[Veno-venous extracorporeal membrane oxygenation for capillary leak syndrome during induction chemotherapy in acute myeloid leukemia].

A 44-year-old woman was diagnosed with acute myeloid leukemia (RUNX1::RUNX1T1 translocation) and received induction chemotherapy with idarubicin hydrochloride and cytosine arabinoside. The pneumonia that had been present since admission worsened, and a drug-induced skin rash appeared. On day 17, she presented with respiratory failure and shock, complicated by hemoconcentration and hypoalbuminemia. This was considered capillary leak syndrome due to pneumonia and drug allergy, so she was started on pulse steroid therapy and IVIG, and was intubated on the same day. On day 18, venovenous-extracorporeal membrane oxygenation (VV-ECMO) was started due to worsening blood gas parameters despite ventilatory management. Bronchoalveolar lavage fluid was serous, and both blood and sputum cultures yielded negative. The patient was weaned from VV-ECMO on day 26 as the pneumonia improved with recovery of hematopoiesis. She was disoriented, and a CT scan on day 28 revealed cerebral hemorrhage. Her strength recovered with rehabilitation. After induction chemotherapy, RUNX1::RUNX1T1 mRNA was not detected in bone marrow. The patient received consolidation chemotherapy, and has maintained complete remission. Severe respiratory failure during induction chemotherapy for acute leukemia can be fatal, but VV-ECMO may be lifesaving.

[Discontinuation of tyrosine kinase inhibitors before epiphyseal closure leading to improved short stature in pediatric chronic myelogenous leukemia].

A 3-year-old boy was referred to our hospital with splenomegaly. Blood tests revealed hyperleukocytosis and bone marrow examination showed major BCR::ABL1 fusion, leading to the diagnosis of chronic myelogenous leukemia (CML). Due to intolerance, the tyrosine kinase inhibitor (TKI) was changed from imatinib to dasatinib to nilotinib. The patient achieved molecular remission but became markedly short in stature, measuring 129.3 cm (height standard deviation score [SDS] -3.3) at the age of 12. TKI therapy was discontinued at age 12 years and 10 months, which was 9 years and 8 months after the start of TKI and 1 year and 6 months after achievement of MR4.0, as discontinuation before epiphyseal closure would not improve short stature. At 2 years and 6 months after discontinuation, the patient's height improved to 156.1 cm (SDS-2.0) without relapse. Growth suppression by TKIs is a problem in the management of pediatric CML. This case illustrates how improvement in severe short stature can be achieved by discontinuing TKI therapy before epiphyseal closure.

Clinical outcomes and treatment patterns in adults with FLT3-ITDmut+ acute myeloid leukemia undergoing allogeneic hemopoietic cell transplantation in the US and Canada.

