Intensive Chemotherapy in Myelodysplastic Syndromes
T. J. Hamblin
S U MM A R Y. Patients with myelodysplastic syndrome (MDS) who have more than 10% blasts in their hone marrow have a very short survival. Treatment has not improved for these patients for the past 10 years and supportive care alone is still the gold standard. Intensive chemotherapy for poor prognosis MDS has heen little tried, hut complete remission rates are higher in such studies than in patients with acute myeloid leukaemia (AML) supervening on the MDS. Although these groups may not he comparable, and neither group is representative of the majority of patients with the MDS who are generally older, a case can he made for a randomised prospective study comparing intensive chemotherapy and supportive care alone in poor prognosis MDS. For patients with the myelodysplastic syndrome intensive chemotherapy may carry especial risks. The involvement of the whole marrow in the neoplastic clone, and the likelihood of anthracycline resistance are two such hazards which may need to he circumvented.
It is probably true that the only way of curing the myelodysplastic syndrome (MDS) is by bone marrow allograft. The Seattle study of 59 patients so treated produced a Kaplan-Meier estimate of disease-free survival at 3 years of 45% f 14%.’ The European Bone Marrow Transplant group produced similar results. Of 44 patients with MDS, the 2-year diseasefree survival was 58% f 19% for refractory anaemia with or without sideroblasts, 74% f 14% for refractory anaemia with excess of blasts and 50% ) 16% for refractory anaemia with excess of blasts in transformation.2 Such a strategy is only available to the minority of patients who are under the age of 50 years, and in view of the high mortality of the procedure it must be used circumspectly, since many patients may have a very prolonged survival with no treatment at all.3 For the vast majority of patients with the MDS other treatments must be employed. T. J. Hamblin DM FRCP FRCPath, Department of Haematology, Royal Bournemouth Hospital. Castle Lane East, Bournemouth BH7 7DW. UK. Bh,d Reww~ 1,992) 6. 215-219 ,’ ,992 Longman Group UK Ltd
In the past 10 years a wide range of agents has been used to treat patients with the MDS. These have included hormones such as corticosteroids,4 androgens5 and Danazol$ differentiating agents such as retinoic acid7 and vitamin D;8 low doses of the following cytotoxic drugs: cytarabine,’ etoposide,” aclarubicin,” idarubicin12 and melphalan;13 and the following cytokines: both alpha-l4 and gammainterferon,15 erythropoietin,16 G-CSF,17 GM-CSF18 and interleukin-3.19 For each agent there have been reports of haematological improvement or even complete remissions. Nevertheless, none of these agents has displaced good supportive care as the treatment of choice for MDS. A controlled trial of low dose cytarabine versus supportive care alone showed identical survival curves for each arm of the study.20 Haematological growth factors have occasionally produced a return to polyclonal haemopoiesis21 but they are essentially adjuncts to supportive care. This is not to say that the treatment of MDS is satisfactory. On the contrary, the prognosis, especially for the subgroups refractory anaemia (RA) with
216
INTENSIVE
CHEMOTHERAPY
IN MYELODYSPLASTIC
excess of blasts and RA with excess of blasts in transformation, is dismal (see Table 1). Our own experience of the past 10 years is that the survival curves of patients diagnosed in successive years are superimposable, indicating no major advances in therapy during this period.30 Attempts have been made by a number of authors to identify subgroups of the MDS which do particularly badly. A variety of scoring systems3%28r31 which mainly rely on the degree of cytopenia and the percentage of bone marrow blast cells all have categories which predict a survival of less than a year. The meta-analysis by Sanz and Sanz3’ which shows that patients with more than 10% blasts in their bone marrows have a median survival of less than 6 months is especially notable. Other adverse prognostic factors include the abnormal localisation of immature precursors on trephine biopsy33 in cases of RA or refractory anaemia with sideroblasts (RAS). The task of identifying these is made much easier by immunocytochemistry which distinguishes myeloblasts from proerythroblasts and micro-megakaryocytes.34 A poor prognostic group is also identified by karyotypic analysis. Deletion of the long arm of chromosome 7, monosomy 7, complex karyotype and karyotypic evolution all bode i1L2’
Intensive Chemotherapy Syndrome
in Myelodysplastic
Although the treatment of AML by intensive chemotherapy has been seen as one of the major successes of haemato-oncology, with complete remission rates in excess of 80%, such good results are only achievable by selecting the most promising patients. The Toronto Leukaemia Study Group34 raised their complete remission rate from 43-85% by excluding patients too frail to contemplate chemotherapy, those over 70 years of age, those who failed to complete one course and those who had had a previous preleukaemic phase or previous chemotherapy. In our own unit a similar exercise raised the complete remission rate from 39-92%. Unfortunately, it eliminated 73% of our patients!36 Table 1 Median survival patients with MDS Author
(date)
Mufti ( 1985)3 Vallespi ( 1985)22 Foucar ( 1985)13 Teerenhovi ( 1986)24 Kerkhofs ( 1987)25 Economopoulos ( 1987)16 Pierre (1989)” Sanz ( 1989)” Goasguen ( 1990)29
SYNDROMES
Implicit in the strategy of supportive care alone for MDS is the supposition that salvage chemotherapy will be available should acute leukaemia supervene. However, as can be seen from Table 2, complete remission rates for AML supervening on MDS are low. There have been relatively few studies of intensive chemotherapy for poor prognosis MDS prior to transformation to AML. However, as can be seen in Table 3, most of such trials show a higher complete remission rate than those reported in Table 2. It would be dangerous to compare these two tables and jump to the conclusion that poor prognosis MDSs should be treated with intensive chemotherapy before transformation to AML occurs. There is no reason to believe that the groups of patients in any of the trials are comparable, nor are they representative of the MDS as a whole, since in both sets of studies most of the patients treated were under the age of 65 years. Moreover, even in younger people the choice between intensive chemotherapy in poor prognosis MDS versus supportive care, until transformation to AML, demands aggressive treatment has not been tested in a randomised prospective trial. It is becoming increasingly recognised that the majority of elderly patients with AML possess features of MDS either prior to therapy or when remission is achieved. 52 This may explain the poor response rate in elderly AML. In the Medical Research Council 8th adult AML trial the complete remission rate for the under 50s was over 70%, Table 2 Aggressive chemotherapy combinations in post-MDS AML Author
