British lournu1 of Huernutology, 1990. 74, 151-155
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) T. DE WITTE,F. ZWAAN, J. HERMANS, J. VERNANT,H. KOLB, J. VOSSEN,B. LONNQVIST, D. BEELEN, A. FERRANT,J. GMUR, J. LIU YIN, X. TROUSSARD, J. C A H N , M. V A N LINT A N D A. GRATWOHLfor the Working Party on Leukaemia, European Cooperative Group for Bone Marrow Transplantation University Hospital Nijmegen, The Netherlands: University of Leiden, The Netherlands; Kantonsspital Basel, Switzerland; Hbpital Henri Mondor, Creteil, France; Ludwig Maximilians Universitiit, Munich, F.R.G.; Huddinge Hospital, Stockholm. Sweden: Universitiitsklinikum Essen, F.R.G.; Cliniques Universitaire St Luc, Brussels, Belgium: University Hospital Zurich, Switzerland: University of Manchester, U.K.; Centre Hospitalier Regional de BesanCon, France; Centre Hospitalier Regional et Universitaire de Caen, France: Ospidale San Martino, Genova, Italy
Received 23 May 1989; accepted for publication 25 September 1989
~~
Summary. This retrospective survey of the EBMT Leukaemia Working Party describes 78 patients with myelodysplasia (MDS) or secondary acute myelogenous leukaemia (sAML) who received an allogeneic bone marrow transplant (BMT). The status of underlying disease at the time of transplantation was prognostic for the 2-year disease-free survival. Thirty-four patients received intensive chemotherapy prior to the conditioning for BMT. The 2-year disease-free survival was 60% for the 1 6 patients transplanted in complete remission. The results were significantly less favourable for those with more advanced disease who only partially responded to prior intensive chemotherapy (2-year diseasefree survival: 18%)while none of those who either relapsed or
were resistant to chemotherapy survived BMT for 2 years. Forty-four patients had not received any prior intensive chemotherapy. The disease-freesurvival at 2 years after BMT was 58 f19%when a patient was transplanted for refractory anaemia (RA(S)). 74+ 14% for refractory anaemia with excess of blasts (RAEB), 5 0 f 16% for RAEB in transformation (RAEBt),and 18 f 11%for secondary AML. Allogeneic BMT can therefore be considered as curative treatment for patients with MDS. Patients with sAML who have a histocompatible donor should be given chemotherapy intensive enough to induce complete remission. If this is achieved these individuals have a prognosis comparable to those with de now AML in first remission after BMT.
Myelodysplastic syndromes (MDS) are a heterogeneous group of haematological malignancies of mainly middle-aged and elderly patients (Koeffler, 1986). They have also been observed in younger patients, mainly as a complication of irradiation or chemotherapy (Tucker et al, 1987). Survival after diagnosis varies considerably, but the majority of patients die within 1-2 years due to leukaemic transformation or the complications of pancytopenia. The management of MDS consists of supportive therapy with or without steroids and/or androgens until the development of overt leukaemia (Pederson-Bjergaard et al, 1981). The long-term
disease-free survival following intensive chemotherapy has been disappointing (Kantarjian et al, 1986). although encouraging results have been reported (Preisler et al, 1983). Young patients with the morphological picture of refractory anaemia with excess of blasts (RAEB)who have not received prior treatment with cytotoxic therapy may have a favourable response to intensive chemotherapy and achieve complete remission (Armitage et al, 1981). Most remissions. however, are of short duration (Preisler et al, 1983; Kantarjian et al, 1986; Armitage et al. 1981; Larson et al, 1988). Alternative approaches, such as treatment with low-dose cytarabine (Baccarani et al, 19831, analogues of vitamins A and D (Clark et al, 1987). interferons, and recombinant granulocyte/macrophage colony stimulating factor (GMCSF) (Vadhan-Raj et al, 1987) may have improved the
Correspondence: Dr T. De Witte. Division of Haematology. Department of Internal Medicine. University Hospital Nijmegen, Geert Grooteplein 8. Postbox 9190, 6500 HB Nijmegen, The Netherlands.
