A comprehensive case study on successful multimodal therapy in philadelphia chromosome-positive acute myeloid leukemia with NPM1 and IDH2 mutations.

A 67-year-old female came to Tampa General Hospital with Philadelphia chromosome-positive (Ph+) acute myeloid leukemia (AML) featuring an intriguing combination of mutations, including NPM1 and IDH2 mutations. Novel combination therapy with azacitidine, venetoclax and ponatinib allowed her to successfully achieve a complete response (CR) and undergo an allogeneic hematopoietic stem cell transplant (HSCT). This case report provides an overview of her clinical course, emphasizing the significance of integrated therapy and the challenges associated with balancing treatment for AML. It also underscores the importance of a multidisciplinary approach and careful monitoring of patients with complex hematologic conditions.

Clonal Hematopoiesis Is Associated with Increased Risk of Severe Neurotoxicity in Axicabtagene Ciloleucel Therapy of Large B-Cell Lymphoma.

To explore the role of clonal hematopoiesis (CH) in chimeric antigen receptor (CAR) T-cell therapy outcomes, we performed targeted deep sequencing on buffy coats collected during the 21 days before lymphodepleting chemotherapy from 114 large B-cell lymphoma patients treated with anti-CD19 CAR T cells. We detected CH in 42 (36.8%) pretreatment samples, most frequently in PPM1D (19/114) and TP53 (13/114) genes. Grade ≥3 immune effector cell-associated neurotoxicity syndrome (ICANS) incidence was higher in CH-positive patients than CH-negative patients (45.2% vs. 25.0%, P = 0.038). Higher toxicities with CH were primarily associated with DNMT3A, TET2, and ASXL1 genes (DTA mutations). Grade ≥3 ICANS (58.9% vs. 25%, P = 0.02) and ≥3 cytokine release syndrome (17.7% vs. 4.2%, P = 0.08) incidences were higher in DTA-positive than in CH-negative patients. The estimated 24-month cumulative incidence of therapy-related myeloid neoplasms after CAR T-cell therapy was higher in CH-positive than CH-negative patients [19% (95% CI, 5.5-38.7) vs. 4.2% (95% CI, 0.3-18.4), P = 0.028]. SIGNIFICANCE: Our study reveals that CH mutations, especially those associated with inflammation (DNMT3A, TET2, and ASXL1), are associated with severe-grade neurotoxicities in lymphoma patients receiving anti-CD19 CAR T-cell therapy. Further studies to investigate the mechanisms and interventions to improve toxicities in the context of CH are warranted. See related content by Uslu and June, p. 382. This article is highlighted in the In This Issue feature, p. 369.

PET/CT scan and biopsy-driven approach for safe anti-PD-1 therapy discontinuation in patients with advanced melanoma.

BACKGROUND: Limited data exist on safe discontinuation of antiprogrammed cell death protein 1 (PD-1) therapy in responding patients with advanced melanoma. The use of 18fluorodeoxyglucose (18FDG)-PET/CT scan and tumor biopsy for assessment of active disease may be an effective predictive biomarker to guide such treatment decisions. METHODS: A retrospective study of 122 patients with advanced melanoma treated with anti-PD-1 monotherapy or anti-PD-1/anticytotoxic T-lymphocyte-associated protein 4 combination therapy at Georgetown Lombardi Comprehensive Cancer Center was conducted. Uveal melanoma patients and those receiving concurrent experimental therapy were excluded. Baseline characteristics, treatment outcomes, and survival were analyzed. Patients who decided to come off treatment typically after 12 months using CT scan radiographic complete response (CR), 18FDG-PET/CT scan complete metabolic response (CMR) or tumor biopsy of a non-CR/CMR tumor site negative for active disease (possible pathological CR) were identified and compared with patients who discontinued treatment due to toxicity while their disease was in control. Event-free survival (EFS) was assessed from the last dose of anti-PD-1 therapy to progression requiring subsequent treatment (surgery, radiation, and/or systemic therapy) or referral to hospice/death due to melanoma. RESULTS: 24 (20%) patients discontinued treatment by choice with no active disease and 28 (23%) patients discontinued treatment due to toxicity with disease control after 12-month and 4-month median treatment durations, respectively. Similar baseline characteristics were observed between cohorts except higher prior receipt of ipilimumab (29% vs 7%; p=0.036) and fewer BRAF mutant positive disease (17% vs 41%; p=0.064) in patients off treatment by choice. Three-year EFS rates were 95% and 71%, respectively. No significant associations between EFS and sex, disease stage, lactate dehydrogenase elevation, BRAF status, prior systemic therapy, ECOG performance status, presence of brain metastases, or combination versus monotherapy were observed. Tumor biopsies led to alternative management in 3/10 patients due to active metastatic melanoma or second malignancy. CONCLUSIONS: Anti-PD-1 therapy discontinuation after 12 months when no active disease is observed on CT scan, PET/CT scan or tumor biopsy may have low rates of disease relapse in patients with advanced melanoma. Biopsy of residual disease may frequently lead to a change in management. These findings are undergoing validation in the EA6192 trial.

Genomic characteristics and prognostic significance of co-mutated ASXL1/SRSF2 acute myeloid leukemia.

