Early Bone Marrow Transplantation Research Articles

MDS-670 Early Bone Marrow Transplantation in GATA2 Deficiency-Induced MDS

MDS-670 Early Bone Marrow Transplantation in GATA2 Deficiency-Induced MDS

POSTER: MDS-198 Early Bone Marrow Transplantation in GATA2 Deficiency-Induced Myelodysplastic Neoplasms

POSTER: MDS-198 Early Bone Marrow Transplantation in GATA2 Deficiency-Induced Myelodysplastic Neoplasms

MDS-198 Early Bone Marrow Transplantation in GATA2 Deficiency-Induced Myelodysplastic Neoplasms

MDS-198 Early Bone Marrow Transplantation in GATA2 Deficiency-Induced Myelodysplastic Neoplasms

POSTER: MDS-670 Early Bone Marrow Transplantation in GATA2 Deficiency-Induced MDS

POSTER: MDS-670 Early Bone Marrow Transplantation in GATA2 Deficiency-Induced MDS

Progressive Ataxia and Neurologic Regression in RFXANK-Associated Bare Lymphocyte Syndrome.

ObjectiveTo identify the genetic cause of a late-onset immunodeficiency and subacute progressive neurodegenerative disease affecting cognition, motor, visual, and cerebellar systems in a patient with a family history of 2 younger siblings with an early-onset immunodeficiency disease.MethodsPhysical examinations, immunologic, brain MRI, whole-exome sequencing, and segregation studies were used to identify the genetic and neuroimmunologic etiology of disease in this family.ResultsWe identified a homozygous loss-of-function (LOF) mutation (c.271+1G>C) in the RFXANK gene in the index patient and one of his younger affected siblings. Biallelic mutations in the RFXANK gene are known to cause bare lymphocyte syndrome (BLS) type II, complementation group B. The clinical and immunologic investigations were consistent with a clinical diagnosis of BLS type II. MRI demonstrated global cerebral and cerebellar atrophy with white matter signal changes in the index case.ConclusionsIn addition to BLS type II, our study has expanded and further characterized the phenotype associated with the LOF of RFXANK to include progressive neurodegenerative disease. Our study also provides evidence for the impact of LOF on brain development and function. Thus, early bone marrow transplantation, as a standard of care for BLS, could prove to be protective against the neurologic phenotypes in this group of patients.

Transplant Outcomes for IDH-Mutated AML: Good Outcomes Thanks to Keeping Good Company