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prognosis of certain subgroups of patients with MDS, but sustained haematological responses appear to be rare. Young patients with a histocompatible sibling are potential candidates for allogeneic bone marrow transplantation (BMT). Encouraging results have been reported in patients with refractory anaemia (RA) or RAEB (Appelbaum et al, 1987) but as yet only case reports have been published for patients with KAEB in transformation (RAEBt) or secondary acute myelogenous leukaemia (sAML) (Marmont & Tura. 1986: De Witte et al. 1984).For this reason the Leukaemia Working Party of the EBMT conducted a survey of patients transplanted because of MDS and sAML. Preliminary results were presented at the EBMT and Transplantation Society meetings (De Witte et al, 1988, 1989). We present here the outcome of 78 patients given allogeneic BMT for MDS or sAML during the period 1980-88. PATIENTS AND METHODS Study population. Questionnaires were sent to all centres which had reported cases of MDS or sAML to the Leukaemia Working Party of the European Cooperative Group for Bone Marrow Transplantation (EBMT). Centres were asked to report all patients transplanted for these diseases and to provide additional information. Data were collected on 78 patients treated between 1980 and 1988 from 21 centres. The mean age of patients at transplantation was 32 years (range 2-52 years): 35 patients were female and 43 male. 65 patients had a myelodysplastic syndrome (MDS) classified according to the proposals of the French-American-British (FAB) cooperative group (Bennett et al, 1982). MDS was secondary to chemoradiotherapy for Hodgkin’s disease in seven patients and to therapy for other malignant diseases in five patients. The remaining 53 cases were classified as denow MDS. Secondary AML was defined as AML supervening after a period of MDS of at least 3 months’ duration or AML secondary to myelotoxic agents or therapy. 30 patients had sAMI,. MDS had progressed to AML prior to BMT in 1 7 out of 65 patients with MDS, and 13 patients presented without a clinically overt phase of MDS. AML without a prior phase of MDS was secondary to radio/chemotherapy in 12 patients and to benzene in one patient. The status of acute leukaemia was determined prior to pretransplant chemoradiotherapy and was based upon criteria described by Cancer and Leukemia Group B (Ohnuma et nl, 1971 ). Patients with < 5% blasts in the marrow and a normal blood count were considered to be in complete remission, those with 5 2 5 % bone-marrow blasts to be in partial remission and those with > 2 5% blasts in the bonemarrow to be in relapse. The median time from the diagnosis of MDS to transplant was 7 months (range 1-1 59 months). In the 1 3 patients with sAML without overt preceding MDS. transplantation was performed at a median time of 4 months (range 0.5-65 months) after diagnosis. Seventy-four donors were HLA-identical siblings, three were identical twins, and one was a haplo-identical sibling (mismatched at two loci). The data were analysed as of 1 5 November 1988. The
median follow-up time from transplant for the 3 5 surviving patients was 27 months (range 2-91 months). Actuarial disease-free survival curves were prepared by the life-table method (Cutles & Ederer, 1958). lntrnsive chernotherayg prior to transplantation. Intensive chemotherapy aiming to induce complete remission (CR) was given to 34 patients. Of 1 6 patients transplanted in complete remission (first CR: 1 5 patients: second CK: one patient) nine were treated for sAML. six for refractory anaemia with excess of blasts in transformation (RAEBt). and one for RAEB. 10 patients were transplanted during hypoplasia following intensive chemotherapy or while in partial remission (partial responders). Three were patients with sAML, RAEBt, or RAEB, and one had chronic myelomonocytic leukaemia (CMMoL). Of eight patients who had either relapsed after chemotherapy or were resistant to chemotherapy seven had developed sAML, and one RAEBt prior to chemotherapy. The remaining 44 patients had not received intensive chemotherapy prior to transplantation. Nine patients had RA, 1 2 patients RAEB, 10 RAEBt, and 13 patients untreated sAML. The stage of disease at onset of conditioning for transplantation is summarized in Table I. The reason for transplantation in eight patients with RA was profound cytopenia including a neutrophil count of < 1.0 x 109/l. Five patients also had thrombocytopenia of < 30 x 109/1just prior to conditioning for BMT. Transplantation was carried out in the last case because the patient had a high transfusion requirement but no profound cytopenia. One patient had RA with ring sideroblasts; his neutrophil count was 0.8 x 10y/l,platelet count 28 x 1Oy/l, and cytogenetic analysis revealed a trisomy 8. The median duration of KA was 6 months (range 1-2 1 months) before BMT. RESULTS
Bone inarrow trcinsplantation Seventy-eight patients were transplanted for MDS or sAML between March 1981 and July 1988. The conditioning regimens varied from centre to centre but 69 patients were given total body irradiation (TBI) in addition to chemotherapy. The remaining nine patients received only bonemarrow ablative chemotherapy, mainly consisting of busulphan and cyclophosphamide (seven patients). T-cell depletion was performed for 22 of the transplants. Acute graft-versus-host disease (GVHD)greater than grade I occurred in 22 patients and chronic GVHD in 12 patients. 3 5 of the 78 patients are alive and disease-free at 2-91 months post-transplant. 2 5 patients died from transplantrelated complications. mainly interstitial pneumonitis (nine patients), pneumonia caused by AspcrgiIIm / m i g a t u s (seven patients), and GVHD (seven patients). 18 patients relapsed after BMT. Complete rernissior~ Sixteen patients were transplanted for sAML or RAEB(t)in complete remission after intensive chemotherapy. 10 of these 1 6 patients are alive without evidence of disease 6-91 months (median 3 5 months) after transplantation. Two patients suffered a recurrence of disease 3 and 18 months respectively after transplantation. This last patient has been
1 53
R M T f o r Secondarg Leukaeinia and Myelodysplasia Table I. Disease status at transplantation and outcome of bone marrow transplantation for myelodysplasia or secondary acute myelogenous leukaemia ~
Disease status at transplantation
No.
Kelapse
16
2 2 1
Transplant-related mortality
Alive and disease-free
-~
Prior intensive chemotherapy Complete remission Partial responders Advanced disease
10
8
No intensive chemotherapy
sAML RAEBt KAEB RA RAS
I
sAML: secondary acute myelogenous leukaemia;KAEB(t):refractory anaemia with excess of blasts (in transformation):RA(S): refractory anaemia (with ring sideroblasts). RELAPSE FREE
RELAPSE FREE SURVNU
A
SURVNAL
R
loo
75
0 RA+Rps
(N=S)
RAEB A RAEBt
(N=12)
0 CR
(N=18)
(N=10) (N=13)
A PR
(N=10)
*
8AML
100
*
-
75
50
50
25
25
0 0
B
Res.Dle. (N=8)
0
0
12
18
24
30
36
M O M H S A F T E R BMT
0
0
12
18
24
30
30
M O N T H S A F E R BMT
Fig 1. Probability of relapse-free survival according to the diagnosis and to stage of disease. (A) No prior intensive chemotherapy. RA +RAS ( 0 ) : refractory anaemia+RA with ring sideroblasts: RAEB (m): refractory anaemia with excess of blasts: RAEBt (A): W E B in transformation: sAML (*): secondary acute myelogenous leukaemia: (B) Prior intensive chemotherapy. CR ( 0 ) :complete remission: PR (A):partial responder;Res.Dis. (*): advanceddisease. Symbols indicate surviving patients without evidence of leukaemia or MDS. except for the symbol of advanced disease (*) which indicatesthe end of the curve: patients survivingbeyond 33 months after BMT are indicated by symbols between 3 3-36 months post BMT. retransplanted 3 months after relapse and is currently disease-free and well 4 months after the second transplantation. but he was censored at 18 months for the present analysis (Fig 1B). The actuarial disease-free survival 2 years after BMT is 60 f 13% (one standard error), see Fig 1 B.
