Early Hematopoietic Stem Cell Transplantation Research Articles

Does FLT3 mutation impact survival after hematopoietic stem cell transplantation for acute myeloid leukemia? A Center for International Blood and Marrow Transplant Research (CIBMTR) analysis.

Patients with FMS like tyrosine kinase 3 (FLT3)-mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT). Data from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes. In total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild-type (WT) group (38% [95% confidence interval (CI), 30%-45%] vs 28% [95% CI, 24%-33%]; P = .04; relative risk, 1.60 [95% CI, 1.15-2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia-free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3-year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%-57%; WT group: 55%, 95% CI, 50%-60%; P = .20). The current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long-term survivors. Cancer 2016;122:3005-3014. © 2016 American Cancer Society.

Current Updates on Classification, Diagnosis and Treatment of Hemophagocytic Lymphohistiocytosis (HLH).

Hemophagocytic lymphohistiocytosis (HLH) is a life threatening hyperinflammatory syndrome characterized by excessive activation of macrophages and T cells resulting from defective cytotoxicity. Severe hyperinflammation caused by uncontrolled proliferation of activated lymphocytes and histiocytes (macrophages) secreting high amounts of inflammatory cytokines threatens the life of the patient and may lead to death unless arrested by appropriate treatment. HLH can be caused either by certain underlying genetic diseases (familial HLH), or may also occur due to particular triggers in patients with no known inherited disorder (acquired HLH). Due to life threatening nature of the disease, early diagnosis and initiation of immunosuppressive therapy is extremely important. HLH diagnosis is based on constellation of clinical manifestations and laboratory parameters which often overlap with those of severe infection or sepsis. Identification of patients with familial HLH and their underlying genetic defects requires specialized laboratory tests and is important for predicting relapses and planning early therapeutic hematopoietic stem cell transplantation (HSCT). A high suspicion and thorough clinical, immunological and genetic work-up is required for diagnosis of HLH. Prompt initiation of adequate treatment is essential for the survival. Substantial progress has been made in exploring the complex cause and pathophysiology of HLH and also in management of HLH patients.

Early Diagnosis and Hematopoietic Stem Cell Transplantation for IL10R Deficiency Leading to Very Early-Onset Inflammatory Bowel Disease Are Essential in Familial Cases.

Alterations of immune homeostasis in the gut may result in development of inflammatory bowel disease. A five-month-old girl was referred for recurrent respiratory and genitourinary tract infections, sepsis in neonatal period, chronic diarrhea, perianal abscess, rectovaginal fistula, and hyperemic skin lesions. She was born to second-degree consanguineous, healthy parents. Her elder siblings were lost at 4 months of age due to sepsis and 1 year of age due to inflammatory bowel disease, respectively. Absolute neutrophil and lymphocyte counts, immunoglobulin levels, and lymphocyte subsets were normal ruling out severe congenital neutropenia and classic severe combined immunodeficiencies. Quantitative determination of oxidative burst was normal, excluding chronic granulomatous disease. Colonoscopy revealed granulation, ulceration, and pseudopolyps, compatible with colitis. Very early-onset colitis and perianal disease leading to fistula formation suggested probability of inherited deficiencies of IL-10 or IL-10 receptor. A mutation at position c.G477A in exon of the IL10RB gene, resulting in a stop codon at position p.W159X, was identified. The patient underwent myeloablative hematopoietic stem cell transplantation from full matched father at 11 months of age. Perianal lesions, chronic diarrhea, and recurrent infections resolved after transplantation. IL-10/IL-10R deficiencies must be considered in patients with early-onset enterocolitis.

Acute kidney injury and tubular biomarkers after hematopoietic stem cell transplantation

