Autotransplants for Hodgkin's disease in first relapse or second remission: a report from the autologous blood and marrow transplant registry (ABMTR).

Although patients with relapsed Hodgkin's disease have a poor prognosis with conventional therapies, high-dose chemotherapy and autologous hematopoietic stem cell transplantation (autotransplantation) may provide long-term progression-free survival. We reviewed data from the Autologous Blood and Marrow Transplant Registry (ABMTR) to determine relapse, disease-free survival, overall survival, and prognostic factors in this group of patients. Detailed records from the ABMTR on 414 patients with Hodgkin's disease in first relapse (n = 295) or second complete remission (CR) (n = 119) receiving an autotransplant from 1989 to 1995 were reviewed. Median age was 29 (range, 7-64) years. Median time from diagnosis to relapse was 18 (range, 6-219) months; median time from relapse to transplant was 5 (range, <1-215) months. Most patients received high-dose chemotherapy without total body irradiation for conditioning (n = 370). The most frequently used high-dose regimen was cyclophosphamide, BCNU, VP-16 (CBV) (n = 240). The graft consisted of bone marrow (n = 246), blood stem cells (n = 112), or both (n = 56). Median follow-up was 46 (range, 5-96) months. One hundred-day mortality (95% confidence interval) was 7 (5-9)%. One hundred and sixty-five of 295 patients (56%) transplanted in relapse achieved CR after autotransplantation. Of these, 61 (37%) recurred. Twenty-four of 119 patients (20%) transplanted in CR recurred. The probability of disease-free survival at 3 years was 46 (40-52)% for transplants in first relapse and 64 (53-72)% for those in second remission (P < 0.001). Overall survival at 3 years was 58 (52-64)% after transplantation in first relapse and 75 (66-83)% after transplantation in second CR (P < 0.001). In multivariate analysis, Karnofsky performance score <90% at transplant, abnormal serum LDH at transplant, and chemotherapy resistance were adverse prognostic factors for outcome. Progression of Hodgkin's disease accounted for 69% of all deaths. Autotransplantation should be considered for patients with Hodgkin's disease in first relapse or second remission. Future investigations should focus on strategies designed to decrease relapse after autotransplantation, particularly in patients at high risk for relapse.

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)

Fluconazole vs low-dose amphotericin B for the prevention of fungal infections in patients undergoing bone marrow transplantation: a study of the North American Marrow Transplant Group.

Systemic fungal infections are a major problem in bone marrow transplant recipients who have prolonged neutropenia or who receive high-dose corticosteroids. Prophylaxis with Fluconazole or low-dose amphotericin B reduces, but does not eliminate these infections. To determine which prophylactic agent is better, we performed a prospective randomized study. Patients undergoing allogeneic (related or unrelated) or autologous marrow or peripheral stem cell transplantation were randomized to receive Fluconazole (400 mg/day p. o. or i.v.) or amphotericin B (0.2 mg/kg/day i.v.) beginning 1 day prior to stem cell transplantation and continuing until recovery of neutrophils to >500/microl. Patients were removed from their study drug for drug-associated toxicity, invasive fungal infection or suspected fungal infection (defined as the presence of fever >38 degrees C without positive culture while on broad-spectrum anti-bacterial antibiotics). Proven or suspected fungal infections were treated with high-dose amphotericin B (0.5-0.7 mg/kg/day). Patients were randomized at each institution and stratified for the type of transplant. The primary end-point of the study was prevention of documented fungal infection; secondary endpoints included fungal colonization, drug toxicity, duration of hospitalization, duration of fever, duration of neutropenia, duration and total dose of high-dose amphotericin B and overall survival to hospital discharge. From July 1992 to October 1994, a total of 355 patients entered into the trial with 159 patients randomized to amphotericin B and 196 to Fluconazole. Patient groups were comparable for diagnosis, age, sex, prior antibiotic or antifungal therapy, use of corticosteroids prior to transplantation and total duration of neutropenia. Amphotericin B was significantly more toxic than Fluconazole especially in related allogeneic transplantation where 19% of patients developed toxicity vs 0% of Fluconazole recipients (p < 0.05). Approximately 44% of all patients were removed from prophylaxis for presumed fungal infection. Proven fungal infections occurred in 4.1% and 7.5% of Fluconazole and amphotericin-treated patients, respectively. Proven fungal infections occurred in 9.1% and 14.3% of related allogeneic marrow recipients receiving Fluconazole or amphotericin B, respectively, and 2.1% and 5.6% of autologous marrow recipients receiving Fluconazole or amphotericin B, respectively (P > 0.05). In this prospective trial, low-dose amphotericin B prophylaxis was as effective as Fluconazole prophylaxis, but Fluconazole was significantly better tolerated.

