Kamar Godder

Long-term survival and late deaths after allogeneic bone marrow transplantation

Background and Methods It is uncertain whether mortality rates among patients who have undergone bone marrow transplantation return to the level of the mortality rates of the general population. We analyzed the characteristics of 6691 patients listed in the International Bone Marrow Transplant Registry. All the patients were free of their original disease two years after allogeneic bone marrow transplantation. Mortality rates in this cohort were compared with those of an age-, sex-, and nationality-matched general population. Cox proportional-hazards regression was used to identify risk factors for death more than two years after transplantation (late death). Results Among patients who were free of disease two years after transplantation, the probability of living for five more years was 89 percent (95 percent confidence interval, 88 to 90 percent). Among patients who underwent transplantation for aplastic anemia, the risk of death by the sixth year after transplantation did not differ significantly from ...

Outcomes of pediatric bone marrow transplantation for leukemia and myelodysplasia using matched sibling, mismatched related, or matched unrelated donors

Although some trials have allowed matched or single human leukocyte antigen (HLA)-mismatched related donors (mmRDs) along with HLA-matched sibling donors (MSDs) for pediatric bone marrow transplantation in early-stage hematologic malignancies, whether mmRD grafts lead to similar outcomes is not known. We compared patients < 18 years old reported to the Center for International Blood and Marrow Transplant Research with acute myeloid leukemia, acute lymphoblastic leukemia, chronic myeloid leukemia, and myelodysplastic syndrome undergoing allogeneic T-replete, myeloablative bone marrow transplantation between 1993 and 2006. In total, patients receiving bone marrow from 1208 MSDs, 266 8/8 allelic-matched unrelated donors (URDs), and 151 0-1 HLA-antigen mmRDs were studied. Multivariate analysis showed that recipients of MSD transplants had less transplantation-related mortality, acute graft-versus-host disease (GVHD), and chronic GVHD, along with better disease-free and overall survival than the URD and mmRD groups. No differences were observed in transplant-related mortality, acute and chronic GVHD, relapse, disease-free survival, or overall survival between the mmRD and URD groups. These data show that mmRD and 8/8 URD outcomes are similar, whereas MSD outcomes are superior to the other 2 sources. Whether allele level typing could identify mmRD recipients with better outcomes will not be known unless centers alter practice and type mmRD at the allele level.

Human T cells express CD25 and Foxp3 upon activation and exhibit effector/memory phenotypes without any regulatory/suppressor function

BackgroundFoxp3 has been suggested to be a standard marker for murine Tregs whereas its role as marker for human Tregs is controversial. While some reports have shown that human Foxp3+ T cells had no regulatory function others have shown their role in the inhibition of T cell proliferation.MethodsT cell activation was performed by means of brayostatin-1/ionomycin (B/I), mixed lymphocyte reaction (MLR), and CD3/CD28 activation. T cell proliferation was performed using BrdU and CFSE staining. Flow cytometry was performed to determine Foxp3 expression, cell proliferation, viabilities and phenotype analyses of T cells.ResultsBoth CD4+ and CD8+ T cells expressed Foxp3 upon activation in vitro. Expression of Foxp3 remained more stable in CD4+CD25+ T cells compared to that in CD8+CD25+ T cells. The CD4+CD25+Foxp3+ T cells expressed CD44 and CD62L, showing their effector and memory phenotypes. Both FoxP3- responder T cells and CD4+FoxP3+ T cells underwent proliferation upon CD3/CD28 activation.ConclusionExpression of Foxp3 does not necessarily convey regulatory function in human CD4+CD25+ T cells. Increased FoxP3 on CD44+ effector and CD44+CD62L+ memory T cells upon stimulation suggest the activation-induced regulation of FoxP3 expression.

