High-risk Leukemia Research Articles

Diagnosis and management of concurrent metastatic melanoma and chronic myelomonocytic leukemia.

While the association between chronic lymphocytic leukemia (CLL) and a higher incidence of melanoma is well documented, the diagnosis of concurrent high-risk chronic myelomonocytic leukemia (CMML) and metastatic melanoma (MM) has not previously been described. Moreover, the treatment of MM and CMML differ greatly in the mechanism of action of their corresponding antineoplastic therapies: treatment of MM frequently involves immune checkpoint inhibitors (ICI), while patients with CMML receive myelosuppressive agents. Simultaneous management of these malignancies can be nuanced due to the potential impact of one treatment's constituents on the activity of the other and the broad and nonoverlapping array of potential adverse effects of these agents. Here, we describe the clinical course of a patient who was diagnosed with concurrent MM and CMML and our approach to the challenging balance of delivering ICI concurrently with the hypomethylating agent azacitidine and the BCL-2 inhibitor venetoclax.

Literature-Guided 6-Gene Signature for the Stratification of High-Risk Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) shows significant heterogeneity in therapeutic responses. We aimed to develop a gene signature for the stratification of high-risk pediatric AML using publicly available AML datasets, with a focus on literature-based prognostic gene sets. We identified 300 genes from 12 well-validated studies on AML-related gene signatures. Clinical and gene expression data were obtained from three datasets: TCGA-LAML, TARGET-AML, and BeatAML. Least absolute shrinkage and selection operator (LASSO)-Cox regression analysis was used to perform the initial gene selection and to construct a prognostic model using the TCGA database (n=132). The final gene signature was validated with two independent cohorts: BeatAML (n=411) and TARGET-AML (n=187). We identified a six-gene signature (ETFB, ARL6IP5, PTP4A3, CSK, HS3ST3B1, PLA2G4A), referred to as the literature-based signature 6 (LBS6), that was significantly associated with lower overall survival rates across the TCGA (HR=4.2, 95% CI: 2.59-6.81, p<0.0001), BeatAML (HR=1.52, 95% CI: 1.17-1.96, p=0.0013), and TARGET (HR=2.05, 95% CI: 1.36-3.08, p<0.001) datasets. The high-LBS6 score group exhibited significantly poorer five-year event-free survival compared to the low-LBS6 score group (HR=2.09, 95% CI: 1.38-3.15, p<0.001). After adjusting for key risk factors, including gene mutations (WT1, FLT3, and NPM1), protocol-based risk group, WBC count, and age, the LBS6 score was independently associated with worse survival rates in validation cohorts. Our literature-driven approach identified a robust gene signature that stratifies AML patients into distinct risk groups. The LBS6 score shows promise in redefining initial risk stratification and identifying high-risk AML patients.

Efficacy and safety of low-dose TBI combined MAC regimen for HSCT in high-risk AML patients with active disease

Background The management of high-risk acute myeloid leukaemia (AML) remains challenging, highlighting the need for innovative conditioning strategies beyond current regimens. Methods In the present single-arm study, a FACT regimen comprised of low-dose total body irradiation (TBI) with fludarabine, cytarabine and cyclophosphamide was employed to treat cytogenetically high-risk AML patients exhibiting pre-transplant active disease. This clinical trial is registered in the Chinese Clinical Trial Registry with the registration number ChiCTR2000035111. Results In this study, 21 high-risk AML patients with pre-transplant disease statuses including primary induction failure, relapse and measurable residual disease positivity, were enrolled to undergo FACT conditioning. The FACT group demonstrated a 1-year non-relapse mortality (NRM) rate of 9.5%, indicating a similar level of safety and tolerability among the conditioning regimens. The estimated cumulative incidence of grade 2–4 acute graft-versus-host disease (GVHD) at one year was 30.7%. Additionally, the cumulative incidence of chronic GVHD was 36.0% at one year and increased to 43.0% at two years. Conclusions The FACT regimen is an effective myeloablative conditioning (MAC) strategy for high-risk AML patients, potentially reducing relapse risk without increasing NRM, warranting further research.

TIM-3 marks measurable residual leukemic stem cells responsible for relapse after allogeneic stem cell transplantation.

