Allogeneic hematopoietic cell transplantation for mycosis fungoides and Sezary syndrome.

We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and Sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the International Blood and Marrow Transplant from 2000-2009. Median time from diagnosis to transplant was 30 (4-206) months and most subjects were with multiply relapsed/ refractory disease. The majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared with myeloablative recipients (median age 51 vs 44 years, P=0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95% confidence interval (CI) 12-27%) and 22% (95% CI 15-31%), respectively. Risk of disease progression was 50% (95% CI 41-60%) at 1 year and 61% (95% CI 50-71%) at 5 years. PFS at 1 and 5 years was 31% (95% CI 22-40%) and 17% (95% CI 9-26%), respectively. OS at 1 and 5 years was 54% (95% CI 45-63%) and 32% (95% CI 22-44%), respectively. Allogeneic HCT in MF/SS results in 5-year survival in approximately one-third of patients and of those, half remain disease-free.

The effect of graft purging with 4-hydroperoxycyclophosphamide in autologous bone marrow transplantation for acute myelogenous leukemia.

BACKGROUND: Autologous bone marrow transplantation is an important therapy for patients with acute myelogenous leukemia (AML). However, leukemia in the graft may contribute to posttransplant relapse. Treatment of the graft with 4-hydroperoxycyclophosphamide (4HC) is sometimes used to decrease numbers of infused leukemia cells (4HC purging). No large controlled trials evaluating efficacy and toxicity of 4HC purging are reported. METHODS: We studied 294 patients reported to the Autologous Blood and Marrow Registry receiving either a 4HC-purged (n = 211) or unpurged (n = 83) autograft for AML in first (n = 209) or second (n = 85) remission. Analyses were restricted to patients transplanted less than 6 months after achieving remission. Using Cox proportional hazards regression, we compared time to treatment failure (death or relapse, inverse of leukemia-free survival) after 4HC-purged vs unpurged transplants while controlling for important prognostic factors. RESULTS: Median duration of posttransplant neutropenia was 40 (range, 10-200) days after 4HC-purged transplants and 29 (9-97) days after unpurged transplants (p < 0.01). Transplant-related mortality was similar in the two groups. In multivariate analysis, patients receiving 4HC-purged transplants had lower risks of treatment failure than those receiving unpurged transplants (relative risk, 0.69, p = 0.12 in the first posttransplant year; relative risk, 0.28, p < 0.0001 thereafter). Adjusted three-year probabilities of leukemia-free survival (95% confidence interval) were 56% (47-64%) and 31% (18-45%) after 4HC-purged and unpurged transplants in first remission, respectively. Corresponding probabilities in second remission were 39% (25-53%) and 10% (1-29%). CONCLUSION: Grafts purged with 4HC are associated with higher leukemia-free survival after autologous bone marrow transplants for AML.

Impact of donor type on outcome of bone marrow transplantation for Wiskott-Aldrich syndrome: collaborative study of the International Bone Marrow Transplant Registry and the National Marrow Donor Program.

Human leukocyte antigen (HLA)-identical sibling bone marrow transplantation is an effective treatment for Wiskott-Aldrich syndrome. However, most children with this disease lack such donors and many patients receive transplants from alternative donors. This study compared outcomes of HLA-identical sibling, other related donor, and unrelated donor transplantation for Wiskott-Aldrich syndrome. The outcome of 170 transplantations for Wiskott-Aldrich syndrome, from 1968 to 1996, reported to the International Bone Marrow Transplant Registry and/or National Marrow Donor Program were assessed. Fifty-five were from HLA-identical sibling donors, 48 from other relatives, and 67 from unrelated donors. Multivariate proportional hazards regression was used to compare outcome by donor type and identify other prognostic factors. Most transplant recipients were younger than 5 years (79%), had a pretransplantation performance score greater than or equal to 90% (63%), received pretransplantation preparative regimens without radiation (82%), and had non-T-cell-depleted grafts (77%). Eighty percent received their transplant after 1986. The 5-year probability of survival (95% confidence interval) for all subjects was 70% (63%-77%). Probabilities differed by donor type: 87% (74%-93%) with HLA-identical sibling donors, 52% (37%-65%) with other related donors, and 71% (58%-80%) with unrelated donors (P =.0006). Multivariate analysis indicated significantly lower survival using related donors other than HLA-identical siblings (P =.0004) or unrelated donors in boys older than 5 years (P =.0001), compared to HLA-identical sibling transplants. Boys receiving an unrelated donor transplant before age 5 had survivals similar to those receiving HLA-identical sibling transplants. The best transplantation outcomes in Wiskott-Aldrich syndrome are achieved with HLA-identical sibling donors. Equivalent survivals are possible with unrelated donors in young children.

