Search PubMed⌕ Search

Biomedical subjects

M M Horowitz

Publications and source records attributed to M M Horowitz.

At least 73 records · Page 4Linked to original sources
PubMed1996

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.

Adolescent↗
PubMed1995

Use of unrelated marrow grafts compensates for reduced graft-versus-leukemia reactivity after T-cell-depleted allogeneic marrow transplantation for chronic myelogenous leukemia.

The effect of donor/recipient histocompatibility on relapse in patients receiving T-cell-depleted (TCD) grafts for chronic myelogenous leukemia (CML) was evaluated. Specifically, we sought to determine whether TCD results in an attenuation of the graft-versus-leukemia (GVL) effect on recipients of unrelated marrow grafts similar to that observed in HLA-identical sibling marrow transplantations. This question was addressed by comparative analysis of the relapse rates in marrow grafts who otherwise received identical preparative regimens and graft-versus-host disease (GVHD) prophylaxis schedules (T-cell depletion with T10B9 monoclonal antibody and complement plus posttransplant cyclosporine) and by serial molecular analyses using the polymerase chain reaction (PCR) to detect the bcr/abl RNA transcript in patients transplanted with unrelated donor grafts. Patients transplanted with advanced disease (accelerated phase or blast crisis) had equally high relapse rates, regardless of whether they received HLA-identical sibling (56%;95% confidence interval [CI], 29% to 82%) or unrelated marrow grafts (8%; 95% CI, 0% to 28%) had a significantly lower incidence of relapse than did patients transplanted with HLA-identical marrow grafts (47%; 95% CI, 23% to 71%; P = .002). Because all patients were similarly treated, these data indicate that the lower relapse rate in these unrelated patients was caused by an augmented GVL effect that was most likely attributable to increased HLA disparity between donor and recipient. The probability of developing both acute and chronic GVHD was significantly increased in chronic-phase recipients of unrelated marrow grafts, suggesting that the enhanced GVL effect was at least partly GVHD-associated. The lack of such a finding in advanced disease patient receiving unrelated marrow grafts raises the possibility that clinically significant GVL effect after TCD marrow transplantation was limited and confined to patients with more indolent disease. Serial PCR analyses for the presence of the bcr/abl RNA transcript showed that the vast majority of patients transplanted in chronic phase with unrelated marrow grafts were persistently PCR-negative, indicating that the GVL effect was durable in these patients. Most of these patients were observed to become PCR negative within 1 to 2 months after transplantation, showing that early eradication of leukemia was possible with TCD marrow grafts. This study shows that the use of unrelated marrow grafts compensates for reduced GVL reactivity associated with TCD in patients transplanted for CML. Furthermore, these data indicate that, in selected patient populations with CML, TCD can be used to reduce GVHD without a commensurate compromise in the GVL effect.

Adolescent↗
PubMed1995

Bone marrow transplantation for Fanconi anemia.

Fanconi anemia is a genetic disorder associated with diverse congenital abnormalities, progressive bone marrow failure, and increased risk of leukemia and other cancers. Affected persons often die before 30 years of age. Bone marrow transplantation is an effective treatment, but there are few data regarding factors associated with transplant outcome. We analyzed outcomes of HLA-identical sibling (N = 151) or alternative related or unrelated donor (N = 48) bone marrow transplants for Fanconi anemia performed between 1978 and 1994 and reported to the International Bone Marrow Transplant Registry. Fanconi anemia was documented by cytogenetic studies in all cases. Patient, disease, and treatment factors associated with survival were determined using Cox proportional hazards regression. Two-year probabilities (95% confidence interval) of survival were 66% (58% to 73%) after HLA-identical siblings transplants and 29% (18% to 43%) after alternative donor transplants. Younger patient age (P .0001), higher pretransplant platelet counts (P = .04), use of antithymocyte globulin (P = .005), and use of low-dose (15 to 25 mg/kg) cyclophosphamide plus limited field irradiation (P = .009) for pretransplant conditioning and cyclosporine for graft-versus-host disease prophylaxis (P = .002) were associated with increased survival. Bone marrow transplants are effective therapy for Fanconi anemia. The adverse impact of increasing age and lower pretransplant platelet count on transplant outcome favors earlier intervention, especially when there is an HLA-identical sibling donor.

Adolescent↗
PubMed1995

Long-term follow-up of adults with acute lymphoblastic leukemia in first remission treated with chemotherapy or bone marrow transplantation. The Acute Lymphoblastic Leukemia Working Committee.

