenic assays and in vivo response [3]. More studies need to be performed to evaluate the role of erythropoietin in MDS. In a small fraction of MDS patients a decrease in RBC transfusion need was seen during administration of GM-CSF, G-CSF or IL-3 [5-12] (see Table 2).
TnE myelodysplastic syndromes are acquired clonal hematologic malignancies with an increased risk of evolution to acute myeloid leukemia and progressive cytopenia. The major complications are related to cytopenia and the progression to acute leukemia. CYTOPENIA Anemia
Supportive therapy with blood products has been the mainstay of therapy for patients with MDS, who are often elderly and may have underlying cardiopulmonary disease. It is good policy to give red blood cell transfusions only to patients with cardiopulmonary complaints or antecedents. Excessive trans-
Abbreviations: MDS, myelodysplastic syndromes; RA, refractory anemia; RAS, refractory anemia with ring sideroblasts; RAEB, refractory anemia with excess of blasts; CMML, chronic myelomonocytic leukemia; RAEBt, refractory anemia with excess of blasts in transformation; AML, acute myeloid leukemia; BMT, bone marrow transplantation. Correspondence to: Guido J. Tricot, M.D., Ph.D., Division of Hematology/Oncology, Indiana University Hospital, W608, 926 West Michigan Street, Indianapolis, IN 46202-5250, U.S.A.
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TABLE1. TREATMENTOFMDS ANDRECOMBINANTHUMANERYTHROPOIETIN
Hirashima et al. [2] Hohaus et al. [3] Hellstrom et al. [4]
No.
Dose/week
10 6 10
3000--24000u x 3 50--400u/kg x 3 200-1000u/kg x 3
Duration (weeks) Response >4 4--12 12
Transfusionindependent
2 9 4*
1 0 2
*Response was seen in 4/6 without ring sideroblasts, but in 0/4 with ring sideroblasts.
TABLE2. RESULTS OF TREATMENT WITH HEMATOPOIETIC GROWTH FACTORS IN PATIENTS WITH MDS
Source Vadhan-Raj et al. [5] Antin et al. [6] Ganser et al. [7] Thompson et al. [8] Herrmann etal. [9] Kobayashi et al. [10] Negrin et al. [11] Ganser et al. [12]
Growth factor
Route
GM-CSF GM-CSF GM-CSF GM-CSF GM-CSF G-CSF G,CSF IL-3
IV IV IV IV IV IV SC SC
Significant Decrease in increase in No. RBCtransfusion granulocytes 8 7 11 16 4 4 12 9
2 0 0 0 0 0 2 1"
8 5 9 12 4 4 10 7
Significant increase in platelets
Leukemia transformation
3 0 0 2* 0 0 1 2
0 0 4 1 4t 0 0 1
*Only a transient effect during administration of the growth factor. tAll four patients had excess of bone marrow blasts.
Neutropenia
Thrornbocytopenia
Prompt institution of broad-spectrum antibiotics in case of infection is required. Even if they are not severely neutropenic, these patients should be treated as if they were. Granulocyte function is abnormal in at least 50% of MDS patients [13,14]. Granulocytes may show decreased adhesion, deficient chemotaxis, decreased phagocytosis and impaired microbicidal capacity. Patients with recurrent infections should be placed on prophylactic antibiotics, mainly directed against aerobic gramnegative bacilli, such as ciprofloxacin. The neutrophil count can be increased in the large majority of patients by using hematopoietic growth factors (Table 2). Whether neutrophils induced by these growth factors function normally remains to be demonstrated. The optimal dose, schedule and preparation are still unknown. Since the growth factors are not curative, patients are expected to require intermittent therapy to maintain peripheral counts at an acceptable level. Moreover, hematopoietic growth factors do not only induce cellular differentiation, they can also stimulate proliferation of leukemic cells in vitro [15-18] and might accelerate development of acute leukemia. A significant increase in the percentage of bone marrow blasts is seen in about 30% of patients; acute myeloid leukemia developed in 17% of patients, often with rapid onset and generally not reversible with discontinuation of the growth factor [19].