Autologous transplantation for diffuse aggressive non-Hodgkin's lymphoma in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry.

PURPOSE: To evaluate the results of high-dose chemotherapy and autologous hematopoietic stem-cell transplantation (autotransplants) in patients with diffuse aggressive non-Hodgkin's lymphoma (NHL) who never achieve a complete remission with conventional chemotherapy. PATIENTS AND METHODS: Detailed records from the Autologous Blood and Marrow Transplant Registry (ABMTR) on 184 patients with diffuse aggressive NHL who never achieved a complete remission with conventional chemotherapy and subsequently received an autotransplant were evaluated. Transplants were performed between 1989 and 1995 and were reported to the ABMTR by 48 centers in North and South America. RESULTS: Seventy-nine (44%) of 184 patients achieved a complete remission or a complete remission with residual imaging abnormalities of unknown significance after autotransplantation. Thirty-four (19%) of 184 had a partial remission and 55 (31%) of 184 had no response or progressive disease. Eleven patients (6%) were not assessable for response because of early death. The probabilities of progression-free and overall survival at 5 years after transplantation were 31% (95% confidence interval [CI], 24% to 38%) and 37% (95% CI, 30% to 45%), respectively. In multivariate analysis, chemotherapy resistance, Karnofsky performance status score less than 80 at transplantation, age > or = 55 years at transplantation, receiving three or more prior chemotherapy regimens, and not receiving pre- or posttransplant involved-field irradiation therapy were adverse prognostic factors for overall survival. CONCLUSION: High-dose chemotherapy and autologous hematopoietic stem-cell transplantation should be considered for patients with diffuse aggressive NHL who never achieve a complete remission but who are still chemotherapy-sensitive and are otherwise transplant candidates.

Effect of postremission chemotherapy before human leukocyte antigen-identical sibling transplantation for acute myelogenous leukemia in first complete remission.

Allogeneic bone marrow transplantation is an effective postremission strategy for patients with acute myelogenous leukemia (AML) in first complete remission (CR). The value of administering consolidation chemotherapy before human leukocyte antigen (HLA)-identical sibling transplantation is not established. Outcomes of patients with AML in first CR receiving no consolidation therapy, standard-dose cytarabine consolidation therapy, and high-dose cytarabine consolidation therapy before HLA-identical sibling transplantation were compared. Five-year treatment-related mortality rates were 30% (95% confidence interval [CI], 18% to 42%) in patients receiving no consolidation chemotherapy, 22% (95% CI, 17% to 28%) in those receiving standard-dose cytarabine consolidation, and 24% (95% CI, 17% to 31%) in those receiving high-dose cytarabine (P = NS). Five-year cumulative incidences of relapse were 19% (10% to 30%), 21% (16% to 27%), and 17% (11% to 24%), respectively (P = NS). Five-year probabilities of leukemia-free survival were 50% (36% to 63%), 56% (49% to 63%), and 59% (50% to 66%), respectively (P = NS). Five-year probabilities of overall survival were 60% (46% to 71%), 56% (49% to 63%), and 60% (51% to 67%), respectively (P = NS). The data indicate that postremission consolidation with cytarabine before allogeneic transplantation for AML in first CR is not associated with improved outcome compared to proceeding directly to transplantation after successful induction. (Blood. 2000;96:1254-1258)

Blood stem cells compared with bone marrow as a source of hematopoietic cells for allogeneic transplantation. IBMTR Histocompatibility and Stem Cell Sources Working Committee and the European Group for Blood and Marrow Transplantation (EBMT).