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)

Comparison of preparative regimens in transplants for children with acute lymphoblastic leukemia.

PURPOSE: Preparative regimens involving total-body irradiation (TBI) produce significant late toxicities in some children who receive bone marrow transplants, including impaired growth and intellectual development. Busulfan is often used as an alternative to TBI, but there are few data regarding its relative efficacy. PATIENTS AND METHODS: We compared outcomes of HLA-identical sibling transplants for acute lymphoblastic leukemia (ALL) in children (< 20 years of age) who received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning. Patients received transplants between 1988 and 1995 and their results were reported to the International Bone Marrow Transplant Registry by 144 participating institutions. The CY/TBI and Bu/CY groups did not differ in gender, immune phenotype, leukocyte count at the time of diagnosis, chromosome abnormalities, remission status, or length of initial remission. T-cell depletion was used more frequently in the CY/TBI group; the Bu/CY group included a higher proportion of children who were less than 5 years of age. The median follow-up period was 37 months. RESULTS: The 3-year probabilities of survival were 55% (95% confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%) with Bu/CY (univariate P =.003). The 3-year probabilities of leukemia-free survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively (univariate P =.005). In a multivariate analysis, the risks of relapse were similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P =.1). Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P =.012). Death and treatment failure (relapse or death, inverse of leukemia-free survival) were more frequent in the Bu/CY group (RR, 1. 39; P =.017 for death; RR, 1.42; P =.006 for treatment failure). CONCLUSION: These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.

Mobilization of peripheral blood stem cells in high-risk breast cancer patients using G-CSF after standard dose docetaxel.

Chemotherapy, in addition to recombinant growth factors, has been effective in mobilizing stem cells. Unfortunately, the use of chemotherapy for this purpose has resulted in profound myelosuppression and increased morbidity. Docetaxel, the single most active agent in the treatment of advanced breast cancer, was evaluated for its potential to mobilize stem cells when given at conventional doses followed by granulocyte colony-stimulating factor (G-CSF). Sixteen high-risk breast cancer patients were mobilized with a regimen consisting of docetaxel (100 mg/m2) followed by daily G-CSF (10 microg/kg), beginning 72 h after the docetaxel, and continuing until completion of the apheresis. The median white blood cell count (WBC) nadir was 1,000/microl (range 500 to 4000/microl ) occurring a median of 6 days (range 4 to 9 days) after the docetaxel. No patient experienced a neutropenic febrile episode due to the mobilization regimen. The median time interval for initiating the apheresis was 8 days (range 6 to 11 days) following the docetaxel. The median number of apheresis was 2 (range 1 to 3) in each patient. Stem cell recovery as measured by the CD34 cell count x 10(6)/kg was a median of 5.2 (range 1.4 to 15.1). A significant correlation was found between CFU-GM, BFU-E, and CFU-GEMM/kg and CD34 cells/kg (r = 0.891, 0.945, and 0.749, respectively, p < 0.001). When our results were compared to a matched cohort receiving G-CSF alone, the docetaxel group demonstrated a superior CD34 cells/kg yield (p = <0.001). Following myeloablative chemotherapy consisting of thiotepa and cyclophosphamide with or without carboplatinum, the hematopoetic recovery determined by an absolute neutrophil count (ANC) of greater than 500/microl and an unsupported platelet count of > or =20,000/microl for 48 h, was a median of 10 days (range 9 to 14 days) and 10 days (range 8 to 30 days), respectively. The results demonstrate that conventional dose docetaxel, combined with G-CSF, is an effective mobilization regimen with minimal toxicity in high-risk breast cancer patients.

[Experimental study on ex vivo expansion of CD(34)(+) umbilical cord blood cells].

