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Biomedical subjects

N A Kernan

Publications and source records attributed to N A Kernan.

At least 19 recordsLinked to original sources
PubMed2006

Topotecan, thiotepa, and carboplatin for neuroblastoma: failure to prevent relapse in the central nervous system.

We report on a three-drug myeloablative regimen designed to consolidate remission and to prevent central nervous system (CNS) relapse of high-risk neuroblastoma (NB). Sixty-six NB patients received topotecan 2 mg/m2/day, x 4 days; thiotepa 300 mg/m2/day, x 3 days; and carboplatin approximately 500 mg/m2/day, x 3 days. Post-SCT treatments included radiotherapy, immunotherapy, 13-cis-retinoic acid, +/-oral etoposide. Significant nonhematologic toxicities were mucositis and skin-related in all patients, convulsions in three patients, and cardiac failure and venocclusive disease of liver in one patient each. Grade 2 hepatotoxicity led to truncating cytoreduction in two patients; both later relapsed in brain. Among 46 patients transplanted in first complete/very good partial remission (CR/VGPR), event-free survival is 54% (s.e.+/-8%) at 36 months post-SCT; notable events were three non-NB-related deaths (adenovirus on day +9, bowel necrosis at 5 months, multiorgan failure at seven months) and four relapses in brain. Of 12 patients transplanted with evidence of NB, two became long-term event-free survivors and two relapsed in the brain. Of eight patients transplanted in second or greater CR/VGPR, one became a long-term event-free survivor and seven relapsed though not in the CNS. This regimen has manageable toxicity but does not prevent CNS relapse.

Adolescent↗
PubMed2001

Lung transplantation after allogeneic marrow transplantation in pediatric patients: the Memorial Sloan-Kettering experience.

BACKGROUND: Chronic lung disease and pulmonary failure are complications that can occur after bone marrow transplantation (BMT) and are associated with severe morbidity and mortality. METHODS: We report on four patients who developed chronic, progressive, and irreversible lung disease 1 to 3 years after allogeneic BMT in childhood. These patients had chronic graft-versus-host disease (n=3) or radiation-related pulmonary fibrosis (n=1). Three patients underwent double lung transplants and one patient underwent a single lung transplant 2 to 14 years after BMT. RESULTS: All four patients tolerated the lung transplantation procedure well and showed significant clinical improvement with normalization of pulmonary function tests by 1 year posttransplant. One patient died from infectious complications 3 years after lung transplantation, and one patient died after chronic rejection of the transplanted lungs 6 years posttransplant. Two patients remain alive without significant respiratory impairment 2 and 7 years after lung transplantation. CONCLUSION: We conclude that lung transplantation offers a viable therapeutic option for patients who develop respiratory failure secondary to BMT.

Adolescent↗
PubMed2001

Donor characteristics as risk factors in recipients after transplantation of bone marrow from unrelated donors: the effect of donor age.

The National Marrow Donor Program (NMDP) maintains a registry of approximately 4 million volunteer unrelated donors for patients in need of a stem cell transplant. When several comparably HLA-matched volunteers are identified for a patient, various criteria are used to select a donor. A retrospective analysis of 6978 bone marrow transplantations facilitated by the NMDP from 1987 to 1999 was conducted to study the effects of various donor characteristics on recipient outcome. The evaluation addressed possible effects of donor age, cytomegalovirus serologic status, ABO compatibility, race, sex, and parity on overall and disease-free survival, acute and chronic graft-versus-host disease (GVHD), engraftment, and relapse. Age was the only donor trait significantly associated with overall and disease-free survival. Five-year overall survival rates for recipients were 33%, 29%, and 25%, respectively, with donors aged 18 to 30 years, 31 to 45 years, and more than 45 years (P =.0002). A similar effect was observed among HLA-mismatched cases (28%, 22%, and 19%, respectively). A race mismatch between recipient and donor did not affect outcome. The cumulative incidences of grade III or IV acute GVHD were 30%, 34%, and 34%, respectively, with donors aged 18 to 30 years, 31 to 45 years, and more than 45 years (P =.005). The corresponding incidences of chronic GVHD at 2 years were 44%, 48%, and 49% (P = 0.02). Recipients with female donors who had undergone multiple pregnancies had a higher rate of chronic GVHD than recipients with male donors (54% versus 44%; P <.0001). The use of younger donors may lower the incidence of GVHD and improve survival after bone marrow transplantation. Age should be considered when selecting among comparably HLA-matched volunteer donors.