Peripheral blood cells are increasingly used in place of bone marrow as a source of hematopoietic stem cells for allogeneic transplantation. The relative efficacy of these 2 approaches is unknown. This retrospective multivariate analysis compared results of 288 HLA-identical sibling blood stem cell transplantations with results of 536 HLA-identical sibling bone marrow transplantations. No transplants were T-cell depleted. Median follow-up was 12 months, and analyses focused on 1-year outcomes. Recipients of blood stem cell transplants had more rapid recovery of neutrophils to at least 0.5 x 10(9)/L (median time to recovery, 14 days, compared with 19 days for marrow transplants; P <.001) and of platelets to at least 20 x 10(9)/L (median time, 18 days, compared with 25 days for marrow transplants; P <.001). There was no significant difference in the incidence of grades II to IV acute graft versus host disease (GVHD). The incidence of chronic GVHD was significantly higher after blood stem cell transplantation (1-year probability [95% confidence interval], 65% [56%-72%] compared with 53% [47%-59%]; P =.02) Relapse incidence in the 2 transplant groups did not differ significantly. Treatment-related mortality rates were lower and leukemia-free survival rates were higher with blood stem cell transplants in patients with advanced leukemia (acute leukemia in second remission or chronic myelogenous leukemia in accelerated phase) but not in early leukemia (acute leukemia in first remission or chronic myelogenous leukemia in chronic phase). The median time from transplantation to hospital discharge was 23 days after blood stem cell transplantation and 28 days after bone marrow transplantation (P =.003). Further study with longer follow-up is necessary to definitively establish the role of blood stem cells for allogeneic transplantation, especially in patients with good-risk disease. (Blood. 2000;95:3702-3709)

T-cell depletion of bone marrow transplants for leukemia from donors other than HLA-identical siblings: advantage of T-cell antibodies with narrow specificities.

T-cell depletion of donor marrow decreases graft-versus-host disease resulting from transplants from unrelated and human leukocyte antigen (HLA)-mismatched related donors. However, there are diverse strategies for T-cell-depleted transplantation, and it is uncertain whether any improve leukemia-free survival (LFS). To compare strategies for T-cell-depleted alternative donor transplants and to compare T-cell depleted with non-T-cell-depleted transplants, we studied 870 patients with leukemia who received T-cell-depleted transplants from unrelated or HLA-mismatched related donors from 1982 to 1994. Outcomes were compared with those of 998 non-T-cell-depleted transplants. We compared LFS using different strategies for T-cell-depleted transplantation considering T-cell depletion technique, intensity of pretransplant conditioning, and posttransplant immune suppression using proportional hazards regression to adjust for other prognostic variables. Five categories of T-cell depletion techniques were considered: narrow-specificity antibodies, broad-specificity antibodies, Campath antibodies, elutriation, and lectins. Strategies resulting in similar LFS were pooled to compare T-cell-depleted with non-T-cell-depleted transplants. Recipients of transplants T-cell depleted by narrow-specificity antibodies had lower treatment failure risk (higher LFS) than recipients of transplants T-cell depleted by other techniques. Compared with non-T-cell-depleted transplants (5-year probability +/- 95% confidence interval [CI] of LFS, 31% +/- 4%), 5-year LFS was 29% +/- 5% (P = NS) after transplants T-cell depleted by narrow-specificity antibodies and 16% +/- 4% (P <.0001) after transplants T-cell depleted by other techniques. After alternative donor transplantation, T-cell depletion of donor marrow by narrow-specificity antibodies resulted in LFS rates that were higher than those for transplants T-cell depleted using other techniques but similar to those for non-T-cell-depleted transplants. (Blood. 2000;95:3996-4003)

Effect of short-term interferon therapy on the outcome of subsequent HLA-identical sibling bone marrow transplantation for chronic myelogenous leukemia: an analysis from the international bone marrow transplant registry.