OBJECTIVE: To investigate the potential possibility that to expanse ex vivo umbilical cord blood (UCB) cells to an amount sufficient adults transplantation. METHOD: Purified CD(34)(+) UCB cells from 10 fresh UCB samples were cultured for 7 days in IMDM mediums containing 20% FBS and one of the following three combinations: Group A (IL-1beta + IL-3 + IL-6 + G-CSF + Epo + FL), Group B (SCF + IL-1beta + IL-3 + IL-6 + G-CSF + Epo) and Group C (FL + SCF + IL-1beta + IL-3 + IL-6 + G-CSF + Epo). RESULT: (1) There was no significant difference between Groups A and B in expansion of UCB cells. But in group C, the expansion was greater than that in group A (P < 0.01) or group B (P < 0.05). The effects of FL and SCF were synergistic. (2) Over 50 x 10(6) CD(34)(+) cells which are sufficient for adult transplantation were obtained in 30% of UCB samples in group C. (3) The expanded CD(34)(+) UCB cells retained original clonogenic efficiency, the primitive CD(34)(+)CD(38)(-) proportion and the expansion potential were the same as fresh UCB cells. CONCLUSION: The ex vivo expansion of CD(34)(+) UCB cells might provide sufficient hematopoietic stem cells for adult transplantation.

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.

Protracted results of dose-intensive therapy using cyclophosphamide, carmustine, and continuous infusion etoposide with autologous stem cell support in patients with relapse or refractory Hodgkin's disease: a phase II study from the North American Marrow Transplant Group.

To determine the long-term results of high-dose chemotherapy and stem cell support in relapsed or primary refractory Hodgkin disease patients. One hundred and thirty-one patients with relapsed or primary refractory Hodgkin's disease were treated with a dose-intensive therapy protocol consisting of etoposide (2400 mg/m2 continuous intravenous infusion) cyclophosphamide (7200 mg/m2 intravenously), and carmustine (300-600 mg/m2 intravenously) CBVi. All patients had previously failed conventional chemoradiotherapy. Severe toxicities were related to infectious, hepatic, and pulmonary complications. Fatal, regimen-related toxicity was 19%; liver and lung dysfunction, as well as infection, were the most frequent problems. Ninety-one (69%) of the patients achieved a complete response (CR) (95% CI = 59% to 75%) after CBVi and autologous stem cell infusion. With a median follow-up of 5.1 years (range 3.0 to 9.5 years), overall and event-free survival are 44% (95% CI = 33% to 47%) and 38% (95% CI = 28% to 46%) respectively. While univariate analysis did not reveal a statistically significant variable to predict a better response, responsiveness to therapy demonstrated a trend. We conclude that CBVi is an effective therapy for relapsed or refractory Hodgkin's disease, producing long-term, durable remissions.

Dose-intensive chemotherapy for breast cancer with brain metastases: a case series.

Most clinical trials using dose-intensive chemotherapy exclude patients with brain metastases. This exclusion was based on anecdotal experience reflecting high treatment-related mortality. We analyzed the outcome of 11 patients with metastatic breast cancer who had brain metastases, diagnosed either before or during high-dose chemotherapy. In three patients, the death was attributed to non-central nervous system (CNS) regimen-related toxicity. Five patients died as a results of non-CNS disease progression. One patient died as a result of both CNS and non-CNS disease progression. Two patients are alive without disease progression with follow-up of 13.4 and 7.3 months, respectively. Of the five patients who have survived 1 year, four have hormone receptor expression and continued on antihormone therapy after high-dose therapy. These results are the first to show that breast cancer patients having brain metastases who receive high-dose chemotherapy do not experience more treatment-related complications or treatment failure as a result of the metastatic CNS disease. To this end, exclusion of these patients from high-dose therapy trials, especially those with expression of hormone receptors, needs to be reevaluated.

The transfusion needs of an autologous bone marrow transplant patient with IgA deficiency.

BACKGROUND: Transfusion management of the patient who is undergoing a marrow or peripheral blood stem and progenitor cell transplantation is often challenging. The situation is further complicated when the patient is IgA deficient with circulating anti-IgA. CASE REPORT: This report describes an approach to transfusion therapy primarily using red cells washed by automated techniques and cryopreserved autologous plateletpheresis components. Additional platelet support was provided with manually washed allogeneic plateletpheresis components. Autologous fresh-frozen plasma was collected concurrently, and IgA-deficient allogeneic units were ordered and kept in storage, but they were not needed during transplantation. The patient experienced no transfusion sequelae as a result of the IgA deficiency. CONCLUSION: With this approach, the transfusion needs of an IgA-deficient patient were adequately met during bone marrow transplantation.

Ex vivo expansion of CD34+ umbilical cord blood cells in a defined serum-free medium (QBSF-60) with early effect cytokines.

