Atypical BCR-ABL1 transcript in mixed phenotype acute leukemia with bone marrow necrosis.

Mixed phenotype acute leukemia (MPAL) is a type of acute leukemia in which encompasses mixed features of myeloid, T-lymphoid, and/or B-lymphoid differentiation. Philadelphia chromosome-positive (Ph+) MPAL is a rare subgroup with a poor prognosis and accounts for ＜1% of adult acute leukemia. Until now, there is still no consensus on how to best treat Ph+ MPAL. Here, we report a 62-year-old male with Ph+ (atypical e13a2 BCR-ABL1 fusion protein) MPAL. This patient presented with recurrent and intense bone pain due to bone marrow necrosis (BMN). Besides, he did not achieve a complete remission for the first two chemotherapies, until he received flumatinib combined with hyper-CVAD (B) (a dose-intensive regimen include methotrexate and cytarabine). To our knowledge, this is the first report to describe the coexistence of BMN and atypical e13a2 BCR-ABL1 transcripts in patients with MPAL. This finding will bring new understandings in the diagnosis and treatment of Ph+ MPAL.

Eficacia y seguridad de uso pediátrico de blinatumomab, para el tratamiento de leucemia linfoblástica aguda de precursores de células B con cromosoma philadelphia negativo en recidiva o refractaria / Efficacy and safety of pediatric use of blinatumomab, for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia with Philadelphia chromosome negative