Adolescent↗
PubMed2000

Engraftment and survival after unrelated-donor bone marrow transplantation: a report from the national marrow donor program.

We analyzed engraftment of unrelated-donor (URD) bone marrow in 5246 patients who received transplants facilitated by the National Marrow Donor Program between August 1991 and June 1999. Among patients surviving at least 28 days, 4% had primary graft failure (failure to achieve an absolute neutrophil count > 5 x 10(8)/L before death or second stem-cell infusion). Multivariate logistic regression analysis showed that engraftment was associated with marrow matched at HLA-A, HLA-B, and DRB1; higher cell dose; younger recipient; male recipient; and recipient from a non-African American ethnic group. More rapid myeloid engraftment was associated with marrow serologically matched at HLA-A and HLA-B, DRB1 match, higher cell dose (in non-T-cell-depleted cases), younger recipient, recipient seronegativity for cytomegalovirus (CMV), male donor, no methotrexate for graft-versus-host disease prophylaxis, and transplantation done in more recent years. A platelet count higher than 50 x 10(9)/L was achieved by 47% of patients by day 100. Conditional on survival to day 100, survival at 3 years was 61% in those with platelet engraftment at day 30, 58% in those with engraftment between day 30 and day 100, and 33% in those without engraftment at day 100 (P <.0001). Factors favoring platelet engraftment were higher cell dose, DRB1 allele match, recipient seronegativity for CMV, HLA-A and HLA-B serologically matched donor, and male donor. Secondary graft failure occurred in 10% of patients achieving initial engraftment, and 18% of those patients are alive. These data demonstrate that quality of engraftment is an important predictor of survival after URD bone marrow transplantation.

Adolescent↗
PubMed2000

Successful treatment of metastatic retinoblastoma.

BACKGROUND: In the past, patients with metastatic retinoblastoma have had a poor prognosis when treated with conventional modalities. In the current study, the authors evaluated the use of combined intensive conventional chemotherapy, high dose chemotherapy with autologous stem cell rescue (ASCR), and radiation therapy. METHODS: Four patients with metastatic retinoblastoma were treated. All had orbital and bone marrow metastases. In addition, three patients had bone metastases and two patients had liver metastases. None had central nervous system disease. Patients received intensive conventional chemotherapy that included vincristine, cyclophosphamide, etoposide, and either cisplatin or carboplatin. Stem cells were harvested after bone marrow disease was no longer detectable. High dose chemotherapy with carboplatin (500 mg/m(2)/day x 3 days or area under the curve = 7 via the Calvert formula) and thiotepa (300 mg/m(2)/day x 3 days) with (n = 3 patients) or without (n = 1 patient) etoposide (250 mg/m(2)/day x 3 days) was administered with ASCR. Sites that originally harbored bulky disease were irradiated after recovery from the high dose chemotherapy. RESULTS: The therapy was associated with substantial acute hematopoietic and mucosal toxicities. At last follow-up, all four patients had survived event free from 46-80 months after the diagnosis of metastatic disease. CONCLUSIONS: The treatment strategy described in the current study is effective for patients with metastatic retinoblastoma that does not involve the central nervous system. However, a multicenter trial should be considered to evaluate it in a larger group of patients.

Adolescent↗
PubMed2000

Unrelated donor marrow transplantation for chronic myelogenous leukemia: 9 years' experience of the national marrow donor program.