Allogeneic bone marrow transplantation (BMT) is the only curative therapy for chronic myelogenous leukemia (CML), though several studies indicate that prolonged survival can result from interferon-alpha (IFN-alpha) treatment. IFN-alpha is now often used as initial therapy for CML, before donor availability is known. Because identifying potential donors can take several weeks to months, it is important to know whether IFN-alpha adversely affects outcome of a subsequent BMT. If it does, initiation of IFN-alpha therapy might be delayed until donor availability is determined and avoided in patients for whom BMT is planned. We studied 873 patients who received HLA-identical sibling BMT for chronic-phase CML in 153 centers participating in the International Bone Marrow Transplant Registry. The object was to compare outcome in the 664 who received only hydroxyurea before BMT with outcome in the 209 who received IFN-alpha with or without hydroxyurea. The median duration of IFN-alpha therapy was 2 months (range, 1 to 39 months). Cox proportional hazards analysis was used to compare engraftment, graft-versus-host disease (GVHD), nonrelapse mortality, relapse, survival, and leukemia-free survival after adjustment for other prognostic variables. We found a higher risk of nonengraftment among patients given IFN-alpha than among those given hydroxyurea alone (2% versus 0.2%; P = 0.01). Patients who received IFN-alpha had a lower risk of relapse (relative risk, 0.17; 95% confidence interval, 0.04-0.70). Probabilities of GVHD, nonrelapse mortality, survival, and leukemia-free survival were similar in the two treatment groups. These results suggest that a short course of IFN-alpha does not adversely affect survival after a subsequent HLA-identical sibling BMT for chronic-phase CML. (Blood. 2000;95:410-415)

New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia.

PURPOSE: To determine the incidence of and risk factors for second malignancies after allogeneic bone marrow transplantation (BMT) for childhood leukemia. PATIENTS AND METHODS: We studied a cohort of 3, 182 children diagnosed with acute leukemia before the age of 17 years who received allogeneic BMT between 1964 and 1992 at 235 centers. Observed second cancers were compared with expected cancers in an age- and sex-matched general population. Risks factors were evaluated using Poisson regression. RESULTS: Twenty-five solid tumors and 20 posttransplant lymphoproliferative disorders (PTLDs) were observed compared with 1.0 case expected (P <.001). Cumulative risk of solid cancers increased sharply to 11.0% (95% confidence interval, 2.3% to 19.8%) at 15 years and was highest among children at ages younger than 5 years at transplantation. Thyroid and brain cancers (n = 14) accounted for most of the strong age trend; many of these patients received cranial irradiation before BMT. Multivariate analyses showed increased solid tumor risks associated with high-dose total-body irradiation (relative risk [RR] = 3.1) and younger age at transplantation (RR = 3.7), whereas chronic graft-versus-host disease was associated with a decreased risk (RR = 0.2). Risk factors for PTLD included chronic graft-versus-host disease (RR = 6.5), unrelated or HLA-disparate related donor (RR = 7. 5), T-cell-depleted graft (RR = 4.8), and antithymocyte globulin therapy (RR = 3.1). CONCLUSION: Long-term survivors of BMT for childhood leukemia have an increased risk of solid cancers and PTLDs, related to both transplant therapy and treatment given before BMT. Transplant recipients, especially those given radiation, should be monitored closely for second cancers.

Factors correlated with progression-free survival after high-dose chemotherapy and hematopoietic stem cell transplantation for metastatic breast cancer.