ANTECEDENTES: El presente dictamen ha sido elaborado en el marco de la metodología ad hoc para evaluar solicitudes de tecnologías sanitarias, la cual fue aprobada mediante la Resolución N° 111-IETSI-ESSALUD-2021 del Instituto de Evaluación de Tecnologías en Salud e Investigación (IETSI). Bajo dicho contexto, el presente documento expone la evaluación de la eficacia y seguridad del uso pediátrico de blinatumomab, para el tratamiento de leucemia linfoblástica aguda de precursores de células B con cromosoma Philadelphia negativo en recidiva o refractaria. ASPECTOS GENERALES: La leucemia linfoblástica aguda (LLA) es la neoplasia hematológica más frecuente de la etapa infantil, potencialmente curable hasta en un 90 % de los casos (Hunger y Mullighan 2015). En Perú, se ha estimado una incidencia esperada de 270 a 360 casos nuevos de LLA por año en niños menores de 14 años (Castro-Arechaga et al. 2018). La LLA se clasifica, según la Organización Mundial de la Salud, en LLA de células B, LLA de células T y leucemia de células de Burkitt, tomando en cuenta la morfología y perfil citogenético de los blastos leucémicos (Terwilliger y Abdul-Hay 2017). La LLA de células B es la forma más común de LLA (Inaba y Mullighan 2020). El cromosoma Philadelphia aparece por una translocación recíproca entre los cromosomas 9 y 22 t (9;22) (q34; q11.2), llegando a estar presente en el 3 % al 5 % de los niños con leucemia linfoblástica aguda (Kaczmarska et al. 2021). Además, se ha observado que en los pacientes con LLA que no presentan el cromosoma Philadelphia (cromosoma Philadelphia negativo o Ph-) presentan una tasa de remisión completa de la enfermedad hasta en un 90 % de los casos con una sobrevida global a los 5 años de 43 % (Huguet et al. 2009). METODOLOGÍA: Se realizó una búsqueda de la literatura con respecto a la eficacia y seguridad del uso pediátrico de blinatumomab, para el tratamiento de leucemia linfoblástica aguda de precursores de células B con cromosoma Philadelphia negativo en recidiva o refractaria. Esta búsqueda se realizó utilizando los buscadores: National Library of Medicine (PubMed-MEDLINE), Cochrane Library, LILACS y Web of Science. Adicionalmente, se realizó una búsqueda manual del listado de referencias bibliográficas de los estudios seleccionados a fin de identificar otros estudios que pudieran ser útiles para la presente evaluación. Por otro lado, se amplió la búsqueda revisando la evidencia generada por grupos internacionales que realizan revisiones sistemáticas (RS), evaluación de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), tales como The National Institute for Health and Care Excellence (NICE) y The Canadian Agency for Drugs and Technologies in Health (CADTH). Esta búsqueda se completó revisando publicaciones de grupos dedicados a la educación, investigación y mejora de la práctica clínica oncológica y hematológica dentro de América y Europa, como The National Comprehensive Cancer Network (NCCN), American Society of Clinical Oncology (ASCO), The European Society of Medical Oncology (ESMO), y The British Society for Haematology (BSH). Finalmente, se hizo una búsqueda adicional en la página web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.gov/) e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para poder identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. Las estrategias de la búsqueda para identificar la evidencia de ECA se encuentran en las Tabla A, B, C y D del Material Suplementario. La búsqueda de literatura considero GPC, priorizando aquellas que elaboraran recomendaciones basadas en la evidencia; considerando además aquellas guías de referencia para los servicios de oncología y hematología de la institución; ETS; revisiones sistemáticas con metaanálisis de ECA basado en comparaciones directas; y ECA que abordaran la pregunta PICO del presente dictamen. Al no encontrar ECA que ayudara a responder de manera específica la PICO de interés, se pasó a revisar los ensayos pivotales de aprobación de uso del fármaco blinatumomab en la población de interés. Se incluyeron las publicaciones en inglés y español. Se excluyeron estúdios observacionales, series de casos, reportes de casos, cartas al editor, los comentarios, las editoriales, suplementos y los resúmenes de congresos. RESULTADOS: GPC: guía de práctica clínica; ETS: evaluación de tecnologías sanitarias; RS: revisión sistemática; ECA: ensayo clínico aleatorizado; LiLACS: Literatura Latinoamericana y del Caribe en Ciencias de la Salud; BRISA: Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas. Flujograma adaptado de: Page MJ, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021;372:n71. De los 7 artículos que se recuperaron para ser leídos a texto completo (Yu, Wang, y Huang 2019; von Stackelberg et al. 2016; Queudeville y Ebinger 2021; Ponvilawan et al. 2021; Halford et al. 2021; Brown et al. 2021; Locatelli et al. 2021), ninguno aportó información específica para la pregunta PICO. En la búsqueda manual, se encontraron dos guías de práctica clínica: una de NCCN (NCCN 2022) y otra del Comité Canadiense de Revisión de Medicamentos Oncológicos (Pan-Canadian Oncology Drug Review), comité asesor adscrito a CADTH (pCODR-CADTH 2017). Además, se decidió incluir un ensayo de fase 1/fase II (von Stackelberg et al. 2016), al no haber ECA de fase III que respondieran de manera directa la PICO de interés. Este ensayo es el estudio pivotal con el que FDA dio autorización a blinatumomab para el tratamiento de pacientes pediátricos con LLA de precursores de células B en recaída o refractarios (FDA 2018). Asimismo, se incluyó el estudio sin grupo de comparación RIALTO (Locatelli et al. 2022) por ser un ensayo clínico que proporciona información adicional sobre la seguridad de blinatumomab en la población pediátrica. CONCLUSIÓN: Por todo lo expuesto, el IETSI no aprueba el uso pediátrico de blinatumomab, para el tratamiento de leucemia linfoblástica aguda de precursores de células B con cromosoma Philadelphia negativo en recidiva o refractaria.

Resultados preliminares tras la instauración del programa con medicamentos CAR-T en leucemia aguda linfoblástica en un centro pediátrico / Building a CAR-T cell therapy program in a pediatric hemato-oncology department. Preliminary data

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Blinatumomabe para leucemia linfoblástica aguda (LLA) B derivada pediátrica em primeira recidiva medular de alto risco / Blinatumomab for pediatric B-derived acute lymphoblastic leukemia (ALL) in first high-risk spinal cord relapse

INTRODUÇÃO: A leucemia linfoblástica aguda (LLA) pediátrica é uma neoplasia maligna agressiva e heterogênea caracterizada pela proliferação clonal e acúmulo de linfoblastos na medula óssea e sangue periférico. Entre os pacientes pediátricos, mais de 95% atingem remissão completa após o primeiro tratamento e 75% a 85% permanecem livre de doença por cinco anos após o diagnóstico. Porcentagens de 15% a 20% sofrem recidiva que são classificadas em risco padrão (RP) ou alto risco (AR). Em crianças com primeira recidiva medular de alto risco a sobrevida global é de 20%. A recidiva após o tratamento inicial é a segunda maior causa de mortalidade relacionada ao câncer em crianças. Crianças que apresentam recidiva de alto risco ao tratamento inicial são candidatas ao transplante de células hematopoiéticas após atingirem uma segunda remissão completa, entretanto, as chances de remissão diminuem significativamente entre a primeira, segunda e terceiras recidivas. Nessa população, a presença de doença residual

Use of midostaurin in mixed phenotype acute leukemia with FLT3 mutation: A case series.

