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Biomedical subjects

Robert Peter Gale

Publications and source records attributed to Robert Peter Gale.

At least 19 recordsLinked to original sources
PubMed2006

Pretransplantation consolidation chemotherapy decreases leukemia relapse after autologous blood and bone marrow transplants for acute myelogenous leukemia in first remission.

Controversy exists over whether pretransplantation consolidation chemotherapy affects the outcome of subsequent autotransplantation for acute myelogenous leukemia (AML). The current study was undertaken to determine the association between previous consolidation and outcome of autotransplantation for AML in first remission. Posttransplantation outcomes of 146 patients receiving no consolidation were compared with those of 244 patients receiving standard-dose (<1 gm/m(2)) and 249 patients receiving high-dose (1-3 gm/m(2)) cytarabine, using proportional hazards regression to adjust for differences in prognostic variables. One-year transplantation-related mortality was similar among the cohorts. Five-year relapse rates were 49% (95% confidence interval CI} = 39%-58%) with no consolidation, 35% (95% CI = 29%-42%) with standard-dose cytarabine, and 40% (95% CI = 33%-48%) with high-dose cytarabine (P = .07). Five-year leukemia-free survival rates were 39% (95% CI = 30%-47%) with no consolidation, 53% (95% CI = 46%-60%) with standard-dose cytarabine, and 48% (95% CI = 40%-56%) with high-dose cytarabine (P = .03). Similarly, 5-year overall survival was better in those patients receiving consolidation: 42% (95% CI = 34%-51%) with no consolidation, 59% (95% CI = 52%-65%) with standard-dose cytarabine, and 54% (95% CI = 46%-61%) with high-dose cytarabine (P = .01). Although most patients received 1 or 2 cycles of consolidation, the number of courses had no detectable effect on transplantation outcome. In multivariate analysis, risks of relapse and treatment failure were lower in the patients receiving consolidation, especially among those patients receiving blood cell grafts. Outcomes with standard-dose and high-dose cytarabine were similar. Based on our findings, we recommend that patients with AML in first remission receive consolidation before undergoing autotransplantation.

Adolescent↗
PubMed2006

A comparison of cyclophosphamide and total body irradiation with etoposide and total body irradiation as conditioning regimens for patients undergoing sibling allografting for acute lymphoblastic leukemia in first or second complete remission.

We compared the outcomes of 298 patients with acute lymphoblastic leukemia in first or second complete remission (CR1 or CR2) receiving HLA-matched sibling allografts after cyclophosphamide and total body irradiation (Cy-TBI) conditioning with 204 patients receiving etoposide and TBI. Consequently, 4 groups were compared: Cy-TBI <13 Gy (n = 217), Cy-TBI > or =13 Gy (n = 81), etoposide-TBI <13 Gy (n = 53), and etoposide-TBI > or =13 Gy (n = 151). Analyses of relapse, leukemia-free survival (LFS), and survival were performed separately for CR1 and CR2 transplantations. Transplant-related mortality did not differ by conditioning regimen. In CR1, there were also no significant differences in relapse, LFS, or survival by conditioning regimen. In CR2, these outcomes differed among conditioning groups. In comparison with Cy-TBI <13 Gy, the risks of relapse, treatment failure (inverse of LFS), and mortality tended to be lower with etoposide (regardless of TBI dose) or with TBI doses > or =13 Gy. For both CR1 and CR2 transplantations, causes of death were similar among the groups; disease recurrence accounted for 47% of deaths. We conclude that for HLA-identical sibling allografts for acute lymphoblastic leukemia in CR2, there is an advantage in substituting etoposide for Cy or, when Cy is used, in increasing the TBI dose to > or =13 Gy.

Adolescent↗
PubMed2006

Autologous or allogeneic stem cell transplantation in patients with Waldenstrom's macroglobulinemia.

