Successful Allogeneic Bone Marrow Transplantation Research Articles

CT-282 Case Report: Successful Management of Severe Veno-Occlusive Disease after Allogeneic Stem Cell Transplantation Using a Transjugular Intrahepatic Portosystemic Shunt

Veno-occlusive disease (VOD), also called sinusoidal obstruction syndrome (VOD/SOS), of the liver is a complication of allogeneic bone marrow or peripheral stem cell transplantation and is known to be an unpredictable, life-threatening complication with high mortality. We report here a case of a 24-year-old male patient who was diagnosed in 2019 at Gustave Roussy institute with AML. The patient was treated with the AML protocol 3+7 in December 2019 with a complete cytologic response and a positive MRD. Leukemia relapse was observed in September 2020, treated by gemtuzumab ozogomycin and cytarabine with a negative MRD. A successful allogeneic bone marrow transplantation from an HLA-matched pheno-identical related donor was conducted on December 22, 2020, using a myeloablative conditioning regimen. The patient was always controlled by a daily blood test and controlled blood transfusions, and a weekly repeated Doppler ultrasound examination did not indicate a high-risk profile of VOD. However, 12 days post transplant, the patient's condition deteriorated with the appearance of abdominal ascites, weight gain of 6 kg (per base 76 kg), and liver cytolysis with ASAT 72 UI/L, ALAT 86 UI/L, and normal bilirubin. Worsening cytolysis was observed, with ASAT 659 UI/L, ALAT 557 UI/L, and normal bilirubin. A Doppler ultrasound found 5 positive criteria of VOD (hepatomegaly, portal dilation, enlargement of the gall bladder wall, splenomegaly, ascites, decrease in the diameter of the subhepatic veins). Defibrotide was initiated. The patient's condition worsened and was refractory to medical therapy. Transjugular intrahepatic portosystemic shunting (TIPS) was performed 13 days after transplantation without technical complications in any case. The median hepatic venous pressure gradient prior to the procedure was 20 mmHg with a drop to 12 mmHg. An abdominal CT scan showed an under hepatic hematoma with hemorrhagic syndrome. Ascites puncture with abdominal drain installation was done. In summary, following TIPS, the patient showed clinical improvement, and VOD resolved subsequently with a complete remission post allogeneic transplant.

A case of RCVS with PRES diagnosed by thunderclap headache, result in successful allogeneic bone marrow transplantation with continuing tacrolimus

A case of RCVS with PRES diagnosed by thunderclap headache, result in successful allogeneic bone marrow transplantation with continuing tacrolimus

Successful allogeneic bone marrow transplantation using immunosuppressive conditioning regimen for a patient with red blood cell transfusiondependent pyruvate kinase deficiency anemia.

Pyruvate kinase deficiency (PKD) is the rare glycolytic enzyme defect causing hemolytic anemia. Treatments are mainly red cell transfusion and/or splenectomy, leading to iron overload. Allogeneic bone marrow transplantation (BMT) is alternatively curative treatment for severe PKD. The intensity of conditioning is often controversial because of higher risk of graft failure and organ damage. Here, we present a transfusion-dependent PKD patient undergoing BMT from an HLA-identical sibling using intensively immunosuppressive conditioning regimen. This report suggests that BMT using immunosuppressive conditioning regimen may be a feasible and effective treatment for patients with severe PKD with iron overload. We suggest the timing of the transplantation at an earlier age in severe PKD predicted from gene mutation is preferred before cumulative damage of transfusion.

A Case of Successful Allogeneic Bone Marrow Transplantation for Secondary Pulmonary Alveolar Proteinosis Complicating Myelodysplastic Syndrome

A Case of Successful Allogeneic Bone Marrow Transplantation for Secondary Pulmonary Alveolar Proteinosis Complicating Myelodysplastic Syndrome

Late Immune Reconstitution and Its Relationship with Infections in Patients with Fanconi Anemia and Bone Marrow Transplantation