BACKGROUND: Allogeneic hematopoietic cell transplantation (alloHCT) is used to treat patients with acute myeloid leukemia (AML) with internal tandem duplication of the FMS-like tyrosine kinase 3 gene (FLT3-ITDmut+). However, the effect of different characteristics on outcomes after transplant is not fully understood. OBJECTIVE: To determine the impact of patient, disease, and transplant characteristics on clinical outcomes and trends in maintenance therapy for patients with FLT3-ITDmut+ AML who underwent their first alloHCT. STUDY DESIGN: This was an observational cohort study of adults ≥18 years who were recipients of human leukocyte antigen identical sibling, haploidentical, 8/8 or 7/8 unrelated, or cord blood donor alloHCT in the United States and Canada between 2014‒2019. Patient, disease, and transplant characteristics were collected from CIBMTR (Center for International Blood & Marrow Transplant Research) between 2014‒2022. Patients enrolled in the MORPHO clinical trial (NCT02997202) were excluded. Clinical outcomes were measured from the time of alloHCT by disease status: first complete remission (CR1), second or greater CR (≥CR2) or relapsed/refractory (R/R). The primary endpoints of this study were overall survival (OS) and leukemia-free survival (LFS). Key secondary endpoints included relapse after alloHCT, non-relapse mortality (NRM), time from diagnosis to complete remission, time from complete remission to alloHCT, and maintenance therapy before and after alloHCT. Univariate analyses were conducted with Gray's test and log-rank test, while multivariable analyses were conducted using Cox proportional hazards models. RESULTS: A total of 3147 eligible patients (CR1, n=2389; ≥CR2, n=340; R/R, n=418) were included. Most patient, disease, and transplant characteristics were similar between different disease statuses. In univariate analyses, disease status of CR1 compared with ≥CR2 or R/R was significantly (p<0.001) associated with improved OS and LFS, and decreased probability of relapse; NRM likely differed across cohorts after alloHCT (p=0.003). In multivariable analyses, patients with a disease status of ≥CR2 and R/R compared with CR1 had significantly shorter OS (hazard ratio [HR] 95% confidence interval [CI], 1.43 [1.19-1.72], p=0.0001, and 2.14 [1.88-2.44], p<0.0001, respectively). Patients with a disease status of CR1 at ≤2.6 months had better LFS compared with ≥CR2 and R/R (HR [95% CI], 2.03 [1.56-2.63], p<0.0001 and 3.98 [3.07-5.17], p<0.0001, respectively). Patients with a ≥CR2 or R/R disease status at ≤2.6 months had an increased likelihood of relapse compared with CR1 (HR [95% CI], 2.46 [1.82-3.33], p<0.0001 and 4.68 [3.46-6.34], p<0.0001, respectively). Disease status was not significantly associated with NRM. We also identified several additional patient, disease, and transplant characteristics that may be associated with inferior OS and/or LFS and greater relapse and/or NRM. Maintenance therapy usage after alloHCT increased from 2014 to 2019 primarily due to increased FLT3 inhibitor use. CONCLUSION: In this largest study to date of patients from the US and Canada with FLT3-ITDmut+ AML, disease status of CR1 at the time of alloHCT was associated with better clinical outcomes. Additional factors were identified that may also impact clinical outcomes, and in total, have the potential to inform clinical decision-making.

A comparative analysis of the clinical and genetic profiles of blast phase BCR::ABL1-negative myeloproliferative neoplasm and acute myeloid leukemia, myelodysplasia-related.

INTRODUCTION: The classic Philadelphia chromosome-negative myeloproliferative neoplasms (Ph (-) MPNs), have variable potential for progression to the blast phase (MPN-BP) of the disease. Except initiated by distinct driver mutations, MPN-BP frequently carry similar genetic abnormalities defining acute myeloid leukemia myelodysplasia-related (AML-MR). Because of dissimilar initial pathogenesis, MPN-BP and AML-MR are retained under different disease categories. To determine if separately classifying these entities is justified, we compare MPN-BP with AML-MR patients based on mutational landscape and clinical parameters. METHODS: 104 MPN-BP patients and 145 AML-MR patients were identified with available clinical, cytogenetic, and genetic data. RESULTS: AML-MR patients presented with a higher blast count (median, 51% vs. 30%) while MPN-BP patients had higher WBC counts, platelet counts and bone marrow cellularity (all p<0.0001). Patients with MPN-BP showed similar genetic mutations with similar mutation pattern (functional domain, hotspot and locus involved by the mutations) but a different mutation rate from AML-MR, with more frequent JAK2, CALR, MPL, ASXL1, IDH2, SETBP1 and SRSF2 mutations and less frequent TP53 and DNMT3A mutations. The overall survival (OS) of MPN-BP (OS post-BP-progression) is comparable to that of AML-MR (median OS, 9.5 months vs. 13.1 months, p=0.20). In addition, the subgroups of MPN-BP show similar OS as AML-MR. When harboring certain mutation such as TP53, ASXL1, DNMT3A, TET2, RUNX1, IDH1, IDH2, EZH2, U2AF1, BCOR and SRSF2, MPN-BP and AML-MR patients carrying the same somatic mutation show no difference in OS. CONCLUSION: MPN-BP and AML-MR harbor similar somatic mutations and clinical outcomes, suggesting a unified clinical disease entity.

Flow Cytometric Assessment of CD26-Positive Leukemic Stem Cells: A Rapid and Valuable Tool in the Diagnosis and Follow-Up of Chronic Myeloid Leukemia.