The role of hematopoietic stem cell transplantation (SCT) in Waldenstrom's macroglobulinemia (WM) has not been extensively studied. To determine the potential for long-term disease control using SCT in WM, we performed a retrospective review of 36 patients with WM who received autologous (n = 10) or allogeneic (n = 26) SCT and were reported to the Center for International Blood and Marrow Transplant Research between 1986 and 2002. The following outcomes were described: nonrelapse mortality (NRM), relapse, progression-free survival (PFS), and overall survival (OS). Median age at the time of SCT was 51 years (range, 30-76 years), and median time from initial treatment to SCT was 29 months (range, 2-198 months). A total of 78% of the patients had 2 or more previous chemotherapy regimens, and 52% had disease resistant to salvage chemotherapy. In the allogeneic SCT group, 58% of the patients received myeloablative conditioning regimens containing total body irradiation (TBI), and of the allograft recipients, 19% received nonmyeloablative/reduced-intensity conditioning. After a median follow-up of 65 months, 15 of the 36 patients (42%) are alive. Primary disease accounted for 29% of the deaths in the allogeneic SCT group and 25% of the deaths in the autologous SCT group. The relapse rate at 3 years was 29% (95% confidence interval [CI], 14%-48%) in the allogeneic group and 24% (95% CI, 4%-54%) in the autologous group. PFS at 3 years was 31% (95% CI, 14%-50%) in the allogeneic group and 65% (95% CI, 32%-91%) in the autologous group; OS was 46% (95% CI, 27%-65%) in the allogeneic group and 70% (95% CI, 40%-93%) in the autologous group. NRM at 3 years was 40% (95% CI, 23%-59%) in the allogeneic group and 11% (95% CI, 0-36%) in the autologous group. Autologous SCT is a safe and feasible treatment option for patients with WM, especially for those who present with adverse prognostic factors. Allogeneic SCT carries a much higher (40%) risk of NRM and should not be considered outside the context of a clinical trial.

Adult↗
PubMed2006

Autotransplantation versus HLA-matched unrelated donor transplantation for acute myeloid leukaemia: a retrospective analysis from the Center for International Blood and Marrow Transplant Research.

Most acute myeloid leukaemia (AML) patients lack human leucocyte antigen-identical sibling donors for transplantation. Autotransplants and unrelated donor (URD) transplants are therapeutic options. To compare autologous versus URD transplantation for AML in first (CR1) or second complete remission (CR2), we studied the outcomes of 668 autotransplants were compared with 476 URD transplants reported to the Center for International Blood and Marrow Transplant Research. Proportional hazards regression adjusted for differences in prognostic variables. In multivariate analyses transplant-related mortality (TRM) was significantly higher and relapse lower with URD transplantation. Adjusted 3-year survival probabilities were: in CR1 57 (53-61)% with autotransplants and 44 (37-51)% URD (P = 0.002), in CR2 46 (39-53)% and 33 (28-38)% respectively (P = 0.006). Adjusted 3-year leukaemia-free survival (LFS) probabilities were: CR1 53 (48-57)% with autotransplants and 43 (36-50)% with URD (P = 0.021), CR2 39 (32-46)% and 33 (27-38)% respectively (P = 0.169). Both autologous and URD transplantation produced prolonged LFS. High TRM offsets the superior antileukaemia effect of URD transplantation. This retrospective, observational database study showed that autotransplantation, in general, offered higher 3-year survival for AML patients in CR1 and CR2. Cytogenetics, however, were known in only two-thirds of patients and treatment bias cannot be eliminated.

Acute Disease↗
PubMed2005

Impact of posttransplantation G-CSF on outcomes of allogeneic hematopoietic stem cell transplantation.