In this study, we investigated the measurable residual leukemic stem cell (MR-LSC) population after allogeneic stem cell transplantation (allo-SCT) for high-risk acute myeloid leukemia (AML), utilizing T-cell immunoglobulin mucin-3 (TIM-3) expression as a functional marker of AML leukemic stem cells (LSCs). Analysis of the CD34+CD38- fraction of bone marrow cells immediately after achievement of engraftment revealed the presence of both TIM-3+LSCs and TIM-3- donor hematopoietic stem cells (HSCs) at varying ratios. Genetic analysis confirmed that TIM-3+ cells harbored patient-specific mutations identical to those found in AML clones, whereas TIM-3- cells did not, indicating that TIM-3+CD34+CD38- cells represent residual AML LSCs. In 92 allo-SCT occasions involving 83 AML patients, we enumerated the frequencies of TIM-3+LSCs immediately after achieving hematologic complete remission with complete donor cell chimerism. Notably, only 22.2% of patients who achieved a TIM-3+MR-LSClow status (<60%) experienced relapse, with a median event-free survival (EFS) of 1581 days (median follow-up duration was 2177 days among event-free survivors). Conversely, 87.5% of patients with TIM-3+MR-LSCint/high (≥60%) relapsed, with a median EFS of 140.5 days. Furthermore, MR-LSC status emerged as a significant independent risk factor for relapse (hazard ratio, 8.56; p < 0.0001), surpassing the impact of patient disease status prior to allo-SCT, including failure to achieve complete remission (hazard ratio, 1.98; p = 0.048). These findings suggest that evaluating TIM-3+ MR-LSCs immediately after engraftment, which reflects the competitive reconstitution of residual TIM-3+ LSCs and donor HSCs, may be valuable for predicting outcomes in AML patients undergoing allo-SCT.

Transplant in ALL: who, when, and how?

Allogeneic hematopoietic stem cell transplantation (allo-HCT) remains a cornerstone in the treatment of high-risk acute lymphoblastic leukemia (ALL), yet optimal patient selection is challenging in the era of rapidly changing modern therapy. Refined molecular characterization allows for better risk assessment, sparing low-risk patients from allo-HCT toxicity while identifying those who may benefit from intensified approaches. Measurable residual disease (MRD) has emerged as a powerful predictor of relapse irrespective of treatment strategy, challenging the necessity of transplant in MRD-negative patients. Further, expanded donor options, particularly haploidentical transplantation coupled with reduced intensity conditioning, have extended the applicability of allo-HCT to a broader range of patients. Finally, immunotherapies and targeted treatments are increasingly integrated into both initial and relapsed treatment protocols yielding deep remission and allowing for successful transplant in patients with a history of advanced disease. In this review, we provide an overview of the contemporary role of transplant in adult patients with ALL, focusing on indications for allo-HCT in first remission, optimal sequencing of transplant with novel therapies, and advancements in donor selection and conditioning regimens.

Targeting menin for precision therapy in high-risk acute myeloid leukemia.

This mini-review provides an overview of the current evidence for Revumenib, a first-in-class menin inhibitor, in treating AML with KMT2A rearrangements or NPM1 mutations. This therapy represents a promising advancement by selectively disrupting leukemogenic pathways. The clinical promise of Revumenib in genetically defined AML highlights its potential role in shaping the future treatment landscape. This mini-review underscores the need for ongoing trials to define optimal dosing, safety protocols, and combination therapies, with the ultimate goal of establishing Revumenib as a standard of care for high-risk AML subsets.

Targeted Therapy with CX4945 Biomimetic Nanodrug Delivery System for High-Risk B-Cell Acute Lymphoblastic Leukemia

Targeted Therapy with CX4945 Biomimetic Nanodrug Delivery System for High-Risk B-Cell Acute Lymphoblastic Leukemia

River-52: A Multicenter, Open-Label Clinical Trial of RVU120 in Patients with Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia

River-52: A Multicenter, Open-Label Clinical Trial of RVU120 in Patients with Relapsed or Refractory High-Risk Myelodysplastic Syndrome or Acute Myeloid Leukemia

Co-Targeting BCL-2 and MCL1 (via CDK9) in Pre-Clinical Models of High-Risk Acute Lymphoblastic Leukemia

Co-Targeting BCL-2 and MCL1 (via CDK9) in Pre-Clinical Models of High-Risk Acute Lymphoblastic Leukemia

Automated and closed clinical-grade manufacturing protocol produces potent NK cells against neuroblastoma cells and AML blasts

