Complete Hematologic Recovery Research Articles

Clinical Profile of Adults with Inherited Bone Marrow Failure Syndromes: Results of an Ambispective Clinical Single-Center Study

BACKGROUND. Inherited bone marrow failure syndromes (IBMFS) is a heterogenous group of rare genetically determined diseases with variable hematologic and nonhematologic manifestations. The implementation of highly specific methods of genetic diagnosis advanced the understanding of IBMFS and allowed its application also beyond pediatrics. That presupposes an awareness of clinical features and reference points for recognizing IBMFS in adults. AIM. To describe the clinical profile of adult IBMFS patients. MATERIALS & METHODS. This ambispective single-center study enrolled 35 patients (10 women and 25 men) with IBMFS. Patients were aged 18–51 years (median 26 years). The following IBMFS were identified: congenital dyskeratosis (n = 10; 28 %), Diamond-Blackfan anemia (n = 9; 26 %), Fanconi anemia (n = 7; 20 %), GATA2 deficiency (n = 3; 8 %), Shwachman-Diamond syndrome (n = 1; 3 %), GATA2 deficiency (n = 1; 3 %), amegakaryocytic thrombocytopenia (n = 1; 3 %), bone marrow failure syndrome type 3 (n = 1; 3 %), severe congenital neutropenia (n = 1; 3 %), bone marrow failure with SAMD9 mutation (n = 1; 3 %). These diseases were analyzed in terms of hematologic and nonhematologic manifestations as well as main diagnosis stages and factors that contribute to recognizing IBMFS. RESULTS. Monolinear cytopenia, bilinear cytopenia, and pancytopenia were identified at hematologic onset in 18 (52 %), 6 (17 %), and 11 (31 %) patients, respectively. The median age of patients by hematologic onset was 15 years (range 0–43 years), in 14 (40 %) patients cytopenia was newly diagnosed at the age of > 18 years. In 23 (63 %) patients hypocellular bone marrow was reported, 7 (20 %) and 5 (14 %) patients had pure red cell aplasia and multilineage myelodysplasia, respectively. Chromosomal aberrations were identified in 2 patients. Paroxysmal nocturnal hemoglobinuria clone was detected in none of 27 examined patients. In 12 (34 %) patients, the criteria for non-severe aplastic anemia were met. Temporary partial or complete spontaneous hematologic recovery was observed in 6 (17 %) patients. Abnormalities with partial or complete organ dysfunctions were identified in 14 patients, whereas all patients showed minor congenital defects. All 7 Fanconi anemia patients and 9 out of 10 congenital dyskeratosis patients demonstrated organ damage specific to these diseases. Family history predominantly showing malignant neoplasms in relatives was reported in 15 (43 %) patients. Initial hematological examination yielded suspect of IBMFS in 12 (34 %) patients with the median time to diagnosis of 6 months. In 23 (66 %) patients, hematologic defects with cytopenia were erroneously accounted for by various acquired diseases, which led to a delayed correct diagnosis (median 7 years). The key factors in suspecting IBMFS were organ abnormalities and positive family history. The IBMFS diagnosis was verified by the next-generation sequencing (NGS) in 29 (83 %) patients and by other specific methods in 4 (11 %) patients. In 2 patients, the diagnosis was established on the basis of complete clinical criteria alone. CONCLUSION. IBMFS is a matter of current concern and a difficult-to-recognize clinical challenge in adult hematology patients. Differential diagnosis of acquired and congenital bone marrow failure needs to be performed irrespective of patient’s age. A detailed physical examination of patients, family history, and critical analysis of clinical profile and disease course allow for early suspicion of IBMFS. Suspected IBMFS is an indication for referral of patients to specialized centers and performing genetic diagnostics including NGS.

Multicenter Campus ALL Study on Infectious Complications in Ph- Acute Lymphoblastic Leukemia Patients Treated in the Real Life with the Gimema LAL1913 Protocol

