DISCUSSION
Hyperglycemia, toxicity, toxicities, hyperglycemia, mucositis, myelosuppression, ALL
HYPERGLYCEMIA, HYPERGLYCEMIA, DISEASE, MUCOSITIS
ALL in adults continues to be a challenging disease with a high relapse rate despite intensive treatment with multi‐agent chemotherapy. The addition of immunotherapy (rituximab, ofatumumab) may help in decreasing relapse and improving outcomes when compared to historical data (especially in patients younger than 60 years old).In terms of safety, no G5 toxicity was encountered. Hyperglycemia was seen in 4 (25%) of patients at a median time of 6 days and was managed with oral hypoglycemics (2 patients with G2 and 2 patients with G3). Other toxicities included mucositis in 3 patients. It is unknown whether the mucositis was related to disease itself, prior chemotherapy or direct drug toxicity. One could argue that safety information about sapanisertib in ALL is limited because most patients had 1 cycle or less of treatment, and long‐term side effects could not be assessed in this population.Sapanisertib clearly failed to demonstrate efficacy as monotherapy in this study population. In particular, no patient achieved a CR or CRi. Instead, the best response was stable disease in 2 patients (12.5%). This does not compare favorably with other studies of mTOR inhibitors in ALL. Everolimus, an mTORC1 inhibitor, was combined with Hyper‐CVAD in a Phase I/II study in patients with r/r ALL by Daver et al.The laboratory studies conducted in conjunction with the present trial permit at least a partial analysis of the lack of efficacy of sapanisertib monotherapy. The sapanisertib pharmacokinetics observed in this study were similar to those found in other trials.Analysis of paired samples harvested prior to therapy and on Day 8 failed to convincingly demonstrate inhibition of mTOR‐induced phosphorylations (Figure In conclusion, single‐agent sapanisertib exhibited the expected toxicity profile, including hyperglycemia and mucositis. As a single agent, it induced myelosuppression in several cases but did not display objective activity against ALL on the dose and schedule administered. Further work using an mTOR inhibitor that is more selectively targeted toward lymphoid cells or a TORC1/2 inhibitor as part of combination therapy might be warranted in this population with unmet needs.