Recovery Of Peripheral Blood Counts Research Articles

Effect of prior lenalidomide or daratumumab exposure on hematopoietic stem cell collection and reconstitution in multiple myeloma.

The roles of Lenalidomide (Len) and Daratumumab (Dara) in multiple myeloma treatment are well-established, yet their influences on hematopoietic stem cell harvesting and reconstitution remain disputed. We conducted a systematic database review to identify cohort studies or RCTs evaluating the effect of the use of Len or Dara on hematopoietic stem cell collection and peripheral blood count recovery in multiple myeloma patients. Effects on hematopoietic collection or reconstitution were estimated by comparing standardized mean differences (SMD) and mean differences (MD), or median differences. Eighteen relevant studies were identified, summarizing mobilization results. For Len, data from 13 studies were summarized, including total CD34+ cell yield, collection failure rate, and time to neutrophil and platelet engraftment. Results indicated that Len exposure led to decreased stem cell collection [SMD=-0.23, 95% CI (-0.34, -0.12)]. However, collection failure (<2×106) could be mitigated by plerixafor [OR=2.14, 95% CI (0.96, 4.77)]. For Dara, two RCTs and three cohort studies were included, showing that Dara exposure resulted in a reduction in total stem cells even with optimized plerixafor mobilization [SMD=-0.75, 95% CI (-1.26, -0.23)], and delayed platelet engraftment recovery [MD=1.20, 95% CI (0.73, 1.66)]. Our meta-analysis offers a comprehensive view of Len and Dara's impacts on hematopoietic stem cell collection and reconstitution in multiple myeloma. Len usage could lead to reduced stem cell collection, counteracted by plerixafor mobilization. Dara usage could result in diminished stem cell collection and delayed platelet engraftment.

Time of Attainment of Clinical Remission and Peripheral Blood Count Recovery during Induction Chemotherapy for Childhood Acute Lymphoblastic Leukemia

Background: Acute lymphoblastic leukemia(ALL) is the most common pediatric malignancy. Infection and bleeding are the leading cause of death during induction chemotherapy in childhood ALL. So, proper knowledge about anticipated infection and bleeding are very important during this period. But the duration of clinical remission and recovery of peripheral blood count during induction chemotherapy is not well reported in literature. Objective: The aim of the study was to determine the time of attainment of clinical remission and recovery of peripheral blood count after initiation of induction chemotherapy and to determine if the duration of clinical remission and peripheral blood count recovery differs between therapeutic risk groups. Methods: This prospective observational study was conducted from January 2021 to December 2021 in the Department of Paediatric Haematology and Oncology, BSMMU. Newly diagnosed admitted Eighty-Six ALL of both sexes aged 1 to 17.9 years were included. After commencing chemotherapy, physical examination was recorded every day until clinical remission and complete blood count (CBC) was recorded one to two days interval until peripheral blood count recovery. The number of packed red blood cell (PRBC) and platelet transfusions and the number of days of intravenous antibiotics were recorded. Results: Mean duration of clinical remission, complete Hemoglobin (Hb), Absolute neutrophil count(ANC) and platelet recovery was 8.4 ± 4.5 days, 25±7.9 days, 23.3±5.6 days and 21.8±6.4 days respectively (p&lt;0.01). Time to attain partial recovery of platelet was 14.0±4.9 days in high risk and 19.2±5.3 days in standard risk group. PRBC transfusion requirement was 2.2±1.2 units in high risk group and 1.7±0.8 units in standard risk group (p&lt;0.05). Time to attain partial recovery of ANC, number of days with I/V antibiotics and duration of treatment interruption were higher in high risk group. Conclusion: Time of clinical remission was similar between risk group. Platelet recovery occurred earlier than Hemoglobin (Hb) and absolute neutrophil count (ANC) recovery. Transfusion and supportive care requirement were more in high risk group during induction chemotherapy. So, more supportive care should be arranged up to three weeks of induction period to increase survival of high risk childhood ALL. Bangladesh Med Res Counc Bull 2023; 49: 177-182

Venetoclax in Combination with Intermediate Doses of Cytarabine in Consolidation Phase for Acute Myeloid Leukemia Patients in First Complete Remission; Results of the Part 1 of the Phase 1/2 Multicentric Covenidac Study

For authors: Please: L Gastaud and P Peterlin: co-primary, H dombret et C Recher: co-last Background: The French ALFA-FILO AML intergroup launched the BIG-1 trial (EudraCT No.: 2014-000699-24) in 2015 to evaluate different intensive chemotherapy (ICT) strategies aiming at improving the survival of younger adults with acute myeloid leukemia (AML). All patients (pts) with previously untreated non-APL and non-CBF AML aged 18-60 years were eligible for this trial. The trial design included several randomization types. Results of the R1 and R2 randomizations, namely idarubicin vs daunorubicin for induction and IDAC vs HDAC for consolidation, will be reported at this meeting. In patients who achieved first complete remission (CR), randomizations R4 consisted of nested randomized Phase 2 or 1/2 studies evaluating the addition of new drugs to the IDAC/HDAC consolidation cycles. The protocol was designed to allow several sequential multicenter R4 evaluations of various new agents over the trial period. Venetoclax (VEN) has proved its efficacy when combined to azacitidine or low dose cytarabine in unfit AML pts (DiNardo et al. 2020; Wei et al. Blood 2020). Its role in fit patients treated with ICT is still under investigation. The COVENIDAC Phase 1/2 R4 sub-study is evaluating the safety and efficacy of VEN added to IDAC during the consolidation cycles of CR pts. We report herein the result of the Phase 1 part. Methods: The primary objective of this Phase 1 study was to determine the maximum tolerated dose (MTD) of VEN in combination with IDAC during the consolidation cycles, which will be the recommended dose for the Phase 2 (RP2D). Dose limiting toxicities (DLTs) were assessed during the first cycle of consolidation (C1) according to a 3+3 design. A maximum of 3 consolidation cycles was planned depending on the AML risk group. Hematological DLT was defined as no peripheral blood count recovery within 56 days from day 1 of the cycle. Non-hematological DLTs were defined as Grade ≥4 toxicities or Grade ≤3 toxicities which have not recovery by day 56 and deemed related to VEN per investigator opinion. VEN was started at dose level (DL) 1: 100 mg/d from day 1 to 8. In the absence of DLTs at DL1, 3 others DL were planned: 200 mg/d from day 1 to 8 (DL2); 400 mg/d from day 1 to 8 (DL3), and 400 mg/d from day 1 to 14 (DL4). IDAC was administrated at 1.5 gr/m² twice daily on day 1/3/5 for DL1, DL2 and DL3 pts, then on day 1/2/3 for DL4 pts after a protocol amendment. Main inclusion criteria were: pts in first CR following 1 or 2 courses of induction chemotherapy fit for further ICT; favorable and intermediate risk AML as defined by the protocol; ECOG PS ≤2; written informed consent. Measurable residual disease (MRD) was assessed by multiparametric flow cytometry (MFC) in all pts as well as NPM1-qPCR in NPM1-mutated pts. Results: Between 06/2021 and 04/2022, 15 pts from 9 centers were screened and enrolled. Pt characteristics were as follows: median age, 42 years (IQR, 30-49); 2 males/7 females; ECOG-PS, 0 in 10 pts and 1 in 5 pts; favorable/intermediate/adverse ELN-2017 risk, 9/2/4. Neutropenia and thrombocytopenia durations are shown in Table 1. Only 1 hematological DLT was observed at DL3 (platelet count of 96 giga/L at day 56 in a patient who was infected by Covid-19). Overall, there were very few non hematological AEs ( Table 2, no grade 4) and only 4 SAEs (1 related to IDAC/VEN during C1, 3 non-related). No non-hematological DLT was observed. No patient died during the DLT observation period, 1 experienced a septic shock (C2, DL2). One pt received only C1 (due to DLT), 7 received 2 cycles, and 7 received 3 cycles. Median time between initiation of subsequent consolidation cycles was 37.5 days (IQR, 35-41) for C1/C2 and 40 days (IQR, 35-43) for C2/C3. One pt had to stop VEN during C3. Six pts received an allogeneic HSCT (5 in CR1, 1 after salvage). With a median follow-up of 13.5 months, 3 pts relapsed and 2 died. MRD results will be presented. Conclusion: VEN/IDAC combination appears to be feasible and safe as consolidation therapy, with expected thrombocytopenia and neutropenia durations. These durations appeared even shorter at DL4, when IDAC was given on 3 consecutive days. VEN at 400 mg/d from day 1 to 14 combined with IDAC on day 1/2/3 was thus retained as RP2D for the randomized Phase 2 with RFS as primary endpoint. This phase 2 has already recruited 29 of the 200 pts planned.