Advanced disease Eight patients were transplanted for chemotherapy-resistant disease or relapse after intensive chemotherapy. None of these patients survived: four died from transplant-related complications and four from relapse.
Partial responders Patients treated with intensive chemotherapy and transplanted during ensuing hypoplasia or in partial remission showed less favourable results. Transplant related mortality was high and accounted for six fatalities after BMT. Two patients relapsed and only two patients are currently alive in remission a t 16 and 2 5 months post-transplant.
Secondary A M L Forty-four patients were transplanted without prior intensive chemotherapy. A transplant for untreated sAML was given to 1 3 patients. Only three patients are alive without evidence of disease a t 2. 59 and 65 months after transplantation. Five patients relapsed and the remaining five patients died due to transplant-associated complications resulting in a diseasefree survival at 2 years of 1 8 &11%(Fig 1 A ) .
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RAEBt and RAEB Ten patients were given a marrow transplant for untreated RAEBt and 12 patients for RAEB. Two patients with RAEBt relapsed and three with RAEB. Transplant related complications contributed to death in two patients of each group. Overall disease-free survival at 2 years was 74 f14%when a patient was transplanted for RAEB, and 50* 16%for RAEBt (Fig 1A). Refractorg anaemia N o relapses have been observed in patients transplanted for RA. Two patients died from transplant-related complications. The disease-free survival at 2 years was 5 8 f 19% (Fig 1A). So, the best results were obtained when patients were transplanted in either complete remission or with untreated myelodysplasia (RA, RAS, RAEB, RAEBt). DISCUSSION Myelodysplastic syndromes form a heterogeneous group of diseases with a variable prognosis. The FAB Cooperative Group has proposed a morphological classification (Bennett et a/, 1982) and Mufti e t a / (1985) have added some clinical characteristics to identify a good prognosis group of RA and RAS without profound cytopenia. This group was characterized by a low risk of transformation and a median survival time usually exceeding 30 months. The remaining groups have median survival times varying from less than 6 months to 18 months (Bennett et a/, 1982: Mufti et a/, 1985). mainly due to the high risk of developing acute leukaemia. Acceptable treatment is not yet available for these patients. Patients younger than 50 years who have MDS may benefit from intensive antileukaemic therapy followed by BMT if a suitable donor is available (Appelbaum et a/, 1987; O’Donnellata/, 1987; Belanger et a/, 1988). 2 3 patients with RA or RAEB were treated with total body irradiation (TBI) and cyclophosphamide in Seattle and 1 2 patients were alive and disease-free at the time of reporting while two patients with RAEB had recurrent disease (Appelbaum et al, 1987). These cases may represent a selected group, since a substantial number were referred for transplantation with the diagnosis of aplastic anaemia and reclassified as MDS (Appelbaum et al, 1987). In another series, 20 patients were transplanted for advanced preleukaemic conditions (O’Donnell et a/, 1987). An increase of marrow blasts of > l o % seemed to have a negative impact on disease-free survival since three out of four relapses were in this group. Only two of 10 patients with this characteristic survival, as compared with six out of 10 patients who had less than 10%marrow blasts at the time when preparation for BMT was begun. Experience of BMT as treatment for secondary AML is limited tocasereports (Marmont &Tura, 1986: De Witteet a/, 1984). Of four cases with AML secondary to Hodgkin’s disease transplanted in complete remission two are alive and diseasefree more than 1 year after grafting (Geller et a/, 1988). Five patients with AML secondary to Hodgkin’s disease who were transplanted without any attempt to achieve prior remission all died due to either relapse or to transplant-related causes. This data presented by the EBMT Leukaemia Working Party shows that the success of allogeneic BMT for MDS and sAML