Natural killer (NK) cells are a promising allogeneic immunotherapy option due to their natural ability to kill tumor cells, and due to their apparent safety. This study describes the development of a GMP-compliant manufacturing protocol for the local production of functionally potent NK cells tailored for high-risk acute myeloid leukemia (AML) and neuroblastoma (NBL) patients. Moreover, the quality control strategy and considerations for product batch specifications in early clinical development are described. The protocol is based on the CliniMACS Prodigy platform and Natural Killer Cell Transduction (NKCT) (Miltenyi Biotec). NK cells are isolated from leukapheresis through CD3 depletion and CD56 enrichment, followed by a 12-hour activation with IL-2 and IL-15 cytokines. Three CliniMACS Prodigy processes demonstrated the feasibility and consistency of the modified NKCT process. A three-step process without expansion, however, compromised the NK cell yield. T cells were depleted effectively, indicating excellent safety of the product. Characterization of the NK cells before and after cytokine activation revealed a notable increase in the expression of activation markers, particularly CD69, consistent with enhanced functionality. Intriguingly, the NK cells exhibited increased killing efficacy against patient-derived CD33 + AML blasts and NBL cells in vitro, suggesting a potential therapeutic benefit in AML and NBL.

Population Pharmacokinetic and Exposure-Response Analysis to Support a Dosing Regimen of CPX-351 (NS-87) in Japanese Adult and Pediatric Patients with Untreated High-Risk Acute Myeloid Leukemia

CPX-351 (NS-87; Vyxeos®) has a characteristic liposomal formulation and contains cytarabine and daunorubicin at a 5:1 molar ratio, which demonstrates synergistic activity in both in vitro and in vivo animal models. It has been approved in several countries for the treatment of newly diagnosed, therapy-related acute myeloid leukemia (t-AML) or AML with myelodysplasia-related changes (AML-MRC). Since there are very few Asian patients, especially Japanese adult and pediatric patients, only a small clinical study has been conducted in Japanese adult patients and no study in Japanese pediatric patients. Therefore, we need to continue collecting data to ensure efficacy, especially in Japan. The objectives of this study were to evaluate the exposure and efficacy of CPX-351 in adult and pediatric Japanese patients. For these purposes, population pharmacokinetic and exposure-response analysis was conducted based on the established model/analysis using non-Japanese data by incorporating the results of newly obtained Japanese clinical trial. No significant differences in pharmacokinetic exposure and efficacy were observed between non-Japanese adult patients and Japanese adult or pediatric patients. This information supports CPX-351 as a treatment option for untreated Japanese t-AML/AML-MRC patients on the basis of efficacy and safety when referred to the evidence from non-Japanese subjects.

Asciminib stands out as the superior tyrosine kinase inhibitor to combine with anti-CD20 monoclonal antibodies for the treatment of CD20+ Philadelphia-positive B-cell precursor acute lymphoblastic leukemia in preclinical models.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCP-ALL) is a high-risk subtype of acute lymphoblastic leukemia characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab, an anti-CD20 monoclonal antibody is administered to adult BCP-ALL patients with ≥20% CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of rituximab in combination with TKI. Consequently, we examined the influence of TKI on the antitumor effectiveness of anti-CD20 monoclonal antibodies by evaluating levels of CD20 on the cell surface and conducting in vitro functional assays. All tested TKI were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of rituximab-mediated complement- dependent cytotoxicity. Interestingly, these TKI displayed varied effects on natural killer (NK) cell-mediated antibody- dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-monoclonal antibody-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity in patients' blood, as determined by an ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKI for combination therapy with anti-CD20 monoclonal antibodies.

A phase 2, multicenter, clinical trial of CPX-351 in older patients with secondary or high-risk acute myeloid leukemia: PETHEMA-LAMVYX.

LAMVYX was a multicenter, single-arm, phase 2 trial designed to validate the safety and efficacy of CPX-351 in patients aged 60-75 years with newly diagnosed, secondary acute myeloid leukemia and to generate evidence on key issues not addressed in the preceding regulatory pivotal trial. The primary end point of the study was the complete remission (CR)/CR with incomplete hematologic recovery (CRi) rate after induction. Eligible patients were recommended to undergo allogeneic hematopoietic stem cell transplantation after the first consolidation cycle. Alternatively, patients could undergo up to six maintenance cycles with CPX-351. Twenty-nine patients (49%; 95% exact confidence interval [CI], 37%-62%) patients achieved a CR/CRi after one or two cycles of induction, with a measurable residual disease negativity rate of 67% as assessed by centralized, multiparameter flow cytometry. Among patients who had serial next-generation sequencing analyses available, clearance of somatic mutations that were present at diagnosis was achieved in 7 (35%). The median follow-up among survivors was 16.8 months (range, 8.7-24.3 months). The median event-free survival was 3.0 months (95% CI, 1.4-7.3 months), and the median overall survival was 7.4 months (95% CI, 3.7-12.7 months). In landmark analyses at day +100 from diagnosis, the 1-year overall and event-free survival rate among patients who underwent allogeneic hematopoietic stem cell transplantation was 70% (95% CI, 47%-100%) and 70% (95% CI, 47%-100%), respectively. The corresponding values were 89% (95% CI, 71%-100%) and 44% (95% CI, 21%-92%), respectively, for patients who entered the maintenance phase. No significant longitudinal changes were observed in severity index or quality-of-life visual analog scale scores. The current data provide novel insights that might inform the clinical positioning and optimal use of CPX-351, complementing previous results (ClinicalTrials.gov identifier NCT04230239).

