Effect of aldehyde dehydrogenase inhibitors on the ex vivo sensitivity of human multipotent and committed hematopoietic progenitor cells and malignant blood cells to oxazaphosphorines.

The ex vivo sensitivity of human multipotent and committed hematopoietic progenitor cells and several cultured human malignant blood cell lines to analogues of "activated" cyclophosphamide, namely, 4-hydroperoxycyclophosphamide and mafosfamide, and to phosphoramide mustard was quantified with and without concurrent exposure to an inhibitor of aldehyde dehydrogenase activity, namely, disulfiram, cyanamide, diethyldithiocarbamate, or ethylphenyl(2-formylethyl)phosphinate. Inhibitors of aldehyde dehydrogenase activity potentiated the cytotoxic action of 4-hydroperoxycyclophosphamide and mafosfamide toward all of the hematopoietic progenitors; they did not potentiate the cytotoxic action of phosphoramide mustard toward these cells. Potentiation of the cytotoxic action of mafosfamide toward cultured human malignant blood cells was minimal. Spectrophotometric assay revealed little NAD-linked aldehyde dehydrogenase activity present in the cultured human tumor cell lines as compared to that found in normal mouse liver or oxazaphosphorine-resistant L1210 cells. Cellular aldehyde dehydrogenases are known to catalyze the oxidation of 4-hydroxycyclophosphamide/aldophosphamide, the major intermediate in cyclophosphamide bioactivation, to the relatively nontoxic acid, carboxyphosphamide. Thus, our findings indicate that human multipotent hematopoietic progenitor cells contain the relevant aldehyde dehydrogenase activity, the relevant activity is retained upon differentiation to progenitors committed to the megakaryocytoid, granulocytoid/monocytoid, and erythroid lineages, and the relevant activity may be lost or diminished upon transformation of hematopoietic progenitors to malignant cells.

Unrelated-donor bone marrow transplantation for Philadelphia chromosome-positive chronic myelogenous leukemia in children.

PURPOSE: Bone marrow transplantation (BMT) for Philadelphia chromosome-positive (Ph1) chronic myelogenous leukemia (CML) results in a 55% to 64% disease-free survival (DFS) rate in 20% to 30% of cases with a matched-sibling donor (MSD). Studies that include primarily adults with CML, using unrelated-donor (URD) BMT, have expanded this option to those without an MSD. We review and compare the efficacy of URD and MSD BMT in children with Ph1 CML. PATIENTS AND METHODS: Eleven children with URD BMTs were reviewed and compared with 11 children with MSD BMTs for Ph1 CML. Among the URD BMT recipients, there were three with fully matched marrows and 10 with advanced CML. The median time from diagnosis to transplant was 2.6 years. Among the MSD BMT recipients, 11 had fully matched marrows and five had advanced CML. The median time from diagnosis to BMT was 0.7 years. All received non-T-depleted marrows after cyclophosphamide and fractionated total-body irradiation. RESULTS: Both groups had similar engraftment times. Late graft failure occurred in two URD patients. Graft-versus-host disease (GVHD), > or = grade II, was similar in both groups (77% for URD BMT, 45% for MSD BMT), although more severe acute disease and more persistent chronic disease was seen in the URD group. The Kaplan-Meier estimate of DFS was 45% +/- 15% (SE) and 78% +/- 14% (SE) in the URD and MSD groups, respectively, at 3 years. All had Karnofsky scores of more than 70%, except one URD patient debilitated from GVHD. CONCLUSION: CML is eventually fatal to all patients without BMT. The high survival rate seen among children who receive a URD BMT, despite several adverse factors, opens this important therapeutic option to those without an MSD.

Allogeneic bone marrow transplantation for acute lymphoblastic leukemia in remission: prolonged survival associated with acute graft-versus-host disease.

Forty remission patients with high-risk acute lymphoblastic leukemia (ALL) underwent matched allogenic bone marrow transplantation (BMT) following preparation with cyclophosphamide and fractionated total body irradiation (TBI). As of March 1987, the median follow-up is more than 3 1/2 years. Thirteen patients are alive (11 relapse free) between 2 and 4 1/2 years post-BMT. Neither age, sex, remission number, prior extramedullary leukemia, nor WBC at diagnosis of ALL was statistically significant as a predictor of relapse-free survival. The development of acute graft-v-host disease (GVHD) in 17 patients was found, with time-dependent Cox regression analysis, to be associated with a significant reduction in post-BMT relapse risk (P = .04) and improved disease-free survival (P = .11). A prospective, randomized trial of maintenance chemotherapy with oral methotrexate and mercaptopurine did not demonstrate improvement in relapse risk or survival for those assigned maintenance chemotherapy (P = .7). These results suggest that allogeneic BMT can result in extended relapse-free survival for some patients with high-risk ALL. More effective preparative chemoradiotherapy and exploitation of the apparent graft-v-leukemia effect may be useful in future trials.