BackgroundFanconi anemia (FA) is a condition characterized by congenital malformations, low height, and progressive bone marrow failure during childhood, genomic instability and hypersensitivity to DNA cross-linking agents. Bone marrow transplantation (BMT), is currently the only treatment capable to restore normal hematopoiesis and improve survival of these patients. To achieve a successful allogeneic BMT, a normal T-cell immunity reconstitution is required.1,2ObjectiveTo describe the kinetics of immune reconstitution in six patients with FA after BMT, having used a reduce intensity conditioning regimen, well as associated infections during the post-transplant process.MethodsWe describe the distribution in peripheral blood of CD3+ T lymphocytes, CD16 +/CD56+ NK cells, CD4+ helper T lymphocytes, CD8+ cytotoxic T lymphocytes and CD19+/CD20+ B cells, in six patients with FA, after BMT from an HLA-matching sibling and complete chimerism, on days +90, +120, +150, +180, +210 and +360. The conditioning regimen employed consisted of fludarabine (Flu) 150 mg/m2, cyclophosphamide 20 mg/kg and rabbit anti-thymocyte globulin (r-ATG) 20 mg/kg. Infection was determined by a positive reaction of the DNA polymerase chain to Cytomegalovirus (CMV), Epstein-Barr virus, Adenovirus and BK virus (BKV), as well as galactomannan antigen and antibodies against Candida sp, or positive bacterial cultures.ResultsWe observed different kinetics regarding the recovery of different lymphocyte subpopulations, starting from day +90. CD16+/CD56+ NK cells recovered first, between days 90 and 120, followed by CD8+ T lymphocytes between day +120 and +150, CD19+/CD20+ B cells between day +180 and +210, and finally, CD4+ T lymphocytes starting from day 210. Five patients presented infection in the post-BMT stage. Four patients before +90, developed CMV infection, based on positive reaction of the CMV polymerase chain. All patient responses to ganciclovir therapy and no CMV disease were documented. The fifth patient presented with meningitis due to Lysteria monocitogenes and BKV hemorrhagic cystitis at day +153; this patient had the diagnosis of chronic-graft versus host disase, and was treated with ampicillin, rifampicin and intravenous immunoglobulin, evolving satisfactorily. All patients remain alive and well.DiscussionMost patients in our report developed CMV infection, as being reported with FLU and anti-thymocyte globulin combination. We observed a later reconstitution in comparison with patients in whom lower doses of r-ATG (<10 mg/kg) have been used3. In our group of patients, reconstitution of NK cells and CD8+ T lymphocytes, helped to reduce the frequency of asymptomatic viral infections, as reconstitution of innate immunity and cytotoxic CD8+ T lymphocytes can achieve effective antiviral effector responses, allowing for the control of viral infections, until reconstitution of CD4+ T lymphocytes were fully achieved. The infectious complications associated with this prolonged state of profound immunosuppression and late immune reconstitution, can be attenuated with a closely follow-up for these infectious agents through PCR-mediated detection techniques, which allows an early diagnosis and prompt treatment.ConclusionImmunological reconstitution after a BMT in FA patients is determinant for morbidity and mortality, mainly due to opportunistic infections and GVHD. We observed that recovery kinetics of different lymphocyte populations is different in cases in which higher doses of r-GAT are used, also an early detection and prompt treatment of opportunistic infections may be determinant for patient's survival.Conflict-of-interest disclosure: The authors declare they have nothing to disclose.BibliographyOgonek J, Kralj Juric M, Ghimire S, Varanasi PR, Holler E, Greinix H, et al. Immune reconstitution after allogenic hematopoietic stem cell transplantation. Front immunol. 2016; 7 (507):1-15.Smith AR, Wagner JE. Current clinical management of Fanconi anemia. Expert Rev Hematol. 2012; 5 (5): 513-522.Perlingeiro-Beltrame M, Malvezzi M, Bonfim C, Tadeu Covas D, Pasquini R. Immune reconstitution in patients with Fanconi anemia after allogeneic bone marrow transplantation. Cytotherapy. 2014; 0: 1e14. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Diagnosis of GATA2 haplo-insufficiency in a young woman prompted by pancytopenia with deficiencies of B-cell and dendritic cell development

