Prophylaxis and hemophilia care in LATAM: Baring it all-Highlights from the CLAHT 2021 symposium.

A large group of countries constitute Latin American (LATAM) countries, where hemophilia care is as varied as the landscape of this region. To better understand the care provided to persons with bleeding disorders, especially hemophilia, a symposium was organized as part of the CLAHT Congress 2021 in Colombia to highlight the issues of hemophilia care and challenges faced by persons with hemophilia in four LATAM countries, Colombia, Peru, Argentina, and Mexico. A summary of the symposium is provided. Four clinicians highlighted the issues in their own country, the status, and the path forward to bring the standard of care to the international level in each of these countries. The geography of the country, the health infrastructure, and the resources available are obstacles in these countries to provide state-of-the-art care to the bleeding disorder community. However, depending on the country, its infrastructure and the resources available, progress is being made to upend the care provided. Indeed, the care of persons with hemophilia has been greatly improved, including personalized prophylaxis. The information summarized here first emphasizes how the geography of a country and the different healthcare infrastructures play a major role in how care is offered. It also provides a path for other countries to evaluate these issues in their own realities. In parallel, these data provide hope to many developing countries; despite obstacles, strides can be made in the care of the bleeding disorder community.

Significant reduction in hemarthrosis in boys with severe hemophilia A: The China hemophilia individualized low-dose secondary prophylaxis study.

INTRODUCTION: In countries with restricted access to clotting factor concentrates, early implementation of low-dose prophylaxis is recommended over episodic treatment. OBJECTIVE: The objective of this 1-year prospective secondary prophylaxis study was to evaluate the efficacy of a dose/frequency escalating protocol in young boys with hemophilia A in China. METHODS: Boys were started on a low-dose protocol (minimum 10-15 IU/kg of factor VIII [FVIII] twice weekly). Escalation was based on index joint bleeding, swelling/persistent joint swelling, and serial ultrasound (gray scale and color Doppler) examinations of index joints. RESULTS: Thirty-three boys, median age 4.8 years (interquartile range, 3.8-6.1) were enrolled in a 3-month observation period that preceded a 1-year prophylaxis phase. A significant reduction in total bleeding events (43.0%, P = .001), index joint bleeds (53.2%, P = .002), and target index joint bleeds (70.0%, P = 0.02) was observed during the prophylaxis phase. During the prophylaxis period, 40% of target joints resolved. The percentage of boys with zero index joint bleeds increased significantly (P = .004) from 51.5% during the observation phase to 81.8% in last quarter of the prophylaxis phase (months 10-12). There was no progression of arthropathy based on physical examination (Hemophilia Joint Health Score), X-ray, and ultrasound obtained at entry into the prophylaxis phase and at study exit. The median FVIII consumption over the prophylaxis phase was 1786 IU/kg/y. CONCLUSION: A low-dose, individualized prophylaxis protocol, guided by individual bleeding profiles and serial assessment of joint status, enables escalation of treatment intensity in boys with severe hemophilia A, leading to a significant reduction in bleeding events and reduction in target joint bleeding.

Perspective - The case for zero bleeds and drug bioequivalence in the treatment of congenital hemophilia A in 2021.

Not all patients with severe hemophilia A (HA) respond optimally to a given dose of a given product. Within-individual variance in cross-over studies makes each patient unique in the response to each standard half-life (SHL) factor VIII (FVIII) product in pharmacokinetic (PK) terms. This hampers the prediction of efficacy when a SHL FVIII product is employed. PK data showing that half-lives of SHL rFVIII are unsatisfactory to achieve zero bleeding in individual HA patients provide the rationale for switching from SHL to extended half-life (EHL) products. However, not all subjects receiving prophylaxis with EHL products achieve zero bleeding, the most cogent objective of personalized prophylaxis. Known determinants of FVIII half-life (age, von Willebrand factor [VWF] levels, blood group) cumulatively account for one third of the total inter-individual variation in FVIII clearance in subjects with severe HA. Investigations into precision, and accuracy of laboratory measurement to be employed; newer pathways for the clearance of both free-FVIII and VWF-bound FVIII, and adequately powered studies on omics and phenotypic heterogeneity, are likely to provide additional information on the remaining two thirds of inter-individual variation in FVIII clearance in HA. Variability in the clinical response has also been documented in patients when FVIII activity is mimicked by fixed subcutaneous doses of the bispecific antibody emicizumab. National registries that collect PK data of available FVIII products and ad hoc information on the individual response to emicizumab should be encouraged, to establish newer standards of care and ease personalized clinical decisions to achieve zero bleeding.