Granulocyte colony-stimulating factor (G-CSF) is often administered after hematopoietic-cell transplantation (HCT) to accelerate neutrophil recovery, but it is unclear what impact G-CSF has on long-term transplantation outcomes. We analyzed within the database of the Center for International Blood and Marrow Transplant Research the impact of giving posttransplantation G-CSF on the outcomes of allogeneic HCT for acute myelogenous leukemia and chronic myelogenous leukemia in 2719 patients who underwent transplantation between 1995 and 2000. These included 1435 recipients of HLA-identical sibling bone marrow (BM), 609 recipients of HLA-identical peripheral-blood stem cells (PBSCs), and 675 recipients of unrelated donor BM transplants. Outcomes were compared between patients receiving or not receiving G-CSF within 7 days of HCT according to graft type. Median follow-up was more than 30 months (range, 2-87 months). G-CSF shortened the posttransplantation neutropenic period, but did not affect days +30 and +100 treatment-related mortality (TRM). Probabilities of acute and chronic graft-versus-host disease (GVHD), leukemia-free survival (LFS), and overall survival were similar whether or not G-CSF was given. Multivariate analyses confirmed that giving G-CSF did not affect the risk of GVHD, TRM, LFS, or survival. In conclusion, results of this study found no long-term benefit or disadvantage of giving G-CSF after transplantation to promote hematopoietic recovery.

Adolescent↗
PubMed2005

ABO blood group barrier in allogeneic bone marrow transplantation revisited.

Reports have shown a worse outcome for donor-recipient pairs mismatched for ABO blood groups in bone marrow transplantation (BMT). These studies, however, included small and heterogeneous study populations, and not all considered bidirectional ABO incompatibility separately. Because the issue remains controversial, we analyzed the effect of ABO mismatch on the overall survival, transplant-related mortality, and occurrence of acute and chronic graft-versus-host disease (GVHD) in a large homogenous group of patients undergoing allogeneic BMT. A total of 3103 patients with early-stage leukemia who underwent transplantation between 1990 and 1998 with bone marrow from an HLA-identical sibling and who were reported to the Center for International Blood and Marrow Transplant Research were studied. The median follow-up was 54 months. A total of 2108 (67.9%) donor-recipient pairs were ABO identical, 451 (14.5%) had a minor mismatch, 430 (13.9%) had a major mismatch, and 114 (3.7%) had a bidirectional ABO mismatch. The groups did not differ significantly in patient or donor characteristics except for more female-to-male sex mismatch in the bidirectional ABO mismatch group (P = .017). In multivariate models of overall survival, transplant-related mortality, and grade II to IV acute GVHD, there were no significant differences among the 4 groups. Bidirectional ABO mismatch was associated with a significantly higher risk of grade III or IV acute GVHD (hazard ratio, 1.869; 95% confidence interval, 1.192-2.93; P = .006). Patients with major ABO mismatch received red blood cell transfusions (P = .001) for a longer timer after transplantation and had a slightly slower neutrophil recovery (P < .001). There was no evidence of a substantial effect of ABO blood group incompatibility on the outcome of conventional BMT among patients with leukemia.

ABO Blood-Group System↗
PubMed2004

Comparison of graft-versus-host-disease and survival after HLA-identical sibling bone marrow transplantation in ethnic populations.

The association of ethnicity with the incidence of graft-versus-host disease (GVHD) and other clinical outcomes after transplantation is controversial. We compared the results of HLA-identical sibling bone marrow transplantations for leukemia, performed between 1990 and 1999, among different ethnic populations, including 562 Japanese, 829 white Americans, 71 African Americans, 195 Scandinavians, and 95 Irish. Results for adults and children were analyzed separately. Multivariate analyses of adult patients showed that white Americans, African Americans, and Irish cohorts were at significantly higher risk for acute GVHD than Japanese or Scandinavian cohorts (relative risk [RR] = 1.77, P < .001; RR = 1.84, P < .006; RR = 2.22, P < .001, respectively). White Americans, African Americans, and Irish, but not Scandinavians, were at significantly higher risk for early (within 3 months of transplantation) transplant-related mortality (TRM) compared with Japanese (RR = 2.99, P < .001; RR = 5.88, P < .001; RR = 2.66, P < .009, respectively). No differences in the risk for chronic GVHD, relapse, and overall survival were noted. In the pediatric cohort (limited to Japanese and white Americans), white Americans were at significantly higher risk for acute (RR = 1.93; P = .04) and chronic (RR = 3.16; P = .002) GVHD. No differences in other clinical outcomes were noted. Our findings suggest that ethnicity may influence the risk for GVHD, though overall survival rates after transplantation remain similar.