Mixed phenotype acute leukemia (MPAL) is a rare type of acute leukemia where blasts present phenotypes from more than one lineage. A poor prognostic has been associated with this disease, and limited data are currently available to guide the choice of therapy. Regarding FLT3-positive MPAL, only one case treated with midostaurin has been published to date. Here, we report the successful use of midostaurin to treat three FLT3-positive MPAL T/myeloid and B/myeloid patients. Midostaurin was successfully added to intensive induction (two patients) and consolidation chemotherapy (three patients) without significant adverse events requiring a dose adjustment or discontinuation. The therapy received resulted in complete remission for two patients and complete remission with an incomplete hematologic recovery for the third. All patients proceeded to HSCT and stayed in remission after an extended follow-up respectively at 28, 31, and 11 months later. These results suggest that the addition of midostaurin during induction and consolidation therapy may represent a treatment option for FLT3-positive MPAL.

Deubiquitinating enzyme inhibitor alleviates cyclin A1-mediated proteasome inhibitor tolerance in mixed-lineage leukemia.

Drug resistance is a significant obstacle to effective cancer treatment. Drug resistance develops from initially reversible drug-tolerant cancer cells, which offer therapeutic opportunities to impede cancer relapse. The mechanisms of resistance to proteasome inhibitor (PI) therapy have been investigated intensively, however the ways by which drug-tolerant cancer cells orchestrate their adaptive responses to drug challenges remain largely unknown. Here, we demonstrated that cyclin A1 suppression elicited the development of transient PI tolerance in mixed-lineage leukemia (MLL) cells. This adaptive process involved reversible downregulation of cyclin A1, which promoted PI resistance through cell-cycle arrest. PI-tolerant MLL cells acquired cyclin A1 dependency, regulated directly by MLL protein. Loss of cyclin A1 function resulted in the emergence of drug tolerance, which was associated with patient relapse and reduced survival. Combination treatment with PI and deubiquitinating enzyme (DUB) inhibitors overcame this drug resistance by restoring cyclin A1 expression through chromatin crosstalk between histone H2B monoubiquitination and MLL-mediated histone H3 lysine 4 methylation. These results reveal the importance of cyclin A1-engaged cell-cycle regulation in PI resistance in MLL cells, and suggest that cell-cycle re-entry by DUB inhibitors may represent a promising epigenetic therapeutic strategy to prevent acquired drug resistance.

¿SARS-CoV-2 o Pneumocystis jirovecii? A propósito de un caso / SARS-CoV-2 or Pnuemocystis jirovecii? A case report

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Acute lymphoblastic leukemia-like treatment regimen provides better response in mixed phenotype acute leukemia: a comparative study between adults and pediatric MPAL patients.

Mixed phenotype acute leukemia (MPAL) is a rare type of leukemia with a limited number of studies conducted to characterize its clinical spectrum and most importantly the best treatment modality. MPAL blasts show more than one phenotype either myeloid/monocytic with T- or B-lymphoid or extremely rare triple lineage associated phenotypic markers. This study aimed to characterize MPAL cases with special emphasis on comparing adult and pediatric age groups, exploring treatment regimens, and clinical outcome. Among 2571 acute leukemia patients, 102 MPAL cases fulfilling the 2008/2016 WHO diagnostic criteria of MPAL were recruited in the study. The incidence of MPAL was 4% of acute leukemia patients. Pediatric cases were 54 (53%) while adults were 48/102 (47%). Myeloid/B-lymphoid phenotype was found in 86/102 (84%), with BCR-ABL fusion gene transcript detected in 14/102(13.7%) patients. ALL-like treatment showed better response rates as compared with the myeloid based regimen (p = 0.001). MPAL behaves in a manner that resembles in clinical features, their lymphoid progenitor counterpart leukemias both in adults and pediatric patients with superior treatment response to ALL-like regimen, especially in adults.