was closely related to the stage of disease, as is the case for any leukaemia (Report from EBMTG, 1988). Patients with untreated RA had an actuarial disease-free survival of 58% 2 years after BMT, compared with 74% when tranplanted with untreated RAEB, 50% with RAEBt, and 18%with untreated AML. Those transplanted when the disease had relapsed after intensive chemotherapy or who had proved to be resistant to chemotherapy had a poor prognosis, no patient surviving beyond 2 years. In contrast, patients in complete remission induced by chemotherapy had a good prognosis with a disease-free survival of 60% at 2 years with six patients surviving longer. An intermediate outcome was recorded for those transplanted in hypoplasia or in partial remission with 18%surviving without disease. These results together with those reported by others (Appelbaumet al, 1987; O’Donnellet al, 1987; Belanger et ul, 1988: Geller et a/, 1988) clearly show that allogeneic BMT is feasible for young patients with MDS or secondary AML. The outcome is most favourable when the transplant is performed during the ‘preleukaemic’phase, such as RA, RAEB, or even RAEBt. Hence, allogeneic BMT should be considered as the treatment of choice in patients with MDS younger than 50 years of age, preferably before development of overt leukaemia, provided that a HLA-identical sibling donor is available. Transplantation using partially-matched related or unrelated donors may be considered in children and adolescents (Bunin et a/, 1988). The results of BMT for patients with overt sAML or sAML not in complete remission after treatment with chemotherapy are unfavourable (Sargur et al, 1987) analogous to patients transplanted for relapsed de-novo AML (Thomas et a/, 1977). However, BMT performed after induction of complete remission with intensive chemotherapy results in excellent disease-free survival comparable to BMT for de-novo AML in complete remission (Thomas et a/, 1982). This does not necessarily imply that patients with AML secondary to MDS should receive intensive chemotherapy prior to the conditioning for BMT, especially as secondary leukaemias with hypocellular or myelofibrotic bone marrow are unlikely to respond favourably to intensive chemotherapy. The timing of BMT implies a careful analysis and evaluation of the prognostic factors in patients with MDS. Larger numbers of patients are required to show whether or not intensive chemotherapy with the intention to induce complete remission prior to the conditioning for allogeneic BMT improves outcome or simply selects the best candidates. ACKNOWLEDGMENTS We wish to thank Dr Peter Donnelly for his assistance with the English style and grammar. Institutes and physicians contributing patient data for this report: Karolinska Institutet, Huddinge, Sweden: Dr B. Lonnqvist; Ludwig Maximilians Universitat Munchen, Federal Republic Germany: Dr H. Kolb; Kantonsspital Basel, Switzerland: Dr A. Gratwohl; University Hospital Nijmegen, Nijmegen, The Netherlands: Dr T. De Witte; Hapita1 Henri Mondor, CrCteil. France: Dr J. Vernant; Ospidale San Martino, Genova, Italy: Dr M. Van Lint; Academisch Ziekenhuis Leiden, Department of Pediatrics, Leiden. The Netherlands:
B MT for Secoridary Leukaeniia and Myelodysylnsia Dr J. Vossen; Cliniques Universitaire St Luc, Brussels, Belgium: Dr A. Ferrant: University of Manchester, Manchester, U.K.: Dr J. Liu Yin; Universitatsklinikum Essen, Essen. Federal Republic of Germany: Dr D. Beelen: Centre Hospitalier Regional de Besanqon. Besanqon, France: Dr J. Cahn; Centre Hospitalier Regional et Universitaire de Caen, Caen, France: Dr X. Troussard: University Hospital Utrecht, Utrecht, The Netherlands: Dr L. Verdonk: Centre Hospitalier RCgional de Nancy, Nancy, France: Dr P. Bordigoni; Dr Daniel den Hoedkliniek, Rotterdam, The Netherlands: Dr B. Lowenberg: Academisch Ziekenhuis Leiden, Department of Haematology (adults). Leiden, The Netherlands: Dr F. Zwaan; University Hospital Zurich, Zurich, Switzerland: Dr J. Gmur: Medizinische Universitatsklinik, Vienna, Austria: Dr W. Hinterberger: Hospital for Sick Children, Great Ormond Street. London, U.K.: Dr Simpson: East Birmingham Hospital, Birmingham, U.K.: Dr D. Milligan: Royal Free Hospital, London, U.K.: Dr G. Prentice. REFERENCES Appelbauin. F.M., Storb. R.. Ramberg, R.E., Shulman, H.M.. Buckner. C.D., Clift. R.A.. Deeg. J.H., Fefer. A,. Sanders, J., Self, S., Singer, 1.. Stewart, P., Sullivan. J., Witherspoon,R. &Thomas. D.E. (1987) Treatment of preleukemic syndromes with marrow transplantation. Blood, 69, 92-96. Armitage. O., Dick. F.R..Needleman,S.W.&Burns.C.P. (1981)Effect of chemotherapy for the dysmyelopoietic syndrome. Cancer Treatrnerit Reports. 65, 601-605. Baccarani. M., Zaccaria. A,. Bandini. G., Cavazini. G.. Fanin, R. & Tura, S. (1983) Low dose arabinosyl cytosine for treatment of myelodysplastic syndromes and subacute myeloid leukemia. Leukeniiu Research, 7, 539-545. Belamger. R., Gyger, M., Perrault. C.. Bonny, Y. & St-Louis,J. (1988) Bone marrow transplantation for myelodysplastic syndromes. British Journal of Hnenmtology. 69, 29-33. Bennett. J.M.. Catovsky, D.. Daniel. M.D., Flandrin, G.. Galton. D.A.G., Gralnick. H.R. & Sultan. C. (FAB Cooperative Group) ( 1 982) Proposals for the classification of the myelodysplastic syndromes. British lournal of Haenintology. 51, 189-199. Bunin. N.1.. Casper. J.T.. Chitambar. C.. Hunter. J.. Truitt. K.. Menitove, 1.. Camitta. B.M. & Ash, R. (1988) Partially matchcd marrow transplantation in patients with myelodysplastic syndromes. lourrinl of Clinical Oncology. 