Over a period of 8.5 years (February 1988 to October 1996), 1423 patients with chronic myelogenous leukemia (CML) underwent unrelated donor (URD) bone marrow transplants (BMTs) facilitated by the National Marrow Donor Program (NMDP) at 85 transplant centers. One hundred thirty-seven evaluable (9.9%) patients failed to engraft, and an additional 83 (6.6%) evaluable patients experienced late graft failure. Grade III/IV acute graft-versus-host disease (GVHD) developed in 33% of patients (95% confidence interval [CI], 30%-36%). The incidence of extensive chronic GVHD was 60% (95% CI, 56%-63%) at 2 years. Only 5.7% of patients (95% CI, 3.6%-7.8%) transplanted in chronic phase developed hematologic relapse at 3 years. Several factors were independently associated with improved disease-free survival (DFS), including transplant in chronic phase, transplant within 1 year of diagnosis, younger recipient age, a cytomegalovirus seronegative recipient, and development of no or mild acute GVHD. The combined effect of these factors on outcome is manifest in a subset (n = 157) of young (less than 35 years), chronic phase patients transplanted within 1 year of diagnosis using HLA-matched donors who had 63% (95% CI, 53%-73%) DFS at 3 years. URD BMT therapy for CML is both feasible and effective with more frequent and more rapid identification of suitable donors. Early URD transplant during chronic phase yields good results and should be considered in CML patients otherwise eligible for transplant but without a suitable related donor.

Age Factors↗
PubMed2000

Treatment of relapsed leukemia after unrelated donor marrow transplantation with unrelated donor leukocyte infusions.

The efficacy and toxicity of donor leukocyte infusions (DLI) after unrelated donor bone marrow transplantation (BMT) is largely unknown. We identified 58 recipients of unrelated DLI (UDLI) for the treatment of relapsed disease from the National Marrow Donor Program database. A retrospective analysis was performed to determine response, toxicity, and survival after UDLI and to identify factors associated with successful therapy. UDLI was administered for relapsed chronic myelogenous leukemia (CML) (n = 25), acute myelogenous leukemia (AML) (n = 23), acute lymphoblastic leukemia (ALL) (n = 7), and other diseases (n = 3). Eight patients were in complete remission (CR) before UDLI, and 50 were evaluable for response. Forty-two percent (95% confidence interval [CI], 28%-56%) achieved CR, including 11 of 24 (46%; 95% CI, 26%-66%) with CML, 8 of 19 (42%; 95% CI, 20%-64%) with AML, and 2 of 4 (50%; 95% CI, 1%-99%) with ALL. The estimated probability of disease-free survival (DFS) at 1 year after CR was 65% (95% CI, 50%-79%) for CML, 23% (95% CI, 9%-38%) for AML, and 30% (95% CI, 6%-54%) for ALL. Acute graft-versus-host disease (GVHD) complicated UDLI in 37% of patients (grade II-IV, 25%). A total of 13 of 32 evaluable patients (41%) developed chronic GVHD. There was no association between cell dose administered and either response or toxicity. In a multivariable analysis, only a longer interval from BMT to relapse and BMT to UDLI was associated with improved survival and DFS, respectively. UDLI is an acceptable alternative to other treatment options for relapse after unrelated donor BMT. (Blood. 2000;95:1214-1221)

Analysis of Variance↗
PubMed2000

Daclizumab, a humanized anti-interleukin-2 receptor alpha chain antibody, for treatment of acute graft-versus-host disease.