Pharmacokinetic characteristics of the triple inactivated plasma-derived Kedrion FIX concentrate: data from the KB037 clinical trial.

The pharmacokinetics data of phase I/II clinical trials (EudraCT Number: 2005-006186-14) of the new, triple inactivated plasma-derived Kedrion FIX concentrate was designed according to the recommendations of SSC-ISTH [1,2]: 11 post-infusion FIX/time points samples during the first 72 h. The PK data were also analysed by a modified, less dense, 9 FIX/time points, sample design. The outcomes of the safety and efficacy study and the pharmacokinetics' results have been previously and partially described [3,4]. The single-dose PK at enrolment (PK I) and the end of the trial (PK II) were analyzed by WinNonlin 7.0 (Pharsight) and according to three different methods: Non-Compartment Analysis (NCA), One Compartment Method (OCM), and Two-Compartment Method (TCM). The outcomes of PK parameters by TCM show that a higher number of FIX/time concentration points may not always give a better definition of the decay curve. On the other hand, the Terminal HL of NCA is deeply affected by the goodness of the last two-three points. The quite long Kedrion FIX HL may allow for a cost/effective tailoring of prophylaxis in haemophilia B patients.

Pathologic Features of Down Syndrome Myelodysplastic Syndrome and Acute Myeloid Leukemia: A Report From the Children's Oncology Group Protocol AAML0431.

CONTEXT.­: Detailed diagnostic features of acute myeloid leukemia in Down syndrome are lacking, leading to potential misdiagnoses as standard acute myeloid leukemia occurring in patients with Down syndrome. OBJECTIVE.­: To evaluate diagnostic features of acute myeloid leukemia and myelodysplastic syndrome in patients with Down syndrome. DESIGN.­: Diagnostic bone marrow samples from 163 patients enrolled in the Children's Oncology Group study AAML0431 were evaluated by using central morphologic review and institutional immunophenotyping. Results were compared to overall survival, event-free survival, GATA1 mutation status, cytogenetics, and minimal residual disease results. RESULTS.­: Sixty myelodysplastic syndrome and 103 acute myeloid leukemia samples were reviewed. Both had distinctive features compared to those of patients without Down syndrome. They showed megakaryocytic and erythroid but little myeloid dysplasia, and marked megakaryocytic hyperplasia with unusual megakaryocyte morphology. In acute myeloid leukemia cases, megakaryoblastic differentiation of blasts was most common (54 of 103, 52%); other cases showed erythroblastic (11 of 103, 11%), mixed erythroid/megakaryoblastic (20 of 103, 19%), or no differentiation (10 of 103, 10%). Myelodysplastic syndrome and acute myeloid leukemia cases had similar event-free survival and overall survival. Leukemic subgroups showed interesting, but not statistically significant, trends for survival and minimal residual disease. Cases with institutional diagnoses of French American British M1-5 morphology showed typical features of Down syndrome disease, with survival approaching that of other cases. CONCLUSIONS.­: Myelodysplastic syndrome and acute myeloid leukemia in Down syndrome display features that allow discrimination from standard cases of disease. These distinctions are important for treatment decisions, and for understanding disease pathogenesis. We propose specific diagnostic criteria for Down syndrome-related subtypes of acute myeloid leukemia and myelodysplastic syndrome.

Cerebral microbleeds: hearing through the silence-a narrative review.

OBJECTIVE: The term cerebral microbleed (CMB) refers to lesions documented as unexpected findings during computed tomography or magnetic resonance imaging examination of the brain. Initially, a CMB was thought to represent hemosiderin-laden macrophages marking an area of a tiny hemorrhage. Recently, histopathologic studies have shown that the structure of a CMB can be variable. To aid in dealing with this finding and judging its clinical significance, this review addresses important aspects of a CMB, including the definition, prevalence, and incidence in various populations, end-organ damage, associated conditions, and whether any action or treatment by the clinician might be indicated. METHODS: PubMed Medline, EMBASE, BIOSIS, Current Contents, and Derwent Drug Files databases were searched for the keywords "microbleeds-detection-damage", "silent bleeds", "microbleeds", or "silent bleeds AND hemophilia" from 2011-2016. References of retrieved articles were also reviewed and included if applicable. RESULTS: The published data are found primarily in the imaging literature and focus on diagnostic techniques. Some publications address relationships with diverse, co-existing clinical conditions and implications for treatment, especially in stroke, intracranial hemorrhage, and antithrombotic therapy. CONCLUSIONS: It is critical for non-radiologist clinicians (primary care, internists, neurologists, hematologists) to be aware of the potential importance of the finding of a CMB, and the fact that these lesions are not always truly silent or without important clinical consequences. As additional studies appear, clinicians may be able to "hear" more clearly through the silence of the CMB and understand potential clinical implications in patients.

