[Show abstract][Hide abstract] ABSTRACT: Hepatic veno-occlusive disease, also called sinusoidal obstruction syndrome (VOD/SOS), is a potentially life-threatening complication of hematopoietic stem cell transplantation (HSCT). Untreated hepatic VOD/SOS with multi-organ failure (MOF) is associated with >80% mortality. Defibrotide has shown promising efficacy treating hepatic VOD/SOS with MOF in phase 2 studies. This phase 3 study investigated the safety and efficacy of defibrotide in adult and pediatric patients with established hepatic VOD/SOS and advanced MOF. Patients (n=102) given 25 mg/kg/day defibrotide were compared with 32 historical controls identified out of 6867 medical charts of HSCT patients by a blinded independent medical review committee. Baseline characteristics between groups were well balanced. The primary objective was to compare survival at Day+100 post-HSCT; observed rates equaled 38.2% in the defibrotide group and 25.0% in the control group (estimated difference of 23.0%; 95.1% confidence interval [CI] 5.2%-40.8%; P=.0109, using a propensity-adjusted analysis based on 4 prognostic factors of survival). Observed Day+100 complete response (CR) rates equaled 25.5% for defibrotide and 12.5% in the controls (19.0% difference using similar methodology; 95.1% CI 3.5-34.6; P=.0160). Defibrotide was generally well-tolerated with manageable toxicity. Related adverse events included hemorrhage or hypotension; there was no difference in the incidence of common hemorrhagic adverse events (including pulmonary alveolar [11.8% and 15.6%] and gastrointestinal [7.8% and 9.4%]) between the defibrotide and control groups, respectively. Defibrotide was associated with significant improvement in Day+100 survival and CR rate. The historical-control methodology offers a novel, meaningful approach for phase 3 evaluation of orphan diseases associated with high mortality. This study is registered to www.clinicaltrials.gov as NCT00358501.
[Show abstract][Hide abstract] ABSTRACT: Fifty-two children with symptomatic sickle cell disease (43) or transfusion dependent thalassemia (9) received matched sibling donor marrow (46), marrow and cord product (5) or cord blood (1) allografts following reduced intensity conditioning with alemtuzumab, fludarabine and melphalan between March 2003 and May 2014*. The Kaplan-Meier probabilities of overall and event free survival at a median of 3.42 (range, 0.75-11.83) years were 94.2% and 92.3% for the group, 93% and 90.7% for sickle cell disease, and 100% and 100% for thalassemia respectively. Treatment related mortality (all related to graft versus host disease) was noted in three (5.7%) recipients, all 17-18 years of age. Acute and chronic graft versus host disease was noted in 23% and 13% respectively, with 81% of recipients off immunosuppression by one year. Graft rejection was limited to the single umbilical cord blood recipient who had prompt autologous hematopoietic recovery. Fourteen (27%) had mixed chimerism at one year and beyond; all had discontinued immunosuppression between four and twelve months from transplant with no subsequent consequence on graft versus host disease or rejection. Infectious complications included predominantly bacteremia (48% were staphylococcus) and CMV reactivation (43%) necessitating preemptive therapy. Lymphocyte recovery beyond six months was associated with subsidence of infectious complications. All patients who engrafted were transfusion independent; no strokes or pulmonary complications of sickle cell disease were noted, and pain symptoms subsided within 6 months post-transplant. These findings support using reduced intensity conditioning for patients with hemoglobinopathy undergoing matched sibling marrow transplantation (*www.ClinicalTrials.gov: NCT00920972, NCT01050855, NCT02435901). This article is protected by copyright. All rights reserved.
No preview · Article · Sep 2015 · American Journal of Hematology
[Show abstract][Hide abstract] ABSTRACT: Hepatic veno-occlusive disease (VOD) is a serious complication of stem cell transplantation in children. VOD is characterized by rapid weight gain, hepatomegaly, hyperbilirubinemia and ascites. The pathogenesis of VOD is thought to involve chemotherapy and radiation-induced damage to the sinusoidal endothelium, resulting in endothelial injury, microthrombosis, subendothelial damage and cytokine activation. These processes lead to concomitant progressive hepatocellular dysfunction and subsequent fluid retention and renal impairment. Severe VOD is typically associated with multiorgan failure and high mortality. A number of possible strategies for the prevention and/or treatment of VOD in children have been investigated. The most promising agent to date is defibrotide, a novel polydeoxyribonucleotide with fibrinolytic properties but no major bleeding risk. Numerous studies, including Phase II/III trials, have shown clinical benefit in pediatric patients with the use of defibrotide treatment and prophylaxis. This review discusses VOD in children and focuses on therapeutic options, including defibrotide, in this patient population.