Adult↗
PubMed2004

Autologous hematopoietic stem-cell transplantation for children with acute myeloid leukemia in first or second complete remission: a prognostic factor analysis.

PURPOSE: To determine prognostic factors correlated with outcomes after autologous hematopoietic stem-cell transplantation (HSCT) in children with acute myeloid leukemia (AML). PATIENTS AND METHODS: We studied 219 children who received autologous HSCT for AML in first complete remission (CR) and 73 children in second CR and who were reported to the Autologous Blood and Marrow Transplant Registry. Among 29 of 73 patients who underwent transplantation in second CR, duration of first CR was > or = 12 months. RESULTS: Three-year cumulative incidences of relapse were 37% (95% CI, 31% to 44%), 60% (95% CI, 41% to 74%), and 36% (95% CI, 20% to 53%) for children in first CR, second CR after a short (< 12 months) first CR, and second CR after a long (> or = 12 months) first CR, respectively. Corresponding 3-year probabilities of leukemia-free survival were 54% (95% CI, 47% to 60%), 23% (95% CI, 10% to 39%), and 60% (95% CI, 42% to 75%). In multivariate analyses, risks of relapse, mortality, and treatment failure (relapse or death, inverse of leukemia-free survival) were higher for patients in second CR after a short first CR than for the other two groups. Transplant-related mortality, treatment failure, and overall mortality rates were higher in older (> 10 years) children. CONCLUSION: Duration of first CR seems to be the most important determinant of outcome. Results in children who experience treatment failure with conventional chemotherapy support the use of autologous transplantation as salvage therapy if such patients achieve a subsequent CR.

Acute Disease↗
PubMed2004

Myeloablative allogeneic hematopoietic stem cell transplantation in patients who experience relapse after autologous stem cell transplantation for lymphoma: a report of the International Bone Marrow Transplant Registry.

Myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) is increasingly used in patients with lymphoma who experience disease relapse after autologous hematopoietic stem cell transplantation (auto-HSCT) because the allograft is tumor free and may induce a graft-versus-tumor effect. We analyzed 114 patients treated with this approach from 1990 to 1999 to assess disease progression, progression-free survival (PFS), and overall survival (OS). Cumulative incidence of disease progression at 3 years was 52%, whereas treatment-related mortality was 22%, lower than previously reported. Three-year probabilities of OS and PFS were 33% and 25%, respectively. With prolonged follow-up, however, nearly all patients experienced disease progression, and 5-year probabilities were 24% and 5%, respectively. Complete remission at the time of allo-HSCT and use of total body irradiation (TBI) in patients with non-Hodgkin lymphoma (NHL) were associated with lower rates of disease progression and higher rates of OS. In summary, allo-HSCT is feasible for patients with lymphoma who have relapses after auto-HSCT and can result in prolonged survival for some, but it is usually not curative. Most likely to benefit are patients who have HLA-matched sibling donors, are in remission, and have good performance status.

Adolescent↗
PubMed2004

A decision analysis of allogeneic bone marrow transplantation for the myelodysplastic syndromes: delayed transplantation for low-risk myelodysplasia is associated with improved outcome.

Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.

Adolescent↗
PubMed2004

Autologous transplantation for diffuse aggressive non-Hodgkin lymphoma in first relapse or second remission.

