The median survival is about 3 years for patients with Rai stage 3 or 4 disease [1]. Prognostic variables associated with reduced survival include high blood lymphocyte levels, short lymphocyte doubling time, chromosome abnormalities, and a diffuse pattern of bone marrow infiltration with leukemia cells [1-7].

The short median survival of patients with Rai stage 3 or 4 CLL and of those with additional adverse prognostic features has led to studies of intensive treatments [8-10]. Bone marrow transplants from HLA-identical siblings reportedly result in long-term survival in some patients [11]. We analyzed results of HLA-identical sibling bone marrow transplantation for CLL in 54 patients who were younger than 60 years old; these transplantations were done between 1984 and 1992 and reported to either the European Group for Blood and Marrow Transplantation or the International Bone Marrow Transplant Registry. We estimate that this analysis includes more than half of all HLA-identical sibling donor transplants for CLL done before 1993 [12].

Methods

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Patients

Data on 54 patients receiving HLA-identical sibling bone marrow transplants for CLL were reported to the European Group for Blood and Marrow Transplantation or the International Bone Marrow Transplant Registry or both between 1984 and 1992. Patient and disease characteristics are described in Table 1. The median age of the 54 patients was 41 years (range, 21 to 58 years). The median interval from diagnosis to transplantation was 37 months (range, 5 to 130 months). Seventeen patients have been previously described [11]. Six transplantations were done in the first year after diagnosis; 17 were done 1 to 3 years after diagnosis; 19 were done 3 to 5 years after diagnosis; and 12 were done more than 5 years after diagnosis. Forty-seven patients had B-cell CLL, and the immunotype was unknown in 7 patients.

The therapy administered before transplantation varied. Four patients received no treatment; 19 received chlorambucil alone or with prednisone; 5 received cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP); and 21 received cyclophosphamide, vincristine, doxorubicin, bleomycin, and interferon, alone or in combination. No data on previous treatment were available in 5 patients. Two patients received local irradiation and 3 received total lymphoid irradiation and chemotherapy. Ten patients had a splenectomy. Of 47 evaluable patients, 7 were considered to have disease responsive to chemotherapy at the time of transplantation, 19 had stable disease, and 21 had progressive disease according to previously published criteria [13]. Patients were selected for transplantation according to criteria set at each transplantation center. Most received transplants for advanced (Rai stage 3 or 4) or longstanding disease. In patients with Rai stage 0 to 2 CLL whose disease had been diagnosed less than 3 years previously, indications varied from consolidation of a good response to chemotherapy, poor response to conventional-dose therapy, or young age.

Donors

Donors were HLA-identical siblings; 39 were men and 15 were women. The median age was 41 years (range, 21 to 55 years).

Pretransplant Conditioning

All patients received cyclophosphamide (median dose, 120 mg/kg body weight; range, 90 to 150 mg/kg). Fifty-one also received total body irradiation (median dose, 12 Gy [range, 8 to 14 Gy]; median fractions, 5 [range, 1 to 9 fractions]). Three patients received cyclophosphamide and busulfan (16 mg/kg) without irradiation. Nineteen patients received one or more additional drugs including etoposide (n = 13), cytarabine (n = 5), chlorambucil (n = 1), melphalan (n = 1), and daunorubicin (n = 1).

Prophylaxis for Graft-versus-Host Disease

All patients received prophylactic therapy for graft-versus-host disease. Two received methotrexate, 8 received cyclosporine, and 35 received both methotrexate and cyclosporine. Eight patients received a T-cell-depleted graft; 7 of these patients also received cyclosporine. One patient received a monoclonal anti-interleukin-2 receptor antibody and cyclosporine. Four patients had prednisone added to these regimens.

Outcome Measures

Patients were considered evaluable for engraftment if they survived more than 30 days after transplantation. Those with engraftment who survived more than 21 days were considered at risk for acute graft-versus-host disease, and those with engraftment who survived more than 100 days were considered at risk for chronic graft-versus-host disease. Hematologic remission was defined as normalization of leukocyte counts, hemoglobin level, and platelet counts and absence of lymphadenopathy and hepatosplenomegaly. There was no requirement for bone marrow normalization. The focus of the study was hematologic remission and survival; we did not study leukemia-free survival because bone marrow examinations were not routinely done after transplantation and because leukemia-free survival is poorly defined in CLL. Data from immunologic and molecular tests were not used to define remission; tests for assessing clonality, such as immunoglobulin gene rearrangement and dual antibody-labeling flow cytometry, are not commonly done and are of unproven clinical significance. However, these data are reported when available. Kaplan-Meier survival estimates and CIs were calculated using BMDP software (BMDP Statistical Software, Los Angeles, California).