A case report of lineage switch from T-cell acute leukemia to B-cell acute leukemia.

RATIONALE: ALL is the most common form of leukemia (75% to 80%), it is characterized by clonal expansion of the lymphoid blasts in bone marrow, blood, and other tissues, which can be divided into T lineage and B lineage. Although relapse of acute leukemia is common, a change of immunophenotype at relapse only occurs rarely. Some of these cases have been labeled "lineage switch". PATIENT CONCERNS: A 31-year-old man had multiple lymph nodes in the neck, and the lymph nodes on the right side adhered to the surrounding tissues. His lymphocytes ratio in blood was up to 86.3%. Flow cytometry of the bone marrow aspirate showed positive results for CD2, CD5, CD7, cCD3, TDT, CD4, CD8, and CD10, negative results for CD34, CD117, CD33, HLA-DR, CD19, and CD20. Twenty six months later, the patient felt pain in the neck and shoulder after touching. His lymphocytes of blood were 109.9×109 /L. 43 fusion genes and positive BCR/ABL was detected. Flow cytometry of the bone marrow aspirate showed pro B lymphocytes accounted for 85.54%, and positive expression of CD38, CD10, CD34, CD33, TDT, CD9, and HLA-DR. Moreover, the RT-PCR data showed the patient expressed high level of T cell and B cell development transcription factors. DIAGNOSES: Upon examination, the patient was initially diagnosed with T-lineage pro cell ALL. BM morphologic analysis presented complete remission (CR) after systemic chemotherapy. Twenty six months later, we discovered the patient was diagnosed with B-lineage acute lymphocytic leukemia. INTERVENTIONS: Systemic chemotherapy is first given when a patient was diagnosed with T-cell acute lymphoblastic leukemia. After the patient happened linage switch, we adjusted the treatment plan, and the patient was complete remission after 1 course of treatment. OUTCOMES: Our case provides information of lineage switch from T-ALL to B-ALL in this report, which is never seen in our knowledge. LESSONS: This lineage switch from T-ALL to B-ALL is never reported beforemoreover, the RT-PCR data showed the patient expressed high level of T cell and B cell development transcription factors. Its early recognition can let doctor provides appropriate therapy to patient.

Tocilizumab en niño con leucemia linfoblástica aguda y síndrome de liberación de citoquinas asociado a COVID-19 / Tocilizumab in a child with acute lymphoblastic leukaemia and COVID-19-related cytokine release syndrome

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Favorable outcomes of acute leukemias of ambiguous lineage treated with hyperCVAD: a multi-center retrospective study.

Acute leukemias of ambiguous lineage (ALAL) are rare hematologic malignancies with poor outcomes. Retrospective studies have suggested that acute lymphoblastic leukemia (ALL) regimens are more effective than acute myeloid leukemia (AML) regimens. We retrospectively examined the effectiveness of the widely-used adult ALL regimen hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyperCVAD) as initial therapy in patients with ALAL at five academic institutions. Twenty-five patients were identified, including 23 with mixed phenotype acute leukemia (MPAL) and two with acute undifferentiated leukemia. Five of 8 tested (63%) had FLT3-ITD and 3 of 25 (12%) were Philadelphia chromosome-positive. The complete remission (CR) rate was 76%, with CR with incomplete count recovery (CRi) in an additional 8%, for an overall response rate of 84%. Median number of cycles to CR/CRi was 1. There were no deaths in the first 30 days. Of the 21 patients achieving CR or CRi, 14 (66%) proceeded to allogeneic hematopoietic stem cell transplantation. With a median follow-up time of 31.6 months, median overall survival for the entire cohort was not reached, and the estimated 2-year survival was 63%. HyperCVAD can be considered an effective and tolerable front-line regimen for patients with ALAL, and warrants further prospective study.

Exosomes mediate intercellular transfer of non-autonomous tolerance to proteasome inhibitors in mixed-lineage leukemia.