No preview · Article · Jun 2012 · Expert Review of Hematology
[Show abstract][Hide abstract] ABSTRACT: The Sickle Cell Unrelated Donor Transplant Trial (SCURT trial) of the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) is a phase II study of the toxicity and efficacy of unrelated donor hematopoietic cell transplantation in children with severe sickle cell disease (SCD) using a reduced-intensity conditioning regimen. Here we report the results for the cord blood cohort of this trial. Eight children with severe SCD underwent unrelated donor cord blood transplantation (CBT) following alemtuzumab, fludarabine, and melphalan. Cyclosporine or tacrolimus and mycophenolate mofetil were administered for graft-versus-host disease (GVHD) prophylaxis. Donor/recipient HLA match status was 6 of 6 (n = 1) or 5 of 6 (n = 7), based on low/intermediate-resolution molecular typing at HLA -A, -B, and high-resolution typing at -DRB1. Median recipient age was 13.7 years (range: 7.4-16.2 years), and median weight was 35.0 kg (range: 25.2-90.2 kg). The median pre-cryopreservation total nucleated cell dose was 6.4 × 10(7) /kg (range: 3.1-7.6), and the median postthaw infused CD34 cell dose was 1.5 × 10(5) /kg (range: 0.2-2.3). All patients achieved neutrophil recovery (absolute neutrophil count >500/mm(3)) by day 33 (median: 22 days). Three patients who engrafted had 100% donor cells by day 100, which was sustained, and 5 patients had autologous hematopoietic recovery. Six of 8 patients had a platelet recovery to >50,000/mm(3) by day 100. Two patients developed grade II acute GVHD. Of these, 1 developed extensive chronic GVHD and died of respiratory failure 14 months posttransplantation. With a median follow-up of 1.8 years (range: 1-2.6), 7 patients are alive with a 1-year survival of 100%, and 3 of 8 are alive without graft failure or disease recurrence. Based upon the high incidence of graft rejection after unrelated donor CBT, enrollment onto the cord blood arm of the SCURT trial was suspended. However, because this reduced-intensity regimen has demonstrated a favorable safety profile, this trial remains open to enrollment for unrelated marrow donor transplants. Novel approaches aimed at improving engraftment will be needed before unrelated CBT can be widely adopted for transplanting patients with severe SCD.
No preview · Article · Feb 2012 · Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: A non-total body irradiation-containing preparative regimen was studied in young children (<4 years old) undergoing unrelated donor cord blood transplantation as part of the Cord Blood Transplantation trial for the treatment of acute lymphoblastic leukemia (n = 14), acute myeloid leukemia (n = 13), undifferentiated leukemia (n = 1), juvenile myelomonocytic leukemia (n = 2), and myelodysplastic syndromes (n = 2). Donor/recipient HLA matching based on low-/intermediate-resolution molecular typing for HLA-A and -B and high-resolution HLA-DRB1 typing was 5/6 or 6/6 (n = 21) or 4/6 (n = 11). The preparative therapy consisted of busulfan, melphalan, and antithymocyte globulin, with cyclosporine and corticosteroids for graft-versus-host disease (GVHD) prophylaxis. The median age was 1.6 years (range, 0.5-3.9 years), and the median weight was 10.5 kg (range, 5.8-19.5 kg). Cord blood grafts contained a median of 10.7 x 10 7 nucleated cells per kilogram (range, 4.6-29.2) and 2.6 x 10(5) CD34+ cells per kilogram (range, 0.7-8.3). The cumulative incidence (CINC) of neutrophil recovery (absolute neutrophil count >500/microL) at day 42 was 0.59 (95% confidence interval [CI], 0.44-0.78) at a median of 31 days (range, 23-55 days). The CINC and Kaplan-Meier estimates of platelet engraftment at day 180 were 0.53 (95% CI, 0.34-0.69) and 0.82 (95% CI, 0.61-1.00), respectively. CINC estimates of grade III/IV acute GVHD at day 100 and chronic GVHD at 1 year were 0.25 (95% CI, 0.09-0.41) and 0.26 (95% CI, 0.09-0.44), respectively. The CINC estimate of relapse was 0.31 (95% CI, 0.16-0.47) at 2 years. With a median follow-up of 27.8 months (range, 23.4-46.7 months), the probability of survival at 1 year was 0.47 (95% CI, 0.30-0.64). A preparative regimen containing a busulfan/melphalan/antithymocyte globulin preparative regimen is well tolerated in the setting of unrelated donor cord blood transplantation for childhood leukemia and can serve as a platform preparative regimen for intensifying host immunosuppression and antileukemic therapy to allow for improved engraftment and improved relapse-free survival.