No. of cases
(year)
Mertelsman ( 1980)37 Keating ( 1981)38 Tricot ( 1986)39 Preisler (I 987)@ Lazzarino (1987)“l Martiat ( 1988)42 Hoyle ( 1989)43 Au1 ( 1989)” Gajewski ( 1989)45 De Witte ( 1990)4” Fenaux (1991)47
and RAEBt
No. of CRs (%) 5 7 2 2 6 6 15 4 18 9 5
(31%) (22%) (33%) (18%) (40%) (24%) (42%) (36%) (41%) (64%) (31%)
79 (35%)
in large series of CR = complete
No. of cases of MDS
Median months RAEB
141 101 109 162 231 131 247 310 503
10.5 13 I 21 9 13 24 9 19
RAEB = refractory anaemia with excess of blasts RAEBt = RAEB in transformation MDS = myelodysplastic syndrome
16 32 6 11 15 25 36 II 44 14 16 226
Total in RAEB
with anthracycline-cytarabine
survival in for RAEBt 5 2.5 5 13 6 10 12 5 I1
remission
Table 3 Aggressive chemotherapy combinations in MDS Author
No. of cases
(year)
Scoazec ( 1985)48 Tricot ( 1986)38 Michels ( 1989)49 Aul ( 1989)46 Advani (1989)5” Van Gee] (1989)‘l De Witte (1990)46 Fenaux ( 1991)47
5 9 31 5 14 35 14 31 144
Total CR = complete
with anthracycline-cytarabine
remission
No. of CRs (%) 4 6 19 5 9 21 9 17
(80%) (66%) (61%) (100%) (64%) (60%) (64%) (55%)
90 (62.5%)
BLOOD
between 60 and 69 it was 52% and in the over 70s for the intensive only 26%. 43 No such comparisons treatment of MDS at different ages have been made, but it is likely, although not certain, that they would be similar. There is therefore even more justification in the elderly group for offering supportive care alone in preference to intensive chemotherapy until it can be shown in a randomised prospective study that the latter is more effective.
Reasons for Poor Responses in the Elderly One reason for low response rates in elderly patients, and especially those with MDS, might be a poorer ability to survive the period of pancytopenia. This hypothesis may be tested by examining the number of early deaths due to cytopenia in various series. Rates of 21,45 25,43 44,53 5338 and 640h4’ suggest that this is an important cause of treatment failure. Greater susceptibility to infection during the pancytopenic phase might be a consequence of impaired granulocyte and monocyte function in the MDS. In addition, Fialkow et aLs4 using X-linked clonality studies, demonstrated that, whereas in younger patients with AML, erythrocytes and platelets at presentation and erythrocytes, platelets and granulocytes in remission all derived from normal stem cells, in elderly AMLs all haemopoietic cells at presentation belonged to the leukaemic clone, and often remained so during apparent complete clinical remission. Thus, with little if any normal marrow reserve, the period of chemotherapy induced pancytopenia might well be prolonged. In fact, De Witte et a146 found that the period of pancytopenia was longer in patients with AML supervening on the MDS than in those with de novo AML. Nevertheless, in both this study and that of Hoyle.43 early toxic deaths were no more common in post MDS AML than in de novo AML, suggesting that recent advances in supportive care have made it possible for patients to weather intensive chemotherapy more effectively. The other possible reason for low complete remission rates is drug resistance.
Drug Resistance in Myelodysplastic
Syndrome
The low response rate of post-MDS AML in the Medical Research Council’s 9th AML trial was attributed to resistant disease (57% of those failing to achieve complete remission).43 Although a number of mechanisms for drug resistance in leukaemias have been recognised, only the over-expression of the mdrl gene which codes for the membrane protein P-glycoprotein and whose presence is associated with the rapid efflux of natural toxic products from the ce1155 has been studied in any detail in the MDL. Sato et als6 demonstrated increased mdr 1 mRNA transcripts in 5/5 cases of post-MDS AML compared with 3/8 cases of de novo AML. Holmes et al” found elevated levels of P glycoprotein mRNA in 7/19 cases of MDS
Table 4 Mediation duration of complete with MDS or post-MDS AML Author
Median
(year)
duration > 45 < 45
remission
duration
2 17
in patients
of remission
24* I? IO 7 9 13* I,* 12’ 25’ 7 9
Scoazec ( 1985)48 Tricot ( 1988)39 Lazzarino (1987P’ Martiat ( 1988)42 Au1 (1989)” Gajewski ( 1989)J5 Hoyle ( 1989)4” Michels (I 989)49 Michels (I 989)4” De Witte ( 1990)46 Fenaux (1991)“’ *-median l-patients ?-patients
REVIEWS
of survival
in complete
remrtters
compared with 2/8 cases of de novo AML. Similarly Marie et al 58 found elevated exp ression in all three cases of post-MDS AML but in only 12/19 de novo AMLs. Two studies58.59 have shown an inverse correlation between complete remission achieved with daunorubicin-cytarabine combinations, and elevated expression of mdrl mRNA. Although this information is not comprehensive it may lead designers of trials of intensive chemotherapy in MDS to opt for regimes which include the newer anthracyclines which are reputed to be less affected by P glycoprotein. For example, Berman and McBride have demonstrated that idarubicin is better taken up and retained than daunorubicin in leukaemic cell lines expressing the MDR phenotype. Furthermore, idarubicin was much more efficient in inhibiting the clonogenic growth of these cell lines.“’
Duration of Remission factors Keating et al 61 found that the following determined the length of remission in AML: (1) serum lactic dehydrogenase (a measure of tumour mass); (2) the number of courses of chemotherapy required for complete remission and the rate of fall of blast count after chemotherapy (measures of drug resistance) and, (3) age. In post-MDS AML most series have reported a median duration of complete remission of less than 1 year (Table 4) reflecting the common scenario of a drug resistant myelodysplastic syndrome clone having subsumed the whole bone marrow in a patient older than average. Such short remissions are a disincentive to treat intensively. Nevertheless, they might provide a longer and a better quality life than supportive care alone. This premise needs to be tested in a randomised prospective study which gives particular emphasis to cost, time out of hospital and quality of life measurements.