Context Chronic myeloid leukemia (CML) is a clonal myeloproliferative neoplasm. Recent studies have suggested that CD26-positive leukemic stem cells (LSCs) circulating in peripheral blood are specific for CML. Objective This study was undertaken to determine the proportion of CD26-positive LSCs at diagnosis and its change during tyrosine kinase inhibitor therapy. Design This prospective study was conducted on 43 cases of CML at diagnosis. For flow cytometry, peripheral blood cells were stained with CD45, CD34, CD38, CD3, and CD26. A sequential gating strategy with CD45/SSC (side scatter), CD34/SSC, and CD34/CD38 was applied to identify CD45+/34+/38- populations, from which CD26-positive stem cells were identified and compared with controls. Data analysis was done with Kaluza software. Results All patients diagnosed with CML were detected with CD26-positive LSCs. The median percentage of CD26-positive CML LSCs was 0.02 with a range of 0.001 to 1.77. None of the control samples showed CD26 positivity. The percentage and absolute count of CD26-positive CML LSCs were reduced after six months of tyrosine kinase therapy in patients with complete hematological remission. Conclusion Flow cytometric analysis of circulating CD26-positive CML LSCs is a non-invasive, rapid, and useful tool in the diagnosis and follow-up of CML.

The predictive value of T-cell chimerism for disease relapse after allogeneic hematopoietic stem cell transplantation.

Introduction: Chimerism is closely correlated with disease relapse after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, chimerism rate is dynamic changes, and the sensitivity of different chimerism requires further research. Methods: To investigate the predictive value of distinct chimerism for relapse, we measured bone marrow (BM), peripheral blood (PB), and T-cell (isolated from BM) chimerism in 178 patients after allo-HSCT. Results: Receiver operating characteristic (ROC) curve showed that T-cell chimerism was more suitable to predict relapse after allo-HSCT compared with PB and BM chimerism. The cutoff value of T-cell chimerism for predicting relapse was 99.45%. Leukemia and myelodysplastic syndrome (MDS) relapse patients' T-cell chimerism was a gradual decline from 2 months to 9 months after allo-HSCT. Higher risk of relapse and death within 1 year after allo-HSCT. The T-cell chimerism rates in remission and relapse patients were 99.43% and 94.28% at 3 months after allo-HSCT (P = 0.009), 99.31% and 95.27% at 6 months after allo-HSCT (P = 0.013), and 99.26% and 91.32% at 9 months after allo-HSCT (P = 0.024), respectively. There was a significant difference (P = 0.036) for T-cell chimerism between early relapse (relapse within 9 months after allo-HSCT) and late relapse (relapse after 9 months after allo-HSCT) at 2 months after allo-HSCT. Every 1% increase in T-cell chimerism, the hazard ratio for disease relapse was 0.967 (95% CI: 0.948-0.987, P<0.001). Discussion: We recommend constant monitoring T-cell chimerism at 2, 3, 6, and 9 months after allo-HSCT to predict relapse.

Community-Acquired Methicillin-Resistant Staphylococcus aureus Strain Positive for the Panton-Valentine Leucocidin Gene in a Middle-Aged Patient With Multiple Septic Pulmonary Emboli.

A 59-year-old man suffered from fever and chest pain for three days following an accidental bite to a lip ulcer. His lower lip showed swelling and tenderness, and chest computed tomography showed multiple bilateral nodules. He was diagnosed with septic pulmonary embolism and a lip abscess, and blood, sputum, and lip abscess cultures confirmed the presence of methicillin-resistant Staphylococcus aureus (MRSA). Despite the initiation of vancomycin, he rapidly developed respiratory failure and septic shock, necessitating intubation and noradrenaline support. Gentamicin was added on the seventh day of admission due to an insufficient effect, and vancomycin was switched to linezolid on the 14th day of admission. However, his respiratory failure persisted as bilateral pneumothorax developed. Blood culture was negative on the 14th day after admission, but the patient died on the 15th day after admission. The MRSA isolate was tested for the presence of the Panton-Valentine leukocidin (PVL) gene in conjunction with the USA300 strain. The prevalence of community-acquired (CA)-MRSA in the USA300 clone is increasing but still low in Japan, and this type of infection is commonly observed in people of all ages; this case is the first instance reported in Japan of a middle-aged patient with septic pulmonary embolism. Given the anticipated global increase in CA-MRSA infection caused by the USA300 clone and the emergence of USA300 with altered pathogenicity, it may be crucial to suspect PVL-positive CA-MRSA infections even in middle-aged or elderly patients presenting with septic pulmonary embolism as community infections.

