Hematologic Recovery Research Articles

Long-term remission and survival in patients with relapsed or refractory multiple myeloma after treatment with LCAR-B38M CAR T cells: 5-year follow-up of the LEGEND-2 trial

BackgroundThe autologous anti–B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T-cell therapy LCAR-B38M has been approved for the treatment of relapsed and refractory multiple myeloma in many countries across the world under the name ciltacabtagene autoleucel. LEGEND-2 was the first-in-human trial of LCAR-B38M and yielded deep and durable therapeutic responses. Here, we reported the outcomes in LEGEND-2 after a minimal 5-year follow-up.MethodsParticipants received an average dose of 0.5 × 106 cells/kg LCAR-B38M in split or single unfractionated infusions after cyclophosphamide-based lymphodepletion therapy. Investigator-assessed response, survival, safety and pharmacokinetics were evaluated.ResultsSeventy-four participants enrolled and had a median follow-up of 65.4 months. The 5-year progression-free survival (PFS) and overall survival (OS) rates were 21.0% and 49.1%, with progressive flattening of the survival curves over time. Patients with complete response (CR) had longer PFS and OS, with 5-year rates of 28.4% and 65.7%, respectively. Twelve patients (16.2%) remained relapse-free irrespective of baseline high-risk cytogenetic abnormality and all had normal humoral immunity reconstituted. An ongoing CR closely correlated with several prognostic baseline indices including favorable performance status, immunoglobulin G subtype, and absence of extramedullary disease, as well as a combination cyclophosphamide and fludarabine preconditioning strategy. Sixty-two (83.8%) suffered progressive disease (PD) and/or death; however, 61.1% of PD patients could well respond to subsequent therapies, among which, the proteasome inhibitor-based regimens benefited the most. Concerning the safety, hematologic and hepatic function recovery were not significantly different between non-PD and PD/Death groups. A low rate of second primary malignancy (5.4%) and no severe virus infection were observed. The patients who tested positive for COVID-19 merely presented self-limiting symptoms. In addition, a sustainable CAR T population of one case with persistent remission was delineated, which was enriched with indolently proliferative and lowly cytotoxic CD4/CD8 double-negative functional T lymphocytes.ConclusionsThese data, representing the longest follow-up of BCMA-redirected CAR T-cell therapy to date, demonstrate long-term remission and survival with LCAR-B38M for advanced myeloma.Trial registrationLEGEND-2 was registered under the trial numbers NCT03090659, ChiCTRONH-17012285.

Variable Clinical Courses of Varicella Zoster Virus Infection-related or Vaccination-related Bone Marrow Failure.

We report 5 children with bone marrow failure (BMF) after primary varicella zoster virus (VZV) infection or VZV vaccination, highlighting the highly variable course. Two patients were treated with intravenous immunoglobulins; one had a slow hematologic recovery, and the other was rescued by allogeneic hematopoietic stem cell transplantation (HSCT). Of the 2 patients treated with immunosuppressive therapy with antithymocyte globulin and cyclosporine, one had a complete response, and the other was transplanted for nonresponse. One patient underwent a primary allograft. All patients are alive. This study demonstrated that VZV-associated BMF is a life-threatening disorder that often requires HSCT.

Abstract CT127: A macrophages-based immunotherapy of solid tumors microenvironment: Preliminary results of the TEM-GBM_01 study

