Survival of patients with chronic myelogenous leukaemia relapsing ...

British Journal of Haematology, 1997, 99, 23–29

Survival of patients with chronic myelogenous leukaemia relapsing after bone marrow transplantation: comparison with patients receiving conventional chemotherapy M EI -J I E Z H A NG , 1 M I C H E L E B ACCAR A NI , 2 R O BE RT P E T E R G A L E , 3 P H I L I P B. M C G L AVE , 4 K E R RY AT K I N S O N , 5 R I C H A R D E. C H A M P L I N , 6 K A R E L A. D I C K E , 7 S E RG I O G I R A LT, 8 E L IA N E G L U C K M A N , 6 J O HN M. G O L DM A N , 9 J OHN P. K L E IN , 1 R O G E R H. H E R Z I G , 1 0 T O H RU M A S AO K A , 11 R I C H A R D J. O’R E I L LY, 1 2 C I R I L R O Z M A N , 1 3 P H I L I P A. R OWL ING S , 1 K AT H L E E N A. S O B O C I N S K I , 1 B RU N O S PE C K , 14 F E R RY E. Z WAA N 1 5 A ND M A RY M. H OROW IT Z 1 1 International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, Wisconsin, U.S.A., 2 Department of Bone Marrow Transplantation, Udine University and General Hospital, Udine, Italy, 3 Division of Bone Marrow and Stem Cell Transplantation, Salick Health Care Inc., Los Angeles, California, U.S.A., 4 University of Minnesota, Minneapolis, Minnesota, U.S.A., 5 St Vincent’s Hospital, Darlinghurst, Australia, 6 M. D. Anderson Cancer Center, Houston, Texas, U.S.A., 7 Arlington Cancer Center, Arlington, Texas, U.S.A., 8 Service d’He´matologie, Hoˆpital Saint-Louis, Paris, France, 9 Hammersmith Hospital and Royal Postgraduate Medical School, London, U.K., 10 Brown Cancer Center, University of Louisville, Louisville, Kentucky, U.S.A., 11 The Centre for Adult Diseases, Osaka, Japan, 12 Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York, U.S.A., 13 Escuela de Hematologia, Universidad de Barcelona, Barcelona, Spain, 14 Medizisches Universita¨tsklinik, Kantonsspital Basel, Basel, Switzerland, and 15 Department of Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia Received 19 November 1996; accepted for publication 2 July 1997

Summary. Treatment with busulphan and/or hydroxyurea rarely produces remission in patients with chronic myelogenous leukaemia (CML) in chronic phase. HLA-identical sibling transplants almost always produce remission, and only about 20% of patients relapse post-transplant. The increased anti-leukaemic efficacy of transplants results from intensive pretransplant treatment and immune-mediated anti-leukaemia effects. We studied 433 patients surviving 2 years after diagnosis of CML to determine if patients who have relapsed after a transplant in chronic phase have longer survival from diagnosis than comparable subjects receiving chemotherapy. The chemotherapy cohort included 344 adults < 50 years of age treated on consecutive trials of the Italian Cooperative Study Group on CML between 1973 and 1986. The transplant cohort included 89 patients reported to the International Bone Marrow Transplant Registry who relapsed after an HLA-identical sibling bone marrow transplant carried out between 1978 and 1992.

Survivals in the two groups were compared using Cox proportional hazards regression to adjust for prognostic variables. Median survival was 65 months in the chemotherapy cohort and 86 months in the transplant cohort. The 7-year probability (95% confidence interval) of survival was 34% (28–39%) in the chemotherapy cohort and 57% (43–70%) in the transplant cohort (P¼0.003). There was no difference in survival of patients relapsing after T-cell depleted and non-T-cell-depleted transplants. We conclude that patients who relapse after an HLA-identical sibling bone marrow transplant for CML in chronic phase have longer survival from diagnosis than comparable patients receiving chemotherapy. This effect is most likely to be the result of intensive chemotherapy and/or radiation given for pretransplant conditioning.

Correspondence: Dr Mary M. Horowitz, International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, 8701 Watertown Plank Road, P.O. Box 26509, Milwaukee, WI 53226, U.S.A.