Mutation analysis of BCR-ABL1 kinase domain in chronic myeloid leukemia patients with tyrosine kinase inhibitors resistance: a Malaysian cohort study.

OBJECTIVE: Mutational analysis of BCR::ABL1 kinase domain (KD) is a crucial component of clinical decision algorithms for chronic myeloid leukemia (CML) patients with failure or warning responses to tyrosine kinase inhibitor (TKI) therapy. This study aimed to detect BCR::ABL1 KD mutations in CML patients with treatment resistance and assess the concordance between NGS (next generation sequencing) and Sanger sequencing (SS) in detecting these mutations. RESULTS: In total, 12 different BCR::ABL1 KD mutations were identified by SS in 22.6% (19/84) of patients who were resistant to TKI treatment. Interestingly, NGS analysis of the same patient group revealed an additional four different BCR::ABL1 KD mutations in 27.4% (23/84) of patients. These mutations are M244V, A344V, E355A, and E459K with variant read frequency below 15%. No mutation was detected in 18 patients with optimal response to TKI therapy. Resistance to TKIs is associated with the acquisition of additional mutations in BCR::ABL1 KD after treatment with TKIs. Additionally, the use of NGS is advised for accurately determining the mutation status of BCR::ABL1 KD, particularly in cases where the allele frequency is low, and for identifying mutations across multiple exons simultaneously. Therefore, the utilization of NGS as a diagnostic platform for this test is very promising to guide therapeutic decision-making.

RUNX1::RUNX1T1 Acute Myeloid Leukemia Cytogenetically Showing t(6;8)(p23;q22).

Runt-related transcription factor 1 (RUNX1)::RUNX1 partner transcriptional co-repressor 1 (RUNX1T1) acute myeloid leukemia (AML) is a subtype of acute leukemia primarily classified as French American British M2. RUNX1::RUNX1T1 transcript is formed by a reciprocal translocation between chromosomes 8q22 and 21q22. However, we encountered a case of AML that showed molecular positivity for RUNX1::RUNX1T1 fusion transcript but exhibited cytogenetically atypical translocation t(6;8). Fluorescence in situ hybridization (FISH) analysis, in combination with G-banding, clarified the three-way translocation t(6;21;8)(p25;q22;q22), which was partially cryptic. The case emphasizes the importance of employing molecular analysis alongside cytogenetics to determine disease subtypes in patients with acute leukemia.

Metronomic chemotherapy in hematology: Lessons from preclinical and clinical studies to build a solid rationale for future schedules.

Metronomic chemotherapy (mCHEMO), based on frequent, regular administration of low, but pharmacologically active drug doses, optimizes antitumor efficacy by targeting multiple targets and reducing toxicity of antineoplastic drugs. This minireview will summarize preclinical and clinical studies on cytotoxic drugs given at weekly, daily, or at continuous metronomic schedules alone or in combination with novel targeted agents for hematological malignancies, including lymphoma, multiple myeloma, and leukemia. Most of the preclinical in vitro and in vivo studies have reported a significant benefit of both mCHEMO monotherapy and combinatorial regimens compared with chemotherapy at the maximum tolerated dose. However, the combination of mCHEMO with targeted drugs is still little explored in the hematologic clinical setting. Data obtained from preclinical studies on low dose metronomic chemotherapy in hematological malignancies clearly suggested the possibility to clinically investigate more tolerable and effective strategies for the treatment of patients with advanced hematological malignancies, or at least for those frail and elderly patients, who are not eligible or resistant to standard treatments.

Identification of cells of leukemic stem cell origin with non-canonical regenerative properties.

Despite most acute myeloid leukemia (AML) patients entering remission following chemotherapy, outcomes remain poor due to surviving leukemic cells that contribute to relapse. The nature of these enduring cells is poorly understood. Here, through temporal single-cell transcriptomic characterization of AML hierarchical regeneration in response to chemotherapy, we reveal a cell population: AML regeneration enriched cells (RECs). RECs are defined by CD74/CD68 expression, and although derived from leukemic stem cells (LSCs), are devoid of stem/progenitor capacity. Based on REC in situ proximity to CD34-expressing cells identified using spatial transcriptomics on AML patient bone marrow samples, RECs demonstrate the ability to augment or reduce leukemic regeneration in vivo based on transfusion or depletion, respectively. Furthermore, RECs are prognostic for patient survival as well as predictive of treatment failure in AML cohorts. Our study reveals RECs as a previously unknown functional catalyst of LSC-driven regeneration contributing to the non-canonical framework of AML regeneration.