Background: Mutations in the isocitrate dehydrogenase (IDH) 1 and 2 genes are found in approximately 20% of patients with acute myeloid leukemia (AML). Although independent prognostic data are lacking, our program often moves patients with IDH-mutated AML (mIDH) towards allogeneic bone marrow transplant (BMT). Reports on the impact of mIDH on BMT outcomes are conflicting. One study (Quek L, et al. Blood Adv. 2016; 1(3):19320) found improved rates of relapse (RR), relapse free survival (RFS) and overall survival (OS) for patients with mIDH1, whereas another study (Salhotra A, et al. Clin Lymphoma, Myeloma Leuk. 2019 Jul 1;19(7):e400-5) reported higher RR, but no differences in RFS or OS for patients with mIDH1/2. In light of the approved IDH1/2 inhibitors, the role of early BMT for such patients requires additional study. We examined the BMT outcomes of patients with mIDH AML compared to wildtype (wt)-IDH AML. Patients and methods: Patients with AML who underwent a first allo-BMT at Johns Hopkins between 2014 and 2020 and had molecular testing for IDH mutation status were included. Patients were grouped according to IDH mutation status (mIDH versus wt-IDH). Patient demographics, molecular genetics, initial treatment response, and BMT characteristics were compared. Post-BMT RR, RFS and OS were then compared between groups. Multivariate models were used to assess the prognostic significance of mIDH after controlling for co-variates. We also examined the relationship between peri-BMT IDH inhibitor use and IDH mutation status at the time of post-BMT relapse. Results: We identified 109 patients with mIDH AML, 70 (64%) of whom underwent BMT. 210 BMT patients with wt-IDH AML were used as a comparison. Outcomes between patients with mIDH1 and mIDH2 AML were similar and they were combined for all further analyses. Patients with mIDH were generally older (mean age at diagnosis 61 (range 28-75) vs. 54 (range 19-76), p < .001), less likely to have poor-risk cytogenetics, more likely to have a haploidentical donor, and more likely to receive non-myeloablative conditioning (Table 1). mIDH AML was associated with co-mutations in SRSF2 and DNMT3A mutations and less likely to have TET2 and KRAS co-mutations. Patients with mIDH had significantly improved post-BMT RR, RFS and OS compared to patients with wt-IDH (log rank p = 0.04, .01, and .01 respectively, Figure 1). In a multivariate model controlling for ELN risk classification, mIDH was associated with improved OS with a trend towards significance (HR 0.51, 95% CI 0.24 - 1.10, p = 0.085). Recognizing that significant heterogeneity exists within ELN risk groups, we examined the specific components of poor ELN risk classification in each group and found that poor risk in the wt-IDH group was primarily driven by complex karyotypes and TP53 mutations, whereas the ELN poor risk was driven by RUNX1 or ASXL1 co-mutation in the mIDH group. In a model controlling for specific genetic abnormalities (complex karyotype, TP53 mutation, and KRAS mutation) IDH mutation status was not an independent prognostic factor (HR 0.66, 0.34 - 1.28, p = 0.2, Table 2). We also assessed whether improved outcomes might be associated with use of IDH inhibitors in the pre or post-BMT setting. 22 (31%) of the 70 patients with mIDH AML received pre-BMT IDH inhibitors and an additional 4 patients received post-BMT maintenance. Of the 15 patients with mIDH who relapsed post-BMT, 13 had mIDH at the time of relapse. 11 of the 11 patients who had never received an IDH inhibitor had mIDH at relapse compared to 2 of 4 (50%) patients who had received IDH inhibitors (p = .057). Conclusion: In our cohort, patients with mIDH AML had significantly better OS, RFS, and RR following BMT compared to patients with wt-IDH. However, our analyses suggest that IDH mutations are associated with favorable genetic abnormalities and that the differences in BMT outcome are likely attributable to these differing genetic profiles as opposed to the presence of the mIDH. Differences in outcome were specifically driven by a lower prevalence of complex cytogenetics, TP53 mutations, and KRAS mutations amongst mIDH AML and were incompletely captured by ELN risk classification. In addition, the frequency with which post-BMT relapsed AML bears the IDH-mutant clone suggests that incorporation of IDH inhibitors into the peri-BMT setting, as is currently being studied in large randomized trials (NCT03564821, NCT03515512), may further improve outcomes. Disclosures DeZern: Celgene: Consultancy, Honoraria; Astex: Research Funding; Abbvie: Consultancy; MEI: Consultancy. Levis:Astellas: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; FujiFilm: Honoraria, Research Funding; Amgen: Honoraria; Menarini: Honoraria. Smith:Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