Results

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Patient outcomes are shown in Table 1. Forty-five of 49 evaluable patients (92%) had stable engraftment, and 4 (8%) had graft failure. Acute (grade II-IV) graft-versus-host disease developed in 17 of 46 patients at risk (37%); 9 of these patients (53%) died. Chronic graft-versus-host disease developed in 17 of 35 patients at risk (49%) and was extensive in 6.

Thirty-eight patients (70%) achieved hematologic remission. Twenty-four were alive at a median of 27 months (range, 5 to 80 months) after transplantation. Three-year survival probability was 46% (95% CI, 32% to 60%) (Figure 1). The 3 patients receiving transplants at Rai stage 0 were alive 21, 32, and 45 months after transplantation. Three-year survival probabilities were 68% (CI, 38% to 98%) in the 10 patients receiving transplants at Rai stage 1, 30% (CI, 2% to 58%) in the 10 patients receiving transplants at Rai stage 2, 57% (CI, 21% to 93%) in the 7 patients receiving transplants at Rai stage 3, and 34% (CI, 12% to 56%) in the 22 patients receiving transplants at Rai stage 4. Three-year survival probability was 86% (CI, 62% to 100%) in patients with disease responsive to pretransplant chemotherapy; 61% (CI, 38% to 84%) in those with stable disease; and 23% (CI, 2% to 44%) in those with progressive disease.

View larger version (13K): [in this window] [in a new window]   Figure 1. Probability of survival among 54 patients after HLA-identical sibling bone marrow transplantation for chronic lymphocytic leukemia. Numbers in parentheses indicate patients at risk for dying at each time point.

Of the 24 transplant recipients who are alive, 23 (96%) are in hematologic remission. Ten of these 23 patients had immune phenotyping of the peripheral blood: Seven had a normal profile (patients 7, 10, 12, 21, 23, 27, and 42), whereas 3 (patients 3, 24, and 30) had an excess of cluster differentiation antigen 5 (CD5) expression, which is known to be associated with CLL. Four patients had molecular studies after transplantation; these studies did not show gene rearrangement that would suggest persistent leukemia (patients 12, 21, 27, and 49).

Of the 30 patients who died, 5 died of disease and 25 died of treatment-related causes. Ten treatment-related deaths were from acute or chronic graft-versus-host disease; 4 from hepatic veno-occlusive disease; 2 each from graft failure, adult respiratory distress syndrome, interstitial pneumonitis, and bacterial infection; and 1 each from hemorrhage, fungal infection, and viral infection.

Discussion

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The 54 patients we evaluated all had CLL, were less than 60 years of age, and received HLA-identical sibling transplants. About half of this patient group achieved hematologic remission. Although we studied data from more than half the transplant recipients for CLL worldwide, the small number of patients precluded adjustment for potential prognostic variables like interval from diagnosis to transplantation and response to conventional chemotherapy.

Treatment-related mortality in this study was high—nearly 50%—a figure similar to that observed after allografts for adults with acute lymphoblastic leukemia in first remission, acute myelogenous leukemia in second remission, and Hodgkin disease [14-16]. It may result, in part, from effects of extensive previous treatment.

The focus of this study was on hematologic remission and survival after transplantation. We did not consider leukemia-free survival, because this is poorly defined in CLL. We also did not use data from immunologic or molecular tests because these are not uniformly performed and are of unproven clinical import.

Our study was not designed to evaluate the role of HLA-identical sibling bone marrow transplantation in the treatment of CLL. However, we believe that the results in 54 patients treated at different centers suggest that allogeneic transplantation is feasible in patients less than 60 years of age. These results must be compared with those for other therapies, such as traditional chemotherapy, fludarabine, 2-chlorodeoxyadenosine, and autotransplantation [17-20].

