Significance of additional high-dose cytarabine in combination with cyclophosphamide plus total body irradiation regimen for allogeneic stem cell transplantation.

The combination of cyclophosphamide (CY) and total body irradiation (TBI) has been used as a standard conditioning regimen for allogeneic transplantation. Several studies showed an advantage of adding high-dose cytarabine (HDCA) to this regimen. To clarify the significance of additional HDCA, we conducted a retrospective multicenter study and compared the clinical results of these two regimens. From June 1985 to March 2003, 219 patients with hematological malignancies underwent allogeneic transplantation after conditioning with CY+TBI 12Gy (n=73) or CA+CY+TBI 12Gy (n=146). Engraftment, overall survival, transplant-related mortality (TRM), relapse rate and incidence of graft-versus-host disease (GVHD) were compared according to risks and donors. Addition of HDCA had no impact on the relapse rate in all subgroups, and it was associated with lower TRM among standard-risk patients after related transplantation, and with higher TRM and worse survival among standard-risk patients after unrelated transplantation. The incidence of acute GVHD was not significantly different between the two regimens, and HDCA resulted in a higher incidence of chronic GVHD among standard-risk patients after related transplantation. In summary, addition of HDCA is not beneficial for high-risk patients, and is not recommended for standard-risk patients receiving unrelated transplantation.

Risk and prognostic factors for Japanese patients with chronic graft-versus-host disease after bone marrow transplantation.

The incidence and prognostic factors for chronic graft-versus-host disease (cGVHD) were evaluated for 255 Japanese patients who survived more than 100 days after bone marrow transplantation, and of whom 119 (47%) developed cGVHD. Prior acute GVHD (grade 2-4) and use of an unrelated donor were significantly associated with the onset of cGVHD. Presence of cGVHD did not have an impact on mortality (hazard ratio (HR) = 0.89; 95% confidence interval (CI), 0.59-1.3). Three factors at diagnosis were associated with cGVHD-specific survival: presence of infection (HR = 4.1; 95% CI, 1.6-10.3), continuing use of corticosteroids at the onset of cGVHD (HR = 3.9; 95% CI, 1.7-9.1), and a Karnofsky performance score <80 (HR = 4.7; 95% CI, 2.0-11.3). The probability of cGVHD-specific survival at 4 years was 79% (95% CI, 70-86%). The severity and death rate of Japanese patients with cGVHD was lower than those for populations in Western countries, which might be the result of greater genetic homogeneity of Japanese ethnics. Our patients could not be accurately classified when the proposed prognostic models from Western countries were used, thus indicating the need for a different model to identify high-risk patients.

Myeloablative allogeneic hematopoietic stem cell transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia in adults: significant roles of total body irradiation and chronic graft-versus-host disease.

Disease-free survival in Philadelphia chromosome-positive ALL (Ph + ALL) is very poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently considered the only procedure with curative potential. To identify factors affecting transplant outcome, we analyzed the data from 197 Ph + ALL patients aged 16 years or older who had undergone allo-HSCT. The 5-year survival rates were 34% for patients in first complete remission (CR), 21% for those in second or subsequent CR, and 9% for those with active disease (P < 0.0001). Multivariate analysis showed four pre-transplant factors as significantly associated with better survival: younger age, CR at the time of transplantation, conditioning with total body irradiation, and HLA-identical sibling donor (P < 0.0001, P < 0.0001, P = 0.0301, P = 0.0412, respectively). Severe acute GVHD increased the risk of treatment-related mortality (TRM) without diminishing the risk of relapse, whereas chronic GVHD reduced the risk of relapse without increasing the risk of TRM. Thus, patients who developed extensive chronic GVHD had better survivals (P = 0.0217), and those who developed grade III-IV acute GVHD had worse survivals (P = 0.0023) than did the others.

Induction therapy by frequent administration of doxorubicin with four other drugs, followed by intensive consolidation and maintenance therapy for adult acute lymphoblastic leukemia: the JALSG-ALL93 study.