Background The Italian national program of pediatric-inspired chemotherapy GIMEMA LAL1913 trial for adult Ph- acute lymphoblastic leukemia (Ph- ALL) has reported favorable results particularly in the younger subgroup of patients (pts) aged 18-40 years (Bassan et al, Blood Adv 2023). After the closure of the trial, this treatment scheme was adopted in the clinical practice by many Italian hematology centers for the treatment of newly diagnosed adult Ph- ALL. The safety of this intensive treatment in terms of infectious complications deserves to be investigated in the real life. Aims To evaluate in the context of the real life the incidence of infectious complications in Ph- ALL pts treated off protocol according to the GIMEMA LAL1913 chemotherapy scheme and to assess the impact of the prophylactic measures adopted. Methods We retrospectively collected data on 178 Ph- ALL pts treated in 13 Italian hematology centers participating to the Campus ALL network in Italy. Pts were homogeneously treated following the GIMEMA LAL1913 scheme, but the use of anti-infective prophylaxis differed among centers and among cycles. We analyzed data with regard to the type and site of the infections, the cycles of treatment during which the infections occurred. Finally, we correlated the incidence of the infections with the presence or absence of anti-infective prophylaxis. Results A total of 301 infectious events were diagnosed during the treatment of 134 of the 178 Ph- ALL pts (75%), including 98 episodes of fever of unknown origin (FUO) reported in 58 pts (33%). The distribution of the different types of documented infections for a total of 195 is reported in Table 1. The severity grading of infections (CTCAE.5) was available in 137 events and was ≥3 in 101. SARS COV2 infection accounted for 22% of the viral infections (8/36 cases). We diagnosed 24 pulmonary infections (in 21 pts): 15 mycotic (13 probable and 2 possible), 6 bacterial and 3 viral infections. The number of pts undergoing an infection/cycle is shown in Table 2: 69 patients had at least one infection during cycle 1 (39% of treated pts); infections were mainly bacterial and occurred in prevalence during cycle 1. Two patients died of sepsis by Pseudomonas aeruginosa during cycle 1 (mortality rate: 1.1%). Pts receiving antibacterial prophylaxis were 94/178 (53%). Bacterial infections were reported in 47 pts receiving prophylaxis and in 41 pts who did not undergo prophylaxis; the difference between the two groups was not significant (p: 0.8). Patients receiving antifungal prophylaxis were 119/178 (67%). Mycotic infections were reported in 14 pts, and in 10 pts who did not receive prophylaxis; again, no significant difference was recorded between the two groups (p: 0.3). Patients receiving antiviral prophylaxis were 151/178 (85%). Viral infections were reported in 30 pts and in 4 pts not receiving prophylaxis; no statistical difference was observed (p: 0.4). Summary/Conclusion The intensive GIMEMA LAL1913 treatment applied in the real life to newly diagnosed adult Ph- ALL pts is associated with a non-negligible rate of infections; >75% of treated pts suffered from at least one infection. Moreover, the large majority of these infections were severe with a CTCAE.5 grading ≥3. However, the infection-related mortality was very low (1.%); the anti-infective treatment together with the achievement of a complete hematologic recovery were able to control and resolve the infectious complications. Bacterial infections were prevalent and bacteremias/sepsis represented 70% of events. Cycle 1 was most affected by infectious complications of all types; mycotic and viral infections were mostly reported during cycle 1, while they decreased markedly during the following cycles. Also incidence of bacterial events decreased during treatment, though they continued to occur also in the late phases of the management suggesting that a high level of attention should be maintained up to the end of treatment. Anti-infective prophylaxis was heterogeneously applied, but it remains unclear if it is necessary. The first analysis of this survey does not show an advantage of prophylaxis in reducing infections; however, particularly for fungal complications, the numbers are too limited to consider these results as conclusive. Data collection is still ongoing, and a larger sample size will allow more robust conclusions.

Oral Iron Treatment for Children with Nutritional Anaemia and Factors that Affect the Results

Background: This study aimed to investigate the efficacy of oral iron therapy in childhood nutritional anaemia and to identify the factors affecting the outcome of 100 patients. Data was collected from the medical records of the patients. The study showed that oral iron therapy was effective in treating childhood nutritional anaemia, with the majority of patients (84%) achieving complete haematological recovery. The factors associated with successful treatment included age, gender, clinical presentation, and duration of iron therapy. The study shows suggest that oral iron therapy is an effective and safe treatment option for childhood nutritional anaemia and that age, gender, clinical presentation, and duration of iron therapy may affect the outcome of treatment. Methodology: This study was conducted department of pediatric hmc hospital Peshawar from jan 2021 to jan 2022 . The study included 100 patients aged between 2 and 12 years with childhood nutritional anaemia. Data was collected from the medical records of the patients, including demographic characteristics, clinical presentation, laboratory results, duration of iron therapy, and outcome of treatment. Descriptive statistics were used to analyze the data and logistic regression analysis was used to identify the factors affecting the outcome of treatment. Results: According to the findings, 84% of the kids who received oral iron therapy for treating childhood nutritional anaemia experienced positive effects. Age (OR=2.5, 95% CI: 1.3-4.7), male gender (OR=2.1, 95% CI: 1.1-4.3), clinical presentation (OR=2.8, 95% CI: 1.3-5.8), and length of iron therapy (OR=1.2, 95% CI: 1.1-1.3) were all linked with successful treatment. Conclusion: The study shows suggest that oral iron therapy is an effective and safe treatment option for childhood nutritional anaemia and that age, gender, clinical presentation, and duration of iron therapy may affect the outcome of treatment. Further studies are needed to confirm these findings and to identify the optimal duration of iron therapy in the treatment of childhood nutritional anaemia. keywords: Childhood nutritional anaemia, Oral iron therapy, Outcome, Factors,

Eculizumab in the management of drug-induced thrombotic microangiopathy: A scoping review of the literature

Drug-induced TMA (DI-TMA) is a thrombotic microangiopathy (TMA) caused by certain drugs, usually managed by drug discontinuation and supportive measures. Data on the use of complement-inhibition with eculizumab in DI-TMA is scarce, and its benefit in cases of severe or refractory DI-TMA is unclear. We conducted a comprehensive search in PubMed, Embase and MEDLINE databases (2007–2021). We included articles that reported on DI-TMA patients treated with eculizumab and its clinical outcomes. All other causes of TMA were excluded. We evaluated the outcomes of hematologic recovery, renal recovery, and a composite of both (complete TMA recovery). 35 studies fulfilled our search criteria, which included 69 individual cases of DI-TMA treated with eculizumab. Most cases were secondary to chemotherapeutic agents, and the most implicated drugs were gemcitabine (42/69), carfilzomib (11/69), and bevacizumab (5/69). The median number of eculizumab doses given was 6 (range 1–16). 55/69 (80 %) patients achieved renal recovery, after 28–35 days (5–6 doses). 13/22 (59 %) patients were able to discontinue hemodialysis. 50/68 (74 %) patients achieved complete hematologic recovery after 7–14 days (1–2 doses). 41/68 (60 %) patients met criteria for complete TMA recovery. Eculizumab was safely tolerated in all cases, and appeared to be effective in achieving both hematologic and renal recovery in DI-TMA refractory to drug discontinuation and supportive measures, or with severe manifestations associated with significant morbidity or mortality. Our findings suggest that eculizumab may be considered as a potential treatment for severe or refractory DI-TMA that does not improve after initial management, although larger studies are needed.