Analysis of the Role of Hematopoietic Stem-Cell Transplantation in Infants With Acute Lymphoblastic Leukemia in First Remission and MLL Gene Rearrangements: A Report From the Children's Oncology Group

PURPOSE Although the majority of children with acute lymphoblastic leukemia (ALL) are cured with current therapy, the event-free survival (EFS) of infants with ALL, particularly those with mixed lineage leukemia (MLL) gene rearrangements, is only 30% to 40%. Relapse has been the major source of treatment failure for these patients. The parallel Childrens Cancer Group (CCG) 1953 and Pediatric Oncology Group (POG) 9407 studies were designed to test the hypothesis that more intensive therapy, including dose intensification of chemotherapy, and hematopoietic stem-cell transplantation (HSCT) would improve the outcome for this group of patients. PATIENTS AND METHODS One hundred eighty-nine infants (CCG 1953, n = 115; POG 9407, n = 74) were enrolled between October 1996 and August 2000. For infants with the MLL gene rearrangement and an appropriate donor, HSCT was the preferred treatment on CCG 1953 and investigator option on POG 9407 after completion of the second phase of therapy. Fifty-three infants underwent HSCT. RESULTS The 5-year EFS rate was 48.8% (95% CI, 33.9% to 63.7%) in patients who received HSCT and 48.7% (95% CI, 33.8% to 63.6%) in patients treated with chemotherapy alone (P = .60). Transplantation outcomes were not affected by the preparatory regimen or donor source. CONCLUSION Our data suggest that routine use of HSCT for infants with MLL-rearranged ALL is not indicated. However, limited by small numbers, this study should not be considered the definitive answer to this question.

Randomized trial of hydroxychloroquine for newly diagnosed chronic graft-versus-host disease in children: a Children's Oncology Group study.

The Childrens Oncology Group conducted a multicenter Phase III trial for chronic graft-versus-host disease (cGVHD). The double-blind, placebo-controlled, randomized study evaluated hydroxychloroquine added to standard therapy for children with newly diagnosed cGVHD. The study also used a novel grading and response scoring system and evaluated clinical laboratory correlates of cGVHD. The primary endpoint was complete response (CR) after 9 months of therapy. Fifty-four patients (27 on each arm) were enrolled before closure because of slow accrual. The CR rate was 28% in the hydroxychloroquine arm versus 33% in the placebo arm (odds ratio [OR] = 0.77, 95% confidence interval [CI]: 0.20-2.93, P = .75) for 42 evaluable patients. For 41 patients with severity assessment at enrollment, 20 (49%) were severe and 18 (44%) moderate according to the National Institutes of Health Consensus Conference global scoring system. The CR rate was 15% for severe cGVHD and 44% for moderate cGVHD (OR = 0.24, 95% CI: 0.05-1.06, P = .07). Although the study could not resolve the primary question, it provided important information for future cGVHD study design in this population.

Chronic transfusion practices for prevention of primary stroke in children with sickle cell anemia and abnormal TCD velocities