In order to improve the disappointing prognosis of adult patients with acute lymphoblastic leukemia (ALL), we applied similar induction therapy as that used for acute myeloid leukemia (AML), ie frequent administration of doxorubicin (DOX). DOX 30 mg/m(2) was administered from days 1 to 3 and from days 8 to 10 together with vincristine, prednisolone, cyclophosphamide and L-asparaginase, followed by three courses of consolidation and four courses of intensification. From December 1993 to February 1997, 285 untreated adult patients with de novo ALL were entered. Of 263 evaluable patients (age 15 to 59; median 31), 205 (78%) obtained complete remission (CR). At a median follow-up period of 63 months, the predicted 6-year overall survival (OS) rate of all patients was 33%, and disease-free survival (DFS) rate of CR patients was 30%, respectively. By multivariate analysis, favorable prognostic factors for the achievement of CR were age <40 and WBC <50 000/microl; for longer OS were age <30 and WBC <30 000/microl; and for longer DFS of CR patients were FAB L1 and ALT <50 IU/l. Among 229 patients who had adequate cytogenetic data, 51 (22%) had Philadelphia (Ph) chromosome. Ph-negative chromosome was a common favorable prognostic factor for CR, longer OS and DFS. DFS was not different between early sequential intensification (n = 48) and intermittent intensification (n = 43) during the maintenance phase. Among CR patients under 40 years old, the 6-year survival was not different between the allocated related allo-BMT group (34 patients) and the allocated chemotherapy group (108 patients). However, among patients with Ph-positive ALL, the survival of patients who actually received allo-BMT was superior to that of patients who received chemotherapy (P = 0.046).

Gamma-interferon production capacity and T lymphocyte subpopulation after allogeneic bone marrow transplantation.

T cell phenotypes after bone marrow transplantation (BMT) were investigated using monoclonal antibodies (moAbs) reactive to lymphocyte cell surface antigens. Patients' T cells showed decreased percentages of OKT4, 4A and 9.3-positive T cells, and increased percentages of OKT8, human Ia, and Leu-7-positive T cells. These changes in T cell phenotype persisted for a long period after BMT and had no correlation with the occurrence of graft-versus-host disease (GVHD). No lymphocyte activation antigens such as TIA (Tac) or transferrin receptor (5E9) were detected after BMT. The capacity of the patients' lymphocytes to produce gamma-interferon (IFN-gamma) was measured after incubation of lymphocytes with mitogen. Patients' lymphocytes produced significantly lower levels of IFN-gamma than the normal controls. This failure of IFN-gamma production showed no correlation with stimulation index of mitogen blastogenesis or changes of T cell population. Thus, not only T cell phenotype but also measurement of IFN-gamma production of lymphocyte may be useful in detecting immunological abnormalities in patients who receive BMT.

Epstein-Barr virus-negative high grade B cell lymphoma of donor origin developing 19 months after unrelated allogeneic bone marrow transplantation.

A 22-year-old man, in first complete remission of acute myelogenous leukemia, developed a high grade B cell lymphoma 19 months after an allogeneic bone marrow transplant (allo-BMT) from an HLA-identical unrelated donor. Biopsy of a cervical lymph node revealed a lymphoma that was negative for Epstein-Barr virus-encoded small nuclear RNAs (EBERs) in situ hybridization. Genotypic analyses identified the lymphoma to be of donor origin, and there was no evidence of the Epstein-Barr virus (EBV) DNA in the lymphoma by Southern blot analysis. The lymphoma went into complete remission, following four courses of combination chemotherapy, but relapsed after a month and the patient died of congestive heart failure. The patient was thought to be persistently immunosuppressed 11 months after cessation of immunosuppressants, and the lymphoma was thought to be induced by one or more factors other than EBV.

Autologous BMT in high risk patients with CALLA-positive ALL: possible efficacy of ex vivo marrow leukemia cell purging with monoclonal antibodies and complement.

Autologous BMT (auto-BMT) has been conducted for 17 high-risk common ALL antigen (CALLA)-positive non-T cell type ALL patients. Ex vivo purging of leukemia cells from infused BM cells was performed using complement and three kinds of mouse monoclonal antibodies reactive to CALLA-positive leukemia cells: NL-1 (IgG2a), NL-22 (IgM), and HL-47 (IgM). Minimal residual leukemia cells in BM were examined by PCR method in Philadelphia chromosome (Ph1)-positive ALL cases. BCR/ABL chimeric transcript, which was positive in BM samples before purging, was shown to be absent after ex vivo purging in all three cases tested. Among four Ph1-positive cases transplanted in first CR, three cases survived in CR remission 77, 29 and 26 months after BMT, and one case died without relapse 4 months after BMT. The other four Ph1-negative cases transplanted in the first CR also remained in CR except one who relapsed. The results of minimal residual leukemia cell studies and clinical data indicate the effectiveness of our ex vivo leukemia cell purging method and auto-BMT in the early stage of CR for patients with high risk ALL.