We evaluated the results of high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with diffuse aggressive non-Hodgkin lymphoma (NHL) in first relapse (Rel 1) or second complete remission (CR 2). Data were evaluated from the Autologous Blood and Marrow Transplant Registry on 429 patients with diffuse aggressive NHL who underwent transplantation in Rel 1 or CR 2. Transplantations were performed between 1989 and 1996 and were reported to the Autologous Blood and Marrow Transplant Registry by 93 centers in North and South America. The probability of 3-year survival was 44% (95% confidence interval [CI], 33%-55%). The probability at 3 years of progression-free survival was 31% (95% CI, 27%-36%). Patients who underwent transplantation in CR 2 had a 3-year probability of progression-free survival of 38% (95% CI, 30%-46%) compared with 28% (95% CI, 22%-33%) for those who were not in remission at the time of transplantation (P <.001). In multivariate analysis, chemotherapy resistance, increased lactic dehydrogenase at diagnosis, an interval of <12 months from diagnosis to relapse, age >or=40 years, and use of myeloid growth factors to accelerate posttransplantation bone marrow recovery were adverse predictors of survival. High-dose chemotherapy and autologous hematopoietic stem cell transplantation for patients with diffuse aggressive NHL in CR 2 or Rel 1 resulted in better outcome for patients with chemotherapy-sensitive disease, longer relapse-free intervals, and age <40 years. Exposure to myeloid growth factors to accelerate recovery for recipients of bone marrow grafts may increase the risk of disease progression or death.

Adolescent↗
PubMed2003

Modeling minimal residual disease (MRD)-testing.

There is considerable effort to develop more sensitive methods to detect minimal residual disease (MRD) in bone marrow and blood samples of persons with cancer. Results of MRD-testing are used to predict clinical outcome and determine if more anti-cancer therapy is needed. Mathematical models were developed to assess factors affecting sensitivity and specificity of MRD-testing at diverse cancer cell prevalences. Modeling results and predictions were compared to results of large published studies.Accuracy of MRD-testing depends on cancer cell prevalence and distribution in the blood or bone marrow of the subject, sensitivity and specificity of the MRD-test and sample size. In subjects with low cancer cell prevalences (< or = 10(-4)) results of MRD testing are likely inaccurate. Increasingly sensitive MRD-tests are only marginally useful; the major obstacle to accuracy is inadequate sampling. Increasing sensitivity of methods to detect MRD is unlikely sufficient to increase accuracy of MRD-testing. In contrast, increased sampling (size and frequency) and assigning a high cut-off value (for example, > or = 10(-3)) to declare a MRD-test positive will increase sensitivity and specificity, respectively.

Biomarkers↗
PubMed2003

Decreased treatment failure in recipients of HLA-identical bone marrow or peripheral blood stem cell transplants with high CD34 cell doses.

We studied the association between CD34 cell dose and transplant outcomes in 359 bone marrow (BM) and 511 peripheral blood stem cell (PBSC) transplant recipients from human leucocyte antigen (HLA)-identical siblings, reported to the International Bone Marrow Transplant Registry (IBMTR). Transplants for leukaemia were performed between 1995 and 1998. Patients were divided into those receiving below or above the median CD34+ dose, for BM (3 x 106/kg) and PBSC (6 x 106/kg) grafts respectively. Cox proportional hazards regression was used to adjust for baseline patient-, disease- and transplant-related characteristics. Analysis of the BM recipients showed that high CD34 cell dose was associated with lower transplant-related mortality [relative risk (RR) = 0.60, P = 0.033] and treatment failure (inverse of leukaemia-free survival, RR = 0.69, P = 0.032). Among PBSC recipients, high CD34 dose was associated with faster recovery of neutrophils to > 0.5 x 109/l (RR = 1.38, P < 0.001) and platelets to > 20 x 109/l (RR = 1.34, P = 0.003), lower risk of relapse (RR = 0.62, P = 0.029) and treatment failure (RR = 0.74, P = 0.03). We conclude that higher CD34 cell doses decrease treatment failure in recipients of HLA-identical sibling BM and PBSC transplants.

Acute Disease↗
PubMed2002

The mutational spectrum of brachydactyly type C.