Daclizumab, a humanized monoclonal IgG1 directed against the alpha chain of the interleukin-2 receptor (IL-2R), is a competitive inhibitor of IL-2 on activated lymphocytes. To test the hypothesis that specific inhibition of activated lymphocytes in patients with ongoing acute graft-versus-host disease (GVHD) might ameliorate the process, we treated 43 patients with advanced or steroid-refractory GVHD with daclizumab. The first cohort of 24 patients was treated with daclizumab 1 mg/kg on days 1, 8, 15, 22, and 29. On day 43, the complete response (CR) rate was 29% (95% confidence interval [CI], 13%-51%). Survival on day 120 was 29% (95% CI, 13%-51%). A second cohort of 19 patients was treated with daclizumab 1 mg/kg on days 1, 4, 8, 15, and 22. For these patients, the CR rate on day 43 was 47% (95% CI, 24%-71%), and survival on day 120 was 53% (95% CI, 29%-76%). There were no infusion-related reactions and no serious side effects related to daclizumab. Following treatment, there was a reduction in serum concentrations of soluble IL-2R and peripheral blood CD3( + )25(+) lymphocytes, but these changes were not predictive of response. Daclizumab has substantial activity for the treatment of acute GVHD, and the second regimen evaluated is recommended for a controlled study. (Blood, 2000; 95:83-89)

Adolescent↗
PubMed2000

Stem cell transplantation for the treatment of Fanconi anaemia using a fludarabine-based cytoreductive regimen and T-cell-depleted related HLA-mismatched peripheral blood stem cell grafts.

We have employed a new cytoreductive regimen to transplant two patients with Fanconi anaemia (FA), using T cell-depleted two HLA-allele disparate related peripheral blood stem cell transplants (PBSCTs). Patient 1, a 5-year-old male with FA and aplastic anaemia, initially received an HLA two-antigen mismatched unrelated cord blood transplant and failed to engraft. He received fludarabine (Flu) and cyclophosphamide (Cy), followed by a CD34(+) E-rosette(-) (CD34(+)E(-)), T cell-depleted, granulocyte colony-stimulating factor (G-CSF)-mobilized PBSCT from his HLA B-DRB1 mismatched father. He received anti-thymocyte globulin (ATG), steroids, FK506 and G-CSF after transplant for rejection and graft-versus-host disease (GVHD) prophylaxis. The patient is now 23 months after SCT with no evidence of GVHD and with full haematopoietic and immune reconstitution. Patient 2, a 10-year-old boy with FA and myelodysplastic syndrome, received single-dose total body irradiation (SDTBI), Flu and Cy followed by a CD34(+)E(-), T-cell-depleted, G-CSF-mobilized PBSCT from his HLA B-DRB1 mismatched sister. He also received ATG, steroids, FK506 and G-CSF after transplant. The patient is now 12 months after SCT in complete remission with no evidence of GVHD. Absolute neutrophil counts (ANC) of > 1 x 10(9)/l were achieved on day 11 and day 10 post transplant respectively. Both patients are fully engrafted. In summary, we report two successful T-cell-depleted stem cell transplants from mismatched related donors for the treatment of Fanconi anaemia, using a fludarabine-based cytoreduction. Both patients experienced minimal toxicity, rapid engraftment and no GVHD.

Child, Preschool↗
PubMed1999

The probability of HLA-C matching between patient and unrelated donor at the molecular level: estimations based on the linkage disequilibrium between DNA typed HLA-B and HLA-C alleles.

