Acute Myeloid Leukemia, Version 3.2023, NCCN Clinical Practice Guidelines in Oncology.

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of myeloid blasts in the peripheral blood, bone marrow, and/or other tissues. It is the most common form of acute leukemia among adults and accounts for the largest number of annual deaths from leukemias in the United States. Like AML, blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a myeloid malignancy. It is a rare malignancy characterized by the aggressive proliferation of precursors of plasmacytoid dendritic cells that frequently involves the bone marrow, skin, central nervous system, and other organs and tissues. This discussion section focuses on the diagnosis and management of BPDCN as outlined in the NCCN Guidelines for AML.

Cellular and Molecular Biomarkers Predictive of Response to Immunotherapy in Acute Myeloid Leukemia.

Immunotherapy has without question revolutionized the treatment of both hematologic and solid malignancies. Over the last several years novel strategies are being developed to incorporate these groundbreaking therapies into the care of patients with AML. Here we present an overview of the recent developments in immunotherapy for AML with a focus on biomarkers of response. Topics reviewed include antibody drug conjugates, BiTEs, DARTs, checkpoint inhibitors, and cellular therapy as well as the development of biomarkers predictive of response in each class.

Targeting acute myeloid leukemia through multimodal immunotherapeutic approaches.

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy with a dismal prognosis. Immunotherapeutic approaches using single agent checkpoint inhibitors have thus far shown limited success. We hypothesized that successful adaptive anti-AML specific immune responses require additional modulation of innate immunity. DMXAA exposure resulted in modest apoptosis of C1498 AML cells with a subtle increase in PD-L1 expression and limited production of IL-6 and IFN-ß. In contrast, DMXAA + anti-PD-1 ab, but not either agent alone, significantly decreased in vivo disease burden and prolonged overall survival in C1498 engrafted leukemic mice. Combination-treated mice demonstrated increased memory T-cells and mature dendritic cells, lower numbers of regulatory T-cells and evidence of leukemia apoptosis. Furthermore, these effects were associated with markedly increased serum levels of type I interferon (IFN) and IFN gamma. We demonstrate that combining an innate immune agonist with a checkpoint inhibitor synergistically improved anti-tumor activity in a preclinical AML model.

Emerging trends of therapy related myeloid neoplasms following modern cancer therapeutics in the United States.

Clonal hematopoiesis (CH) is a risk factor for the development of therapy-related myelodysplastic syndromes (tMDS) and acute myeloid leukemia (tAML). Adoption of targeted-immunotherapeutics since 2011, may alter the risk of CH progression to tMDS/AML. To study this, we evaluated risk of tMDS and tAML in 667 588 ≥ 1-year survivors of non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), melanoma and multiple-myeloma (MM) diagnosed during: 2000-2005, 2006-2010 and 2011-2016. The risk of tMDS increased significantly after NSCLC across all time periods (Ptrend = 0.002) while tAML risk decreased from 2006-2010 to 2011-2016, coinciding with increasing use of non-chemotherapeutic agents. tAML risk after RCC decreased (Ptrend = 0.007) whereas tMDS risk did not significantly change over time. After melanoma, tMDS and tAML risks were similar to the general population. tMDS and tAML risk after MM increased from the first to second time-period, however, only risk of tMDS decreased during last period. We report diverging trends in the risk of tAML and tMDS after adoption of modern cancer therapies for specific cancers. It is imperative to further explore impact of contemporary treatment strategies on clonal evolution. Modern treatments via their discrete mechanism of actions on pre-existing CH may alter the risk of subsequent tMDS and tAML.

Acute Lymphoblastic Leukemia, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

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.

Outcomes of Adult Acute Myeloid Leukemia Treated With Gemtuzumab-Ozogamicin: Cue To Optimized Chemotherapy Backbone.

