Transcriptomic and proteomic differences in BTK-WT and BTK-mutated CLL and their changes during therapy with pirtobrutinib.

Covalent Bruton's tyrosine kinase inhibitors (cBTKi), which bind to the BTK C481 residue, are now primary therapeutics for chronic lymphocytic leukemia (CLL). Alterations at C481, primarily C481S, prevent cBTKi binding and lead to the emergence of resistant clones. Pirtobrutinib is a noncovalent BTKi that binds to both wild-type (WT) and C481S-mutated BTK and has shown efficacy in BTK-WT and -mutated CLL patient groups. To compare baseline clinical, transcriptomic, and proteomic characteristics and their changes during treatment in these 2 groups, we used 67 longitudinal peripheral blood samples obtained during the first 3 cycles of treatment with pirtobrutinib from 18 CLL patients (11 BTK-mutated, 7 BTK-WT) enrolled in the BRUIN trial. Eastern Cooperative Oncology Group performance status, age, and Rai stage were similar in both groups. At baseline, lymph nodes were larger in the BTK-mutated cohort. All patients achieved partial remission within 4 cycles of pirtobrutinib. Lactate dehydrogenase and 2-microglobulin levels decreased in both cohorts after 1 treatment cycle. Expression analysis demonstrated upregulation of 35 genes and downregulation of 6 in the BTK-mutated group. Gene set enrichment analysis revealed that the primary pathways enriched in BTK-mutated cells were involved in cell proliferation, metabolism, and stress response. Pathways associated with metabolism and proliferation were downregulated in both groups during pirtobrutinib treatment. Proteomic data corroborated transcriptomic findings. Our data identified inherent differences between BTK-mutated and -WT CLL and demonstrated molecular normalization of plasma and omics parameters with pirtobrutinib treatment in both groups.

Cytogenetic and Molecular Associations with Outcomes in Higher-Risk Myelodysplastic Syndromes Treated with Hypomethylating Agents plus Venetoclax.

PURPOSE: Hypomethylating agents (HMA) combined with venetoclax are an emerging therapeutic strategy for higher-risk myelodysplastic syndromes (HR-MDS). The cytogenetic and molecular factors associated with outcomes with this combination for HR-MDS are incompletely understood. EXPERIMENTAL DESIGN: We pooled patient data from 3 prospective trials evaluating HMA-venetoclax in HR-MDS to study associations between cytogenetic and molecular factors and overall response rate (ORR), overall survival (OS), and event-free survival (EFS). The Kaplan-Meier method was used to estimate time-to-event endpoints. Univariate and multivariate analyses using logistic regression (for ORR) or the Cox proportional hazards model (for OS and EFS) were used to identify associations between clinical, cytogenetic, and molecular factors and outcomes. RESULTS: A total of 80 patients (52 HMA-naïve, 28 HMA-failure) were included. ORR was 90% in HMA-naïve and 57% in HMA-failure. Median OS was 28.2 and 8.3 months in HMA-naïve and HMA-failure, respectively. Median EFS was 17.9 and 5.5 months in HMA-naïve and HMA-failure, respectively. In addition, 24/52 (46%) of the HMA-naïve and 3/28 (11%) of the HMA-failure patients proceeded to allogeneic stem cell transplantation (SCT). Factors associated with inferior outcomes were prior HMA failure, complex cytogenetics, trisomy 8, TP53 mutations, and RAS pathway mutations. Mutations in RNA splicing, DNA methylation, and ASXL1 appeared favorable. Blast percentage was not predictive of outcomes. CONCLUSIONS: Knowledge of cytogenetic and molecular alterations may help identify which patients with HR-MDS benefit the most from venetoclax.

Resistance to targeted therapies: delving into FLT3 and IDH.