References 1. Appelbaum F R, Barrall J, Storb R et al 1990 Bone marrow transplantation for patients with myelodysplasia.
218
2.
3.
4.
5.
6. 7.
8.
9.
IO.
Il.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21
INTENSIVE
CHEMOTHERAPY
IN MYELODYSPLASTIC
Pretreatment variables and outcome. Annals of Internal Medicine 112: 590-597 De Witte T, Zwaan F, Hermans .I et al 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). British Journal of Haematology 74: 151ll55 Mufti G J, Stevens J R, Oscier D G, Hamblin T J. Machin D 1985 Myelodysplastic syndromes: a scoring system with prognostic significance. British Journal of Haematology 59: 4255433 Bagby G C Jr. Gabourel J D, Linman J W. 1980 Glucocorticoid therapy in the preleukemia syndrome (hemopoietic dysplasia): identification of responsive patients using in-vitro techniques. Annals of Internal Medicine 92: 55-58 Najean Y. Pecking A. 1977 Refractory anaemia with excess of myeloblasts in the bone marrow: a clinical trial of androgens in 90 patients. British Journal of Haematology 37: 25-33 Cines C B, Cassileth P A, Kiss J E 1985 Danazol therapy in myelodysplasia. Annals of Internal Medicine 103: 58860 Koeffler H D, Heitgen D, Mertelsmann R et al 1988 Randomised study of 13 cis-retinoic acid vs placebo in the myelodysplastic disorders. Blood 71: 703-708 Koeffler H D, Hirji K, Itri L 1985 1,25 dihydroxyvitamin D3: in vivo and in vitro effects of human preleukemic and leukemic cells. Cancer Treatment Reports69: 1399-1407 Cheson B D. Jasoerse 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. Journal of Clinical Oncology 4: 1857-1864 Oscier D G, Worsley A, Hamblin T J, Mufti G J 1989 Treatment of chronic myelomonocytic leukaemia with low dose etoposide. British Journal of Haematology 71: 468-471 Shibuya T, Akashi K, Harada M et al 1991 Low dose aclarubicin therapy for myelodysplastic syndromes. In: Miyazaki T, Takaku F, Uchino H (eds) Myelodysplastic Syndrome and Cytokines. Elsevier, Amsterdam, pp. 2399248 Johnson E, Parapia L A 1987 Successful oral chemotherapy with idarubicin in refractory anaemia with excess blasts. European Journal of Haematology 39: 278-28 1 Omoto E, Kimura I 1991 Effect of low dose mephalan for the treatment of myelodysplastic syndrome. In: Miyazaki T, Takaku F. Uchino H (eds) Myelodysplastic Syndrome and Cytokines. Elsevier. Amsterdam. pp. 249-256 Galvani D W, Nethersell A B W, Cawley J C 1988 Alphainterferon in myelodysplasia: clinical observations and effects of NK cells. Leukemia Research 12: 257-262 Maiolo A T. Cortelezzi A, Calori R, Polli E E, for the Italian Study Group 1990 Recombinant gamma interferon as first line therapy for high risk myelodysplastic syndrome. Leukemia 4: 480-485 Ganser A, Hoelzer D 1992 Treatment of myelodysplastic syndromes with haematopoietic growth factors. Hematology/ Oncologv Clinics of North America 6: 633-654 Negrinx S, Nagler A. Kobayashi Y et al 1990 Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony stimulating factor. Blood 76: 36-43 Gamer A, Volkers B, Greher J et al 1989 Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes-a phase I/II trial. Blood 73: 31-37 Ganser A, Seipelt G, Lindemann A et al 1990 Effects of recombinant human interleukin-3 in patients with mvelodvsolastic svndromes. Blood 76: 455-462 Bdnneti J M, Miller K B, Kim K et al 1992 Phase III evaluation of low dose cytosine arabinoside versus supportive care in the treatment of adults with myelodyplastic syndrome: an intergroup study by the Eastern Co-operative Oncology Group and the South West Oncology Group-preliminary results. In: Schmalzl F, Mufti G J (eds) Myelodysplastic syndromes. Springer, Berlin, pp. 2355258 Vadham-Raj S, Broxmeyer H E. Spitzer G et al 1989 Stimulation of non-clonal haematopoiesis and suppression of the neoplastic clone after treatment with recombinant human
SYNDROMES
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32. 33.
34.
35.
36.
37.
38.
39.
40.
41.