Full-text · Article · Aug 2005 · Biology of Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Allogeneic bone marrow transplantation (BMT) from HLA-identical siblings is an accepted treatment for both thalassemia and sickle cell disease (SCD). However, it is associated with decided risk of both transplant-related mortality (TRM) and chronic graft-versus-host disease (GVHD). We analyzed 44 patients (median age, 5 years; range, 1-20 years) given an allogeneic related cord blood transplant for either thalassemia (n = 33) or SCD (n = 11). Thirty children were given cyclosporin A (CsA) alone as GVHD prophylaxis, 10 received CsA and methotrexate (MTX), and 4 patients received other combinations of immunosuppressive drugs. The median number of nucleated cells infused was 4.0 x 10(7)/kg (range, 1.2-10 x 10(7)/kg). No patient died and 36 of 44 children remain free of disease, with a median follow-up of 24 months (range, 4-76 months). Only one patient with SCD did not have sustained donor engraftment as compared with 7 of the 33 patients with thalassemia. Three of these 8 patients had sustained donor engraftment after BMT from the same donor. Four patients experienced grade 2 acute GVHD; only 2 of the 36 patients at risk developed limited chronic GVHD. The 2-year probability of event-free survival is 79% and 90% for patients with thalassemia and SCD, respectively. Use of MTX for GVHD prophylaxis was associated with a greater risk of treatment failure. Related CBT for hemoglobinopathies offers a good probability of success and is associated with a low risk of GVHD. Optimization of transplantation strategies could further improve these results.
[Show abstract][Hide abstract] ABSTRACT: Chronic lung disease and pulmonary failure are complications that can occur after bone marrow transplantation (BMT) and are associated with severe morbidity and mortality.
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.
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.
We conclude that lung transplantation offers a viable therapeutic option for patients who develop respiratory failure secondary to BMT.
[Show abstract][Hide abstract] ABSTRACT: 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).
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
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%).
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.
No preview · Article · Feb 1999 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: To evaluate the reliability of CD34/CD33 subset enumeration as a predictor of hematopoietic repopulating potential in autologous blood stem-cell transplantation and to determine which patient and treatment-related factors affect the timing, quantity, and type of blood stem cells mobilized.
We analyzed blood stem-cell collections from 410 consecutive cancer patients who received mobilization therapy and evaluated factors, including CD34+ subset quantities, that might influence engraftment kinetics and transfusion requirements in autologous blood stem-cell recipients.
The majority of patients (97%) mobilized CD34+33- cells, which were usually collected in the greatest quantity on the first day of apheresis. Patients who received only growth factor mobilized the highest percentage of CD34+33- cells. Extensive prior chemotherapy limited the collection of CD34+33- cells. In addition to patient diagnosis (P < .006) and total CD34+ cell dose (P = .0001), CD34+33- cell dose (P < .005) and percentage of CD34+33- cells (P < .005) were identified as independent factors significantly predictive of engraftment kinetics. CD34+33- cell dose (R2 < or = .177; P < .0001) was a strong and the only significant predictor of RBC and platelet transfusion requirements. Furthermore, independent of the total CD34+ cell dose, as the CD34+33- cell dose increased, days to neutrophil recovery, days to platelet recovery, and transfusion requirements decreased.
These findings show that CD34+33- cells are readily collected in most cancer patients and significantly influence engraftment kinetics and transfusion requirements in autologous blood stem-cell recipients. CD34+33- cell quantity of the blood stem-cell graft appears to be a more reliable predictor of hematopoietic recovery rates than total CD34+ cell quantity in this setting.