Recent advances in FLT3 and IDH targeted inhibition have improved response rates and overall survival in patients with mutations affecting these respective proteins. Despite this success, resistance mechanisms have arisen including mutations that disrupt inhibitor-target interaction, mutations impacting alternate pathways, and changes in the microenvironment. Here we review the role of these proteins in leukemogenesis, their respective inhibitors, mechanisms of resistance, and briefly ongoing studies aimed at overcoming resistance.

A Phase II Study of Azacitidine, Venetoclax, and Trametinib in Relapsed or Refractory Acute Myeloid Leukemia Harboring RAS Pathway-Activating Mutations.

INTRODUCTION: RAS pathway mutations are common mechanisms of resistance to acute myeloid leukemia (AML) therapies. Trametinib, an oral MEK inhibitor, has been shown to have single-agent activity in relapsed/refractory AML and preclinical synergy with venetoclax. METHODS: We conducted a single-center, open-label, phase 2 trial of the combination of azacitidine, venetoclax, and trametinib in patients with relapsed or refractory AML harboring a RAS pathway-activating mutation. RESULTS: Sixteen patients were treated. The patients were heavily pretreated with a median number of 4 prior therapies; 13 (81%) had received a prior hypomethylating agent (HMA) with venetoclax, and 8 (50%) had undergone prior stem cell transplant. Four patients (25%) responded (CR, n = 1; CRi, n = 1; MLFS, n = 2). Two of the 3 patients (67%) who had not previously received HMA plus venetoclax responded; in contrast, only 2 of the 13 patients (15%) who had previously received HMA plus venetoclax responded. The median OS was 2.4 months, and the 6-month OS rate was 31%. Related grade 3-4 adverse events occurred in 50% of patients, and 50% of patients required a dose adjustment of trametinib. CONCLUSIONS: The combination of azacitidine, venetoclax, and trametinib had only modest activity in patients with relapsed/refractory AML, with a response rate that was similar to previous reports of trametinib monotherapy. Substantial toxicity was observed with this combination. Given the established role of RAS pathway mutations in mediating resistance to AML therapies, future studies of better tolerated, more active inhibitors of this pathway are still needed.

BTK inhibitor selection for chronic lymphocytic leukemia: which drug for which patient?

INTRODUCTION: The development of BTK inhibitors has revolutionized the management of CLL. Currently, there are 3 BTK inhibitors available to treat CLL: ibrutinib, acalabrutinib, and zanubrutinib (the latter not yet approved for this disease but included in the NCCN guidelines). In this review, we will elucidate our approach to the selection of BTK inhibitor and provide insight into the future of BTK directed therapy. AREAS COVERED: This review utilizes data from published prospective trials, specifically RESONATE, RESONATE-2, ELEVATE-TN, ASCEND, ELEVATE-RR, and the ongoing FLAIR, SEQUOIA, and ALPINE trials. EXPERT OPINION: The choice of BTK inhibitor is guided by the setting (frontline vs relapsed) in conjunction with patient disease characteristics and comorbidities. In this review, we will elucidate our approach to the selection of BTK inhibitor and provide insight into the future of BTK directed therapy.

Advances in Immunology: A Cornerstone in Diagnosis and Therapy of Merkel Cell Carcinoma.

Merkel cell cancer (MCC) is a rare cutaneous malignancy arising from neuroendocrine cells. This rare but lethal malignancy (mortality greater than 30%) has also tripled in incidence over the last two decades. The role of immunodeficiency in pathogenesis of this rare malignancy is well established, with elucidation of viral pathogenesis by Merkel cell polyoma virus (MCPyV), a novel polyoma virus, in a majority of patients. Viral neoantigens while playing an important role in oncogenesis can also aid in early immunologic detection of recurrent disease. Viral neoantigens can also be targets for immunotherapy. Immune checkpoint inhibitors (ICI) have established role in frontline therapy in addition to recurrence of metastatic MCC. ICI therapy is being explored in adjuvant and neoadjuvant settings as well. We would like to illustrate curative potential of early diagnosis of recurrence and prompt use of ICI in treatment of oligometastatic disease in our case presentation.