BackgroundGATA2 deficiency presents with a spectrum of phenotypes including increased susceptibility to viral and bacterial infections, multi-lineage cytopenias, aplastic anemia, leukemic transformation and lymphedema. Allogeneic transplantation is only curative therapy for GATA2 deficiency, but is associated with significant treatment related morbidity and mortality. Given the spectrum of clinical presentation, accurate diagnosis of GATA2 deficiency is necessary to identify patients early in their disease course when allogeneic bone marrow transplantation may be of clinical benefit.Case presentationIn this report, we present a GATA2 mutation diagnosed in 23-year-old woman presenting with pancytopenia, recurring oral blisters, fatigue and chronic pain. We describe markedly low levels of mature B-cells in the blood and bone marrow and the absence of detectable blood dendritic cells with normal serum immunoglobulin levels and normal numbers of marrow plasma cells. She was ultimately diagnosed with GATA2 haplo-insufficiency due to a GATA2 germ-line mutation and underwent a successful allogeneic bone marrow transplant from a 10/10 HLA matched unrelated donor.ConclusionsThe case illustrates the diagnostic difficulties in identifying GATA2 deficiencies and the importance of family history and genetic testing. GATA2 plays an important role in B-cell and dendritic cell development, and decreased numbers of those cells is a characteristic feature that should prompt consideration of GATA2 deficiency in a patient with pancytopenia. Maturation of B-cells to long-lived plasma cells is relatively unaffected in GATA2 deficiency. Allogeneic stem cell transplantation can correct immune-deficiencies and prevent leukemic transformation in patients with GATA2 deficiency.

To the Editor

To the Editor

Successful allogeneic bone marrow transplantation with reduced intensity conditioning regimen for a pediatric relapsed ALK positive anaplastic large cell lymphoma.

Pediatric anaplastic large cell lymphoma (ALCL) is a chemosensitive malignancy, but about 30% of patients experience relapse. In most of these patients, a second complete remission is obtainable with salvage chemotherapy, though relapse free survival rates are as low as 30-60%. Herein, we report a 6-year-old boy with relapsed anaplastic lymphoma kinase (ALK) positive ALCL successfully treated with vinblastine monotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT), with a reduced intensity conditioning (RIC) regimen, from his father. One HLA locus from the father was mismatched. The boy had neither severe graft-versus-host disease nor transplantation related complications. He is currently well and has remained disease free for 10 months, to date, since transplantation. Allo-HSCT with a RIC regimen may be a promising treatment strategy for relapsed ALK positive ALCL based on obtaining graft-versus lymphoma effects as well as reducing transplantation-related mortality.

Preemptive Bone Marrow Transplantation and Event-Free Survival in Fanconi Anemia

Background: Fanconi anemia (FA) is a primarily autosomal recessive bone marrow failure and cancer predisposition syndrome associated with mutations in the FA/BRCA DNA damage response pathway. The median age at diagnosis of FA is 7 years; the diagnosis is often made due to recognition of characteristic birth defects. Over half of patients with FA develop severe bone marrow failure (BMF) by age 50 years, one in ten develop acute myeloid leukemia (AML), and one in four develop a solid tumor (ST) as their first event. Successful allogeneic bone marrow transplantation (BMT) is potentially curative of FA's hematologic manifestations but introduces risks of transplant-related mortality (TRM) and morbidity. We hypothesized that preemptive bone marrow transplantation (PE-BMT) for individuals diagnosed prior to the development of BMF, AML, or ST, would increase event-free survival (EFS) if the risks associated with transplantation were sufficiently low.Methods: We developed a mathematical decision model (Markov) of EFS with the assumption that successful PE-BMT would eliminate the risks of BMF and AML, but would introduce a procedural risk of TRM. We modeled the EFS of PE-BMT at variable ages at decision ranging from birth to 30 years, and without and with an increase in the rate of ST following BMT above the level in untransplanted patients with FA. We developed our model using empirical estimates of the age-specific conditional probabilities of BMF, AML, and ST (Alter et al, BJH, 2010), and a 4.4-fold estimated increased risk of ST following BMT (Rosenberg et al, Blood, 2005). We tested the sensitivity of the model over a range of values for TRM and an increased risk of ST following BMT, and evaluated the model using TreeAge Pro 2014 (TreeAge Software, Inc, Williamstown MA, http://www.treeage.com).Results: Children diagnosed at age 7 years receiving standard care could expect to live an additional 16 years before experiencing BMF, ST, or AML, and thus survive free of an event until an average age of 23 years. If those children instead received PE-BMT with a 10% risk of TRM, they could expect to survive an additional 29 years and be cancer-free until an average age of 36 years. However, if PE-BMT were to increase the rate of ST 4.4-fold, PE-BMT would only increase the mean EFS by 2 years over standard care, until an average age of 25 years. PE-BMT would increase the mean EFS at all ages if TRM was ≤10% and the risk of ST was the same as in untransplanted patients. PE-BMT would decrease the mean EFS when performed after age 9 years if there was 10% TRM and a 4.4-fold increased rate of ST. PE-BMT at age 18 years with 10% TRM would increase the mean EFS if it did not affect the trajectory to ST, but would decrease the mean EFS if it modestly increased the rate of ST (≥2.2-fold).Conclusions: PE-BMT in patients with FA may provide an event-free survival benefit so long as the risk of TRM appears to be low (≤10%) and the regimen has little or no impact on the development of ST. The decision was particularly sensitive to the increase in ST following BMT. Our model suggests that older ages at decision, higher risks of TRM, and greater relative risks of ST following transplant would lead to PE-BMT being a less desirable strategy. Our estimates of event-free survival may be used to inform shared decision making between providers and families, with attention paid to patient values and the morbidity associated with BMT. DisclosuresNo relevant conflicts of interest to declare.