BACKGROUND: Recent evidence suggests a more significant role of HLA-C as a target of alloreactions after bone marrow transplantation than previously suspected. Although linkage disequilibrium (LD) between HLA-B and -C serogroups is well documented, the level of LD at the allelic level is not known. In this study, we determine the LD between HLA-B and -C alleles and estimate the probability of molecular HLA-C matching between unrelated individuals who match for both HLA-B alleles. METHODS: The study included 727 haplotypes from 849 individuals who were HLA-A, -B, -C and -DRB1 typed by high-resolution PCR-SSOP technique. Zelterman's statistic was used to test for global LD between HLA loci. LD between specific HLA-B and -C allelic combinations was calculated from their observed and expected frequencies in the study haplotypes. The probability of HLA-C matching for specific HLA-B allele was estimated from contingency table generated from the HLA-B and -C haplotypes. RESULTS: HLA-C was found to exist in LD with HLA-A and -B, as well as -DRB1, loci; however, it was strongest between HLA-B and -C loci. A marked variability in the level of LD between specific HLA-B and -C alleles was noticed. A strong LD was seen in some allele pairs like B*0702-C*w0702, B*3501-Cw*0401, and B*0801-Cw*0701. The overall estimated probability of HLA-C matching between unrelated individuals that match for both HLA-B alleles is 42.25%. For 237 (72.9%) of 325 combinations involving the 25 commonest HLA-B alleles, the estimated probability that the HLA-B-matched unrelated individuals will match for both HLA-C alleles is less than 50%. In addition, a 100% probability of matching for both HLA-C alleles is expected only if both individuals bear either B*0801/ B*0801 or B*4901/B*4901 or B*0801/B*4901. Probability tables for common alleles are presented. CONCLUSIONS: We conclude that, despite matching for both HLA-B alleles by high resolution DNA typing and the presence of a strong LD between HLA-B and HLA-C loci, unrelated individuals are more likely to mismatch rather than match for one or both HLA-C alleles.

Alleles↗
PubMed1999

DNA typing for HLA-A and HLA-B identifies disparities between patients and unrelated donors matched by HLA-A and HLA-B serology and HLA-DRB1.

High incidences of graft failure and graft-versus-host disease in the recipients of bone marrow transplantations (BMT) from unrelated donors (URD) may reflect the existence of allelic disparities between the patient and the URD despite apparent HLA identity at HLA-A, HLA-B, and HLA-DRB1 loci. To identify the extent and pattern of allelic disparities at HLA-A and HLA-B loci, 128 patients and 484 potential URD were evaluated by DNA typing. DNA typing for HLA-A, HLA-B, and HLA-DRB1 was performed at Memorial Sloan Kettering Cancer Center. HLA-A and HLA-B serotyping on URD was provided by the registries. By original typing (serology for HLA-A and HLA-B; DNA typing for DRB1) 187, 164, and 133 URD were 6/6, 5/6, and 4/6 matches, respectively. Following DNA typing, however, only 52.9% of the originally 6/6 matched URD remained 6/6, while 38.5%, 7.5%, and 1.1% were found to be 5/6, 4/6, and 3/6 matches. The level of disparity was higher in the originally 5/6 (P <.01) and 4/6 (P <.01) matched URD. A higher level of disparity was seen for HLA-B as compared to HLA-A. In addition, a serotype related variation was also noticed. For example, 24.1% of HLA-A2 and 60.1% of HLA-B35 seromatched URD were genotypically disparate, but no disparities were seen for HLA-A1 and HLA-B8. A higher percentage of HLA-A (67. 4%) compared with HLA-B (35.4%) serologic homozygous URD remained genotypically homozygous (P =.01). The level of allelic disparity was lower (P <.01 for 6/6; P =.02 for 5/6) if the patient had one of the 15 most common haplotypes (A1B8DR3, A2B7DR15, A3B7DR15, etc) in comparison to the rest of the group. Outcome studies will answer the question whether these disparities are associated with a higher rate of immunological complications seen with URD-BMT.

Bone Marrow Transplantation↗
PubMed1999

HLA-C disparity between patients and unrelated donors matched for HLA-A, -B, and -DRB1 alleles: impact of serological vs. DNA typing for HLA-A and -B loci.