Many patients with MDS are not only thrombocytopenic, their platelet function is also frequently impaired. The observed defects are similar to those found in myeloproliferative disorders, the most consistent finding being defective aggregation [20]. Platelet transfusions are only administered to thrombocytopenic patients in case of surgery or of severe bleeding problems, such as gastro-intestinal or retinal bleeding, and following cytotoxic therapy. Thrombocytopenic patients with severe infections are at high risk for life-threatening hemorrhage and are temporarily given prophylactic platelet transfusions. Since MDS patients will usually require transfusions for prolonged periods of time, RBC and platelet transfusions should be leucocyte-depleted to prevent HLA-alloimmunization. The best way to do this is to use bedside filtration. These filters remove 99.9% of the WBC [21]. In occasional patients a significant rise in platelet counts can be observed after treatment with GM-CSF, G-CSF or IL-3 (see Table 2). IL-6 promotes maturation of megakaryocytes and may prove to be of value in MDS patients with thrombocytopenia [22 25]. ACUTE LEUKEMIA Leukemic transformation occurs in 20-40% of patients. Patients at high risk of evolution to A M L are those with excess of bone marrow blasts [26-29],
Complicationsand treatment of MDS chromosomal anomalies [30, 31] especially complex chromosomal abnormalities and - 7 [32, 33], therapyrelated MDS [33, 34], and abnormal growth in in vitro cultures [34, 35]. U N C O M M O N COMPLICATIONS Patients with MDS have an increased incidence of immunologic abnormalities. Mufti et al. [36] found 12.5% of patients with MDS to have a monoclonal gammopathy. His group also reported 20 cases in which there was a coexistent lymphoid or plasma cell neoplasm [37]. The direct antiglobulin test was positive in 8% of cases and other circulating autoantibodies were found in 22%, though this was not higher than in age-matched controls. Both monoclonal gammopathies and auto-antibodies are particularly common in patients with chronic myelomonocytic leukemia [36, 38] (CMML). In some patients fever is the major manifestation of MDS [39]. Patients with CMML may present or develop serous effusions, skin infiltrations, hepatosplenomegaly, gingival hypertrophy and lymphodenopathy [38, 40, 41]. Cutaneous vasculitis and polyarthritis are also seen [42-44]. Non-hematologic malignancy during follow-up of MDS occurs at a higher than expected rate [45]. THERAPY The median survival for untreated MDS patients in different series varies between 7.5 and 27 months and largely depends upon the proportion of patients in the study with and without excess of bone marrow blasts [29]. The outlook for those patients with excess of bone marrow blasts, pancytopenia, complex chromosomal abnormalities and treatment-related MDS is very grim. Effective therapy would be highly desirable for these patients. The advantage of treating patients in the myelodysplastic phase is that the tumor load is low, but there is an obvious risk of premature death due to drug toxicity. Therapy in MDS patients over the age of 50 should aim at prolonging survival by reducing the neoplastic clone and more importantly by increasing blood counts. While in AML the attainment of a complete remission is an absolute prerequisite for prolonged survival, complete remission may not be necessary to substantially increase survival in MDS. The primary goal in younger MDS patients, should be eradication of the disease and cure. Low-dose cytosine arabinoside therapy The idea behind this therapy was that low doses of cytosine arabinoside would induce differentiation of
119
immature myeloid cells, while not very toxic. It could be given subcutaneously on an out-patient basis. A review of data on low-dose cytosine arabinoside in 170 MDS patients showed a complete remission rate of 16% with 21% partial responders [46]. The median duration of complete remission was 10.5 months. The median survival of all patients treated was 15 months, with little evidence that achieving a complete remission had a substantial influence on survival. Myelotoxicity was noted in 88% of patients; treatmentrelated mortality was 15%, confirming earfier findings that this treatment modality is associated with substantial toxicity and is difficult to administer on an outpatient basis [47]. A trend toward a higher responsive rate is observed in patients treated while still in the myelodysplastic phase as compared with