Recurrent Colon Cancer: Presentation With Disseminated Intravascular Coagulation From Disseminated Carcinomatosis of the Bone Marrow.

Diffuse carcinomatosis of the bone marrow (DCBM) is a rare clinical condition characterized by diffuse bone marrow involvement with hematological changes. This case study concerns a patient who presented with DCBM secondary to colon cancer with diffuse intravascular coagulation. This is a rare presentation of DCBM in colon cancer. The case study also elaborates on clinical features, pathogenesis, and therapy of this unique presentation.

Chronic Myelomonocytic Leukemia Presenting With Polyserositis and Seropositivity for Rheumatoid Arthritis.

Chronic myelomonocytic leukemia (CMML) is a rare clonal stem cell disorder associated with clinical and pathologic of myelodysplasia and myeloproliferation. Systemic autoimmune/inflammatory disorders (SAID) and polyserositis have been associated with CMML. These manifestations can be observed concomitantly, shortly before diagnosis or anytime along the course of illness. We report a case of myeloproliferative CMML who presented with polyserositis and positive serology for rheumatoid arthritis. Retrospective studies of myelodysplasia/CMML have reported 15% to 25% incidence of SAID. The most commonly observed disorders include systemic vasculitis, connective tissue diseases, polychondritis, seronegative arthritis, and immune thrombocytopenia. SAID does not confer adverse prognosis in retrospective studies. Polyserositis is less common; this may result from leukemic infiltrate or result from autoimmunity. Treatment of serositis includes steroids and cytoreductive agents. Serositis may confer poor prognosis and hypomethylating therapy may improve the outcome.

Statin-Induced Rhabdomyolysis Due to Pharmacokinetic Changes From Biliary Obstruction in a Patient With Metastatic Prostate Cancer.

Statins work synergistically with androgen receptor blockers and androgen biosynthesis inhibitors, improving survival in patients with metastatic castration resistant prostate cancers (mCRPCs). Survival improvement is more pronounced for patients receiving androgen biosynthesis inhibitors compared with patients receiving androgen receptor blockers. A rare adverse interaction between simvastatin and abiraterone (Zytiga), an androgen biosynthesis inhibitor, was observed in a patient with mCRPC due to pharmacokinetic changes resulting from obstructive jaundice.

Capillary Leak Syndrome From Rituximab Therapy of Lymphoma.

Capillary leak syndrome (CLS) is characterized by plasma extravasation into the interstitium with resultant hypotension, anasarca, hemoconcentration, and hypoalbuminemia in the absence of albuminuria. Initially reported in Clarkson's disease (systemic capillary leak syndrome), CLS has been observed in multiple disease settings, the most common being sepsis. In oncology, CLS has been reported more often as a complication from therapy, and less often from malignancy. In this case study, we documented clinical manifestation, laboratory features, and radiological findings of CLS from rituximab therapy when employed in combination with a multi-agent chemotherapy regimen (EPOCH-R). Differentiating drug-induced CLS from sepsis, which presents with the same clinical features, is important in avoiding further exposure to rituximab, which could be fatal to the patient.

Delayed acute pancreatitis induced by nilotinib in a patient with chronic myeloid leukemia attaining sustained complete molecular response.

Advent of tyrosine kinase inhibitors (TKI) have revolutionized therapy of chronic myeloid leukemia. Imatinib was the first agent utilized in the therapy of CML. Nilotinib, a second generation TKI, results in an increase in number of patients achieving major molecular response at an earlier time point. Asymptomatic elevations in pancreatic enzyme is common and acute pancreatitis within weeks to months from start of therapy has been observed. Delayed onset pancreatitis has not been reported. We report a case of delayed onset pancreatitis in a patient with sustained complete molecular response. On account of the deep response, we were able to avoid starting alternate tyrosine kinase inhibitors that could also result in pancreatitis as a class effect.