A prospective randomized comparison of total body irradiation-etoposide versus busulfan-cyclophosphamide as preparatory regimens for bone marrow transplantation in patients with leukemia who were not in first remission: a Southwest Oncology Group study

Two novel preparatory regimens for conditioning of patients with leukemia for allogeneic bone marrow transplantation (BMT) from histocompatible sibling donors have been tested in a phase III trial under the auspices of the Southwest Oncology Group (SWOG 8612). These two regimens consisted either of fractionated total body irradiation and etoposide (FTBI/VP-16) or high-dose busulfan with cyclophosphamide (BU/CY). Only patients who had failed prior conventional management at least once were study eligible, ie, no patients with acute leukemia in first remission (CR) or in first chronic phase (CP) of chronic myelogenous leukemia (CML) participated. Patients were stratified according to the following risk criteria: "good-risk" patients were those who were in second CR of their acute leukemia or in accelerated phase (AP) of CML; "poor-risk" patients had further advanced stages of leukemia. During a 52-month period, 131 patients were registered of whom 122 (93%) were study eligible. Sixty-one eligible patients were randomized to the FTBI/VP-16 arm and 61 to the BU/CY regimen. Of these 122 patients, 114 (93%) proceeded to BMT according to protocol. Posttransplant immunosuppression to prevent graft-versus-host disease (GVHD) consisted of cyclosporine and prednisone (CSA/PSE). Neither overall survival nor disease-free survival (DFS) differed significantly between the two treatment groups (P = .89 and .69, respectively). Estimated DFS for "good-risk" patients who had been prepared with the FTBI/VP-16 regimen was 55% +/- 11%, as compared with patients treated with BU/CY whose DFS figure was 34% +/- 10% (P = .30). For "poor-risk" candidates, the DFS rates at 24 months were 17% +/- 6% (for FTBI/VP-16) and 24% +/- 8% (for BU/CY), respectively (P = .81). These figures do not differ significantly, especially in view of the fact that the "good- risk" patients prepared with the FTBI/VP-16 regimen were younger than those treated with BU/CY. Both regimens were well tolerated with no regimen-related deaths encountered during the 6-week period after BMT. This study also confirmed the efficacy of the CSA/PSE combination in the prevention of GVHD with 23 of 113 (20%) of BMT recipients developing moderate to severe acute GVHD. The leading cause for treatment failure was leukemic relapse (45 of the 114 BMT recipients suffered a recurrence of their leukemia), whereas 38 patients died without evidence of relapse. Thirty-one patients are alive and in continued CR after marrow transplantation; four are alive in relapse.(ABSTRACT TRUNCATED AT 400 WORDS)     

Human herpesvirus 6: infection and disease following autologous and allogeneic bone marrow transplantation

Human herpesvirus 6 activity (HHV-6) was studied in 15 allogeneic and 11 autologous marrow transplantation patients. After transplantation, HHV-6 was isolated from the peripheral blood mononuclear cells of 12 of 26 patients (6 allogeneic and 6 autologous). All isolates were variant B. Eleven of 26 and 12 of 19 patients showed salivary shedding of HHV-6 DNA before and after transplantation, respectively. The antibody titer increased in 7 of 26 patients. Thus, 23 of 26 patients showed evidence of active HHV-6 infection either by virus isolation, salivary shedding, or increases in antibody titers. The fraction of saliva specimens positive in 19 patients was negatively associated with their antibody titers (P= .005). The proportion of cultures positive increased after transplantation (P = .007). Sinusitis was associated with HHV-6 isolation in autologous recipients (P= .002). In allogeneic patients, active human cytomegalovirus infection was associated with HHV-6 isolation (P = .04). No association was observed between HHV-6 infection and GVHD, pneumonia, delay in engraftment, or marrow suppression. Of the 120 clinical events analyzed in 26 patients, HHV-6 was defined as a probable cause of 16 events in 9 patients based on the propinquity of HHV-6 activity and the clinical event plus the absence of other identified causes of the event.     