Intraocular retinoblastoma group V: an analysis of prognostic factors.

A retrospective analysis of the University of Minnesota (Minneapolis) experience with retinoblastoma is presented. Seventy-five patients were diagnosed with retinoblastoma between 1958 and 1983, of which 53 (71%) had at least one Reese-Ellsworth group V eye. Nineteen group V patients and one group II patient developed extraocular disease recurrence. The cumulative actuarial rate of recurrence at 12 years was 36% for patients with group V disease. The median time from diagnosis to recurrence for unilateral patients was seven months and for bilateral patients 28 months (P = .001). Patients developing extraocular disease had a 10-year actuarial survival rate postrecurrence of 34%. The four long-term survivors of extraocular recurrences had had isolated orbital or local soft tissue recurrences only. Features of group V patients associated with extraocular recurrences were identified by univariate life table analyses. Clinical poor-risk factors included the nongenetic form of the disease (P = .03) and male sex (P = .02). Pathologic poor risk factors included rubeosis (P = .01), undifferentiated histology (P = .03), large tumor size (P = .05), and intraocular extension to the anterior segment (P = .02), retinal pigment epithelium (P = .03), choroid (P less than .001), and optic nerve beyond the lamina cribrosa (P = .02). Treatment-associated poor-risk factors included an optic nerve length of less than 5 mm removed at enucleation (P = .003). Multivariate life table analyses demonstrated the following parameters to be independent poor-prognostic factors: optic nerve length of less than 5 mm removed at enucleation (P = .001), optic nerve involvement (P = .004), and large tumor size (P = .01). These results will help to identify patients with retinoblastoma who are at greatest risk for extraocular recurrence.

Successful reinduction of patients with acute lymphoblastic leukemia who relapse following bone marrow transplantation.

At the present time, there is limited information on the outcome of patients with acute lymphoblastic leukemia (ALL) who relapse after bone marrow transplantation (BMT). Intuitively, it might be expected that leukemia recurring after BMT would be refractory to further treatment. In an attempt to improve survival in patients with ALL who relapse after BMT, we used standard chemotherapy for reinduction and maintenance. Of 65 patients who relapsed following allogeneic, autologous, or syngeneic BMT, 12 elected to receive no further chemotherapy, and their median survival from relapse was 36 days (range 13 to 167 days). The 53 patients who received therapy had a significantly longer median survival of 168 days (range 18 days to 4.7 years). With multidrug induction regimens there were 29 of 52 (56%) complete remissions. Six patients are currently alive, with two off therapy. In the patients who received therapy, the following factors were independent predictors of prolonged survival: longer time from BMT to relapse; younger age at diagnosis; and the use of a preparative regimen containing fractionated total body irradiation. In conclusion, leukemia recurring after BMT remains sensitive to standard therapy in many patients. We recommend that patients with ALL who relapse after BMT receive reinduction and maintenance therapy as additional good quality survival time is achieved in patients who attain a remission.

Phase I trial of 13-cis-retinoic acid in children with neuroblastoma following bone marrow transplantation.