treatment after progression to AML [48]. Most of the available data suggest that the main effect of low-dose cytosine arabinoside is cytotoxicity [48]. This therapy should not be considered as standard treatment for MDS. Aggressive chemotherapy Aggressive chemotherapy has generally been considered ineffective and contraindicated in MDS patients because of its extraordinary toxicity and the assumption that the bone marrow of MDS patients is incapable of recovering normal functions even if the dysplastic clone could be eradicated. However, complete remissions have been reported with aggressive chemotherapy, the rate varying between 15-70% [48-50]. The duration of hypoplasia induced by remission induction chemotherapy tended to be longer in MDS patients when compared to de novo AML, but the difference was not statistically significant [49, 50]. Although, prolonged remissions can be obtained with aggressive chemotherapy, most patients have experienced only short remissions in spite of intensive consolidation therapy [48, 51]. Nevertheless, younger patients with MDS should be treated with aggressive chemotherapy in case of severe cytopenia and/or excess of bone marrow blasts. Bone marrow transplantation Although MDS is a disease of later life, about 1020% of patients are under 50 years. Moreover, many patients with therapy-related MDS are younger persons, who are potential candidates for allogeneic bone marrow transplantation (BMT). Eradication of the disease has proved possible after both syngeneic and allogeneic BMT. Fifty-nine patients with severe myelodysplasia were treated by the Seattle Marrow Transplant Team with cyclophosphamide and either total body irradiation or busulphan. The projected 3years survival was 45 + 7%. Disease recurrence, interstitial pneumonitis and graft-vs-host disease
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were the most c o m m o n causes of death accounting for 8 deaths each [52]. In a multi-variate analysis, younger age and the presence of an abnormal karyotype were independent indicators of better diseasefree and overall survival. Patients who were transplanted with few blasts in their bone marrow had a lower probability of relapse of the disease. The European Bone Marrow Transplantation Group has reported on 78 patients with MDS or secondary AML, who received an allogeneic B M T [53]. Thirtyfour patients received intensive chemotherapy prior to the BMT. The 2-year disease-free survival was 60% for the 16 patients transplanted in complete remission. Forty-four patients had not received any intensive chemotherapy. The disease-free survival at 2 years after B M T was 58% for R A and RAS patients, 74% for R A E B , 50% for R A E B - t and 18% for untreated AML. In MDS patients under 50 years of age with poor prognostic markers or progressive disease, allogeneic B M T is the therapy of choice. In those patients with low tumor load B M T can be performed as first-line therapy. Patients with a high percent of bone marrow blasts will probably benefit from A M L remission induction therapy before undergoing BMT.
REFERENCES 1. Marcus R. E. & Huehns E. R. (1985) Review. Transfusional iron overload. Clin. Lab. Haemat. 195212. 2. Hirashima K., Jinnai I. & Bessho M. (1990) Clinical effect of recombinant erythropoietin (rEpo) on anemia of patients with hematological disorders. Expl. Hemat. 18, 600. 3. Hohaus S., Haas R., Ogniben E., Ho A. D. & Hunstein W. (1990) Erythropoietin for the treatment of anemia due to primary bone marrow failure. Expl. Hemat. 18, 605. 4. Hellstrom E., Birgegard G., Lockner D., Helmets C., Wide L. & Ost A. (1990) Treatment of myelodysplastic syndromes with recombinant human erythropoietin. Blood 76 (suppl. 1), 279a. 5. Vadhan-Raj S., Keating M., LeMaistre A., Hittelman W. N., McCredie K., Trujillo J. M., Broxmeyer H. E., Henney C. & Gutterman J. U. (1987) Effects of recombinant human granulocyte-macrophage colonystimulating factor in patients with myelodysplastic syndromes. New Engl. J. Med. 317, 1545-1552. 6. Antin J. H., Smith B. R., Holmes W. & Rosenthal D. S. (1988) Phase I/II study of recombinant human granulocyte-macrophage colony-stimulating factor in aplastic anemia and myeiodysplastic syndrome. Blood 72, 705-713. 7. Ganser A., Volkers B., Greher J., Ottmann O. G., Walther F., Becher F., Bergmann L., Schulz G. & Hoelzer D. (1989) Recombinant human granulocytemacrophage colony-stimulating factor in patients with myelodysplastic syndromes--A phase I/II trial. Blood 73, 31-37.