Hereditary antithrombin deficiency: heterogeneity of the molecular basis and mortality in Dutch families

We studied the molecular basis and genetic heterogeneity of hereditary antithrombin (III) deficiency in nine Dutch families. Polymerase chain reaction (PCR) amplification and direct sequencing of all antithrombin gene exons and flanking intronic regions identified mutations in eight families. Given the opportunity to correlate the molecular basis with survival, we addressed the relevance of molecular defects to mortality in inherited antithrombin deficiency. The defects included single nucleotide deletions (7671 del G, 7768-69 del G) and insertions (5501 ins A, 2463 G-->TC) that lead to frameshifts, a single base substitution [5381 C-->T (129Arg-->stop)] leading to a premature termination codon, and single base substitutions resulting in amino acid substitutions [2652 A-->C (63Tyr-->Ser), 13380 T-->C (421Ile-- >Thr), and 13407 G-->T (430Cys-->Phe)]. All affected individuals were heterozygous for the defects. Previously we found in Dutch families that antithrombin deficiency did not lead to higher mortality compared with the general population. In accordance with these findings, we observed no excess mortality in the nine families [Observed:Expected, 52:52.6; standardised mortality ratio (SMR) 1.0, 95% confidence interval (CI), 0.7-1.3]. Our findings confirmed a considerable genetic heterogeneity underlying antithrombin deficiency. We therefore concluded that the lack of excess mortality in these families is not caused by a Dutch mild defect. We suggest that the longevity is not affected by molecular defects in the antithrombin gene and hypothesize that differences in mortality or natural history between families most likely result from other (genetic) risk factors.     

Allogeneic bone marrow transplantation for 93 patients with myelodysplastic syndrome

We treated 93 patients with myelodysplastic syndrome using cyclophosphamide and either total body irradiation (n = 88) or busulfan (n = 5) followed by marrow transplantation. Sixty-five marrow donors were genotypically HLA-identical siblings and 28 were other family members or unrelated donors. Before transplantation all patients had either severe neutropenia or thrombocytopenia or had greater than 5% blasts in the marrow or peripheral blood. The probabilities of disease- free survival, relapse, and non-relapse mortality at 4 years were 41%, 28%, and 43%, respectively. Multivariate analysis revealed that younger age and shorter disease duration were significantly associated with improved disease-free survival and decreased non-relapse mortality. Relapse was seen only in patients with excess blasts at the time of transplantation (51% at 4 years). Patients younger than age 40 and without excess blasts had a 4-year disease-free survival of 62%. This study confirms that allogeneic marrow transplantation can cure some patients with myelodysplasia. Because of the favorable outcome in younger patients without excess blasts, we recommend that transplantation be considered early for patients younger than age 40, before disease progression or development of life-threatening cytopenias. For older patients and those with excess blasts, changes in the transplant procedure will be necessary to improve outcome.     

Allogeneic marrow transplantation for multiple myeloma: an analysis of risk factors on outcome

Between September 1987 and December 1994, 80 patients with multiple myeloma (MM) received high-dose busulfan and cyclophosphamide without (n = 57) or with modified total body irradiation (n = 23) followed by marrow from allogeneic donors. At transplant, 71% of the patients had disease that was refractory to chemotherapy. Thirty-five patients died of transplant-related causes within 100 days and 11 deaths occurred later. The actuarial probabilities of survival and progression-free survival were .24 +/- 0.17 and .20 +/- 0.10 at 4.5 years. Complete remissions were obtained in 36% of patients who had actuarial probabilities of survival and event-free survival of .50 +/- 0.21 and .43 +/- 0.17 at 4.5 years. In a multivariate analysis, adverse risk factors for outcome endpoints included: transplantation greater than 1 year from diagnosis; beta-2 microglobulin > 2.5 at transplant; female patients transplanted from male donors; patients who had received greater than eight cycles of chemotherapy before transplant and Durie stage 3 disease at the time of transplant. These results indicate that allografting for patients with MM can result in long-term disease-free survival for a minority of patients. Efforts to reduce transplant- related mortality should focus on earlier transplantation, less toxic treatment regimens, better supportive care, and improved prevention and treatment of graft-versus-host disease (GVHD).     

