IntroductionChromosomal translocations often lead to creation of chimeric fusion genes that define cancer subtypes and act as initiating events in oncogenesis. Fusion genes can acquire novel biologic features via their fusion partners, yet retain important functions of the wild-type protein. When chromosomal rearrangements involve genes encoding DNA-binding proteins, chimeric fusion proteins can serve as aberrant transcription factors leading to genome-wide dysregulation in gene expression. Studies have shown that fusion transcription factors may gain novel specificity in target gene selection. The EWS/FLI1 oncogenic transcription factor modulates a specific set of genes that are not bound by wild-type FLI1 in vivo. 1 The AML1-ETO fusion protein preferentially binds to duplicated AML-1 DNA-binding sequences. 2 In acute promyelocytic leukemia (APL), the PML/RAR␣ fusion protein is selectively targeted to regions containing PU.1 consensus and RARE (retinoic acid response elements) half sites. The majority of those sites do not correspond to canonical RAREs. 3 Chromosomal translocations involving the MLL (mixed-lineage leukemia) gene result in the formation of a chimeric transcription factor. It remains unknown whether the MLL fusion protein shares the same set of target genes compared with the wild-type MLL protein.The histone methyltransferase MLL gene is frequently targeted by chromosomal translocations in acute myeloid, lymphoid, and biphenotypic leukemias, and rearrangement of MLL is associated with a poor prognosis. Wild-type MLL is critical for the maintenance of expression of its target genes. This activity is mediated by its carboxyl-terminal SET domain, which acts as a histone 3 lysine-4 (H3K4) methyltransferase. 4,5 The critical consequence of 11q23 chromosomal translocations is the formation of a chimeric oncogenic transcription factor that retains the N-terminus of MLL but replaces carboxyl-terminal domains with sequences from its partner proteins. As a result of 11q23 gene rearrangements, MLL fuses in frame with Ͼ 60 different partner proteins. 6 The most common partners are AF4, AF9, ENL, AF10, and ELL, which together account for Ͼ 85% of all MLL-rearranged leukemias. AF4, ENL, AF9, and AF10 form a complex that promotes H3K79 methylation through recruitment of histone methyltransferase DOT1L. 7,8 Aberrant H3K79 methylation has been shown to be a key molecular mechanism in MLL fusion-induced dysregulation of gene expression. 9,10 MLL is targeted to a specific set of gene loci, presumably via its own DNA binding domain, recognition of local histone modifications, and/or recruitment by sequence-specific transcription factors. 11 However, the target genes of MLL fusion proteins compared with wild-type MLL remain poorly understood. In MLL-AF4-expressing mouse acute lymphoid leukemia cells, thousands of gene promoters exhibited increased levels of H3K79 methylation in comparison to normal control lymphocytes, suggesting MLL-AF4 has widespread targets in the leukemic genome. 12 In contrast, by looking for co...

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.

The NCCN Guidelines for Acute Lymphoblastic Leukemia (ALL) focus on the classification of ALL subtypes based on immunophenotype and cytogenetic/molecular markers; risk assessment and stratification for risk-adapted therapy; treatment strategies for Philadelphia chromosome (Ph)-positive and Ph-negative ALL for both adolescent and young adult and adult patients; and supportive care considerations. Given the complexity of ALL treatment regimens and the required supportive care measures, the NCCN ALL Panel recommends that patients be treated at a specialized cancer center with expertise in the management of ALL This portion of the Guidelines focuses on the management of Ph-positive and Ph-negative ALL in adolescents and young adults, and management in relapsed settings.

Survival outcomes for older adults with acute lymphoblastic leukemia (ALL) are poor and optimal management is challenging due to higher-risk leukemia genetics, comorbidities, and lower tolerance to intensive therapy. A critical understanding of these factors guides the selection of frontline therapies and subsequent treatment strategies. In addition, there have been recent developments in minimal/measurable residual disease (MRD) testing and blinatumomab use in the context of MRD-positive disease after therapy. These NCCN Guidelines Insights discuss recent updates to the NCCN Guidelines for ALL regarding upfront therapy in older adults and MRD monitoring/testing in response to ALL treatment.

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