Hematopoietic Stem Cell Transplantation in Juvenile Myelomonocytic Leukemia: A Case Report and Literature Review

Juvenile myelomonocytic leukemia (JMML) is a rare hematological malignancy of early childhood, classified by the World Health Organization as a myelodysplastic/myeloproliferative disease and is associated with a poor prognosis. Allogeneic hematopoietic stem cell transplantation is the only curative treatment. A two-year-old male child was diagnosed with JMML and was given induction chemotherapy. One year after diagnosis, the patient received allogeneic hematopoietic stem cell transplantation from an HLA sibling donor after a myeloablative conditioning regimen. The patient remained free of disease after 5 years of follow-up, healthy, with complete clinical, immunologic and hematologic recovery, without signs of JMML. Transplantation is the only modality to achieve a cure in JMML patients. The most widely practiced approach is the use of bone marrow or peripheral blood stem cells after a myeloablative conditioning regimen. Post-transplant monitoring chimerism can help identify the patients who are at risk of relapse.

Characterization and Prognosis of Temozolomide-Induced Aplastic Anemia

Introduction: Temozolomide-induced aplastic anemia (TIAA) is a very rare and highly challenging complication of temozolomide (TMZ) chemotherapy. TMZ is a mainstay of therapy in patients with central nervous system (CNS) malignancies. Single-patient case reports and small case series have described variable morbidity and mortality associated with TIAA. However, quantitative evidence describing prognosis, clinical characteristics, and treatment of this entity is absent or very limited.Methods: We performed a 5-center, 22-year observational cohort study of patients with CNS malignancies treated with temozolomide who developed TIAA, retrospectively analyzing prognosis, complications, and recovery. We compared patients who achieved meaningful hematologic recovery [partial hematologic recovery (PHR) or complete hematologic recovery (CHR)] to those who did not recover [refractory disease (RD)]. We used descriptive statistics, T-tests, and chi-square tests to evaluate patient characteristics, outcomes, and laboratory values. Overall time to hematologic recovery and overall survival of patients with PHR, CHR, and RD were estimated using the Kaplan-Meier method and compared using the log-rank test, and a multivariable logistic model evaluated potential predictors of achieving CHR. TIAA was defined using adapted evidence-based severe aplastic anemia criteria incorporating profound cytopenias and a minimum duration (4 weeks) without hematologic recovery (TABLE 1).Results:Study Population and TIAA Prevalence. Of 3,821 patients with CNS malignancies receiving TMZ, 34 patients (0.89%) met criteria for TIAA (FIGURE 1). Onset was rapid, with 29 patients (85.3%) developing TIAA before completing a second TMZ cycle (TABLE 2).Complications and Outcomes of Hematologic Recovery. 23 patients (67.6%) ultimately achieved a hematologic recovery and the remaining 11 patients (32.4%) had refractory disease. Figure 2A illustrates the time from TIAA diagnosis to PHR and CHR for the cohort. In Kaplan-Meier survival analysis, the median time from TIAA diagnosis to PHR was 84 days and the median time to CHR was 134 days. Patients without recovery were more likely to develop serious complications (TABLE 3), including febrile neutropenia (72.7% vs. 30.4%, P=0.03), major infection (45.5% vs. 8.7%, P=0.02), hospitalization (81.8% vs. 43.5%, P=0.04), and death (100.0% vs. 60.9%, P=0.02). This increased risk of complications in patients not achieving hematologic recovery was observed despite a similar median time from TMZ initiation to TIAA diagnosis in the two groups (45 days vs. 40 days). Figure 2B illustrates the overall survival in the entire cohort and by each hematologic recovery subgroup. In Kaplan-Meier survival analysis, median overall survival from the time of TIAA diagnosis was as follows: entire cohort, 355 days; achieved PHR, 752 days; achieved CHR, 1414 days; refractory disease, 28 days (P<0.0001 for comparison of PHR, CHR, and refractory disease). In a multivariable logistic model, none of the evaluated covariates (age, sex, TMZ dose, body surface area, and use of hematopoietic growth factors) were significantly associated with achieving CHR.Treatment of TIAA and Outcomes of Therapy. 29 patients (85.3%) received hematopoietic growth factors (TABLE 3); no patients were treated with immunosuppression or hematopoietic stem cell transplant. Hematologic recovery rates were numerically higher in patients receiving thrombopoietin receptor agonists vs. those who did not (81.8% vs. 54.2%, P=0.15), but were not higher in patients receiving granulocyte colony stimulating factors vs. those who did not (68.0% vs. 66.7%, P=0.99).Conclusions: TIAA occurs in less than 1% of patients receiving temozolomide for CNS malignancies, occurring rapidly after TMZ initiation, but is highly morbid and often fatal when it occurs, precluding further use of cytotoxic therapy in the vast majority of patients. In the one-third who do not recover, risks of febrile neutropenia, infection, and hospitalization are increased, and overall survival greatly diminished. Hematologic recovery is potentially aided by the use of thrombopoietin receptor agonists, as has been demonstrated in classical autoimmune aplastic anemia. Further study of TIAA treatment is needed for this serious complication of TMZ therapy. [Display omitted] DisclosuresForst: Eli Lilly: Current holder of individual stocks in a privately-held company. Al-Samkari: Rigel: Consultancy; Argenx: Consultancy; Moderna: Consultancy; Novartis: Consultancy; Amgen: Research Funding; Dova/Sobi: Consultancy, Research Funding; Agios: Consultancy, Research Funding.