Oral Decitabine/Cedazuridine with Venetoclax in High-Risk Myelodysplastic Syndrome or Chronic Myelomonocytic Leukemia: Analysis By Different Response Criteria

Introduction: Patients with higher-risk myelodysplastic syndromes (HR-MDS) have poor survival. The standard of care for HR-MDS are hypomethylating agents (HMA). The addition of venetoclax (Ven) to HMA has been shown to improve outcomes in acute myeloid leukemia (AML) and potentially in HR-MDS. The combination of oral decitabine/cedazurridine (DEC-C) with Ven has been shown to induce high response rates in patients with HR-MDS. Herein we analyze the responses of patients treated with DEC-C with Ven according to different response criteria. Additionally, we analyze the cytogenetic responses and mutation dynamics. Methods: We analyzed patients included in a phase I/II single center clinical trial (NCT04655755). diagnosed with treatment-naïve MDS (IPSS intermediate-2 or high) or CMML with excess blasts. Responses were analyzed by the International Working Group (IWG) criteria for MDS of 2006 and 2023, as well as the European LeukemiaNet (ELN) criteria for AML (2022). Cytogenetic responses and mutations were analyzed by conventional cytogenetics/FISH and NGS, respectively. Results: Between January 2021 and January 2023, 39 patients were enrolled. The median age of the entire cohort was 71 years old (range, 27-94), with 26 (70%) male patients. The WHO 2016 diagnosis was MDS with excess-blasts 1 (n=6, 16%), MDS with excess-blasts 2 (n=24, 65%), CMML-2 (n=6, 16%) and atypical chronic myeloid leukemia (n=1, 3%). The cytogenetic risk according to IPSS was good (n=11, 30%), intermediate (n=12, 32%) and adverse (n=14, 38%). The most common mutations found were ASXL1 (n=18, 49%), RUNX1 (n=14, 38%), SRSF2 (n=11, 30%), TET2 (n=8, 22) and TP53 (n=7, 19%). According to the IWG-2006 classification, the overall response rate was 95%, with 17 (43%) patients achieving complete remission (CR) and 20 (52%) patients achieving marrow CR (mCR). When using the IWG-2023 criteria, the overall response rate was 82%, with 23 (59%) patients achieving CR and 9 (23%) achieving CR with limited count recovery/CR with partial hematologic recovery. Of note, 5 patients achieved mCR according to the IWG-2006 but did not achieved CR by the IWG-2023 due to the peripheral blood count. Moreover, we did not find differences in overall survival (OS) between CR and mCR (OS of 60% for both groups, p=0.5). When using the ELN 2022 criteria for acute myeloid leukemia, the ORR was 80% with 2 patients not responding and 2 patients in a morphologic leukemia-free status (MLFS) (Figure 1). Both IWG-2006 and 2023 define cytogenetic response as complete disappearance of chromosomal abnormalities present at diagnosis. 14 patients out of 29 (48%) with cytogenetic abnormalities achieved cytogenetic response after a median of 2 courses of treatment (1-9). The IPSS cytogenetic risk of patients responding was good in 1 (7%) patient, intermediate in 8 (57%) patients and poor in 5 (36%) patients, including 3 patients with complex karyotype. Among patients not achieving cytogenetic response, 5 (33%) and 10 (67%) patients had an intermediate and adverse IPSS cytogenetic risk, respectively. Although molecular responses are not defined in the IWG-2023, we studied the molecular dynamics between diagnosis and best response. 23 patients of the study had molecular data in paired samples at diagnosis and at CR while on treatment. When analyzing the dynamics of each individual mutation, STAG2 (11/11, 100%), NRAS (3/3, 100%), BCOR (4/5, 80%) and IDH1 (2/3, 67%) showed the higher rate of clearance from diagnosis to CR. On the contrary, ZRSR2 (3/4, 75%), U2AF1 (3/4, 75%), TP53 (3/4, 75%), SRSF2 (5/7, 71%) and ASXL1 (10/14, 71%) showed the higher rate of persistence from diagnosis to CR (Figure 2). Among all patients in the study, 19 (49%) proceeded to hematopoietic stem cell transplantation (HSCT). Eleven patients had molecular data after HSCT, all achieving complete mutation clearance after HSCT. Conclusion: DEC-C with Ven achieves a high rate of responses, although with the IWG-2023 criteria responses are lower due to the disappearance of mCR and more strict criteria in terms of peripheral blood count recovery. Almost half of patients with cytogenetic abnormalities can acquire cytogenetic responses, including poor risk cytogenetics. Subclonal mutations (like STAG2 or NRAS) can be cleared with this combination while founding mutations (like ASXL1 or TP53) tend to persist, although HSCT has a potential to eliminate them.