PURPOSE: Treatment of neuroblastoma cell lines with 13-cis-retinoic acid (cis-RA) can cause sustained inhibition of proliferation. Since cis-RA has demonstrated clinical responses in neuroblastoma patients, it may be effective in preventing relapse after cytotoxic therapy. This phase I trial was designed to determine the maximal-tolerated dosage (MTD), toxicities, and pharmacokinetics of cis-RA administered on an intermittent schedule in children with neuroblastoma following bone marrow transplantation (BMT). PATIENTS AND METHODS: Fifty-one assessable patients, 2 to 12 years of age, were treated with oral cis-RA administered in two equally divided doses daily for 2 weeks, followed by a 2-week rest period, for up to 12 courses. The dose was escalated from 100 to 200 mg/m2/d until dose-limiting toxicity (DLT) was observed. A single intrapatient dose escalation was permitted. RESULTS: The MTD of cis-RA was 160 mg/m2/d. Dose-limiting toxicities in six of nine patients at 200 mg/m2/d included hypercalcemia (n = 3), rash (n = 2), and anemia/thrombocytopenia/emesis/rash (n = 1). All toxicities resolved after cis-RA was discontinued. Three complete responses were observed in marrow metastases. Serum levels of 7.4 +/- 3.0 mumol/L (peak) and 4.0 +/- 2.8 mumol/L (trough) at the MTD were maintained during 14 days of therapy. The DLT correlated with serum levels > or = 10 mumol/L. CONCLUSION: The MTD of cis-RA given on this intermittent schedule was 160 mg/m2/d. Serum levels known to be effective against neuroblastoma in vitro were achieved at this dose. The DLT included hypercalcemia, and may be predicted by serum cis-RA levels. Monitoring of serum calcium and cis-RA levels is indicated in future trials.

Unrelated donor bone marrow transplantation for children with acute leukemia.

PURPOSE: To test the use of unrelated donor bone marrow transplantation (URD BMT) to cure children with high-risk acute leukemias. PATIENTS AND METHODS: Between June 1985 and December 1994, 50 children with acute leukemia (15 acute myelogenous leukemia [AML], 35 acute lymphoblastic leukemia [ALL]; 22 greater than second complete remission [CR]) received BMT from a URD at the University of Minnesota. Ages ranged from 0.9 to 17.5 years (median, 8.8). Median follow-up is 2.1 years (range, 1 to 7.3). Thirty patients (60%) received bone marrow fully matched at HLA-A,B and DRB1; 20 (40%) received bone marrow with a major or minor mismatch at a single HLA-A or B locus. RESULTS: The median time to neutrophil engraftment was day 24 (range, 14 to 42 days) in those receiving matched and day 25 (range, 15 to 32 days) in those receiving mismatched marrow (P = .35). The incidence of grades III to IV graft-versus-host disease (GVHD) was 23% (95% confidence interval [CI], 7% to 39%) in matched and 32% (95% CI, 8% to 52%) in HLA-mismatched patients (P = .57). The incidence of chronic GVHD was 50% (95% CI, 28% to 72%) in matched and 57% (95% CI, 23% to 91%) in mismatched patients (P = .80). Disease-free survival for patients with ALL is 37% (95% CI, 21% to 53%) at 1 year and 30% (95% CI, 15% to 46%) at 2 years; for patients with AML, 53% (95% CI, 28% to 78%) at 1 year and 33% (95% CI, 6% to 60%) at 2 years. CONCLUSION: URD BMT is an effective treatment for children with poor-prognosis acute leukemia and should be considered for all high-risk patients. Early referral of patients is strongly recommended.

Allogeneic versus autologous purged bone marrow transplantation for neuroblastoma: a report from the Childrens Cancer Group.

PURPOSE: We have compared the toxicity, relapse rate, and progression-free survival (PFS) of high-risk neuroblastoma patients receiving identical induction therapy and myeloablative chemotherapy plus total-body irradiation (TBI) followed by allogeneic or autologous purged bone marrow transplantation (BMT). PATIENTS AND METHODS: Fifty-six patients with high-risk neuroblastoma underwent BMT at investigator and parent option if they did not have progressive disease after induction chemotherapy with cisplatin, cyclophosphamide, doxorubicin, and etoposide. After surgery and local radiation to residual tumor, myeloablative therapy consisting of etoposide, melphalan, cisplatin, and TBI was given followed by BMT. Patients with human leukocyte antigen (HLA)-compatible siblings received allogeneic bone marrow (n = 20). The remaining patients (n = 36) received autologous bone marrow that had undergone multimodality purging and had no remaining detectable tumor cells by immunocytology. RESULTS: Four of 20 allogeneic patients had a treatment-related death, compared with three of 36 autologous patients (P = .21). The relapse rate among allogeneic BMT patients was 69%, compared with 46% for autologous BMT patients (P = .14). The estimated PFS rates 4 years after BMT were 25% for allogeneic BMT patients and 49% for autologous BMT patients (P = .051). CONCLUSION: Overall outcome for patients with neuroblastoma given this same induction therapy followed by autologous purged marrow was similar to that with allogeneic marrow, although bias in patients selection cannot be excluded in a nonrandomized comparison.

