Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study

Karol, Seth E.; Alexander, Thomas; Budhraja, Amit; Pounds, Stanley; Canavera, Kristin; Wang, Lei; Wolf, Joshua; Klco, Jeffery M.; Mead, Paul E.; Gupta, Saurabh; Kim, Su Y.; Salem, Ahmed Hamed; Palenski, Tammy L.; Lacayo, Norman J.; Pui, Ching‐Hon; Opferman, Joseph T.; Rubnitz, Jeffrey E.

doi:10.1016/s1470-2045(20)30060-7

Cited by 104 publications

(102 citation statements)

References 29 publications

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“…S6). A best response of CR/CR i /CR p was achieved by 61.5% (n = 8/13), 42.9% (n = 3/7), 50.0% (n = 3/6), and 53.8% (n = 7/13) of patients previously treated with blinatumomab, inotuzumab ozogamicin, CAR T-cell therapy, and HCT, respectively. Of the 4 patients who had received prior venetoclax, 1 patient achieved CR i .…”

Section: Efficacymentioning

confidence: 98%

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Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

et al. 2021

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Combining venetoclax, a selective BCL-2 inhibitor, with low-dose navitoclax, a BCL-X L /BCL-2 inhibitor, may allow targeting of both BCL-2 and BCL-X L without dose-limiting thrombocytopenia associated with navitoclax monotherapy. The safety and preliminary efficacy of venetoclax with low-dose navitoclax and chemotherapy was assessed in this phase I dose escalation study (NCT03181126) in pediatric and adult patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Forty-seven patients received treatment. A recommended phase II dose of 50 mg navitoclax for adults and 25 mg for patients <45 kg with 400 mg adultequivalent venetoclax was identified. Delayed hematopoietic recovery was the primary safety finding. The complete remission rate was 60%, including responses in patients who had previously received hematopoietic cell transplantation or immunotherapy. Thirteen patients (28%) proceeded to transplantation or CAR T-cell therapy on study. Venetoclax with navitoclax and chemotherapy was well tolerated and had promising efficacy in this heavily pretreated patient population. Statement of Significance In this phase I study, venetoclax with low-dose navitoclax and chemotherapy was well tolerated and had promising efficacy in patients with relapsed/refractory acute lymphoblastic leukemia or lymphoblastic lymphoma. Responses were observed in patients across histological and genomic subtypes and in those who failed available therapies including stem cell transplant. Research.

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Section: Efficacymentioning

confidence: 98%

“…Cryopreserved blood or bone marrow cells were stained with B-, T-, or ETP-ALL-specific surface antibodies and permeabilized as previously described (42)(43)(44). BAD, BID, HRK, and NOXA peptides were tested for induction of cytochrome c loss from the mitochondria of digitonin-permeabilized blasts.…”

Section: Bh3 Profiling By Intracellular Staining (Ibh3)mentioning

confidence: 99%

Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

et al. 2021

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“…In adults, venetoclax with HMAs or low-dose cytarabine is both tolerable and improves response rates when used as part of low-intensity front-line therapies, but its utility in relapse remains unclear [ 90 ]. Pediatric studies are still in early phases, but initial studies demonstrated a CR of 70% when used in combination with cytarabine with or without idarubicin [ 91 ]. Preclinical studies also suggest that venetoclax works synergistically with FLT3 inhibitors midostaurin and gilteritinib to induce apoptosis in AML cells, and may provide another therapeutic avenue [ 92 ].…”

Section: New Therapymentioning

confidence: 99%

Acute Myeloid Leukemia in Children: Emerging Paradigms in Genetics and New Approaches to Therapy

Conneely

Stevens

2021

Curr Oncol Rep

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Purpose of Review Acute myeloid leukemia (AML) in children remains a challenging disease to cure with suboptimal outcomes particularly when compared to the more common lymphoid leukemias. Recent advances in the genetic characterization of AML have enhanced understanding of individualized patient risk, which has also led to the development of new therapeutic strategies. Here, we review key cytogenetic and molecular features of pediatric AML and how new therapies are being used to improve outcomes. Recent Findings Recent studies have revealed an increasing number of mutations, including WT1, CBFA2T3-GLIS2, and KAT6A fusions, DEK-NUP214 and NUP98 fusions, and specific KMT2A rearrangements, which are associated with poor outcomes. However, outcomes are starting to improve with the addition of therapies such as gemtuzumab ozogamicin and FLT3 inhibitors, initially developed in adult AML. Summary The combination of advanced risk stratification and ongoing improvements and innovations in treatment strategy will undoubtedly lead to better outcomes for children with AML.