CONTEXT: Women with breast cancer are the most frequent recipients of high-dose chemotherapy followed by autologous hematopoietic stem cell transplantation (autotransplants) in North America. Despite widespread use, controversy exists about the benefits of and appropriate patients for this therapy. OBJECTIVE: To determine factors associated with disease progression or death after autotransplantation in women with metastatic breast cancer. DESIGN: Analysis of data collected retrospectively (January 1989 to 1992) and prospectively (1992 through January 1995) for the Autologous Blood and Marrow Transplant Registry. SETTING: Sixty-three hospitals in North America, Brazil, and Russia. PARTICIPANTS: A total of 1188 consecutive women aged 18 to 70 years receiving autotransplants for metastatic or locally recurrent breast cancer, with a median follow-up of 291/2 months. MAIN OUTCOME MEASURE: Time to treatment failure (disease progression, disease recurrence, or death) after autotransplantation. RESULTS: Factors associated with significantly (P<.05) increased risk of treatment failure in a Cox multivariate analysis included age older than 45 years (relative hazard, 1.17; 95% confidence interval [CI], 1.02-1.33), Karnofsky performance score less than 90% (1.27; 95% CI, 1.07-1.51), absence of hormone receptors (1.31; 95% CI, 1.15-1.51), prior use of adjuvant chemotherapy (1.31; 95% CI, 1.10-1.56), initial disease-free survival interval after adjuvant treatment of no more than 18 months (1.99; 95% CI, 1.62-2.43), metastases in the liver (1.47; 95% CI, 1.20-1.80) or central nervous system (1.56; 95% CI, 0.99-2.46 [approaches significance]) vs soft tissue, bone, or lung, 3 or more sites of metastatic disease (1.32; 95% CI, 1.13-1.54), and incomplete response vs complete response to standard-dose chemotherapy (1.65; 95% CI, 1.36-1.99). Receiving tamoxifen posttransplantation was associated with a reduced risk of treatment failure in women with hormone receptor-positive tumors (relative hazard, 0.60; 95% CI, 0.47-0.87). Women with no risk factors (n = 38) had a 3-year probability of progression-free survival of 43% (95% CI, 27%-61 %) vs 4% (95% CI, 2%-8%) for women with more than 3 risk factors (n = 343). CONCLUSION: These data indicate that some women are unlikely to benefit from autotransplantation and should receive this treatment only after being provided with prognostic information and in the context of clinical trials attempting to improve outcome.

Increased incidence of Hodgkin's disease after allogeneic bone marrow transplantation.

PURPOSE: Immune dysregulation associated with allogeneic bone marrow transplantation (BMT) is linked to an increased risk of posttransplant lymphoproliferative disorders (PTLD); however, reports of Hodgkin's disease (HD) after transplantation are rare. PATIENTS AND METHODS: We evaluated the risk of HD among 18,531 persons receiving allogeneic BMT between 1964 and 1992 at 235 centers. The number of HD cases was compared with that expected in the general population. Risk factors were identified using Poisson regression and a nested case-control study. RESULTS: Risk of HD was increased in the postBMT population compared with the general population with an observed-to-expected incidence ratio (O/E) of 6.2 (observed cases, n = 8; 95% confidence interval [CI], 2.7 to 12). A significantly increased risk of HD remained after excluding two human immunodeficiency virus-positive patients (observed cases, n = 6; O/E = 4.7, 95% CI, 1.7 to 10.3). Mixed cellularity subtype predominated (five of eight cases, 63%). Five of six assessable cases contained Epstein-Barr virus (EBV) genome. Posttransplant HD differed from PTLD by later onset (> 2.5 years) and lack of association with established risk factors (such as T-cell depletion and HLA disparity). Patients with HD were more likely than matched controls to have had grade 2 to 4 acute graft-versus-host disease (GVHD), required therapy for chronic GVHD, or both (P =.002), although analysis included small numbers of patients. CONCLUSION: The increased incidence of HD among BMT recipients adds support to current theories which link overstimulation of cell-mediated immunity and exposure to EBV with various subtypes of HD. The long latency of HD after transplant and lack of association with risk factors for PTLD is noteworthy and should be explored further for possible insights into pathogenesis.

Risk of lymphoproliferative disorders after bone marrow transplantation: a multi-institutional study.