NEONATAL SCREENING IN UKRAINE: THE NEW CHALLENGES

Introduction. The priority of modern pediatrics and neonatology is to improve the organizational forms and methods of providing medical care to children, reducing morbidity, mortality and disability prevention. Severe Combined Immunodeficiency (SCID) is a group of primary immunodeficiency conditions with particularly severe dysfunction or absence of T and B cells, and sometimes NK lymphocytes. Late diagnosis of primary immunodeficiency, namely SCID, leads to the development of severe infectious complications, significantly complicates the further treatment and survival of patients, often leading to death from infancy. Today there are results of SCID treatment, with early diagnosis the effectiveness of therapy and survival of children is more than 90% in the world. A number of countries around the world conduct neonatal screening at the state level for early diagnosis of SCID. Modern neonatal screening in Ukraine is provided for 4 nosologies, while in other countries it covers from 8 to 60 genetic pathologies. The aim of our study is the early detection and diagnosis of severe primary immunodeficiency by neonatal screening, prevention of severe infections and complications in this group of patients, timely radical treatment, improving survival and quality of life of children with severe primary immunodeficiency. Materials and methods. For the first time in Ukraine, it is planned to conduct a pilot study of screening of newborns to detect severe primary immunodeficiencies, which will be based on the determination of T- and B-lymphopenia by TRECs and KRECs. The prevalence of T- and B-lymphopenias among 19 newborns, their importance in the diagnosis of severe combined immunodeficiencies and severe antibody disorders will be determined. Based on the results of the study, a protocol for the detection of primary immunodeficiencies by TRECs and KRECs and further tactics for infection prevention, treatment and surveillance of such children will be developed. For the first time, the clinical and economic feasibility of introducing neonatal screening for severe immunodeficiencies in Ukraine will be substantiated. Expected results. After studying the prevalence of T- and B-lymphopenia in infants, their importance in the diagnosis of SCID and severe antibody disorders will be formulated. Conclusions. Early diagnosis of primary immunodeficiency is extremely important to improve the patient's quality of life, as delayed diagnosis leads to a lack of adequate therapy and, consequently, to further serious infections that interfere with daily life, increasing the risk of various non-infectious complications. It is known that these disorders negatively affect the health of the patient, the quality of life of his family and people caring for him. In addition, existing research in the world proves that early diagnosis and bone marrow transplantation is an effective way to reduce the incidence and mortality of patients with SCID and lymphopenia

Osteomielite maxilar aguda em paciente acometido por osteopetrose infantil maligna: relato de um caso raro de sobrevida

A osteopetrose infantil maligna (OIM) é a forma mais grave de osteopetrose (OP), que é um grupo de desordens raras e hereditárias que acometem o esqueleto humano, tornando-o mais denso. Uma das suas principais consequências é a invasão medular por esclerose óssea, levando a progressiva insuficiência medular e aplasia, o que predispõe a inúmeras infecções graves, incluindo a osteomielite. É uma doença que possui mortalidade de 99% até os dez anos de idade, com incidência de 1:500.000 nascidos vivos, cujo único tratamento disponível é o transplante de medula óssea precoce. O caso relatado é de um paciente do sexo masculino, 14 anos, com diagnóstico de OIM desde a infância, admitido na emergência do Hospital Infantil Albert Sabin com edema e dor facial à direita de início há um mês. Com base no exame físico e nos exames complementares foi diagnosticada osteomielite maxilar aguda. Além do quadro atual, o paciente possuía diversas sequelas da sua doença de base. Evoluiu com sepse durante a internação, fez uso de antibioticoterapia, e obteve alta hospitalar após um mês para cuidados paliativos domiciliares.

Murine Models of Steroid Refractory Graft-versus-Host Disease

Corticosteroids are the first line therapy for acute graft-versus-host disease (GVHD). However, the outcome of steroid refractory GVHD (SR-GVHD) is poor due to a lack of effective treatments. The development of therapies for SR-GVHD is limited by an incomplete understanding of its pathophysiology partly because of the absence of clinically relevant animal models of SR-GVHD. Here we addressed the need for a SR-GVHD animal model by developing both MHC matched multiple minor histocompatibility antigens (miHAs) mismatched and MHC mismatched haploidentical murine models of SR-GVHD. We demonstrate that animals can develop SR-GVHD regardless of whether steroids are initiated early or late post allogeneic bone marrow transplantation (allo-BMT). In general, we observed increased GVHD specific histopathological damage of target organs in SR-GVHD animals relative to steroid responsive animals. Interestingly, we found no significant differences in donor T cell characteristics between steroid refractory and responsive animals suggesting that donor T cell independent mechanisms may play more prominent roles in the pathogenesis of SR-GVHD than was considered previously.

Intracranial Calcification after Probable Disseminated Bacillus Calmette–Guérin Infection in a Child with Severe Combined Immunodeficiency

AbstractBacillus Calmette–Guérin (BCG) vaccine is administered to infants in countries with a high prevalence of tuberculosis. Severe combined immunodeficiency (SCID) is one of the most severe forms of primary immunodeficiency disease, rendering patients prone to disseminated BCG infection. Early intensive antimycobacterial treatment and bone marrow transplantation may be lifesaving in patients with BCG infection and SCID. The central nervous system is rarely involved in BCG infection. We report a case of disseminated BCG infection with diffuse intracranial calcification, including periventricular white matter, subcortical area, pons and cerebellar white matter after bone marrow transplantation.