Treatment of adult T cell leukemia with mega-dose cyclophosphamide and total body irradiation followed by allogeneic bone marrow transplantation.

A 43-year-old patient with adult T cell leukemia (ATL) was treated with mega-dose cyclophosphamide and total body irradiation (TBI) followed by bone marrow transplantation (BMT) from his HLA-identical sibling who was not a carrier of ATL virus. After BMT, ATL cells rapidly decreased and disappeared, and the engraftment of marrow was confirmed on day 20. The patient showed normal hematologic recovery. However, he died on day 205 with interstitial pneumonitis caused by cytomegalovirus infection. Neither autopsy findings nor serologic and cytologic examinations showed any evidence of ATL relapse after BMT. This pilot study suggests that mega-dose chemotherapy and TBI followed by allogeneic BMT should be considered for such treatment of ATL.

Improved outcome of adult T cell leukemia/lymphoma with allogeneic hematopoietic stem cell transplantation.

Adult T cell leukemia/lymphoma (ATL) is a poor prognosis T cell malignancy. In order to improve the outcome, we employed allogeneic stem cell transplantation (allo-SCT) for ATL in 10 patients, nine of whom were from HLA-identical siblings and one from an unrelated donor. Conditioning regimens varied among the patients except that all received total body irradiation. The patients tolerated the regimens well with mild, if any toxicity, and engraftment occurred in all cases. Median leukemia-free survival after allo-SCT was 17.5+ months (range 3.7-34.4+). Six of the 10 patients developed acute GVHD (one case each with grade I, III or IV, and three cases with grade II) and three patients developed extensive chronic GVHD. Four patients died after allo-SCT during the study period from either acute GVHD (grade IV), pneumonitis, gastrointestinal bleeding or renal insufficiency. Two of the 10 cases with no symptoms of GVHD relapsed with clinical ATL. These results strongly suggest that allo-SCT may improve the survival in ATL if a controlled degree of GVHD develops.

Cytomegalovirus antigenemia and outcome of patients treated with pre-emptive ganciclovir: retrospective analysis of 241 consecutive patients undergoing allogeneic hematopoietic stem cell transplantation.

CMV disease remains a major infectious complication after allogeneic hematopoietic stem cell transplantation (HSCT). To investigate the relationship between CMV antigenemia, treatment with ganciclovir (GCV), and outcome, we retrospectively analyzed 241 consecutive patients at risk for CMV infection who underwent allogeneic HSCT. Antigenemia-guided pre-emptive strategy with GCV was used for all patients. CMV antigenemia developed in 169 patients (70.1%), and CMV disease in 18 patients (7.5%). Multivariate analysis showed that acute GVHD (grades II-IV) was the only risk factor for developing antigenemia, and acute GVHD and advanced age for CMV disease. GCV use, as well as acute GVHD and advanced age, significantly increased the risk for bacterial and fungal infection after engraftment. Those who developed CMV antigenemia had a poorer outcome than those who did not (log-rank, P=0.0269), although the development of CMV disease worsened the outcome with only borderline significance (log-rank, P=0.0526). In conclusion, detection of antigenemia proved to be a poor prognostic factor for HSCT patients, which may be attributed to a combination of factors, including CMV disease itself, the effect of treatment, and a host status that allows for reactivation of CMV. Optimal pre-emptive strategy needs to be determined.

Analysis of 500 bone marrow transplants from unrelated donors (UR-BMT) facilitated by the Japan Marrow Donor Program: confirmation of UR-BMT as a standard therapy for patients with leukemia and aplastic anemia.