Abstract Glioblastoma multiforme (GBM) is an incurable tumor affecting the central nervous system. The reported median survival in the unfavorable patients′ subgroup with unmethylated MGMT promoter is 12.7 months with less than the 15% of patient surviving up to 2–years. Despite immunotherapies being able to slow or eradicate numerous tumors, none so far have extended survival in GBM. Using genetically modified autologous CD34+ HSPCs, we developed an advance medicinal product, (Temferon) designed to deliver interferon–α2 within the TME by Tie–2 expressing macrophages (TEMs). Temferon is currently in the clinic in a Phase 1/2a dose-escalation non-randomized open label study in newly diagnosed GBM with unmethylated MGMT. The study aims to evaluate the short– (up to 90 days) and long– (up to 2 years) term tolerability and safety of 5 escalating doses in up to 27 GBM patients. Following a sub–myeloablative conditioning regimen (Thiotepa + BCNU or Thiotepa + Busulfan or Busulfan alone), up to 3 million Temferon cells/kg are administered with a fixed dose of non–manipulated CD34+ supporter cells As of 27th July 2023, 21 GBM patients in 7 cohorts received incremental Temferon doses and 5 patients were still alive with a 17 months median OS and a 8.3 months median PFS (95% CI) post surgery. To date, no DLTs have been identified. In all patients, rapid engraftment and fast hematological recovery have been observed within 2 weeks from the transplantation. Grade 4 or 5 serious adverse events (n=7 patients), were mostly attributed to the conditioning chemotherapy, but steroid usage or disease progression were also listed. 1 SUSAR (persistent GGT elevation) occurred. The higher transduced cells proportion in the BM was observed 30 days after Temferon with a chimerism for the highest dose tested up to 40%, still detectable in the long–term. Very low IFNα concentrations were detected in the plasma, indicating a tight vector expression regulation. 7 patients underwent second surgery and genetically engineered cells were detected (in 85%) within the bulk tumor lesion (>3% in 3 patients). IFN–responsive genes (IGS) were up–regulated, suggesting a local IFNα release by TEMs. In 1 patient, a stable lesion, compared to a synchronous, progressing lesion, had a higher proportion of T cells & TEMs, an increased IGS e and myeloid re–programming. TCR blood and tumor sample sequencing showed a post–treatment increase of peripherally expanded clones frequency in the tumor samples, as evidence of a crosstalk between peripheral and tumor T cell repertoires . These data corroborate the initial evidence on safety and tolerability of Temferon and suggest that Temferon has potential to counteract disease progression in patients affected by unmethylated MGMT GBM. Clinical Trial Registry (if applicable): NCT03866109 Citation Format: Francesca Farina, Bernhard Gentner, Gaetano Finocchiaro, Marica Eoli, Alessia Capotondo, Elena Anghileri, Matteo Barcella, Valentina Brambilla, Matteo Carrabba, Valeria Cuccarini, Quintino Giorgio D'alessandris, Francesco DiMeco, Valeria Ferla, Paolo Ferroli, Filippo Gagliardi, Federico Legnani, Stefania Mazzoleni, Alessandro Olivi, Roberto Pallini, Marco Saini, Luigi Naldini, Carlo Russo, Fabio Ciceri. A macrophages-based immunotherapy of solid tumors microenvironment: Preliminary results of the TEM-GBM_01 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT127.

Abstract CT115: A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in a hematologic malignancies cohort

Abstract Background: Mutations in genes encoding RNA splicing factors such as SF3B1, SRSF2, U2AF1, and ZRSR2, are common genetic aberrations in many forms of myeloid neoplasms. CTX-712 is a first-in-class, orally available, highly potent, and selective small molecule inhibitor of CDC2-like kinase (CLK), a key regulator of RNA splicing. Preclinical data show that CTX-712 demonstrated anti-proliferative activity in in-vitro and in-vivo models derived from hematologic malignancies. A phase I study of CTX-712 was conducted to evaluate the safety and the preliminary efficacy of CTX-712 in patients with relapsed or refractory acute myeloid leukemia (AML) and higher-risk myelodysplastic syndrome (MDS). Methods: The objectives of this cohort were to evaluate the dose-limiting toxicity (DLT), safety, pharmacokinetic (PK)/pharmacodynamic (PD) profiles, and preliminary efficacy of CTX-712 in patients with hematologic malignancies. A 3+3 design was used in two dose levels (70 mg and 105 mg twice a week (TW)) based on the safety data from the previous dose escalation cohort in patients with solid tumors. Results: As of data cutoff on November 20, 2023, a total of 14 patients (12 AML and 2 MDS) were enrolled in 70 mg TW (n=8) and 105 mg TW dose levels (n=6). DLT of Grade 4 pneumonia was observed in 1 of 3 DLT-evaluable patients in the 105 mg TW group. In the 70 mg TW group, no DLT was observed in 6 DLT-evaluable patients. Among the safety analysis population (n=14), median treatment duration was 76 days (Range 15-974 days). At data cutoff, treatment was ongoing in 1 patient and discontinued in 13 patients. The common any-grade adverse events (AEs) (≥30%) were diarrhea (57.1%) and nausea (42.9%). The most common Grade 3 or higher AE were white blood cell count decreased and tumor lysis syndrome (14.3%). In AML patients (n=12), complete remission (CR) was observed in 3 patients (25.0%), and CR with incomplete hematologic recovery (CRi) was observed in 1 patient (8.3%). The median time to remission was 67 days (Range 29-113 days), and the median duration of response was 281 days (Range 56-924 days). In MDS patients (n=2), CR was observed in 1 patient (50.0%). PK/PD profiles of the hematologic malignancies dose escalation cohort were comparable with those of the solid tumor cohort at the same dosage. Conclusions: CTX-712 demonstrated a manageable and tolerable safety profile and showed anti-tumor efficacy in patients with hematologic malignancies. Currently, a Phase I/II Study of CTX-712 in relapsed/refractory AML and higher risk MDS is ongoing using a new tablet formulation in the United States. Clinical trial information: jRCT2080224127 Citation Format: Hisayuki Yokoyama, Noriko Fukuhara, Koji Ando, Hiroatsu Iida, Takahiro Yamauchi, Suguru Fukuhara, Koji Izutsu, Yasushi Tanoue, Maki Yamamoto, Hirokazu Tozaki, Eiji Takahara, Shingo Shoji, Akio Mizutani, Daisuke Morishita, Robert W. Oda, Hiroshi Miyake, Noboru Yamamoto. A first-in-human phase I study of CTX-712 in patients with advanced, relapsed or refractory malignant tumors (CTX-712-CL-01 study): Efficacy and safety in a hematologic malignancies cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT115.