The Microbiome and Graft Versus Host Disease

Allogeneic hematopoietic bone marrow transplantation (BMT) is an established and curative treatment for many aggressive hematological malignancies. However, the success of allogeneic BMT is limited by graft versus host disease (GVHD) due to the attack of recipient organs. There is growing evidence that the commensal microbiota is dysregulated following allogeneic BMT. Recent studies have made significant strides in examining the role of the host and donor microbiome on GVHD severity and pathogenesis. In this review, we summarize the current knowledge of the complex roles of the microbiome on GVHD, as well as the role of the metabolome through which it confers its effects.

Successful outcome of allogeneic stem cell transplantation in Seckel syndrome

Seckel syndrome is a rare autosomal recessive disease, genetically heterogeneous, characterized by short stature, prenatal microcephaly, intellectual disability, dysmorphic features, chromosomal instability, and hematological disorders. We report the case of a six-yr-old boy with Seckel syndrome and aplastic anemia who underwent successful allogeneic bone marrow transplantation from ten of ten HLA matched unrelated donor. Currently the patient is on D+771, in good health conditions and with no further complications. In conclusion, this case indicates that bone marrow transplantation is an acceptable therapeutic option for Seckel syndrome complicated by hematological alterations.

Long-term therapeutic efficacy of allogenic bone marrow transplantation in a patient with mucopolysaccharidosis IVA

Mucopolysaccharidosis IVA (MPS IVA) is one of the lysosomal storage diseases. It is caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase. Deficiency of this enzyme leads to accumulation of the specific glycosaminoglycans keratan sulfate and chondroitin-6-sulfate. This accumulation has a direct impact on cartilage and bone development, resulting in systemic skeletal dysplasia. There is no curative therapy for this skeletal dysplasia.This report describes long-term therapeutic efficacy in a 15-year-old boy with a severe form of MPS IVA who received successful allogeneic bone marrow transplantation (BMT) from his HLA-identical carrier sister. The level of the GALNS enzyme in the recipient's lymphocytes reached almost half of normal level within two years after BMT. For the successive 9+years post-BMT, GALNS activity in his lymphocytes maintained the same level as the donor's, and the level of urinary uronic acid was reduced. Lumbar bone mineral density increased around 50% one year later post-BMT and was kept consistent. Radiographs showed that the figures of trochanter major and minor appeared, while the epiphyseal dysplasia in the femoral cap was almost unchanged. Loud snoring and apnea disappeared. Vital capacity increased to around 20% for the first two years and was maintained. Activity of daily life (ADL) was improved in work/study efficacy, respiratory status, sleep, joint pain, and frequency of infection.In conclusion, the long-term study of hematopoetic stem cell transplantation has shown clinical improvements in respiratory function, radiograph findings, ADL, and biochemical findings, suggesting that it is a potential therapeutic option for patients with MPS IVA.