8. Thompson J. A., Lee D. J., Kidd P., Rubin E., Kaufmann J., Bonnem E. M. & Fefer A. (1989) Subcutaneous granulocyte-macrophage colonystimulating factor in patients with myelodysplastic syndrome: toxicity, pharmacokinetics, and hematological effects. J. clin. Oncol. 7, 629-637. 9. Herrmann F., Lindemann A., Klein H., Lubbert M., Schulz G. & Mertelsmann R. (1989) Effect of recombinant human granulocyte-macrophage colonystimulating factor in patients with myelodysplastic syndrome with excess blasts. Leukemia 3, 335-338. 10. Kobayashi Y., Okabe T., Ozawa K., Chiba S., Hino M., Miyazono K., Urabe A. & Takaku F. (1989) Treatment of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor: A preliminary report. Am. J. Med. 86, 178-182. 11. Negrin R. S., Haeuber D. H., Nagler A., Olds L. C., Donlon T., Souza L. M. & Greenberg P. L. (1989) Treatment of myelodysplastic syndromes with recombinant human granulocyte colony-stimulating factor. Ann. Int. Med. 110, 976-984. 12. Ganser A., Seipelt G., Lindemann A., Ottmann O. G., Falk S., Eder M., Herrmann F., Becher R., Hoffkin K., Buchner T., Klausmann M., Frish J., Schulz G., Mertelsmann R. & Hoelzer D. (1990) Effects of recombinant human interleukin-3 in patients with myelodysplastic syndromes. Blood 76, 455-462. 13. Martin S., Baldock B. C., Ghoneim A. T. M. & Child J.A. (1983) Defective neutrophil function and microbicidal mechanisms in the myelodysplastic disorders. J. din. Pathol. 36, 1120. 14. Boogaerts M. A., Nelissen V., Roelant C. & Goossens W. (1983) Blood neutrophil function in primary myelodysplastic syndromes. Br. J. Haemat. 55, 217. 15. Vellenga E., Young D. C., Wagner K., Wiper D., Ostapovicz D. & Griffin J. D. (1987) The effects of GM-CSF and G-CSF in promoting growth of clonogenic cells in acute myeloblastic leukemia. Blood 69, 1771-1776. 16. Delwel R., Dorssers L., Touw I., Wagemaker G. & Lowenberg B. (1987) Human recombinant multilinage colony stimulating factor (interleukin-3): stimulator of acute myelocytic leukemia progenitor cells in vitro. Blood 70, 333-336. 17. Lotem J. & Sachs L. (1988) In vivo control of differentiation of myeloid leukemia cells in recombinant granulocyte-macrophage colony-stimulating factor and interleukin-3. Blood 71, 375-382 18. Nara N., Murohashi I., Suzuki T., et al. (1988) Effects of purified human active granulocyte colony-stimulating factor (G-CSF) on proliferation of blast progenitors in acute myeloblastic leukemia. Am. J. Haemat. 27, 84-88. 19. Cheson B. D. (1990) The myelodysplastic syndromes: Current approaches to therapy. Ann. Int. Med. 112, 932-941. 20. Lintula R., Rasi V., Ikkala E., et al. (1981) Platelet function in preleukaemia. Scand. J. Haemat. 26, 65. 21. Wenz B. (1990) Clinical and laboratory precautions that reduce the adverse reactions, alloimmunization, infectivity, and possibly immunomodulation associated with homologous transfusions. Trans. Med. Rev. 4 (suppl. 1), 3-7. 22. Hill R. J., Warren K., Stenberg P., Levin J., Corash L., Drummond R., Baker G., Levin F. & Mok Y.
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(1991) Stimulation of megakaryocytopoiesis in mice by human recombinant interleukin-6. Blood 77, 42--48. Asano S., Okano A., Ozawa K., Nakahata T., Ishibashi T., Koike K., Kimura H., Tanioka Y., Shibuya A., Hirano T., Kishimoto T., Takaku F. & Akiyama Y. (1990) In vivo effects of recombinant human interleukin-6 in primates: stimulated production of platelets. Blood 75, 1602-1605. Shabo Y., Lotem J., Rubinstein M., Revel M., Clark S. C., Wolf S. F., Kamen R. & Sachs L. (1988) The myeloid blood cell differentiation-inducing protein MGI-2A is interleukin-6. Blood 72, 2070-2073. Van Snick J. (1990) Interleukin-6: An overview. Ann. Rev. lmmun. 8, 253-278. Mufti G. J., Stevens J. R., Oscier D. G., Hamblin T. J. & Machin D. (1985) Myelodysplastic syndromes: a scoring system with prognostic significance. Br. J. Haemat. 59, 425-533. Kerkhofs H., Hermans J., Haak H. L. & Leeksma C. H. W. (1987) Utility of the FAB classification for myelodysplastic syndromes: investigation of prognostic factors in 237 cases. Br. J. Haemat. 65, 73-81. Oguma S., Yoshida Y., Uchino H. & Maekawa T. (1987) Factors influencing nonleukemic death in refractory anemia, refractory anemia with ring sideroblasts, and refractory anemia with excess of blasts. Cancer Res. 47, 3599-3602. Tricot G., Vlietinck R. & Verwilghen R. L. (1986) Prognostic factors in the myelodysplastic syndromes: A review. Scand. J. Haemat. 36 (suppl. 