OBJECTIVE: To determine whether the conclusions of a 1991 study, which showed that adults with acute lymphoblastic leukemia in first remission had similar leukemia-free survival rates when treated with chemotherapy or HLA-identical sibling bone marrow transplantation, remain valid after more than 4 years of additional follow-up. DESIGN: Retrospective comparison of two cohorts of patients using left-truncated Cox regression to adjust for differences in baseline characteristics and time to treatment. SETTING AND PATIENTS: Chemotherapy recipients were 484 consecutive patients with acute lymphoblastic leukemia in first remission treated in 44 hospitals in Germany that were participating in two consecutive trials of the German Acute Lymphoblastic Leukemia Therapy Trials Group. Transplant recipients were 234 consecutive recipients of HLA-identical sibling bone marrow transplants for acute lymphoblastic leukemia in first remission in 98 centers, worldwide, reporting data to the International Bone Marrow Transplant Registry. INTERVENTIONS: Intensive combination chemotherapy or HLA-identical sibling bone marrow transplantation preceded by high-dose chemotherapy with or without total body irradiation. MEASUREMENTS: Relapse, treatment-related mortality, and leukemia-free survival rate 9 years after first complete remission. RESULTS: The conclusions of our previous analyses were confirmed. Actuarial relapse probabilities at 9 years were 66% (95% CI, 61% to 70%) for chemotherapy and 30% (CI, 22% to 37%) for transplantation (P < 0.0001). The leukemia-free survival rates at 9 years were 32% (CI, 27% to 37%) for chemotherapy and 34% (CI, 28% to 40%) for transplantation (P > 0.02). CONCLUSIONS: Fewer relapses but more treatment-related deaths were seen with transplantation than with chemotherapy. Thus, leukemia-free survival rates were similar in adults receiving transplantation and adults receiving chemotherapy for acute lymphoblastic leukemia in first remission.

Antineoplastic Agents↗
PubMed1995

Allogeneic marrow grafts from donors with congenital chromosomal abnormalities in marrow cells.

To determine whether siblings with chromosomal abnormalities in marrow cells which are associated with cellular defects (e.g. Down syndrome or heterozygosity for Fanconi syndrome) are suitable donors for allogeneic bone marrow transplants, we have reviewed the patient files at the Fred Hutchinson Cancer Research Center (FHCRC) and carried out a survey among member centres of the International Bone Marrow Transplant Registry (IBMTR). The 57 of 253 (23%) member centres which responded to the survey reported seven transplants from donors with the following conditions: Down syndrome (n = 2), suspected heterozygotes for Fanconi syndrome (n = 3), and 47,XXX syndrome (n = 2), among a total of 5,561 allogeneic transplants from HLA-identical siblings. Adding the three cases seen at the Fed Hutchinson Cancer Research Center among 2,927 HLA-identical sibling transplants during 1992 resulted in 10 transplants among 8,488 cases transplanted overall: four with Down syndrome, four suspected of being heterozygous for Fanconi syndrome, and two trisomy X. Three out of four grafts from siblings with Down syndrome had complications, including poor graft function (n = 2) and graft failure (n = 1). Two of four recipients of marrow from presumed Fanconi syndrome heterozygotes presented with poor graft function and a third recipient developed graft failure after initial evidence of engraftment. The two patients given marrow from siblings with 47,XXX syndrome engrafted uneventfully. The experience reported here shows a low frequency of encountering an HLA-identical sibling donor who has chromosomal abnormalities in marrow cells consistent with Down syndrome or heterozygosity for Fanconi syndrome, about one case among 1,000 transplants. The much higher than expected incidence of graft problems with marrow from such a donor would make it reasonable to look either for an alternative marrow donor or consider an autologous transplant, in case a sibling marrow donor with Down syndrome or heterozygosity for Fanconi syndrome is encountered, although a donor with trisomy X seems acceptable.

Adolescent↗
PubMed1995

Impact of cytogenetic abnormalities on outcome of bone marrow transplants in acute myelogenous leukemia in first remission.

This study analyzed the impact of cytogenetic abnormalities on outcome of 1516 HLA-identical sibling bone marrow transplants for acute myelogenous leukemia (AML) in first remission reported to the International Bone Marrow Transplant Registry by 188 centers. 708 patients (47%) had cytogenetic studies performed. Transplant outcome in these subjects was similar to the 808 in whom cytogenetic studies were not performed. One or more cytogenetic abnormalities were detected in 284 (40%) of subjects studied. Relapse rates were higher and leukemia-free survival lower in patients with poor prognosis abnormalities vs those with no abnormality or with good or intermediate prognosis abnormalities (relative risk of relapse 2.40, P < 0.01; relative risk of treatment failure 1.68, P < 0.03). We conclude that cytogenetic abnormalities correlated with increased relapse in patients treated with chemotherapy. HLA-identical sibling transplants are similar.