Perforin Is Important For Both CD4+ and CD8+ T Cell-Mediated Graft-Versus-Tumor Effect But Plays Differential Roles In CD4+ and CD8+ T Cell Expansion After Allogeneic Transplantation

Graft versus tumor (GVT) effect is the desired and integral outcome for successful allogeneic bone marrow transplantation (allo-BMT) for cancer patients. This effect is dependent on T cell mediated recognition and elimination of residual host tumor cells present after allo-BMT. T cell killing is mediated primarily via three pathways: perforin/granzymes, Fas/FasL, and cytotoxic cytokines. Recent work from our lab has revealed a detrimental role for granzyme B (GzmB) in GVT effect due to its role in activation induced cell death (AICD) of CD8+ T cells. As a result, GzmB-/- CD8+ T cells exhibited higher expansion after allo-BMT and subsequently provided better tumor control.Our current study sought to determine the role of perforin (Prf1) in GVT effect mediated by both CD4+ and CD8+ T cells. Using the MHC-mismatched C57BL/6 (H-2b) to BALB/c (H-2d) allo-BMT model, we first confirmed previous findings that when transplanting CD8+ T cells along with T cell depleted (TCD) BM cells, donor CD8+ T cells require Prf1 to mediate GVT effect against allogeneic A20 lymphoma (Fig 1A, Prf1-/- (n=4) vs WT (n=4), *P<0.05). In addition, our data suggest that Prf1 is also required for CD4+ T cells to effectively mediate GVT effect against A20, as transplant with Prf1-/- CD4+CD25- T cells does not control tumor growth as well as WT controls (Fig 1B).Our previous work showed that GzmB deficiency allows for less AICD and subsequently more CD8+ T cell expansion. New data now show a similar effect for Prf1 in CD8+ T cell accumulation, as Prf1-/- CD8+ T cells outcompete WT CD8+ T cells (CD45.1+) when these two genotypes are mixed in equal numbers and transplanted into tumor bearing BALB/c mice (n=5/time point, *P=0.02 day 9)(Fig 1C). This competitive advantage was due to less AICD in the Prf1-/- CD8+ T cells. However, Prf1 appears to be required for efficient GVT activity, because the higher number of Prf1-/- CD8+ T cells are still less capable than WT counterparts in controlling tumor growth.We next tested the effect of Prf1 in AICD in CD4+CD25- T cells, and again co-transplanted WT CD45.1+ and Prf1-/- CD4+CD25- T cells into tumor bearing mice for a competition assay. Unexpectedly, WT CD4+CD25- T cells accumulate to significantly higher numbers when in direct competition with Prf1-/- CD4+CD25- T cells (n=4/time point, **,P<0.01)(Fig 1D). When we measured apoptotic cells with Annexin V staining, we found that WT CD4+CD25- T cells still had significantly more AICD (Prf1-/- 38.3 ± 4.2% vs. WT 48.1 ± 5.1%, P<0.01 on day 7 post-BMT; Prf1-/- 12.7 ± 1.0% vs. WT 18.1 ± 3.4%, P<0.03 on day 9 post-BMT). This result suggests that while Prf1 has an important role in AICD, it may also play a role in another feature of CD4+ T cell biology. We then explored the hypothesis that may Prf1 promote CD4+ T cell proliferation by evaluating Hoescht staining on day 9 post-BMT. Preliminary results suggest that Prf1 may enhance T cell proliferation, as Prf1-/- CD4+ T cells have less actively dividing cells at this time point. Therefore, Prf1 appears to have a surprising role after allo-BMT in sustaining T cell expansion for CD4+ T cells, but not for CD8+ T cells.Another factor influencing GVT effect may be T cell phenotype. Our previous work with CD8+ T cells suggests that more effector memory (CD62LLOWCD44HIGH) T cells accumulate in the absence of GzmB, and that GzmB-/- CD8+ T cells exhibited higher GVT activity than WT controls. We now found that while Prf1-/- CD4+ T cells also skewed towards the effector memory phenotype (CD62LLOWCD44HIGH), loss of Prf1 still reduced the ability of CD4+ T cells to control tumor growth in this model of allo-BMT.In summary, our results suggest that Prf1 plays an important role in GVT responses mediated not only by CD8+ T cells but also by CD4+ T cells, which were shown in previous literature to mainly utilize Fas ligand and cytokine systems to mediate GVT activity. In addition, Prf1 can cause AICD to both CD4+ and CD8+ T cells after allo-BMT. While Prf1-induced AICD reduces CD8+ T cell expansion, Prf1 appears to play a previously unrecognized role enhancing CD4+ T cell proliferation via an unidentified mechanism. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Immunosuppressive Effects of Multipotent Mesenchymal Stromal Cells on Graft-Versus-Host Disease in Rats Following Allogeneic Bone Marrow Transplantation