The Efficacy and Safety of Venetoclax Combined with Azacitidine in the Treatment of Adult Patients with Acute Myeloid Leukemia Who Are Unfit for Intensive Chemotherapy

To observe the clinical efficacy and safety of venetoclax (VEN) combined with azacitidine (AZA) in the treatment of adult acute myeloid leukemia (AML) patients who are unfit for intensive chemotherapy. The clinical data of 21 adult patients with unfit AML who were treated with VEN combined with AZA in the Second Hospital of Shanxi Medical University from January 2021 to May 2022 were collected, and the efficacy and safety were analyzed retrospectively. After one course of treatment with VEN and AZA, 16 out of 21 unfit AML patients reached complete remission (CR)/CR with incomplete hematologic recovery (CRi), 2 patients reached partial remission (PR), the overall response rate (ORR) was 85.7%. Among the 16 patients with CR/CRi, 13 achieved minimal residual disease (MRD) negativity. Among the 11 patients with adverse prognosis, 8 achieved CR/CRi. By the deadline of follow-up, the median overall suivival (OS) of the entire cohort was not reached, with 1-year OS rate of 61.7%. The main adverse events of VEN combined with AZA were myelosuppression, gastrointestinal reactions and infections. There were 13 cases of leukopenia, 7 cases of neutropenia, 7 cases of anemia, 4 cases of thrombocytopenia, and these hematologic adverse events were all grade 3-4. There were 11 cases with gastrointestinal reactions and 7 cases with infections. The above adverse events were controllable and tolerable. No tumor lysis syndrome or infection related death occurred. VEN combined with AZA can quickly achieve deep remission in adult patients with unfit AML, and it shows a good safety profile.

Olutasidenib in post-venetoclax patients with mutant isocitrate dehydrogenase 1 (mIDH1) acute myeloid leukemia (AML)

Olutasidenib, a potent, selective, oral, mutant isocitrate dehydrogenase 1 (mIDH1) inhibitor, is FDA-approved for relapsed/refractory (R/R) acute myeloid leukemia (AML). Here we report efficacy and safety of olutasidenib in 18 patients with mIDH1 AML who were relapsed (10), refractory (6) or had complete remission with incomplete hematologic recovery (CRi; 2) to a venetoclax combination. Of the 16 patients who were R/R, 4 (25%) achieved complete remission (CR), one (6.3%) achieved CR with partial hematologic recovery (CRh), and 7 (43.8%) achieved a composite complete remission (CRc). Median time to CRc was 1.9 months (range 1–2.8). As of data cutoff (18 June 2021), median duration of CRc was not reached (range, 1.2-NR, ongoing at 30.4+ months). Both patients with CRi at study entry achieved a CR. Safety was consistent with the overall profile of olutasidenib. Olutasidenib offers a valuable treatment option for patients with mIDH1 AML previously treated with venetoclax.

Low‑dose venetoclax combined with azacitidine in older and frail patients with newly diagnosed acute myeloid leukaemia.