Chronic transfusions are recommended for children with sickle cell anemia (SCA) and abnormal transcranial Doppler (TCD) velocities ( 200 cm/sec) to help prevent the occurrence of a primary stroke [1]. The goal is usually to maintain the sickle hemoglobin concentration (HbS) <30%; however, this goal is often difficult to achieve in clinical practice. The NHLBI-sponsored trial ‘‘TCD With Transfusions Changing to Hydroxyurea (TWiTCH)’’ will compare standard therapy (transfusions) to alternative therapy (hydroxyurea) for the reduction of primary stroke risk in this patient population. Transfusions will be given according to current transfusion practices at participating sites. To determine current academic community standards for primary stroke prophylaxis in children with SCA, 32 clinical sites collected data on 340 children with abnormal TCD velocities receiving chronic transfusions to help prevent primary stroke. The average (mean ± 1 SD) pretransfusion HbS was 34 ± 11% (institutional average 23–48%); the 75th and 90th percentiles were 41 and 50%, respectively. Lower %HbS was associated with higher pretransfusion Hb values and receiving transfusions on time. These data indicate variable current transfusion practices among academic pediatric institutions and in practice, 30% HbS may not be an easily attainable goal in this cohort of children with SCA and abnormal TCD. Children with sickle cell anemia (SCA) compose a high risk group for the development of stroke. If untreated, 11% will experience a clinical stroke by 20 years of age [2]. Adams et al. have shown that children with SCA who are at risk for primary stroke can be identified by measuring time-averaged mean blood flow velocities in the internal carotid or middle cerebral arteries by TCD [3]. Abnormal TCD velocities ( 200 cm/sec) are associated with high risk for stroke and warrant transfusion therapy to reduce the risk of primary stroke. First stroke can be successfully prevented in 90% of children with SCA and abnormal TCD velocities by the use of chronic transfusion therapy, with a goal of keeping HbS concentrations less than 30% [1]. TCD with Transfusions Changing to Hydroxyurea (TWiTCH) is an NHLBIsponsored, Phase III, multicenter trial comparing standard therapy (monthly transfusions) to alternative therapy (daily hydroxyurea) to reduce the risk of primary stroke in children with SCA and documented abnormal TCD velocities. Since transfusions compose the standard treatment arm, accurate %HbS values achieved in actual clinical practice were needed for protocol development. The majority of our information about transfusing patients with SCA to prevent stroke comes from secondary stroke prevention, i.e., the use of chronic red blood cell transfusions to prevent a second stroke after a first clinical stroke has occurred. Classically, transfusions are administered at 4-week intervals to maintain HbS at less than 30%. After several years of transfusion therapy, a few centers increase transfusion interval to 5–6 weeks and allow HbS to increase toward 50% in selected patients [4,5]. Our previous study in 295 children with SCA who received transfusions for secondary stroke prevention revealed an average pretransfusion HbS of 35 ± 11% with highly variable institutional %HbS levels ranging from 22 to 51% [6] In order to determine the current clinical standard of transfusion therapy for primary stroke prevention for elevated TCD velocities, we performed a larger survey of potential TWiTCH sites. We hypothesized that average pretransfusion HbS values achieved at pediatric academic centers would be higher than 30%. This study defines the current practice at academic medical centers in provision of chronic transfusion therapy to help reduce the risk of primary stroke in children with SCA. A total of 340 children with SCA and history of abnormal TCD velocities receiving chronic PRBC transfusions for primary stroke prophylaxis were identified at 32 institutions (Table I). The number of patients per site ranged from 3 to 33 (median 9 per site). A total of 3,970 transfusions were administered over the 12-month period, with a mean of 11.7 ± 2.8 transfusions per patient. Results were similar when analyzed by each patient contributing equally or each transfusion contributing equally (Table II). The predominant transfusion type by patient was defined as the technique used 6 times over the 12-month period. Most children (79%) received primarily simple transfusions, while 19% had primarily exchange transfusions (11% partial / manual exchange, 8% erythrocytapheresis), and 2% multiple transfusion types. The transfusion goal was <30% at almost all sites (84%), while at five sites, the %HbS was allowed in selected patients to increase to 50% after a period of clinical stability. The majority (95%) of the transfusions were administered within the defined 7-day window. On average, late transfusions were given 1.3 ± 5.5 days after the defined 7-day window. Thirty percent of the patients had at least one late transfusion and 14% had 2 or more late transfusions in the 1-year period. For the 3,653 transfusions with reported %HbS values (representing 92% of the 3,970 transfusions), the mean pretransfusion HbS percentage was 33.2 ± 14.0% (median 32%). The 75th percentile for HbS values was 41%, while the 90th percentile was 51%. There were substantial differences among institutional pretransfusion %HbS values, ranging from 23 ± 14% HbS at one institution where HbS was reported for 103 transfusions given to nine patients during the 12-month period, to 48 ± 15% at another institution where HbS was reported for 95 transfusions administered to nine patients during the same time frame (Table III). The five sites with increased HbS goals to 50% in selected patients did not have higher values than others. For each transfusion, subjects were less likely to have pretransfusion HbS <30% if they were older [OR 0.92 for each year increase in age, 95% CI (0.89, 0.96)] and on transfusions for a longer period of time [OR 0.90 for each year increase in duration, 95% CI (0.86, 0.94)]. Patients with higher pretransfusion Hb levels were more likely to have pretransfusion HbS <30% [OR 1.63 for each g/dL increase in Hb, 95% CI (1.46, 1.83)] and late transfusions were less likely to be associated with a pretransfusion HbS <30% [OR 0.27, 95% CI (0.18, 0.41)]. The Hb result does not appear to be a function of late transfusions since both covariates remained significant when modeled jointly. History of alloor autoantibodies, TCD velocity, and erythrocytapheresis use were not significant predictors of a pretransfusion HbS <30%. During the initial STOP study, transfusions were given to maintain pretransfusion HbS values at less than 30% [3]. However, there were frequent transient rises of HbS above this level [7]. Furthermore, extended follow-up results from the STOP study showed that pretransfusion %HbS values during the post-trial follow-up were higher than those during the STOP study [8]. The average %HbS per patient was 27.5 ± 12.4, still within the desired goal of 30%. However, pretransfusion HbS levels were 30–34.9% in 12%, 35–39.9% in 7%, and greater than 40% in 12% of the transfusions. In the STOP2 study, where children with abnormal TCD velocities whose Doppler readings became normal were randomly assigned to continue or stop transfusions, 24% of the patients had pretransfusion HbS levels greater than 30% [9]. These findings indicate that even in the context of a prospective clinical trial, maintaining HbS <30% was difficult to achieve. With the subsequent recommendation to treat all children with SCA who are at risk for primary stroke with transfusions to maintain HbS <30%, the feasibility of this approach in actual clinical practice is not known. Possible Letters