Griscelli syndrome subtype 2 with hemophagocytic lympho-histiocytosis: A case report and review of literature

Griscelli syndrome (GS) is a rare autosomal recessive disorder resulting in pigmentary dilution of the skin and hair with variable phenotypes depending upon subtypes. Mutations in 3 distinct genes MYO5A, RAB27A, MLPH are responsible for 3 subtypes (GS1, GS2, and GS3) of GS respectively. GS subtype 2 commonly develops hemophagocytic lymphohistiocytosis (HLH) and recurrent infections due to immunodeficiency. We hereby report a 20 month old male child presenting with silvery gray hair, hypomelanosis and features of hemophagocytosis. The diagnosis of a type 2 GS was made in response to a set of clinical features: hypopigmentation of skin and the silvered reflection of the hair, absence of psychomotor retardation, the occurrence of an accelerated phase (hemophagocytosis) and, above all, a pathognomonic appearance by microscopic examination of a hair. The absence of giant granules in the nucleated cells made it possible to eliminate Chediak-Higashi syndrome, which shares a close clinical spectrum with GS. This case promotes awareness about this rare case of GS as a high indicator of suspicion about this potentially fatal condition and aids in prompt diagnosis and foresees complications. Early bone marrow transplant is the only curative treatment for GS-2.

Primary Lung Adenocarcinoma as Secondary Malignancy After Bone Marrow Transplantation

SESSION TITLE: Student/Resident Case Report Poster - Lung Cancer I SESSION TYPE: Student/Resident Case Report Poster PRESENTED ON: Tuesday, October 25, 2016 at 01:30 PM - 02:30 PM INTRODUCTION: Bone marrow transplant (BMT) recipients have a higher risk of developing secondary malignancies. Majority of secondary malignancies are cutaneous or oral mucosal cancers. Secondary cancers most often occur late, usually after 100 days from transplantation. Death caused by malignant neoplasm less than 5 years after transplantation is rare. We report a case of adenocarcinoma of the lung presenting as a secondary malignancy 71 days after bone marrow transplantation. CASE PRESENTATION: 54 year old Female in remission from Stage IV low grade follicular Non-Hodgkins Lymphoma underwent a matched sibling donor allogenic stem cell transplant for acute lymphoblastic lymphoma. She was treated with fludarabine and melphalan conditioning therapy as well as tacrolimus for graft vs host disease (GVHD) prophylaxis and presented 71 days following BMT as a transfer with dyspnea. Previous positron emission tomography (PET) showed resolving but persistent hypermetabolic ground glass opacifications in the right lower lobe thought to be resolving infectious/inflammatory process. Few months prior, computed tomography of chest revealed stable bilateral pulmonary micronodules without lymphadenopathy. On physical examination the patient was afebrile, tachypnic and tachycardic. Pulmonary auscultation revealed decreased right breath sounds and rhonchi. Chest X-ray revealed large right pleural effusion. The patient subsequently developed acute respiratory failure requiring intubation and diagnostic and therapeutic thoracentesis. Pleural fluid cytology was positive for adenocarcinoma consistent with lung primary. Despite best efforts, patient’s respiratory status continued to deteriorate and patient passed away in intensive care unit. DISCUSSION: Although BMT is a successful and recognized treatment option for malignant hematologic disorders, patients have increased risk for secondary malignancies. Conditioning chemotherapy, radiation therapy and immunosuppression therapy for GVHD increase secondary malignancy risk by mechanisms of direct organ toxicity and depletion of lymphocyte tumor regulation. Our patient developed a secondary malignancy as an unusual early complication of BMT after chemotherapy conditioning and GVHD prophylaxis with an aggressive primary lung adenocarcinoma. PET scan is known to poorly detect adenocarcinoma in situ and minimally invasive adenocarcinoma. Early stage malignancy may have been already present and overlooked. Further immunosuppression in context of BMT may have provided an environment for proliferation and rapid progression of disease. CONCLUSIONS: We report a rare presentation of lung adenocarcinoma as an early BMT complication. Due to profound immunosuppression, malignancy in BMT patients can present quickly and aggressively. Thorough follow up is needed for any resolving hypermetabolic states seen on PET scan. Reference #1: Bhatia, Smita, et al. “Solid cancers after bone marrow transplantation.” Journal of Clinical Oncology 19.2 (2001): 464-471. DISCLOSURE: The following authors have nothing to disclose: Tasneem Kaleem, Jordan Ray, John Moss, Laura Finn No Product/Research Disclosure Information