Improved outcomes for myeloid leukemia of Down syndrome: a report from the Children's Oncology Group AAML0431 trial.

Patients with myeloid leukemia of Down syndrome (ML-DS) have favorable event-free survival (EFS), but experience significant treatment-related morbidity and mortality. ML-DS blast cells ex vivo have increased sensitivity to cytarabine (araC) and daunorubicin, suggesting that optimizing drug dosing may improve outcomes while reducing toxicity. The Children's Oncology Group (COG) AAML0431 trial consisted of 4 cycles of induction and 2 cycles of intensification therapy based on the treatment schema of the previous COG A2971 trial with several modifications. High-dose araC (HD-araC) was used in the second induction cycle instead of the intensification cycle, and 1 of 4 daunorubicin-containing induction cycles was eliminated. For 204 eligible patients, 5-year EFS was 89.9% and overall survival (OS) was 93.0%. The 5-year OS for 17 patients with refractory/relapsed leukemia was 34.3%. We determined the clinical significance of minimal residual disease (MRD) levels as measured by flow cytometry on day 28 of induction I. MRD measurements, available for 146 of the 204 patients, were highly predictive of treatment outcome; 5-year disease-free survival for MRD-negative patients (n = 125) was 92.7% vs 76.2% for MRD-positive patients (n = 21) (log-rank P = .011). Our results indicated that earlier use of HD-araC led to better EFS and OS in AAML0431 than in past COG studies. A 25% reduction in the cumulative daunorubicin dose did not impact outcome. MRD, identified as a new prognostic factor for ML-DS patients, can be used for risk stratification in future clinical trials. This trial was registered at www.clinicaltrials.gov as #NCT00369317.

Baby hamster kidney cell-derived recombinant factor VIII: a quarter century of learning and clinical experience.

INTRODUCTION: Management and care of individuals with hemophilia A advanced immensely with the introduction of recombinant factor VIII (rFVIII) replacement products. This review provides a historical overview of rFVIII development with a focus on Bayer's rFVIII (with albumin) and sucrose-formulated rFVIII (rFVIII-FS), the only rFVIII products cloned in baby hamster kidney (BHK) cells with >25 years of proven safety and efficacy. Areas covered: We review the advances in rFVIII technology and the efficacy and safety data for BHK-derived rFVIII/rFVIII-FS from clinical trials, investigator-initiated studies, and observational studies. Innovative products with new treatment potentials (eg, BAY 81-8973 and BAY 94-9027) built on this established safety and efficacy profile are also briefly discussed. The literature search strategy included targeted searches (PubMed) with manual article selection and other product-specific searches. Expert commentary: Development of rFVIII products and related improvements in viral safety and manufacturing efficiency have guaranteed an adequate supply of factor products worldwide and increased prophylaxis use. The net effects have been joint health preservation, reduction in morbidity and mortality, and quality-of-life enhancements. Current treatment challenges include lack of adherence to prophylaxis and inhibitor development; extended-half-life rFVIII products and non-FVIII replacement therapies in development may help overcome these challenges.

Practical considerations in choosing a factor VIII prophylaxis regimen: Role of clinical phenotype and trough levels.

Current therapy for haemophilia A is guided by severity of the disease, which in turn is best reflected in patients' endogenous factor VIII activity levels. For patients with severe haemophilia (particularly children), prophylaxis with continuous routine factor replacement has become standard of care in developed countries and is gradually becoming the standard of care in developing countries. The question arises then: what is an appropriate prophylaxis regimen to prevent bleeding events and arthropathy, while also maximizing patient quality of life and taking into consideration the costs of prophylaxis? Should all patients be treated with one standard, fixed prophylaxis regimen, or should prophylaxis be individualised for each patient? If so, what factors need to be considered in choosing the appropriate dose and frequency of factor administration? If prophylaxis is tailored to the individual patient, then patient-related factors (bleeding phenotype, activity profiles, age, joint status) and product-specific factors (half-life of the replacement factor in the individual patient) will determine the choice of regimen, whether it be a fixed-regimen prophylaxis or prophylaxis that is tailored to patient activity and bleeding risk. Regardless of the choice of prophylaxis regimen, for any regimen to be effective, adherence to therapy is key to optimising outcomes.