In December 1991, the Japan Marrow Donor Program (JMDP) was established with the cooperation of the Japanese Red Cross and Japan Marrow Donor Foundation under the auspices of the Ministry of Health and Welfare in Japan. By December 1998, 122365 HLA-A,B typed volunteer marrow donors and 7207 patients had been cumulatively registered in the JMDP. The results of HLA-matching between donors and patients revealed that 5684 out of 7207 (78.9%) patients could have at least one HLA-A,B,DR serologically matched donor. Among these matched pairs, 1829 unrelated bone marrow transplants (UR-BMT) were performed. The initial 500 UR-BMT transplanted from January 1993 to October 1995 were analyzed as of July 1998. Engraftment was achieved in 95% of cases. Probability of the occurrence of grade III and IV acute GVHD was 18.4%. The rate of disease-free survival (DFS) of the patients who had standard-risk leukemia and did not suffer from grade III or IV acute GVHD (n = 154) was 60-71% and the rate of survival of patients with aplastic anemia was 56%. It can be stated that UR-BMT is a modality of treatment which is as effective as related BMT if the occurrence of grade III or IV acute GVHD is predicted and prevented.

Molecular remission achieved by interferon therapy in a patient with cytogenetically relapsed chronic myelogenous leukemia after syngeneic bone marrow transplantation.

A patient with chronic myelogenous leukemia (CML) in chronic phase (CP) had been treated with a syngeneic bone marrow transplantation (BMT). Cytogenetic remission was confirmed 3 months later. One year after transplantation, hematological remission persisted while cytogenetic analysis revealed a recurrence of Philadelphia chromosome (Ph1). Five months later, we began treatment with human lymphoblastoid interferon (HLBI), a natural interferon (IFN)-alpha. Fourteen months after initiation of HLBI administration, cytogenetic analysis of the patient's bone marrow showed disappearance of Ph1 positive cells. One year after confirming cytogenetic remission, the absence of bcr-abl transcripts by polymerase chain reaction (PCR) assay indicated molecular remission. IFN therapy appears to be the first choice of treatment for cytogenetic relapse after syngeneic BMT. The efficacy of IFN appears to be due to an anti-malignancy effect, not to graft versus leukemia (GVL) effect.

Early treatment of CMV antigenemia with ganciclovir for prevention of fatal CMV disease in patients receiving marrow from HLA-matched unrelated donors.

The effect of early treatment of cytomegalovirus (CMV) antigenemia with ganciclovir (DHPG) for the prevention of CMV disease was evaluated in 25 patients with hematological malignancy who had received marrow from human leukocyte antigen-matched unrelated donors at our institution. CMV antigenemia occurred in 17 of 25 patients, a high rate of 68%, and was initially detected between 4 and 8 weeks after bone marrow transplantation (BMT) (median time 5 weeks). The incidence of CMV antigenemia was statistically higher in those patients given steroids or antithymocyte globulin (P < 0.01). All 17 CMV antigenemia-positive patients were treated with DHPG until antigenemia was cleared, and this treatment was resumed if antigenemia occurred. CMV antigenemia eventually became negative in all cases. One major drawback of DHPG was that leukopenia was observed in six patients (35%). CMV disease occurred in six patients despite early treatment of CMV antigenemia with DHPG (24%, 6 of 25 patients). Four of them developed CMV disease in the early phase (within six months) and two in the late phase (more than six months). All CMV diseases in the early phase were easily cured by treatment with DHPG while monitoring CMV antigenemia, but CMV disease in the late phase did not respond to DHPG and led to the death of one patient. On the other hand, there were no patients who developed CMV disease in the antigenemia-negative group. Thus, although early treatment using our method was effective in clearing CMV antigenemia in unrelated BMT, it did not totally prevent CMV disease. A further method of early treatment for the prevention of fatal CMV disease is required.

Allogenic bone marrow transplantation as a treatment for adult T-cell leukemia.

We performed allogenic bone marrow transplantation (BMT) in two adult T-cell leukemia (ATL) patients with HLA-identical siblings as donors. One patient, with acute ATL, relapsed 3 months after BMT. The other, with chronic ATL, has become free of disease over 18 months after the BMT from his human T-cell lymphotropic virus type 1 (HTLV-1)-negative sibling, and we were unable to detect HTLV-1 in the patient's peripheral blood. Based on our results and those of others, although there have been limited numbers of patients, BMT may represent the only potentially curative treatment for ATL, and the presence of graft-vs.-host disease tends to be related to good results, which suggests the possibility that graft-vs.-leukemia effects may play an important role in allogenic BMT for ATL.

A new marrow T cell depletion method using anti-CD6 monoclonal antibody-conjugated magnetic beads and its clinical application for prevention of acute graft-vs.-host disease in allogeneic bone marrow transplantation: results of a phase I-II trial.