To determine the value of molecular biomarkers (BMs) associated with tubular epithelial damage in developing and predicting acute kidney injury (AKI) after hematopoietic stem cell transplantation (HSCT). The open-label observational prospective study enrolled 90 patients (46 males and 44 females) who had undergone HSCT. The concentrations of BMs (calbindin, clusterin, interleukin-18 (IL-18), kidney injury molecules-1 (KIM-1), glutathione S-transferase-π (GST-π), and monocyte chemoattractant protein-1 (MCP-1) were measured in urinary samples 7 days before HSCT (week 0) and at weeks 1, 2, 3, 4, and 5. Main clinical parameters were simultaneously monitored. AKI was diagnosed and stratified according to the Kidney Disease Improving Global Outcomes (KDIGO) guidelines. At weeks 1, 2, 3, 4, and 5 after HSCT, the proportion of AKI cases was 7.8, 8.9, 12.5, 27.3, and 35.9%, respectively. The elevated urinary levels of BMs (above the median) were found to be substantially more common than AKI cases. The urinary excretion of the majority of BMs dramatically increased in the early HSCT period. The median number of simultaneously elevated BMs was 3 (2; 5) during the entire follow-up period. Clusterin, MCP-1 and KIM-1 positively and significantly correlated with serum creatinine at the week following the determination of BMs in the multivariate linear regression models adjusted for other confounders. The higher urinary KIM-1 and/or MCP-1 excretion regardless of other clinical indicators was associated with the higher relative risk (RR) of AKI, which increased by 2.3 times with a rise in one of these indicators and by 3.4 times with a rise in both indicators. Multiple renal toxic effects after HSCT result in a substantial and simultaneous elevation of urinary excretion of BMs for tubular damage. Among the BMs studied, KIM-1 and MCP-1 seem to be the most suitable molecules for assessing the risk of AKI in this cohort of patient within the predictive diagnostic approach.

Early hematopoietic stem cell transplantation improve treatment outcome of aggressive ATL.

Aggressive ATL is one of the most intractable peripheral T cell malignancies and outcome of chemotherapy is still unsatisfactory. Hematopoietic stem cell transplantation (HSCT) is a promising strategy to improve treatment results of aggressive ATL but the proportion of the ATL patients who received HSCT in the potential candidates is low. In this study we treated 45 consecutive aggressive ATL patients with intensive combination chemotherapies (mainly mLSG15) followed by HSCT if indicated. We started to search HSC donor as soon as possible after starting chemotherapy in order to advance HSCT. In a total of 45 patients, 39 were acute type, 4 were lymphoma type, and 2 were unfavorable chronic type. The median age of the patients was 59 years (range 28-68). Thirty-one patients finally received allo-HSCT (related BMT/PBSCT 5, unrelated BMT 26). The proportion of the patients who received HSCT was 68.9%. Disease status at transplantation was CR in 2, PR in 17, SD in 7 and PD in 4 patients. Median time to HSCT from beginning of chemotherapy was 166 days. Three-year overall survival (OS) of the all patients receiving HSCT and those who receive HSCT in CR/PR were 60.0% and 76.5% respectively. Three-year OS of total 45 patients was 41.5%. Among 13 patients who could not receive HSCT, 6 relapsed after initial response to chemotherapy (median time to relapse from the beginning of chemotherapy was130 days) and 2 were in primary refractory state, which were the reason they could not receive HSCT. Those 6 relapsed patients might receive HSCT if they could find suitable HSC donor earlier. Our study suggest that early surveillance of HSCT donor along with remission induction chemotherapy raise up the proportion of patients receiving HSCT and improve treatment results in aggressive ATL.

Acute monocytic leukaemia with t(11; 12) (p15; q13) chromosomal changes: A case report and literature review.

Acute myeloid leukaemia (AML) is a type of heterogeneous disease derived from haematopoietic stem cells. Cytogenetic characterisation is essential for diagnosis and prognosis stratification. Here, we present the case of a 43-year-old female diagnosed with leukaemia, who demonstrated a rare chromosomal change of t(11; 12) (p15; q13) along with a positive FLT3-ITD mutation. The patient had a white blood cell count of 76.41×109/l. Bone marrow morphology revealed that monoblasts accounted for 25.5% of cells, and premonocytes accounted for 49.0%. This patient strongly responded to idarubicin and Ara-c (cytarabine) chemotherapy, which rapidly eliminated the leukaemia cell clones. However, the proliferation rate of the leukaemia cells was high during the intermission of chemotherapy. Subsequently, following two courses of chemotherapy, full haematological remission could not be attained. AML patients with t(11; 12) (p15; q13) combined with FLT3-ITD mutations are expected to have a short life expectancy; however, early haematopoietic stem cell transplantation therapy may improve the treatment outcome for these patients.