42
granulocyte-macrophage colony-stimulating factor in a patient with therapy related myelodysplastic syndrome. Blood 74: 1491-1498 Vallespi T, Torrabadella M, Julia A et al 1985 Myelodysplastic syndromes: a study of 101 cases according to the FAB classification. British Journal of Haematology 61: 83-92 Foucar K, Langdon R M, Armitage J 0, Olsen D B, Carrol f J Jr 1985 Myelodysplastic syndromes. A clinical and pathological analysis of 109 cases. Cancer 56: 533-561 Teerenhovi L, Lintala R 1986 Natural cause of myeiodysplastic syndrome-Helsinki experience. Scandinavian Journal of Hematology 36: 102-106 Kerkhoffs H, Hermans J, Haak H L, Leeksman C H W 1987 Utility of the FAB classification for myelodysplastic syndromes. Investigation of prognostic factors in 256 cases. British Journal of Haematology 65: 73381 Economopoulas T. Stathakis N. Foudoulakis A et al 1987 Myelodysplastic syndromes. Analysis of 13 1 cases according to the FAB classification, European Journal of Haematology 38: 3388341 Pierre R V, Catovsky D, Mufti G J et al 1989 Clinical cytogenetic correlations in myelodysplasia (preleukaemia). Cancer Genetics and Cytogenetics 45: 149-161 Sanz G F, Sanz M A, Vallespi T et al 1989 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: 3955408 Goasguen J E, Garand R, Bizet M et al 1990 Prognostic factors of myelodysplastic syndromes. A simplified 3-D scoring system. Leukemia Research 14: 255-261 Revnolds P. Kruger A, Sadullah S. Hamblin T. Oscier D 1991 Has survival improved in the past ten years? Leukemia Research 15 (Suppl): 11 (abstr) Aul C. Gutterman N. Heyll A, Germing U, Denigs G. Schneider W 1992 Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring system. Leukemia 6: 52-59 Sanz G, Sanz M 1992 Prognostic factors in myelodysplastic syndromes. Leukemia Research 16: 77-86 Tricot G. De Wolf-Peeters C, Veietinck R. Verwighen R L 1984 Bone marrow histology in myelodyplastic syndromes. II. Prognostic value of abnormal localisation of immature precursors in MDS. British Journal of Haematology 58: 217-225 Mangi M H. Mufti G J 1992 Primary myelodysplastic syndromes: diagnostic and prognostic significance of immunobiochemical assessment of bone marrow biopsies. Blood 79: 198-205 Toronto Study Group 1986 Results of chemotherapy for unselected patients with acute myeloblastic leukaemia: effect of exclusions on interpretation of results. Lancet i: 7866788 Copplestone J A, Smith A G, Oscier D Cl, Hamblin T J 1986 True outlook in acute myeloblastic leukaemia. Lancet i: 1104 Mertelsmann R, Thaler H T, To L et al 1980 Morphological classification, response to therapy and survival in 263 adult patients with acute non-lymphoblastic leukemia. Blood 56: 773-78 1 Keating M J, McCredie K B, Benjamin R S et al 1981 Treatment of patients over 50 years of age with acute myelogenous leukemia with a combination of rubidazone and cytosine arabinoside, vincristine and prednisone (ROAP). Blood 58: 584-591 Tricot Cl, Boogaerts M A 1986 The role of aggressive chemotherapy-m the treatment of myelodysplastic svndromes. British Journal of Haematology 63: 477-483 Preisler H D. Raza A, Barcos M et al 1987 High dose cytosine arabinoside as the initial treatment of poor risk patients with acute non-lymphocytic leukemia. Journal of Clinical Oncology 5: 72-82 Lazzarino M. Morra E. Alessandrino E M et al 1987 Etoposide-cytarabine therapy for acute leukemia following myelodysplastic syndromes or secondary to treatment for malignant disease. Haematoiogica 72: 341-345 Martiat P, Ferrant A, Michaux J-L, Sokal G 1988 Intensive chemotherapy for acute non-lymphoblastic leukemia after primary myelodysplastic syndrome. Haematological Oncology 6: 299-305
BLOOD 43. Hoyle C F, de Bastos M. Wheatley K et al 1989 AML associated with previous cytotoxic therapy, MDS or myeloproliferative disorders: results from the MRC’s 9th AML trial. British Journal of Haematology 72: 45-53 44. Au1 C. Schneider W 1989 The role of low dose cytosine arabinoside and aggressive chemotherapy in advanced myelodysplastic syndrome. Cancer 64: 1812-1818 45. Gajewski J L, Ho W G. Nimer S D et al 1989 Efficacy of intensive chemotherapy for acute myelogenous leukemia associated with a preleukemic syndrome. Journal of Clinical Oncology 7: I637- 1645 46. 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 47. Fenaux P, Morel P. Rose C et al 1991 Prognostic factors in adult de novo myelodysplastic syndromes treated by intensive chemotherapy. British Journal of Haematology 77: 497-501 4x. Scoarec J-Y. Imbert M. Crofts M et al 1985 Myelodysplastic syndrome or acute myeloid leukemia. Cancer 55: 2390-2394 49. Michels S D, Saumur J, Arthur D C. Robison L L. Brunning R D 1989 Refractory anemia with excess of blasts m transformation. hematologic and clinical study of 52 patients. Cancer 64: 2340-3346 of 50. Advani S H. Giri N K, Dole M G et al 1989 Limitations the therapeutic regimes for myelodysplastic syndrome. Indian Journal of Medicine 90: 248-253 E, Wijermans 51. Van Gee1 B M. Huijgens P C. Ossenkoppel P W. Langenhuijsen M M 1989 Standard induction of low dose ara-c treatment in patients over 60 with AML or MDS. Netherlands Journal of Medicine 35: 128-136 52 Nagai K, Mutsuo T. Atoyami S et al 1992 Remission with morphological myelodysplasia in de nova acute myeloid
53.
54.
55.
56.
57.
58.
59.
60.
61.
REVIEWS
219
leukaemia: implications for early relapse. British Journal of Haematology sl: 33-39 Fenaux P. Lai J L. Jouet J P. Pollet J P. Bauters F 1988 Aggressive chemotherapy in adult primary myelodysplastic syndromes. Blut 57: 297-302 Fialkow P, Singer J W, Raskind W H et al 1987 Clonal development, stem cell differentiation and clinical remissions in acute non-lymphocytic leukemia. New England Journal of Medicine 317: 468-473 Kaye S B, Kerr D J 1991 Multidrug resistance: clinical relevance in haematological malignancies. Blood Reviews 5: 38-41 Sato H, Gottesman M M, Goldstein L J et al 1990 Expression of the multidrug resistance gene in myeloid leukemias. Leukemia Research 14: 1 l-21 Holmes J, Jacobs A. Carter G, Janowska-Weiczorek A, Padud R 1989 Multidrug resistance in haemopoietic cell lines. myelodysplastic syndromes and acute myeloblastic leukaemia. British Journal of Haematology 72: 40-44 Marie J-P, Zittoun R. Sikic B I 1991 Multidrug resistance (mdsl) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity. Blood 78: 5866592 Pinker R, Wallner J, Geissler K et al 1991 MDRI gene expression and treatment outcome in acute myeloid leukaemia. Journal of the National Cancer Institute 83: 708-7 14 Berman E, McBride E 1992 Comparative cellular pharmacology of daunorubicin and idarubicin in human multidrug-resistant leukemic cells. Blood 79: 3267-3273 Keating M J, Smith T L, Gehan E A et al 1980 Factors related to length of complete remission in adult acute leukemia. Cancer 45: 2017-2029
T. J. Hamblin
S U MM A R Y. Patients with myelodysplastic syndrome (MDS) who have more than 10% blasts in their hone marrow have a very short survival. Treatment has not improved for these patients for the past 10 years and supportive care alone is still the gold standard. Intensive chemotherapy for poor prognosis MDS has heen little tried, hut complete remission rates are higher in such studies than in patients with acute myeloid leukaemia (AML) supervening on the MDS. Although these groups may not he comparable, and neither group is representative of the majority of patients with the MDS who are generally older, a case can he made for a randomised prospective study comparing intensive chemotherapy and supportive care alone in poor prognosis MDS. For patients with the myelodysplastic syndrome intensive chemotherapy may carry especial risks. The involvement of the whole marrow in the neoplastic clone, and the likelihood of anthracycline resistance are two such hazards which may need to he circumvented.