No preview · Article · Jul 1998 · Journal of Clinical Oncology
[Show abstract][Hide abstract] ABSTRACT: Peripheral blood progenitor cells (PBPC) reside within the mononuclear cell (MNC) component of the blood and can be collected using a number of apheresis devices, including the Fenwal CS3000 Plus Blood Cell Separator. Increased MNC collection efficiency, therefore, may reduce the number of apheresis required to achieve collection goals. In this study, patients were divided into groups by absolute MNC count to determine the effect of interface detector offset (I/O) adjustment on MNC collection efficiency. Apheresis products from 104 procedures collected using a standard I/O setting of 100 were compared with 121 collections for which the I/O setting was adjusted according to the preapheresis MNC count. Adjustment of the I/O setting in this manner had no statistically significant impact on the per kilogram dose of MNC collected. The data did show that MNC collection efficiency was reduced as both the MNC count and I/O setting increased, as the collection efficiency was greatest for patients with the lowest peripheral MNC counts and was inversely correlated with the preapheresis MNC count. Although contamination of the product with platelets was drastically reduced at higher I/O settings, there was a concomitant rise in RBC contamination. We conclude that a standard setting of 100 is preferable to adjustment of the I/O setting as a function of the preapheresis MNC count.
No preview · Article · Feb 1998 · Journal of Hematotherapy
[Show abstract][Hide abstract] ABSTRACT: Children with severe aplastic anemia (SAA) are treated with bone marrow transplantation (BMT) if a human leukocyte antigen (HLA) compatible sibling donor is available, or alternatively with immunosuppressive therapy (IST). Three retrospective trials examining BMT vs IST in pediatric patients treated from 1970-1988 found BMT resulted in a superior survival rate. Advances have been made in general supportive care and in the approach to each of these treatment modalities in the last decade. To compare survival following BMT and IST in a more recent era, we retrospectively analyzed the results of 48 consecutively treated children with SAA presenting to Memorial Sloan-Kettering Cancer Center (MSKCC) between 1983 and 1992. In contrast to the previous studies, the estimated survival of the BMT and IST groups at 120 months are equivalent, 75.6% and 73.8%, respectively. The IST results in our series are superior to the 42-48% (2-10 year) survival previously published, but similar to survival data observed in more recent IST trials employing more intensive immunosuppression (antithymocyte globulin and cyclosporine). The overall BMT survival rates are similar to those previously published, although BMT results improved dramatically during the latter five years of this analysis, with all 11 patients transplanted surviving with a minimum follow-up of 3 years. No surviving BMT patient has extensive chronic graft-versus-host disease (GvHD), a major cause of long-term mortality post-BMT. Therefore, it is likely the BMT survival curve will remain stable. In contrast, the survival curve of the IST patients is likely unstable, since patients are still at risk for relapse or development of clonal disease. Thus, despite overall similar survival rates, we continue to recommend BMT as first-line therapy in pediatric SAA patients with matched sibling donors.
No preview · Article · May 1997 · Biology of Blood and Marrow Transplantation
[Show abstract][Hide abstract] ABSTRACT: Bilateral renal enlargement was noted on ultrasonography during an extensive renal evaluation for severe hypokalemic metabolic acidosis with an increased anion gap in a 12-year-old Hispanic boy who had normal results of a physical examination and complete blood count. The patient was found to have acute lymphoblastic leukemia. Resolution of the lactic acidosis and bilateral renal enlargement occurred with initiation of chemotherapy and recurred with each subsequent relapse. (J PEDIATR 1994;125:584-6).
No preview · Article · Nov 1994 · Journal of Pediatrics
[Show abstract][Hide abstract] ABSTRACT: To assess the immunosuppressive capacity of hyperfractionated total lymphoid irradiation and cyclophosphamide for transplantation of unmodified allogeneic marrow in sensitized aplastic anemia patients.
From February 1983 to September 1990, 23 multiply transfused aplastic anemia patients underwent unmodified bone marrow transplantation from HLA genotypically identical sibling donors following preparation with 6 Gy hyperfractionated total lymphoid irradiation and 160 mg/kg cyclophosphamide. Graft-versus-host disease prophylaxis included steroids in one patient, methotrexate in four, cyclosporine in seven, and methotrexate/cyclosporine in 12. There were 17 males and 6 females with a median age of 13 (range: 2.5-32).
One patient died early before engraftment of bacterial sepsis. Twenty-two patients were evaluable for engraftment. Three experienced graft failure including one primary, and two late graft failures associated with cyclosporine withdrawal. Acute graft-versus-host disease occurred in 7/22 (> or = grade II in 6), and chronic graft-versus-host disease in 3/17 patients. Except for a patient who received total body irradiation for a second transplant, no patient in this series developed interstitial pneumonia. Fifteen patients are alive with follow-up of 38-125 months (median 68). The overall actuarial survival at 5 years is 69%, at 8 years it is 60%, with one late death. The survival of adult patients was similar to that of younger patients (> or = 16 years old: 63%, < 16 years old: 55%). The development of acute graft-versus-host disease adversely influenced survival (88% with Grade 0-I, 17% with grade II-IV; p = 0.002). No hypothyroidism or secondary malignancies have been documented in this series.