A prospective outcome study of patients with profound combined immunodeficiency (P-CID)

This is a prospective outcome study of patients with profound combined immunodeficiency (P-CID) (study number DRKS00000497). Combined immunodeficiencies (CID) are a heterogeneous group of inherited immune disorders with impaired T-cell development and (or) function manifesting through increased susceptibility to infections and (or) immune dysregulation. They can be delineated from severe CID (SCID) by their manifestation beyond the first year of life. Profound CID (P-CID) is a potentially life-threatening form of CID, in which stem cell transplant (SCT) is a relevant consideration at diagnosis. The primary objective of the study is to provide natural history data on patients with P-CID, irrespective of whether they undergo hematopoietic stem cell transplant (HSCT) or not. The goals are to determine survival, the frequency of severe events, and quality of life (QOL) 5 years after study inclusion. The secondary objective is to develop a risk model for P-CID patients. The model is developed from a set of clinical and laboratory parameters obtained at diagnosis, at study inclusion, and yearly thereafter. The tertiary objectives of this study are to determine the effects of donor, recipient, and treatment factors on the outcome of HSCT. The goal is to determine the quality of engraftment and immunological reconstitution and to determine the effects of these parameters on clinical outcome. The main hypothesis is that P-CID patients undergoing early HSCT have a better 5-year survival rate than patients who undergo late HSCT or are not transplanted. This is a prospective multi-centre international cohort study (observational study). Enrolled patients will be evaluated and treated according to local institutional protocols. They will receive comparable baseline and follow-up evaluations across all participating centres, irrespective of the therapeutic strategy at the individual site. There will be at least 6 study visits (scheduled yearly) for all patients. Because of the variable history prior to study inclusion, a morbidity score is determined for each patient at study visit 1. For those patients undergoing HSCT, an additional 6 month post-HSCT visit will be scheduled. The study visits will document immunological parameters, severe events including major infections, and major manifestations of immune dysregulation, severe transplant-related events, and QOL.

Projet de mise en place du dépistage néonatal systématique des déficits immunitaires combinés sévères : présentation de l’étude DEPISTREC

Severe combined immunodeficiencies (SCID) are a group of inherited diseases of the immune system characterized by profound abnormalities of T-cell development. Infants with SCID require prompt clinical intervention to prevent life-threatening infection and studies show significantly improved survival in babies diagnosed at birth based on previous family history. SCID follows the criteria for population-based newborn screening because it is asymptomatic at birth and fatal within the 1st year of life if there is no intervention, the confirmation of the disease is easy, there is a curative treatment, and it is known that early hematopoietic stem cell transplantation significantly improves survival, the quality of immune reconstitution, and quality of life. Quantification of T-cell receptor excision circles (TRECs) in DNA extracted from Guthrie samples is a sensitive and specific screening test for SCID. We conducted a nationwide prospective study of neonatal screening of SCID in a population of 200,000 French newborns over a period of 2 years. The objective was to study the clinical utility and the cost-effectiveness ratio, and to demonstrate that universal SCID screening could result in a substantial benefit to detect individuals, making screening relatively cost-effective in spite of the low incidence of the disease.

Sorafenib treatment following hematopoietic stem cell transplant in pediatric FLT3/ITD acute myeloid leukemia.

FLT3/ITD is associated with poor outcomes in adult and pediatric acute myeloid leukemia (AML). Allogeneic hematopoietic stem cell transplantation (HSCT) can improve cure rates, however relapse is still common. Recent studies demonstrate the activity of FLT3 inhibitors, including sorafenib, in targeting the underlying mutation. We conducted a retrospective study of 15 pediatric patients with FLT3/ITD+ AML treated with sorafenib within 18 months after receiving HSCT. Sorafenib was administered either as prophylaxis in patients considered at very high risk for relapse (n = 6) or at the time of disease recurrence (n = 9). Sorafenib was initiated at a median of 100 days post HSCT. Overall, 11/15 (73%) of patients experienced medically significant toxicities. Among patients who experienced toxicity, 6/11 (55%) received treatment at doses above what was later determined to be the maximum tolerated dose of sorafenib for pediatric leukemia. Importantly, sorafenib did not appear to exacerbate graft versus host disease. Our findings suggest that sorafenib may be of particular efficacy in patients with minimal residual disease (MRD); all patients who received sorafenib for MRD immediately prior to transplant or with emergence post-HSCT are alive and remain in complete remission at a median of 48 months post HSCT. Our case series suggests that sorafenib administration is feasible and tolerable in pediatric FLT3/ITD+ AML patients early post HSCT. Ongoing prospective controlled studies are needed to further define the dosing of sorafenib in the post-HSCT period and to determine the optimal context for this treatment approach.