Comparative small molecule screening of primary human acute leukemias, engineered human leukemia and leukemia cell lines

Targeted therapeutics for high-risk cancers remain an unmet medical need. Here we report the results of a large-scale screen of over 11,000 molecules for their ability to inhibit the survival and growth in vitro of human leukemic cells from multiple sources including patient samples, de novo generated human leukemia models, and established human leukemic cell lines. The responses of cells from de novo models were most similar to those of patient samples, both of which showed striking differences from the cell-line responses. Analysis of differences in subtype-specific therapeutic vulnerabilities made possible by the scale of this screen enabled the identification of new specific modulators of apoptosis, while also highlighting the complex polypharmacology of anti-leukemic small molecules such as shikonin. These findings introduce a new platform for uncovering new therapeutic options for high-risk human leukemia, in addition to reinforcing the importance of the test sample choice for effective drug discovery.

A multiomics approach reveals RNA dynamics promote cellular sensitivity to DNA hypomethylation

The search for new approaches in cancer therapy requires a mechanistic understanding of cancer vulnerabilities and anti-cancer drug mechanisms of action. Problematically, some effective therapeutics target cancer vulnerabilities that have poorly defined mechanisms of anti-cancer activity. One such drug is decitabine, a frontline therapeutic approved for the treatment of high-risk acute myeloid leukemia (AML). Decitabine is thought to kill cancer cells selectively via inhibition of DNA methyltransferase enzymes, but the genes and mechanisms involved remain unclear. Here, we apply an integrated multiomics and CRISPR functional genomics approach to identify genes and processes associated with response to decitabine in AML cells. Our integrated multiomics approach reveals RNA dynamics are key regulators of DNA hypomethylation induced cell death. Specifically, regulation of RNA decapping, splicing and RNA methylation emerge as important regulators of cellular response to decitabine.

AML typical mutations (CEBPA, FLT3, NPM1) identify a high-risk chronic myelomonocytic leukemia independent of CPSS molecular

AbstractMutations commonly associated with acute myeloid leukemia (AML), such as CEBPA, FLT3, IDH1/2, and NPM1, are rarely found in chronic myelomonocytic leukemia (CMML), and their prognostic significance in CMML has not been clearly identified. In 127 patients with CMML, we have retrospectively analyzed next-generation sequencing and polymerase chain reaction data from bone marrow samples collected at the time of CMML diagnosis. Seven patients harbored CEBPA mutations, 8 FLT3 mutations, 12 IDH1 mutations, 26 IDH2 mutations, and 11 NPM1 mutations. Patients with CMML harboring CEBPA, FLT3, and/or NPM1 mutations (mutCFN) more frequently had the myeloproliferative subtype, a high prevalence of severe cytopenia, and elevated blast counts. Regardless of their CMML Prognostic Scoring System molecular classification, mutCFN patients with CMML had a poor prognosis, and the multivariate analysis identified mutCFN as an independent marker of overall survival. The genetic profile of these mutCFN patients with CMML closely resembled that of patients with AML, with higher-risk clinical characteristics. Our findings lead us to suggest including the assessment of these mutations in CMML prognostic models and treating these patients with AML-type therapies, including intensive chemotherapy and allogeneic stem cell transplantation, whenever feasible. Furthermore, certain targeted therapies approved for use in AML should be considered.

Maintenance Therapy Post-Hematopoietic Stem Cell Transplantation in Acute Myeloid Leukemia.