We established a simple method of T cell depletion using anti-CD6 monoclonal antibody-conjugated immunomagnetic beads. Preliminary experiments using this method demonstrated that CD3+ T cells could be partially depleted without depleting CD56+ NK cells. A phase I-II clinical study was performed to assess the safety and efficacy of this partial T cell depletion method for the prevention of acute graft-vs.-host disease (GVHD) in 10 leukemia patients at high risk for GVHD (defined as 1) unrelated transplant from MLC-positive or HLA-DRB1 mismatched donor or 2) related transplant from serologically HLA-A, -B, or -DR one-locus mismatched donor). Cyclosporine (CSP) and methotrexate (MTX) were used for additional prophylaxis against GVHD in all cases. Sustained engraftment occurred in 9 of the 10 patients. Although acute GVHD developed in 6 of the 9 evaluable patients, none developed more than grade III severe acute GVHD. Five patients were alive in remission at a median follow-up of 32 months after bone marrow transplantation, and no relapse of leukemia was observed. We conclude from this pilot study that selective T cell depletion with anti-CD6 monoclonal antibody coupled with CSP and MTX posttransplant immunosuppressive therapy is safe. Further analysis of the phase II-III study is needed to confirm the effectiveness of this protocol.

Posttreatment nadir M-protein level is a stronger discriminator of survival following plateau attainment than is percent reduction in M-protein in patients with IgG myeloma.

We conducted a retrospective study of patients with IgG or IgA myeloma who attained plateau to evaluate the relationships between survival and posttreatment nadir M-protein levels and between survival and the response to treatment evaluated by the percent reduction in M-protein. Of the 127 patients comprising 92 IgG and 35 IgA myeloma patients with disease stages II or III, 51 (40.2%) attained plateau. For IgG myeloma patients who attained plateau, survival time was not affected by the percent reduction in M-protein (median survival, 59.5 months for responding patients versus 54.4 months for nonresponding patients, P = .6910). Posttreatment nadir M-protein level, however, did affect survival time (median survival, 61.2 months for <3000 mg/dL versus 25.7 months for >3000 mg/dL, P = .0439). These findings suggest that the posttreatment nadir M-protein level is a stronger discriminator of survival following plateau attainment than the percent reduction of M-protein in patients with IgG myeloma.

Multicenter prospective study of interferon-alpha and conventional chemotherapy versus bone marrow transplantation for newly diagnosed patients with chronic myelogenous leukemia. Kouseisho Leukemia Study Group.

We compared interferon-alpha (IFN-alpha therapy with bone marrow transplantation (BMT) after initial conventional chemotherapy in patients with chronic myelogenous leukemia (CML) in a multicenter prospective study. Ninety patients with Philadelphia chromosome-positive CML in chronic phase were enrolled between 1991 and 1994. Sixty-six of 89 evaluable patients received IFN-alpha after conventional chemotherapy with hydroxyurea or busulfan (IFN-alpha group). Twenty-three patients received allogeneic BMT (BMT group). Fifteen of them received transplants from HLA-identical family donors and 8 from HLA-matched unrelated donors. Forty-seven of 66 patients (71%) in the IFN-alpha group and 17 of 23 patients (74%) in the BMT group achieved complete hematologic response, and 12% in the IFN-alpha group and 13% in the BMT group achieved partial hematologic response. Complete cytogenetic response was induced in 5 (8%), partial cytogenetic response in 8 (12%), and minor cytogenetic response in 12 (18%) in the IFN-alpha group. At a median follow-up of 54 months (range, 30-76 months), in the IFN-alpha group, the predicted 6-year survival rate was 54.5% and the predicted 6-year rate of those remaining in chronic phase was 45.7%. Compared with patients with no cytogenetic response, the patients with some cytogenetic response after IFN-alpha treatment had significantly superior survival and duration of the chronic phase even after correction for the time to response using landmark analysis (P < .05). In the BMT group, the predicted 5-year survival rate was 93.3% for family-donor BMT and 21.9% for unrelated-donor BMT Acute graft-versus-host disease of grade III or IV was observed in 1 of 15 patients who received family-donor BMT and 3 of 8 patients who received unrelated donor BMT. Prior treatment with conventional cytotoxic drugs induced early hematologic response and did not reduce the effect of IFN-alpha on CML. Unrelated-donor transplantation should be offered to some patients according to patient age, HLA-matching status, time from diagnosis to BMT, and risk factors.