Q-HAM: a multicenter upfront randomized phase II trial of quizartinib and high-dose Ara-C plus mitoxantrone in relapsed/refractory AML with FLT3-ITD

BackgroundAbout 50% of older patients with acute myeloid leukemia (AML) fail to attain complete remission (CR) following cytarabine plus anthracycline-based induction therapy. Salvage chemotherapy regimens are based on high-dose cytarabine (HiDAC), which is frequently combined with mitoxantrone (HAM regimen). However, CR rates remain low, with less than one-third of the patients achieving a CR. FLT3-ITD has consistently been identified as an unfavorable molecular marker in both relapsed and refractory (r/r)-AML. One-quarter of patients who received midostaurin are refractory to induction therapy and relapse rate at 2 years exceeds 40%. The oral second-generation bis-aryl urea tyrosine kinase inhibitor quizartinib is a very selective FLT3 inhibitor, has a high capacity for sustained FLT3 inhibition, and has an acceptable toxicity profile.MethodsIn this multicenter, upfront randomized phase II trial, all patients receive quizartinib combined with HAM (cytarabine 3g/m2 bidaily day one to day three, mitoxantrone 10mg/m2 days two and three) during salvage therapy. Efficacy is assessed by comparison to historical controls based on the matched threshold crossing approach with achievement of CR, complete remission with incomplete hematologic recovery (CRi), or complete remission with partial recovery of peripheral blood counts (CRh) as primary endpoint. During consolidation therapy (chemotherapy and allogeneic hematopoietic cell transplantation), patients receive either prophylactic quizartinib therapy or measurable residual disease (MRD)-triggered preemptive continuation therapy with quizartinib according to up-front randomization.The matched threshold crossing approach is a novel study-design to enhance the classic single-arm trial design by including matched historical controls from previous clinical studies. It overcomes common disadvantages of single-armed and small randomized studies, since the expected outcome of the observed study population can be adjusted based on the matched controls with a comparable distribution of known prognostic and predictive factors. Furthermore, balanced treatment groups lead to stable statistical models. However, one of the limitations of our study is the inability to adjust for unobserved or unknown confounders.Addressing the primary endpoint, CR/CRi/CRh after salvage therapy, the maximal sample size of 80 patients is assessed generating a desirable power of the used adaptive design, assuming a logistic regression is performed at a one-sided significance level α=0.05, the aspired power is 0.8, and the number of matching partners per intervention patient is at least 1. After enrolling 20 patients, the trial sample size will be recalculated in an interim analysis based on a conditional power argument.ConclusionCurrently, there is no commonly accepted standard for salvage chemotherapy treatment. The objective of the salvage therapy is to reduce leukemic burden, achieve the best possible remission, and perform a hemopoietic stem-cell transplantation. Thus, in patients with FLT3-ITD mutation, the comparison of quizartinib with intensive salvage therapy versus chemotherapy alone appears as a logical consequence in terms of efficacy and safety.Ethics and disseminationEthical approval and approvals from the local and federal competent authorities were granted. Trial results will be reported via peer-reviewed journals and presented at conferences and scientific meetings.Trial registrationClinicalTrials.gov NCT03989713; EudraCT Number: 2018-002675-17.

Novel Evidence That NADPH Oxidase 2 (Nox-2) Enhances Trafficking of Hematopoietic Stem Progenitor Cells (HSPCs) By Involving ROS Mediated Activation of Nlrp3 Inflammasome

Background. NADPH oxidase 2 (Nox-2) is a superoxide-generating enzyme that forms reactive oxygen species (ROS) to regulate the redox state involved in the self-renewal of hematopoietic stem/progenitor cells (HSPCs). Moreover, ROS are released from Nox-2 expressed by cell surface and mitochondria membranes and are potent activators of intracellular pattern recognition receptor Nlrp3 inflammasome, which regulates several aspects of HSPCs biology, including their trafficking, proliferation, and metabolism. Our previous research demonstrated a novel role of Nlrp3 inflammasome in the migration, mobilization, homing, and engraftment of HSPCs (Leukemia 2022;36(1):23-32;Stem Cell Rev Rep. 2020 16(5):954-967). The role of ROS was extensively studied in the proliferation of hematopoietic cells; however, its role in the migration of HSPCs is not very well understood. Aim of the study.Based on the role of Nox-2 in activating Nlrp3 inflammasome, we hypothesized that activation of Nox-2-ROS-Nlrp3 inflammasome axis in both HSPCs and BM microenvironment orchestrates trafficking of HSPCs.Materials and Methods. First, we studied in Transwells chemotaxis of Nox-2 deficient cells to bone marrow (BM) chemoattractants, including SDF-1, S1P, and eATP. Next, to shed more light on the role of Nox2 in the trafficking of HSPCs, we performed in Nox-2-KO animals G-CSF- and AMD3100-induced pharmacological mobilization. We also studied homing and engraftment of Nox-2-KO cells in BM of wild-type (WT) animals and homing and engraftment o WT BM cells in Nox-2-KO recipients. Nox-2-KO mice were also sublethal irradiated, and we followed the recovery of peripheral blood counts in these animals. Activation of Nlrp3 inflammasome in Nox-2-KO murine Sca-1+c-kit+lineage- HSPCs was evaluated by Glow assay. To ''bypass'' Nox-2-ROS activation in control experiments, nigericin has been employed as a direct activator of Nlrp3 inflammasome. Since membrane lipid rafts (MLRs) play a crucial role optimal migration of HSPCs, we evaluated the formation of membrane lipid rafts by employing confocal analysis in Nox-2-KO cells stimulated with SDF-1. We also studied the expression of enzymes (SREBP2, HMGCs, and HMGCR) involved in providing lipid components for MLRs assemble in activated Nox-2-KO cells. Results. We noticed that Nox-2-KO animals have a profound defect in the trafficking of HSPCs as evidenced by impaired chemotaxis to BM chemoattractants, decrease in pharmacological mobilization, and defect in homing and engraftment after transplantation. Nox-2-KO mice have also defect in recovery from sublethal irradiation. At the molecular level, HSPCs from Nox-2-KO mice displayed a defect in activation of Nlrp3 inflammasome and in cholesterol and sphingolipids synthesizing enzymes, which provide lipid components required for optimal assemble of MLRs. These defects were partially ameliorated by using direct activator of Nlrp3 inflammasome that is nigericin. Conclusions. We provide for the first time evidence that Nox-2-ROS-Nlrp3 inflammasome axis operates in normal HSPCs and is crucial for regulating trafficking and post-irradiation recovery of these cells. These effects are mediated by providing components for MLRs required for optimal migration and signaling in HSPCs