45), 107-113. Jacobs R. H., Cornbleet M. A., Vardiman J. W., Larson R. A., LeBeau M. M. & Rowley J. D. (1986) Prognostic implications of morphology and karyotype in primary myelodysplastic syndromes. Blood 67, 1765-1772. Suciu S., Kuse R., Weh H. J. & Hossfeld D. K. (1990) Results of chromosome studies and their relation to morphology, course, and prognosis in 120 patients with de novo myelodysplastic syndrome. Cancer Genet. Cytogenet. 44, 15-26. Musilova J. & Michalova K. (1988) Chromosome study of 85 patients with myelodysplastic syndrome. Cancer Genet. Cytogenet. 33, 39-50. Anderson R. L. & Bagby G.C. (1982) The prognostic value of chromosome studies in patients with the preleukemic syndrome (hemopoietic dysplasia). Leukemia Res. 6, 175-181. Koeffler H. P. (1986) Myelodysplastic syndromes (preleukemia). Semin. Hemat. 23, 284-299. Greenberg P. L. (1986) In vitro culture techniques defining biological abnormalities in the myelodysplastic syndromes and myeloproliferative disorders. Clin. Haemat. 15, 973-993. Mufti G. J., Figes A., Hamblin T. J., Oscier D. G. & Copplestone J. A. (1986) Immunological abnormalities in myelodysplastic syndromes: Serum immunoglobulins and autoantibodies. Br. J. Haemat. 63, 143147. Copplestone J. A., Mufti G. J., Hamblin T. J. & Oscier D. G. (1986) Immunological abnormalities in myelodysplastic syndromes. II. Coexistent lymphoid or plasma cell neoplasms: a report of 20 cases unrelated to chemotherapy. Br. J. Haemat. 63, 149-159. Solal-Celigny P., Desaint B., Herrera A., Chastang C., Amar M., Vroclans M., Brousse N., Mancilla F., Renoux M., Bernard J.F. & Boivin P. (1984) Chronic
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myelomonocytic leukemia according to FAB classification: Analysis of 35 cases. Blood 63, 634-638. Zanger & Dorsey H. N. (1976) Fever-A manifestation of preleukemia. J A M A 236, 1266-1268. Fenaux P., Jouet J. P., Zandecki M., Lai J. L., Simon M., Pollet J. P. & Bauters F. (1987) Chronic and subacute myelomonocytic leukaemia in the adult: a report of 60 cases with special reference to prognostic factors. Br. J. Haemat. 65, 101-106. Worsley A., Scier D. G., Stevens J., Darlow S., Figes A., Mufti G. J. & Hamblin T. J. (1988) Prognostic features of chronic myelomonocytic leukaemia: a modified Bournemouth score gives the best prediction of survival. Br. J. Haemat. 68, 17-21. Doutre M. S., Beylot C., Beylot J., Courouge-Dorcier D., Reiffers J., Broustet A. & Bioulac-Sage P. (1987) Refractory anemia with an excess of blasts and cutaneous vasculitis. Ann. Dermatol. Venereol. 114, 97-100. Green A. R., Shuttleworth D., Bowen D. T. & Bentley D. P. (1990) Cutaneous vasculitis in patients with myelodysplasia. Br. J. Haemat. 74, 364-365. Marti J. M., Cervantes F., Ribera J. M., MartinOrtega E. & Roxman C. (1987) Polyarthritis cutaneous vasculitis and migrant thrombophlebitis of possible immune origin associated with chronic myelomonocytic leukemia. Sangre 32, 502-505. Clark R. E., Payne H. E., Jacobs A. & West R. R. (1987) Primary myelodysplastic syndrome and cancer. Br. Med. J. 294, 937-938. Cheson B. D., Jasperse D. M., Simon R. & Friedman M. A. (1986) A critical appraisal of low-dose cytosine arabinoside in patients with acute non-lymphocytic leukemia and myelodysplastic syndromes. J. clin. Oncol. 4, 1857-1864. Tricot G., DeBock R., Dekker A. W., Boogaerts M. A., Peetermann M., Punt K. & Verwilghen R. L. (1984) Low dose cytosine arabinoside (Ara C) in myelodysplastic syndromes. Br. J. Haemat. 58, 231-240. Tricot G. J., Lauer R. C., Appelbaum F. R., Jansen J. & Hoffman R. (1987) Management of the myelodysplastic syndromes. Semin. Oncol. 14, 444-453. Tricot G. & Boogaerts M. A. (1986) The role of aggressive chemotherapy in the treatment of the myelodysplastic syndromes. Br. J. Haemat. 63, 477483. De Witte T., Muus P., De Pauw B. & Haanen C. (1990) Intensive antileukemic treatment of patients younger than 65 years with myelodysplastic syndromes and secondary acute myelogenous leukemia. Cancer 66, 831-837. Gajewski J. L., Go W. G., Nimer S. D., Hirji K. F., Gekelman L., Jacobs A. D. & Champlin R. E. (1989) Efficacy of intensive chemotherapy for acute myelogenous leukemia associated with a preleukemic syndrome. J. clin. Oncol. 7, 1637-1645. Appelbaum F. R. & Buckner C. D. (1989) Marrow transplantation for patients with severe myelodysplasia. Bone Marrow Transplant. 4 (suppl. 2), 40. De Witte T., Zwaan F., Hermans J., Vernant J., Kolb H., Vossen J., Lonnqvist B., Beelen D., Ferrant A., Gmur J., Yin J. L., Troussard X., Cahn J., Van Lint M. & Gratwohl A. (1990) Allogeneic bone marrow transplantation for secondary leukaemia and myelodysplastic syndrome: a survey by the Leukaemia Working Party of the European Bone Marrow Transplantation Group (EBMTG). Br. J. Haemat. 74, 151-155.