We evaluated 18,014 patients who underwent allogeneic bone marrow transplantation (BMT) at 235 centers worldwide to examine the incidence of and risk factors for posttransplant lymphoproliferative disorders (PTLD). PTLD developed in 78 recipients, with 64 cases occurring less than 1 year after transplantation. The cumulative incidence of PTLD was 1.0% +/- 0.3% at 10 years. Incidence was highest 1 to 5 months posttransplant (120 cases/10,000 patients/yr) followed by a steep decline to less than 5/10,000/yr among >/=1-year survivors. In multivariate analyses, risk of early-onset PTLD (<1 year) was strongly associated (P <.0001) with unrelated or human leukocyte antigen (HLA) mismatched related donor (relative risk [RR] = 4.1), T-cell depletion of donor marrow (RR = 12.7), and use of antithymocyte globulin (RR = 6.4) or anti-CD3 monoclonal antibody (RR = 43.2) for prophylaxis or treatment of acute graft-versus-host disease (GVHD). There was a weaker association with the occurrence of acute GVHD grades II to IV (RR = 1.9, P =.02) and with conditioning regimens that included radiation (RR = 2.9, P =.02). Methods of T-cell depletion that selectively targeted T cells or T plus natural killer (NK) cells were associated with markedly higher risks of PTLD than methods that removed both T and B cells, such as the CAMPATH-1 monoclonal antibody or elutriation (P =.009). The only risk factor identified for late-onset PTLD was extensive chronic GVHD (RR = 4.0, P =.01). Rates of PTLD among patients with 2 or >/=3 major risk factors were 8.0% +/- 2.9% and 22% +/- 17.9%, respectively. We conclude that factors associated with altered immunity and T-cell regulatory mechanisms are predictors of both early- and late-onset PTLD.

Long-term survival and late deaths after allogeneic bone marrow transplantation. Late Effects Working Committee of the International Bone Marrow Transplant Registry.

BACKGROUND AND METHODS: It is uncertain whether mortality rates among patients who have undergone bone marrow transplantation return to the level of the mortality rates of the general population. We analyzed the characteristics of 6691 patients listed in the International Bone Marrow Transplant Registry. All the patients were free of their original disease two years after allogeneic bone marrow transplantation. Mortality rates in this cohort were compared with those of an age-, sex-, and nationality-matched general population. Cox proportional-hazards regression was used to identify risk factors for death more than two years after transplantation (late death). RESULTS: Among patients who were free of disease two years after transplantation, the probability of living for five more years was 89 percent (95 percent confidence interval, 88 to 90 percent). Among patients who underwent transplantation for aplastic anemia, the risk of death by the sixth year after transplantation did not differ significantly from that of a normal population. Mortality remained significantly higher than normal throughout the study among patients who underwent transplantation for acute lymphoblastic leukemia or chronic myelogenous leukemia and through the ninth year among those who underwent transplantation for acute myelogenous leukemia. Recurrent leukemia was the chief cause of death among patients who received a transplant for leukemia, whereas chronic graft-versus-host disease was the chief cause among those who received a transplant for aplastic anemia. Advanced, long-standing disease before transplantation and active chronic graft-versus-host disease were important risk factors for late death. CONCLUSIONS: In patients who receive an allogeneic bone marrow transplant as treatment for acute myelogenous or lymphoblastic leukemia, chronic myelogenous leukemia, or aplastic anemia and who are free of their original disease two years later, the disease is probably cured. However, for many years after transplantation, the mortality among these patients is higher than that in a normal population.

Autotransplants for Hodgkin's disease in patients never achieving remission: a report from the Autologous Blood and Marrow Transplant Registry.

PURPOSE: Hodgkin's disease patients who never achieve complete remission with conventional chemotherapy (i.e., those with primary induction failure) have a poor prognosis. Some subjects who receive high-dose therapy with autologous hematopoietic progenitor-cell infusion experience prolonged progression-free survival. PATIENTS AND METHODS: Detailed records from the Autologous Blood and Marrow Transplant Registry (ABMTR) on 122 Hodgkin's disease patients who failed to achieve complete remission after one or more conventional therapy regimens and subsequently received an autotransplant between 1989 and 1995 were reviewed. RESULTS: Median age was 27 years (range, 7 to 57 years). Median time from diagnosis to transplantation was 14 months (range, 5 to 38 months). Most patients received high-dose chemotherapy without radiation for pretransplantation conditioning (n = 107). The regimen most frequently used was cyclophosphamide, carmustine, and etoposide (n = 47). Fifteen patients received total-body irradiation (n = 15). The graft consisted of bone marrow (n = 86), blood stem cells (n = 25), or both (n = 11). The 100-day mortality was 12% (95% confidence interval, 7% to 19%). Sixty patients (50%) were considered to have achieved complete remission after autotransplantation; 37 of these had negative imaging studies, whereas scan abnormalities of unknown significance persisted in 23 patients. Twenty-seven patients (22%) had no response or progressive disease after transplantation. Probabilities of progression-free and overall survival at 3 years were 38% (95% confidence interval, 28% to 48%) and 50% (95% confidence interval, 39% to 60%), respectively. In multivariate analysis, "B" symptoms at diagnosis and poor performance score at transplantation were adverse prognostic factors for outcome. CONCLUSION: Autotransplants should be considered for patients with Hodgkin's disease who do not achieve complete remission with conventional therapy.

