Managing hyperglycemia and rash associated with alpelisib: expert consensus recommendations using the Delphi technique

Abstract

Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is appropriate to start alpelisib in patients with HbA1c 6.5% (diabetes) to <8%, or at highest risk for developing hyperglycemia, if they have a pre-treatment endocrinology consult. Recommend prophylactic metformin in patients with baseline HbA1c 5.7% to 6.4%. Metformin is the preferred first-line anti-hyperglycemic agent. Per the rash panel, initiate prophylactic nonsedating H1 antihistamines in patients starting alpelisib. Nonsedating H1 antihistamines and topical steroids are the preferred initial management for rash. In addition to clinical trial evidence, these recommendations will help address gaps encountered in clinical practice.

Fig. 1. Consensus treatment algorithm for the management of the first episode of hyperglycemia associated with alpelisib.

ALP alpelisib, FBG fasting blood glucose, HbA1c glycosylated hemoglobin, MTD maximum-tolerated dose, ULN upper limit of normal. ^aUnless otherwise stated for all statements about increasing metformin, assume extended-release or short-acting, and up to MTD. ^bIn certain circumstances (e.g., select patients who continue to have HbA1c < 8.0% or those who are asymptomatic and intolerant to metformin), it may be appropriate to continue ALP without initiating or changing metformin dose. ^cIt may also be appropriate to temporarily hold ALP (with the intent to restart at same dose) and increase metformin in certain high-risk patients (e.g., HbA1c > 5.7%). ^dIf FBG > 250 to ≤500 mg/dL, it may also be appropriate to hold or dose reduce ALP without first holding and continue metformin without a dose increase (metformin not at MTD) while simultaneously initiating a second agent. ^eWith the goal of titrating to maximum dose of 2000 mg/day within 1 week. ^fIf FBG > ULN to ≤250 mg/dL, it may also be appropriate to either (1) continue ALP while simultaneously initiating metformin and a second agent or, (2) hold ALP while simultaneously initiating metformin and a second agent in certain high-risk patients (e.g., HbA1c ≥ 6.5%).

Fig. 2. Consensus treatment algorithm for the management of subsequent episodes of hyperglycemia associated with alpelisib.

ALP alpelisib, DPP4i dipeptidyl peptidase-4 inhibitor, FBG fasting blood glucose, GLP-1 RA glucagon-like peptide 1 receptor agonist, HbA1c glycosylated hemoglobin, SGLT2i sodium-glucose co-transporter 2 inhibitor, TZDs thiazolidinediones, ULN upper limit of normal. ^aMetformin: 2 weeks, SGLT2i: 2 days, DPP4i: 1 week, TZDs: 6 weeks, GLP-1 RA: 1 week. ^bIt may also be appropriate to intensify non-insulin anti-hyperglycemic therapy depending on the specific circumstances. ^cIt may be appropriate to consult an endocrinologist to assist with intensifying anti-hyperglycemic treatments. It may also be appropriate to temporarily hold ALP and intensify anti-hyperglycemic treatment. ^dIt may be appropriate to continue ALP either with or without intensifying anti-hyperglycemic therapy, or to temporarily hold ALP and intensify anti-hyperglycemic therapy. ^eIt may be appropriate to give insulin, depending on individual circumstances. It may also be appropriate to either continue or hold ALP. ^fOr have the patient evaluated in the emergency department if circumstances warrant it. ^gIt may also be appropriate to continue ALP and add standing insulin. ^hInsulin may reverse catabolic weight loss caused by sustained hyperglycemia. Exercise caution on the use of insulin when holding ALP. Holding ALP may likely cause hyperglycemia to resolve, and adding insulin may lead to hypoglycemia. ⁱDepending upon individual patient circumstances. Insulin can achieve rapid control of hyperglycemia but carries the potential risk of PI3K pathway stimulation. ^jIt may also be appropriate to permanently discontinue ALP depending on the patient’s clinical status.

Fig. 3. Consensus treatment algorithm for managing rash associated with alpelisib.

ADL activities of daily living, ALP alpelisib, BSA body surface area, CTCAE Common Terminology Criteria for Adverse Events, FBG fasting blood glucose, OCS oral corticosteroids. ^aIf angioedema persists or reoccurs, it is appropriate to permanently discontinue ALP and consult a specialist (which can include a dermatologist or allergist) or seek hospital admission for severe or systemic symptoms. ^bOr if it covers >30% BSA but produces only mild symptoms, or if it limits instrumental ADLs (e.g., preparing meals, shopping for groceries or clothes, using the telephone, managing money, etc) regardless of BSA affected. Descriptors are consistent with CTCAE v5.0. ^cWith moderate or severe symptoms, or if it limits self-care ADLs (e.g., bathing, dressing, and undressing, feeding self, using the toilet, taking medications, and not bedridden) regardless of BSA affected. ^dConsult a specialist (such as a dermatologist or allergist) or hospital admission for severe or systemic symptoms. ^eFirst dose reduction to 250 mg and the second dose reduction to 200 mg. No further dose reductions typically considered. ^fFor patients receiving the prednisone equivalent of ≥20 mg daily for ≥4 weeks, consider prophylaxis against Pneumocystis jirovecii pneumonia^,.

Fig. 4. Consensus recommendations for the use of antihistamines to manage rash in patients receiving alpelisib.

ALP alpelisib. ^aAdding a sedating H1 antihistamine to standard-dose nonsedating H1 antihistamine is also appropriate, but escalating nonsedating H1 antihistamines is preferred over adding sedating antihistamines.

Fig. 5

Delphi technique methodology.