0145-2126/92 $5.00 + .00 Pergamon Press plc
COMPLICATIONS AND TREATMENT OF THE MYELODYSPLASTIC SYNDROMES GUIDO J. TRICOT Division of Hematology/Oncology, Department of Medicine, Indiana University Medical Center, Indianapolis, Indiana, U.S.A. Abstract--The major complications of the myelodysplastic syndromes (MDS) are related to cytopenia and evolution to acute myeloid leukemia (AML). Hematopoietic growth factors are only of limited benefit to alleviate the cytopenia. Therapy in MDS patients over the age of 50 should aim at prolonging survival while limiting the risk of toxicity. Those with stable disease should only receive supportive care; those with progressive cytopenia should have a trial with low-dose chemotherapy. Aggressive chemotherapy should only be reserved for those failing low-dose therapy. Therapy in MDS patients under the age of 50 should aim at cure of the disease. Although aggressive chemotherapy can induce complete remission in the majority of these patients, remission is usually short. Allogeneic bone marrow transplantation is probably the only curative option in these patients and should be the treatment of choice. Key words: Myelodysplastic syndromes, cytopenia, acute myeloid leukemia, hematopoietic growth factors, chemotherapy, bone marrow transplantation.
INTRODUCTION
fusions and consequent iron overload should be avoided. A substantial percentage of patients with refractory anemia (RA), but especially with R A with ring sideroblasts (RAS) will require transfusions for a prolonged period of time and may die from organ failure secondary to hemochromatosis. Younger patients with RA and RAS will benefit from iron chelation therapy with subcutaneous desferoxamine and vitamin C [1]. Recombinant human erythropoietin has been studied in patients with MDS [2--4]. The results are listed in Table 1. Twenty-six patients were treated for >4 weeks with different doses of erythropoietin. A response was observed in 6 patients, but only 3 became transfusion-independent. Hellstrom et al. used the highest dose of erythropoietin and had the best results [4]. It is interesting to note that a positive response was seen in 4/6 patients without ring sideroblasts in the bone marrow, while in 0/4 patients with ring sideroblasts. Serum erythropoietin levels prior to therapy were above normal range [3]. There seems to be little correlation between response in clonogenic assays and in vivo response [3]. More studies need to be performed to evaluate the role of erythropoietin in MDS. In a small fraction of MDS patients a decrease in RBC transfusion need was seen during administration of GM-CSF, G-CSF or IL-3 [5-12] (see Table 2).
TnE myelodysplastic syndromes are acquired clonal hematologic malignancies with an increased risk of evolution to acute myeloid leukemia and progressive cytopenia. The major complications are related to cytopenia and the progression to acute leukemia. CYTOPENIA Anemia
Supportive therapy with blood products has been the mainstay of therapy for patients with MDS, who are often elderly and may have underlying cardiopulmonary disease. It is good policy to give red blood cell transfusions only to patients with cardiopulmonary complaints or antecedents. Excessive trans-
Abbreviations: MDS, myelodysplastic syndromes; RA, refractory anemia; RAS, refractory anemia with ring sideroblasts; RAEB, refractory anemia with excess of blasts; CMML, chronic myelomonocytic leukemia; RAEBt, refractory anemia with excess of blasts in transformation; AML, acute myeloid leukemia; BMT, bone marrow transplantation. Correspondence to: Guido J. Tricot, M.D., Ph.D., Division of Hematology/Oncology, Indiana University Hospital, W608, 926 West Michigan Street, Indianapolis, IN 46202-5250, U.S.A.
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TABLE1. TREATMENTOFMDS ANDRECOMBINANTHUMANERYTHROPOIETIN
Hirashima et al. [2] Hohaus et al. [3] Hellstrom et al. [4]
No.