High incidences of graft failure, graft-vs.-host disease (GVHD), and serious infections following unrelated donor (URD) marrow transplantation, despite apparent human leukocyte antigen (HLA) identity, may reflect the presence of molecular disparities, including those for HLA-C alleles between the patient and the URD. The level of these disparities could be significant, because as many as 42 alleles are currently known for HLA-C locus. We studied 84 patients and 251 potential URDs to evaluate 1) the extent of HLA-C disparity between the patient and the URD identified by serology for HLA-A and -B and by DNA typing for -DRB1 and 2) the level of HLA-C disparity between patients and URDs matched by high-resolution DNA typing for HLA-A, -B, and -DRB1. The DNA typing was performed at the Memorial Sloan Kettering Cancer Center, and the serotyping was provided by the registries. Of 251 URDs matched by HLA-A and -B serology and -DRB1 (sA_sB_dnaDRB1 ); 94, 75, and 82 were 6/6, 5/6, and 4/6 matches, respectively. Of 94 sA_sB_dnaDRB1 6/6 URDs, 51 (54.3%) were matched for both HLA-C alleles. In contrast, 31 (41.3%) 5/6 (p=0.12) and 15 (18.3%) 4/6 (p < 0.01) sA_sB_dnaDRB1 URDs were matched for both HLA-C alleles. Following DNA typing for HLA-A and -B, 52 (55.3%) of 94 6/6, 30 (40%) of 75 5/6, and 25 (30.5%) of 82 4/6 sA_sB_dnaDRB1 URDs remained 6/6, 5/6, and 4/6 matches at the DNA level (dnaA_B_DRB1). HLA-C disparities continued to exist in the dnaA_B_DRB1 URD group. Of 54 dnaA_B_DRB1 6/6 URDs, 41 (75.9%) were matched for both HLA-C alleles. Only 45.3% of the 5/6 (p=0.01) and 22.2% of the 4/6 (p < 0.01) dnaA_B_DRB1 URDs were matched for both HLA-C alleles. In the 6/6 category, the frequency of HLA-C matching improved (75.9 vs. 54.3%; p=0.01) following DNA matching for HLA-A and -B. In comparison to mismatching for HLA-B locus, mismatching for either HLA-DRB1 or -A resulted in a lower odds ratio for HLA-C disparity. The presence of a common haplotype in the sA_sB_dnaDRBl (p=0.06) URD category improved the level of HLA-C matching. We identified alleles that are associated with high (B*1501, B*4402, B*5101, DRB1*0101, A*0201, A*1101, A*2301, and A*3201) or low (B*0702, B*0801, B*1302, B*3502, DRB1*0301, DRB1*1104, A*0101, A*3001, and A*6801) probability of HLA-C disparity. Overall, sA_sB_dnaDRB1 as well as dnaA_B_DRB1 matched URDs for non-Caucasian patients were more likely to have HLA-C disparity in comparison to the matched URDs of Caucasian patients. However, a high incidence of HLA-C disparities was identified even in the URDs for Caucasian patients. Whether the disparities demonstrated by this study contribute to the higher immunological complications noted following URD bone marrow transplantation is unclear. Outcome analysis and studies aimed at understanding the functional role of HLA-C may provide an answer.

Bone Marrow Transplantation↗
PubMed1999

Allogeneic bone marrow transplantation versus chemotherapy for the treatment of childhood acute lymphoblastic leukemia in second remission: a single-institution study.