An Updated Analysis on Safety and Efficacy of Avapritinib in Patients with Advanced Systemic Mastocytosis from the Explorer Clinical Study: Long-Term Efficacy and Safety

Introduction: Systemic mastocytosis (SM) is a rare myeloid neoplasm driven by KIT D816V mutations in ~95% of patients. Advanced SM (AdvSM) includes three subtypes: aggressive SM (ASM), mast cell leukemia (MCL), and SM with an associated hematologic neoplasm (SM-AHN; most common), all typically with poor prognoses. Avapritinib, an oral, highly selective inhibitor of KIT D816V, is approved in the USA for treatment of adult patients with AdvSM, and in Europe after ≥1 prior systemic therapy. Avapritinib is not recommended for the treatment of patients with AdvSM with platelet counts of <50×109/L. The aim of the multi-center, international, phase 1 EXPLORER (NCT02561988) clinical study was to determine maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), safety, and tolerability. Earlier data from this and the phase 2 PATHFINDER (NCT03580655) studies showed rapid, deep, and durable responses to avapritinib treatment regardless of prior therapy, AdvSM subtype, or presence of high-risk mutations. Here we present long-term analyses from EXPLORER showing sustained efficacy, deepening responses, mature progression-free survival (PFS), updated overall survival (OS), and consistent safety profile. Methods: Analyses included patients aged ≥18 years with centrally confirmed AdvSM who initiated 30-400 mg once daily avapritinib. Primary endpoints were MTD and RP2D, safety, and tolerability. Secondary endpoints included overall response rate (ORR) per modified International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (mIWG-MRT-ECNM) response criteria defined as complete remission with full (CR) or partial (CRh) recovery of peripheral blood counts, partial remission, or clinical improvement, as well as changes in objective disease burden measures (bone marrow mast cell [BM MC] burden, serum tryptase, KIT D816V variant allele fraction [VAF], and spleen volume), PFS, and OS. Results: As of April 5, 2022, 69 patients with AdvSM were enrolled; 12% (n=8) had ASM, 19% (n=13) MCL, and 70% (n=48) SM-AHN. Median age (range) was 67 years (34-83), 59% were male, 30% had Eastern Cooperative Oncology Group performance status 2-3, and 59% had prior systemic therapy. Median duration of treatment (range) was 23 months (2-67); after 24 weeks most patients (69%) were receiving 100 mg or 200 mg daily. ORR (95% confidence interval [CI]) per mIWG-MRT-ECNM criteria for evaluable patients (N=57) was 77% (64-87) (Table) with ORR of 100% (40-100), 85% (55-98), and 72% (56-85), for ASM, MCL, and SM-AHN subtypes, respectively. There were 4 additional CRs (n=57) since the previous analysis of 53 evaluable patients at median follow-up of 23 months and ORR of 75%. Median duration of response (DOR) for all responders was not reached (NR). In patients with no prior therapy, median DOR (95% CI) was 38 months (22-not evaluable [NE]) and NR for patients with at least one prior therapy. Most patients had observed reductions in objective measures of disease burden including ≥50% reduction in BM MC burden (94%, n=61/69), serum tryptase (99%, n=68/69), KIT D816V VAF (75%, n=50/69), and ≥35% reduction in spleen volume (83%, n=55/69). 52 (80%) patients had total clearance of neoplastic BM MC aggregates. Median PFS (95% CI) in response-evaluable patients was 49 months (31-NE). With a median follow-up of 45 months, only 17 (25%) patients had disease progression, including 7 who progressed to acute myeloid leukemia. Median OS was NR in all AdvSM, ASM, and MCL, and was 46.9 months (95% CI 29.6-NE) in SM-AHN (Table, Figure). The most frequent treatment-related adverse events (TRAEs; any grade) were periorbital edema (64%), anemia (42%), thrombocytopenia (36%), nausea (33%), and peripheral edema (33%). Grade ≥3 TRAEs were observed in 74% of patients. There were no additional intracranial bleeding events since previous reports. Cognitive effects were experienced by 44% of patients, mostly grade 1 and 2. There was no negative impact on clinical efficacy despite 73% of patients having dose reductions or 83% having dose interruptions due to TRAEs. TRAEs led to discontinuations in 27% of patients. Conclusions: At almost 4 years of follow-up, survival benefit was ongoing with median OS not reached. Among all patients treated with avapritinib, rapid, durable responses were observed. Avapritinib was generally well tolerated with a safety profile consistent with previous reports. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Avapritinib As First-Line Therapy in Patients with Advanced Systemic Mastocytosis: Efficacy and Safety from the Pathfinder Clinical Study