In the present study, the aim was to evaluate the clinical efficacy and safety of low-dose venetoclax combined with azacitidine for the treatment of older and frail patients with newly diagnosed acute myeloid leukaemia (AML). Data of 26 older patients with newly diagnosed AML admitted to Yuyao People's Hospital (Yuyao, China) between January 2021 and May 2023 were retrospectively analysed. The treatment regimens were as follows: Subcutaneous injection of 100 mg azacitidine on days 1-5 and 100 mg oral venetoclax on days 3-16 or 200 mg oral venetoclax on days 3-30. The median age of the 26 patients was 73 years. After the first course of treatment, the complete remission (CR) and CR with incomplete haematological recovery rate was 84.6%, and the objective response rate was 96.2%. The most common adverse events noted during treatment were haematological adverse events including grade 3/4 granulocytosis (57.7%), febrile neutropenia (30.8%), pulmonary infection (32.0%), thrombocytopenia (42.3%) and anaemia (42.3%). A total of 13 (50.0%) patients did not require platelet (PLT) infusion during treatment. The main non-haematological adverse reactions included gastrointestinal reactions such as nausea, vomiting and diarrhoea. Patients were followed up until December 2023, with a median follow-up time of 9.5 months (range, 1.9-26.0 months). Of the 26 patients, nine (34.6%) patients experienced relapse, with a mean recurrence time of 5.9 months. In conclusion, preliminary results indicated that low-dose venetoclax combined with azacitidine is effective and safe for the treatment of older and frail patients with newly diagnosed AML, providing a new treatment option for these patients.

A phase 1/2 study of NS-87/CPX-351 (cytarabine and daunorubicin liposome) in Japanese patients with high-risk acute myeloid leukemia

ObjectivesNS-87/CPX-351 is a dual-drug liposomal encapsulation of cytarabine and daunorubicin. NS-87/CPX-351 exerts antileukemic action by maintaining a synergistic molar ratio of cytarabine to daunorubicin of 5:1 within the liposome while in circulation. Patients with high-risk acute myeloid leukemia (AML), which includes therapy-related AML and AML with myelodysplasia-related changes (AML-MRC), have poorer outcomes than those with other AML.MethodologyThis open-label phase 1/2 (P1/2) study was conducted in 47 Japanese patients aged 60–75 years with newly diagnosed high-risk AML to evaluate the pharmacokinetics, safety, and efficacy of NS-87/CPX-351.ResultsIn the 6 patients enrolled in the P1 portion, no dose-limiting toxicities (DLTs) were reported, and 100 units/m2 during the induction cycle was found to be acceptable. Cytarabine and daunorubicin had a long half-life in the terminal phase (32.8 and 28.7 h, respectively). In the 35 patients enrolled in the P2 portion, composite complete remission (CRc; defined as complete remission [CR] or CR with incomplete hematologic recovery [CRi]) was achieved in 60.0% (90% CI: 44.7–74.0) of the patients. Adverse events due to NS-87/CPX-351 were well tolerated.OutcomesNS-87/CPX-351 can be considered as a frontline treatment option for Japanese patients with high-risk AML.

Efficacy and safety of mitoxantrone, etoposide, and cytarabine for treatment of relapsed or refractory acute myeloid leukemia

Background/rationaleMost patients with acute myeloid leukemia (AML) develop relapsed or refractory (R/R) disease after receiving initial induction chemotherapy. Salvage chemotherapy followed by allogeneic hematopoietic stem cell transplantation (alloHSCT) is the only curative therapy for R/R AML. Mitoxantrone, etoposide, and cytarabine (MEC) is the current standard of care salvage regimen for R/R AML at Cleveland Clinic. The primary objective was to determine the overall remission rate (ORR: defined as patients achieving complete remission (CR) or complete remission with incomplete hematologic recovery (CRi)) in R/R AML patients who received MEC. MethodsAdult patients with R/R AML treated with MEC between July 1, 2014 and September 30, 2022 were included. ORR and its association with baseline characteristics were determined. Secondary outcomes included overall survival (OS), event-free survival (EFS), relapse-free survival (RFS), and safety. ResultsSixty patients were evaluated. The ORR was 51.7% (33.3% CR and 18.3% CRi). The median time from receipt of MEC to CR/CRi was 7.7 weeks. Patients with bone marrow blasts ≤20% and peripheral blood blasts ≤30% at MEC initiation were more than twice as likely to achieve CR/CRi compared to those with a higher blast burden. The median OS was 6.3 months. Twenty-four (40.0%) patients proceeded to alloHSCT. Twenty-one (35.0%) patients were transferred to the intensive care unit (ICU) during their admission. ConclusionsMEC is an effective salvage regimen for patients with R/R AML, especially among those with low disease burden at initiation. Febrile neutropenia, infections, and severe oral mucositis were common with MEC administration.