To investigate the clinically applicable conditions that support substantial expansion of both primitive and more mature hematopoietic cells of umbilical cord blood (UCB) for transplantation in adults, enriched CD34+ cells from 8 fresh UCB samples and 4 expanded UCB products were cultured in defined serum-free medium (QBSF-60) in the presence of a cytokine combination of SCF, Flt-3-ligand (FL), thrombopoietin (TPO), IL-3 for up to 2 weeks. Fresh medium with cytokines was supplemented or exchanged at day 4, day 7, and day 10. The proliferative response was assessed at day 7, day 10, and day 14 by evaluating the following parameters: nucleated cell (NC), clonogenic progenitors (colony-forming unit-granulocyte-macrophage [CFU-GM], burst-forming unit-erythrocyte [BFU-E], CFU-GEMM, and high-proliferative potential colony-forming cell [HPP-CFC]), immunophenotypes (CD34+ cells and CD34+ subpopulations), and LTCIC. Simultaneously numerical expansion of various stem/progenitor cells, including primitive CD34+CD38-HLA-DR- subpopulation and LTCIC, CD34+ cells, and clonogenic progenitors to mature nucleated cells, were continuously observed during the culture. An average 103.32 +/- 71.37 x 10(6) CD34+ cells (range 10.12 x 10(6)-317.9 x 10(6)) could be obtained from initial 1.72 +/- 1.13 x 10(6) UCB CD34+ cells after 10-14 days cultured under the described conditions. Sufficient CD34+ cells (>50.0 x 10(6)) for transplantation in adults would be available in all but one UCB collections after 10-14 days expansion. The expanded CD34+ cells sustained most of the in vitro characteristics of initial unmanipulated CD34+ cells, including clonogenic efficiency (of both primitive and committed progenitors), the proportion of CD34+CD38-HLA-DR- subpopulation, and the expansion potential. Initial addition of IL-3 to the cocktail of SCF + FL + TPO had positive effects on the expansion of both primitive and, especially, the more mature hematopoietic cells. It accelerated the expansion speed and shortened the optimal culture time from 14 days to 10 days. These results indicated that our proposed short-term culture system, consisting of QBSF-60 serum-free medium with a simple early acting cytokine combination of SCF + FL + TPO, could substantially support simultaneous expansion of various stem/progenitor cell populations involved in the different phases of engraftment. It would be a clinically applicable protocol for ex vivo expansion of CD34+ UCB cells.

Phase III study comparing methotrexate and tacrolimus (prograf, FK506) with methotrexate and cyclosporine for graft-versus-host disease prophylaxis after HLA-identical sibling bone marrow transplantation.

We report the results of a phase III open-label, randomized, multicenter trial comparing tacrolimus/methotrexate to cyclosporine/methotrexate for graft-versus-host disease (GVHD) prophylaxis after HLA-identical sibling marrow transplantation in patients with hematologic malignancy. The primary objective of this study was to compare the incidence of moderate to severe (grade II-IV) acute GVHD. Secondary objectives were to compare the relapse rate, disease-free survival, overall survival, and the incidence of chronic GVHD. Patients were stratified according to age (<40 v >/=40) and for male recipients of a marrow graft from an alloimmunized female. There was a significantly greater proportion of patients with advanced disease randomized to tacrolimus arm (P = . 02). The incidence of grade II-IV acute GVHD was significantly lower in patients who received tacrolimus than patients in the cyclosporine group (31.9% and 44.4%, respectively; P = .01). The incidence of grade III-IV acute GVHD was similar, 17.1% in cyclosporine group and 13.3% in the tacrolimus group. There was no difference in the incidence of chronic GVHD between the tacrolimus and the cyclosporine group (55.9% and 49.4%, respectively; P = .8). However, there was a significantly higher proportion of patients in the cyclosporine group who had clinical extensive chronic GVHD (P = . 03). The relapse rates of the two groups were similar. The patients in the cyclosporine arm had a significantly better 2-year disease-free survival and overall survival than patients in the tacrolimus arm, 50.4% versus 40.5% (P = .01) and 57.2% versus 46.9% (P = .02), respectively. The significant difference in the overall and disease-free survival was largely the result of the patients with advanced disease, 24.8% with tacrolimus versus 41.7% with cyclosporine (P = .006) and 20.4% with tacrolimus versus 28% with cyclosporine (P = .007), respectively. There was a higher frequency of deaths from regimen-related toxicity in patients with advanced disease who received tacrolimus. There was no difference in the disease-free and overall survival in patients with nonadvanced disease. These results show the superiority of tacrolimus/methotrexate over cyclosporine/methotrexate in the prevention of grade II-IV acute GVHD with no difference in disease-free or overall survival in patients with nonadvanced disease. The survival disadvantage in advanced disease patients receiving tacrolimus warrants further investigation.