Sucrose-Formulated Recombinant Factor VIII Dosing Flexibility in Prophylaxis Regimens: Experience from Postmarketing Surveillance Studies.

Objectives. Prophylaxis regimens for severe hemophilia A allowing more flexible dosing while maintaining efficacy may improve adherence and decrease the cost of prophylaxis. Here, we compared the clinical effectiveness of once- or twice-weekly versus ≥3-times-weekly prophylaxis with sucrose-formulated recombinant factor VIII (rFVIII-FS) in a "real-world" practice setting. Methods. Data from 3 postmarketing studies were pooled. Patients with severe hemophilia A receiving ≥1 prophylaxis infusion/wk of rFVIII-FS for ≥80% of a prophylaxis observation period (≥5 months) were included. Patients were categorized based on physician-assigned treatment regimens of 1-2 prophylaxis injections/wk (n = 63) or ≥3 prophylaxis injections/wk (n = 76). Descriptive statistics were determined for annualized bleeding rates (ABRs). Results. Median (quartile 1; quartile 3) ABR for all bleeds was 2.0 (0; 4.0) in the 1-2 prophylaxis injections/wk group and 3.9 (1.5; 9.3) in the ≥3 prophylaxis injections/wk group. Median ABRs for joint, spontaneous, and trauma-related bleeds were numerically lower with 1-2 prophylaxis injections/wk. As an estimate of prophylaxis success, 63% (≥3 prophylaxis injections/wk) to 84% of patients (1-2 prophylaxis injections/wk) had ≤4 annualized joint bleeds. Conclusions. Dosing flexibility and successful prophylaxis with rFVIII-FS were demonstrated. Very good bleeding control was achieved with both once-twice-weekly and ≥3-times-weekly prophylaxis dosing regimens.

Health economic models in hemophilia A and utility assumptions from a clinician's perspective.

BACKGROUND: The clinical benefits of prophylaxis in patients with hemophilia are well-established and include the following: reduced bleeding episodes, prevention of joint damage, decreased inhibitor development, and improved health-related quality of life. However, the cost-effectiveness of prophylaxis is still not clear. PROCEDURES: We reviewed the published hemophilia prophylaxis economic models focusing on utility assumptions. RESULTS: We found six cost-utility studies that compared prophylaxis and on-demand regimens. These studies reported remarkably different results, using utility values based on different assumptions and data sources. CONCLUSIONS: We suggest that cooperation among key stakeholders (clinicians, patient organizations and health-care decision makers) as a means of collecting evidence-based and experiential data to represent both the utility and the quality of life changes for patients with Hemophilia A who are treated with prophylaxis or receive on-demand treatments may represent a winning strategy with which to resolve the outstanding issues related to health technology assessments in the care of patients with hemophilia.

Benefits of prophylaxis versus on-demand treatment in adolescents and adults with severe haemophilia A: the POTTER study.

Rigorous evidence is lacking on long-term outcomes of factor VIII (FVIII) prophylaxis initiated in adolescent or adult patients with severe haemophilia A. The prospective, open-label Prophylaxis versus On-demand Therapy Through Economic Report (POTTER) study (ClinicalTrials.gov NCT01159587) compared long-term late secondary prophylaxis (recombinant FVIII-FS 20-30 IU/kg thrice weekly) with on-demand treatment in patients aged 12 to 55 years with severe haemophilia A. The annual number of joint bleeding episodes (primary endpoint), total bleeding episodes, orthopaedic and radiologic (Pettersson) scores, health-related quality of life (HRQoL), pharmacoeconomic impact, and safety were evaluated over a > 5-year period (2004-2010). Fifty-eight patients were enrolled at 11 centres in Italy; 53 (27 prophylaxis, 26 on demand) were evaluated and stratified into 2 age subgroups (12-25 and 26-55 years). Patients receiving prophylaxis experienced a significantly lower number of joint bleeding episodes vs the on-demand group (annualised bleeding rate, 1.97 vs 16.80 and 2.46 vs 16.71 in younger and older patients, respectively; p=0.0043). Results were similar for total bleeding episodes. Prophylaxis was associated with significantly fewer target joints (p< 0.001), better orthopaedic (p=0.0019) and Pettersson (p=0.0177) scores, better HRQoL, and fewer days of everyday activities lost (p< 0.0001) but required significantly higher FVIII product consumption. The POTTER study is the first prospective, controlled trial documenting long-term benefits of late secondary prophylaxis in adolescents and adults with severe haemophilia A. The benefits of reduced bleeding frequency, improved joint status, and HRQoL may offset the higher FVIII consumption and costs.