Associations of granulocyte colony-stimulating factor with toxicities and efficacy of chimeric antigen receptor T-cell therapy in relapsed or refractory B-cell acute lymphoblastic leukemia.

Few studies have reported the associations of granulocyte colony-stimulating factor (G-CSF) with cytokine release syndrome (CRS), neurotoxic events (NEs) and efficacy after chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We present a retrospective study of 67 patients with R/R B-ALL who received anti-CD19 CAR T-cell therapy, 41 (61.2%) patients received G-CSF (G-CSF group), while 26 (38.8%) did not (non-G-CSF group). Patients had similar duration of grade 3-4 neutropenia between the two groups. The incidences of CRS and NEs were higher in G-CSF group, while no differences in severity were found. Further stratified analysis showed that the incidence and severity of CRS were not associated with G-CSF administration in patients with low bone marrow (BM) tumor burden. None of the patients with low BM tumor burden developed NEs. However, there was a significant increase in the incidence of CRS after G-CSF administration in patients with high BM tumor burden. The duration of CRS in patients who used G-CSF was longer. There were no significant differences in response rates at 1 and 3 months after CAR T-cell infusion, as well as overall survival (OS) between the two groups. In conclusion, our results showed that G-CSF administration was not associated with the incidence or severity of CRS in patients with low BM tumor burden, but the incidence of CRS was higher after G-CSF administration in patients with high BM tumor burden. The duration of CRS was prolonged in G-CSF group. G-CSF administration was not associated with the efficacy of CAR T-cell therapy.

UBE2C promotes the proliferation of acute myeloid leukemia cells through PI3K/AKT activation.

This study aims to investigate the role and mechanism of tubiquitin-conjugating enzyme E2 C (UBE2C) in acute myeloid leukemia (AML). Initially, UBE2C expression in leukemia was analyzed using the Cancer Genome Atlas database. Further, we silenced UBE2C expression using small-hairpin RNA (sh-RNA). UBE2C expression was detected via the quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) and Western blot analysis. Apoptotic events and reactive oxygen species (ROS) levels were detected by flow cytometry. A xenograft model of leukemia cells were established, and the protein levels of UBE2C, KI-67, and cleaved-caspase 3 were detected by immunohistochemistry. We reported an overexpression of UBE2C in leukemia patients and cell lines (HL60, THP-1, U937, and KG-1 cells). Moreover, a high expression level of UBE2C was correlated with a dismal prognosis in AML patients. UBE2C knockdown inhibited the viability and promoted apoptosis in AML cells by regulating the phosphatidylinositol-3-kinase (PI3K)/protein kinase B (AKT) signaling pathway. Furthermore, UBE2C knockdown increased cellular Fe2+ and ROS levels, and enhanced erastin-induced ferroptosis in a proteasome-dependent manner. UBE2C knockdown also suppressed the tumor formation of AML cells in the mouse model. In summary, our findings suggest that UBE2C overexpression promotes the proliferation and inhibits ferroptosis in AML cells by activating the PI3K/AKT pathway.

Association of Leukemia With ABO Blood Group Distribution and Discrepancy: A Review Article.

The ABO system is an essential blood group in clinical transfusion medicine implicated in several human diseases. The ABO system has been investigated for over a century, with various studies exploring potential links to disease susceptibility. The study examines the possible relationship between leukemia and the distribution and the ABO blood group system discrepancy. A comprehensive review was conducted on the recommended databases to review the ABO blood groups, their association with leukemia, and the expected changes in blood groups among leukemia patients. The study highlights different kinds of leukemia, such as acute lymphocytic leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and chronic lymphocytic leukemia (CLL), their characteristics, and their relationship with ABO blood groups. The document concludes that studying ABO blood group distributions among leukemia patients showed that the most common blood group in acute leukemia is the A group, while in chronic leukemia, the O group is predominant; more studies are required. This study also confirmed an association between leukemia and ABO blood group discrepancy.