Results of treatment of malignant germ cell tumors in 93 children: a report from the Childrens Cancer Study Group.

We report treatment results in 93 children entered on study from 1978 to 1984 with malignant germ cell tumors (MGCTs), excluding dysgerminoma and tumors of the testis or brain. The estimated 4-year survival and event-free survival (EFS) for all 93 patients were 54% and 49%, respectively. For 30 children with ovarian tumors, the estimated 4-year survival was 67% and EFS was 63%. For 63 children with nongonadal tumors, survival and EFS were 48% and 42%, respectively. The comparison of EFS between ovarian and nongonadal tumors was significant at P = .03. The treatment plan included a second-look surgical procedure after 18 weeks of chemotherapy. Over half of 36 patients evaluated as having a residual mass present immediately before second-look surgery had no malignant tumor after review of surgical specimens. Age greater than 11 years at diagnosis, incomplete removal of tumor at first surgery, and more than one structure or organ involved at diagnosis increased the risk for adverse event. The histologic subtype of the primary tumor was not related to outcome. Diagnosis was verified by independent pathologic review, and treatment was uniform. Seventeen percent of all registered patients (21 of 127) were excluded because of ineligible pathologic diagnoses; sixty percent (13 of 21) were immature teratomas.

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.

Stimulation of human committed bone marrow stem cells (CFU-GM) by chloramphenicol.

Chloramphenicol, an antibiotic associated with reversible bone marrow suppression and fatal aplastic anemia, was found to increase human bone marrow granulocyte-macrophage colonies (CFU-GM) in vitro. Maximal stimulation was at a concentration of 1.0 micrograms/ml (3.1 microM), with inhibition at concentrations greater than 10 micrograms/ml. This effect was noted in normal donors and in children with neutropenia of various etiologies. Stimulation was ablated by depletion of bone-marrow-adherent cells and was restored by addition of peripheral-blood-adherent mononuclear cells. The stimulatory effect appears to be specific for chloramphenicol, as numerous structural analogues of chloramphenicol, including its three stereoisomers, did not show stimulation. The stimulation was present at plateau concentrations of colony-stimulating activity, suggesting that the stimulatory effect is not due to elaboration of excess colony-stimulating activity by chloramphenicol. We hypothesize that low concentrations of chloramphenicol stimulate CFU-GM by a highly specific interaction with adherent mononuclear cells and elaboration of an undefined growth factor.

Role of myeloablative therapy in improved outcome for high risk neuroblastoma: review of recent Children's Cancer Group results.

The use of new strategies for dose intensification using peripheral blood stem cell or autologous purged bone marrow rescue has raised expectations for cure in advanced neuroblastoma, although conflicting reports exist regarding the efficacy of these approaches. Using risk groups based on both biological and clinical staging, the Children's Cancer Group (CCG) has conducted a series of pilot studies to test new induction, consolidation and myeloablative regimens to attempt to improve outcome. We summarise below the outcome and prognostic factor analysis for the pilot chemotherapy trial, CCG-(CCG-321P2), and the use of high dose myeloablative chemoradiotherapy with allogeneic (CCG-321P1) or autologous purged bone marrow rescue (CCG-321P3) for high risk neuroblastoma patients who were progression-free at the end of induction chemotherapy. After autologous bone marrow transplantation (ABMT), progression-free survival (PFS) at 4 years was 38% (median follow-up 4 years). Prognostic factors for relapse after ABMT included pre-BMT disease status, bone marrow tumour content at harvest, extent of primary resection at diagnosis, and time to ABMT. MYCN amplification, age, stage, and pre-BMT myeloablative regimen were not significant. Allogeneic BMT did not have a better outcome than ABMT. In a retrospective, non-randomised comparison of ABMT and chemotherapy, there was a significant difference in PFS for stage IV patients. High risk subgroups possibly benefiting from ABMT could be identified, including those with tumour MYCN amplification, over 2 years at diagnosis, and those not in complete remission at the end of induction. A randomised prospective trial comparing myeloablative therapy with ABMT to continuous infusion consolidation chemotherapy is currently underway in CCG to determine the relative benefit.

Thyroid dysfunction among long-term survivors of bone marrow transplantation.