Impact of plerixafor use in the mobilization of blood grafts for autologous hematopoietic cell transplantation.

Plerixafor (PLER), a reversible antagonist of the CXC chemokine receptor type 4, has been in clinical use for mobilization of blood grafts for autologous hematopoietic cell transplantation (AHCT) for about 15 years. Initially PLER was investigated in placebo-controlled trials with the granulocyte colony-stimulating factor (G-CSF) filgrastim. It has also been used in combination with chemotherapy plus G-CSF in patients who had failed a previous mobilization attempt or appeared to mobilize poorly with current mobilization (preemptive use). This review summarizes what is known regarding addition of PLER to standard mobilization regimens. PLER increases mobilization of CD34+ cells, decreases the number of apheresis sessions needed to achieve collection targets and increases the proportion of patients who can proceed to AHCT. It appears also to increase the amount of various lymphocyte subsets in the grafts collected. In general, hematologic recovery after AHCT has been comparable to patients mobilized without PLER, although slower platelet recovery has been observed in some studies of patients who mobilize poorly. In phase III studies, long-term outcome has been comparable to patients mobilized without PLER. This also appears to be the case in patients receiving plerixafor for poor or suboptimal mobilization of CD34+ cells. In practice, PLER is safe and has not been shown to increase tumor cell mobilization.

Bidirectional ABO Mismatch Is Associated With Elevated Mortality in Hematopoietic Stem Cell Transplantation: Insights From a Single-Center Experience.

Background Hematopoietic stem cell transplantation (HSCT) is a promising therapy for various disorders and provides new opportunities for patients. ABO incompatibility in allogeneic HSCT (allo-HSCT) remains a topic of debate because of its potential impact on clinical outcomes. This study aimed to analyze the survival outcomes of patients who underwent ABO-incompatible HSCT and evaluate the occurrence of pure red cell aplasia. Methods This retrospective study included 20 patients who underwent ABO-incompatible HSCT. Data on patient characteristics, transplant details, and follow-ups were collected. Conditioning regimens and graft-versus-host disease (GVHD) prophylaxis strategies were employed. Results Neutrophil and platelet engraftment durations did not differ significantly between major and bidirectional mismatches. Pure red cell aplasia occurred in 4 patients (20%) with major mismatches, all of whom responded well to bortezomib treatment. Patients with a bidirectional mismatch exhibited a 3.57-fold increase (hazard ratio [HR]: 0.28; p<0.05) in the risk of mortality compared to those in the major mismatch group. Conclusion The results indicate that ABO mismatch, whether bidirectional or major, does not significantly affect neutrophil and platelet engraftment duration, suggesting that ABO incompatibility may not be a major factor influencing hematological recovery in allo-HSCT. Interestingly, patients with bidirectional mismatch exhibited a significantly higher mortality rate than those with major mismatch. This finding suggests that a bidirectional ABO mismatch may have an unfavorable prognosis in terms of overall survival in allo-HSCT patients.

Monitoring of Red Cell Donor Chimerism in Oncohematological Patients After Allogeneic Hematopoietic Stem Cell Transplantation

Background. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a definitive therapy for patients with different oncological and hematological diseases. The study of red cell chimerism is a crucial process for diagnosing transplant engraftment and functioning during the post-transplantation period.&#x0D; Aim. To assess the effect of immunohematological (АВО and HLA donor–recipient matching) and medical (conditioning regimens) parameters on the onset time of post-transplantation donor chimerism which is determined by RBC antigens.&#x0D; Materials &amp; Methods. The study enrolled 54 patients at the Kirov Research Institute of Hematology and Transfusiology in Russia (25 female and 29 male patients) aged 3–60 years (median 32 years). All of them received allo-HSCT in 2013–2021. Acute leukemias were identified in 39 patients, 8 patients were reported to have malignant lymphoproliferative diseases, 3 patients had myeloproliferative neoplasms, and 4 patients were diagnosed with aplastic anemia. RBC antigens of donors and recipients were analyzed by gel hemagglutination using Bio-Rad (USA) reagents and equipment.&#x0D; Results. The onset time of donor chimerism depends neither on the degree of HLA donor–recipient matching, nor on conditioning regimen. Donor chimerism in recipients with major ABO-incompatibility occurs significantly later than in patients with minor АВО-incompatibility and ABO-identity.&#x0D; Conclusion. Monitoring of post-transplantation donor chimerism is an important diagnostic and prognostic tool to assess donor hematopoietic cell engraftment, hematologic recovery, graft rejection, and relapse of the disease. After allo-HSCT, first donor red cells occur in pairs with major АВО-incompatibility later than in pairs with minor АВО-incompatibility or ABO antigen compatibility. Other immunohematological and medical parameters do not affect the development rate of donor chimerism determined by RBC antigens.