Triangulation of epidemiological evidence and risk of bias evaluation: A proposed framework and applied example using formaldehyde exposure and risk of myeloid leukemias.

Evidence triangulation may help identify the impact of study design elements on study findings and to tease out biased results when evaluating potential causal relationships; however, methods for triangulating epidemiologic evidence are evolving and have not been standardized. Building upon key principles of epidemiologic evidence triangulation and risk of bias assessment, and responding to the National Academies of Sciences, Engineering, and Medicine (NASEM) call for applied triangulation examples, the objective of this manuscript is to propose a triangulation framework and to apply it as an illustrative example to epidemiologic studies examining the possible relationship between occupational formaldehyde exposure and risk of myeloid leukemias (ML) including acute (AML) and chronic (CML) types. A nine-component triangulation framework for epidemiological evidence was developed incorporating study quality and ROB guidance from various federal health agencies (i.e., US EPA TSCA and NTP OHAT). Several components of the triangulation framework also drew from widely used epidemiological analytic tools such as stratified meta-analysis and sensitivity analysis. Regarding the applied example, fourteen studies were identified and assessed using the following primary study quality domains to explore potential key sources of bias: 1) study design and analysis; 2) study participation; 3) exposure assessment; 4) outcome assessment; and 5) potential confounding. Across studies, methodological limitations possibly contributing to biased results were observed within most domains. Interestingly, results from one study - often providing the largest and least-precise relative risk estimates, likely reflecting study biases, deviated from most primary study findings indicating no such associations. Triangulation of epidemiological evidence appears to be helpful in exploring inconsistent results for the identification of study results possibly reflecting various biases. Nonetheless, triangulation methodologies require additional development and application to real-world examples to enhance objectivity and reproducibility.

Treatment of relapsed/refractory chronic lymphocytic leukemia with Zanubrutinib after progressing on other BTK inhibitors.

Chronic Lymphocytic Leukemia (CLL) is the most common type of leukemia in the US, representing approximately 1.1% of all new cancers diagnosed. Most patients with CLL can be monitored without treatment, and the indicated treatment options include a CD20 monoclonal antibody with or without bruton tyrosine kinase (BTK) inhibitors, phosphatidylinositol 3-kinase (PI3K) inhibitors, and B-cell lymphoma 2 (BCL2) antagonists. We review the case of a 77-year-old female with a long-standing history of CLL predominant lymphocytosis, transfusion -independent anemia, and thrombocytopenia. Patient responded to zanubrutinib after initial failure of idelalisib, rituximab, and acalabrutinib and venetoclax.

Limited efficacy of 3 + 7 plus gemtuzumab ozogamycin in newly diagnosed fit intermediate genetic risk acute myeloid leukemia patients.

BACKGROUND: Gemtuzumab-ozogamycin (GO) is approved in combination with high-dose chemotherapy for treatment-naïve low- and intermediate-risk acute myeloid leukemia (AML). AIMS: In this retrospective real-life multicenter study, we reported efficacy and safety of GO plus high-dose chemotherapy in newly diagnosed AML patients. METHODS AND RESULTS: A total of 31 fit low- and intermediate-risk AML patients treated with GO-based regimens were retrospectively included in this real-life multicenter study, and results were compared with a control cohort treated with 3 + 7 alone. Complete remission (CR) rate after induction was 77%, and most responders (45%) underwent two GO-based consolidation, and minimal residual disease (MRD) negativity was observed in 17 cases (55%) after the end of consolidation. Low genetic risk was associated with increased CR rate compared with intermediate-risk AML (88% vs. 33%; p < .001), as well as prolonged overall survival (OS; hazard ratio, 0.16; 95% confidential interval, 0.02-0.89; p < .001). GO addition resulted in a survival benefit for low-risk AML (median OS not reached vs. 25 months; p = .19) while not for intermediate-risk subjects (10 vs. 13 months; p = .92), compared with the control group. Moreover, GO-treated patients experienced fever of unknown origin or sepsis in 42% or 36% of cases, respectively, with one death during induction due to septic shock, with similar rates compared with the control group (p = .3480 and p = .5297, respectively). No cases of veno-occlusive disease after allogeneic transplantation were observed. CONCLUSIONS: Our real-life multicenter study confirmed GO-based treatment efficacy with high MRD negativity rates in fit newly diagnosed AML patients, especially in those with low genetic risk and core binding factor, while limited benefits were observed in intermediate-risk AML. However, further validation on larger prospective cohorts is required.