Introduction: Systemic mastocytosis (SM) is a rare myeloid neoplasm driven by the KIT D816V mutation in ~95% of patients. Patients with advanced SM (AdvSM) have a poor prognosis and treatment options are limited. Avapritinib, an oral, potent, highly selective inhibitor of KIT D816V, is approved in the USA for treatment of adults with AdvSM, and in Europe after ≥1 prior systemic therapy. Avapritinib is not recommended for the treatment of patients with AdvSM with platelet counts <50×109/L. Data from the multi-center, international, phase 1 EXPLORER (NCT02561988) and phase 2 PATHFINDER (NCT03580655) clinical studies demonstrated that responses to avapritinib treatment were rapid, deep, and durable regardless of prior therapy, AdvSM subtype, or presence of high-risk mutations. Here we present analyses from patients with AdvSM treated with avapritinib as first-line therapy in PATHFINDER. Methods: Analyses included adult patients with centrally confirmed AdvSM without prior antineoplastic treatment for AdvSM (treatment-naïve) who initiated 200 mg once-daily avapritinib in the PATHFINDER study. The primary endpoint was overall response rate (ORR), centrally evaluated according to the modified International Working Group-Myeloproliferative Neoplasms Research and Treatment-European Competence Network on Mastocytosis (mIWG-MRT-ECNM) response criteria defined as complete remission with full (CR) or partial (CRh) recovery of peripheral blood counts, partial remission (PR), or clinical improvement (CI). Secondary endpoints included, but were not limited to, mean change from baseline measures of disease burden (bone marrow mast cell [BM MC] burden, serum tryptase, blood KIT D816V variant allele fraction [VAF], and spleen volume), duration of response (DOR), time to response (TTR), overall survival (OS) and safety. Results: As of April 20, 2021, 107 patients with centrally confirmed AdvSM were enrolled, of whom 38 were treatment-naïve; 18% (n=7/38) had ASM, 74% (n=28/38) SM-AHN, and 8% (n=3/38) MCL. Median age (range) was 68 years (39-88), 53% were male, 16% had Eastern Cooperative Oncology Group performance status 2-3, and 95% exhibited KIT D816V. In 25 of 38 (66%) mIWG-MRT-ECNM response-evaluable patients, the ORR (95% CI) was 84% (n=21/25; 64-96) with 32% (n=8/25) achieving CR or CRh, 48% (n=12/25) achieving PR, and 4% (n=1/25) CI (Table). The median TTR (range) was 2.0 months (0.3-12.2). Median DOR across all subtypes was not reached at the time of analysis; however, the DOR rate (95% CI) was 100% (100-100) at 12 months and 86% (60-100) at 18 months. For patients with ASM, the DOR rate was 100% (100-100) at 12 and 18 months. In patients with SM-AHN, the DOR rate was 100% (100-100) at 12 months and 83.3% (53.5-100) at 18 months. After a median follow-up of 9.7 months, median OS in all patients was not reached. The OS rate was 96% (95% CI: 87-100) at 12 months and 88% (95% CI: 71-100) at 24 months. The OS rate at 12 months was 100% for patients with ASM or MCL and 94% (84-100) for patients with SM-AHN. At 24 months, OS rate was 86% (67-100) for patients with SM-AHN. In almost all patients, reductions of ≥50% in measures of disease burden including reduction in BM MC burden (84%, n=32/38), serum tryptase (95%, n=36/38), KIT D816V VAF (89%, n=34/38), and ≥35% reduction in spleen volume (66%, n=25/38) were observed. Total clearance of neoplastic MC aggregates in BM was achieved in 63% of patients (n=24/38). The most frequent (≥25% of N=38) treatment-related adverse events (TRAEs) were (any grade, grade ≥3) periorbital edema (53%, 5%), thrombocytopenia (45%, 21%), peripheral edema (37%, 3%), and anemia (26%, 13%). In total, 7 (18%) patients experienced cognitive effects, all grade 1 or 2; no intracranial bleeding events and no treatment-related deaths were reported. 28 (74%) patients had dose reductions and 25 (66%) had dose interruptions due to TRAEs. Thrombocytopenia was the most common TRAE leading to dose reduction (21%, n=8/38) and dose interruption (26%, n=10/38). 4 (10%) patients discontinued treatment due to TRAEs; 1 discontinuation each was due to neutropenia, thrombocytopenia, cognitive effects, and worsening weight loss. Conclusions: Avapritinib demonstrated a high level of efficacy as the first-line therapy for patients with AdvSM across all disease subtypes with an ORR of 84% and an OS rate of 88% at 2 years. Avapritinib treatment with a 200 mg once-daily starting dose was generally well-tolerated. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A Phase II Study of the Combination of Decitabine, Venetoclax and Ponatinib in Patients with Chronic Myeloid Leukemia (CML) in Myeloid Blast Phase (MBP) or Philadelphia-Chromosome Positive (Ph+) Acute Myeloid Leukemia (AML)

Background: Advanced phases of CML and Ph+ AML are therapeutic challenges. Preclinical and early clinical data have shown that combining venetoclax (VEN) with a tyrosine kinase inhibitor (TKI) works synergistically in Ph+ myeloid leukemias (Leonard et. al., Sci Transl Med 2016 and Maiti et. al., Acta Haematologica 2020). We hypothesized that combining a potent TKI (ponatinib) with a hypomethylating agent plus VEN backbone might lead to high rates of response that could facilitate potentially curative allogeneic stem cell transplantation (SCT). Methods: This is a single-arm phase II study (NCT04188405) that enrolled patients (pts) ≥ 18 years (yrs) of age with newly diagnosed or relapsed/refractory advanced phase CML [CML in accelerated phase (CML-AP) or CML-MBP] or Ph+ AML. Pts were required to have an ECOG PS ≤ 3 and adequate liver and renal function. Pts with clinically significant cardiovascular comorbidities, including recent or active myocardial infarction, heart failure, clinically significant arrhythmias, cerebrovascular accident, venous thromboembolism or uncontrolled hypertension were excluded. Pts were treated with a combination of decitabine (DAC) (20 mg/m2/day) x 5 days, VEN (400 mg equivalent dose/day) x 21 days, and ponatinib (45mg/day) x 21 days in cycle 1 and then continuously in cycle 2+ (Fig. 1A). Ponatinib was reduced to 30mg/day for pts in CR/CRi and to 15 mg/day for pts in CMR. For C1 only, pts who had not received ponatinib prior to trial initiation had a lead-in phase of ponatinib monotherapy for 7 days before the initiation of DAC and VEN. Cycles were repeated every 28 days, as permitted by peripheral blood count recovery, and pts could receive a maximum of 24 cycles. Intrathecal prophylaxis with 4 doses of cytarabine was recommended. The primary objective was to determine the overall response rate of the regimen. Results: From July 2020 to May 2022, 12 pts were treated, 1 pt with de novo Ph+ AML and 11 pts with advanced phase CML (2 pts with CML-AP and 9 pts with CML-MBP). The median age of the pts was 45 yrs (range, 28-71 yrs). Three pts (25%) had received no prior therapy (1 each with Ph+ AML, CML-AP and CML-MBP). Nine pts (75%) had prior TKI exposure (including prior ponatinib exposure in 4 pts) and 3 pts (25%) had received prior chemotherapy. Eleven pts (92%) had the p210 transcript of BCR::ABL1. Eight pts (67%) had additional cytogenetic abnormalities, including 5 pts with complex karyotype and 2 pts with a MECOM rearrangement. 4 of 11 tested pts (36%) had an ABL1 kinase domain mutation detected at enrollment (T315I, Q252H, L384M and E255K in 1 pt each). The median number of cycles received was 2 (range, 1-7). Nine pts (75%) responded, including 1 with CR, 3 with CRi and 5 with MLFS as best response. The CR/CRi rate was 33%. Best response was achieved after cycle 1 in 7 of 9 responders. Both pts with CML-AP responded, and 2 of 3 pts without prior TKI exposure responded. One of the responders achieved an MMR. After a median follow-up of 9.1 months, the median overall survival (OS) is 9.5 months, and the estimated 9-month OS is 64%. The median relapse-free survival 5.1 months. Among the 9 responders, 3 pts are in continuous response without SCT, 1 pt proceeded to SCT and is still alive, 3 pts did not undergo SCT and relapsed (2 of whom had a complex karyotype), 1 pt died in MLFS, and 1 pt was lost to follow-up (Fig. 1B). The one pt who proceeded to SCT achieved MLFS as best response pre-SCT and remains in MRD-negative CR 22 months post-SCT. The toxicity profile of the regimen was similar to historical expectations with DAC plus VEN. One pt developed grade 3 mucositis, which was considered related to study therapy. No grade 4-5 related non-hematological adverse events were observed. Related grade 1-2 non-hematological adverse events included rash in 2 pts, and transaminitis, creatinine elevation and mucositis in 1 pt each. Of the 8 pts who received > 1 cycle of study therapy, 4 pts had delay (>1 week) in initiation of a subsequent treatment cycle due to cytopenias; for 2 of these pts the duration of VEN was reduced. The 60-day mortality rate was 0%. Two pts died on the study, one from leukemia and one from infection while in MLFS. Conclusion: The triplet combination of DAC, VEN and ponatinib was well-tolerated in pts with advanced Ph+ myeloid leukemias. In this poor-risk population, a marrow remission rate of 75% was achieved, although durations of remission were modest in the absence of consolidative SCT. This study continues to accrue pts. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Durable Engraftment and Excellent Overall Survival After CD34-Selected Peripheral Blood Stem Cell Boost in Pediatric Patients With Poor Graft Function Following Allogeneic Stem Cell Transplantation