Aspacytarabine (BST-236) As Monotherapy Is Safe, Well-Tolerated and Effective for the Treatment of Adults with Newly Diagnosed Acute Myeloid Leukemia Unfit for Intensive Therapy. Results of a Phase 2 Study

Aspacytarabine (BST-236) As Monotherapy Is Safe, Well-Tolerated and Effective for the Treatment of Adults with Newly Diagnosed Acute Myeloid Leukemia Unfit for Intensive Therapy. Results of a Phase 2 Study

Complete Versus Incomplete Hematologic Recovery after CAR T Cell Therapy: Implications for Relapse Free Survival and Overall Survival in Pediatric and Young Adult Patients with Relapsed/Refractory B-ALL

Background: Anti-CD19 Chimeric Antigen Receptor (CAR) T cell therapy has emerged as a mainstay in the treatment of patients with relapsed/refractory (r/r) B-cell acute lymphoblastic leukemia (ALL). While trials have shown encouraging survival rates, up to 50% of patients receiving CART eventually relapse. Identification of risk factors for subsequent relapse is crucial, as this could allow tailored surveillance and treatment approaches for high-risk patients, potentially leading to improved morbidity and mortality. Complete remission with incomplete hematologic recovery (CRi) has been associated with decreased remission duration and overall survival in acute leukemias. As count suppression following CAR T cell therapy is frequently seen, this study evaluated CRi as a prognostic marker for worse relapse-free (RFS) and overall survival (OS) after CAR T cell therapy in comparison to complete remission with hematologic recovery (CR).Methods: Patients with r/r ALL who achieved a complete morphologic remission after receiving anti-CD19 CAR T cell treatment with the 4-1BB-containing products CTL019 or humanized CART19 in the context of a clinical trial (NCT01626495, NCT02374333, NCT02228096, NCT02435849, NCT02906371) or commercial product (tisagenlecleucel) at Children's Hospital of Philadelphia from 4/2012-4/2019 were identified. Patients who received prior CAR therapy, and those with Trisomy 21 were excluded. Demographic, disease and treatment characteristics, and outcome data were abstracted from the medical record or clinical trial datasets. CR was defined as achieving a morphologic remission with both an absolute neutrophil count (ANC) ≥1,000/µL and a transfusion-independent platelet count ≥100,000/µL at any time between 27-33 days after CAR T cell infusion, whereas those achieving a morphologic remission without complete hematologic recovery were defined as CRi. RFS and OS were described for each cohort. Exposure-outcome association was assessed via the log-rank test and multivariable Cox proportional hazard regression.Results: Of the 206 patients included in the analysis, 104 (51%) achieved CR, 102 (49%) CRi. Forty patients (39%) met criteria for CRi with both ANC <1000/µL and platelets <100,000/µL, 40 (39%) for isolated thrombocytopenia, and 20 (20%) for neutropenia alone. Median age at leukemia diagnosis was 7 years (range 0.2-24), and at CAR T cell infusion was 12 years (range 1-29), with 48% undergoing a prior allogeneic stem cell transplant (HSCT), 32% with high risk cytogenetics, and 10% with prior blinatumomab treatment, none of which differed between the CR and CRi groups (Table 1). The number of relapses prior to CAR T cell referral was different between the groups (p=0.003), with more CR patients having been referred for primary refractory disease (25% vs 9.8%), and more CRi patients for first relapse (34% vs 18%). More CRi patients had >25% bone marrow blasts (43% vs 19%) at infusion, whereas more CR patients were MRD-negative (50% vs 30%) at infusion (p=0.002). CRi patients were also more likely to have Grade 3/4 CRS (38% vs 6.7%). Median length of follow-up for patients with CR was 39 months (range 7-89), which was not statistically significantly different than for those patients with CRi (41 months, 11-98, p=0.875). There was no difference in RFS when stratified by hematologic recovery (Figure 1, p=0.2165), with RFS at 36 months for CR of 57% (47-69) and CRi of 46% (36-59). OS was significantly lower (Figure 2, p=0.0081) for those with CRi, with 36-month OS for CR of 81% (74-89), and for CRi of 63% (54-73). In multivariable analysis adjusting for sex, prior blinatumomab, relapse number, disease burden at infusion, and maximum CRS grade, CR was not associated with either RFS (HR 0.76 [95%CI 0.50-1.17] p=0.2182) or OS (HR 0.74 [95%CI 0.43-1.29] p=0.2908), in comparison to CRi, Table 2.Discussion: Complete remission with incomplete hematologic recovery, manifesting as neutropenia and/or thrombocytopenia, at the first disease assessment following CAR T cell infusion should not be regarded as a harbinger of relapse and demonstrates that patients with CRi have similar probability of durable remission without further therapy. Anticipatory guidance should be provided to patients, and their families, that CRi is more frequently seen in patients who experience high grade CRS, who have high disease burden at infusion, and who are treated in first relapse. [Display omitted] DisclosuresCallahan: Novartis: Speakers Bureau. Rheingold: Optinose: Other: Spouse's current employment; Pfizer: Research Funding. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Novartis, Kite, Vertex, and Servier: Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding. Maude: Wugen: Consultancy; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding.