SMS121, a new inhibitor of CD36, impairs fatty acid uptake and viability of acute myeloid leukemia.

Acute myeloid leukemia (AML) is the most common form of acute leukemia in adults and the second most common among children. AML is characterized by aberrant proliferation of myeloid blasts in the bone marrow and impaired normal hematopoiesis. Despite the introduction of new drugs and allogeneic bone marrow transplantation, patients have poor overall survival rate with relapse as the major challenge, driving the demand for new therapeutic strategies. AML patients with high expression of the very long/long chain fatty acid transporter CD36 have poorer survival and very long chain fatty acid metabolism is critical for AML cell survival. Here we show that fatty acids are transferred from human primary adipocytes to AML cells upon co-culturing. A drug-like small molecule (SMS121) was identified by receptor-based virtual screening and experimentally demonstrated to target the lipid uptake protein CD36. SMS121 reduced the uptake of fatty acid into AML cells that could be reversed by addition of free fatty acids and caused decreased cell viability. The data presented here serves as a framework for the development of CD36 inhibitors to be used as future therapeutics against AML.

Graft failure after allogeneic hematopoietic stem cell transplantation in pediatric patients with acute leukemia: autologous reconstitution or second transplant?

BACKGROUND: Graft failure (GF) is a rare but serious complication after allogeneic hematopoietic stem cell transplantation (HSCT). Prevention of graft failure remains the most advisable approach as there is no clear recommendation for the best strategies for reversing this complication. Administration of growth factor, additional hematopoietic progenitor boost, or a salvage HSCT are current modalities recommended for the treatment of GF. Autologous recovery without evidence of disease relapse occurs rarely in patients with GF, and in the absence of autologous recovery, further salvage transplantation following a second conditioning regimen is a potential treatment option that offers the best chances of long-term disease-free survival. The preconditioning regimens of second HSCT have a significant impact on engraftment and outcome, however, currently there is no consensus on optimal conditioning regimen for second HSCT in patients who have developed GF. Furthermore, a second transplant from a different donor or the same donor is still a matter of debate. OBSERVATIONS: We present our experience in managing pediatric patients with acute leukemia who encountered graft failure following stem cell transplantation. CONCLUSIONS AND RELEVANCE: Although a second transplantation is almost the only salvage method, we illustrate that some pediatric patients with acute leukemia who experience graft failure after an allogeneic stem cell transplant using Myeloablative conditioning (MAC) regimen may achieve long-term disease-free survival through autologous hematopoiesis recovery.

Impact of the COVID-19 pandemic on utilization and cost for care of pediatric and young adult ALL.

OBJECTIVE: Acute lymphoblastic leukemia (ALL) is the most common childhood malignancy and among the most common malignancies in young adults and requires a unique pattern of healthcare utilization including an acute/emergent presentation and an intensive initial 8 months of therapy followed by two years of outpatient treatment. The COVID-19 pandemic caused massive global disruptions in healthcare use and delivery. This report aims to examine the effects of the COVID-19 pandemic on the presentation, diagnosis and continued management of childhood and young adult ALL in regard to utilization and cost of care among commercially insured individuals in the United States. RESULTS: Utilizing a commercial insurance claims database, 529 pediatric and young adult patients were identified who were diagnosed with ALL between January 2016 and March 2021. New diagnoses were evaluated by era and demographics. Utilization was measured by COVID-related era as number of inpatient and outpatient encounters, inpatient days, and cumulative cost during the initial 8 months of therapy. None of these cost or utilization factors changed significantly during or shortly after the pandemic. These findings reinforce that the necessary care for pediatric and young adult ALL was unwavering despite the massive shifts in the healthcare system caused by the COVID-19 pandemic. This provides a valuable benchmark as we further examine the factors that influence the pandemic's impact on health equity and access to care, especially in vulnerable pediatric and young adult populations. This is the first investigation of the effect of the COVID-19 pandemic on utilization and cost of care in pediatric and young adult cancer.