Bone Marrow Histopathological Changes in Neoplastic and Non-Neoplastic Diseases

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Abstract

Inhibition of the B-cell receptor pathway, and specifically of Bruton tyrosine kinase (BTK), is a leading therapeutic strategy in B-cell malignancies, including chronic lymphocytic leukemia (CLL). Target occupancy is a measure of covalent binding to BTK and has been applied as a pharmacodynamic parameter in clinical studies of BTK inhibitors. However, the kinetics of de novo BTK synthesis, which determines occupancy, and the relationship between occupancy, pathway inhibition and clinical outcomes remain undefined. In the randomized phase 2 study the safety, efficacy, and pharmacodynamics of a selective BTK inhibitor acalabrutinib at 100 mg twice daily (BID) or 200 mg once daily (QD) in 48 patients with relapsed/refractory or high-risk treatment-nave CLL was investigated. Acalabrutinib was well tolerated and yielded an overall response rate (ORR) of partial response or better of 95.8% (95% confidence interval CI, 78.9-99.9) and an estimated progression-free survival (PFS) rate at 24 months of 91.5% (95% CI, 70.0-97.8) with BID dosing and an ORR of 79.2% (95% CI, 57.9-92.9) and an estimated PFS rate at 24 months of 87.2% (95% CI, 57.2-96.7) with QD dosing. BTK resynthesis was faster in patients with CLL than in healthy volunteers. BID dosing maintained higher BTK occupancy and achieved more potent pathway inhibition compared with QD dosing. Small increments in occupancy attained by BID dosing relative to QD dosing compounded over time to augment downstream biological effects. The impact of BTK occupancy on long-term clinical outcomes remains to be determined. High-risk cytogenetics and minimal residual disease (MRD) after chemoimmunotherapy (CIT) predict unfavorable outcome in chronic lymphocytic leukemia. A phase 2 study investigated risk-adapted CIT in treatment-nave CLL. Patients with high-risk cytogenetics received induction with fludarabine, cyclophosphamide, and ofatumumab. Those without high-risk cytogenetics received fludarabine and ofatumumab. After induction, MRD positive (MRD+) patients received 4 doses of ofatumumab consolidation. MRD negative (MRD-) patients had no intervention. Of 28 evaluable for response, all responded to induction and 10 (36%) achieved MRD-. Two-year progression-free survival (PFS) was 71.4% (CI95, 56.5-90.3%). There was no significant difference in median PFS between the high-risk and the standard-risk groups. Ofatumumab consolidation didn't convert MRD + to MRD-. In the MRD + group, there was a selective loss of CD20 antigens during therapy. We concluded that the loss of targetable CD20 likely reduces efficacy of consolidation therapy. Ibrutinib, a Bruton tyrosine kinase inhibitor, has impressive clinical efficacy in chronic lymphocytic leukemia, being able to improve progression-free survival (PFS) and overall survival (OS), compared to conventional chemoimmunotherapy in treatment-nave patients with chronic lymphocytic leukemia (CLL). Despite representing a major therapeutic advance, single-agent ibrutinib has limitations. While responses to ibrutinib can be durable, the depth of responses are infrequently deep, reflected in low rates of complete responses (CRs) and undetectable minimal residual disease (U-MRD). We sought to investigate whether targeting T cells with an abbreviated course of fludarabine could enhance the effects of ibrutinib, while avoiding myelotoxicity and the risk of secondary malignancies associated with intense chemoimmunotherapy. There was a rapid reductions in the number of T cells and potentially favorable remodeling of the T cell compartment. The number of T cells were elevated at pre-treatment and normalized after treatment with ibrutinib and a short course of fludarabine. Notably, the addition of two cycles of fludarabine in our study did not cause prolonged T cell depletion. Further, TFH and Treg, two potentially tumor-supportive T cell populations, significantly decreased during therapy. In summary, the combination of ibrutinib and short-course fludarabine led to 44% of treatment-nave CLL patients achieving a CR at 2years, a rate higher than what has been reported for patients treated with ibrutinib and rituximab (17%). The addition of two cycles of fludarabine to ibrutinib did not increase the risk of high-grade hematologic toxicities or infection. Most cytopenias were low-grade and resolved after the completion of fludarabine.