Dose/week
10 6 10
3000--24000u x 3 50--400u/kg x 3 200-1000u/kg x 3
Duration (weeks) Response >4 4--12 12
Transfusionindependent
2 9 4*
1 0 2
*Response was seen in 4/6 without ring sideroblasts, but in 0/4 with ring sideroblasts.
TABLE2. RESULTS OF TREATMENT WITH HEMATOPOIETIC GROWTH FACTORS IN PATIENTS WITH MDS
Source Vadhan-Raj et al. [5] Antin et al. [6] Ganser et al. [7] Thompson et al. [8] Herrmann etal. [9] Kobayashi et al. [10] Negrin et al. [11] Ganser et al. [12]
Growth factor
Route
GM-CSF GM-CSF GM-CSF GM-CSF GM-CSF G-CSF G,CSF IL-3
IV IV IV IV IV IV SC SC
Significant Decrease in increase in No. RBCtransfusion granulocytes 8 7 11 16 4 4 12 9
2 0 0 0 0 0 2 1"
8 5 9 12 4 4 10 7
Significant increase in platelets
Leukemia transformation
3 0 0 2* 0 0 1 2
0 0 4 1 4t 0 0 1
*Only a transient effect during administration of the growth factor. tAll four patients had excess of bone marrow blasts.
Neutropenia
Thrornbocytopenia
Prompt institution of broad-spectrum antibiotics in case of infection is required. Even if they are not severely neutropenic, these patients should be treated as if they were. Granulocyte function is abnormal in at least 50% of MDS patients [13,14]. Granulocytes may show decreased adhesion, deficient chemotaxis, decreased phagocytosis and impaired microbicidal capacity. Patients with recurrent infections should be placed on prophylactic antibiotics, mainly directed against aerobic gramnegative bacilli, such as ciprofloxacin. The neutrophil count can be increased in the large majority of patients by using hematopoietic growth factors (Table 2). Whether neutrophils induced by these growth factors function normally remains to be demonstrated. The optimal dose, schedule and preparation are still unknown. Since the growth factors are not curative, patients are expected to require intermittent therapy to maintain peripheral counts at an acceptable level. Moreover, hematopoietic growth factors do not only induce cellular differentiation, they can also stimulate proliferation of leukemic cells in vitro [15-18] and might accelerate development of acute leukemia. A significant increase in the percentage of bone marrow blasts is seen in about 30% of patients; acute myeloid leukemia developed in 17% of patients, often with rapid onset and generally not reversible with discontinuation of the growth factor [19].
Many patients with MDS are not only thrombocytopenic, their platelet function is also frequently impaired. The observed defects are similar to those found in myeloproliferative disorders, the most consistent finding being defective aggregation [20]. Platelet transfusions are only administered to thrombocytopenic patients in case of surgery or of severe bleeding problems, such as gastro-intestinal or retinal bleeding, and following cytotoxic therapy. Thrombocytopenic patients with severe infections are at high risk for life-threatening hemorrhage and are temporarily given prophylactic platelet transfusions. Since MDS patients will usually require transfusions for prolonged periods of time, RBC and platelet transfusions should be leucocyte-depleted to prevent HLA-alloimmunization. The best way to do this is to use bedside filtration. These filters remove 99.9% of the WBC [21]. In occasional patients a significant rise in platelet counts can be observed after treatment with GM-CSF, G-CSF or IL-3 (see Table 2). IL-6 promotes maturation of megakaryocytes and may prove to be of value in MDS patients with thrombocytopenia [22 25]. ACUTE LEUKEMIA Leukemic transformation occurs in 20-40% of patients. Patients at high risk of evolution to A M L are those with excess of bone marrow blasts [26-29],
Complicationsand treatment of MDS chromosomal anomalies [30, 31] especially complex chromosomal abnormalities and - 7 [32, 33], therapyrelated MDS [33, 34], and abnormal growth in in vitro cultures [34, 35]. U N C O M M O N COMPLICATIONS Patients with MDS have an increased incidence of immunologic abnormalities. Mufti et al. [36] found 12.5% of patients with MDS to have a monoclonal gammopathy. His group also reported 20 cases in which there was a coexistent lymphoid or plasma cell neoplasm [37]. The direct antiglobulin test was positive in 8% of cases and other circulating autoantibodies were found in 22%, though this was not higher than in age-matched controls. Both monoclonal gammopathies and auto-antibodies are particularly common in patients with chronic myelomonocytic leukemia [36, 38] (CMML). In some patients fever is the major manifestation of MDS [39]. Patients with CMML may present or develop serous effusions, skin infiltrations, hepatosplenomegaly, gingival hypertrophy and lymphodenopathy [38, 40, 41]. Cutaneous vasculitis and polyarthritis are also seen [42-44]. Non-hematologic malignancy during follow-up of MDS occurs at a higher than expected rate [45]. THERAPY The median survival for untreated MDS patients in different series varies between 7.5 and 27 months and largely depends upon the proportion of patients in the study with and