γδ T Lymphocytes in the Diagnosis of Human T Cell Receptor Immunodeficiencies.

Human T cell receptor (TCR) immunodeficiencies (TCRID) are rare autosomal recessive disorders caused by mutations affecting TCR, CD3, or CD247 chains, which share developmental, functional, and TCR expression defects (1). Their rapid diagnosis is fundamental for patient survival and early hematopoietic stem cell transplantation. Here, we propose that studying γδ T cells, which are often neglected, can be helpful for a timely diagnosis. We thus offer a diagnostic flowchart and some lab tricks based on published cases.

DOCK8 deficiency: clinical and immunological phenotype and treatment options - a review of 136 patients.

Mutations in DOCK8 result in autosomal recessive Hyper-IgE syndrome with combined immunodeficiency (CID). However, the natural course of disease, long-term prognosis, and optimal therapeutic management have not yet been clearly defined. In an international retrospective survey of patients with DOCK8 mutations, focused on clinical presentation and therapeutic measures, a total of 136 patients with a median follow-up of 11.3 years (1.3-47.7) spanning 1693 patient years, were enrolled. Eczema, recurrent respiratory tract infections, allergies, abscesses, viral infections and mucocutaneous candidiasis were the most frequent clinical manifestations. Overall survival probability in this cohort [censored for hematopoietic stem cell transplantation (HSCT)] was 87 % at 10, 47 % at 20, and 33 % at 30 years of age, respectively. Event free survival was 44, 18 and 4 % at the same time points if events were defined as death, life-threatening infections, malignancy or cerebral complications such as CNS vasculitis or stroke. Malignancy was diagnosed in 23/136 (17 %) patients (11 hematological and 9 epithelial cancers, 5 other malignancies) at a median age of 12 years. Eight of these patients died from cancer. Severe, life-threatening infections were observed in 79/136 (58 %); severe non-infectious cerebral events occurred in 14/136 (10 %). Therapeutic measures included antiviral and antibacterial prophylaxis, immunoglobulin replacement and HSCT. This study provides a comprehensive evaluation of the clinical phenotype of DOCK8 deficiency in the largest cohort reported so far and demonstrates the severity of the disease with relatively poor prognosis. Early HSCT should be strongly considered as a potential curative measure.

Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in the Imatinib-Era: Update on the Survival Outcome Following Allogeneic HSCT after Imatinib Failure; Results of the German CML Study IV