PURPOSE: A retrospective analysis of the treatment of childhood acute lymphoblastic leukemia (ALL) in second remission (CR2) was undertaken at our institution to compare the outcome and prognostic factors of patients treated with chemotherapy or allogeneic bone marrow transplantation (BMT). PATIENTS AND METHODS: Seventy-five children who suffered a medullary relapse and achieved a second remission were treated with either an unmodified allogeneic HLA-matched sibling BMT after hyperfractionated total body irradiation (TBI) and cyclophosphamide (n = 38) or chemotherapy according to institutional chemotherapy protocols (n = 37). To avoid the bias of survival from the attainment of second remission in favor of BMT, the final comparative statistical analysis used the landmark approach and comprised 37 and 29 patients from the BMT and chemotherapy groups, respectively RESULTS: The disease-free survival (DFS) rate was 62% and 26% at 5 years, respectively, for the BMT and the chemotherapy groups (P = .03), with relapse rates of 19% and 67%, respectively, for these two groups (P = .01). There was an overall advantage for the BMT therapeutic approach, as compared with chemotherapy, for patients with ALL in CR2 (1) for patients with a WBC count (at diagnosis) of 20 x 10(9)/L or higher (DFS, 40% v 0%) and those with a WBC count of less than 20 x 10(9)/L (DFS, 73% v35%), (2) for patients whose duration of CR1 was less than 24 months (DFS 48% v 9%) and for patients whose duration of CR1 was 24 months or longer (DFS, 81% v 37%) and (3) for patients who were initially treated with intensive regimens incorporating more than five chemotherapy agents (DFS, 57% v 20%) and for patients treated with five agents or fewer (DFS, 72% v 32%). CONCLUSION: In our single-institution series, unmodified HLA-matched allogeneic sibling transplants using hyperfractionated TBI and cyclophosphamide for patients with ALL in CR2 have resulted in superior outcome with a significantly improved probability of DFS and a lower relapse rate, as compared with those for patients treated with chemotherapy, regardless of the duration of first remission, the disease characteristics at diagnosis, or the intensity of prior treatment during first remission.

Antineoplastic Agents↗
PubMed1998

T-cell-depleted allogeneic bone marrow transplantation as postremission therapy for acute myelogenous leukemia: freedom from relapse in the absence of graft-versus-host disease.

Thirty-one consecutive patients with acute myelogenous leukemia (AML) in first complete remission and 8 with AML in second complete remission received T cell-depleted allogeneic bone marrow transplants from HLA-identical sibling donors. Patients received myeloablative cytoreduction consisting of hyperfractionated total body irradiation, thiotepa, and cyclophosphamide. Those patients at risk for immune-mediated graft rejection received additional immune suppression with antithymocyte globulin and methylprednisolone in the early peritransplant period. Patients with AML who underwent allogeneic T-cell-depleted bone marrow transplantations (BMT) in first or second remission have achieved respective disease-free survival (DFS) probabilities of 77% (median follow-up at approximately 56 months) and 50% (median follow-up at approximately 48 months). Ten of 31 patients transplanted in first remission were > or = 40 years old and have attained a DFS at 4 years of 70%. For patients with AML transplanted in first or second remission, the respective cause-specific probabilities of relapse were 3.2% or 12.5%, and those of nonleukemic mortality were 19.4% or 37.5%. There were no cases of immune-mediated graft rejection and no cases of grade II to IV acute graft-versus-host disease (GVHD). All survivors enjoy Karnofsky performance scores (KPS) of 100%, except 2 patients with KPS of 80% to 90%. T-cell-depleted allogeneic BMT can provide durable DFS together with an excellent performance status in the majority of patients with de novo AML. In addition, GVHD is not an obligatory correlate of the graft-versus-leukemia benefit or freedom from relapse afforded by allogeneic BMT administered as postremission therapy for AML. This study provides a basis for prospective comparison with other postremission therapies considered standard in the management of patients with this disease.

Adolescent↗
PubMed1998

Cord Blood Transplantation Study (COBLT): cord blood bank standard operating procedures.

In 1995, the National Heart Lung and Blood Institute (NHLBI) solicited requests for a proposal (RFP) entitled "Transplant Centers for Clinical Research on Transplantation of Umbilical Cord Stem and Progenitor Cells." Three banks, six transplant centers, and one medical coordinating center (MCC) (Table 1) were funded with the overall goal of banking cord blood units (CBU) using a single manual of operations. Furthermore, the clinical protocols to evaluate the transplant outcome for adult and pediatric recipients of these well-characterized CBU would be analyzed in a uniform fashion. Because of the intense interest of the transplantation community in the policies and procedures for cord blood collection and processing, the principal investigators of the cord blood banks (CBB) and NHLBI elected to submit for publication the rationale and an abridged, but detailed, version of the standard operating procedures (SOP) developed between October 1996 and July 1998 prior to the initiation of the clinical protocols to be performed with these CBU. As the SOP will be refined over time, the complete SOP and subsequent amendments will be published and continually updated on the websites from the MCC-The EMMES Corporation (www.EMMES.com). All forms referred to in this document may be obtained from the EMMES website. It is hoped that the publication of this document will lay down a framework that will not only facilitate the development of other CBB but also help us more rapidly define what constitutes an "acceptable" CBU product.