Adolescent↗
PubMed1995

Therapeutic plasma exchange does not appear to be effective in the management of thrombotic thrombocytopenic purpura/hemolytic uremic syndrome following bone marrow transplantation.

Recognition of thrombotic thrombocytopenic purpura (TTP)/hemolytic uremic syndrome (HUS) following BMT has increased in recent years. The pathogenesis and etiology may be related to endothelial cell damage secondary to irradiation and/or CsA. Optimal management of this condition remains unclear. Due to similarity between this syndrome and classical TTP, patients with TTP/HUS following BMT are commonly treated with therapeutic plasma exchange (TPE). We describe our experience with 9 such patients who were treated with TPE (8 cases) and immunoadsorption with a Staphylococcal Protein A column (1 case). The exchanges were done with fresh frozen plasma and/or cryoprecipitate-depleted frozen plasma. Out of 8 patients treated with TPE, 6 died within 2 months of TPE due to secondary infections, metabolic disturbances and progression of TTP/HUS. Of these 6 patients, 5 had no hematological response, while 1 had hematological improvement. Two patients are alive 4 and 3 years later, however, they had shown only minimal hematological response at the end of 28 and 20 TPE, respectively. Their renal function remains stable but severely reduced. The ninth patient who received Staphylococcal Protein A column treatment died within 5 days of treatment without hematological improvement. Thus, in contrast to its effectiveness in classical TTP, TPE does not appear to be as effective in the management of well established TTP/HUS following BMT.

Adolescent↗
PubMed1995

Bone marrow transplantation for Diamond-Blackfan anemia.

Diamond-Blackfan anemia (DBA) is a rare disorder usually diagnosed in the first year of life. Although most cases respond to corticosteroids, > 20% are, or become, steroid-resistant. We report 10 children with DBA who received a bone marrow transplant from an HLA-identical sibling (n = 8), maternal (n = 1) or unrelated (n = 1) donor and reported to the International Bone Marrow Transplant Registry. Among eight recipients of HLA-identical sibling transplants, six are alive 5-87 months after transplant with no evidence of DBA and with Karnofsky performance scores of 90-100%. The two recipients of non-HLA-identical sibling transplants died < 2 weeks after transplant. The actuarial 2-year probability of survival for the eight sibling transplants was 72 (37-92)% (95% confidence interval).

Adolescent↗
PubMed1995

Report from the International Bone Marrow Transplant Registry and Autologous Blood and Marrow Transplant Registry - North America.

Allogeneic and autologous bone marrow and blood cell transplants are increasingly used treatments for cancer and disorders of bone marrow and immune function. This is largely due to use of autotransplants to treat common diseases such as breast cancer. The use of blood cells alone for autotransplants was also a significant change in the past 5 years. The IBMTR and ABMTR continue to provide a unique resource for studying outcomes and trends in allogeneic and autologous bone marrow and blood cell transplants.

Adolescent↗
PubMed1994

Bone marrow transplants from HLA-identical siblings as compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission.

BACKGROUND: It is unclear how best to treat children with acute lymphoblastic leukemia who are in a second remission after a bone marrow relapse. For those with HLA-identical siblings, the question of whether to perform a bone marrow transplantation or to continue chemotherapy has not been answered. METHODS: We compared the results of treatment with marrow transplants from HLA-identical siblings in 376 children, as reported to the International Bone Marrow Transplant Registry, with the results of chemotherapy in 540 children treated by the Pediatric Oncology Group. A preliminary analysis identified variables associated with treatment failure in both groups. We selected cohorts by matching these variables. A possible bias associated with differences in the interval between remission and treatment was controlled for by choosing matched pairs in which the duration of the second remission in the chemotherapy recipient was at least as long as the time between the second remission and transplantation in the transplant recipient. A total of 255 matched pairs were studied. RESULTS: The mean (+/- SE) probability of a relapse at five years was significantly lower among the transplant recipients than among the chemotherapy recipients (45 +/- 4 percent vs. 80 +/- 3 percent, P < 0.001). At five years the probability of leukemia-free survival was higher after transplantation than after chemotherapy (40 +/- 3 percent vs. 17 +/- 3 percent, P < 0.001). The relative benefit of transplantation as compared with chemotherapy was similar in children with prognostic factors indicating a high or low risk of relapse (the duration of the first remission, age, leukocyte count at the time of the diagnosis, and phenotype of the leukemic cells). CONCLUSIONS: For children with acute lymphoblastic leukemia in a second remission, bone marrow transplants from HLA-identical siblings result in fewer relapses and longer leukemia-free survival than does chemotherapy.