It is probably true that the only way of curing the myelodysplastic syndrome (MDS) is by bone marrow allograft. The Seattle study of 59 patients so treated produced a Kaplan-Meier estimate of disease-free survival at 3 years of 45% f 14%.’ The European Bone Marrow Transplant group produced similar results. Of 44 patients with MDS, the 2-year diseasefree survival was 58% f 19% for refractory anaemia with or without sideroblasts, 74% f 14% for refractory anaemia with excess of blasts and 50% ) 16% for refractory anaemia with excess of blasts in transformation.2 Such a strategy is only available to the minority of patients who are under the age of 50 years, and in view of the high mortality of the procedure it must be used circumspectly, since many patients may have a very prolonged survival with no treatment at all.3 For the vast majority of patients with the MDS other treatments must be employed. T. J. Hamblin DM FRCP FRCPath, Department of Haematology, Royal Bournemouth Hospital. Castle Lane East, Bournemouth BH7 7DW. UK. Bh,d Reww~ 1,992) 6. 215-219 ,’ ,992 Longman Group UK Ltd
In the past 10 years a wide range of agents has been used to treat patients with the MDS. These have included hormones such as corticosteroids,4 androgens5 and Danazol$ differentiating agents such as retinoic acid7 and vitamin D;8 low doses of the following cytotoxic drugs: cytarabine,’ etoposide,” aclarubicin,” idarubicin12 and melphalan;13 and the following cytokines: both alpha-l4 and gammainterferon,15 erythropoietin,16 G-CSF,17 GM-CSF18 and interleukin-3.19 For each agent there have been reports of haematological improvement or even complete remissions. Nevertheless, none of these agents has displaced good supportive care as the treatment of choice for MDS. A controlled trial of low dose cytarabine versus supportive care alone showed identical survival curves for each arm of the study.20 Haematological growth factors have occasionally produced a return to polyclonal haemopoiesis21 but they are essentially adjuncts to supportive care. This is not to say that the treatment of MDS is satisfactory. On the contrary, the prognosis, especially for the subgroups refractory anaemia (RA) with
216
INTENSIVE
CHEMOTHERAPY
IN MYELODYSPLASTIC
excess of blasts and RA with excess of blasts in transformation, is dismal (see Table 1). Our own experience of the past 10 years is that the survival curves of patients diagnosed in successive years are superimposable, indicating no major advances in therapy during this period.30 Attempts have been made by a number of authors to identify subgroups of the MDS which do particularly badly. A variety of scoring systems3%28r31 which mainly rely on the degree of cytopenia and the percentage of bone marrow blast cells all have categories which predict a survival of less than a year. The meta-analysis by Sanz and Sanz3’ which shows that patients with more than 10% blasts in their bone marrows have a median survival of less than 6 months is especially notable. Other adverse prognostic factors include the abnormal localisation of immature precursors on trephine biopsy33 in cases of RA or refractory anaemia with sideroblasts (RAS). The task of identifying these is made much easier by immunocytochemistry which distinguishes myeloblasts from proerythroblasts and micro-megakaryocytes.34 A poor prognostic group is also identified by karyotypic analysis. Deletion of the long arm of chromosome 7, monosomy 7, complex karyotype and karyotypic evolution all bode i1L2’
Intensive Chemotherapy Syndrome
in Myelodysplastic
Although the treatment of AML by intensive chemotherapy has been seen as one of the major successes of haemato-oncology, with complete remission rates in excess of 80%, such good results are only achievable by selecting the most promising patients. The Toronto Leukaemia Study Group34 raised their complete remission rate from 43-85% by excluding patients too frail to contemplate chemotherapy, those over 70 years of age, those who failed to complete one course and those who had had a previous preleukaemic phase or previous chemotherapy. In our own unit a similar exercise raised the complete remission rate from 39-92%. Unfortunately, it eliminated 73% of our patients!36 Table 1 Median survival patients with MDS Author
(date)
Mufti ( 1985)3 Vallespi ( 1985)22 Foucar ( 1985)13 Teerenhovi ( 1986)24 Kerkhofs ( 1987)25 Economopoulos ( 1987)16 Pierre (1989)” Sanz ( 1989)” Goasguen ( 1990)29
SYNDROMES
Implicit in the strategy of supportive care alone for MDS is the supposition that salvage chemotherapy will be available should acute leukaemia supervene. However, as can be seen from Table 2, complete remission rates for AML supervening on MDS are low. There have been relatively few studies of intensive chemotherapy for poor prognosis MDS prior to transformation to AML. However, as can be seen in Table 3, most of such trials show a higher complete remission rate than those reported in Table 2. It would be dangerous to compare these two tables and jump to the conclusion that poor prognosis MDSs should be treated with intensive chemotherapy before transformation to AML occurs. There is no reason to believe that the groups of patients in any of the trials are comparable, nor are they representative of the MDS as a whole, since in both sets of studies most of the patients treated were under the age of 65 years. Moreover, even in younger people the choice between intensive chemotherapy in poor prognosis MDS versus supportive care, until transformation to AML, demands aggressive treatment has not been tested in a randomised prospective trial. It is becoming increasingly recognised that the majority of elderly patients with AML possess features of MDS either prior to therapy or when remission is achieved. 52 This may explain the poor response rate in elderly AML. In the Medical Research Council 8th adult AML trial the complete remission rate for the under 50s was over 70%, Table 2 Aggressive chemotherapy combinations in post-MDS AML Author
No. of cases
(year)