Treatment of preleukemic syndromes with marrow transplantation

Thirty patients with advanced preleukemic syndromes were treated with marrow transplantation. Most cases were diagnosed by the presence of peripheral pancytopenia and a diagnostic marrow examination but in 6 of the 30 patients pretransplant chromosome studies were instrumental in establishing the diagnosis. Three patients prepared for transplantation with cyclophosphamide alone recurred with their disease within 6 months of transplantation. The other 27 patients were treated with cyclophosphamide and total body irradiation. Twenty of these 27 patients had preleukemia not associated with prior therapy or severe marrow fibrosis. Thirteen of these 20 are alive and well 9 to 56 months from transplant and 7 died, 4 of interstitial pneumonia, 2 of candida septicemia, and 1 of disseminated zoster. There have been no disease recurrences in this group. The remaining preleukemic patients, which include 3 patients transplanted for preleukemia secondary to prior therapy and 4 patients transplanted for preleukemia associated with severe marrow fibrosis, have all died. Major problems in these patients included disease recurrence (2 cases) and, in those with severe marrow fibrosis, graft failure (2 cases). These results suggest that for patients with life-threatening pancytopenia due to spontaneous preleukemia without severe marrow fibrosis, marrow transplantation can prolong disease-free survival and may result in cure of the disease.     

Pregnancies following high-dose cyclophosphamide with or without high- dose busulfan or total-body irradiation and bone marrow transplantation

Patients successfully treated with a marrow transplant often have concerns about fertility and pregnancy. This study was performed to determine pregnancy outcome among patients who had received high-dose chemotherapy alone or with total-body irradiation (TBI) and marrow transplantation for aplastic anemia or hematologic malignancy. Records of 1,326 postpubertal and 196 prepubertal patients currently more than 12 years of age after marrow transplant in Seattle from August 1971 to January 1992 were reviewed to determine the patients with normal gonadal function and pregnancies. Among 708 postpubertal women, 110 recovered normal ovarian function and 32 became pregnant. In addition, nine formerly prepubertal girls with normal gonadal function became pregnant. Among 618 postpubertal men, 157 recovered testicular function and partners of 33 became pregnant. An additional two formerly prepubertal men had partners who became pregnant. Forty-one female patients and partners of 35 male patients had 146 pregnancies after transplant. All 76 patients responded to a questionnaire requesting pregnancy history, outcome, infant birth weight, and congenital anomalies information for all clinically recognized pregnancies. There were 115 live births among 146 (79%) pregnancies. Spontaneous abortion terminated four of 56 (7%) pregnancies for 28 female cyclophosphamide (CY) recipients and six of 16 (37%) pregnancies for 13 TBI recipients (P = .02). Partners of 28 male CY recipients had four of 62 (6.4%) pregnancies terminate with spontaneous abortion, but there were no spontaneous abortions among eight pregnancies of five TBI recipients' partners. Preterm delivery occurred for eight of 44 (18%) and five of eight (63%) live births for 24 CY and eight TBI female recipients (P = .01). This 25% incidence among all female patient pregnancies is higher than the expected incidence of 8% to 10% (P = .0001). The 13 preterm deliveries resulted in 10 low birth weight ([LBW] 1.8 to 2.24 kg) and three very low birth weight ([VLBW] < or = 1.36 kg) infants, for an overall incidence of 25%, which is higher than the expected incidence of 6.5% for the general population (P = .0001). Twelve of the 13 premature infants survive. Congenital anomalies were seen among two of 52 (3.8%) live-born infants of female and six of 63 (9.5%) live-born infants of male patients, which is not different from the 13% of single congenital anomalies reported for the general population. These data demonstrate that clinically recognized pregnancies among women who have received a marrow transplant incorporating TBI are likely to be accompanied by an increased risk of spontaneous abortion. Pregnancies among all women who received a marrow transplant are likely to be accompanied by preterm labor and delivery of LBW or VLBW babies who do not seem to be at an increased risk of congenital anomalies. However, determination of possible adverse effects of parental exposure to high- dose alkylating agents with or without TBI on children born posttransplant requires longer, additional follow-up.     