BACKGROUND: The optimal approach to combine gemtuzumab-ozogamicin (GO) with various chemotherapy backbones and other newer agents safely remains to be determined. MATERIALS AND METHODS: We performed a retrospective analysis of the safety and outcomes of adult patients with newly diagnosed acute myeloid leukemia (AML) treated with GO with intensified versus standard anthracycline doses (daunorubicin dose 90 mg/m2 vs 60 mg/m2) ± FLT3 inhibitors. The χ2 test and Mann-Whitney U test were used to compare categorical and continuous data. Survival estimates were calculated by Kaplan-Meier method and survival comparisons made using log-rank test. RESULTS: We report a 97% overall response rate in 34 patients with newly diagnosed AML with a median age of 54 years (19-75 years) treated with GO and standard induction. The 11 patients (100%) receiving GO plus daunorubicin dose 90 mg/m2 as part of 7 + 3 induction achieved complete response versus 91% (20/22) complete response in the standard daunorubicin dose group (P = NS). No increased toxicity was noted with the higher daunorubicin dose or when GO and 7 + 3 were combined with FLT3 inhibitors in 3 younger patients (<60 years). Two older patients treated with GO+7 + 3 and FLT3i experienced grade 3 or higher cardiotoxicity. We observed a longer estimated event-free survival for patients with newly diagnosed AML in our cohort (median, 24 months; 95% confidence interval, 17.2 to not reached) compared with historical data. CONCLUSION: We demonstrate that anthracycline dose intensification with GO may offer higher response rates without increased toxicity in younger patients presenting with de novo AML across European Leukemia Net risk categories.

NCCN Guidelines Insights: Acute Myeloid Leukemia, Version 2.2021.

The NCCN Guidelines for Acute Myeloid Leukemia (AML) provide recommendations for the diagnosis and treatment of adults with AML based on clinical trials that have led to significant improvements in treatment, or have yielded new information regarding factors with prognostic importance, and are intended to aid physicians with clinical decision-making. These NCCN Guidelines Insights focus on recent select updates to the NCCN Guidelines, including familial genetic alterations in AML, postinduction or postremission treatment strategies in low-risk acute promyelocytic leukemia or favorable-risk AML, principles surrounding the use of venetoclax-based therapies, and considerations for patients who prefer not to receive blood transfusions during treatment.

PARP goes the weasel! Emerging role of PARP inhibitors in acute leukemias.

Poly (ADP-ribose) polymerase (PARP) inhibitors, which induce synthetic lethality of BRCA mutant breast and ovarian cancers, are now under active exploration for treatment of acute leukemias, specifically acute myeloid leukemia (AML). Experimental data has revealed that DNA repair deficiencies similar to those found in BRCA mutant solid tumors function in malignant hematopoietic cells to enhance cell survival and promote therapy resistance. Preclinical studies have demonstrated that inhibition of PARP with a variety of agents can dramatically enhance the efficacy of other therapeutic approaches including cytotoxic and epigenetic chemotherapy, small molecule inhibitors (IDH and FLT3 inhibitors) and antibody drug conjugates. This has led to early stage clinical trials of multiple PARP inhibitors (PARPi) for AML patients. Despite small patient numbers, evidence of modest clinical efficacy and tolerability in combinatorial regimens support the further development of PARP inhibition as a novel therapeutic strategy for AML, particularly in select molecular subsets (MLL rearranged, FLT3 and IDH1 mutant disease.

Herpes zoster during arsenic trioxide therapy for acute promyelocytic leukemia.

Historically, arsenic exposure has been associated with herpes zoster (HZ) infection, however the risk is not well characterized in arsenic trioxide (ATO) treated patients with acute promyelocytic leukemia (APL). We aimed to characterize the risk of HZ in 112 ATO treated patients with APL with and without antiviral prophylaxis (AVP). HZ occurred in 13/112 (11.6%) within 6 months of completing ATO, including one case of HZ encephalitis. AVP reduced the incidence of HZ (17.5% vs. 4.1%, RR 0.24 [95% CI 0.05-1.0, p = .025]) with a number needed to treat of 7.7. HZ despite AVP occurred later than HZ in patients without AVP (7.8 vs. 2.3 months from starting ATO, p = .11). Older age and prior HZ increased the risk of HZ in patients not receiving AVP. Routine AVP should be considered in patients with APL receiving ATO, particularly in older patients and those with a history of HZ.

Low-Level Cytomegalovirus Antigenemia Promotes Protective Cytomegalovirus Antigen-Specific T Cells after Allogeneic Hematopoietic Cell Transplantation.