6, 185 1- 185 5. Clark, K.E.. Jacobs. A.. Lush, C. &Smith. S.A. (1987) Effect of 13-cis retinoic acid on survival of patients with myelodysplastic syndrome. Lancet. i, 763-765. Cutles.S.J.&Ederer.F.(1958)Maximumutilisationofthelifetablein analysing survival. Journal of Chronic Diseases. 5 5 , 699-71 2. De Witte, T., Blacklock, H.. Prentice. H.. De Pauw, B. & Haanen. C. (1984) Allogeneic bone marrow transplantation in a patient with acute myeloid leukemia secondary to Hodgkin's disease. Cmricer. 523, 1507-1 508. De Witte. T.. Zwaan. F.. Gratwohl, A.. Vernant, J.. Gmur. J., Liu Yin. J.. Troussard, X., Cahn, J. & Van Lint, M. (1988) Allogeneic bone marrow transplantation in secondary leukaemias and myelodysplastic syndromes. Bone Marrow Transplantntion. 3 (Suppl. 1 ), 142- 14 3. De Witte. T.. Zwan. F.. Gratwohl. A,, Vernant. J., Kolb. H.J., Vossen. J.. Lonnqvist. B.. Beelen. D.. Ferrant. A,. Gmur. 1.. Liu Yin. J.. Troussard. X.. Cahn. J. & Van Lint, M. (1989)Timing of marrow transplantation in secondary leukemias and myelodysplastic syndromes. Trnnsplanfntion Proceedings, 21, 29 58-29 59. Geller. R.B.. Vogelsang. G.B.. Wingard. J.K.. Yeager. A.M., Burns,
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W.H.. Santos. G.W. & Saral. R. (1988) Successful marrow transplantation for acute myelocytic leukemia following therapy for Hodgkin's disease. Journal of Cliiiiical Oncology. 6 , I S 58- 1 56 1. Kantarjian. H.M.. Keating. H.J.. Walters. R.S.. Smith, T.L.. Cork, A , . McCredie, K.B. & Freireich, E.J. ( 1986) Therapy-related leukemia and myelodysplastic syndrome: clinical, cytogenetic and prognostic features. Cliriical Oncology. 4, 1748-1 757. Koeffler, H.P. (1986) Myelodysplastic syndromes (preleukemia). Seminars in Hematology. 23, 284-289. Larson, R.A., Wernli. M., LeBeau, M.M., Daley, K.M., Paper, L.H.. Rowley. J.D. & Vardiman, J.W. (1988) Short remission durations in therapy-related leukemia cytogenetic complete responses to high dose cytarbine. Blood, 72, 1333-1339. Marmont. A.M. & Tura, S. (1986) Bone marrow transplantation for secondary leukemia: report of 2 cases. Bone Marrow Transpluiitation. 1 (Suppl. 1).191-192. Mufti, G.J.. Stevens, J.R.. Oscier. D.G.. Hamblin. T.J. & Machin. D. (198 5) Myelodysplastic syndromes: a scoring system with prognostic significance. British Journal of Haemntology. 59, 425433. O'Donnell. M.R., Nademanee. A.P.. Synder. D.S.. Schmidt, G.M.. Parker, P.M., Bierman, P.J., Fahey, J.L., Stein, H.S., Dance, R.A.. Stock, A.D., Forman, S.J. & Blume. K.G. (1987) Bone marrow transplantation for myelodysplastic and myeloproliferative syndromes. Journal of CJiniral Oncology. 5, 1822-1826. Ohnuma. T.. Rosner, F.. Levy, R.N., et al(1971) Treatment of adult leukaemia with 1-Asparaginase (NCS-109229). Caricer Chemotherapy Reports, 55, 269-275. Pederson-Bjergaard, J., Philips. B., Mortensen. B.T.. Ersball, J.. Jensen, G., Pandura, J. & Thomsen. M. (1981) Acute nonlymphocytic leukemia, preleukemia. and acute myeloproliferative syndrome secondary to treatment of other malignant diseases. Clinical and cytogenetic characteristics and results of in vitro culture of bone marrow and HLA-typing. Blood. 57, 712-723. Preisler. H.D., Early, A.P., Raza, A., Vlahides. G., Marinello. M.J., Stein, A.M. & Browman, G. (1983) Therapy of secondary, acute nonlymphocytic leukemia with cytarbine. New England ]ouriial of Medicine, 308, 21-23. Report from the Working Party on Leukemia, European Group for Bone Marrow Transplantation (1988) Allogeneic bone marrow transplantation for leukemia in Europe. Lancet. i, 1379-1 382. Sargur, M.. Buckner. C.D., Appelbaum. F.R.. Stewart, P.. Weiden. P.L., Sullivan. K.M.. Fefer. A. & Thomas, E.D. (19871 Marrow transplantation for acute nonlymphocytic leukemia following therapy for Hodgkin's disease. Jourrial of Clinical Oncology, 5, 731734. Thomas, E.D.. Buckner. C.D., Bananji. M., Clift, R.A.. Fefer. A.. Flournoy. N.. Goodell, B.D.. Hickman, KO.. Lerner. K.G.. Neiman. P.E., Sale, G.E., Sanders, J.E.. Singer, J., Stevens, M.. Storb, R. & Weiden. P.L. (1977) One hundred patients with acute leukemia treated by chemotherapy, total body irradiation, and allogeneic marrow transplantation. Blood. 49, 51 1-533. Thomas, E.D., Clift, R.A. & Buckner. C.D. for the Seattle Marrow Transplant Team (1982) Marrow transplantation for patients with acute nonlymphoblastic leukemia who achieve a first remission. Cancer Treatment Reports. 66, 1463-1466. Tucker. M.A.. Meadows, A.T., Boice. J.D., Jr, et al(1987) Leukemia after therapy with alkylating agents in childhood cancer. Journal of the Natiorinl Caricer Institute, 78, 459-464. 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 colony stimulating factor in patients with myelodysplastic syndromes. New Englnrid Journal of Medicine. 3 17, 1545-1552.