High-risk acute myeloid leukemia has been associated with a poor outcome. Hematopoietic stem cell transplantation (HSCT) represents the only curative option for eligible patients. Relapse after HSCT is a dramatic event with poor chances of survival. With the aim of reducing the rate of post-HSCT relapse, maintenance treatment has been investigated in this setting. Results from clinical trials suggest an advantage in the use of a maintenance strategy; however, standardized guidelines are not yet available due to the lack of prospective clinical trials. In this review, we have reported the most important strategies adopted as post-HSCT maintenance, highlighting their efficacy, but the current research also opens questions.

Intermittent micafungin dosing schedule in pediatric oncology patients ‐ safe for outpatient parenteral antimicrobial therapy?

IntroductionAntifungal prophylaxis is an important preventative strategy for high-risk pediatric oncology patients. When triazoles are contraindicated, micafungin is an alternative to polyenes, due to improved tolerability and limited drug-drug interactions. An intermittent dosing schedule is advantageous for outpatient parenteral antimicrobial therapy (OPAT), but studies assessing safety in pediatric patients are limited. MethodsThis single-centre, retrospective, observational study compared the safety and tolerability of daily (1 mg/kg) and intermittent (3 mg/kg) dosing of amphotericin B liposomal (AmB) and micafungin in children under 18 years, with high-risk leukemia. ResultsOf 51 patients, with 76 individual dosing schedules, hepatoxicity and nephrotoxicity were comparable across all four dosing schedules. Severity of hypokalemia was significantly higher amongst patients receiving AmB (p = 0.041), with higher rates of intravenous electrolyte supplementation required. Infusion-related reactions occurred only in the AmB group (22 %). Intermittent administration and dosing of micafungin was well tolerated, with similar effects on liver function and reduced rates of hypokalemia. ConclusionThis study supports the positive safety profile of intermittent micafungin compared with AmB and describes successful OPAT implementation. Prospective studies assessing efficacy are needed to validate these findings.

Methotrexate induced hepatotoxicity in metabolic dysfunction-associated steatotic liver disease.

Hepatotoxicity is an under-recognized and potentially fatal side effect of high-dose methotrexate (HDMTX) chemotherapy, and this risk is compounded in children with metabolic dysfunction-associated steatotic liver disease and/or metabolic-associated steatohepatitis. We present the case of a 12-year-old obese, Hispanic male with elevated hepatic transaminases of unknown etiology at initiation of high-risk B-cell acute lymphoblastic leukemia chemotherapy. He developed acute kidney injury within 24 hours of receiving intravenous HDMTX which progressed to acute hepatic failure. Liver biopsy confirmed methotrexate toxicity aggravated by undiagnosed metabolic dysfunction-associated steatotic liver disease. Rapid deterioration precluded liver transplantation, and he died 21 days after HDMTX treatment. This case highlights the need for comprehensive hepatic evaluation in patients with known or suspected liver disease when administering HDMTX. Dialysis should be considered if delayed methotrexate clearance occurs due to potential for rapid, irreversible hepatotoxicity.

Attention and executive functioning in children and adolescents treated for high-risk acute lymphoblastic leukemia: A report from the Children's Oncology Group (COG).

Survivors of childhood B-acute lymphoblastic leukemia (B-ALL) are at risk for difficulties with attention and executive functioning (EF) as a late effect of treatment. The present study aimed to identify treatment and demographic factors associated with risk for difficulties with EF in youth treated for high-risk B-ALL. Children and adolescents with B-ALL treated on Children's Oncology Group (COG) protocol AALL0232 were randomized to high-dose or escalating-dose methotrexate (MTX), and either dexamethasone or prednisone during the induction phase. Neuropsychological functioning was evaluated via protocol AALL06N1, including performance-based and parent-report measures, for 177 participants (57% female, 81% white; mean age at diagnosis=8.4 years; SD=5.0) 8-24 months following treatment completion. Mean scores for all attention and EF measures were within the average range, with no significant differences as a function of MTX delivery or steroid treatment (all p >0.05). In multivariable models, participants with US public insurance exhibited significantly greater parent-reported EF difficulties than those with US private or non-US insurance (p ≤ 0.05). Additionally, participants diagnosed under 10 years of age performed significantly more poorly on measures of attention (i.e., continuous performance task, p ≤ 0.05) and EF (i.e., verbal fluency and tower planning task, p≤0.05). For survivors of pediatric B-ALL, treatment-related factors were not associated with attention or EF outcomes. In contrast, outcomes varied by demographic characteristics, including age and insurance type, an indicator of economic hardship. Future research is needed to more directly assess the contribution of socioeconomic status on cognitive outcomes in survivors.