Previous studies have reported a beneficial effect from cytomegalovirus (CMV) reactivation after allogeneic hematopoietic stem cell transplantation (alloHCT) on immune reconstitution. We determined the CMV antigenemia level associated with increased CMV antigen-specific T cells (CASTs) at day +100 and decreased CMV reactivation after day +100. CMV reactivation and CASTs were measured with CMV antigenemia and CMV-specific major histocompatibility complex multimers. The analysis consisted of 775 CAST measurements obtained before and 30, 100, and 365 days post-alloHCT from 327 consecutive patients treated between 2008 and 2016. Detectable CASTs correlated with recipient (P < .0001) and donor (P < .0001) CMV seropositivity pre-alloHCT. CMV reactivation before day +100 was associated with a higher proportion of patients who achieved ≥3 CASTs/µL by day +100 (61% with versus 39% without reactivation, P < .001). In alloHCT recipients at high risk for CMV reactivation (R+D±) with a maximum of grade II acute graft-versus-host-disease, reactivating CMV before day +100 and achieving ≥3 versus <3 CASTs/µL at day +100 was associated with reduced CMV reactivation from day +100 to +365 (27% versus 62%, P = .04). This protective effect was observed with low-level but not high-level CMV reactivation (<5 versus ≥5/50,000 polymorphonuclear leukocytes + pp65, respectively). These findings suggest low-level CMV reactivation may be beneficial and that treatment may be delayed until progression. These findings will need validation in prospective clinical trials using CMV PCR and antigenemia assays.

Comparison of induction strategies and responses for acute myeloid leukemia patients after resistance to hypomethylating agents for antecedent myeloid malignancy.

Outcomes in patients with secondary acute myeloid leukemia (sAML) (including therapy related myeloid neoplasms and AML with myelodysplasia related changes (MRC)) are poor. Patients treated with hypomethylating agents (HMAs) for antecedent hematological malignancy (AHM) have suboptimal responses to induction chemotherapy upon transformation to AML. We investigated outcomes after various induction strategies in patients with sAML who had prior HMA exposure. We identified 242 patients with sAML who had prior HMA treatment for AHM and later received induction chemotherapy upon AML transformation and divided into 3 cohorts based on induction regimen: (A) CLAG/M (B) 7 + 3 and (C) CPX-351. The CR/CRi rate was 53% in cohort A, 32% in cohort B and 41.2% in cohort C (p = 0.005 between cohort A and B) (p = 0.329 between cohorts A and C) (p = 0.402 between cohorts B and C). The early death rates were not significantly different among the three cohorts (p = 0.200). In patients who received ≤4 cycles of HMAs prior to AML transformation, response rates to CPX-351 were higher (64.3%) with a trend toward better overall survival (OS) (19.9 vs. 5.5 months) compared to >4 cycles (p = 0.092). There was no significant difference in median OS among the 3 groups: cohort A (7.27 months), cohort B (7.63 months) and cohort C (7.07 months) (p = 0.887). We demonstrate that CLAG/M and CPX-351 yield higher CR/CRi rates compared to 7 + 3 in patients with sAML after HMA failure. Median OS remains poor and did not differ among the 3 groups, illustrating the unmet need for more efficacious therapy for sAML patients following HMA failure.

BITES and CARS and checkpoints, oh my! Updates regarding immunotherapy for myeloid malignancies from the 2018 annual ASH meeting.

It is without question that immune checkpoint inhibitors and adoptive cellular therapies have revolutionized the treatment of solid and hematologic malignancies. Investigators are now developing novel strategies to integrate these groundbreaking modalities into the care of patients with acute myeloid leukemia (AML) and other myeloid malignancies. Here we provide an overview of the most recent developments in immunotherapy for myeloid cancers presented at the 2018 American Society of Hematology annual meeting. Topics discussed include adoptive cellular therapies (CAR-T, NK cell, and vaccines), checkpoint inhibitors, and bispecific T-cell engager (BITE) antibodies. Despite reservations regarding low antigenicity and having long been considered a "cold" tumor, immunotherapy remains a highly promising strategy for patients with aggressive myeloid cancers like myelodysplasia (MDS) and AML.

Predictors of vascular disease in myelodysplastic syndromes.