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) T. DE WITTE,F. ZWAAN, J. HERMANS, J. VERNANT,H. KOLB, J. VOSSEN,B. LONNQVIST, D. BEELEN, A. FERRANT,J. GMUR, J. LIU YIN, X. TROUSSARD, J. C A H N , M. V A N LINT A N D A. GRATWOHLfor the Working Party on Leukaemia, European Cooperative Group for Bone Marrow Transplantation University Hospital Nijmegen, The Netherlands: University of Leiden, The Netherlands; Kantonsspital Basel, Switzerland; Hbpital Henri Mondor, Creteil, France; Ludwig Maximilians Universitiit, Munich, F.R.G.; Huddinge Hospital, Stockholm. Sweden: Universitiitsklinikum Essen, F.R.G.; Cliniques Universitaire St Luc, Brussels, Belgium: University Hospital Zurich, Switzerland: University of Manchester, U.K.; Centre Hospitalier Regional de BesanCon, France; Centre Hospitalier Regional et Universitaire de Caen, France: Ospidale San Martino, Genova, Italy
Received 23 May 1989; accepted for publication 25 September 1989
~~
Summary. This retrospective survey of the EBMT Leukaemia Working Party describes 78 patients with myelodysplasia (MDS) or secondary acute myelogenous leukaemia (sAML) who received an allogeneic bone marrow transplant (BMT). The status of underlying disease at the time of transplantation was prognostic for the 2-year disease-free survival. Thirty-four patients received intensive chemotherapy prior to the conditioning for BMT. The 2-year disease-free survival was 60% for the 1 6 patients transplanted in complete remission. The results were significantly less favourable for those with more advanced disease who only partially responded to prior intensive chemotherapy (2-year diseasefree survival: 18%)while none of those who either relapsed or
were resistant to chemotherapy survived BMT for 2 years. Forty-four patients had not received any prior intensive chemotherapy. The disease-freesurvival at 2 years after BMT was 58 f19%when a patient was transplanted for refractory anaemia (RA(S)). 74+ 14% for refractory anaemia with excess of blasts (RAEB), 5 0 f 16% for RAEB in transformation (RAEBt),and 18 f 11%for secondary AML. Allogeneic BMT can therefore be considered as curative treatment for patients with MDS. Patients with sAML who have a histocompatible donor should be given chemotherapy intensive enough to induce complete remission. If this is achieved these individuals have a prognosis comparable to those with de now AML in first remission after BMT.
Myelodysplastic syndromes (MDS) are a heterogeneous group of haematological malignancies of mainly middle-aged and elderly patients (Koeffler, 1986). They have also been observed in younger patients, mainly as a complication of irradiation or chemotherapy (Tucker et al, 1987). Survival after diagnosis varies considerably, but the majority of patients die within 1-2 years due to leukaemic transformation or the complications of pancytopenia. The management of MDS consists of supportive therapy with or without steroids and/or androgens until the development of overt leukaemia (Pederson-Bjergaard et al, 1981). The long-term
disease-free survival following intensive chemotherapy has been disappointing (Kantarjian et al, 1986). although encouraging results have been reported (Preisler et al, 1983). Young patients with the morphological picture of refractory anaemia with excess of blasts (RAEB)who have not received prior treatment with cytotoxic therapy may have a favourable response to intensive chemotherapy and achieve complete remission (Armitage et al, 1981). Most remissions. however, are of short duration (Preisler et al, 1983; Kantarjian et al, 1986; Armitage et al. 1981; Larson et al, 1988). Alternative approaches, such as treatment with low-dose cytarabine (Baccarani et al, 19831, analogues of vitamins A and D (Clark et al, 1987). interferons, and recombinant granulocyte/macrophage colony stimulating factor (GMCSF) (Vadhan-Raj et al, 1987) may have improved the
Correspondence: Dr T. De Witte. Division of Haematology. Department of Internal Medicine. University Hospital Nijmegen, Geert Grooteplein 8. Postbox 9190, 6500 HB Nijmegen, The Netherlands.
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prognosis of certain subgroups of patients with MDS, but sustained haematological responses appear to be rare. Young patients with a histocompatible sibling are potential candidates for allogeneic bone marrow transplantation (BMT). Encouraging results have been reported in patients with refractory anaemia (RA) or RAEB (Appelbaum et al, 1987) but as yet only case reports have been published for patients with KAEB in transformation (RAEBt) or secondary acute myelogenous leukaemia (sAML) (Marmont & Tura. 1986: De Witte et al. 1984).For this reason the Leukaemia Working Party of the EBMT conducted a survey of patients transplanted because of MDS and sAML. Preliminary results were presented at the EBMT and Transplantation Society meetings (De Witte et al, 1988, 1989). We present here the outcome of 78 patients given allogeneic BMT for MDS or sAML during the period 1980-88. PATIENTS AND METHODS Study population. Questionnaires were sent to all centres which had reported cases of MDS or sAML to the Leukaemia Working Party of the European Cooperative Group for Bone Marrow Transplantation (EBMT). Centres were asked to report all patients transplanted for these diseases and to provide additional information. Data were collected on 78 patients treated between 1980 and 1988 from 21 centres. The mean age of patients at transplantation was 32 years (range 2-52 years): 35 patients were female and 43 male. 65 patients had a myelodysplastic syndrome (MDS) classified according to the proposals of the French-American-British (FAB) cooperative group (Bennett et al, 1982). MDS was secondary to chemoradiotherapy for Hodgkin’s disease in seven patients and to therapy for other malignant diseases in five patients. The remaining 53 cases were classified as denow MDS. Secondary AML was defined as AML supervening after a period of MDS of at least 3 months’ duration or AML secondary to myelotoxic agents or therapy. 30 patients had sAMI,. MDS had progressed to AML prior to BMT in 1 7 out of 65 patients with MDS, and 13 patients presented without a clinically overt phase of MDS. AML without a prior phase of MDS was secondary to radio/chemotherapy in 12 patients and to benzene in one patient. The status of acute leukaemia was determined prior to pretransplant chemoradiotherapy and was based upon criteria described by Cancer and Leukemia Group B (Ohnuma et nl, 1971 ). Patients with < 5% blasts in the marrow and a normal blood count were considered to be in complete remission, those with 5 2 5 % bone-marrow blasts to be in partial remission and those with > 2 5% blasts in the bonemarrow to be in relapse. The median time from the diagnosis of MDS to transplant was 7 months (range 1-1 59 months). In the 1 3 patients with sAML without overt preceding MDS. transplantation was performed at a median time of 4 months (range 0.5-65 months) after diagnosis. Seventy-four donors were HLA-identical siblings, three were identical twins, and one was a haplo-identical sibling (mismatched at two loci). The data were analysed as of 1 5 November 1988. The