Objective: Graft-versus-host disease (GVHD) is a major obstacle to successful allogeneic bone marrow transplantation (allo-BMT). While multipotent mesenchymal stromal cells (MSCs) demonstrate alloresponse in vitro and in vivo, they also have clinical applications toward prevention or treatment of GVHD. The aim of this study was to investigate the ability of MSCs to prevent or treat GVHD in a rat BMT model. Materials and Methods: The GVHD model was established by transplantation of Sprague Dawley rats’ bone marrow and spleen cells into lethally irradiated (950 cGy) SDxWistar rat recipients. A total of 49 rats were randomly assigned to 4 study and 3 control groups administered different GVHD prophylactic regimens including MSCs. After transplantation, clinical GVHD scores and survival status were monitored. Results: All irradiated and untreated control mice with GVHD died. MSCs inhibited lethal GVHD as efficiently as the standard GVHD prophylactic regimen. The gross and histopathological findings of GVHD and the ratio of CD4/CD8 expression decreased. The subgroup given MSCs displayed higher in vivo proportions of CD25+ T cells and plasma interleukin-2 levels as compared to conventional GVHD treatment after allo-BMT. Conclusion: Our results suggest that clinical use of MSCs in both prophylaxis against and treatment of established GVHD is effective. This study supports the use of MSCs in the prophylaxis and treatment of GVHD after allo-BMT; however, large scale studies are needed. Conflict of interest:None declared.

Successful Allogeneic Bone Marrow Transplantation Using Reduced Doses of Cyclophosphamide and Fludarabine Associated to Granulocyte Transfusions in a Patient With Severe Aplastic Anemia Complicated by an Invasive Aspergillosis of Sinuses and a Rhizopus Gingivitis

Successful Allogeneic Bone Marrow Transplantation Using Reduced Doses of Cyclophosphamide and Fludarabine Associated to Granulocyte Transfusions in a Patient With Severe Aplastic Anemia Complicated by an Invasive Aspergillosis of Sinuses and a Rhizopus Gingivitis

Successful Treatment of Congenital Erythropoietic Porphyria Using Matched Unrelated Hematopoietic Stem Cell Transplantation

Congenital erythropoietic porphyria (CEP), or Günther's disease, is an inborn error of metabolism produced by a deficiency of uroporphyrinogen III synthase (UROS), the fourth enzyme of the heme biosynthesis pathway. This enzymatic defect induces the accumulation of isomer I porphyrins in erythrocytes, skin, and tissues, producing various clinical manifestations. Severe cases are characterized by extreme photosensitivity, causing scarring and mutilations, and by hemolytic anemia, reducing life expectancy. CEP is caused by mutations in the UROS gene, and one of the most severe forms of the disease is associated with a cysteine to arginine substitution at residue 73 of the protein (C73R). CEP has been successfully treated only by the transplantation of hematopoietic precursors. We report the case of a male infant with severe postdelivery symptoms diagnosed with CEP and found to be homozygous for the C73R mutation. He underwent successful allogeneic bone marrow transplantation from a matched unrelated donor at 7 months of age. The hemolytic anemia was corrected and the porphyrin overproduction was significantly reduced. The patient remained asymptomatic after 1 year. This new case confirms that patients with severe CEP can benefit from early postnatal hematopoietic stem cell transplantation.

A Case of Donor Cell-derived Diffuse Large B-cell Lymphoma after 24-year Remission of Acute Myeloid Leukemia Followed by Successful Allogeneic Bone Marrow Transplantation

A Case of Donor Cell-derived Diffuse Large B-cell Lymphoma after 24-year Remission of Acute Myeloid Leukemia Followed by Successful Allogeneic Bone Marrow Transplantation