Thyroid function studies were followed serially in 27 long-term survivors (median 33 months) of bone marrow transplantation. There were 15 men and 12 women (median age 13 1/12 years, range 11/12 to 22 6/12 years). Aplastic anemia (14 patients) and acute nonlymphocytic leukemia (eight patients) were the major reasons for bone marrow transplantation. Pretransplant conditioning consisted of single-dose irradiation combined with high-dose, short-term chemotherapy in 23 patients, while four patients received a bone marrow transplantation without any radiation therapy. Thyroid dysfunction occurred in 10 of 23 (43 percent) irradiated patients; compensated hypothyroidism (elevated thyroid-stimulating hormone levels only) developed in eight subjects, and two patients had primary thyroid failure (elevated thyroid-stimulating hormone levels and low T4 index). The abnormal thyroid studies were detected a median of 13 months after bone marrow transplantation. The four subjects who underwent transplantation without radiation therapy have remained euthyroid (median follow-up two years). The only variable that appeared to correlate with the subsequent development of impaired thyroid function was the type of graft-versus-host disease prophylaxis employed; the irradiated subjects treated with methotrexate alone had a higher incidence of thyroid dysfunction compared to those treated with methotrexate combined with antithymocyte globulin and prednisone (eight of 12 versus two of 11, p less than 0.05). The high incidence and subtle nature of impaired thyroid function following single-dose irradiation for bone marrow transplantation are discussed.

Fatal veno-occlusive disease of the liver following high dose chemotherapy, irradiation and bone marrow transplantation.

In two patients fatal veno-occlusive disease of the liver developed after bone marrow transplantation for underlying malignancies. Both had received significant pretransplant chemotherapy, including cystosine arabinoside, and total body irradiation. The diagnosis of veno-occlusive disease should be considered in patients in whom hepatomegaly, ascites and deteriorating liver function tests develop after they have received cancer chemotherapy.

Bone marrow transplantation for non-Hodgkin's lymphoma in children and young adults. A pilot study.

Allogeneic bone marrow transplantation was performed in 10 patients with disseminated Burkitt's lymphoma or poor-prognosis T-cell lymphoblastic lymphoma. All patients received a cytoreduction regimen consisting of cyclophosphamide, cytosine arabinoside, bis-chloro-nitroso-urea, and total-body irradiation. Eight patients received marrow from HLA-matched sibling donors. One patient received marrow from a parent donor and one patient died during initial cytoreduction and did not undergo total-body irradiation or marrow infusion. Six patients had Burkitt's lymphoma stages III and IV at diagnosis, and three of the six are alive at 18, 28, and 73 months. Four patients had T-cell lymphoblastic lymphoma, stages III and IV at diagnosis, and two of the four are alive at 29 and 49 months. Overall survival in the nine patients who underwent transplantation is 56 percent by life-table analysis. Follow up for the surviving patients ranges from 18 to 73 months (median 29 months). All five survivors are at home with unmaintained remissions.

Autologous bone marrow transplantation in non-Hodgkin's lymphoma: monoclonal antibodies plus complement for ex vivo marrow treatment.

PURPOSE: Patients with non-Hodgkin's lymphoma who fail to achieve a complete remission or who relapse are rarely cured with conventional therapies. For this group of patients, intensive therapy and bone marrow rescue may be curative. Our goal was to assess the effects of autologous transplantation in patients with B-cell lymphomas and a poor prognosis. To avoid occult or overt contamination with lymphoma, monoclonal antibodies BA-1, BA-2, and BA-3 were used for ex vivo marrow treatment. PATIENTS AND METHODS: Seventeen patients underwent intensive therapy and autologous bone marrow transplant using the aforementioned marrow. Ten of the 17 patients (Group I) had disease that was in complete or partial remission. The other seven patients either had disease that was not responsive to treatment or had bone marrow transplant as their initial therapy at relapse. RESULTS: The ex vivo treatment did not adversely affect engraftment. For those patients who could be evaluated, the median time to white cell engraftment was 24 days; the median durations of red cell and platelet support were 24 and 29 days, respectively. Eleven of the 17 patients had complete remissions at the evaluation 28 days after transplant. Three patients subsequently experienced a relapse, three died while their disease was in complete remission, and five are alive and disease-free 405 to 1,674 days after transplant. Group I patients had an estimated 40 percent disease-free survival rate at three years compared with 0 percent for Group II patients (p less than 0.01). CONCLUSION: Our data support autologous bone marrow transplantation as an important treatment modality for the non-Hodgkin's lymphomas. With the current preparative regimens available, however, its use should be limited to patients with disease that is still responding to conventional therapies.