Kikuchi-fujimoto disease: clinical and laboratory characteristics and outcome.

INTRODUCTION: Kikuchi-Fujimoto disease is an uncommon disorder with worldwide distribution, characterized by fever and benign enlargement of the lymph nodes, primarily affecting young adults. Awareness about this disorder may help prevent misdiagnosis and inappropriate investigations and treatment. The objective of the study was to evaluate the clinical and laboratory characteristics of histopathologically confirmed cases of Kikuchi's disease from a tertiary care center in southern India. MATERIALS AND METHODS: Retrospective analysis of all adult patients with histopathologically confirmed Kikuchi's disease from January 2007 to December 2011 in a 2700-bed teaching hospital in South India was done. The clinical and laboratory characteristics and outcome were analyzed. RESULTS: There were 22 histopathologically confirmed cases of Kikuchi's disease over the 5-year period of this study. The mean age of the subjects' was 29.7 years (SD 8.11) and majority were women (Male: female- 1:3.4). Apart from enlarged cervical lymph nodes, prolonged fever was the most common presenting complaint (77.3%). The major laboratory features included anemia (54.5%), increased erythrocyte sedimentation rate (31.8%), elevated alanine aminotransferase (27.2%) and elevated lactate dehydrogenase (LDH) (31.8%). CONCLUSION: Even though rare, Kikuchi's disease should be considered in the differential diagnosis of young individuals, especially women, presenting with lymphadenopathy and prolonged fever. Establishing the diagnosis histopathologically is essential to avoid inappropriate investigations and therapy.

Safety and efficacy of recombinant activated factor VII in nonhemophilia children with severe or life-threatening bleeding: a report from the SeveNBleeP registry.

We evaluated efficacy and safety of recombinant activated factor VII (rFVIIa) in nonhemophilia children with life-threatening or severe bleeding. Using data from the SeveNBleeP registry, we analyzed demographic, clinical, laboratory, and treatment data for children who received rFVIIa to treat severe hemorrhage. The SeveNBleeP registry was international registry formed in 2005, to collect information on the use of rFVIIa in the off-label setting of severe bleeding in nonhemophilia patients. There were 191 patient records entered into this registry, of which 164 were validated. Of the 164 records, in 137 patient records, rFVIIa was used for treatment of bleeding episodes. Of these 137 treatment episodes, 42 were in neonates and infants under 1 year of age. Use of rFVIIa significantly improved laboratory parameters (prothrombin time, international normalized ratio, activated partial thromboplastin time, hematocrit), reduced estimated blood loss, and reduced requirements for blood products (packed red blood cells and fresh frozen plasma) in those more than 1 year of age. There was no significant reduction in requirements for blood products after rFVIIa administration in the neonates and infants, but there was a trend to lower frequency of FFP use after rFVIIa administration. There was one thromboembolic event in an infant that was related to administration of rFVIIa. No other serious adverse events were reported that were related to administration of rFVIIa. In nonhemophilia-associated bleeding in children, rFVIIa appears to be safe and efficacious in reducing estimated blood loss in children over 1 year of age, although its effectiveness in infants below 1 year of age was less clear.

AAML03P1, a pilot study of the safety of gemtuzumab ozogamicin in combination with chemotherapy for newly diagnosed childhood acute myeloid leukemia: a report from the Children's Oncology Group.