Poor graft function (PGF) is a life-threatening complication after allogeneic stem cell transplantation (alloSCT). Historically, outcomes of patients with PGF have been very poor, and there are no standardized approaches to treatment. Furthermore, few outcomes after CD34-selected stem cell boost (CD34+SCB) for PGF in pediatric alloSCT recipients have been reported. Here we report on a single center experience with CD34+SCB for PGF after alloSCT in patients treated on the Pediatric Transplant and Cellular Therapy Service at MSK Kids, Memorial Sloan Kettering Cancer Center. A retrospective analysis of patients transplanted for malignant and nonmalignant disorders who received a CD34+SCB between 2008 to 2020 for treatment of PGF defined as the need for granulocyte colony-stimulating factor (G-CSF) and/or packed red blood cell or platelet transfusion support with bone marrow donor chimerism ≥85%. Peripheral blood stem cells from the original donor were the source for CD34+SCB. Durable complete recovery (durable CR) was defined as recovery of peripheral blood counts without recurrent need for G-CSF or transfusion support. The main outcomes of interest were recovery of hematopoiesis and overall survival. Development of graft versus host disease (GVHD) was an additional outcome of interest. Fourteen patients with PGF received a boost. Six patients had no known infection, while 8 patients had PGF associated with an infection. The probability of CR at 60 days was 79% (95% confidence interval [CI], 57%-100%). The overall survival at both 2 and 5 years was 78% (95% CI, 56%-100%). One patient developed GVHD, which was fatal. No other CD34+SCB-related toxicities were observed. While including patients with PGF as recently defined by the American Society for Transplantation and Cellular Therapy, as well as PGF in patients with concomitant infections, we demonstrate that CD34+SCB is safe and can provide for durable trilineage hematopoietic recovery and long-term survival in pediatric patients after alloSCT.

Efficacy and safety of avapritinib in previously treated patients with advanced systemic mastocytosis

AbstractAdvanced systemic mastocytosis (AdvSM) is a rare myeloid neoplasm, driven by the KIT D816V mutation in >90% of patients. Avapritinib, a potent, highly selective D816V-mutant KIT inhibitor, is approved for treatment of adults with AdvSM by the US Food and Drug Administration, regardless of prior therapy, and the European Medicines Agency for patients with prior systemic therapy, based on EXPLORER (#NCT02561988; clinicaltrials.gov) and PATHFINDER (#NCT03580655; clinicaltrials.gov) clinical studies. We present latest pooled efficacy and safety analyses from patients who received ≥1 systemic therapy prior to avapritinib in EXPLORER/PATHFINDER. Overall response rate in response-evaluable patients (n = 31) was 71% (95% confidence interval: 52% to 86%; 22/31), including 19% (6/31) with complete remission (CR)/CR with partial recovery of peripheral blood counts (CRh). Median time to response was 2.3 months, median time to CR/CRh was 7.4 months, and median duration of response (DOR) was not reached. Reductions ≥50% in bone marrow mast cell infiltration (89%), KIT D816V variant allele fraction (66%), serum tryptase (89%), and reductions ≥35% in spleen size (70%) occurred in most patients. Median OS was not reached (median follow-up 17.7 months). Avapritinib was effective in all AdvSM subtypes, regardless of number/type of prior therapies or poor prognostic somatic mutations. Treatment-related adverse events (TRAEs) were observed in 94% of patients, most commonly grade 1/2; 57% had TRAEs of at least grade 3; 81% remained on treatment at 6 months. Avapritinib in adults with AdvSM who received prior systemic therapy was generally well tolerated, with high response rates regardless of prior systemic therapy.

The Orally Available Selective Axl Inhibitor BGB324 Induces Diversification of the Immune Repertoire and Specific Changes in Plasma Biomarker Profiles