Graft-versus-leukemia effects in T lineage and B lineage acute lymphoblastic leukemia.

T and B lineage ALL cells express different levels of HLA-class II antigens, which may serve as targets for graft-versus-host disease (GVHD) and graft-versus-leukemia (GVL). The object of this study was to determine whether GVL effects after HLA-identical sibling bone marrow transplantation differed in T and B lineage ALL. We studied 1132 patients with ALL of T lineage (n = 416) or of B lineage (cALLa+) (n = 716) transplanted in first (n = 605) or second (n = 527) remission with bone marrow from an HLA-identical sibling donor, between 1982 and 1992, and reported to the IBMTR by 165 teams. Cox proportional hazards regression models were used to determine the relative risk (RR) of relapse in patients with acute (grades II-IV) or chronic GVHD vs patients without GVHD. Acute and chronic GVHD were considered as time-dependent covariates. Patients transplanted in first and second remission were analyzed separately. GVHD decreased relapse risks to a similar extent in T and B lineage ALL. For first remission transplants, relative risks of relapse for patients with vs those without GVHD was 0.34 for T lineage ALL and 0.44 for B lineage ALL. Corresponding relative risks in second remission transplants were 0.54 and 0.61. This study confirms earlier findings of an antileukemia effect of GVHD in ALL. This effect was similar in T lineage and B lineage ALL, despite probable differences in HLA-class II antigen expression.

A detailed analysis of charges for hematopoietic stem cell transplantation at a children's hospital.

We analyzed hospital charges for pediatric hematopoietic stem cell transplantation (HSCT) to understand better the medical origin of these charges. Forty-nine patients undergoing HSCT at Kosair Children's Hospital between January 1992 and August 1995 had hospital charges analyzed by cost center, donor type and clinical outcome. Thirty-three autologous, two syngeneic and 14 allogeneic transplants were performed. Twenty-four transplants were performed for hematological malignancies, 22 for solid tumors, and three for non-malignant diseases. Pharmaceutical charges comprised the largest single component of total hospital charges (THC), accounting for 38.9%. Room charges were the next largest group at 33.7% of THC. Other cost centers, in order of magnitude, were central supply (7.9%), transfusion services (7.5%), laboratory (5.8%), microbiology (3.6%), miscellaneous (1.9%), and radiology (1.4%). Within the pharmaceutical cost center, colony-stimulating factors comprised the largest single item, making up 18% of total pharmacy charges and 7% of THC. Antibiotics were the second largest component, at 16% of pharmacy charges and 6% of THC. Patients transferred to the intensive care unit (ICU) had charges 68% greater than non-ICU patients. Allogeneic transplant patients had THC 35% greater than autologous transplant patients, but also a four-fold greater chance of becoming an ICU patient. THC for non-ICU allogeneic transplant patients were 18% greater than for autologous non-ICU patients. THC for allogeneic ICU patients were 21% greater than for autologous ICU patients. Patients who died of transplant-related toxicity prior to day 100 had THC 83% greater than those who survived beyond day 100. This is the first published comprehensive and detailed analysis of charges associated with hematopoietic stem cell transplantation. With increased emphasis on the provision of cost-effective care in both Europe and the USA, medical practices must be examined with the goal of reducing inefficiencies while preserving quality of care. Understanding the genesis of charges in expensive procedures such as stem cell transplantation is an initial step in cost containment.

Survival of patients with chronic myelogenous leukaemia relapsing after bone marrow transplantation: comparison with patients receiving conventional chemotherapy.

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 > or = 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 (P=0003). 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.

HLA-identical sibling bone marrow transplants vs chemotherapy for acute myelogenous leukemia in first remission.