Intensive chemotherapy with or without radiation followed by an HLA-identical sibling transplant is a very effective antileukaemia therapy for chronic myelogenous leukaemia (CML) in chronic phase (Champlin et al, 1988; Clift et al,

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q 1997 Blackwell Science Ltd

Keywords: CML, bone marrow transplant, chemotherapy, busulphan, hydroxyurea.

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Mei-Jie Zhang et al

1993; Silberman et al, 1994). Relapses occur in only about 20% of subjects at 5 years (Clift et al, 1993; Apperley et al, 1988; Sullivan et al, 1989; Horowitz et al, 1990; Marmont et al, 1991; Marks et al, 1992; Goldman et al, 1993). This surprising anti-leukaemia efficacy in a disease incurable with non-transplant therapy (Golde & Champlin, 1985; Tura et al, 1986; Sokal et al, 1988; Kantarjian et al, 1993; Hehlman et al, 1993; Italian Cooperative Study Group on CML, 1994) is thought to result from intensive therapy and immunemediated anti-leukaemia effects (Apperley et al, 1988; Sullivan et al, 1989; Horowitz et al, 1990; Marmont et al, 1991; Marks et al, 1992; Gale et al, 1994). It contrasts with failure of intensive treatment to prolong survival in the nontransplant setting (Golde & Champlin, 1985; Tura et al, 1986; Kantarjian et al, 1993) except for occasional cases with prolonged remission after busulphan overdose (Benjamin et al, 1979; Singer et al, 1984; Sproul et al, 1990; Birnie et al, 1990; Price et al, 1990; Johansson et al, 1990). Although uncommon, some transplant recipients in chronic phase CML relapse. In this study we sought to determine whether the marked reduction in chronic phase CML cells that occurs as a consequence of transplant increases survival. To do this we compared survival from diagnosis of patients with CML in chronic phase receiving non-transplant therapy with that of comparable patients relapsing after transplant. We also studied whether prolonged survival resulted from intensive pretransplant chemotherapy and/or radiation or from immune-mediated anti-leukaemia effects by comparing survival of transplant recipients relapsing after conventional and T-cell-depleted transplants. PATIENTS AND METHODS Patients. This study focused on survival from diagnosis of patients 50 years, for presentation in accelerated or blast phase, because the karyotype was either Ph1-negative or unknown, or because they received a bone marrow transplant; 73 were excluded because they survived < 2 years after diagnosis. The remaining 344 cases (30%) were included in this study. Details of these cases are provided in Table I. These 344 patients were treated with busulphan (n ¼ 96), hydroxyurea (n ¼ 79), busulphan and hydroxyurea (n ¼ 21), busulphan and other drugs (n ¼ 120), hydroxyurea and other drugs (n ¼ 20), busulphan, hydroxyurea and other drugs (n ¼ 60), or other drugs (n ¼ 21). Other drugs included cytarabine, 6-thioguanine, daunorubicin, vincristine and corticosteroids, dibromomannitol, alpha-interferon and 6-mercaptopurine. The reason drugs other than hydroxyurea and busulphan were given so frequently was that many patients were enrolled in two prospective studies of treatment with cytarabine, 6thioguanine, daunorubicin, vincristine and corticosteroids. Previously published results of these studies show that survival did not differ from that of patients treated with busulphan and/or hydroxyurea alone (Baccarani et al, 1981; Italian Cooperative Study Group on CML, 1984, 1988). Median (range) follow-up of survivors in the chemotherapy cohort was 79 (25–208) months. Patients in the transplant cohort were selected from 2869 consecutive HLA-identical sibling bone marrow transplants for CML performed between 1978 and 1992 and reported to the International Bone Marrow Transplant Registry (IBMTR) by 181 centres worldwide. Cases were diagnosed between 1965 and 1991. 1482 patients were excluded for age 1 year after diagnosis (n ¼ 634). Five patients receiving autologous bone marrow after graft failure were also excluded. Another 1239 otherwise eligible subjects were alive without relapse (n ¼ 744) or died of treatment-related events without a prior relapse (n ¼ 495). 59 patients relapsed and died < 2 years after diagnosis of CML. The remaining 89 subjects relapsing post-transplant are included in this study and described in Table I. 18 were from North America, 65 from Europe (11 from Italy) and six from elsewhere. Median (range) interval from diagnosis to transplant was 8.3 (2.9– 11.8) months. Median (range) interval from transplant to relapse was 21 (