ACUTE LYMPHOBLASTIC LEUKEMIA In Qatar: Clinico-Pathological PROFILE and OUTCOME

Abstract 4233 Background:advances in immunophenotyping, cytogenic, and molecular genetics have not only considerably improved our knowledge of the pathophysiology of acute leukemia's, but have also contributed to a refined classification of acute lymphoblastic leukemia(ALL)subtypes and outcome. With the different treatment modalities complete remission (CR) rates of 80–85%and leukemia –free survival (LFS) rates of 30–40%can be achieved in adult acute lymphoblastic leukemia (ALL). Aim:to study the clinico-pathological features and outcomes of adult patients patients with acute lymphoblastic leukemia in Qatar Patients & METHODS:thirty adult patients (age>14 years) diagnosed as all at AL-AMAL Hospital, the oncology hematology center in Qatar, the periode betweenJan06 and Jan 2011 were Retrospectively studied with respect to their clinical. morphological, immunopathologica features at presentation and their treatment outcomes, diagnosis was based on combined morphologic, immunophenotyping and cytogenetic studies.treatment protocols used were BFM mainly for adolescent patients,GMALL and UKALL 12 for adults. RESULTS:ALL constituting 25% of all acute leukemia cases diagnosed during the period the study. the median age was 28.5 years with a male to female ratio 21.six were Qatari and 24 non-Qatari. the most common presentation was with symptomatic anemia and fever (63.3%).laboratory features at presentation revealed.WBC.>30*109/L in13((43.3%).Immunophenotyping showed that 25(83.3%)were B-ALL, only one case9450was of the matureB-phenotype(Burkitt is),twenty two (80%) were CD10positive (common/pre Bsubtypes),two were CD10 negative PreB.non were subtype as proBALL.diagnosis of T-ALL was established in 5 (16.7%)patients.aberrantexpression was noted in14 cases (46.6%)combined expression of both CD13&CD33 being the most common seen in seven cases (50%).OUT OF THE 22 CASES 954.550.Five(22.7) had t (9.22)and one (4.5%)t (4.11).normal in10(45.5%).thirteen patient travelled before having treatment. two pretreatment death (septic shock. two elderly patients with co morbidities were considered for palliative treatment.13patients were treated in doha, 11 out of 13 (84%)went into complete remission(CR) and two (16%) underwent successful allogeneic bone marrow transplant abroad. CONCLUSION:Although.the series is small to have a final conclusion, however, this study showed that almost all of our ALL cases are of the favorable immunological subtypes (common/ pre ALL) with high CR rate. Disclosures:No relevant conflicts of interest to declare.

IL-2-inducible T-cell kinase deficiency: clinical presentation and therapeutic approach

Mutations in the IL-2-inducible T-cell kinase gene have recently been shown to cause an autosomal recessive fatal Epstein Barr virus (EBV) associated lymphoproliferation. We report 3 cases from a single family who presented with EBV-positive B-cell proliferation diagnosed as Hodgkin's lymphoma. Single nucleotide polymorphism array-based genome-wide linkage analysis revealed IL-2-inducible T-cell kinase as a candidate gene for this disorder. All 3 patients harbored the same novel homozygous nonsense mutation C1764G which causes a premature stop-codon in the kinase domain. All cases were initially treated with chemotherapy. One patient remains in durable remission, the second patient subsequently developed severe hemophagocytic lymphohistiocytosis with multi-organ failure and died, and the third patient underwent a successful allogeneic bone marrow transplantation. IL-2-inducible T-cell kinase deficiency underlies a new primary immune deficiency which may account for part of the spectrum of Epstein Barr virus related lymphoproliferative disorders which can be successfully corrected by bone marrow transplantation.

Transmission of Familial Mediterranean Fever Mutation After Bone Marrow Transplantation and Successful Treatment With Anakinra