Allogeneic HSCT has been established as the only curative treatment option for patients with chronic myeloid leukemia (CML). However, after the advent of tyrosine kinase inhibitors (TKI) the proportion of transplanted patients has decreased dramatically. After imatinib failure, most patients receive second or third line therapy with alternative TKIs. In an important minority of patients, SCT is performed too late as more patients are transplanted after disease progression to accelerated phase or blast crisis than in first chronic phase (CP, Saussele et al. BMT 2012). A possible reason is the uncertainty on long-term outcome after SC T in the imatinib-era as reports are scarce and accurate comparative data on the impact of salvage TKI therapy vs allogeneic transplantation are missing.We therefore investigated the outcome of transplanted patients within the CML study IV. Preliminary data were published (Saussele et al. BLOOD 2010). Here, we sought to re-evaluate the outcome of these patients with a longer follow-up.In July 2002, the German CML-Study Group activated a prospective randomized trial comparing different imatinib based strategies in CP CML. Elective early HSCT was considered for patients with EBMT score 0–1 for those with high disease risk, and after imatinib failure.By the end of March 2012, 1551 patients were randomized. In 2008, HSCT was documented in 84 patients. One patient was not evaluable any more due to withdrawal of consent. 52 patients were male (65%), 23 high risk patients (28%) according to the Euro CML score. Median age at diagnosis was 37 years (range, 16-62), median time to HSCT was 12.6 months (range, 3.5-54). EBMT score was 0-1 in 8 (10%), 2 in 10 (12%), 3-4 in 44 (55%), and >=5 in 18 patients (23%), three patients were missing. Median follow-up after HSCT was 86.9 months (range, 0.3-122). Based on the indication for HSCT three groups are defined: 1) early HSCT, n= 19 (23%; low EBMT score (n=9), high risk patients (n=7), patient request (n=3); 2) HSCT after imatinib failure or intolerance in first CP (n=36 patients, 43%), and 3) HSCT in second CP or higher, accelerated phase or blast crisis (n=28 patients, 34%). 26 patients died, 13 deaths were transplant related, 9 CML related 4 either unrelated or unknown. Overall survival rate at 6 years after HSCT was 89% (95%-confidence interval (CI): 72-99%) for group 1, 80% (95%-CI: 66-91%) for group 2, and 49% (31-68%) for group 3.A matched pair analysis could be performed for 53 transplanted patients of group 1 and 2. To each of the transplanted patients two imatinib-treated patients could be matched with regard to age, sex, risk profile, disease phase, and interval to transplantation. Median follow up of this population was 87 months. Overall survival after 8 years was 83% (95%-CI: 71-92%) for transplanted and 89% (95%-CI: 82-94%) for imatinib treated patients without any statistical difference.Data from this update with a longer follow-up support the role of HSCT as an attractive and important salvage therapy for CML patients with imatinib failure or intolerance. In a matched pair comparison of transplanted and non-transplanted patients, we did not find significant differences. DisclosuresSaussele:Novartis: Honoraria, Research Funding, Travel Other; Bristol-Myers Squibb: Honoraria, Research Funding, Travel, Travel Other; Pfizer: Honoraria, Travel, Travel Other. Müller:Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Equity Ownership. Hanfstein:Novartis: Research Funding; Bristol-Myers Squibb: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding. Pfirrmann:Novartis: Consultancy; Bristol-Myers Squibb: Honoraria. Hehlmann:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding.

Efficacy of Hematopoietic Stem Cell Transplantation from Alternative Donors in Pediatric Severe Aplastic Anemia: A Single-Center Experience

Background: Hematopoietic Stem Cell Transplantation (HSCT) from a matched sibling donor (MSD) is the treatment of choice for pediatric patients with severe aplastic anemia (SAA). On the other hand, HSCT from alternative donor (AD-HSCT) is indicated as salvage therapy for patients who failed immunosuppressive therapy (IST) without MSD. However, the outcomes of alternative donor HSCT have been improved with recent advances in HSCT techniques. Therefore the indication of alternative donor HSCT in SAA needs to be reevaluated.Methods: We retrospectively reviewed the medical records of 45 pediatric patients with SAA who received HSCT at Asan Medical Center Children’s Hospital from February 2001 to January 2014. To analyze the efficacy of HSCT from alternative donors, we compared overall survival, incidence of acute and chronic GVHD, incidence of graft failure (GF), and incidence of post HSCT infections including CMV reactivation, PTLD, bacteria and fungi according to the type of donors.Results: Of the 45 patients, 32 were male and 13 were female. Median age at diagnosis was 8.0 years (range, 0.2-17.0). Median age at HSCT was 12.9 years (range, 0.7-21.7). Median CD34+ cell dose was 7.64 X 106 /kg (range, 2-33.8). Ten patients received HSCT from MSD (MSD-HSCT), 15 patients from URD (URD-HSCT) and 20 patients from haploidentical family donor (HFD-HSCT). Twenty-six patients (55.3%) had received IST prior to HSCT. Of 45 patients, eight patients experienced GF (one from MSD, one from URD, and six from HFD). Cumulative incidence (CI) of GF was higher in HFD-HSCT compared to the other type of HSCT (30% vs 8%, P=0.049). Among the 8 patients, 6 patients achieved engraftment after additional HSCT, one died of infection after GF and the remaining one patient was waiting for the second HSCT. The CIs of acute GVHD were 20% for MSD-HSCT, 60% for URD-HSCT and 40% for HFD-HSCT, respectively (P>0.05). The CIs of chronic GVHD were 10% for MSD-HSCT, 46% for URD-HSCT and 16% for HFD-HSCT, respectively (P>0.05). Twenty-two patients developed CMV reactivation, 7 had PTLD and 13 had bacterial infection after HSCT. CI of CMV reactivation was higher in AD-HSCT than that of in MSD (63% vs 0%, P=0.002). Three patients (one with MSD-HSCT, one with URD-HSCT and one with HFD-HSCT) died at 81 days, 405 days, and 456 days after transplantation. Of the three patients, one died of acute GVHD, one died of autoimmune hemolytic anemia and the remaining one died of infection after GF. At a median follow-up of 40.8 months (range, 6.5-162.8), 3 year-OS of all 45 patients was 92.9% (100% for MSD-HSCT, 92.3% URD-HSCT and 89.4% for HFD-HSCT, P>0.05). All survived 42 patients were transfusion-independent.Conclusions: In our study, we suggest that early alternative HSCT including HFD-HSCT could be beneficial to the children with SAA who do not have MSD. However, a larger multicenter study is needed to verify our results. DisclosuresNo relevant conflicts of interest to declare.