Mertelsman ( 1980)37 Keating ( 1981)38 Tricot ( 1986)39 Preisler (I 987)@ Lazzarino (1987)“l Martiat ( 1988)42 Hoyle ( 1989)43 Au1 ( 1989)” Gajewski ( 1989)45 De Witte ( 1990)4” Fenaux (1991)47
and RAEBt
No. of CRs (%) 5 7 2 2 6 6 15 4 18 9 5
(31%) (22%) (33%) (18%) (40%) (24%) (42%) (36%) (41%) (64%) (31%)
79 (35%)
in large series of CR = complete
No. of cases of MDS
Median months RAEB
141 101 109 162 231 131 247 310 503
10.5 13 I 21 9 13 24 9 19
RAEB = refractory anaemia with excess of blasts RAEBt = RAEB in transformation MDS = myelodysplastic syndrome
16 32 6 11 15 25 36 II 44 14 16 226
Total in RAEB
with anthracycline-cytarabine
survival in for RAEBt 5 2.5 5 13 6 10 12 5 I1
remission
Table 3 Aggressive chemotherapy combinations in MDS Author
No. of cases
(year)
Scoazec ( 1985)48 Tricot ( 1986)38 Michels ( 1989)49 Aul ( 1989)46 Advani (1989)5” Van Gee] (1989)‘l De Witte (1990)46 Fenaux ( 1991)47
5 9 31 5 14 35 14 31 144
Total CR = complete
with anthracycline-cytarabine
remission
No. of CRs (%) 4 6 19 5 9 21 9 17
(80%) (66%) (61%) (100%) (64%) (60%) (64%) (55%)
90 (62.5%)
BLOOD
between 60 and 69 it was 52% and in the over 70s for the intensive only 26%. 43 No such comparisons treatment of MDS at different ages have been made, but it is likely, although not certain, that they would be similar. There is therefore even more justification in the elderly group for offering supportive care alone in preference to intensive chemotherapy until it can be shown in a randomised prospective study that the latter is more effective.
Reasons for Poor Responses in the Elderly One reason for low response rates in elderly patients, and especially those with MDS, might be a poorer ability to survive the period of pancytopenia. This hypothesis may be tested by examining the number of early deaths due to cytopenia in various series. Rates of 21,45 25,43 44,53 5338 and 640h4’ suggest that this is an important cause of treatment failure. Greater susceptibility to infection during the pancytopenic phase might be a consequence of impaired granulocyte and monocyte function in the MDS. In addition, Fialkow et aLs4 using X-linked clonality studies, demonstrated that, whereas in younger patients with AML, erythrocytes and platelets at presentation and erythrocytes, platelets and granulocytes in remission all derived from normal stem cells, in elderly AMLs all haemopoietic cells at presentation belonged to the leukaemic clone, and often remained so during apparent complete clinical remission. Thus, with little if any normal marrow reserve, the period of chemotherapy induced pancytopenia might well be prolonged. In fact, De Witte et a146 found that the period of pancytopenia was longer in patients with AML supervening on the MDS than in those with de novo AML. Nevertheless, in both this study and that of Hoyle.43 early toxic deaths were no more common in post MDS AML than in de novo AML, suggesting that recent advances in supportive care have made it possible for patients to weather intensive chemotherapy more effectively. The other possible reason for low complete remission rates is drug resistance.
Drug Resistance in Myelodysplastic
Syndrome
The low response rate of post-MDS AML in the Medical Research Council’s 9th AML trial was attributed to resistant disease (57% of those failing to achieve complete remission).43 Although a number of mechanisms for drug resistance in leukaemias have been recognised, only the over-expression of the mdrl gene which codes for the membrane protein P-glycoprotein and whose presence is associated with the rapid efflux of natural toxic products from the ce1155 has been studied in any detail in the MDL. Sato et als6 demonstrated increased mdr 1 mRNA transcripts in 5/5 cases of post-MDS AML compared with 3/8 cases of de novo AML. Holmes et al” found elevated levels of P glycoprotein mRNA in 7/19 cases of MDS
Table 4 Mediation duration of complete with MDS or post-MDS AML Author
Median
(year)
duration > 45 < 45
remission
duration
2 17
in patients
of remission
24* I? IO 7 9 13* I,* 12’ 25’ 7 9
Scoazec ( 1985)48 Tricot ( 1988)39 Lazzarino (1987P’ Martiat ( 1988)42 Au1 (1989)” Gajewski ( 1989)J5 Hoyle ( 1989)4” Michels (I 989)49 Michels (I 989)4” De Witte ( 1990)46 Fenaux (1991)“’ *-median l-patients ?-patients
REVIEWS
of survival
in complete
remrtters
compared with 2/8 cases of de novo AML. Similarly Marie et al 58 found elevated exp ression in all three cases of post-MDS AML but in only 12/19 de novo AMLs. Two studies58.59 have shown an inverse correlation between complete remission achieved with daunorubicin-cytarabine combinations, and elevated expression of mdrl mRNA. Although this information is not comprehensive it may lead designers of trials of intensive chemotherapy in MDS to opt for regimes which include the newer anthracyclines which are reputed to be less affected by P glycoprotein. For example, Berman and McBride have demonstrated that idarubicin is better taken up and retained than daunorubicin in leukaemic cell lines expressing the MDR phenotype. Furthermore, idarubicin was much more efficient in inhibiting the clonogenic growth of these cell lines.“’
Duration of Remission factors Keating et al 61 found that the following determined the length of remission in AML: (1) serum lactic dehydrogenase (a measure of tumour mass); (2) the number of courses of chemotherapy required for complete remission and the rate of fall of blast count after chemotherapy (measures of drug resistance) and, (3) age. In post-MDS AML most series have reported a median duration of complete remission of less than 1 year (Table 4) reflecting the common scenario of a drug resistant myelodysplastic syndrome clone having subsumed the whole bone marrow in a patient older than average. Such short remissions are a disincentive to treat intensively. Nevertheless, they might provide a longer and a better quality life than supportive care alone. This premise needs to be tested in a randomised prospective study which gives particular emphasis to cost, time out of hospital and quality of life measurements.
References 1. Appelbaum F R, Barrall J, Storb R et al 1990 Bone marrow transplantation for patients with myelodysplasia.
218
2.
3.
4.