Familial Mediterranean fever (FMF) is a recessively inherited autoinflammatory disorder characterized by recurrent episodes of fever accompanied by arthritis, peritonitis, pleuritis, pericarditis, or erysipelas-like erythematosus rash (1). The gene responsible for FMF, MEFV, is located on chromosome 16p13 (2) and encodes a 791-amino acid protein, known as pyrin or marenostrin, which is believed to regulate inflammation by modulating the caspase 1 or interleukin (IL)-1β pathway (3). Herein, we report the transmission of FMF mutations in a 22-year-old male patient who underwent bone marrow transplantation (BMT) for idiopathic aplastic anemia in May 2009 from his FMF-affected human leukocyte antigen (HLA)-identical 19-year-old brother. Informed written consent was obtained from the patient, not carrying any FMF mutations pre-BMT, concerning the risk of transmission of FMF. Conditioning regimen consisted of cyclophosphamide 200 mg/kg and antithymocyte globulin 10 mg/kg, each given intravenously in four doses. Graft-versus-host disease prophylaxis-associated cyclosporine 3 mg/kg was initiated intravenously on day 1 and methotrexate intravenously on days 1, 3, and 6. Engraftment was observed on day 19. On day 23, the patient presented fever and abdominal pain, resistant to broad-spectrum antibiotic therapy. C-reactive protein (CRP) was elevated to 229 mg/L. Thoracic and abdominal computed tomography was normal. Resolution of the febrile episode and normalization of CRP were achieved 24 hr after the administration of methylprednisolone at 0.5 mg/kg per day, intravenously. The patient was dismissed from hospital on day 48 under 0.4 mg/kg per day of oral corticosteroids and oral cyclosporine. Donor chimerism 100% was confirmed by amplification of microsatellite markers by polymerase chain reaction. On day 60, the patient presented with fever, abdominal pain, diarrhea, arthritis, erysipelas-like rash, and renal failure. CRP was increased to 150 mg/L. Cyclosporine was interrupted, and antibiotic treatment was administered. The patient was not receiving any corticosteroid treatment. He was dismissed after improvement, 15 days later. He consulted 6 days after dismissal for another similar episode. A treatment with colchicine 1 mg per day was initiated, and the patient was screened for FMF mutations that were positive for homozygous M694V mutation. On day 110, the patient presented one more FMF flare under colchicine treatment, as well as severe neutropenia (<200/mm3), which was attributed to colchicine. Furthermore, an ultrasound echocardiogram revealed a reduction in the ejection fraction from 62% to 30%. Taking into account, the persistent neutropenia (although granulocyte-colony stimulating factor treatment was given at a dose of 48 μg daily), as well as the recurrence of FMF flares, a treatment with anti-IL1 antagonist (anakinra) at a dose of 100 mg per day subcutaneously was initiated on day 120. Neutrophil count and CRP attained normal values 1 week after the cessation of colchicine. Renal function and left ventricular ejection fraction were also normalized 2 weeks after the discontinuation of colchicine. In a 4-month follow-up, neither FMF crisis nor any side effect of anakinra treatment has been observed. The patient continues to receive a daily subcutaneous injection of anakinra at a dose of 100 mg per day. This is to our knowledge, the first report of successful treatment with anakinra in a patient who acquired FMF mutation after allogeneic BMT and who presented intolerance and resistance to colchicine treatment. Transmission of FMF mutations after BMT has rarely been described (4). MEFV is almost exclusively expressed in monocytes and granulocytes. These two cell lineages are of donor origin after successful allogeneic BMT (5). Therefore, FMF mutations are potentially transferred through BMT. Oral daily treatment with colchicine is the most effective therapy for FMF. Nevertheless, bone marrow suppression, especially neutropenia, is a known side effect of colchicine (6,7). Moreover, side effects of colchicine could be reinforced by the concomitant administration of cyclosporine, which suppresses P-glycoprotein; therefore, increasing the intracellular concentration of colchicine and, which interacts with CYP3A4, thus decreasing the hepatic elimination of colchicine (8). Severe neutropenia, cardiomyopathy, and peripheral neuropathy have recently been described in the context of heart transplantation (9). Furthermore, 10% of patients are unresponsive to colchicine (10). Recent short reports demonstrate the efficacy of IL-1 receptor antagonist therapy (anakinra) in colchicine-resistant FMF patients (3, 11–13). Efficacy of anakinra in colchicine-resistant FMF patients after kidney transplantation has been recently reported (14). Moreover, IL-1 receptor antagonist has been evaluated without toxicity in allogeneic BMT in the prevention of graft-versus-host disease (15). Our observation supports the transmission of FMF mutations after allogeneic BMT and demonstrates that anakinra might be an efficacious and safe treatment in allotransplanted FMF patients with severe colchicine-induced neutropenia or intolerance or colchicine resistance. Anna D. Petropoulou1 Marie Robin1 Gérard Socié1 Lionel Galicier2 1Service Hématologie-Greffe Hôpital Saint-Louis Paris, France 2Service Immunologie Clinique Hôpital Saint-Louis Paris, France