Long-Term Outcomes of Immunosuppressive Therapy for Aplastic Anemia: A Single-Center Experience

Background. Bone marrow transplantation-ineligible aplastic anemia (AA) is most effectively treated with combined immunosuppressive therapy (IST). It yields remissions in most patients. However, it has such disadvantages as frequent relapses, incomplete hematologic recovery, and clonal evolution risk. Besides, АА is not always treated according to standard regimens. For different reasons, some AA patients receive delayed therapy or IST mono-treatment predominantly with cyclosporine A (CsA).&#x0D; Aim. To assess long-term IST outcomes in AA patients followed-up at the Russian Research Institute of Hematology and Transfusiology for 5 years after therapy onset.&#x0D; Materials &amp; Methods. The study enrolled 30 AA patients who received IST for more than 5 years (continuous follow-up of 5.5–33 years) with monitoring of the main hemogram parameters and PNH clone size. Patients were aged 19–73 years (median 29 years). There were 8 women and 12 men. Based on international criteria, severe AA (SAA) was initially diagnosed in 18 patients, and non-severe АА (NAA) was diagnosed in 12 patients. Combined IST was administered to 22 patients (18 SAA patients and 4 NAA patients), the remaining 8 patients received ATG (n = 1) and CsA (n = 7).&#x0D; Results. A response to IST was achieved in 28 (93.3 %) out of 30 patients, 16 (53.3 %) of them showed complete remission. This paper documents the characteristics of hematologic recovery depending on the compliance with standard therapy regimens, as well as on the disease variant, development of late complications and clonal evolution, characteristics of pregnancy and childbirth in 4 female patients in remission. PNH clone increased in more than a half (10 out of 16) patients whose clone was initially &gt; 2.6 %. Long-term clonal evolution to myeloid neoplasia (13 years after IST onset) was registered in 2 (6.7 %) patients with complete AA remission. Aseptic (avascular) osteonecrosis as complication was reported in 6 (20 %) followed-up patients.&#x0D; Conclusion. The results of the study highlight the importance of and the need for early start and adherence to standard combined IST regimens aimed at optimum therapeutic effect in both SAA and NAA patients, as well as for long-term follow-up of patients after completing IST.

Sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production

To date only four recombinant growth factors, including Filgrastim (rhG-CSF), have been approved by FDA as radiomitigators to ameliorate hematopoietic acute radiation syndrome (H-ARS). These approved agents are not stable under room-temperature, needing to be stored at 2–8 °C, and would not be feasible in a mass casualty scenario where rapid and cost-effective intervention is crucial. Delta-tocotrienol (δ-T3H), the most potent G–CSF–inducing agent among vitamin E isoforms, exhibited efficiency and selectivity on G-CSF production in comparison with TLR and STING agonists in mice. Five-dose δ-T3H was utilized as the optimal therapeutic regimen due to long-term G-CSF production and the best peripheral blood (PB) recovery of irradiated mice. Comparable with rhG-CSF, sequential administration of δ-T3H post-irradiation improved hematologic recovery and accelerated the regeneration of hematopoietic stem cells (HSCs) and hematopoietic progenitor cells (HPCs) in the bone marrow (BM) and spleen of 6.5Gy irradiated mice; and consistently enhanced repopulation of BM-HSCs. In 4.0Gy irradiated nonhuman primates, δ-T3H exhibited comparable efficacy as rhG-CSF to promote PB recovery and colony-formation of BM-HPCs. Altogether, we demonstrated that sequential administration of delta-tocotrienol ameliorates radiation-induced myelosuppression in mice and non-human primates through inducing G-CSF production, indicated δ-T3H as a promising radiomitigator for the management of H-ARS, particularly in a mass casualty scenario.