High feasibility and antileukemic efficacy of fludarabine, cytarabine, and idarubicin (FLAI) induction followed by risk‐oriented consolidation: A critical review of a 10‐year, single‐center experience in younger, non M3 AML patients

About 105 consecutive acute myeloid leukemia (AML) patients treated with the same induction-consolidation program between 2004 and 2013 were retrospectively analyzed. Median age was 47 years. The first induction course included fludarabine (Flu) and high-dose cytarabine (Ara-C) plus idarubicin (Ida), with or without gemtuzumab-ozogamicin (GO) 3 mg/m(2) (FLAI-5). Patients achieving complete remission (CR) received a second course without fludarabine but with higher dose of idarubicin. Patients not achieving CR received an intensified second course. Patients not scheduled for early allogeneic bone marrow transplantation (HSCT) where planned to receive at least two courses of consolidation therapy with Ara-C. Our double induction strategy significantly differs from described fludarabine-containing regimens, as patients achieving CR receive a second course without fludarabine, to avoid excess toxicity, and Ara-C consolidation is administrated at the reduced cumulative dose of 8 g/m(2) per cycle. Toxicity is a major concern in fludarabine containing induction, including the recent Medical Research Council AML15 fludarabine, cytarabine, idaraubicin and G-CSF (FLAG-Ida) arm, and, despite higher anti-leukemic efficacy, only a minority of patients is able to complete the full planned program. In this article, we show that our therapeutic program is generally well tolerated, as most patients were able to receive subsequent therapy at full dose and in a timely manner, with a 30-day mortality of 4.8%. The omission of fludarabine in the second course did not reduce efficacy, as a CR rate of 83% was achieved and 3-year disease-free survival and overall survival (OS) were 49.6% and 50.9%, respectively. Our experience shows that FLAI-5/Ara-C + Ida double induction followed by risk-oriented consolidation therapy can result in good overall outcome with acceptable toxicity. Am. J. Hematol. 91:755-762, 2016. © 2016 Wiley Periodicals, Inc.

Suppression of the motor deficit in a mucolipidosis type IV mouse model by bone marrow transplantation.

Mucolipidosis IV (MLIV) is a severe lysosomal storage disorder, which results from loss of the TRPML1 channel. MLIV causes multiple impairments in young children, including severe motor deficits. Currently, there is no effective treatment. Using a Drosophila MLIV model, we showed previously that introduction of trpml+ in phagocytic glia rescued the locomotor deficit by removing early dying neurons, thereby preventing amplification of neuronal death from cytotoxicity. Because microglia, which are phagocytic cells in the mammalian brain, are bone marrow derived, and cross the blood-brain barrier, we used a mouse MLIV model to test the efficacy of bone marrow transplantation (BMT). We found that BMT suppressed the reduced myelination and the increased caspase-3 activity due to loss of TRPML1. Using a rotarod test, we demonstrated that early BMT greatly delayed the motor impairment in the mutant mice. These data offer the possibility that BMT might provide the first therapy for MLIV.

Orthopedic Pathology in Children with Mucopolysaccharidosis Type I

Mucopolysaccharidosis type I is inherited in an autosomal recessive manner and results from the defective activity of the enzyme alpha-L-iduronidase, which leads to the accumulation of glycosaminoglycans (mainly heparan and dermatan sulfate) in the lysosomes and further multiple organ dysfunction. This severe genetic progressive disease can be detected at an early age by skeletal deformities and phenotypic data. Early enzyme replacement therapy and/or bone marrow transplantation can slow down irreversible damages to various organs and systems or reduce their severity and improve the quality of life for a child.