The escalating link between somatic mutations commonly seen in myelodysplastic syndromes (MDS) and atherosclerotic vascular disease has increased the interest in management and associations of these conditions. We present a retrospective study examining clinical and molecular variables associated with vascular disease in patients with MDS. This study included a comprehensive evaluation of 236 patients with MDS. Our study has multiple findings. Mutations in ASXL1 correlated with increased risk of vascular disease for the entire cohort (P = .013). Though this has been replicated in other studies, there are no guidelines at this time for preventing vascular events in these patients. Our study also showed that lower ferritin levels may be linked to increased vascular events (P = .043), therefore the optimal use of supportive red blood cell transfusions in patients with MDS and the overall impact of inflammatory markers such as erythrocyte sedimentation rate and c-reactive protein should be re-addressed. Furthermore, our study showed that patients with Trisomy 8 in the low-risk MDS cohort (based on IPSS-R scores) were protected from vascular events (P = .036). Our findings of lower ferritin being linked with increased risk of vascular events as well as patients with Trisomy 8 being protected from vascular events may impact patient care. There do not appear to be any prior studies with these findings. In addition, given the connection between MDS and atherosclerotic vascular disease, we believe guideline-based management of cardiac risk factors among MDS patients may improve overall outcomes. Further studies with larger patient cohorts are needed to further investigate these findings.

Advancing treatment of acute myeloid leukemia: the future of FLT3 inhibitors.

INTRODUCTION: Mutations of the FLT3 gene are among most common genetic abnormalities occurring in acute myeloid leukemia (AML) and are associated with dismal prognosis. Tremendous effort has been devoted to developing clinically effective FLT3 inhibitors. First generation inhibitors consisted of multi-kinase inhibitors (sorafenib, lestaurtinib, midostaurin), which blocked FLT3 as well as multiple other kinase receptors. The failure of these agents to induce durable responses led to the development of second generation FLT3 tyrosine kinase inhibitors (quizartinib, crenolinib, gilteritinib) exhibiting high potency and specificity for mutant FLT3 kinases and sustained in vivo FLT3 inhibition. These myriad FLT3 inhibitors possess diverse kinase inhibitory properties, toxicity profiles, and pharmacokinetics, which impact on their incorporation into therapeutic regimens. Areas covered: This article reviews the medical literature on current and future FLT3 inhibitors for AML therapy. We provide algorithms for which kinase inhibitor should be utilized for different FLT3 mutations (ITD±TKD) and clinical scenarios (de novo, relapsed/refractory, fit vs. unfit) and discuss novel FLT3 targeted therapeutic approaches. Expert commentary: Integration of clinically active FLT3 inhibitors into all stages of therapy for all individuals with FLT3 mutant AML promises to significantly improve outcomes for this poor prognosis disease.

Advances in immunotherapy for acute myeloid leukemia.

Evasion of the host immune system is a key mechanism to promote malignant progression. Therapeutically targeting immune pathways has radically changed the treatment paradigm for solid and lymphoid tumors but has yet to be approved for myeloid malignancies. Here, we summarize the most recent advances in immunotherapy for acute myeloid leukemia. Topics reviewed here include adoptive cellular approaches (chimeric antigen receptor-T cells, natural killer and other immune cells), checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA-4 and TIM-3) and vaccines (WT-1, HLA-A2 and hTERT). Emphasis is placed on agents with clear evidence of tumor-specific immune responses and/or clinical activity in early-phase trials. Despite concerns regarding heterogeneous antigen expression and cytokine release syndrome, immunotherapy remains a highly promising strategy for acute myeloid leukemia, particularly transplant-ineligible patients and minimal residual disease states.

Inhibitors of LSD1 as a potential therapy for acute myeloid leukemia.

INTRODUCTION: Epigenetic dysregulation plays a critical role in the pathogenesis of acute myeloid leukemia (AML). Alterations in histone methylation lead to aberrant silencing of expression of multiple genes involved in tumor suppression and cell cycling, resulting in myeloid maturation arrest and proliferation of early myeloid progenitors. One promising approach targeting chromatin regulatory proteins is inhibition of lysine specific demethylase-1 (LSD1), an enzyme responsible for demethylation of histone H3 as well as other functions AREAS COVERED: Available literature on LSD1 in normal and malignant hematopoiesis was identified in PubMed and reviewed. Areas addressed here include the biology of LSD1, pharmacologic inhibitors, and preclinical data supporting the rationale for LSD1 inhibition in AML therapy. EXPERT OPINION: LSD1 inhibitors represent a promising novel epigenetic approach for AML therapy. Preclinical studies have revealed that pharmacologic LD1 inhibitors function primarily by altering stem cell programs and restoring myeloid differentiation to AML cells. These effects are markedly enhanced in combination with trans-retinoic acid or histone deacetylase inhibitors with little toxicity. Currently, multiple oral LSD1 inhibitors are undergoing phase 1 investigation in patients with AML. The results of these clinical trials are eagerly awaited.