Growth/differentiation factor-5 (GDF5), also known as cartilage-derived morphogenetic protein-1 (CDMP-1), is a secreted signaling molecule that participates in skeletal morphogenesis. Heterozygous mutations in GDF5, which maps to human chromosome 20, occur in individuals with autosomal dominant brachydactyly type C (BDC). Here we show that BDC is locus homogeneous by reporting a GDF5 frameshift mutation segregating with the phenotype in a family whose trait was initially thought to map to human chromosome 12. We also describe heterozygous mutations in nine additional probands/families with BDC and show nonpenetrance in a mutation carrier. Finally, we show that mutant GDF5 polypeptides containing missense mutations in their active domains do not efficiently form disulfide-linked dimers when expressed in vitro. These data support the hypothesis that BDC results from functional haploinsufficiency for GDF5.

Animals↗
PubMed2002

Severity of chronic graft-versus-host disease: association with treatment-related mortality and relapse.

Chronic graft-versus-host disease (cGVHD) is the leading cause of late treatment-related deaths among recipients of allogeneic bone marrow and blood transplants. However, cGVHD is also associated with fewer relapses. We sought to determine whether severity of cGVHD predicts the magnitude of these effects. One impediment to such an analysis is the current limited/extensive grading system for cGVHD because this classification was designed to identify patients likely to benefit from systemic immune suppression and does not capture the severity of multiorgan involvement. We, therefore, first developed a grading system predictive for survival by using data from 1827 HLA-matched sibling allotransplant recipients reported to the International Bone Marrow Transplant Registry (IBMTR). We found Karnofsky performance score, diarrhea, weight loss, and cutaneous and oral involvement to be independent prognostic variables, from which we generated a grading scheme. We tested this scheme, the limited/extensive classification system, and a classification based on clinical impression of overall cGVHD severity (mild/moderate/severe) in parallel analyses of 1092 HLA-matched sibling transplant recipients from the IBMTR and 553 recipients of unrelated donor marrow from the National Marrow Donor Program. Presence of cGVHD was associated with fewer relapses (relative risk [RR], 0.5-0.6) but more treatment-related mortality (RR, 1.8-2.8) in the 3 analyses. No grading scheme correlated cGVHD severity with relapse rates, but all schemes predicted treatment-related mortality. Survival and disease-free survival of the most favorable cGVHD group in each scheme were similar, or better, than those of patients without cGVHD; these patients may not need aggressive or extended immune suppression.

Adolescent↗
PubMed2002

Effect of tolerance to noninherited maternal antigens on the occurrence of graft-versus-host disease after bone marrow transplantation from a parent or an HLA-haploidentical sibling.

In haploidentical transplantation, the mismatched haplotype of the donor can originate from either of the parents. We refer to such mismatched haplotypes as noninherited maternal antigens (NIMA haplotype) or noninherited paternal antigens (NIPA haplotype). To determine whether exposure to maternal HLA antigens benefits patients undergoing bone marrow transplantation, we analyzed graft failure and graft-versus-host disease (GVHD) after transplantations from parental or haploidentical sibling donors. We studied 269 patients receiving 1 or 2 HLA-A, -B, -DR antigen-mismatched sibling or parental non-T-cell-depleted bone marrow transplants for acute myelogenous leukemia, acute lymphoblastic leukemia, or chronic myelogenous leukemia between 1985 and 1997 that were reported to the International Bone Marrow Transplant Registry. Included were 121 (45%) NIMA-mismatched and 148 (55%) NIPA-mismatched transplantations. Sixty-three (52%) of the NIMA-mismatched transplants and 69 (47%) of the NIPA-mismatched transplants were from haploidentical sibling donors. Sibling transplantations mismatched for NIMA had similar rates of graft failure but lower rates of acute GVHD (P <.02) than NIPA-mismatched sibling transplantations. In the first 4 months after transplantation, mother-to-child transplantations involved significantly less chronic GVHD than father-to-child transplantations (P <.02). Treatment-related mortality (TRM) was significantly higher after parental transplantations (P =.009 for mother; P =.03 for father) than after haploidentical sibling transplantations mismatched for the NIMA. Non-T-cell-depleted bone marrow transplants donated by haploidentical siblings to recipients mismatched for NIPA and transplants donated by parents caused more acute and chronic GVHD and TRM than transplants donated by haploidentical siblings mismatched for NIMA.

Adolescent↗