Predictive Biomarkers of Response to the Polo-like Kinase 1 (PLK1) Inhibitor, Onvansertib, in Combination with Decitabine in Relapsed or Refractory Acute Myeloid Leukemia (R/R AML)

Predictive Biomarkers of Response to the Polo-like Kinase 1 (PLK1) Inhibitor, Onvansertib, in Combination with Decitabine in Relapsed or Refractory Acute Myeloid Leukemia (R/R AML)

Impact of FLT3 Mutation Clearance after Front-Line Treatment with Gilteritinib Plus Azacitidine, or Gilteritinib or Azacitidine Alone in Patients with Newly Diagnosed AML: Results from the Phase 2/3 Lacewing Trial

Impact of FLT3 Mutation Clearance after Front-Line Treatment with Gilteritinib Plus Azacitidine, or Gilteritinib or Azacitidine Alone in Patients with Newly Diagnosed AML: Results from the Phase 2/3 Lacewing Trial

The Whole Exome Analysis and Clinical Relevance in Patients with Atypical Hemolytic Uremic Syndrome

INTRODUCTION:Atypical hemolytic uremic syndrome (aHUS) is a rare, genetic, progressive, life-threatening form of thrombotic microangiopathy (TMA). A genetic mutation has been found as an explanation for constitutive complement activation in 50-60% of cases. In this abstract, we present whole exome analysis data results and their clinical relevance in 12 patients with aHUS.MATERIALS AND METHOD:We have enrolled 24 patients in this study who were diagnosed as aHUS and followed in our clinic since 2012. For exome sequencing, libraries were prepared using SeqCap EZ Human Exome Library v3.0 kit. Real Time Analysis software version with standard parameters was used for real-time image analysis and base calling. Raw sequencing data were aligned to the human genome hg19 reference (Homo sapiens (hg19) sequence) using CLC Genomic Workbench V10 (Qiagen) with standard parameters in paired-end mode. All variants were filtered according to the following criteria: not in dbSNP144 and also 1000 genome MAF <0.01, homozygous in the affected patients and heterozygous in the carrier parents, Genotype Quality (GQ) >30 and coverage (DP) >20 and, in homozygous region.FINDINGS AND RESULTS:We performed whole exome sequencing in all 24 patients but during raw data analysis 12 patients were found to be eligible for further analysis according to QC value. We didn't find any mutation in one of the patients (case 10) who had presented with diarrhea and had very good response to plasmapheresis only. We detected 32 different complement mutations in 4 different genes including CC3, CFI, CFH and membrane MCP in all other 11 patients. These mutations are summarized in the table.Four of the patients have responded to plasmapheresis and eculizumab was not needed. Of the remaining 20 patients eculizumab was aimed to be used. However, two of them died due to acute respiratory distress and thrombosis prior to eculizumab therapy. Case 9 was one of them and we found 21 different mutation including nine in CC3, five in CFH and 7 in MCF. One of our patients died in her 3rd month of eculizumab therapy (Case 2) and she had also seven mutations mostly in CFH gene. We used eculizumab in 18 of the patients and got complete response for thrombotic microangiopathy (TMA) in all. We had very good response to eculizumab in all these patients; even hemodialysis need disappeared in nine of them during eculizumab therapy. We experienced recurrence of renal failure in one patient (Case11) under eculizumab treatment in two years. She had also two different mutations in CFI gene four of the seven mutations in MCP gene and four of the 15 mutations in CC3 gene. This patient was lost due to multiple organ failure.We decided to stop eculizumab at the ninth month of treatment in two of the patients (Case 1 and Case 3) who had complete hematologic and renal recovery. Case 1 relapsed 16 months later and successfully retreated with eculizumab. She had 15 different mutations as eight mutations in CC3, six mutations in CFH, and 1mutation in MCP gene. Case 3 is still under control for three years after stopping eculizumab treatment. But as an interesting finding, this patient was 80 years old and had the heaviest mutation load with 22 different mutations (6 of the 7 mutations in MCP gene, 11 of the 15 mutation in CC3 gene, 4 of the 8 mutation in CFH gene).AHUS has been diagnosed during pregnancy in two of the patients and they had a successful delivery with healthy babies without any complication including ESRD. We also found 14 different mutations mostly in CFH gene in one of them (Case 8).DISCUSSION AND CONCLUSION:We found at least four different mutations in all patients except one case. Although MCP mutations accounts for only 15% of the aHUS cases we also found at least one MCP mutation in 91% of our cases. We found the rarest mutations in CFI gene. Although there are no clinical predictors of outcome, knowledge of the underlying genetic defect is helpful in predicting prognosis. But the patient who had the most number of mutations also had the best prognosis in our cohort. Therefore it is hard to use mutation data for management and prognosis of the syndrome. But the presence of a mutation is clearly important for the ESRD before transplantation decision and also would encourage patients to continue treatment. [Display omitted] DisclosuresYenerel:Alexion: Honoraria. Caliskan:Alexion: Honoraria. Yildiz:Alexion: Honoraria. Turkmen:Alexion: Honoraria.

Efficacy and safety of aspacytarabine (BST-236) as a single-agent, first-line therapy for patients with acute myeloid leukemia unfit for standard chemotherapy.