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“…In our case, because of his high‐risk features and unknown donor options at the time of CMML diagnosis, the decision was made to initiate therapy to prevent progression prior to HSCT. Although standard AML induction was considered, ultimately we chose a more well‐tolerated regimen with evidence of activity and tolerance in pediatric AML 24,25 . Based on preclinical synergy, hypomethylating agents combined with venetoclax, a small molecular inhibitor of the BCL‐2 protein, 26,27 has been shown to be well tolerated in AML 1,28–31 .…”

Section: Figurementioning

confidence: 99%

“…Although standard AML induction was considered, ultimately we chose a more well-tolerated regimen with evidence of activity and tolerance in pediatric AML. 24,25 Based on preclinical synergy, hypomethylating agents combined with venetoclax, a small molecular inhibitor of the BCL-2 protein, 26,27 has been shown to be well tolerated in AML. 1,[28][29][30][31] Our patient tolerated this regimen and achieved disease stabilization, effectively bridging him to HSCT.…”

Section: G Aspirate With Normal Maturing Hematopoiesis (Wg 1000×) Hmentioning

confidence: 99%

Venetoclax/decitabine for a pediatric patient with chronic myelomonocytic leukemia

Molina

Asare

Tuschong

et al. 2020

Pediatric Blood & Cancer

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Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS)/myeloproliferative disorder most commonly seen in the elderly. We describe an adolescent with monosomy 7 CMML presenting as central diabetes insipidus (DI), who was treated with venetoclax and decitabine as a bridge to hematopoietic stem cell transplantation (HSCT). Central DI is a rare manifestation of monosomy 7-associated MDS including CMML, itself a rare manifestation of GATA2 deficiency, particularly in children. Venetoclax/decitabine was effective for treatment of CMML as a bridge to HSCT. Chronic myelomonocytic leukemia (CMML) is a myelodysplastic syndrome (MDS)/myeloproliferative disorder most commonly seen in the elderly. 1,2 We describe an adolescent with GATA2 associated monosomy 7 CMML presenting as central diabetes insipidus (DI), who was Abbreviations: AML, acute myelogenous leukemia; CMML, chronic myelomonocytic leukemia; DDAVP, desmopressin; DI, diabetes insipidus; HSCT, hematopoietic stem cell transplantation; MDS, myelodysplastic syndrome; MRI, magnetic resonance imaging successfully treated with venetoclax and decitabine as a bridge to hematopoietic stem cell transplantation (HSCT). A 15-year-old adolescent male presented to the National Institutes of Health (NIH) for initial evaluation of GATA2 deficiency on the Natural History of GATA2 Deficiency Study (Clinicaltrials.gov NCT01905826) based on his mother and aunt's known diagnoses of GATA2 deficiency. His mother was successfully transplanted for MDS from a partially matched sibling 15 years earlier. Previous sequencing

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Venetoclax in combination with cytarabine with or without idarubicin in children with relapsed or refractory acute myeloid leukaemia: a phase 1, dose-escalation study

Cited by 104 publications

References 29 publications

Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Venetoclax and Navitoclax in Combination with Chemotherapy in Patients with Relapsed or Refractory Acute Lymphoblastic Leukemia and Lymphoblastic Lymphoma

Acute Myeloid Leukemia in Children: Emerging Paradigms in Genetics and New Approaches to Therapy

Venetoclax/decitabine for a pediatric patient with chronic myelomonocytic leukemia

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