without excess of bone marrow blasts [29]. The outlook for those patients with excess of bone marrow blasts, pancytopenia, complex chromosomal abnormalities and treatment-related MDS is very grim. Effective therapy would be highly desirable for these patients. The advantage of treating patients in the myelodysplastic phase is that the tumor load is low, but there is an obvious risk of premature death due to drug toxicity. Therapy in MDS patients over the age of 50 should aim at prolonging survival by reducing the neoplastic clone and more importantly by increasing blood counts. While in AML the attainment of a complete remission is an absolute prerequisite for prolonged survival, complete remission may not be necessary to substantially increase survival in MDS. The primary goal in younger MDS patients, should be eradication of the disease and cure. Low-dose cytosine arabinoside therapy The idea behind this therapy was that low doses of cytosine arabinoside would induce differentiation of
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immature myeloid cells, while not very toxic. It could be given subcutaneously on an out-patient basis. A review of data on low-dose cytosine arabinoside in 170 MDS patients showed a complete remission rate of 16% with 21% partial responders [46]. The median duration of complete remission was 10.5 months. The median survival of all patients treated was 15 months, with little evidence that achieving a complete remission had a substantial influence on survival. Myelotoxicity was noted in 88% of patients; treatmentrelated mortality was 15%, confirming earfier findings that this treatment modality is associated with substantial toxicity and is difficult to administer on an outpatient basis [47]. A trend toward a higher responsive rate is observed in patients treated while still in the myelodysplastic phase as compared with treatment after progression to AML [48]. Most of the available data suggest that the main effect of low-dose cytosine arabinoside is cytotoxicity [48]. This therapy should not be considered as standard treatment for MDS. Aggressive chemotherapy Aggressive chemotherapy has generally been considered ineffective and contraindicated in MDS patients because of its extraordinary toxicity and the assumption that the bone marrow of MDS patients is incapable of recovering normal functions even if the dysplastic clone could be eradicated. However, complete remissions have been reported with aggressive chemotherapy, the rate varying between 15-70% [48-50]. The duration of hypoplasia induced by remission induction chemotherapy tended to be longer in MDS patients when compared to de novo AML, but the difference was not statistically significant [49, 50]. Although, prolonged remissions can be obtained with aggressive chemotherapy, most patients have experienced only short remissions in spite of intensive consolidation therapy [48, 51]. Nevertheless, younger patients with MDS should be treated with aggressive chemotherapy in case of severe cytopenia and/or excess of bone marrow blasts. Bone marrow transplantation Although MDS is a disease of later life, about 1020% of patients are under 50 years. Moreover, many patients with therapy-related MDS are younger persons, who are potential candidates for allogeneic bone marrow transplantation (BMT). Eradication of the disease has proved possible after both syngeneic and allogeneic BMT. Fifty-nine patients with severe myelodysplasia were treated by the Seattle Marrow Transplant Team with cyclophosphamide and either total body irradiation or busulphan. The projected 3years survival was 45 + 7%. Disease recurrence, interstitial pneumonitis and graft-vs-host disease
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were the most c o m m o n causes of death accounting for 8 deaths each [52]. In a multi-variate analysis, younger age and the presence of an abnormal karyotype were independent indicators of better diseasefree and overall survival. Patients who were transplanted with few blasts in their bone marrow had a lower probability of relapse of the disease. The European Bone Marrow Transplantation Group has reported on 78 patients with MDS or secondary AML, who received an allogeneic B M T [53]. Thirtyfour patients received intensive chemotherapy prior to the BMT. The 2-year disease-free survival was 60% for the 16 patients transplanted in complete remission. Forty-four patients had not received any intensive chemotherapy. The disease-free survival at 2 years after B M T was 58% for R A and RAS patients, 74% for R A E B , 50% for R A E B - t and 18% for untreated AML. In MDS patients under 50 years of age with poor prognostic markers or progressive disease, allogeneic B M T is the therapy of choice. In those patients with low tumor load B M T can be performed as first-line therapy. Patients with a high percent of bone marrow blasts will probably benefit from A M L remission induction therapy before undergoing BMT.
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