7007 Background: Aspacytarabine (BST-236) is a prodrug of cytarabine, the backbone of acute myeloid leukemia (AML) standard of care chemotherapy, associated with toxicity which precludes its administration in older patients and patients with comorbidities. Aspacytarabine is inactive in its intact prodrug form until cytarabine is gradually released at pharmacokinetics which decrease the systemic exposure to peak toxic cytarabine levels, resulting in reduced systemic toxicity and relative sparing of normal tissues, enabling therapy with high cytarabine doses to patients otherwise unfit to receive it. Methods: A phase 2b open-label, single-arm study to evaluate the efficacy and safety of aspacytarabine as a first-line single-agent therapy in newly-diagnosed AML patients unfit for standard chemotherapy (NCT03435848). Aspacytarabine is administrated at 4.5 g/m2/d (containing 3 g/m2/d cytarabine) in 1-2 induction and 1-3 consolidation courses, each consisting of 6 daily 1-hour infusions. Patients with secondary AML, prior hypomethylating agent (HMA) therapy, and therapy-related AML, are eligible. Results: To date, in the ongoing study, 46 newly-diagnosed AML patients unfit for standard chemotherapy (median age 75 years) were treated with aspacytarabine and completed 1-4 courses of 4.5 g/m2/d aspacytarabine, including 26 patients (63%) with de novo AML and 17 (37%) with secondary AML. Six patients (13%) were previously treated with HMA (median 12 courses). The baseline median bone marrow blasts was 52%, and 54% and 29% of patients had adverse or intermediate European LeukemiaNet (ELN) score, respectively. Twenty (43%) patients had ECOG 2. Aspacytarabine is safe and well-tolerated in repeated-course administration. Grade &gt; 2 drug-related adverse events include mainly hematological events and infections. The 30-day mortality rate is 11%. Of 43 patients evaluable for efficacy analysis to date, 15 patients (35%) reached a complete remission (CR) following 1 (13 patients) or 2 (2 patients) induction courses, all with complete hematological recovery (median 27.5 days, range 22-39 days). The CR rates in de novo AML patients and patients with adverse ELN score are 46% and 33%, respectively. Of the 11 patients evaluable to date for minimal residual disease (MRD) flow cytometry test, 8 are MRD negative (73%). While aspacytarabine treatment consists of a limited number of courses, median duration of response and median overall survival for responders are not reached at 12 and 24 months, respectively (end of follow up). Updated results will be presented at the meeting. Conclusions: The cumulative clinical data suggest that aspacytarabine, a time-limited single-agent treatment, is safe and efficacious as a first-line therapy for patients who are unfit for intensive chemotherapy, which may establish it as a new tolerable AML chemotherapy backbone. Clinical trial information: NCT03435848.

Successful Allogeneic Peripheral Blood Stem Cell Transplantation in 4 Wiskott-Aldrich Syndrome Patients.

Allogeneic hematopoietic stem cell transplantation is a potential curative treatment in Wiskott-Aldrich syndrome (WAS). Here, we analyzed the outcomes in 4 WAS patients who underwent this procedure with peripheral blood stem cell (PBSC) in our center. Four patients with severe WAS phenotype have received allogeneic hematopoietic stem cell transplantation between January 2014 and December 2019 from matched sibling donors with PBSC. Two different preparative conditioning regimens were provided: the first associated busulfan-cyclophosphamide (2 patients) and the second with busulfan-fludarabine administered to the others. Cyclosporine gave as preferred graft-versus-host disease prophylaxis with a short course of methotrexate. All patients achieved engraftment after PBSC with a median CD34+ cell count: 13.6×106/kg (8 to 24.9×106/kg). Chronic graft-versus-host disease developed in 2 patients treated by cyclosporine-steroids with complete resolution. Chimerism for all the patients was fully donor (>95% donor). After a median follow-up of 41 months (8 to 74 mo), all patients (100%) are alive, healthy, with complete clinical, immunologic, and hematologic recovery, without signs of WAS. This limited study with high-dose PBSC transplantation approach for WAS, demonstrated a safe and effective treatment option, with rapid engraftment, without complications, excellent long-term outcomes, independent of conditioning regimen.

Durable Remissions and Increased Overall Survival in AML Patients Deemed Unfit for Standard Intensive Chemotherapy Achieved with High-Dose BST-236 (Aspacytarabine) Induction and Consolidation

Durable Remissions and Increased Overall Survival in AML Patients Deemed Unfit for Standard Intensive Chemotherapy Achieved with High-Dose BST-236 (Aspacytarabine) Induction and Consolidation

Severe HELLP syndrome masquerading as thrombocytopenic thrombotic purpura: a case report

BackgroundThrombotic microangiopathies (TMAs) occurring in the postpartum period may be difficult to manage. They present as the combination of mechanical hemolytic anemia and consumption thrombocytopenia due to endothelial dysfunction. The cause of this endothelial aggression can be multiple: thrombocytopenic thrombotic purpura (TTP), HELLP syndrome, antiphospholipid syndrome, atypical hemolytic and uremic syndrome or acute fatty liver of pregnancy. TTP results from a severe deficiency of ADAMTS13, which is a protease cleaving specifically von Willebrand factor chiefly produced by liver cells. There are two main causes, the production of anti-ADAMTS13 auto-antibodies and, more rarely, a genetic deficiency in ADAMTS13. First-line treatment is based on plasma exchange. HELLP syndrome occurs in the third trimester of pregnancy usually in association with preeclampsia and represents a form of TMA characterized by damage to the sinusoidal capillaries of the liver. Prompt delivery is the main treatment. We present a case illustrating the challenges in discriminating between different postpartum TMAs, with a focus on the distinction between TTP and HELLP syndrome. Specifically, we highlight how acute liver failure (ALF) stemming from HELLP may lead to TTP with a spectacular response to plasma exchanges.CaseA 28-year-old, 33 + 4 weeks pregnant woman presented with severe preeclampsia complicated by ALF in the setting of partial liver necrosis, disseminated intravascular coagulation, microangiopathic hemolytic anemia and acute kidney injury. Greatly diminished levels of ADAMTS13 (< 5%) activity and neurological impairment suggested an initial diagnosis of thrombotic thrombocytopenic purpura (TTP). Therapeutic plasma exchange (TPE) was initiated and complete renal, neurological, hematological and hepatic recovery was observed. Secondary TTP induced by ALF due to HELLP syndrome was the final diagnosis.ConclusionOur case addresses the overlapping nature of postpartum TMAs and raises the possibility that HELLP-induced ALF may constitute an additional mechanism resulting in TTP, thereby opening a possible indication for TPE.