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.

Clinical ResearchRandomized Trial of Hydroxychloroquine for Newly Diagnosed Chronic Graft-versus-Host Disease in Children: A Children’s Oncology Group Study

The Childrens Oncology Group conducted a multicenter Phase III trial for chronic graft-versus-host disease (cGVHD). The double-blind, placebo-controlled, randomized study evaluated hydroxychloroquine added to standard therapy for children with newly diagnosed cGVHD. The study also used a novel grading and response scoring system and evaluated clinical laboratory correlates of cGVHD. The primary endpoint was complete response (CR) after 9 months of therapy. Fifty-four patients (27 on each arm) were enrolled before closure because of slow accrual. The CR rate was 28% in the hydroxychloroquine arm versus 33% in the placebo arm (odds ratio [OR] = 0.77, 95% confidence interval [CI]: 0.20-2.93, P = .75) for 42 evaluable patients. For 41 patients with severity assessment at enrollment, 20 (49%) were severe and 18 (44%) moderate according to the National Institutes of Health Consensus Conference global scoring system. The CR rate was 15% for severe cGVHD and 44% for moderate cGVHD (OR = 0.24, 95% CI: 0.05-1.06, P = .07). Although the study could not resolve the primary question, it provided important information for future cGVHD study design in this population.

Graft-versus-host disease after solid organ transplantation: a single center experience and review of literature.

BACKGROUND Graft-versus-host disease (GVHD) is an uncommon cause of morbidity and mortality after solid organ transplantation that is most likely under-diagnosed. We describe our single center experience with three cases of GVHD diagnosed over a period of 15 years in a total of 2,271 solid organ transplant recipients. CASE REPORTS We describe three case reports: (1) a 3-week old neonate who developed GVHD 16 months after living-related liver transplant, (2) a 14-year old adolescent who developed GVHD 4 months following an unrelated cadaveric pancreas transplant and; (3) a 27-year old male who developed GVHD 18 days after simultaneous kidney-pancreas transplant from an unrelated donor. GVHD was confirmed through skin biopsies, engraftment profile from bone marrow biopsy and variable number tandem repeat analysis. Treatment strategies included use of corticosteroids and sirolimus monotherapy, corticosteroids and mesenchymal stromal cell therapy and reduction of immunosuppression. We observed that African-American race, sexual and HLA mismatching and cytomegalovirus infection may be high risk factors for development of GVHD following solid organ transplant. CONCLUSIONS GVHD continues to be a rare but fatal complication following solid organ transplantation that demands a high index of clinical suspicion for diagnosis and management. Future approaches may focus on early recognition of risk factors and improving treatment protocols using a combination of mesenchymal stromal cell transplantation with pharmacotherapy.

Preparing Children to Be Bone Marrow Donors

PURPOSE/OBJECTIVES To review literature regarding children as bone marrow donors and describe the evaluation of an individualized intervention to support children who will be donors for parents or siblings. DATA SOURCE Research studies, abstracts, and clinical reports describing interventions or psychosocial issues related to child donors, parent interviews, and clinical experiences. DATA SYNTHESIS Child marrow donors and caregivers benefit from interventions that illuminate the process and provide psychosocial support. Use of a teaching book enhances intervention and provides a tool for parents to use after transplantation. CONCLUSIONS Psychosocial distress in child marrow donors and parents can be minimized through education and therapeutic interventions. Research is needed to validate the efficacy of interventions and determine whether psychosocial complications are decreased. IMPLICATIONS FOR NURSING Child donors, especially those for parents, should receive support and attention for their unique psychosocial needs.