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.
Optimal donor selection is critical for successful allogeneic hematopoietic cell transplantation (HCT). Donor sex and parity are well-established risk factors for graft-versus-host disease (GVHD), ...with male donors typically associated with lower rates of GVHD. Well-matched unrelated donors (URDs) have also been associated with increased risks of GVHD as compared with matched sibling donors. These observations raise the question of whether male URDs would lead to more (or less) favorable transplant outcomes as compared with parous female sibling donors. We used the Center for International Blood and Marrow Transplant Research registry to complete a retrospective cohort study in adults with acute myeloid leukemia, acute lymphoblastic leukemia, or myelodysplastic syndrome, who underwent T-cell replete HCT from these 2 donor types (parous female sibling or male URD) between 2000 and 2012. Primary outcomes included grade 2 to 4 acute GVHD (aGVHD), chronic GVHD (cGVHD), and overall survival. Secondary outcomes included disease-free survival, transplant-related mortality, and relapse. In 2813 recipients, patients receiving male URD transplants (n = 1921) had 1.6 times higher risk of grade 2 to 4 aGVHD (P < .0001). For cGVHD, recipient sex was a significant factor, so donor/recipient pairs were evaluated. Female recipients of male URD grafts had a higher risk of cGVHD than those receiving parous female sibling grafts (relative risk RR = 1.43, P < .0001), whereas male recipients had similar rates of cGVHD regardless of donor type (RR = 1.09, P = .23). Donor type did not significantly affect any other end point. We conclude that when available, parous female siblings are preferred over male URDs.
•Compared with parous female sibling donors, male URDs confer more aGVHD in all patients and more cGVHD in females.•There was no difference in survival, relapse, or transplant mortality between recipients of parous female sibling or male URD grafts.
Display omitted
Summary
Prospective magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), neuropsychological testing and neurological examinations were performed to determine the long‐term effect ...of successful haematopoietic stem cell transplantation on the neurological status of nine children with sickle cell disease. A scoring system for severity of brain parenchymal and vascular lesions was developed and applied. Neurological examinations and neuropsychometric tests were stable, but MRI and MRA studies were not. Transient changes occurred early in two patients. Persistent changes occurred in five. Parenchymal lesions occurred in zero of two patients without prior lacunae or infarcts and in all seven with prior lacunae or infarcts (P = 0·0278).
Targeted kinase inhibitors and camptothecins have shown preclinical and clinical activity in several cancers. This trial evaluated the maximum tolerated dose (MTD) and dose‐limiting toxicities of ...sorafenib and topotecan administered orally in pediatric patients with relapsed solid tumors. Sorafenib was administered twice daily and topotecan once daily on days 1–5 and 8–12 of each 28‐day course. The study utilized a standard 3 + 3 dose escalation design. Three dose levels (DL) were evaluated: (1) sorafenib 150 mg/m2 and topotecan 1 mg/m2; (2) sorafenib 150 mg/m2 and topotecan 1.4 mg/m2; and (3) sorafenib 200 mg/m2 and topotecan 1.4 mg/m2. Pharmacokinetics were ascertained and treatment response assessed. Thirteen patients were enrolled. DL2 was the determined MTD. Grade 4 thrombocytopenia delaying therapy for >7 days was observed in one of six patients on DL2, and grade 4 neutropenia that delayed therapy in two of three patients on DL3. A patient with preexisting cardiac failure controlled with medication developed a transient drop in the left ventricular ejection fraction that improved when sorafenib was withheld. Sorafenib exposure with or without topotecan was comparable, and the concentration‐time profiles for topotecan alone and in combination with sorafenib were similar. One objective response was noted in a patient with fibromatosis. We determined MTD to be sorafenib 150 mg/m2 twice daily orally on days 1–28 combined with topotecan 1.4 mg/m2 once daily on days 1–5 and 8–12. While these doses are 1 DL below the MTD of the agents individually, pharmacokinetic studies suggested adequate drug exposure without drug interactions. The combination had limited activity in the population studied.
We completed a phase I trial of the combination of sorafenib and topotecan in pediatric patients. We found the combination to have similar pharmacokinetic exposure when compared to the single agent studies and all therapy was delivered by mouth. No objective responses were seen in the patients enrolled.
: Iron overload has not been studied extensively and prospectively in pediatric survivors of allogeneic hematopoietic stem cell transplantation (HSCT); therefore, we conducted a prospective ...long‐term study of 133 survivors of childhood leukemia to assess the incidence of and risk factors for iron overload and to investigate its association with organ dysfunction. One yr after HSCT, the mean serum ferritin level was 1158 ng/mL (range, 22–3264 ng/mL), with 124 patients (93.2%) having a serum ferritin level that exceeded the upper limit of the normal range (110 ng/mL). Thereafter, the serum ferritin level declined over time. There was a positive correlation between the level of serum ferritin and that of total bilirubin (r = 0.21, p < 0.001) and glutamate pyruvate transaminase (r = 0.17, p < 0.001). A high concentration of serum ferritin was associated with low cardiac fractional shortening (r = −0.15, p = 0.047). In addition, patients with hypothyroidism and GH deficiency had a higher level of serum ferritin than those without (p < 0.02). We conclude that iron overload is common after HSCT and is associated with hepatic, cardiac, and endocrine dysfunction.