Pretransplant immunosuppression with 6 Gy of hyperfractionated total lymphoid irradiation and 160 mg/kg CY reduces but does not eliminate the incidence of graft failure in sensitized aplastic anemia patients. The dose and the mode of administration of total lymphoid irradiation in this trial may be associated with a lower incidence of late side effects. Survival is comparable to that obtained using preparative regimens without radiation.
No preview · Article · Aug 1994 · International Journal of Radiation OncologyBiologyPhysics
[Show abstract][Hide abstract] ABSTRACT: A two-year-old girl with thrombocytopenia-absent radii syndrome underwent transplantation of allogeneic bone marrow from her histocompatible sibling to correct her persistently low platelet count. Six years after transplantation, she has durable engraftment of allogeneic marrow and a normal platelet count that will allow her to undergo necessary corrective orthopedic procedures.
No preview · Article · Nov 1992 · Journal of Pediatrics
[Show abstract][Hide abstract] ABSTRACT: We prospectively evaluated the efficacy of T-cell-depleted bone marrow transplantation (BMT) in adults with de novo acute nonlymphocytic leukemia (ANLL) in first complete remission (CR), with regard to relapse-free survival and incidence of graft-versus-host disease (GvHD). Thirty-one patients older than 16 years (range, 16.5 to 43.2) received T-cell-depleted grafts for this purpose from related HLA/MLC-compatible donors. Twelve of the patients were older than 30 years at the time of transplantation. Patients were prepared with hyperfractionated total body irradiation (HFTBI; 1,375 to 1,500 cGy) and high-dose cyclophosphamide (120 mg/kg). T cells were removed from the marrow grafts by a two-step soybean lectin agglutination and sheep red blood cell (sRBC)-rosette procedure, achieving a 2.5- to 3-log depletion of clonable T lymphocytes. No additional prophylaxis against GvHD was administered. The median age at transplantation was 28.8 years; the median interval from diagnosis to transplantation was 3.8 months, and from CR was 2.7 months. Seventy-four percent received consolidation after remission induction therapy. The product-limit estimate of disease-free survival (DFS) at 3 years is 45% (95% confidence interval [CI], 24% to 66%), and the cause-specific probability of relapse is 13%. The median follow-up of the survivors is 72 months (range, 34.5 to 95.6). Median time to achieve a sustained absolute neutrophil count of 500 or greater was 16 days, and to maintain an untransfused platelet count of 20,000 or greater was 20 days. Five patients suffered immune-mediated graft rejection. Three patients developed grade I to II acute GvHD limited to the skin, which resolved promptly with brief courses of systemic steroids. None of the patients has developed clinically apparent chronic GvHD or a secondary lymphoproliferative disorder, and no patient is receiving immunosuppressive therapy. T-cell-depleted BMT by the method reported here is a favorable option as postremission therapy for adults with de novo ANLL in first remission who have an HLA/MLC-compatible related donor, and it is not associated with an increased risk of relapse posttransplant.
[Show abstract][Hide abstract] ABSTRACT: Since 1979, a total of 17 patients with Wiskott-Aldrich syndrome have undergone allogeneic bone marrow transplantation at Memorial Sloan-Kettering Cancer Center. Eleven patients received marrow from either human leukocyte antigen (HLA) genotypically identical siblings (nine patients) or an HLA phenotypically identical parent (two patients). Six patients received marrow grafts from HLA-disparate parents. Cytoreduction was accomplished with busulfan and cyclophosphamide for the HLA-identical recipients and total-body irradiation followed by high-dose cytarabine therapy in the mismatched recipients. All 11 recipients of HLA-identical marrow had successful grafts, and 10 of 11 are alive and well 28 to 145 months after transplantation. One patient died 10 months after transplantation of chronic graft-versus-host disease and interstitial pneumonitis caused by cytomegalovirus. Only one of the six mismatched graft recipients survives, 52+ months after transplantation; the other patients have died of extensive chronic graft-versus-host disease (one patient), lymphoma (three patients), or progressive pancytopenia accompanying Candida sepsis (one patient). Thus bone marrow transplantation represents the treatment of choice in patients with Wiskott-Aldrich syndrome who have an HLA-identical donor. However, our approach for patients lacking a histocompatible family donor requires modifications to overcome allogeneic resistance and decrease the posttransplantation immunoincompetence in these patients.
No preview · Article · Jan 1992 · Journal of Pediatrics