Effect of recombinant canine granulocyte-macrophage colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation

Recombinant canine granulocyte-macrophage colony-stimulating factor (rcGM-CSF) was studied in normal dogs and in dogs receiving otherwise lethal total body irradiation (TBI) without marrow transplant. Five normal dogs receiving 25 micrograms/kg of rcGM-CSF by subcutaneous (SC) injection twice daily (BID) for 14 days showed increases in peripheral blood neutrophil counts of three to five times the baseline. Platelet counts decreased during administration of rcGM-CSF to a mean nadir of 52,800. Ten dogs received 400 cGy TBI at 10 cGy/min from two opposing 60Co sources and no marrow graft. Within 2 hours of TBI, rcGM-CSF was begun at a dose of 50 micrograms/kg SC BID for 5 doses and then continued at 25 micrograms/kg SC BID for 21 days. Only 1 of the 10 dogs receiving rcGM-CSF survived with complete and sustained recovery of hematopoiesis. One of 13 historical control dogs survived after 400 cGy with no hematopoietic growth factor or marrow infusion. Results with rcGM-CSF were compared with previous and concurrent data with G-CSF studied in the same model. Of 10 dogs receiving G-CSF, 8 survived with complete and sustained hematopoietic recovery, a significantly better survival than that seen with rcGM-CSF (P = .006). Neutrophil counts were sustained at higher levels after TBI for the first 18 days in the G-CSF group (P < .016) and the neutrophil nadirs were higher. No differences in neutrophil nadirs were noted between the rcGM-CSF and control groups. Dogs treated with rcGM-CSF experienced a more rapid decline of platelet counts than G-CSF-treated or control dogs over the first 18 days (P < .001). The nadir of the platelet count was higher in the control group than in either the G-CSF or rcGM-CSF group and no significant difference was observed between the G-CSF and rcGM-CSF groups. After otherwise lethal TBI (400 cGy) in dogs, rcGM-CSF was not effective in promoting hematopoietic recovery or improving survival.     

Relevance of marrow fibrosis in bone marrow transplantation: a retrospective analysis of engraftment

A retrospective study compared posttransplant engraftment parameters in 203 patients with myelofibrosis (MF) with those in a population of 203 matched controls without MF. There were no significant differences between these groups in the proportions of patients who died without achieving engraftment and in the disease-free survival distributions. Furthermore, comparisons between the two groups of patients reaching the respective endpoints showed no differences in the time distributions for reaching 0.5 or 1.0 x 10(9)/L granulocytes, but the time to platelet transfusion independence was 3 days longer in patients with MF. In further analysis, results for 33 patients with severe MF were compared with those of their respective controls. The proportions of patients with severe MF who died without reaching these engraftment endpoints and the disease-free survival distributions in the two groups were similar. Among patients who reached the respective engraftment endpoints, there was no statistically significant difference in the pace of granulocyte recovery. In patients with severe MF, there was a 7- day delay in the time to reach platelet transfusion independence and a 2-day delay in the time to reach red blood cell independence, but the differences were not statistically significant. The present results do not substantiate concerns raised by earlier studies. MF may delay the time to reach platelet independence by approximately 3 days and may increase platelet transfusion requirements, but no other perturbation of hematopoietic reconstitution was apparent.