The Clinical Significance of Minimal Residual Disease Detected By Multiparametric Flow Cytometry in Acute Leukemia

PurposeMinimal residual disease (MRD) detected by multiparametric flow cytometry is an important method for predicting relapse. According to the dynamic changes of MRD, through the first clinical treatment to prevent relapse in patients with elevated MRD levels.MethodWe retrospectively analyze dynamic level of MRD of 75 patients with acute leukemia in our department of hematology from January 2011 to June 2013. According to the retrospective data, to analyze the expression of LAIP and discuss the relationship between changes of MRD and prognosis.ResultIn this study there were 75 patients, including 20 patients with acute lymphocytic leukemia (ALL) and 55 patients with acute myeloid leukemia (AML). The specific LAIP were detected in 49 patients with AML, and the cross lineage and non-synchronous expression were majority. In cross lineage expression, detected frequency of CD45/CD34/CD33/CD13/CD56 was highest, accounted for 67.3% (33/49). In non-synchronous expression, CD45/CD34/CD117/CD33/CD64 accounted for 57.1% (28/49). In 20 patients with ALL, there were 16 patients with B-ALL and 4 patients with T-ALL. The specific LAIP were detected in all of the patients. In patients with B-ALL, detected frequency of CD45/CD19/CD22/CD10/CD13 was highest, accounting for 43.8% (7/16). In abnormal quantity of antigens, CD45/CD19/CD22/CD10/CD38 was the most common type, accounting for 50%. The abnormal expression of CD7/TDT was detected in four patients with T-ALL. In monitoring period 7 patients relapsed. We analyzed the relationship between the clinical data and replase. The results showed that level of peripheral hemoglobin at diagnosis and the times of remission induction were significantly associated with replase (P=0.021 and P=0.017, respectively). To analyze the relationship between change of MRD and prognosis, the results showed that 0.05% as the threshold was significantly related with recurrence. 20 patients of persistent MRD≥0.05% had significant differences with 28 patients of persistent MRD<0.05% in replase free survival (P=0.005).ConclusionIt has important significance to predict relapse in patients with acute leukemia by detecting minimal residual disease. Patients of MRD ≥ 0.05% should receive early intensive therapy or hematopoietic stem cell transplantation. Even patients without relapse, it should be closely monitor dynamic levels of MRD and highly vigilant extramedullary relapse. DisclosuresNo relevant conflicts of interest to declare.

Transplantation of Maternal Haploidentical TcRαβ-Depleted Stem Cells for Malignant Infantile Osteopetrosis – Optimal Timing and Rapid Hematological Recovery