median follow-up time from transplant for the 3 5 surviving patients was 27 months (range 2-91 months). Actuarial disease-free survival curves were prepared by the life-table method (Cutles & Ederer, 1958). lntrnsive chernotherayg prior to transplantation. Intensive chemotherapy aiming to induce complete remission (CR) was given to 34 patients. Of 1 6 patients transplanted in complete remission (first CR: 1 5 patients: second CK: one patient) nine were treated for sAML. six for refractory anaemia with excess of blasts in transformation (RAEBt). and one for RAEB. 10 patients were transplanted during hypoplasia following intensive chemotherapy or while in partial remission (partial responders). Three were patients with sAML, RAEBt, or RAEB, and one had chronic myelomonocytic leukaemia (CMMoL). Of eight patients who had either relapsed after chemotherapy or were resistant to chemotherapy seven had developed sAML, and one RAEBt prior to chemotherapy. The remaining 44 patients had not received intensive chemotherapy prior to transplantation. Nine patients had RA, 1 2 patients RAEB, 10 RAEBt, and 13 patients untreated sAML. The stage of disease at onset of conditioning for transplantation is summarized in Table I. The reason for transplantation in eight patients with RA was profound cytopenia including a neutrophil count of < 1.0 x 109/l. Five patients also had thrombocytopenia of < 30 x 109/1just prior to conditioning for BMT. Transplantation was carried out in the last case because the patient had a high transfusion requirement but no profound cytopenia. One patient had RA with ring sideroblasts; his neutrophil count was 0.8 x 10y/l,platelet count 28 x 1Oy/l, and cytogenetic analysis revealed a trisomy 8. The median duration of KA was 6 months (range 1-2 1 months) before BMT. RESULTS
Bone inarrow trcinsplantation Seventy-eight patients were transplanted for MDS or sAML between March 1981 and July 1988. The conditioning regimens varied from centre to centre but 69 patients were given total body irradiation (TBI) in addition to chemotherapy. The remaining nine patients received only bonemarrow ablative chemotherapy, mainly consisting of busulphan and cyclophosphamide (seven patients). T-cell depletion was performed for 22 of the transplants. Acute graft-versus-host disease (GVHD)greater than grade I occurred in 22 patients and chronic GVHD in 12 patients. 3 5 of the 78 patients are alive and disease-free at 2-91 months post-transplant. 2 5 patients died from transplantrelated complications. mainly interstitial pneumonitis (nine patients), pneumonia caused by AspcrgiIIm / m i g a t u s (seven patients), and GVHD (seven patients). 18 patients relapsed after BMT. Complete rernissior~ Sixteen patients were transplanted for sAML or RAEB(t)in complete remission after intensive chemotherapy. 10 of these 1 6 patients are alive without evidence of disease 6-91 months (median 3 5 months) after transplantation. Two patients suffered a recurrence of disease 3 and 18 months respectively after transplantation. This last patient has been
1 53
R M T f o r Secondarg Leukaeinia and Myelodysplasia Table I. Disease status at transplantation and outcome of bone marrow transplantation for myelodysplasia or secondary acute myelogenous leukaemia ~
Disease status at transplantation
No.
Kelapse
16
2 2 1
Transplant-related mortality
Alive and disease-free
-~
Prior intensive chemotherapy Complete remission Partial responders Advanced disease
10
8
No intensive chemotherapy
sAML RAEBt KAEB RA RAS
I
sAML: secondary acute myelogenous leukaemia;KAEB(t):refractory anaemia with excess of blasts (in transformation):RA(S): refractory anaemia (with ring sideroblasts). RELAPSE FREE
RELAPSE FREE SURVNU
A
SURVNAL
R
loo
75
0 RA+Rps
(N=S)
RAEB A RAEBt
(N=12)
0 CR
(N=18)
(N=10) (N=13)
A PR
(N=10)
*
8AML
100
*
-
75
50
50
25
25
0 0
B
Res.Dle. (N=8)
0
0
12
18
24
30
36
M O M H S A F T E R BMT
0
0
12
18
24
30
30
M O N T H S A F E R BMT
Fig 1. Probability of relapse-free survival according to the diagnosis and to stage of disease. (A) No prior intensive chemotherapy. RA +RAS ( 0 ) : refractory anaemia+RA with ring sideroblasts: RAEB (m): refractory anaemia with excess of blasts: RAEBt (A): W E B in transformation: sAML (*): secondary acute myelogenous leukaemia: (B) Prior intensive chemotherapy. CR ( 0 ) :complete remission: PR (A):partial responder;Res.Dis. (*): advanceddisease. Symbols indicate surviving patients without evidence of leukaemia or MDS. except for the symbol of advanced disease (*) which indicatesthe end of the curve: patients survivingbeyond 33 months after BMT are indicated by symbols between 3 3-36 months post BMT. retransplanted 3 months after relapse and is currently disease-free and well 4 months after the second transplantation. but he was censored at 18 months for the present analysis (Fig 1B). The actuarial disease-free survival 2 years after BMT is 60 f 13% (one standard error), see Fig 1 B.
Advanced disease Eight patients were transplanted for chemotherapy-resistant disease or relapse after intensive chemotherapy. None of these patients survived: four died from transplant-related complications and four from relapse.
Partial responders Patients treated with intensive chemotherapy and transplanted during ensuing hypoplasia or in partial remission showed less favourable results. Transplant related mortality was high and accounted for six fatalities after BMT. Two patients relapsed and only two patients are currently alive in remission a t 16 and 2 5 months post-transplant.
Secondary A M L Forty-four patients were transplanted without prior intensive chemotherapy. A transplant for untreated sAML was given to 1 3 patients. Only three patients are alive without evidence of disease a t 2. 59 and 65 months after transplantation. Five patients relapsed and the remaining five patients died due to transplant-associated complications resulting in a diseasefree survival at 2 years of 1 8 &11%(Fig 1 A ) .