There is controversy whether adults with acute myelogenous leukemia (AML) in first remission are best treated with chemotherapy or an HLA-identical sibling bone marrow transplant. We studied 1097 adults, 16-50 years old, with AML in first remission. Results of transplants from HLA-identical siblings reported to the International Bone Marrow Transplant Registry (IBMTR; n = 901) were compared with results of chemotherapy in comparable persons treated by the German AML Cooperative Group (GAMLCG; n = 196). Preliminary analyses identified subject- and disease-related variables differing between the cohorts and associated with treatment outcome within each cohort. We adjusted for these variables and differences in time-to-treatment in subsequent comparisons of treatment-related mortality, relapse, survival and leukemia-free survival (LFS). Five-year probability of treatment-related mortality was greater for transplants than chemotherapy (43% (95% confidence interval, 37-49%) vs 7% (3-11%); P< 0.0001). Five-year relapse probability was less for transplants than chemotherapy (24% (20-28%) vs 63% (55-71%); P< 0.0001). Five-year probability of survival was similar with transplants and chemotherapy (48% (43-53%) vs 42% (33-51%); P = 0.24). Five-year LFS probability was higher for transplants than chemotherapy (46% (42-50%) vs 35% (28-41%); P= 0.01). These data indicate that bone marrow transplants from HLA-identical siblings result in comparable survival but greater LFS than chemotherapy in adults with AML in first remission.

High-dose etoposide, cyclophosphamide and total body irradiation with allogeneic bone marrow transplantation for resistant acute myeloid leukemia: a study by the North American Marrow Transplant Group.

We evaluated the toxicity and efficacy of high-dose etoposide, cyclophosphamide and total body irradiation (TBI) followed by allogeneic bone marrow transplantation (BMT) for patients with resistant, acute myeloid leukemia (AML). Between 9/84 and 11/92 we treated 70 patients with etoposide (900-1800 mg/m2), cyclophosphamide (120-180 mg/kg) and TBI (1000-1200 cGy) followed by allogeneic BMT from histocompatible siblings. Forty patients were in untreated first relapse. Median time from diagnosis to transplant was 10 months. Toxicity was similar to that observed with cyclophosphamide/TBI with the median duration of neutropenia (ANC < 500/microliters) being 19 days (range 10-27) and the median duration of thrombocytopenia being 23 days (range 13-173). Twenty-three patients remain in continuous complete remission at a median of 56 months after transplant (range 36-132 months). Probabilities of disease-free survival, persistent/recurrent disease and transplant related mortality are .32, .47, and .37 respectively. Multivariate analysis indicated that grade > or = 2 acute graft-vs-host disease and transplant in untreated first relapse were associated with increased DFS due to reduced relapse risk. We conclude that high-dose etoposide with cyclophosphamide and TBI followed by allogeneic BMT is effective therapy for resistant AML, producing durable remission in approximately one-third of those treated. Disease persistence or recurrence was the major cause of treatment failure. Further improvement in DFS following allogeneic BMT for resistant AML might be achieved by using less intensive GVHD prophylaxis or through infusion of donor peripheral blood cells in patients who fail to develop significant acute GVHD.

Dose-intensive chemotherapy with etoposide-cyclophosphamide for advanced breast cancer. North American Marrow Transplant Group.

Bone marrow and extensive bone involvement have limited the use of chemotherapy with stem cell support for treatment of women with metastatic breast cancer. The toxicity and efficacy of dose-intensive chemotherapy were studied using etoposide and cyclophosphamide without a stem cell support regimen for women with advanced breast cancer. The regimen was well tolerated, with treatment-related mortality similar to dose-intensive therapy with stem cell support. The overall 58% response rate is comparable to the response rate with dose-intensive chemotherapy regimens using stem cell support. The extent of disease, responsiveness to standard therapy, and dose of etoposide affected the response rate. Hematopoietic recovery was fairly prompt and was generally unaffected by the use of hematopoietic growth factors or the presence of breast cancer cells in the marrow. The use of stem cells or recombinant human interleukin-3 (rhIL-3) in combination with recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) resulted in some benefit in neutrophil recovery. It was concluded that in many women with advanced breast cancer, a dose-intensive regimen of etoposide and cyclophosphamide results in response or stabilization of disease. Hematopoietic recovery, particularly platelet recovery, may be accelerated by a combination of rhIL-3 and rhGM-CSF.

High-dose ara-C in older adults with acute leukemia.

The concept of high-dose ara-C (HIDAC) was introduced 15 years ago. Phase I studies established a maximum tolerated dose of 3 g/m2, given every 12 hours for 12 doses. Because dermatologic, gastrointestinal, and central nervous system toxicities were dose-limiting in patients over age 50, a reduction from the maximal dose was suggested. Initial studies with refractory or resistant acute myelogenous leukemia (AML), with or without anthracyclines, demonstrated a significant antileukemic effect of HIDAC, with about 60 percent of patients achieving a complete response. Studies by our group and others have established that older patients can be successfully treated with HIDAC, probably with some added benefit in combining dose-intensive regimens.