Adolescent↗
PubMed1994

Availability and appropriateness of allogeneic bone marrow transplantation for chronic myeloid leukemia in 10 countries.

BACKGROUND: Allogeneic bone marrow transplantation, a sophisticated and expensive procedure, is the only curative therapy for chronic myeloid leukemia (CML). We examined the availability and appropriateness of allogeneic bone marrow transplantation for CML in 10 economically advanced countries with diverse health care systems. For each country we obtained data on the likelihood of transplantation to treat CML in patients under the age of 55 years, the length of time from diagnosis to transplantation, and the stage of disease at the time of transplantation. METHODS: Data were collected on 9873 allogeneic bone marrow transplantations performed at 208 centers in 10 countries from 1989 through 1991. Data were acquired from transplantation registries and by means of a mailed survey of all centers and teams that did not contribute data to registries. Data on the incidence of disease were drawn from national and regional cancer registries. RESULTS: Among the 10 countries there was a twofold difference between the lowest and highest rates of transplantation to treat CML (0.26 to 0.54 per 100,000 population per year); Swedish patients were the most likely to receive a transplant, and German patients the least likely. The median length of time from diagnosis to transplantation ranged from 6.8 to 15.4 months. In all countries, most transplantations were performed in the chronic phase of the disease, but as many as a third of patients received transplants in the less favorable accelerated or blast phase. The values for the United States fell near the middle of those for the 10 countries on all measures. CONCLUSIONS: Our findings challenge the assumption that the United States is unique in providing broad access to high-technology treatments. On no measure of the availability or appropriateness of transplantation for CML did it surpass the other nine countries studied.

Adolescent↗
PubMed1994

Identical-twin bone marrow transplants for leukemia.

OBJECTIVE: To compare outcomes of identical-twin with HLA-identical sibling bone marrow transplants for leukemia. DESIGN: Matched-pair analysis comparing relapse, treatment-related mortality, and leukemia-free survival in cohorts matched for disease and variables correlated with transplant outcome, with and without adjustment for graft-versus-host disease. SETTING: 163 institutions worldwide between 1978 and 1990, reporting to the International Bone Marrow Transplant Registry. PARTICIPANTS: 103 identical-twin transplants: 24 for acute lymphoblastic leukemia (ALL) in first remission, 45 for acute myelogenous leukemia (AML) in first remission, and 34 for chronic myelogenous leukemia (CML) in first chronic phase. Results were compared with those in 1030 concurrent HLA-identical sibling transplants matched for prognostic factors. RESULTS: Three-year probabilities of relapse after identical-twin compared with HLA-identical sibling transplants were as follows: ALL, 36% (95% CI, 17% to 55%) compared with 26% (CI, 20% to 32%); AML, 52% (CI, 37% to 67%) compared with 16% (CI, 12% to 20%); and CML, 40% (CI, 23% to 57%) compared with 7% (CI, 4% to 10%). Increased relapse risks in AML and CML persisted after adjusting for graft-versus-host disease (relative risk, 3.1 [CI, 1.9 to 5.1] and 5.5 [CI, 2.8 to 11.0], respectively). Although twins had less treatment-related mortality than HLA-identical siblings, leukemia-free survival was similar. Three-year leukemia-free survival probabilities after twin compared with HLA-identical sibling transplants were as follows: ALL, 57% (CI, 37% to 77%) compared with 58% (CI, 52% to 64%); AML, 42% (CI, 27% to 57%) compared with 55% (CI, 50% to 60%); and CML, 59% (CI, 42% to 76%) compared with 61% (CI, 56% to 66%). CONCLUSIONS: Identical-twin transplants in AML and CML are associated with increased relapse risk compared with HLA-identical sibling transplants. A similar trend was observed in ALL but was not statistically significant. Increased relapse in twin transplants is not explained by lack of graft-versus-host disease. Leukemia-free survival after twin and HLA-identical sibling transplants is similar because increased relapse in twins is offset by decreased treatment-related mortality.

Bone Marrow Transplantation↗
PubMed1994

Effect of T-cell depletion as graft-versus-host disease prophylaxis on engraftment, relapse, and disease-free survival in unrelated marrow transplantation for chronic myelogenous leukemia.