Immunophenotype predicts radiation resistance in T-lineage acute lymphoblastic leukemia and T-lineage non-Hodgkin's lymphoma.

In the preclinical arm of our study, the radiobiologic features of primary malignant cells from newly diagnosed and relapsed T-lineage acute lymphoblastic leukemia/non-Hodgkin's lymphoma patients were analyzed using clonogenic assays. A marked heterogeneity existed relative to the intrinsic radiation sensitivity of clonogenic T-lineage ALL/NHL cells from 42 patients. The mean SF2 (surviving fraction at 200 cGy) and alpha values (initial slope of the survival curve) were 0.36 +/- 0.04, and 0.558 +/- 0.079 Gy-1. Fourteen cases had SF2 values of > or = 0.50 and alpha values of < or = 0.2 Gy-1, consistent with a marked intrinsic radiation resistance at the level of clonogenic leukemia/lymphoma cells. Of these 14 radiation resistant cases, 12 were CD3+. Furthermore, the SF2 and D0 values of the 28 CD3+ cases were significantly higher than the SF2 and D0 values of the 14 CD3- cases (SF2: 0.441 +/- 0.048 versus 0.189 +/- 0.045, p = 0.002; D0: 189.6 +/- 26.3 cGy versus 108.7 +/- 18.2 cGy, p = 0.047) and CD3+ cases had smaller alpha values than CD3- cases (0.454 +/- 0.087 versus 0.765 +/- 0.152, p = 0.06). Thus, clonogenic cells from CD3+ T-lineage ALL/NHL patients were more resistant to radiation than clonogenic cells from CD3- T-lineage ALL/NHL patients. In the clinical arm of our study, 33 T-lineage ALL/NHL patients received autologous bone marrow transplants during remission. Pretransplant conditioning consisted of total body irradiation combined with high dose chemotherapy. The expression of CD3 antigen predicted the outcome of relapsed T-lineage ALL/NHL patients undergoing autologous bone marrow transplantation following total body irradiation plus high dose chemotherapy. Overall, the Kaplan-Meier estimate and standard error of the probability of remaining in remission at 3.5 years was 11 +/- 9% with a median relapse-free interval of 102 days. The disease-free survival at 3.5 years was 8 +/- 7% with a median disease-free survival time of 96 days. Notably, the expression of CD3 antigen on T-lineage ALL/NHL cells correlated with the probability of relapse after bone marrow transplantation. While 16 of 19 CD3+ patients relapsed after bone marrow transplantation, only 3 of 8 CD3- patients relapsed. The Kaplan-Meier estimates and standard errors of the probability of remaining in remission at 1 year after bone marrow transplantation were 7 +/- 6% (median relapse-free interval = 74 days) for CD3+ patients (n = 19) and 63 +/- 17% for CD3- patients (n = 8) (p = 0.006).(ABSTRACT TRUNCATED AT 400 WORDS)

Intermittent central nervous system irradiation and intrathecal chemotherapy for central nervous system leukemia in children.

Between 1979 and 1985, nine children with recurrent CNS leukemia who had previous radiation of more than 1800 cGy to the brain were treated with intermittent central nervous system irradiation and intrathecal chemotherapy (IIIC). There was no isolated CNS recurrence. Three patients died; one from generalized recurrent disease, two from complications associated with bone marrow transplantation. Six patients are alive without evidence of disease between 9 years and 2 4/12 years from the diagnosis of recurrent CNS leukemia. This experience suggests that IIIC may be an effective treatment for preventing the recurrence of CNS leukemia with minimal side effects.

Autologous bone marrow transplantation in acute myeloid leukemia: the University of Minnesota experience.