Proteasome inhibitors significantly improve cancer outcomes, but their use is eventually followed by proteasome inhibitor resistance and relapse. Current understanding of proteasome inhibitor resistance is limited to cell-autonomous mechanisms; whether non-autonomous mechanisms can be implicated in the development of proteasome inhibitor resistance is unclear. Here, we show that proteasome inhibitor tolerance can be transmitted non-autonomously through exosome-mediated intercellular interactions. We revealed that reversible proteasome inhibitor resistance can be transmitted from cells under therapy stress to naïve sensitive cells through exosome-mediated cell cycle arrest and enhanced stemness in mixed-lineage leukemia cells. Integrated multi-omics analysis using the Tied Diffusion through Interacting Events algorithm identified several candidate exosomal proteins that may serve as predictors for proteasome inhibitor resistance and potential therapeutic targets for treating refractory mixed-lineage leukemia. Furthermore, inhibiting the secretion of exosomes is a promising strategy for reversing proteasome inhibitor resistance in vivo, which provides a novel proof of principle for the treatment of other refractory or relapsed cancers.

Molecular Complete Remission Following Ivosidenib in a Patient With an Acute Undifferentiated Leukemia.

Acute undifferentiated leukemia (AUL) is a subtype of acute leukemias of ambiguous lineage. There is no standard treatment approach for AUL, although acute lymphoblastic leukemia-like regimens for induction therapy have been used. Additional data suggest that AUL may be better treated as acute myeloid leukemia (AML), given their similarities in genetic, cytogenetic, and gene expression patterns. Somatic mutations of IDH1 are found in 7% to 14% of patients with AML; however, the patient in this study was the first patient with IDH1-mutated AUL treated with ivosidenib. In this case, a woman aged 39 years was found to have anemia and thrombocytopenia after presenting to her primary care physician with fatigue, weight loss, and persistent infections. During further workup of the cytopenia, she was diagnosed with AUL and received 7+3 (daunorubicin, 60 mg/m2/d intravenously on days 1-3, and cytarabine, 100 mg/m2 24-hour continuous intravenous infusion on days 1-7) due to the presence of the IDH1 mutation. Bone marrow biopsy performed on day 14 of 7+3 showed persistent disease, and ivosidenib was initiated due to severe HLA alloimmunization (panel-reactive antibody, 100%) and significant bleeding complications. The patient achieved a complete morphologic and molecular remission on ivosidenib monotherapy despite critical bleeding complications during induction. Targeted therapy using ivosidenib may represent an encouraging therapeutic option in patients with AUL and IDH1 mutations. Additional evaluation of ivosidenib in this subgroup of patients with AUL is needed.

DOT1L: a key target in normal chromatin remodelling and in mixed-lineage leukaemia treatment.

Methylation of histone 3 at lysine 79 (H3K79) is one of the principal mechanisms involved in gene expression. The histone methyltransferase DOT1L, which mono-, di- and trimethylates H3K79 using S-adenosyl-L-methionine as a co-factor, is involved in cell development, cell cycle progression, and DNA damage repair. However, changes in normal expression levels of this enzyme are found in prostate, breast, and ovarian cancer. High levels of H3K79me are also detected in acute myeloid leukaemia patients bearing MLL rearrangements (MLL-r). MLL translocations are found in approximately 80% of paediatric patients, leading to poor prognosis. DOT1L is recruited on DNA and induces hyperexpression of HOXA9 and MEIS1. Based on these findings, selective drugs have been developed to induce apoptosis in MLL-r leukaemia cells by specifically inhibiting DOT1L. The most potent DOT1L inhibitor pinometostat has been investigated in Phase I clinical trials for treatment of paediatric and adult patients with MLL-driven leukaemia, showing promising results.

Longitudinal whole-genome sequencing reveals the evolution of MPAL.