The ASXL1 and SRSF2 mutations in AML are frequently found in patients with preexisting myeloid malignancies and are individually associated with poor outcomes. In this multi-institutional retrospective analysis, we assessed the genetic features and clinical outcomes of 43 patients with ASXL1mut SRSF2mut AML and compared outcomes to patients with either ASXL1 (n = 57) or SRSF2 (n = 70) mutations. Twenty-six (60%) had secondary-AML (s-AML). Variant allele fractions suggested that SRSF2 mutations preceded ASXL1 mutational events. Median overall survival (OS) was 7.0 months (95% CI:3.8,15.3) and was significantly longer in patients with de novo vs s-AML (15.3 vs 6.4 months, respectively; P = .04 on adjusted analysis). Compared to ASXL1mut SRSF2wt and ASXL1wt SRSF2mut , co-mutated patients had a 1.4 and 1.6 times increase in the probability of death, respectively (P = .049), with a trend towards inferior OS (median OS = 7.0 vs 11.5 vs 10.9 months, respectively; P = .10). Multivariable analysis suggests this difference in OS is attributable to the high proportion of s-AML patients in the co-mutated cohort (60% vs 32% and 23%, respectively). Although this study is limited by the retrospective data collection and the relatively small sample size, these data suggest that ASXL1mut SRSF2mut AML is a distinct subgroup of AML frequently associated with s-AML and differs from ASXL1mut SRSF2wt /ASXL1wt SRSF2mut with respect to etiology and leukemogenesis.

The promise of macrophage directed checkpoint inhibitors in myeloid malignancies.

To date, many of the most successful checkpoint inhibitor-based therapies in cancer have targeted T-cells and adaptive immunity. However, there is an ongoing search for novel checkpoints with targeting innate immunity via activation of macrophage phagocytosis representing an exciting therapeutic strategy. CD47 is the dominant negative macrophage immune checkpoint expressed on cancer cells which acts as a "don't eat me signal", preventing phagocytosis via its interaction with SIRP-α on macrophages. CD47 has been shown to be upregulated in many cancer types including myeloid malignancies with increased expression associated with inferior OS. Magrolimab, an anti-CD47 antibody, has shown proof-of-principle of efficacy in this therapeutic class with promising early results in both higher risk myelodysplastic syndromes (MDS) and TP53 mutant acute myeloid leukemia (AML). The toxicity profile to date has been shown safe and manageable with on-target anemia related to CD47 being present on aged red blood cells and without evidence of immune related toxicities. Investigation of novel agents targeting this pathway and novel combinations are ongoing. New strategies targeting macrophage checkpoints are encouraging and likely will lead a paradigm shift in the current treatment of myeloid malignancies.

Novel therapies in myelodysplastic syndromes.

PURPOSE OF REVIEW: Currently, there is a rapid expansion of novel, efficacious therapies for the treatment of patients with myelodysplastic syndromes (MDS) at a rate never seen to date. In this review, we will outline new treatment strategies in MDS focusing on novel hypomethylating agents (HMA) and combinations in addition to targeted and immune-based therapies. RECENT FINDINGS: Large-scale gene sequencing and immune-based research has given us a great deal of information regarding the complexity and heterogeneity of MDS. This rapid improvement in our knowledge has provided a framework for development of novel therapies with specific gene and immune-based targets. Additionally, expanding and optimizing our current HMA-based strategies has led us to potentially not only ease administration but also improve outcomes. SUMMARY: Novel therapies in MDS are greatly needed is a disease state where few options are currently available, particularly in the HMA failure setting. Fortunately, through comprehensive genetic profiling, characterization of novel underlying pathogenic drivers, and understanding of the immune microenvironment, the treatment paradigm of patients with MDS is encouraging.

Mutation-Driven Therapy in MDS.

PURPOSE OF REVIEW: Genetic sequencing in myelodysplastic syndrome (MDS) has provided an improved understanding of the complexity and heterozygosity of the disease. More importantly, our molecular understanding of MDS is leading to rapid advancements and personalized therapy for our patients. Herein, we review the current mutation-driven treatment landscape in MDS, first focusing on individual mutations. We then discuss the effect of specific gene mutations on response and outcomes to standard therapies as well as to cutting edge investigational therapies. RECENT FINDINGS: Molecular annotation of MDS can predict response rates and outcomes to our current standard of care therapies including hypomethylating agents, lenalidomide, and allogeneic stem cell transplantation. Clinical trials targeting molecular subsets of MDS are underway with some in very early stages while others advancing to phase III trials. Targeting TP53 and IDH1/2 mutations appear to be promising targets with substantial efficacy seen in several trials to date. Furthermore, novel therapeutic strategies such as immuno-oncology agents are of significant interest with future investigation required to understand the molecular predictors of response. Mutation-driven therapy in MDS is rapidly expanding and has tremendous potential in a disease where limited standard therapy options exist.

T315I-mutated myeloid sarcoma.

Myeloid Sarcoma (MS) is diagnosed by an extramedullary proliferation of immature granulocytic cells. Its association with chronic myeloid leukemia (CML) is rare. CML is characterized by BCR-ABL1 gene rearrangement and therapies with tyrosine kinase inhibitors (TKI) are very effective. However, TKI resistance may occur secondary to the development of ABL1 mutations. T315I is a common mutation that accounts for ∼20% clinical resistance to TKIs. We report the first case of a patient with T315I mutated myeloid sarcoma that occurred after complete cytogenetic response with dasatinib of a chronic phase CML. The patient was successfully treated with induction chemotherapy and ponatinib.

Descriptive analysis of genetic aberrations and cell of origin in Richter transformation.

Richter transformation (RT) is a progression from chronic lymphocytic leukemia (CLL) to a more aggressive lymphoma, most often diffuse large B-cell lymphoma (DLBCL). Due to the rarity of the disease, data regarding the molecular profile and cell of origin (COO) of RT is limited. We performed immunohistochemistry analysis for COO determination and next-generation sequencing for gene mutation analysis in 11 RT patients. Seventy-nine percent of our patients were classified as non-GCB phenotype. Of the 57 unique mutations identified, the three most commonly mutated genes were TP53, TET2, and CREBBP. Neither TET2 nor CREBBP has been previously described in RT. Our analysis provides additional information to help guide further investigation of both the diagnosis and treatment of this complex and heterogeneous disease.