Between January 1988 and March 1993, 48 patients received T-cell-depleted marrow grafts from unrelated donors as treatment for chronic myelogenous leukemia (CML). The median age of the population was 31.7 years (range 5.4 to 53) with 17 of 48 patients greater than 40 years of age. Twenty-seven patients were transplanted in chronic phase, 17 in accelerated phase, and 4 in blast crisis. All patients received a standardized preparative regimen of cyclophosphamide, high-dose cytosine arabinoside, methylprednisolone, and total body irradiation. Marrow grafts were depleted of mature T cells with the alpha beta T-cell receptor antibody T10B9 as graft-versus-host disease (GVHD) prophylaxis. All patients also received posttransplant cyclosporine therapy. Twenty-eight of 48 patients were mismatched with their donors for one or more HLA-A, B, DR, or DQ loci by either serology or high-resolution oligonucleotide genotyping. Nine of 28 were mismatched at multiple HLA loci. Durable engraftment was achieved in 94% (45/48) of patients. The actuarial probability of developing grades II to IV and grades III to IV acute GVHD were 39.6% (95% confidence interval (CI) 26.9 to 53.0) and 8.3% (95% CI 6.1 to 10.9) for the entire cohort. There was no difference in the incidence of grades II to IV acute GVHD between patients receiving matched (36.8%) or mismatched (41.4%) marrow grafts (P = .77). The actuarial probability of relapse at 2 years was 8.8% (95% CI 2.1 to 21.6) for the entire cohort and 18% (95% CI 4 to 41) for patients transplanted in either the accelerated or blast crisis phase (advanced disease). One cytogenetic relapse has occurred among patients transplanted in the chronic phase. The probability of disease-free survival at 2 years was 52% (95% CI 24 to 70) for patients transplanted in chronic phase and 46% (95% CI 25 to 73) for patients transplanted with advanced disease. No difference in disease-free survival was observed between patients receiving matched (49%) or mismatched (51%) marrow grafts (P = .90). This study shows that patients receiving unrelated T-cell-depleted marrow grafts for CML can achieve durable engraftment with a low incidence of severe GVHD and apparent preservation of graft-versus-leukemia reactivity. These data also suggest that T-cell depletion may allow patients who might otherwise experience unacceptable toxicity from GVHD-related complications caused by older age or increased HLA disparity to benefit from unrelated marrow grafts.

Adolescent↗
PubMed1994

Comparison of chemotherapy and bone marrow transplants using two independent clinical databases.

Comparing the outcome of chemotherapy and bone marrow transplants in the absence of a randomized trial is difficult but necessary for diseases where small numbers of patients make such trials difficult if not impossible. To address this issue for adults with acute lymphoblastic leukemia in first remission, we created an empirical database using two separate datasets, one from the International Bone Marrow Transplant Registry and the other from two multicenter chemotherapy studies. Prior to combining the datasets, a study protocol was developed to define inclusion criteria, outcomes to be compared and statistical methods. The main problems of a non-randomized comparison are biases potentially introduced by differences in baseline composition of the two cohorts and differences in time-to-treatment. The source of the latter bias is different distributions of waiting times between achieving complete remission and receiving post-remission therapy. Several techniques to control these biases were evaluated; each gave qualitatively similar results. These methods can easily be applied to other clinical situations where randomized trials are not available.

Adolescent↗
PubMed1994

Bone marrow transplantation in leukemia.

Bone marrow transplants are increasingly being used as treatment for leukemia. Several IBMTR studies have identified variables predicting outcome in allogeneic transplants. These studies have also identified factors like GVL that increase our understanding of leukemia treatment. Following the success of HLA-identical sibling transplants, allografts from related and unrelated donors are now performed frequently and achieve long-term LFS. The use of autologous transplants, with and without marrow treatment, is also increasing and continues to be investigated as an alternative therapy for leukemia.

Bone Marrow Transplantation↗
PubMed1994

Increasing incidence of adenovirus disease in bone marrow transplant recipients.

Adenovirus infections in 201 bone marrow transplant (BMT) recipients over 4 years were retrospectively reviewed. Forty-two patients (20.9%) had positive adenovirus cultures after BMT. There was a higher incidence of adenovirus infections in pediatric patients than in adults (31.3% vs. 13.6%, P = .003). In addition, the time of onset of adenovirus infection after transplant was earlier in pediatric patients (mean, < 30 days) than in adults (> 90 days). Adenovirus type 35 was the most common serotype identified. One-third of adenovirus-positive patients had definite or probable adenovirus disease. Moderate to severe acute graft-versus-host disease and isolation of adenovirus from two or more sites were significant risk factors for adenovirus disease. This report documents a higher incidence of both adenovirus infection and disease than do previous studies. Adenovirus may emerge as a more frequent pathogen as more high-risk BMT transplants are done.

Adenovirus Infections, Human↗