Tumeur à cellules plasmocytoïdes dendritiques blastiques révélée par des lésions ecchymotiques du visage

Cutaneous CD4+CD56+ malignant tumor proliferation was previously called "CD4/CD56 hematodermic neoplasm". However, the most recent studies have shown that the disease develops from plasmacytoid dendritic cells and the tumor has been renamed "Blastic Plasmacytoid Dendritic Cell Neoplasm" (BPDCN). It is an aggressive disease with a poor prognosis and behaves like acute leukemia in the short to moderate term. A 65-year-old man with no particular history consulted for a left laterocervical lesion of ecchymotic aspect that had appeared one year earlier. Topical corticosteroid therapy had been unsuccessful. Examination of biopsies with lymphocyte typing enabled a diagnosis of BPDCN to be made. At the histopathological level, biopsy showed an infiltrate comprising medium to large cells. Immunohistochemical examination was remarkable for the absence of expression of markers of T- and B-cell lines. However, these tumor cells expressed CD4, CD56 and TCL1. Staging of the disease was normal. Treatment with chemotherapy was initiated in collaboration with a team of hematologists. Autologous bone marrow transplant was then performed. BPDCN is a rare malignant blood dyscrasia. It is distinguished by inaugural skin involvement, with systemic manifestations occurring much later. Histopathological examination of a skin biopsy with immunostaining establishes the diagnosis. In terms of phenotype, the tumor population is highly characteristic. The cells are negative for antigens of T- and B- cell lines. However, these cells express CD4, CD56 and TCL1, which are markers of plasmacytoid dendritic cells. The disease carries a poor prognosis and evolves in the short to middle term in the same way as acute leukemia. First-line treatment consists of the chemotherapy regimens used in aggressive lymphoma or acute leukemia. A bone marrow graft is sometimes performed at the time of initial relapse. Average survival is 12 months for chemotherapy alone and 30 months for transplant after first relapse. Early bone marrow transplantation has been shown to improve survival.

Short Survival and High Rates of Transformation Prevail in Chronic Myelomonocytic Leukemia Despite Hypomethylating Agent Therapy.

Abstract 2800 Background:Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder categorized as a mixed myeloproliferative/myelodysplastic disorder in the World Health Organization classification system. Diagnostic criteria include a persistent peripheral blood monocytosis >1 × 109/L and bone marrow dysplasia. Our recent review of SEER Medicare data (ASH 2011 abstract 2784) demonstrated that CMML has a shorter overall survival (OS) and more frequent progression to acute myeloid leukemia (AML), compared to myelodysplastic syndromes (MDS). Due to the heterogeneity of this disease and its differences from MDS, efforts to identify prognostic factors have been ongoing. The MD Anderson prognostic score was previously validated, but was derived from patients treated prior to the availability of the hypomethylating agents (HMAs) azacitidine and decitabine. HMAs have now emerged as standard therapy, with reported response rates of 37–69%, but their impact on survival and AML transformation is unclear. The OS of CMML patients has been reported at 12–18 months and transformation rates have varied between 15–52%. We reviewed our own single-center experience with CMML over the past 12 years. Methods:We conducted a retrospective review of CMML patients evaluated at the University of Maryland Greenebaum Cancer Center between January 2000 and August 2012. Patient and disease characteristics, treatments, complications, progression to AML, and OS were recorded and analyzed. Descriptive statistics were used for baseline characteristics and Kaplan-Meier analysis was performed for all time-to-event data. Statistical analyses were performed using SPSS version 20.0. Results:We identified 35 patients with CMML, 71% were male and 71% white, with a median age of 69 (range 34–86) years; 75% had <10% bone marrow (BM) blasts and 68% had low-risk cytogenetic findings (normal karyotype or -Y). Most patients treated prior to 2005 received hydroxyurea and/or erythropoiesis-stimulating agents or were enrolled on clinical trials, while patients treated since 2005 received HMAs as primary therapy. The median OS of the entire cohort was 19.5 months, with 49% of patients progressing to AML with a median time to progression (TTP) of 16.9 months.Of the entire cohort, patients with <10% and ≥10% BM blasts had an estimated OS of 19.4 and 11.7 months respectively (p=.021). Patients with low-, intermediate-, and high-risk (complex karyotype, +8, or chromosome 7 abnormalities) cytogenetic findings had an estimated OS of 23.3, 16.5, and 12.0 months respectively (p<0.001).Twenty-two patients received HMAs. Their estimated OS was 16.5 months, compared to 23.0 months for patients who did not receive HMAs (p =.683); 50% of patients treated with HMAs had known progression to AML, with TTP varying from 3–28 months. AML-free-survival was 16 months in patients receiving HMAs, compared to 14 months in patients not treated with HMAs (p=0.960). The majority of patients receiving HMA therapy (63%) were treated with ≥ 6 cycles; 57% of these patients transformed to AML despite initial response, often in a sudden and unpredictable manner. Conclusions:Published trials using HMAs in CMML have been limited by small patient numbers, short median follow-up, and paucity of data on AML transformation. Our study had a median follow-up period of 41.1 months. We found a high rate of AML transformation and short OS even in patients who received HMAs. HMA treatment had no statistically significant impact on AML-free survival or OS. Although the results may be confounded by some selection bias, treatment with HMAs was largely based on the date of diagnosis rather than prognostic variables or performance status. Therefore, the favorable response rates previously reported with these agents, and also seen in our patients, do not appear to translate into an OS or AML-free-survival advantage. Our study underscores the continued need for novel agents and the need to prioritize clinical trials for this group of patients. Additionally, based on our data, early bone marrow transplantation should be strongly considered for CMML patients when feasible. Disclosures:Davidoff:Novartis: Research Funding; Celgene: Research Funding; GlaskoSmithKline: Research Funding. Baer:Novartis, Inc.: Research Funding; Celgene, Inc.: Research Funding.