PURPOSE: Mixed phenotype acute leukemia (MPAL) is a rare subtype of acute leukemia and its progressive genomic basis over time remains unclear. We aimed to investigate the longitudinal genomic evolution of MPAL from diagnosis to relapse. METHODS: We performed whole genome sequencing (WGS) on bone marrow (BM) samples obtained at the four stages of this disease in a male patient with Philadelphia chromosome positive (Ph+) MPAL, including primary, complete cytogenetic remission (CCR), complete molecular remission (CMR), and relapse stage during the 3 year follow-up period. RESULTS: 156 single-nucleotide variants (SNVs) and indels were detected, which exhibited distinctive evolutionary behaviors. Seventeen mutations disappeared quickly upon DCTER treatment and never came back. Seven mutations, although disappeared initially, reoccurred with the withdrawal of TKI treatment. Notably, ten mutations emerged in spite of the active DCTER chemotherapy. Moreover, copy number loss played critical roles in monitoring MPAL progression, displaying 7, 0, 0, and 383 losses at the stages of primary, CCR, CMR, and relapse respectively. CONCLUSION: This longitudinal genomic investigation of the Ph+ MPAL patient established one MPAL evolution model in which the primary tumor acquired additional variations leading to tumor relapse. Moreover, the event of copy number loss remained a valuable hallmark in the progression of MPAL.

Small molecular modulators of JMJD1C preferentially inhibit growth of leukemia cells.

Histone demethylases are promising therapeutic targets as they play fundamental roles for survival of Mixed lineage leukemia rearranged acute leukemia (MLLr AL). Here we focused on the catalytic Jumonji domain of histone H3 lysine 9 (H3K9) demethylase JMJD1C to screen for potential small molecular modulators from 149,519 natural products and 33,765 Chinese medicine components via virtual screening. JMJD1C Jumonji domain inhibitor 4 (JDI-4) and JDI-12 that share a common structural backbone were detected within the top 15 compounds. Surface plasmon resonance analysis showed that JDI-4 and JDI-12 bind to JMJD1C and its family homolog KDM3B with modest affinity. In vitro demethylation assays showed that JDI-4 can reverse the H3K9 demethylation conferred by KDM3B. In vivo demethylation assays indicated that JDI-4 and JDI-12 could induce the global increase of H3K9 methylation. Cell proliferation and colony formation assays documented that JDI-4 and JDI-12 kill MLLr AL and other malignant hematopoietic cells, but not leukemia cells resistant to JMJD1C depletion or cord blood cells. Furthermore, JDI-16, among multiple compounds structurally akin to JDI-4/JDI-12, exhibits superior killing activities against malignant hematopoietic cells compared to JDI-4/JDI-12. Mechanistically, JDI-16 not only induces apoptosis but also differentiation of MLLr AL cells. RNA sequencing and quantitative PCR showed that JDI-16 induced gene expression associated with cell metabolism; targeted metabolomics revealed that JDI-16 downregulates lactic acids, NADP+ and other metabolites. Moreover, JDI-16 collaborates with all-trans retinoic acid to repress MLLr AML cells. In summary, we identified bona fide JMJD1C inhibitors that induce preferential death of MLLr AL cells.

Potent antileukemic activity of curaxin CBL0137 against MLL-rearranged leukemia.

Around 10% of acute leukemias harbor a rearrangement of the MLL/KMT2A gene, and the presence of this translocation results in a highly aggressive, therapy-resistant leukemia subtype with survival rates below 50%. There is a high unmet need to identify safer and more potent therapies for MLL-rearranged (MLL-r) leukemia that can be combined with established chemotherapeutics to decrease treatment-related toxicities. The curaxin, CBL0137, has demonstrated nongenotoxic anticancer and chemopotentiating effects in a number of preclinical cancer models and is currently in adult Phase I clinical trials for solid tumors and hematological malignancies. The aim of our study was to investigate whether CBL0137 has potential as a therapeutic and chemopotentiating compound in MLL-r leukemia through a comprehensive analysis of its efficacy in preclinical models of the disease. CBL0137 decreased the viability of a panel of MLL-r leukemia cell lines (n = 12) and xenograft cells derived from patients with MLL-r acute lymphoblastic leukemia (ALL, n = 3) in vitro with submicromolar IC50s. The small molecule drug was well-tolerated in vivo and significantly reduced leukemia burden in a subcutaneous MV4;11 MLL-r acute myeloid leukemia model and in patient-derived xenograft models of MLL-r ALL (n = 5). The in vivo efficacy of standard of care drugs used in remission induction for pediatric ALL was also potentiated by CBL0137. CBL0137 exerted its anticancer effect by trapping Facilitator of Chromatin Transcription (FACT) into chromatin, activating the p53 pathway and inducing an Interferon response. Our findings support further preclinical evaluation of CBL0137 as a new approach for the treatment of MLL-r leukemia.