Copper Deficiency: An Overlooked Cause of Anemia and Leucopenia

Copper deficiency (hypocupremia) is an acknowledged but often overlooked cause of anemia and leukopenia (1-4). It is recognized as a frequent cause of hypochromic microcytic anemia, leukopenia, and neuropathy. Copper deficiency anemia has been reported after gastric resection (e.g., Roux-en-Y) (1, 5, 6), excessive zinc consumption (1, 6-9), and in patients with short bowel syndrome receiving total parenteral or enteral nutrition lacking adequate copper supplementation (1, 2). We report a case of vitamin B12, and iron refractory severe anemia and leucopenia with history of Roux-en-Y surgery. Myelodysplastic syndrome was suspected. Bone marrow biopsy was consistent with copper deficiency and serum copper levels were undetectable. The patient experienced complete hematological recovery after copper replacement therapy.

Long Term Haematological Recovery of Children with Severe Malaria Anaemia in Uganda

Long Term Haematological Recovery of Children with Severe Malaria Anaemia in Uganda Ruth Namazzi, Andrea Conroy, Dibyadyuti Datta, Gloria Kyarisiima Chandy John, Robert Opoka Background Children with severe malaria anaemia are at an increased risk of poor post discharge outcomes including frequent readmissions and clinic visits for malaria. How the post-discharge outcomes affect haematological recovery of children after severe malaria anaemia has not been evaluated. Methods We enrolled and followed up for 12 months 248 children with severe malaria anaemia (SMA) and 120 age matched asymptomatic community controls (CC). Complete blood counts, reticulocyte percentages and erythropoietin levels were done at baseline, 1 month and 12 months after the malaria episode. Children were treated according to national guidelines, which included blood transfusion and anti malarial therapy. We evaluated the relationship between recovery of haematological indices and multiple readmissions in the post-discharge period in SMA children. Results The mean age was 2.12 ± 0.9 and 2.2 ± 1.0 years (p=0.266) for SMA and CC respectively. The mean baseline haemoglobin (Hb), reticulocyte percentage and erythropoietin levels were 3.5 ± 0.9g/dL, 2.6±4.7% and 6843±5891 for SMA, compared to 10.8±1.5g/dL, 1.8±2.6% and 58.5 for CC, respectively. By 1-month, SMA children had made complete haematological recovery with mean Hb, reticulocyte percentage and erythropoietin levels of 11.2 ± 2.2g/dL, 1.8± 2.7% and 20.2 ± 58.3. The hematological recovery was sustained even by month12 follow up; mean Hb level was 10.7±2.1 and 11.6±2.1g/dL for SMA and CC, p =0.07. Reticulocyte percentages were comparable between SMA and CC, 2.5 ± 4.1vs 1.2±1.7,p=0.41. Amongst SMA group, more children who had multiple readmissions during the follow up period were still anemic at 12 months compared to those who did not have multiple readmissions, 7/64(10.9%) vs. 13/168(7.8%). The difference however was not statistically significant (p=0.438). Conclusion Children with SMA achieve hematological recovery by 1 month post-discharge. The hematological recovery was maintained until 12 months post-discharge. Amongst SMA children, multiple readmissions in the post-discharge period did not appear to adversely affect hematological recovery by 12 months. The effect of repeated malaria episodes on long term haematological recovery needs further study. Disclosures Conroy: ALC: Patents &amp; Royalties: angiopoietin-1, angiopoietin-2.

Aspacytarabine (BST-236) Is Safe and Efficacious As a Single-Agent, First-Line Therapy for Patients with Acute Myeloid Leukemia Unfit for Standard Chemotherapy. Integrated Results from a Phase 1/2a and an Ongoing Phase 2b