BACKGROUND: The development of antigen-targeted therapies may provide additional options to improve outcomes in children with acute myeloid leukemia (AML). The Children's Oncology Group AAML03P1 trial sought to determine the safety of adding 2 doses of gemtuzumab ozogamicin, a humanized anti-CD33 antibody-targeted agent, to intensive chemotherapy during remission induction and postremission intensification for children with de novo AML. METHODS: AAML03P1 enrolled 350 children with previously untreated AML. Patients with a matched family donor received 3 courses of chemotherapy followed by hematopoietic stem cell transplantation; those without a matched family donor received 5 courses of chemotherapy. Gemtuzumab ozogamicin 3 mg/m(2)/dose was administered on Day 6 of Course 1 and Day 7 of Course 4. RESULTS: Toxicities observed in all courses of therapy were typical of AML chemotherapy regimens, with infection being most common. Patients achieved a complete remission rate of 83% after 1 course and 87% after 2 courses. The mortality rate was 1.5% after the first gemtuzumab ozogamicin-containing induction course and 2.6% after 2 induction courses. The 3-year event-free survival and overall survival rates were 53 ± 6% and 66 ± 5%, respectively. CONCLUSIONS: This trial determined that it is safe and feasible to include gemtuzumab ozogamicin in combination with intensive chemotherapy. The survival rates compare favorably with the recently published results of clinical trials worldwide.

Safety and efficacy of low molecular weight heparins in children: a systematic review of the literature and meta-analysis of single-arm studies.

Within the last two decades low molecular weight heparins (LMWH) have gained increasing widespread use as anticoagulants in children. The use of LMWH has been implemented into clinical care even though there is a lack of firm evidence on the efficacy and safety of LMWH in this population due to the absence of sufficiently powered randomized controlled trials. In the absence of clinical trials, we performed a meta-analysis of available single-arm studies using LMWH in children. A systematic search of electronic databases (Medline, EMBASE, OVID, Web of Science, The Cochrane Library) for studies published from 1980 to 2010 was conducted using keywords in combination both as MeSH terms and text words. Two authors independently screened citations and those meeting a priori defined inclusion criteria were retained. Data on year of publication, study design, country of origin, number of patients, ethnicity, venous thromboembolic events type, and frequency of recurrence and major bleedings were abstracted. Pooled incidence rates (IR) including 95% confidence intervals (95% CIs) on efficacy and safety data of LMWH administration on primary prophylaxis, as well as on secondary prophylaxis in children following symptomatic thromboembolism (TE) were shown. We included 2251 pediatric patients derived from 35 single-arm studies from 12 study countries who were eligible for analysis in the present systematic review. Pooled incidence rates (95% CI) to develop first TE on primary prophylaxis, further TE event on LMWH secondary prophylaxis, or a major bleeding event on LMWH were 0.047 (0.023 to 0.091), 0.052 (0.037 to 0.073) for efficacy, and 0.054 (0.039 to 0.074) for safety (treatment data only), respectively. Efficacy and safety data are comparable with adult data. The present systematic review suggests that use of LMWH in children as primary prophylaxis and in treatment of symptomatic thrombosis is effective and safe. However, properly designed randomized controlled trials are needed.

Current difficulties and recent advances in bypass therapy for the management of hemophilia with inhibitors: a new and practical formulation of recombinant factor VIIa.

Bypassing agents are the mainstay of treatment for patients with hemophilia with high-titer inhibitors. Whereas the availability of these agents has greatly advanced the management of bleeding episodes in this population, timely administration of bypassing agents continues to be hampered by a number of practical limitations, including the need for refrigerated storage of the agent and its reconstitution at room temperature prior to administration, among others. In this review, the importance of early treatment of bleeds and factors that influence this more timely therapeutic approach are highlighted, together with the advantages offered by the use of a new formulation of recombinant activated factor VII that permits improved storage and portability, potentially optimizing timely bypassing agent administration.

A phase II study of amifostine in children with myelodysplastic syndrome: a report from the Children's Oncology Group study (AAML0121).

Based on its potential role in adult myelodysplastic syndrome (MDS), the Children's Oncology Group (COG) embarked on a phase II study using amifostine in pediatric MDS (WHO 2001 criteria) patients. Responses were evaluated after two cycles. Ten patients were enrolled; five were deemed ineligible, and four withdrew after the first course. Only one patient completed two courses, and was found to be in complete remission. The study was closed after being open for 2 years due to slow accrual. Studying a rare disease like MDS may pose insurmountable obstacles even in a large clinical trials group such as COG, in part because of the changing definitions of MDS and the rarity of adult type MDS in children. The role of amifostine in pediatric MDS was not known at the time of study.