Hypomethylating Agents and Venetoclax for Acute Myeloid Leukemia Relapsed After Hematopoietic Stem Cell Transplant

BackgroundHypomethylating agent + venetoclax is an effective frontline combination for acute myeloid leukemia, but its efficacy and safety in post-allogeneic hematopoietic cell transplant (alloHCT) relapse remain underexplored. Outcomes have been poor for this population, with no standard treatment. Patients and MethodsWe retrospectively analyzed 72 Ven-naïve patients who received hypomethylating agents + venetoclax at relapse following alloHCT and aimed to evaluate the rates of complete remission with or without hematologic recovery (CR/CRi) and minimal residual disease (MRD) negativity, CR/CRi duration, and overall survival. We leveraged our larger sample to analyze the impact of cytogenetic/molecular features on the odds of CR/CRi. ResultsCR/CRi was achieved among 32 of 67 (48%) patients, and MRD negativity was recorded among 10 of 12. NPM1 and IDH 1 or 2 mutations increased the odds of CR/CRi, as did increasing time from alloHCT to relapse. Fourteen patients subsequently received donor lymphocyte infusions or a second alloHCT. Responses lasted a median of 17.8 months (95% CI, 7.2 months to not reached), and responders had a greater median overall survival of 19.7 months (95% CI, 7.6-51.5 months) compared to 2.9 months among nonresponders (95% CI, 1.8-4.4 months; log-rank P < .01). Treatment was well tolerated, but prolonged cytopenias were common and most patients required reduction in the number of venetoclax days per cycle. ConclusionThese data support the efficacy of this combination in the alloHCT relapse setting where we report responses among nearly half of patients, with possibly greater benefit for NPM1 and IDH 1/2-mutated cases. These responses can be durable and profound as evidenced by conversion to MRD negativity.

Prognostic impact of peripheral blood WT1 mRNA dynamics in patients with acute myeloid leukemia treated with venetoclax combination therapy

BackgroundWilms' tumor gene 1 (WT1) mRNA quantification is a useful marker of measurable residual disease in acute myeloid leukemia (AML). However, whether monitoring the WT1 mRNA levels may predict the outcome of venetoclax (VEN) combination therapy in AML is not reported. This study aims to elucidate whether WT1 mRNA dynamics could predict long-term prognosis.Methods33 patients with untreated or relapsed/refractory AML evaluated for peripheral blood WT1 dynamics in VEN combination therapy were analyzed.ResultsThe median age was 73 years (range 39–87). Azacitidine was combined with VEN in 91% of patients. Overall, the median overall survival (OS) was 334 days (95% CI 210–482), and the complete remission (CR) plus CR with incomplete hematologic recovery rate was 59%. A 1-log reduction of WT1 mRNA values by the end of cycle 2 of treatment was associated with significantly better OS and event-free survival (EFS) (median OS 482 days vs. 237 days, p = 0.049; median EFS 270 days vs. 125 days, p = 0.02). The negativity of post-treatment WT1 mRNA value during the treatment was associated with significantly better OS and EFS (median OS 482 days vs. 256 days, p = 0.02; median EFS not reached vs. 150 days, p = 0.005). Multivariate analysis confirmed the significance of these two parameters as strong EFS predictors (HR 0.26, p = 0.024 and HR 0.15, p = 0.013, respectively). The increase in WT1 mRNA values was correlated with relapse.ConclusionThis study demonstrates that WT1 mRNA dynamics can be a useful marker for assessing long-term prognosis of VEN combination therapy for AML.

Value of Reticulocyte Count, Absolute Reticulocyte Count and Platelet Count for Bone Marrow Recovery Status on Remission Induction Phase

Reticulocyte count performed on a supravitally stained blood film is a initial and common laboratory method of determining early hematological recovery. This method is rapidly replaced by automated flow cytometry methods which have the advantage of much greater precision, before other test become positive after chemotherapy. A prospective observational study was carried out in the Department of Laboratory Medicine in collaboration with Paediatric Haematology and Oncology, Bangabandhu Sheikh Mujib Medical University during a period of one year to evaluate the bone marrow recovery in children with acute lymphoblastic leukemia by automated reticulocyte analysis over platelet count. Total fifty patients were enrolled in this study on remission induction phase. All patients were between 8 months to 15 years’ age range with a mean age of 5.5 ± 3.2. At the end of the study out of 50 cases, Ret% and Abs ret count showed early recovery in a median of 6 days before the platelet count recovery and concluded that reticulocyte parameter showed earlier haematopoietic recovery than the platelet count recovery.

Single agent subcutaneous blinatumomab for advanced acute lymphoblastic leukemia.