Introduction: The RTK Axl represents a novel therapeutic target in AML promoting proliferation and therapy resistance. In addition, Axl suppresses immune responses by decreasing antigen presentation and inhibiting NK cells. BGB324 is a first-in-class, orally available, selective Axl kinase inhibitor which is being explored as a therapy for solid tumours and myeloid malignancies. Selective blockade of Axl by BGB324 in AML is currently being explored in the Phase 1/2 trial BGBC003 (NCT02488408). Until now, n=25 patients have been treated in a classical 3+3 dose escalation design and treatment was generally well-tolerated (n=22 with AML and n=3 with MDS). Steady-state levels of BGB324 were achieved between three and six days after initiation of treatment. One AML patient achieved a CRi of five months, a second achieved a PR and another achieved clearance of circulating blasts accompanied by peripheral blood count recovery > three months (ORR 10%). Four additional AML patients (25%) experienced disease stabilisation for more than four months. Two MDS patients experienced a PR.Here, we report the spectrum of plasma proteins modulated by BGB324 in patients with AML/MDS and their relationship to treatment outcome and compound exposure. Furthermore, we analysed the B- and T- cell repertoire in order to assess potential effects of BGB324 on the immune response in AML patients.Methods: We used the DiscoveryMap panel (Myriad RBM) to measure plasma protein biomarker levels in a selection of patients pre-dose and at C2D1 and performed a cross-comparison with samples from an ongoing NSCLC study with BGB324 (BGBC004, NCT02424617) to identify candidates specifically modulated in AML. The TCRß repertoire was quantified by Next Generation Sequencing of DNA isolated from peripheral blood MNCs using an Illumina MiSeq sequencer. TCRß gene containing the entire Vß, Dß and Jß segments were amplified with BIOMED2-TCRß-A and -B primer pools. The IGH repertoire was analysed using BIOMED2-FR1/-FR3 primer pools. Using genomic DNA as template, the amplicons were tagged with Illumina adapters and indices in two consecutive PCR reactions. Demultiplexing and FastQ formated data output was generated by the MiSeq reporter. Analysis of TCRß and IGH data was performed on a Microsoft Cloud using our in-house analysis pipeline Pippa, which relies on MiXCR analysis tools.Results: Treatment with BGB324 significantly modulated Gas6, soluble Axl (sAxl), Angpt2, CXCL1 (GROalpha), SCGB1A1 (uteroglobin, club cell 10kDa protein) and PLAU (uPAR) levels in patient plasma. Of these, Gas6 was modulated after treatment with BGB324 in AML but not in lung cancer patients while CXCL1 and SCGB1A1 were only influenced in lung cancer patients. sAxl levels correlated with BGB324 exposure indicating that the shed Axl receptor represents a novel biomarker of Axl kinase inhibition.Furthermore, we studied the effects of BGB324 on the T- and B- cell receptor repertoire in n=5 available matched PB samples. We could demonstrate diversification of the TCR repertoire in PB by higher abundance of small T-cell clones at C2D1 with BGB324 compared to pre-treatment levels in three out of five analysed patients.The analyses of the IGH repertoire in the PB indicates higher diversity at C2D1 in two out of five available patients.Thus, treatment with BGB324 can increase the diversity of the IGH and TCRb repertoire in the PB of AML patients.Conclusion: BGB324 is well tolerated in AML patients, exhibits anti-leukemic activity and induces exposure-related modulation of biomarker candidates. Furthermore, BGB324 can induce a diversification of the TCR repertoire in AML patients and might hold potential as an immune-activating drug. DisclosuresLoges:BerGenBio ASA: Research Funding. Ben-Batalla:BerGenBio ASA: Research Funding. Micklem:BerGenBio ASA: Employment, Equity Ownership, Patents & Royalties. Brown:BerGenBIo ASA: Employment. Lorens:BerGenBIo ASA: Employment, Equity Ownership, Patents & Royalties, Research Funding. Yule:BerGenBIo ASA: Employment. Fiedler:Amgen: Patents & Royalties; Amgen, ARIAD/Incyte: Membership on an entity's Board of Directors or advisory committees; Amgen, Pfizer: Research Funding; Amgen, Gilead, GSO, Teva, Jazz Pharmaceuticals: Other: Support for meeting attendance. Cortes:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Sun Pharma: Research Funding; Novartis Pharmaceuticals Corporation: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Teva: Research Funding.

Real-World Effectiveness and Safety of Blinatumomab in Adults with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukaemia in Europe: 3-Year Results in Philadelphia Chromosome-Negative Patients and a Subset of Patients with Late First Relapse

Real-World Effectiveness and Safety of Blinatumomab in Adults with Relapsed or Refractory B-Cell Precursor Acute Lymphoblastic Leukaemia in Europe: 3-Year Results in Philadelphia Chromosome-Negative Patients and a Subset of Patients with Late First Relapse

CYP3A inhibitors and impact of these agents on outcomes in patients with acute myeloid leukemia treated with venetoclax plus azacitidine on the VIALE-A study

CYP3A inhibitors and impact of these agents on outcomes in patients with acute myeloid leukemia treated with venetoclax plus azacitidine on the VIALE-A study

Comparison of Bone Marrow Versus Peripheral Blood in Haploidentical Transplantation Using Post-Transplant Cyclophosphamide- a Retrospective Analysis

Comparison of Bone Marrow Versus Peripheral Blood in Haploidentical Transplantation Using Post-Transplant Cyclophosphamide- a Retrospective Analysis

A Review of Clinical and Preclinical Studies on Therapeutic Strategies Using Interleukin-12 in Cancer Therapy and the Protective Role of Interleukin-12 in Hematological Recovery in Chemoradiotherapy.

Interleukin-12 (IL-12), a heterodimeric glycoprotein with α and β subunits covalently bonded with a disulfide bond, is a potent anticancer agent. Its action is accomplished through a linkage of the adaptive and innate immune responses. IL-12 can promote the recovery of the hematopoietic system after cancer chemoradiotherapy by stimulating the physiological processes of stem cells, including cell proliferation and differentiation, reconstitution of hematopoietic function, and peripheral blood count recovery. We review therapeutic strategies using IL-12 in clinical studies, including single-agent and combination strategies in hematological tumors and solid tumors, and studies on the protective effects of IL-12 in chemoradiotherapy. This review highlights promising therapeutic strategies based on the anticancer role of IL-12 and the potential protective effects of IL-12 for cancer patients receiving chemoradiotherapy.

Extensive iron overload in bone marrow: A cause of pancytopenia in a thalassemia major patient – A case report

Iron overload-associated organ damage in transfusion-dependent anemias is a well-known phenomenon. Here, we discuss a case of 28-year-old, poorly chelated thalassemia major patient, whose blood workup revealed pancytopenia and moderately raised serum ferritin levels. His bone marrow examination was performed which revealed massive iron overload. Aggressive iron chelation led to successful recovery of peripheral blood counts in his patient. This case focuses on the importance of early detection and timely management of reversible iron overload toxicities. Serum ferritin although is convenient marker to asses iron overload, but it should not be relied upon to assess the severity of iron overload. Hence, organ-specific diagnostic modalities must be used along with serum ferritin to assess the severity of iron overload to prevent long-term complications in patients with regular blood transfusions.

