Frontline therapy of acute myeloid leukemia with lower intensity regimens: Where are we now and where can we go?

The advent of molecularly targeted therapeutics has transformed the management of patients with acute myeloid leukemia (AML). Particularly for individuals unfit for intensive chemotherapy, lower intensity therapies (LIT) incorporating small molecules have significantly improved patient outcomes. With BCL2, IDH1, IDH2, and FLT3 inhibitors widely used for relapsed AML, combination regimens are now utilized in the frontline. Expansion of these targeted LIT combinations, along with development of novel agents including menin inhibitors, exemplifies the promise of precision medicine. Further understanding of molecular drivers of leukemic transformation and mechanisms of relapse will continue to advance frontline treatment options for patients with AML.

Effect of Digital Health Coaching on Self-Efficacy and Patient-Reported Outcomes in Individuals with Acute Myeloid and Chronic Lymphocytic Leukemia: A Pilot Randomized Controlled Trial.

INTRODUCTION: Promotion of self-efficacy can enhance engagement with health care and treatment adherence in patients with cancer. We report the outcomes of a pilot trial of a digital health coach intervention in patients with leukemia with the aim of improving self-efficacy. METHODS: Adult patients with newly diagnosed acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) were randomized 1:1 to a digital health coach intervention or standard of care. The primary outcome of self-efficacy was measured by the Cancer Behavior Inventory (CBI) score. RESULTS: A total of 147 patients (37 AML, 110 CLL) were enrolled from July 2020 to December 2022. In the AML cohort, there was a mean increase in CBI score of 7.03 in the digital health coaching arm compared to a mean decrease of -3.57 in the control arm at 30 days (p = 0.219). There were no significant associations between the intervention and other patient-reported outcomes for patients with CLL. CONCLUSION: There were numerical, but not statistically significant increases in self-efficacy metrics in AML patients who received digital health coaching. Although this trial was underpowered due to enrollment limitations during a pandemic, digital health coaching may provide benefit to patients with hematologic malignancy and warrants further investigation.

Reverse Phase Proteomic Array Profiling of Asparagine Synthetase Expression in Newly Diagnosed Acute Myeloid Leukemia.

Asparaginase-based therapy is a cornerstone in acute lymphoblastic leukemia (ALL) treatment, capitalizing on the methylation status of the asparagine synthetase (ASNS) gene, which renders ALL cells reliant on extracellular asparagine. Contrastingly, ASNS expression in acute myeloid leukemia (AML) has not been thoroughly investigated, despite studies suggesting that AML with chromosome 7/7q deletions might have reduced ASNS levels. Here, we leverage reverse phase protein arrays to measure ASNS expression in 810 AML patients and assess its impact on outcomes. We find that AML with inv(16) has the lowest overall ASNS expression. While AML with deletion 7/7q had ASNS levels slightly lower than those of AML without deletion 7/7q, this observation was not significant. Low ASNS expression correlated with improved overall survival (46 versus 54 weeks, respectively, p = 0.011), whereas higher ASNS levels were associated with better response to venetoclax-based therapy. Protein correlation analysis demonstrated association between ASNS and proteins involved in methylation and DNA repair. In conclusion, while ASNS expression was not lower in patients with deletion 7/7q as initially predicted, ASNS levels were highly variable across AML patients. Further studies are needed to assess whether patients with low ASNS expression are susceptible to asparaginase-based therapy due to their inability to augment compensatory ASNS expression upon asparagine depletion.

Long-term results of the sequential combination of cladribine and rituximab in Hairy cell leukemia.

We report on the long-term efficacy and safety of a phase 2 trial of sequential cladribine and rituximab in hairy cell leukemia (HCL). One-hundred and thirty-nine patients were enrolled: 111 in the frontline setting, 18 in first relapse, and 10 with variant HCL (HCLv). A complete response (CR) was achieved in 133 of 137 evaluable participants (97%) with measurable residual disease (MRD) negativity in 102 (77%). MRD status was not associated with significant differences in event-free survival (EFS) or overall survival (OS). With a median follow-up of 7.8 years (range: 0.40-18.8), eight patients have experienced disease relapse (5.8%), 4/111 with newly diagnosed HCL (3·6%) and 4/10 with HCLv (40%) (p = 0.002). The 10-year EFS and OS rates were 86.7% and 91.1%, respectively. Grade 3 adverse events were observed in 28 participants (20·1%), mostly due to infections. Treatment of HCL with sequential cladribine followed by rituximab is associated with excellent efficacy and safety results both in the frontline and relapsed settings.