BACKGROUND: Osteopetrosis (OP), characterized by improper bone resorption is in most cases caused by dysfunctional, hematopoietic stem cell (HSC) derived osteoclasts. A number of genetic mutations are described to underlie OP and disease phenotypes varies from benign to very severe, rapidly progressive forms of OP. In most cases hematopoietic stem cell transplantation (HSCT) is the only curative treatment. Especially in infantile malignant OP early HSCT is critical in means to recover allogeneic osteoclast function to inhibit and prevent otherwise mutilating disease progression. The use of an alternative donor is required in the absence of an HLA-identical healthy sibling. While donor search is time consuming, umbilical cord blood transplantation is usually related to higher transplant related morbidity/mortality. We present a case of infantile malignant autosomal recessive OP that illustrates the advantage of the use of haploidentical maternal TcRαβ+ cells depleted graft as an attractive curative approach.PATIENT: The boy, carrying a common mutation involving the TCIRG1 gene was diagnosed with OP at 3 months of age while showing signs of progressing anemia, hypogammaglobulemia, esotropia/exophthalmia with suspicion of blindness, impaired hearing and multiple skeletal malformations. Three weeks later conditioning regimen was initiated and consisted of ATG-F (30mg/kg), i.v. busulfan (TDM; AUC 90mg +/- 5mg/L*h) fludarabin (160mg/m2) and thiotepa (15mg/mg). Maternal G-CSF mobilized mononuclear cells were harvested from peripheral blood and TcRαβ+ cell were depleted from the graft (CliniMACS). The patient was transplanted with a single graft including 44.8x106 CD34+ cells/kg, 48.6x106 TcRγδ+ cells/kg and 0.0011x106 of residual TcRαβ+ cells/kg, followed by post-transplantation in vivo CD20-depletion (Rituximab 375mg/m2). Platelets (>50x109/L) and neutrophils (>0.5x109/L) recovery was reached day +14, respectively day +15 post-HSCT. Immunosuppression consisted of Cyclosporine A and Methylprednisolon and was discontinued 4, respectively 6 weeks post-HSCT without any signs of GvHD. There was no significant transplant related morbidity. OP characteristics did not show obvious progression following HSCT and at one year post-transplant the patient is in a stable general condition with good quality of life. He has decreased but stable hearing performance, deeply impaired vision (already before HSCT), normalization of the phenotypic facial and skeletal characteristics, normal bone marrow function as well as normal physical and mental development. T-cell chimerism showed convertion from initially mixed chimerism (up to 40% of autologous cell) to 100% donor chimersim at 1 year post transplant.CONCLUSION: We conclude that haploidentical HSCT with TcRαβ+ depleted graft is an encouraging approach in infantile malignant OP that enables 1) prompt HSCT with immediate available parental donor and 2) rapid and sustained hematological recovery. DisclosuresNo relevant conflicts of interest to declare.

Human IL-21 and IL-21R deficiencies: two novel entities of primary immunodeficiency.

This review highlights the recent identification of human interleukin-21 (IL-21) and interleukin-21 receptor (IL-21R) deficiencies as novel entities of primary immunodeficiency. We recently described the first patients with IL-21R deficiency who had cryptosporidial infections associated with chronic cholangitis and liver disease. All IL-21R-deficient patients suffered from recurrent respiratory tract infections. Immunological work-up revealed impaired B cell proliferation and immunoglobulin class-switch, reduced T cell effector functions, and variable natural killer cell dysfunctions. Recently, these findings have been extended by the discovery of one patient with a mutation in the IL21 gene. This patient predominantly manifested with very early onset inflammatory bowel disease and recurrent respiratory infections. Laboratory examination showed reduced circulating B cells and impaired B cell class-switch. Human IL-21 and IL-21R deficiencies cause severe, primary immunodeficiency reminiscent of common variable immunodeficiency. Early diagnosis is critical to prevent life-threatening complications, such as secondary liver failure. In view of the critical role of IL-21 in controlling immune homeostasis, early hematopoietic stem cell transplantation might be considered as therapeutic intervention in affected children.

Hematopoietic cell transplantation in patients with intermediate and high-risk AML: results from the randomized Study Alliance Leukemia (SAL) AML 2003 trial.