Introduction: Aspacytarabine (BST-236) is a prodrug of cytarabine, a backbone of acute myeloid leukemia (AML) therapy. Due to its unique pharmacokinetics and metabolism, treatment with aspacytarabine evades peak exposure to free cytarabine, which reduces non-hematological toxicity and enables delivery of high-dose cytarabine also to patients unfit for standard therapy. Data from a completed phase 1/2a and an ongoing phase 2b studies in AML patients unfit for standard therapy, including patients with AML secondary to therapy and myelodysplastic syndrome (MDS) with prior exposure to hypomethylating agents (HMA), demonstrate promising single-agent efficacy and safety of aspacytarabine as a potential first-line AML treatment for this challenging population. Aims: To evaluate the efficacy and safety of aspacytarabine in AML patients unfit for standard induction therapy. Methods: A completed phase 1/2a study and an ongoing phase 2b study evaluate the efficacy and safety of aspacytarabine as a single-agent therapeutic for AML. The phase 1/2a, dose-escalation study enrolled newly-diagnosed patients unfit for standard therapy and patients with relapsed/refractory AML. Patients were treated with 0.3-6 g/m2/d aspacytarabine in 6 dose-escalating cohorts. The ongoing multi-center phase 2b study expands the subgroup of newly-diagnosed AML patients unfit for standard therapy, to evaluate the efficacy and safety of aspacytarabine as a first-line therapy for this population. Secondary AML patients, treated with HMA, chemotherapy, or radiotherapy for a prior condition, are allowed. Patients in the phase 2b study are treated with the selected aspacytarabine dose of 4.5 g/m2/d, containing approximately 3 g/m2/d of cytarabine. Each aspacytarabine treatment course (induction and consolidation) consists of 6 1-hour daily intravenous infusions. Results: To date, 34 AML patients, median age 76 years, received at least 1 dose of aspacytarabine, including 30 patients unfit for standard induction therapy due to age or comorbidities. Overall, 25 patients completed 1 course of aspacytarabine, 4 patients completed 2 courses, 1 patient completed 3 courses, and 1 patient completed 4 courses of aspacytarabine. Three patients (in the phase 1/2a study) did not complete the first course. Aspacytarabine was safe and well-tolerated in repeated-course administration, including in older and unfit patients. Adverse events included mainly hematological "on-target" events with no drug-related mucositis or cerebellar toxicity. Twenty-one patients were newly-diagnosed with AML, either de novo or secondary to MDS or therapy. The patient population was characterized by older age (median 76 years, range 67-88 years), and the majority (67%) of patients had secondary AML, including 10 patients (48%) who were previously treated with HMA (median of 10 courses) or radiotherapy. The median baseline bone marrow blast percentage of this population was 75, and 43% and 48% had intermediate or adverse European LeukemiaNet (ELN) cytogenetic score, respectively. Despite these poor-prognostic characteristics, the 30-day mortality rate in the group of patients receiving ≥4.5 g/m2/d aspacytarabine was 7%. The combined complete remission (CR) rate of all doses was 33%, including 1 patient reaching a CR with partial platelet recovery (CRp). The CR rate in patients treated with at least 4.5 g/m2/d aspacytarabine is 36%, with median time for complete hematological recovery of 27 days (range 21-30) following induction and consolidation. Notably, among the 7 patients who reached a CR/CRp (median age 77), 3 secondary AML patients reached a CR, including 2 patients with prior exposure to HMA (5 and 10 courses) and 1 with prior exposure to radiotherapy (Table 1). Duration of response and overall survival follow up is ongoing and will be presented at the meeting. Conclusions: The accumulating clinical data suggest that aspacytarabine is safe and efficacious for the treatment of AML patients who are unfit for standard induction therapy, including patients with prior exposure to HMA, which may establish aspacytarabine as a new therapeutic backbone for AML, either as a single agent or in combination with targeted therapy. Disclosures Altman: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Glycomimetics: Consultancy, Honoraria, Other: Data Safety and Monitoring Committee; Daiichi Sankyo: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Biosight: Other: US Lead; Novartis: Consultancy; Agios: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Cancer Expert Now: Consultancy; France Foundation: Speakers Bureau; prIME Oncology: Speakers Bureau; PeerView: Speakers Bureau; Theradex: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Luger:Seattle Genetics: Research Funding; Pfizer: Honoraria; Onconova: Research Funding; Kura: Research Funding; Jazz: Honoraria; Genetech: Research Funding; Daichi Sankyo: Honoraria; Cyslacel: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Ariad: Research Funding; Agios: Honoraria. Kota:Takeda: Honoraria; Xcenda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Pfizer: Honoraria. Flaishon:BioSight Ltd.: Employment. Tessler:BioSight Ltd.: Employment. Gengrinovitch:BioSight Ltd.: Employment. Ben Yakar:BioSight Ltd.: Employment. Rowe:BioSight: Consultancy.

Multipotent Mesenchymal Stromal Cells for Poor Graft Function after Allogeneic Hematopoietic Cell Transplantation:a Multicenter Prospective Study

Selleslag: Celyad: Other: Clinical trial research (no honoraria recieved); Novartis: Consultancy, Honoraria, Speakers Bureau.

Clinical Experience With Venetoclax Combined With Chemotherapy for Relapsed or Refractory T-Cell Acute Lymphoblastic Leukemia

BackgroundPatients with relapsed or refractory (R/R) T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) have dismal outcomes. Preclinical studies have suggested that T-ALL cells are sensitive to BCL2 inhibition. The clinical activity of venetoclax, a selective BCL2 inhibitor, in T-ALL is unknown. Patient and MethodsWe retrospectively reviewed the efficacy and safety of venetoclax combined with chemotherapy for patients with R/R T-ALL treated at our institution. ResultsThirteen patients with R/R T-ALL with a median age of 46 years (range, 20-75 years) were treated with venetoclax plus chemotherapy. Five patients (38%) had early T-cell precursor ALL. The patients had received a median of 2 previous lines of therapy (range, 1-11). Venetoclax at a median dose of 200 mg/d for 21 days, generally with a concomitant azole antifungal, was combined with various agents, including hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone), asparaginase, nelarabine, decitabine, or other intensive chemotherapy. Of the 10 patients evaluable for bone marrow response, 6 (60%) achieved a remission with bone marrow blasts < 5%, including 3 with complete hematologic recovery. The median overall survival and relapse-free survival were 7.7 and 4.0 months, respectively. No early death or clinically significant tumor lysis syndrome were reported. The median interval to neutrophil recovery and platelet recovery were 15 days and 44 days, respectively, with prolonged cytopenias observed with venetoclax 400 mg/d or when given for > 14 days per cycle. ConclusionCombination therapy with venetoclax showed promising clinical efficacy in R/R T-ALL. Further studies are warranted to evaluate the clinical benefit of BCL2 inhibitors in T-ALL.