Quality of life in adult patients after stem cell transplantation.

Many articles pertaining to quality of life (QOL) following stem cell transplantation have been published in the US and western Europe. However, since the actions of health insurance systems and overall cultural aspects are strongly associated with QOL, investigations into QOL should be carried out within all countries. Therefore, we have investigated the QOL of adult patients following stem cell transplantation at 31 hospitals in Japan. The survivors, who were surveyed by mail questionnaire, were 20 years or older at the time of this study. The underlying diseases were acute lymphoblastic leukemia, acute myelogenous leukemia, chronic myelogenous leukemia, non-Hodgkin's lymphoma, Hodgkin's disease, myelodysplastic syndrome, and multiple myeloma. Median age at the time of the study was 36 years, and median interval after transplantation was 35.3 months. Of 383 patients surveyed, 282 (73.6%) responded to the questionnaire. One hundred and ninety-two patients were treated with an allogeneic-related transplantation, 52 with allogeneic-unrelated, and 38 with an autologous transplantation. Our data revealed that the length of time since transplantation and the diagnosis of chronic GVHD were associated with QOL. When unrelated and related transplantation recipients were compared, ratings on relief from pain, stability in weight, and confidence in dealing with daily life were lower among unrelated transplantation patients.

Serum thrombopoietin level after allogeneic bone marrow transplantation: possible correlations with platelet recovery, acute graft-versus-host disease and hepatic veno-occlusive disease. Nagoya Bone Marrow Transplantation Group.

Thrombopoietin (TPO) is a growth and differentiation factor for megakaryocytes and platelets. An ELISA was developed for measuring TPO concentrations in human sera. The mean +/- S.D. of TPO level obtained in 29 control subjects was 0.87 +/- 0.35 fmol/ml. We measured the TPO level in 36 patients after allogeneic bone marrow transplantation (BMT) and determined the relationship between blood levels of TPO and changes in the circulating platelet mass. In general, a reciprocal relationship was observed between TPO and platelet count (r = -0.609, P < 0.0001; n = 165). With the decrease in the platelet mass after myeloablative therapy, the TPO level increased proportionally and peaked during the platelet nadir. The peak concentration of TPO ranged from 20-50 fmol/ml. The TPO level decreased with the normalization of the platelet mass. In contrast, the TPO level decreased during acute graft-versus-host disease (GVHD) in several patients. Furthermore, the TPO level was significantly lower in the patients with hepatic veno-occlusive disease (VOD) than in the patients after BMT without GVHD and VOD in the samples of less than 50000/microliters platelets (P < 0.005). These findings suggest that in the patients given allogeneic BMT, TPO has an important role in the physiologic regulation of platelet production and that liver damage due to acute GVHD and VOD may decrease the TPO level.

Effective and safe interferon treatment for Japanese patients with chronic myelogenous leukemia relapse after bone marrow transplantation. The Nagoya Blood and Marrow Transplantation Group.

The purpose of this study was to assess the efficacy and safety of interferon (IFN) treatment in patients with a relapse of chronic myelogenous leukemia (CML) after bone marrow transplantation in Japan. Accordingly, we retrospectively analyzed the results obtained from 8 patients treated with IFN by the Nagoya Blood and Marrow Transplantation Group. One of 3 patients with hematologic relapse and all 5 patients with cytogenetic relapse achieved complete cytogenetic response (CCR). The median time to achieve CCR was 8 months (range, 3-16 months). One patient relapsed 9 months after starting IFN and died of blast crisis. CCR was maintained for a median duration of 47 months (range, 9-79 months) in the remaining 5 patients. The median duration of survival of these 5 patients after starting IFN was 58 months (range, 12-89 months). At the time of this report, 2 patients who did not attain CCR have survived for 81 months and 142 months after starting IFN, respectively. During IFN treatment, 1 patient showed a transient deterioration of chronic graft-versus-host disease, and no treatment-related deaths were observed. These results suggest that treatment with IFN for CML patients who relapse after bone marrow transplantation is effective and safe. A prospective study to compare IFN with donor lymphocyte infusion is necessary to establish the optimal strategy for the treatment of CML patients who relapse after bone marrow transplantation.