The optimal timing of allogeneic hematopoietic stem cell transplantation (HCT) in acute myeloid leukemia (AML) is controversial. We report on 1179 patients with a median age of 48 years who were randomized upfront. In the control arm, sibling HCT was scheduled in the first complete remission for intermediate-risk or high-risk AML and matched unrelated HCT in complex karyotype AML. In the experimental arm, matched unrelated HCT in first remission was offered also to patients with an FLT3-ITD (FMS-like tyrosine kinase 3-internal tandem duplication) allelic ratio >0.8, poor day +15 marrow blast clearance and adverse karyotypes. Further, allogeneic HCT was recommended in high-risk AML to be performed in aplasia after induction chemotherapy. In the intent-to-treat (ITT) analysis, superiority of the experimental transplant strategy could not be shown with respect to overall survival (OS) or event-free survival. As-treated analyses suggest a profound effect of allogeneic HCT on OS (HR 0.73; P=0.002) and event-free survival (HR 0.67; P<0.001). In high-risk patients, OS was significantly improved after allogeneic HCT in aplasia (HR 0.64; P=0.046) and after HCT in remission (HR 0.74; P=0.03). Although superiority of one study arm could not be demonstrated in the ITT analysis, secondary analyses suggest that early allogeneic HCT is a promising strategy for patients with high-risk AML.

Timing of allogeneic stem cell transplantation for myelodysplastic syndromes and aplastic anemia.

Allogeneic hematopoietic stem cell transplantation (HSCT) for myelodysplastic syndrome (MDS) is a potentially curative procedure, but is associated with a significant risk of morbidity and mortality. With the recent approval of disease-modifying agents, the appropriate timing of allogeneic HSCT needs to be addressed. Similarly, the optimal use of these disease-modifying agents before HSCT needs to be determined. In severe aplastic anemia, HSCT is a proven cure, but HLA-matched sibling donors are found in fewer than 25% of newly diagnosed patients. The use of early unrelated donor HSCT is an evolving concept that will become more accepted as improvements in HSCT outcomes continue.

Activities of daily living in patients with Hunter syndrome: Impact of enzyme replacement therapy and hematopoietic stem cell transplantation

The aim of this study was to assess the activities of daily living (ADL) in patients with Hunter syndrome (mucopolysaccharidosis II; MPS II) using a newly designed ADL questionnaire. We applied the questionnaire to evaluate clinical phenotypes and therapeutic efficacies of enzyme replacement therapy (ERT) and hematopoietic stem cell transplantation (HSCT). We also explored early signs and symptoms to make early diagnosis feasible.We devised a new ADL questionnaire with three domains: “movement,” “movement with cognition,” and “cognition.” Each domain has four subcategories rated on a 5-point scale based on level of assistance. We also scored signs and symptoms unique to MPS by 12 subcategories (five points per category), providing 60 points in total. The questionnaire was first administered to 138 healthy Japanese controls (0.33–50years), and successively, to 74 Japanese patients with Hunter syndrome (4–49years). The patient cohort consisted of 51 severe and 23 attenuated phenotypes; 20 patients treated with HSCT, 23 patients treated early with ERT (≤8years), 25 patients treated late with ERT (>8years), and 4 untreated patients. Among 18 severe phenotypic patients treated by HSCT, 10 were designated as early HSCT (≤5years), while 8 were designated as late HSCT (>5years).Scores from patients with severe phenotypes were lower than controls and attenuated phenotypes in all categories. Among patients with severe phenotypes, there was a trend that HSCT provides a higher ADL score than early ERT, and there was a significant difference in ADL scores between late ERT and HSCT groups. Early ERT and early HSCT provided a higher score than late ERT and late HSCT, respectively.In conclusion, we have evaluated the feasibility of a new questionnaire in control population and patients with Hunter syndrome, leading to a novel evaluation method for clinical phenotypes and therapeutic efficacy. Early treatment with HSCT provides a better consequence in ADL of patients.

Outcomes and management strategies for graft failure after umbilical cord blood transplantation.

Graft failure is a life-threatening complication after allogeneic hematopoietic stem cell transplantation (HSCT). Graft failure is more prevalent after umbilical cord blood transplantation (UCBT) compared with conventional adult stem cell sources. We identified 21 consecutive patients who experienced graft failure after UCBT at our center between 2004 and 2013 and describe their treatment strategies and outcomes. Two patients experienced early death. Seven patients had return of autologous hematopoiesis including 1 patient who was given previously collected autologous stem cells. Twelve patients received a second early HSCT, six from separate UCB units and six from a haploidentical donor. With a median follow-up of 33.2 months for surviving patients, 3-year PFS is 23% and 3-year OS is 37%. Of the six long-term survivors without relapse, four received a second HSCT from a haploidentical donor with post-HSCT high-dose cyclophosphamide based GVHD prophylaxis. This strategy appears safe and merits further investigation in this setting.