Immunotherapies shape the treatment landscape for hematologic malignancies

B-cell signaling a ripe target

Beyond immunotherapy, molecularly targeted drugs directed against key drivers of hematologic malignancies are also showing great promise. In particular, the B-cell receptor (BCR) signaling pathway, a central regulator of B-cell function, and its constituent kinases that are frequently dysregulated in B cell malignancies, has emerged as an exciting therapeutic avenue.

A variety of small molecule inhibitors targeting different nodes of the BCR pathway have been developed (Table 4), but the greatest success to date has been achieved with drugs targeting Bruton’s tyrosine kinase (BTK). Their clinical development culminated in the approval of ibrutinib for the treatment of patients with mantle cell lymphoma in 2013 and subsequently for patients with CLL, Waldenström macroglobulinemia, and most recently for patients with marginal zone lymphoma.

More than 100 clinical trials of ibrutinib are ongoing in an effort to further clarify its role in a variety of different disease settings. Furthermore, in an effort to address some of the toxicity concerns with ibrutinib, more specific BTK inhibitors are also being developed.

Other kinases that orchestrate the BCR pathway, including phosphatidylinositol-3-kinase (PI3K) and SYK, are also being targeted. The delta isoform of PI3K is expressed exclusively in hematopoietic cells and a number of PI3K delta inhibitors have been developed. Idelalisib received regulatory approval for the treatment of patients with CLL in combination with rituximab, and for patients with follicular lymphoma and small lymphocytic leukemia.

As with ibrutinib, a plethora of clinical trials are ongoing, however a major setback was suffered in the frontline setting when Gilead Sciences halted 6 clinical trials due to reports of increased rates of adverse events, including deaths.²⁶ Meanwhile, SYK inhibitors have lagged behind somewhat in their development, but one such offering, entospletinib, is showing promise in patients with AML.²⁷

Finally, there has been some success in targeting one of the downstream targets of the BCR signaling pathway, the Bcl2 protein that is involved in the regulation of apoptosis. Venetoclax was approved last year for the treatment of patients with relapsed/refractory CLL in patients who have a chromosome 17p deletion, based on the demonstration of impressive, durable responses.²⁸