The association between HLA matching and outcome in unrelated-donor peripheral blood stem cell (PBSC) transplantation has not yet been established. In the present study, a total of 1933 unrelated ...donor–recipient pairs who underwent PBSC transplantation between 1999 and 2006 for acute myelogenous leukemia, acute lymphoblastic leukemia, myelodysplastic syndrome, or chronic myelogenous leukemia and received high-resolution HLA typing for HLA-A, -B, -C, -DRB1, -DQA1, and -DQB1 were included in the analysis. Outcomes were compared between HLA-matched and HLA-mismatched pairs, adjusting for patient and transplant characteristics. Matching for HLA-A, -B, -C, and -DRB1 alleles (8/8 match) was associated with better survival at 1 year compared with 7/8 HLA-matched pairs (56% vs 47%). Using 8/8 HLA–matched patients as the baseline (n = 1243), HLA-C antigen mismatches (n = 189) were statistically significantly associated with lower leukemia-free survival (relative risk RR, 1.36; 95% confidence interval CI, 1.13-1.64; P = .0010), and increased risk for mortality (RR, 1.41; 95% CI, 1.16-1.70; P = .0005), treatment-related mortality (RR, 1.61; 95% CI, 1.25-2.08; P = .0002), and grade III-IV graft-versus-host disease (RR, 1.98; 95% CI, 1.50-2.62; P < .0001). HLA-B antigen or allele mismatching was associated with an increased risk for acute GVHD grade III-IV. No statistically significant differences in outcome were observed for HLA-C allele (n = 61), HLA-A antigen/allele (n = 136), HLA-DRB1 allele (n = 39), or HLA-DQ antigen/allele (n = 114) mismatches compared with 8/8 HLA–matched pairs. HLA mismatch was not associated with relapse or chronic GVHD. HLA-C antigen–mismatched unrelated PBSC donors were associated with worse outcomes compared with 8/8 HLA–matched donors. The study’s limited power due to small sample size precludes conclusions about other mismatches.
Abstract Reduced-intensity conditioning (RIC) before hematopoietic stem cell transplantation (HCT) in children could result in fewer complications during follow-up compared with myeloablative ...regimens. Hence, many RIC regimens are under investigation, but long-term follow-up is essential. We describe late follow-up beyond 2 years post-HCT in 43 children with nonmalignant disorders who underwent related or unrelated donor (54%) HCT on a multicenter study using a RIC regimen (alemtuzumab, fludarabine, and melphalan) followed by bone marrow (n = 30), peripheral blood (n = 3), or umbilical cord blood (n = 10) HCT for immune dysfunction, bone marrow failure, metabolic disorders, or hemoglobinopathy. Recipients (median age, 7.5 years; range, 3 to 26) underwent HCT 2 to 8 years (median, 3.1 years) before this report. Full donor (67%) or stable mixed chimerism (33%) was noted without late graft rejection. Five patients (12%) required systemic immunosuppression therapy (IST) beyond 2 years post-HCT for graft-versus-host disease (GVHD); 2 patients died 38 and 79 months later, whereas the others improved, enabling an IST wean. Overall, 17 complications were documented in 10 patients (23%). Complications not related to GVHD included hypothyroidism (n = 2), low grade neoplasms (n = 2), and delayed puberty (n = 1). One patient with GVHD had ovarian failure; all other postpubertal females resumed normal ovarian function. Twenty-seven of 28 school-age recipients were functioning at grade level. RIC HCT recipients thus had few regimen-related toxicities during long-term follow-up. However, objective long-term follow-up is still necessary to identify complications so timely intervention may be planned.
We describe outcomes after allogeneic hematopoietic cell transplantation (HCT) for mycosis fungoides and Sezary syndrome (MF/SS). Outcomes of 129 subjects with MF/SS reported to the Center for the ...International Blood and Marrow Transplant from 2000-2009. Median time from diagnosis to transplant was 30 (4-206) months and most subjects were with multiply relapsed/ refractory disease. The majority (64%) received non-myeloablative conditioning (NST) or reduced intensity conditioning (RIC). NST/RIC recipients were older in age compared with myeloablative recipients (median age 51 vs 44 years, P=0.005) and transplanted in recent years. Non-relapse mortality (NRM) at 1 and 5 years was 19% (95% confidence interval (CI) 12-27%) and 22% (95% CI 15-31%), respectively. Risk of disease progression was 50% (95% CI 41-60%) at 1 year and 61% (95% CI 50-71%) at 5 years. PFS at 1 and 5 years was 31% (95% CI 22-40%) and 17% (95% CI 9-26%), respectively. OS at 1 and 5 years was 54% (95% CI 45-63%) and 32% (95% CI 22-44%), respectively. Allogeneic HCT in MF/SS results in 5-year survival in approximately one-third of patients and of those, half remain disease-free.
Ectothermic vertebrates are a diverse group of animals that rely on external sources to maintain a preferred body temperature. Amphibians and reptiles have a preferred optimal temperature zone that ...allows for optimal biological function. Physiologic processes in ectotherms are influenced by temperature; these animals have capabilities in which they make use of behavioral and physiologic mechanisms to thermoregulate. Core body, ambient air, body surface, and surface/water temperatures were obtained from six ectothermic species including one anuran, two snakes, two turtles, and one alligator. Clinically significant differences between core body temperature and ambient temperature were noted in the black rat snake, corn snake, and eastern box turtle. No significant differences were found between core body and ambient temperature for the American alligator, bullfrog, mata mata turtle, dead spotted turtle, or dead mole king snake. This study indicates some ectotherms are able to regulate their body temperatures independent of their environment. Body temperature of ectotherms is an important component that clinicians should consider when selecting and providing therapeutic care. Investigation of basic physiologic parameters (heart rate, respiratory rate, and body temperature) from a diverse population of healthy ectothermic vertebrates may provide baseline data for a systematic health care approach.
PDF