Bone marrow transplants for paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is a rare clonal haematological disorder characterized by intravascular haemolysis and increased risk of thrombosis. PNH is associated with bone marrow failure syndromes including aplastic anaemia, myelodysplasia and leukaemia. Bone marrow transplants are sometimes used to treat PNH, but small series and reporting biases make assessment of transplant outcome difficult. The outcome of 57 consecutive allogeneic bone marrow transplants for PNH reported to the International Bone Marrow Transplant Registry (IBMTR) between 1978 and 1995 was analysed. The 2-year probability of survival in 48 recipients of HLA-identical sibling transplants was 56% (95% confidence interval 49-63%). Two recipients of identical twin transplants remain alive 8 and 12 years after treatment. One of seven recipients of alternative donor allogeneic transplants is alive 5 years after transplant. The most common causes of treatment failure were graft failure and infections. Our results indicate that bone marrow transplantation can restore normal bone marrow function in about 50% of PNH patients.

Chemotherapy vs HLA-identical sibling bone marrow transplants for adults with acute lymphoblastic leukemia in first remission.

There is controversy about whether chemotherapy or an HLA-identical sibling bone marrow transplant is better treatment for adults with acute lymphoblastic leukemia (ALL) in first remission. A previous study of patients treated in 1980-1987 showed similar leukemia-free survivals with these approaches. We re-examined this issue in more recently treated patients receiving different chemotherapy. Chemotherapy subjects (n = 76) participated in trial ALL-87 of the Japan Adult Leukemia Study Group (JALSG). Transplant subjects (n = 214) were reported to the International Bone Marrow Transplant Registry (IBMTR). Treatment-related mortality, relapse and leukemia-free survival were compared after adjusting for differences in subject- and disease-related variables and time-to-treatment. Outcomes differed in persons < or = and >30 years of age. Five-year treatment-related mortality in persons < or =30 years was 3% (95% confidence interval, 0-12%) with chemotherapy vs 32% (23-41%; P < 0.0001) with transplants. The difference was greater among persons >30 years, 13% (2-31%) with chemotherapy vs 57% (43-69%; P < 0.0001) with transplants. Five-year relapse probability in persons < or =30 years was 69% (50-84%) with chemotherapy vs 22% (14-32%; P < 0.0001) with transplants. Among persons >30 years, 5-year relapse was 70% (53-85%) with chemotherapy vs 32% (20-45%; P < 0.0001) with transplants. Leukemia-free survival at 5 years was significantly worse with chemotherapy than with transplants in persons < or =30 years (30% (15-48%) vs 53% (44-63%; P = 0.02)) but not in persons >30 years (26% (13-41%) vs 30% (20-41%; P = 0.70)). We concluded that transplants result in more treatment-related deaths but fewer relapses than chemotherapy. Leukemia-free survival is better with transplants than chemotherapy in persons < or =30 years of age but comparable in older persons.

Allogeneic bone marrow transplantation for low-grade lymphoma.