Adult↗
PubMed1998

High-dose induction chemoradiotherapy followed by autologous bone marrow transplantation as consolidation therapy in rhabdomyosarcoma, extraosseous Ewing's sarcoma, and undifferentiated sarcoma.

PURPOSE: To improve response and survival rates in patients with high-risk rhabdomyosarcoma (RMS), extraosseous Ewing's sarcoma, and undifferentiated sarcoma, we used a short course of induction with multi-agent chemotherapy, hyperfractionated radiotherapy, and surgery when possible. Consolidation was with intensive chemotherapy and autologous bone marrow transplantation (ABMT). PATIENTS AND METHODS: Twenty-six patients (21 with RMS, three with undifferentiated sarcoma, and two with extraosseous Ewing's sarcoma) were entered onto the protocol between June 1990 and March 1994. Induction consisted of ifosfamide, etoposide, doxorubicin, dactinomycin, cyclophosphomide, and vincristine, and a split course of hyperfractionated radiotherapy. Patients who attained a complete response (CR) or good partial response (GPR) received consolidation with high-dose melphalan and etoposide followed by ABMT. RESULTS: Of 26 previously untreated patients 19 (73%) achieved a CR (n=13) or GPR (n=6) at the completion of induction and underwent ABMT. Two-year overall survival (OS) was 56% (95% confidence interval [CI], 36% to 76%) and progression-free survival (PFS) was 53% for the whole group (95% CI, 33% to 73%). CONCLUSION: Consolidation of response by myeloablative chemotherapy was well tolerated. Split-course hyperfractionated radiotherapy did not increase the rate of local control. The results of this short-course therapy were comparable to previous therapies of 1 to 2 years' duration. Induction and consolidation chemotherapy, as well as radiation dose, could be further intensified, since no death due to toxicity occurred among these patients.

Adolescent↗
PubMed1997

Risk of extramedullary relapse following allogeneic bone marrow transplantation for acute myelogenous leukemia with leukemia cutis.

Leukemia cutis (LC) is a rare feature of acute myeloblastic leukemia (AML). Little information is available regarding its prognostic influence on post-transplant outcome. In our institution, 202 patients with AML received an allogeneic HLA-identical marrow transplant from related donors between March 1982 and January 1994. Thirteen patients had prior leukemic involvement of the skin (leukemia cutis or LC group) while 189 patients did not (non-LC group). There was a higher incidence of patients with the M4-M5 FAB subtypes in the LC group (83%) as compared to the non-LC group (33%). In addition, the percentage of patients transplanted in relapse was also higher in the LC group (69 vs 15%). While there were no differences observed in the rates of relapse post-transplant in the LC and non-LC groups when matched for stage of disease at transplant, the sites of relapse differed markedly. Five of six relapses in the LC group involved extramedullary sites as compared to only six of 38 relapses in the non-LC group (P = 0.002), with a 6-year probability of extramedullary relapse of 38.5% in the LC group as compared to 3.9% in the non-LC group. This increased probability of extramedullary relapse was independent of the FAB morphology (50 vs 2% for patients with the M4-M5 subtypes in the LC and the non-LC group respectively) and of disease status at the time of transplant. Moreover, only three relapses post-transplant involved the skin, all of which were in the LC group, with a probability of skin relapse of 23.1% in this group. Patients with AML and leukemia cutis have a remarkable propensity to relapse in extramedullary sites following marrow transplantation. These relapses occur in the skin as well as other organs. Further investigations are needed to understand the biological basis of this clinical feature.

Adult↗