Appendix

Other contributors to this manuscript were Mary M. Horowitz, MD, MS, John P. Klein, PhD, and Mortimer M. Bortin, MD (deceased), of the International Bone Marrow Transplant Registry, Health Policy Institute, Medical College of Wisconsin, Milwaukee, Wisconsin; Kerry Atkinson, MD, of the Department of Hematology, St. Vincent Hospital, Sydney, Australia; John M. Goldman, MD, of the Hematology Department, Royal Postgraduate Medical School, London, United Kingdom; Jean-Pierre Jouet, MD, of the Department of Hematology, Claude Huriez Hospital, Lille, France; Kanti R. Rai, MD, of the Long Island Jewish Medical Center, New Hyde Park, New York; and Bruno Speck, MD, of the Department of Internal Medicine, Division of Hematology, University Hospital, Basel, Switzerland.

The following centers participated in the study by reporting patients to the European Blood and Marrow Transplant Registry or the International Bone Marrow Transplant Registry: A. Michallon Hospital, Grenoble, France (L. Molina, D. Hollard); University Hospital, Basel, Switzerland (A. Gratwohl, B. Speck); San Orsola Hospital, Bologna, Italy (G. Bandini, S. Tura); Clinic I Provincial Hospital, Barcelona, Spain (E. Carreras, E. Montserrat, C. Rozman); San Pao Hospital, Barcelona, Spain (S. Brunet, A. Domingo); Claude Huriez Hospital, Lille, France (J.P. Jouet, F. Bauters); University Hospital, Caen, France (X. Troussard, M. Leporrier); Pontaillou Hospital, Rennes, France (C. Dauriac, P.Y. Leprise); Henri Mondor Hospital, Paris, France (C. Cordonnier, J.P. Vernant); Jean Bernard Hospital, Poitiers, France (A. Sadoun, F. Guilhot); Saint Louis Hospital, Paris, France (H. Esperou-Bourdeau, E. Gluckman); Institut Paoli Calmette, Marseilles, France (D. Blaise, D. Maraninchi); Hotel Dieu Hospital, Nantes, France (N. Milpied, J.L. Harousseau); King Faisal Specialist Hospital and Research Centre, Riyad, Saudi Arabia (P. Ernst); Clinique University Saint Luc, Brussels, Belgium (A. Ferrant); University La Sapienza, Roma, Italy (W. Arcese, F. Mandelli); University of Minnesota, Minneapolis, Minnesota (J. Kersey); Hospital "La Fe," Valencia, Spain (M. Sanz); Emory University, Atlanta, Georgia (R. Saral, J. Wingard); St. Vincent's Hospital, Darlinghurst, Australia (K. Atkinson, J. Biggs); Royal Free Hospital, London, United Kingdom (H.G. Prentice); Medical College of Wisconsin, Milwaukee, Wisconsin (N. Flomenberg); University of Helsinki, Helsinki, Finland (T. Ruutu); University of Kentucky Medical Center, Lexington, Kentucky (E. Romond); Hospital de Clinicas, Parana, Brazil (R. Pasquini); Hospital de la Princesa, Madrid, Spain (J.M. Fernandez-Ranada); University of Nebraska, Omaha, Nebraska (M. Bishop); University Hospital of Wales, Cardiff, United Kingdom (J.A. Whittaker); Vancouver General Hospital, Vancouver, Canada (G.L. Phillips); H. Lee Moffitt Cancer Center, Tampa, Florida (G. Elfenbein).

Dr. Archimbaud: Service d'Hematologie, Hopital Edouard Herriot, Place d'Arsonaval, Pavillion E, 69437 Lyon Cedex 03, France.

Dr. Bandini: Hematology, St. Orsola University Hospital, Via G Massarenti 9, 40138 Bologna, Italy.

Dr. Rowlings: IBMTR, Medical College of Wisconsin, 8701 Watertown Plank Road, PO Box 26509, Milwaukee, WI 53226.

Dr. Deeg: Fred Hutchinson Cancer Research Center, 1124 Columbia Street, M-318, Seattle, WA 98104.

Dr. Gahrton: Department of Medicine, Karolinska Institute, Huddinge Hospital, S-14186 Huddinge, Sweden.

Drs. Montserrat and Rozman: Postgraduate School of Hematology, Hospital Clinic, University of Barcelona, Villaroel 170, E-08036 Barcelona, Spain.

Dr. Gratwohl: Department Innere medizin, Abteilung Hamatologie, Kantonsspital Basel, CH-4031 Basel, Switzerland.

Dr. Gale: Salick Health Care, Inc., 8201 Beverly Boulevard, Los Angeles, CA 90048-4520.