Efficacy and Safety of Blinatumomab in Asian Adults with Relapsed/Refractory B-Precursor ALL

Introduction: Blinatumomab is a bispecific T-cell engager (BiTE®) targeted immuno-oncology therapy with dual specificity for cluster of differentiation (CD) 19 and CD3 that redirects the patient's CD3-positive cytotoxic T cells to lyse CD19-positive malignant cells. Global studies have evaluated blinatumomab in patients with advanced Philadelphia chromosome-negative relapsed/refractory acute lymphoblastic leukemia (Ph- R/R ALL). In the global phase 3 TOWER study, blinatumomab monotherapy vs standard-of-care chemotherapy resulted in a significantly higher rate of complete remission (CR)/CR with partial hematologic recovery of peripheral blood counts (CRh)/CR with incomplete hematologic recovery of peripheral blood counts (44% vs 25%; P &lt; 0.001) and longer median overall survival (7.7 vs 4.0 months; P = 0.01) (Kantarjian H, et al. NEJM. 2017;376:836-47). There are limited data on the efficacy and safety of blinatumomab in Asian patients, whose immunologic genetic background may differ from other patient populations. Therefore, we conducted a patient-level pooled analysis of the efficacy and safety of blinatumomab in 45 Asian adult patients with Ph- R/R ALL-19 from the blinatumomab arm of TOWER (NCT02013167) and 26 from a phase 1b/2 study in Japanese adults (NCT02412306). Methods: Patients in both studies were ≥ 18 years old and had Ph- R/R ALL, &gt; 5% blasts, Eastern Cooperative Oncology Group performance status 0-2, and no central nervous system pathology. Patients received a maximum of 2 cycles of induction blinatumomab for 4 weeks by continuous intravenous infusion (cycle 1/week 1: 9 μg/day; cycle 1/weeks 2-4: 28 μg/day; subsequent cycles: 28 μg/day) followed by 2 weeks of no blinatumomab (each 6-week cycle). Responders (≤ 5% bone marrow blasts within 2 induction cycles) received blinatumomab 28 μg/day up to a maximum of 5 induction/consolidation cycles. In TOWER, patients who continued morphologic remission received up to 12 months of maintenance therapy. Patients could undergo stem cell transplantation at any time following the first treatment cycle. Results: Of the 45 Asian patients enrolled (26 female; median [range] age, 43 [18-75] years; prior hematopoietic stem cell transplantation, 20 [44.4%]; ≥ 1 prior salvage therapy, 30 [66.7%]), 44 received at least 1 cycle of blinatumomab 9-28 μg/day. Responses in the first 12 weeks of treatment (CR/CRh and minimal residual disease response) are shown in the Table. The Kaplan-Meier (KM) median overall survival time was 11.9 (95% CI: 9.9-17.1) months, and the KM median relapse-free survival time was 8.9 (95% CI: 3.8-10.7) months; median overall survival in the blinatumomab arm of TOWER was 7.7 months. Forty-one (93.2%) patients had grade ≥ 3 treatment-emergent adverse events (TEAEs), and 5 (11.4%) had fatal AEs. Grade ≥ 3 events TEAEs of interest included neurologic events (4.5%), cytokine release syndrome (2.3%), cytopenias (6.8%), and infections (20.5%). Conclusions: The safety and efficacy of blinatumomab in Asian patients were comparable with previous global studies with similar disease response rates and a favorable safety profile with no new safety signals. Disclosures Kobayashi: Astellas Amgen BioPharma: Research Funding, Speakers Bureau; Pfizer: Research Funding, Speakers Bureau; SymBio: Consultancy. Iida:Chugai Pharmaceutical Co., Ltd.: Research Funding. Minami:Astellas: Research Funding; Bayer: Honoraria, Other: Clinical trial, Research Funding; Taiho: Honoraria, Other: Clinical trial, Research Funding; Taisho-Toyama: Research Funding; Takeda: Honoraria, Research Funding; CSL Behring: Research Funding; Genomic Health: Honoraria; Daiichi Sankyo: Other: Clinical trial, Research Funding; Sumitomo Dainippon Pharma: Honoraria, Research Funding; Eizai: Honoraria, Research Funding; Janssen: Honoraria; Kowa: Honoraria; Kyowa-Kirin: Honoraria, Research Funding; Nihon Shinyaku: Research Funding; Eli Lilly: Honoraria, Research Funding; Merck Serono: Honoraria, Research Funding; MSD: Honoraria, Other: Clinical trial, Research Funding; Nippon Chemiphar: Honoraria, Research Funding; Ono Yakuhin: Honoraria, Other: Clinical trial, Research Funding; BMS: Honoraria, Other: Clinical trial, Research Funding; Celgene: Honoraria; AstraZeneca: Other: Clinical trial; Boehringer: Honoraria, Research Funding; Otsuka: Honoraria; Pfizer: Honoraria, Other: Clinical trial, Research Funding; Sanofi: Honoraria, Research Funding; Shire Japan: Honoraria; Abbvie: Honoraria; Nihon Medi-Physics: Honoraria; Asahi-Kaseo Pharma: Research Funding; Amgen Inc: Other: Clinical trial; Nihon Kayaku: Research Funding; Shionogi: Research Funding; Novartis: Honoraria, Other: Clinical trial; Chugai: Honoraria, Other: Clinical trial, Research Funding; Yakult: Research Funding; Teijin Pharma: Research Funding. Maeda:Mundipharma Co Ltd.: Honoraria; Kyowa Kirin Co. Ltd.: Honoraria; Astellas Pharma Inc.: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Yoon:Novartis: Consultancy, Honoraria; Yuhan Pharma: Research Funding; MSD: Consultancy; Kyowa Hako Kirin: Research Funding; Genentech, Inc.: Research Funding; Janssen: Consultancy; Amgen: Consultancy, Honoraria. Tran:Amgen: Employment, Equity Ownership. Morris:Amgen: Employment, Equity Ownership. Franklin:Amgen: Employment, Equity Ownership. Chong:Amgen Asia Holding Limited: Employment, Equity Ownership. Kiyoi:Astellas Pharma Inc.: Honoraria, Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Pfizer Japan Inc.: Honoraria; FUJIFILM Corporation: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Bristol-Myers Squibb: Research Funding; Takeda Pharmaceutical Co., Ltd.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Daiichi Sankyo Co., Ltd: Research Funding; Perseus Proteomics Inc.: Research Funding.

Treatment of Adults with Relapsed/Refractory Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia with Blinatumomab in a Real-World Setting: Results from the Neuf Study

Treatment of Adults with Relapsed/Refractory Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia with Blinatumomab in a Real-World Setting: Results from the Neuf Study

Treatment of Adults with Minimal Residual Disease (MRD) Positive Acute Lymphoblastic Leukemia with Blinatumomab in a Real-World Setting: Results from the Neuf Study

Treatment of Adults with Minimal Residual Disease (MRD) Positive Acute Lymphoblastic Leukemia with Blinatumomab in a Real-World Setting: Results from the Neuf Study