PURPOSE: To report the outcome of autologous bone marrow transplantation for patients with acute myeloid leukemia (AML) in first or greater complete remission (CR) treated by autologous bone marrow transplantation using two different preparatory regimens. METHODS AND MATERIALS: Between September 1986 and August 1993, 75 patients with AML ranging in age from 6 months to 58 years underwent autologous bone marrow transplantation using previously harvested and frozen unpurged (n = 6) or 4-hydroperoxycyclophosphamide purged marrows (n = 69). Patients were in first CR (n = 44) or beyond first CR (n = 31). The preparative regimen consisted of 120 mg/kg of cyclophosphamide (CY) and 1320 cGy total body irradiation (TBI) in eight fractions over 4 days (CY/TBI) in 29 patients; and 16 mg/kg of Busulfan (BU) and 200 mg/kg of CY (BU/CY) in 46 patients. Thirty-five of these 75 patients (18 CY/TBI and 17 BU/CY) were part of a randomized trial comparing the two preparative regimens. RESULTS: At 2 years, overall survival and disease-free survival (DFS) were 49% [95% confidence interval (C.I.) 37-61%] and 43% (95% C.I. 32-55%), respectively. Patients in first CR had a significantly better outcome than patients beyond first CR with an estimated 2-year DFS of 59% (95% C.I. 44-74%) vs. 21% (95% C.I. 5-36%, log-rank p = 0.0001), respectively. For patients conditioned with CY/TBI, the estimated 2-year DFS was 52% compared to 39% for BU/CY (log-rank p = 0.35). Estimated 2-year relapse rates were 44% vs. 56% (log-rank p = 0.40), respectively. For patients in first CR, no differences in DFS were observed between the two regimens (2-year estimates 69% vs. 55% log-rank p = 0.52). Patients beyond first CR had a significantly improved DFS with the CY/TBI regimen (2-year estimates of 38% vs. 7%, log-rank p = 0.04). No differences were found between the two regimens in terms of time to WBC engraftment, absolute neutrophil count of > 500, incidence of bacteremias, or median time to hospital discharge. Interstitial pneumonitis developed in two patients (one BU/CY, one CY/TBI) and venoocclusive disease developed in seven BU/CY patients (Fishers exact test p = 0.04). CONCLUSIONS: For patients beyond first CR, the CY/TBI regiment provided a better outcome, with a significantly better disease-free survival and less venoocclusive disease. For patients in first CR, no significant difference between the two regimens was found. The high relapse rate, especially for patients with advanced disease, emphasizes the need for early transplantation and for new strategies to improve outcome.

Randomized comparison of cyclophosphamide-total body irradiation versus busulfan-cyclophosphamide conditioning in autologous bone marrow transplantation for acute myeloid leukemia.

PURPOSE: This prospective trial of autologous bone marrow transplantation for acute myeloid leukemia was undertaken to compare the outcome using two different preparative regimens. METHODS AND MATERIALS: Between October 1987 and April 1993, 35 patients with acute myeloid leukemia in first (n = 12) or greater (n = 23) remission were stratified by remission status and randomized to undergo 4-hydroperoxycyclophosphamide purged autologous bone marrow transplantation after either cyclophosphamide (120 mg/kg) and total body irradiation (1320 Gy in eight fractions over 4 days) (CY/TBI), or busulfan (16 mg/kg) and cyclophosphamide (200 mg/kg) (BU/CY) conditioning. RESULTS: At 2 years, overall survival and disease-free survival were 39% (95% confidence intervals (CI) 22-57%) and 36% (95% CI 19-52%), respectively. Patients in first complete remission had a significantly better outcome with a 2-year disease free survival of 57% (95% CI 28-86%) compared to others at 24% (95% CI 6-43%, log rank p = 0.048). For patients conditioned with CY/TBI, the estimated 2-year disease-free survival was 50% compared to 24% for patients conditioned with BU/CY (log rank p = 0.12). Estimated 2-year relapse rates were 43% vs. 70% (log rank p = 0.17), respectively. For patients in first complete remission no differences in disease-free survival (2-year estimates 67% vs. 50%, log rank p = 0.69), between the two regimens were observed. For patients in greater than first complete remission there was a trend towards improved disease-free survival in the CY/TBI arm (2-year estimates 42% vs. 9%, log rank p = 0.06). There were no differences in time to white blood cell count (WBC) engraftment, absolute neutrophil count of > 500, incidence of bacteremias, or median time to hospital discharge between the two regimens. Acute toxicities were similar. Interstitial pneumonitis developed in two patients (one on each arm), while veno occlusive disease developed in three BU/CY patients, but none of the CY/TBI patients (log rank p = 0.07). CONCLUSIONS: Cyclophosphamide-total body irradiation provided an equivalent or better outcome to BU/CY, particularly in advanced patients, and should remain the standard by which new regimens are judged. The high relapse rate with both regimens, especially patients who were in greater than in first complete remission, emphasizes the need for early transplant and for new strategies to improve outcome.