TP53 Mutations Are Associated with Increased Infections and Reduced Hematopoietic Cell Transplantation Rates in Myelodysplastic Syndrome and Acute Myeloid Leukemia.

Although allogeneic hematopoietic cell transplantation (HCT) is the sole potentially curative therapy for patients with poor-risk myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), only a minority of these patients undergo HCT. Patients with TP53-mutated (TP53MUT) MDS/AML are at particularly high risk, yet fewer TP53MUT patients undergo HCT compared with poor-risk TP53-wild type (TP53WT) patients. We hypothesized that TP53MUT MDS/AML patients have unique risk factors affecting the rate of HCT and thus investigated phenotypic changes that may prevent patients with TP53MUT MDS/AML from receiving HCT. In this single-center retrospective analysis of outcomes for adults with newly diagnosed MDS or AML (n = 352), HLA typing was used as a surrogate for physician "intent to transplant." Multivariable logistic regression models were used to estimate odds ratios (ORs) for factors associated with HLA typing, HCT, and pretransplantation infections. Multivariable Cox proportional hazards models were used to create predicted survival curves for patients with and those without TP53 mutations. Overall, significantly fewer TP53MUT patients underwent HCT compared to TP53WT patients (19% versus 31%; P = .028). Development of infection was significantly associated with decreased odds of HCT (OR, .42; 95% CI, .19 to .90) and worse overall survival (hazard ratio, 1.46; 95% CI, 1.09 to 1.96) in multivariable analyses. TP53MUT disease was independently associated with increased odds of developing an infection (OR, 2.18; 95% CI, 1.21 to 3.93), bacterial pneumonia (OR, 1.83; 95% CI, 1.00 to 3.33), and invasive fungal infection (OR, 2.64; 95% CI, 1.34 to 5.22) prior to HCT. Infections were the cause of death in significantly more patients with TP53MUT disease (38% versus 19%; P = .005). With substantially more infections and decreased HCT rates in patients with TP53 mutations, this raises the possibility that phenotypic changes occurring in TP53MUT disease may affect infection susceptibility in this population and drastically impact clinical outcomes.

Challenges and Advances in Chimeric Antigen Receptor Therapy for Acute Myeloid Leukemia.

The advent of chimeric antigen receptor (CAR) T-cell therapy has led to dramatic remission rates in multiple relapsed/refractory hematologic malignancies. While CAR T-cell therapy has been particularly successful as a treatment for B-cell malignancies, effectively treating acute myeloid leukemia (AML) with CARs has posed a larger challenge. AML not only creates an immunosuppressive tumor microenvironment that dampens CAR T-cell responses, but it also lacks many unique tumor-associated antigens, making leukemic-specific targeting difficult. One advantage of CAR T-cell therapy compared to alternative treatment options is the ability to provide prolonged antigen-specific immune effector and surveillance functions. Since many AML CAR targets under investigation including CD33, CD117, and CD123 are also expressed on hematopoietic stem cells, CAR T-cell therapy can lead to severe and potentially lethal myeloablation. Novel strategies to combat these issues include creation of bispecific CARs, CAR T-cell "safety switches", TCR-like CARs, NK CARs, and universal CARs, but all vary in their ability to provide a sustained remission, and consolidation with an allogeneic hematopoietic cell transplantation (allo-HCT) will be necessary in most cases This review highlights the delicate balance between effectively eliminating AML blasts and leukemic stem cells, while preserving the ability for bone marrow to regenerate. The impact of CAR therapy on treatment landscape of AML and changing scope of allo-HCT is discussed. Continued advances in AML CAR therapy would be of great benefit to a disease that still has high morbidity and mortality.