Specificities of sclerosing cholangitis in childhood

Sclerosing cholangitis (SC) is a chronic cholestatic disease characterized by inflammation and obliterative fibrosis of the bile ducts, leading to biliary cirrhosis and ultimately to liver failure. Four main clinical forms can be distinguished in children: i) neonatal SC, most probably a genetic disease transmitted by autosomal recessive inheritance; ii) SC associated with strong features of autoimmunity (referred as autoimmune sclerosing cholangitis) with quite good response to immuno-suppression iii) primary SC of unknown etiology (i.e. without features of autoimmunity) and iv) SC secondary to various diseases, including Langerhans cell histiocytosis and immunodeficiencies. Ursodesoxycholic acid is considered the treatment of choice for all forms of SC but without proof of its effectiveness in preventing progression to secondary biliary cirrhosis. In patients with immunodeficiencies, early bone marrow transplantation is the only way to prevent secondary SC. Liver transplantation remains the only validated treatment in children with biliary cirrhosis. Recurrence of SC after liver transplantation has not been clearly demonstrated in children; however, recurrence of Langerhans cell histiocytosis with bile duct injury has been reported. For patients with severe immunodeficiency, a two-step liver then bone marrow transplantation protocol may be proposed.

Long-Term Outcome of All-Trans-Retinoic-Acid(ATRA)+Intensive Chemotherapy in Acute Promyelocytic Leukemia(APL),