Advanced low-grade lymphomas are usually incurable with conventional-dose chemotherapy. It is uncertain whether cures are possible with high-dose therapy and bone marrow transplant from a human leukocyte antigen (HLA)-identical sibling. We sought to determine the outcome of HLA-identical sibling bone marrow transplants in advanced low-grade lymphoma in an observational study of 113 patients conducted at 50 centers participating in the International Bone Marrow Transplant Registry (IBMTR). The median patient age was 38 years (range, 15 to 61). Eighty percent had stage IV disease at the time of transplantation. The median number of prior chemotherapy regimens was two (range, 0 to 5). Thirty-eight percent had refractory disease and 29% a Karnofsky performance score (KPS) less than 80%. All patients underwent allogeneic bone marrow transplantation from a HLA-identical sibling donor. The conditioning regimen included total-body irradiation (TBI) in 82% of patients; cyclosporine was used for graft-versus-host disease prophylaxis in 74%. Survival, disease-free survival, recurrence rate, treatment-related mortality, and causes of death were determined. Three-year probabilities of recurrence, survival, and disease-free survival were 16% (95% confidence interval [CI], 9% to 27%), 49% (95% CI, 39% to 60%), and 49% (95% CI, 39% to 59%), respectively. Higher survival was associated with pretransplant KPS >/=90%, chemotherapy-sensitive disease, use of a TBI-containing conditioning regimen, and age less than 40 years. We conclude that high-dose therapy followed by transplantation from a HLA-identical sibling leads to prolonged survival in some patients with advanced low-grade lymphoma. Most mortality is treatment-related, and recurrences are rare.

Unrelated and HLA-nonidentical related donor marrow transplantation for thalassemia and leukemia. A combined report from the Seattle Marrow Transplant Team and the International Bone Marrow Transplant Registry.

Allogeneic marrow transplantation is curative therapy for thalassemia, but fewer than 30% of patients have an HLA-identical sibling marrow donor. Selection of alternative donors of hematopoietic stem cells (unrelated individuals or HLA-nonidentical family members) has been aided by establishment of world-wide donor registries now exceeding 3.6 million volunteers and by DNA-based HLA typing to more closely match potential donors. Coupled with improved methods to control graft-versus-host disease and prevent fungal and cytomegalovirus infection, remarkable progress has been made in alternative donor transplantation. For patients 50 years of age or younger, with recently diagnosed chronic myelogenous leukemia (CML) in chronic phase, 1- and 5-year survivals after HLA-A, B, DRB1 identical unrelated marrow transplantation in Seattle are 82% and 74%, respectively. These results are essentially identical to outcome in similar patients given HLA-matched sibling allografts. However, the world-wide number of alternative donor transplants for thalassemia remains limited to date: 4 unrelated and 60 HLA-nonidentical related transplants have been reported to the IBMTR since 1969 with actuarial overall survival of 75%. Using the paradigm of CML, it is likely that access to curative therapy of thalassemia will improve with optimal HLA typing and donor selection early in the course of disease.

Influence of protective isolation on outcome of allogeneic bone marrow transplantation for leukemia.

Various isolation strategies are used to prevent infections during bone marrow transplantation; data on their efficacy are lacking. We studied whether use of high efficiency particulate air filtration (HEPA) and/or laminar airflow (LAF) units affect transplant-related mortality (TRM) or survival in the first year after allogeneic transplantation. 5065 patients with leukemia receiving bone marrow transplants from an HLA identical sibling (n = 3982) or alternative related or unrelated donors (n = 1083) between 1988 and 1992 were reported to the International Bone Marrow Transplant Registry by 222 teams. Two types of isolation were considered: (1) conventional protective isolation with single patient room and any combination of hand-washing, gloves, mask and gown; and (2) HEPA and/or LAF. Cox proportional hazards regression models were used to determine the relative risks (RRs) of transplant-related mortality (TRM) and of deaths from any cause in patients treated in HEPA/LAF units compared to patients treated in conventional isolation. HLA-identical sibling and alternative donor transplants were analyzed separately. Risks of TRM and overall mortality in the first 100 days post-transplant were significantly lower among patients treated in HEPA/LAF units than in those treated conventionally. RRs of TRM were 0.76 (P = 0.009) for recipients of HLA-identical sibling transplants and 0.65 (P = 0.003) for recipients of alternative donor transplants. Correspondingly RRs of overall mortality were 0.80 (P = 0.02) and 0.65 (P = 0.0006). Decreased risks of TRM and of death in the first 100 days post-transplant resulted in significantly higher 1-year survival rates in patients treated in HEPA/LAF rather than in conventional isolation units. Use of HEPA and/or LAF to prevent infections decreases TRM and increases survival after allogeneic bone marrow transplants for leukemia.