5.
6. 7.
8.
9.
IO.
Il.
12.
13.
14.
15.
16.
17.
18.
19.
20.
21
INTENSIVE
CHEMOTHERAPY
IN MYELODYSPLASTIC
Pretreatment variables and outcome. Annals of Internal Medicine 112: 590-597 De Witte T, Zwaan F, Hermans .I et al 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). British Journal of Haematology 74: 151ll55 Mufti G J, Stevens J R, Oscier D G, Hamblin T J. Machin D 1985 Myelodysplastic syndromes: a scoring system with prognostic significance. British Journal of Haematology 59: 4255433 Bagby G C Jr. Gabourel J D, Linman J W. 1980 Glucocorticoid therapy in the preleukemia syndrome (hemopoietic dysplasia): identification of responsive patients using in-vitro techniques. Annals of Internal Medicine 92: 55-58 Najean Y. Pecking A. 1977 Refractory anaemia with excess of myeloblasts in the bone marrow: a clinical trial of androgens in 90 patients. British Journal of Haematology 37: 25-33 Cines C B, Cassileth P A, Kiss J E 1985 Danazol therapy in myelodysplasia. Annals of Internal Medicine 103: 58860 Koeffler H D, Heitgen D, Mertelsmann R et al 1988 Randomised study of 13 cis-retinoic acid vs placebo in the myelodysplastic disorders. Blood 71: 703-708 Koeffler H D, Hirji K, Itri L 1985 1,25 dihydroxyvitamin D3: in vivo and in vitro effects of human preleukemic and leukemic cells. Cancer Treatment Reports69: 1399-1407 Cheson B D. Jasoerse 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. Journal of Clinical Oncology 4: 1857-1864 Oscier D G, Worsley A, Hamblin T J, Mufti G J 1989 Treatment of chronic myelomonocytic leukaemia with low dose etoposide. British Journal of Haematology 71: 468-471 Shibuya T, Akashi K, Harada M et al 1991 Low dose aclarubicin therapy for myelodysplastic syndromes. In: Miyazaki T, Takaku F, Uchino H (eds) Myelodysplastic Syndrome and Cytokines. Elsevier, Amsterdam, pp. 2399248 Johnson E, Parapia L A 1987 Successful oral chemotherapy with idarubicin in refractory anaemia with excess blasts. European Journal of Haematology 39: 278-28 1 Omoto E, Kimura I 1991 Effect of low dose mephalan for the treatment of myelodysplastic syndrome. In: Miyazaki T, Takaku F. Uchino H (eds) Myelodysplastic Syndrome and Cytokines. Elsevier. Amsterdam. pp. 249-256 Galvani D W, Nethersell A B W, Cawley J C 1988 Alphainterferon in myelodysplasia: clinical observations and effects of NK cells. Leukemia Research 12: 257-262 Maiolo A T. Cortelezzi A, Calori R, Polli E E, for the Italian Study Group 1990 Recombinant gamma interferon as first line therapy for high risk myelodysplastic syndrome. Leukemia 4: 480-485 Ganser A, Hoelzer D 1992 Treatment of myelodysplastic syndromes with haematopoietic growth factors. Hematology/ Oncologv Clinics of North America 6: 633-654 Negrinx S, Nagler A. Kobayashi Y et al 1990 Maintenance treatment of patients with myelodysplastic syndromes using recombinant human granulocyte colony stimulating factor. Blood 76: 36-43 Gamer A, Volkers B, Greher J et al 1989 Recombinant human granulocyte-macrophage colony-stimulating factor in patients with myelodysplastic syndromes-a phase I/II trial. Blood 73: 31-37 Ganser A, Seipelt G, Lindemann A et al 1990 Effects of recombinant human interleukin-3 in patients with mvelodvsolastic svndromes. Blood 76: 455-462 Bdnneti J M, Miller K B, Kim K et al 1992 Phase III evaluation of low dose cytosine arabinoside versus supportive care in the treatment of adults with myelodyplastic syndrome: an intergroup study by the Eastern Co-operative Oncology Group and the South West Oncology Group-preliminary results. In: Schmalzl F, Mufti G J (eds) Myelodysplastic syndromes. Springer, Berlin, pp. 2355258 Vadham-Raj S, Broxmeyer H E. Spitzer G et al 1989 Stimulation of non-clonal haematopoiesis and suppression of the neoplastic clone after treatment with recombinant human
SYNDROMES
22.
23.
24.
25.
26.
27.
28.
29.
30.
31.
32. 33.
34.
35.
36.
37.
38.
39.
40.
41.