Abstract 3604 Background:ATRA has improved treatment of APL and particularly made remission induction therapy easier. However, there is no post-remission therapy that can surely cure APL. As ATRA alone is unlikely to cure the disease, a new combination therapy that uses ATRA and can attain a high rate of cure is needed. Objective: To cure APL by a combination of intensive remission induction therapy and post-remission therapy with ATRA. Also, to give supportive therapy under careful monitoring to avoid death due to chemotherapy. Subjects and Methods: Sixty-five consecutive patients with previously untreated APL who visited our hospital between January 2000 and January 2011 were treated. The t (15;17) or PML-RARA translocation was observed respectively in chromosome analysis and genotyping in all patients. The age range was 16 to 79 (median: 51). Nineteen were aged 60 or older. Thirty-four and thirty-one were men and women, respectively. Remission induction therapy was started with ATRA at 45 mg/m2 (P.O.) immediately after diagnosis of APL. Idarubicin (IDR) at 10 mg/m2 (Days 1, 3, 5, and 7) and behenoyl-ara-C (BH-AC) at 350 mg/m2 (Days 1 through 7) were also administered. DIC was treated with continuous infusion of gabexate mesilate, platelet transfusion (to maintain a platelet count of ≥ 50,000/mm3), and frozen plasma transfusion (to maintain fibrinogen ≥ 100 mg/dL). The remission induction therapy was given in a sterile room. After completion of chemotherapy, macrophage colony-stimulating factor (M-CSF) was given for 10 days. Subsequently, granulocyte colony-stimulating factor (G-CSF) was administered until neutrophil recovery. After remission, the post-remission therapy commonly used in AML patients at our hospital (ASH, 2009, abstract, no. 1052) was given for 1 year. ATRA was given at 40 mg/body daily with chemotherapy. Patients received ATRA daily at the same dose for 3 years after completion of the post-remission therapy. The post-remission therapy involved high-dose-cytarabine (2 g/m2 BID for 5 days but 1 g/m2 × BID for 5 days for those aged 60 or older) combined with mitoxantrone (MIT) at 7 mg/m2/day for 3 days (HD-AC + MIT) given immediately after complete remission (CR). Subsequently, a combination of BH-AC at 350 mg/m2 × 4 + aclarubicin at 20 mg/body × 6 and another combination of BH-AC at 350 mg/m2 + IDR at 10 mg/m2 × 1 were given repeatedly in an alternating manner (35 days each). M-CSF (for 7 days) was administered followed by G-CSF after completion of each chemotherapy combination. Each patient was transferred to a sterile room when the WBC count decreased below 1,000. Results: CR was achieved in 63/65(97%). Early deaths (ED) occurred in 2/65 (aged 74 and 79) due to interstitial pneumonia. The follow-ups of patients lasted from 3 to 142 months (median: 74 months). Three patients have experienced a relapse of APL, and relapse of hematological malignancy (myelodysplastic syndrome [MDS]) was seen in 5 patients. A chromosomal aberration not observed at first visit was found at relapse in all 5 patients who developed MDS. Six patients have died from relapsed APL (2), MDS (2), pneumonia following HD-AC + MIT (1), or liver cancer (1). For 63 patients who achieved CR, the overall survival (OS) calculated by the Kaplan-Meier method was 87% at 13 years. The disease-free survival (DFS) was 82% at 13 years. The OS and DFS for patients younger than 60 were respectively 93% and 80%. They were respectively 78% and 87% for patients aged 60 or older, showing no difference between the age groups. The DFS was 83% and 80% for patients treated with HDAC (52) and not treated with HDAC (11), respectively, showing little difference. When analyzed using the risk-based prognostic system of Sanz, et al., the OS was 70, 87, and 100% respectively for patients classified into the low (18), intermediate (27), and high risk (18) groups. The DFS was 72, 81, 94%, respectively. The analysis showed the best results for the high-risk group. Discussion: ATRA + intensive chemotherapy and long-term ATRA can attain a high rate of long-term survival (cure) for patients with APL regardless of age and risk group. Despite the use of intensive chemotherapy, only one patient died due to chemotherapy. This seems to be due to the selection of appropriate supportive therapy. Early diagnosis and bone marrow transplantation in patients with relapse (MDS) may further improve the rate of cure in patients with APL. Disclosures:No relevant conflicts of interest to declare.

The effects of early and late bone marrow transplantation in siblings with alpha‐mannosidosis. Is early haematopoietic cell transplantation the preferred treatment option?

This article documents both the neurological and physical outcomes of the first published set of siblings undergoing transplantation at differing ages for α-mannosidosis. The older brother, the index case, was diagnosed at the age of 3years and underwent transplantation at 13years for the treatment of increasing somatic problems and recurrent infections. The younger brother had undergone transplantation pre-symptomatically at 6months of age. Their clinical, radiological and developmental outcomes are documented and compared with the previous published cases, with the case for early transplantation being weighted against other potential therapies.