Blinatumomab is a BiTE® (bispecific T-cell engager) molecule that redirects CD3+ T-cells to engage and lyse CD19+ target cells. Here we demonstrate that subcutaneous (SC) blinatumomab can provide high efficacy and greater convenience of administration. In the expansion phase of a multi-institutional phase 1b trial (ClinicalTrials.gov, NCT04521231), heavily pretreated adults with relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) received SC blinatumomab at two doses: (1) 250 μg once daily (QD) for week 1 and 500 μg three times weekly (TIW) thereafter (250 μg/500 μg) or (2) 500 μg QD for week 1 and 1000 μg TIW thereafter (500 μg/1000 μg). The primary endpoint was complete remission/complete remission with partial hematologic recovery (CR/CRh) within two cycles. At the data cutoff of September 15, 2023, 29 patients were treated: 14 at the 250 μg/500 μg dose and 13 at 500 μg/1000 μg dose. Data from two ineligible patients were excluded. At the end of two cycles, 12 of 14 patients (85.7%) from the 250 μg/500 μg dose achieved CR/CRh of which nine patients (75.0%) were negative for measurable residual disease (MRD; <10-4 leukemic blasts). At the 500 μg/1000 μg dose, 12 of 13 patients (92.3%) achieved CR/CRh; all 12 patients (100.0%) were MRD-negative. No treatment-related grade 4 cytokine release syndrome (CRS) or neurologic events (NEs) were reported. SC injections were well tolerated and all treatment-related grade 3 CRS and NEs responded to standard-of-care management, interruption, or discontinuation. Treatment with SC blinatumomab resulted in high efficacy, with high MRD-negativity rates and acceptable safety profile in heavily pretreated adults with R/R B-ALL.

'Double whammy': An Unusual Co-occurrence of Idiosyncratic phenytoin-induced agranulocytosis and acute liver failure in a child.

Idiosyncratic adverse events to phenytoin therapy, such as agranulocytosis and acute liver failure, though rare, may be life-threatening. Simultaneous occurrence of both adverse events is exceedingly rare; only two cases have been reported in the literature to date. We describe such a case in a 15-year-old girl. Prompt haematological and hepatic recovery occurred after discontinuation of the drug. Given the widespread use of phenytoin in seizure disorders, clinicians prescribing this drug should be aware of its potential complications. Early recognition can considerably improve outcomes.

Azacitidine, Venetoclax, and Gilteritinib in Newly Diagnosed and Relapsed or Refractory FLT3-Mutated AML.

Azacitidine plus venetoclax is a standard of care for patients with newly diagnosed AML who are unfit for intensive chemotherapy. However, FLT3 mutations are a common mechanism of resistance to this regimen. The addition of gilteritinib, an oral FLT3 inhibitor, to azacitidine and venetoclax may improve outcomes in patients with FLT3-mutated AML. This phase I/II study evaluated azacitidine, venetoclax, and gilteritinib in two cohorts: patients with (1) newly diagnosed FLT3-mutated AML who were unfit for intensive chemotherapy or (2) relapsed/refractory FLT3-mutated AML (ClinicalTrials.gov identifier: NCT04140487). The primary end points were the maximum tolerated dose of gilteritinib (phase I) and the combined complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate (phase II). Fifty-two patients were enrolled (frontline [n = 30]; relapsed/refractory [n = 22]). The recommended phase II dose was gilteritinib 80 mg once daily in combination with azacitidine and venetoclax. In the frontline cohort, the median age was 71 years and 73% of patients had an FLT3-internal tandem duplication (ITD) mutation. The CR/CRi rate was 96% (CR, 90%; CRi, 6%). Sixty-five percent of evaluable patients achieved FLT3-ITD measurable residual disease <5 × 10-5 within four cycles. With a median follow-up of 19.3 months, the median relapse-free survival (RFS) and overall survival (OS) have not been reached and the 18-month RFS and OS rates are 71% and 72%, respectively. In the relapsed/refractory cohort, the CR/CRi rate was 27%; nine additional patients (41%) achieved a morphologic leukemia-free state. The most common grade 3 or higher nonhematologic adverse events were infection (62%) and febrile neutropenia (38%), which were more frequent in the relapsed/refractory cohort. The combination of azacitidine, venetoclax, and gilteritinib resulted in high rates of CR/CRi, deep FLT3 molecular responses, and encouraging survival in newly diagnosed FLT3-mutated AML. Myelosuppression was manageable with mitigative dosing strategies.