42
granulocyte-macrophage colony-stimulating factor in a patient with therapy related myelodysplastic syndrome. Blood 74: 1491-1498 Vallespi T, Torrabadella M, Julia A et al 1985 Myelodysplastic syndromes: a study of 101 cases according to the FAB classification. British Journal of Haematology 61: 83-92 Foucar K, Langdon R M, Armitage J 0, Olsen D B, Carrol f J Jr 1985 Myelodysplastic syndromes. A clinical and pathological analysis of 109 cases. Cancer 56: 533-561 Teerenhovi L, Lintala R 1986 Natural cause of myeiodysplastic syndrome-Helsinki experience. Scandinavian Journal of Hematology 36: 102-106 Kerkhoffs H, Hermans J, Haak H L, Leeksman C H W 1987 Utility of the FAB classification for myelodysplastic syndromes. Investigation of prognostic factors in 256 cases. British Journal of Haematology 65: 73381 Economopoulas T. Stathakis N. Foudoulakis A et al 1987 Myelodysplastic syndromes. Analysis of 13 1 cases according to the FAB classification, European Journal of Haematology 38: 3388341 Pierre R V, Catovsky D, Mufti G J et al 1989 Clinical cytogenetic correlations in myelodysplasia (preleukaemia). Cancer Genetics and Cytogenetics 45: 149-161 Sanz G F, Sanz M A, Vallespi T et al 1989 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: 3955408 Goasguen J E, Garand R, Bizet M et al 1990 Prognostic factors of myelodysplastic syndromes. A simplified 3-D scoring system. Leukemia Research 14: 255-261 Revnolds P. Kruger A, Sadullah S. Hamblin T. Oscier D 1991 Has survival improved in the past ten years? Leukemia Research 15 (Suppl): 11 (abstr) Aul C. Gutterman N. Heyll A, Germing U, Denigs G. Schneider W 1992 Primary myelodysplastic syndromes: analysis of prognostic factors in 235 patients and proposals for an improved scoring system. Leukemia 6: 52-59 Sanz G, Sanz M 1992 Prognostic factors in myelodysplastic syndromes. Leukemia Research 16: 77-86 Tricot G. De Wolf-Peeters C, Veietinck R. Verwighen R L 1984 Bone marrow histology in myelodyplastic syndromes. II. Prognostic value of abnormal localisation of immature precursors in MDS. British Journal of Haematology 58: 217-225 Mangi M H. Mufti G J 1992 Primary myelodysplastic syndromes: diagnostic and prognostic significance of immunobiochemical assessment of bone marrow biopsies. Blood 79: 198-205 Toronto Study Group 1986 Results of chemotherapy for unselected patients with acute myeloblastic leukaemia: effect of exclusions on interpretation of results. Lancet i: 7866788 Copplestone J A, Smith A G, Oscier D Cl, Hamblin T J 1986 True outlook in acute myeloblastic leukaemia. Lancet i: 1104 Mertelsmann R, Thaler H T, To L et al 1980 Morphological classification, response to therapy and survival in 263 adult patients with acute non-lymphoblastic leukemia. Blood 56: 773-78 1 Keating M J, McCredie K B, Benjamin R S et al 1981 Treatment of patients over 50 years of age with acute myelogenous leukemia with a combination of rubidazone and cytosine arabinoside, vincristine and prednisone (ROAP). Blood 58: 584-591 Tricot Cl, Boogaerts M A 1986 The role of aggressive chemotherapy-m the treatment of myelodysplastic svndromes. British Journal of Haematology 63: 477-483 Preisler H D. Raza A, Barcos M et al 1987 High dose cytosine arabinoside as the initial treatment of poor risk patients with acute non-lymphocytic leukemia. Journal of Clinical Oncology 5: 72-82 Lazzarino M. Morra E. Alessandrino E M et al 1987 Etoposide-cytarabine therapy for acute leukemia following myelodysplastic syndromes or secondary to treatment for malignant disease. Haematoiogica 72: 341-345 Martiat P, Ferrant A, Michaux J-L, Sokal G 1988 Intensive chemotherapy for acute non-lymphoblastic leukemia after primary myelodysplastic syndrome. Haematological Oncology 6: 299-305
BLOOD 43. Hoyle C F, de Bastos M. Wheatley K et al 1989 AML associated with previous cytotoxic therapy, MDS or myeloproliferative disorders: results from the MRC’s 9th AML trial. British Journal of Haematology 72: 45-53 44. Au1 C. Schneider W 1989 The role of low dose cytosine arabinoside and aggressive chemotherapy in advanced myelodysplastic syndrome. Cancer 64: 1812-1818 45. Gajewski J L, Ho W G. Nimer S D et al 1989 Efficacy of intensive chemotherapy for acute myelogenous leukemia associated with a preleukemic syndrome. Journal of Clinical Oncology 7: I637- 1645 46. 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 47. Fenaux P, Morel P. Rose C et al 1991 Prognostic factors in adult de novo myelodysplastic syndromes treated by intensive chemotherapy. British Journal of Haematology 77: 497-501 4x. Scoarec J-Y. Imbert M. Crofts M et al 1985 Myelodysplastic syndrome or acute myeloid leukemia. Cancer 55: 2390-2394 49. Michels S D, Saumur J, Arthur D C. Robison L L. Brunning R D 1989 Refractory anemia with excess of blasts m transformation. hematologic and clinical study of 52 patients. Cancer 64: 2340-3346 of 50. Advani S H. Giri N K, Dole M G et al 1989 Limitations the therapeutic regimes for myelodysplastic syndrome. Indian Journal of Medicine 90: 248-253 E, Wijermans 51. Van Gee1 B M. Huijgens P C. Ossenkoppel P W. Langenhuijsen M M 1989 Standard induction of low dose ara-c treatment in patients over 60 with AML or MDS. Netherlands Journal of Medicine 35: 128-136 52 Nagai K, Mutsuo T. Atoyami S et al 1992 Remission with morphological myelodysplasia in de nova acute myeloid
53.
54.
55.
56.
57.
58.
59.
60.
61.
REVIEWS
219
leukaemia: implications for early relapse. British Journal of Haematology sl: 33-39 Fenaux P. Lai J L. Jouet J P. Pollet J P. Bauters F 1988 Aggressive chemotherapy in adult primary myelodysplastic syndromes. Blut 57: 297-302 Fialkow P, Singer J W, Raskind W H et al 1987 Clonal development, stem cell differentiation and clinical remissions in acute non-lymphocytic leukemia. New England Journal of Medicine 317: 468-473 Kaye S B, Kerr D J 1991 Multidrug resistance: clinical relevance in haematological malignancies. Blood Reviews 5: 38-41 Sato H, Gottesman M M, Goldstein L J et al 1990 Expression of the multidrug resistance gene in myeloid leukemias. Leukemia Research 14: 1 l-21 Holmes J, Jacobs A. Carter G, Janowska-Weiczorek A, Padud R 1989 Multidrug resistance in haemopoietic cell lines. myelodysplastic syndromes and acute myeloblastic leukaemia. British Journal of Haematology 72: 40-44 Marie J-P, Zittoun R. Sikic B I 1991 Multidrug resistance (mdsl) gene expression in adult acute leukemias: correlations with treatment outcome and in vitro drug sensitivity. Blood 78: 5866592 Pinker R, Wallner J, Geissler K et al 1991 MDRI gene expression and treatment outcome in acute myeloid leukaemia. Journal of the National Cancer Institute 83: 708-7 14 Berman E, McBride E 1992 Comparative cellular pharmacology of daunorubicin and idarubicin in human multidrug-resistant leukemic cells. Blood 79: 3267-3273 Keating M J, Smith T L, Gehan E A et al 1980 Factors related to length of complete remission in adult acute leukemia. Cancer 45: 2017-2029