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T. De Witte et a1
RAEBt and RAEB Ten patients were given a marrow transplant for untreated RAEBt and 12 patients for RAEB. Two patients with RAEBt relapsed and three with RAEB. Transplant related complications contributed to death in two patients of each group. Overall disease-free survival at 2 years was 74 f14%when a patient was transplanted for RAEB, and 50* 16%for RAEBt (Fig 1A). Refractorg anaemia N o relapses have been observed in patients transplanted for RA. Two patients died from transplant-related complications. The disease-free survival at 2 years was 5 8 f 19% (Fig 1A). So, the best results were obtained when patients were transplanted in either complete remission or with untreated myelodysplasia (RA, RAS, RAEB, RAEBt). DISCUSSION Myelodysplastic syndromes form a heterogeneous group of diseases with a variable prognosis. The FAB Cooperative Group has proposed a morphological classification (Bennett et a/, 1982) and Mufti e t a / (1985) have added some clinical characteristics to identify a good prognosis group of RA and RAS without profound cytopenia. This group was characterized by a low risk of transformation and a median survival time usually exceeding 30 months. The remaining groups have median survival times varying from less than 6 months to 18 months (Bennett et a/, 1982: Mufti et a/, 1985). mainly due to the high risk of developing acute leukaemia. Acceptable treatment is not yet available for these patients. Patients younger than 50 years who have MDS may benefit from intensive antileukaemic therapy followed by BMT if a suitable donor is available (Appelbaum et a/, 1987; O’Donnellata/, 1987; Belanger et a/, 1988). 2 3 patients with RA or RAEB were treated with total body irradiation (TBI) and cyclophosphamide in Seattle and 1 2 patients were alive and disease-free at the time of reporting while two patients with RAEB had recurrent disease (Appelbaum et al, 1987). These cases may represent a selected group, since a substantial number were referred for transplantation with the diagnosis of aplastic anaemia and reclassified as MDS (Appelbaum et al, 1987). In another series, 20 patients were transplanted for advanced preleukaemic conditions (O’Donnell et a/, 1987). An increase of marrow blasts of > l o % seemed to have a negative impact on disease-free survival since three out of four relapses were in this group. Only two of 10 patients with this characteristic survival, as compared with six out of 10 patients who had less than 10%marrow blasts at the time when preparation for BMT was begun. Experience of BMT as treatment for secondary AML is limited tocasereports (Marmont &Tura, 1986: De Witteet a/, 1984). Of four cases with AML secondary to Hodgkin’s disease transplanted in complete remission two are alive and diseasefree more than 1 year after grafting (Geller et a/, 1988). Five patients with AML secondary to Hodgkin’s disease who were transplanted without any attempt to achieve prior remission all died due to either relapse or to transplant-related causes. This data presented by the EBMT Leukaemia Working Party shows that the success of allogeneic BMT for MDS and sAML
was closely related to the stage of disease, as is the case for any leukaemia (Report from EBMTG, 1988). Patients with untreated RA had an actuarial disease-free survival of 58% 2 years after BMT, compared with 74% when tranplanted with untreated RAEB, 50% with RAEBt, and 18%with untreated AML. Those transplanted when the disease had relapsed after intensive chemotherapy or who had proved to be resistant to chemotherapy had a poor prognosis, no patient surviving beyond 2 years. In contrast, patients in complete remission induced by chemotherapy had a good prognosis with a disease-free survival of 60% at 2 years with six patients surviving longer. An intermediate outcome was recorded for those transplanted in hypoplasia or in partial remission with 18%surviving without disease. These results together with those reported by others (Appelbaumet al, 1987; O’Donnellet al, 1987; Belanger et ul, 1988: Geller et a/, 1988) clearly show that allogeneic BMT is feasible for young patients with MDS or secondary AML. The outcome is most favourable when the transplant is performed during the ‘preleukaemic’phase, such as RA, RAEB, or even RAEBt. Hence, allogeneic BMT should be considered as the treatment of choice in patients with MDS younger than 50 years of age, preferably before development of overt leukaemia, provided that a HLA-identical sibling donor is available. Transplantation using partially-matched related or unrelated donors may be considered in children and adolescents (Bunin et a/, 1988). The results of BMT for patients with overt sAML or sAML not in complete remission after treatment with chemotherapy are unfavourable (Sargur et al, 1987) analogous to patients transplanted for relapsed de-novo AML (Thomas et a/, 1977). However, BMT performed after induction of complete remission with intensive chemotherapy results in excellent disease-free survival comparable to BMT for de-novo AML in complete remission (Thomas et a/, 1982). This does not necessarily imply that patients with AML secondary to MDS should receive intensive chemotherapy prior to the conditioning for BMT, especially as secondary leukaemias with hypocellular or myelofibrotic bone marrow are unlikely to respond favourably to intensive chemotherapy. The timing of BMT implies a careful analysis and evaluation of the prognostic factors in patients with MDS. Larger numbers of patients are required to show whether or not intensive chemotherapy with the intention to induce complete remission prior to the conditioning for allogeneic BMT improves outcome or simply selects the best candidates. ACKNOWLEDGMENTS We wish to thank Dr Peter Donnelly for his assistance with the English style and grammar. Institutes and physicians contributing patient data for this report: Karolinska Institutet, Huddinge, Sweden: Dr B. Lonnqvist; Ludwig Maximilians Universitat Munchen, Federal Republic Germany: Dr H. Kolb; Kantonsspital Basel, Switzerland: Dr A. Gratwohl; University Hospital Nijmegen, Nijmegen, The Netherlands: Dr T. De Witte; Hapita1 Henri Mondor, CrCteil. France: Dr J. Vernant; Ospidale San Martino, Genova, Italy: Dr M. Van Lint; Academisch Ziekenhuis Leiden, Department of Pediatrics, Leiden. The Netherlands:
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