The treatment of recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) with everolimus results in clinical responses and mobilization of CLL cells into the circulation

Abstract

BACKGROUND:Patients with recurrent/refractory chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) often have chemotherapy-resistant disease, resulting in poor prognosis. The aim of this study was to learn if inhibition of the mammalian target of rapamycin (mTOR) would produce tumor responses. METHODS: This was a phase 2 study of oral single-agent everolimus (10 mg/day) for recurrent/refractory indolent lymphoid malignancies including CLL. RESULTS: Four of 22 patients with CLL (18%; 95% confidence interval, 5%-40%) achieved a partial remission to therapy. An unanticipated finding in this study was an increase in absolute lymphocyte count (ALC) associated with a decrease in lymphadenopathy in 8 (36%) patients. ALC increased a median of 4.8-fold (range, 1.9-to 25.1-fold), and the clinically measurable lymphadenopathy decreased a median of 75.5% (range, 38%-93%) compared with baseline measurements. CONCLUSIONS: Everolimus has modest antitumor activity against CLL and can mobilize malignant cells from nodal masses into the peripheral circulation in a subset of CLL patients. Because CLL cells in lymphatic tissue and bone marrow can be more resistant to therapy than circulating CLL cells, the ability of everolimus to mobilize CLL cells into the circulation could be used in combination therapeutic regimens. Cancer 2010;116:2201-7.

Idelalisib, an inhibitor of phosphatidylinositol 3-kinase p110δ, for relapsed/refractory chronic lymphocytic leukemia

“…This clinical observation is consistent with preclinical data showing that PI3Kd inhibition reduces chemokine-mediated signaling between lymphocytes and stromal cells, releasing B cells from lymph nodes and other tissue sites. 12,21 This treatment-induced lymphocytosis is not unique to idelalisib but has also been observed in patients with CLL who are administered other drugs that affect the B-cell receptor and Akt/ mTOR signaling pathways, including agents inhibiting Syk, 22 mTOR, 23 and BTK. [24][25][26] According to iwCLL 2008 criteria, a $50% increase in ALC (with a total ALC of $5.0 3 10 9 cells/L) represents CLL progression.…”

The phosphoinositide 3′-kinase delta inhibitor, CAL-101, inhibits B-cell receptor signaling and chemokine networks in chronic lymphocytic leukemia

“…Clinical data have demonstrated this effect with inhibitors of spleen tyrosine kinase (Syk), 28 Bruton's tyrosine kinase (Btk), 29 and mTOR. 30 This suggests that modulation of leukemia cell trafficking and homing via chemokine receptor function is a more general and potentially critical mechanism of action of this group of kinase inhibitors. What remains to be better defined are the relative contributions of CLL cell mobilization and direct CLL cell killing to the treatment effects of these drugs.…”

The mTORC1 inhibitor everolimus has antitumor activity in vitro and produces tumor responses in patients with relapsed T-cell lymphoma

“…The study allowed the accrual of uncommon lymphomas on an exploratory basis. The results of the trial for other major lymphoma subtypes (diffuse large B-cell lymphoma [DLBCL], mantle cell lymphoma [MCL], and Waldenström macroglobulinemia) have been reported [13][14][15][16][17] ; however, the results for the TCL patients have never been reported. This study was conducted through the Mayo Clinic Cancer Center and was approved by the Mayo Clinic Institutional Review Board.…”

“…We have reported that the PI3K/mTOR pathway is activated in NHL cells 12 and that mTORC1 inhibitors have activity in relapsed B-cell NHL. [13][14][15][16][17][18][19][20][21] TCLs account for approximately 10% of all NHL in the United States. 22 Just as in B-cell NHL, there are a number of clinicopathological types that vary in presentation and outcome.…”