Table 2.

Major questions and future challenges with KIT inhibitors in AdvSM

• What are the most predictive biomarkers of prolonged response and survival?

• Will response criteria based on pure pathologic criteria (eg, BM MC burden, serum tryptase level, blood counts), without confounding by lingering C-findings, better predict long-term end points such as overall survival?

• How do we define and harmonize molecular evaluation of MRD?

• Is time-limited treatment with KIT inhibitors feasible in patients who achieve a minimum duration of complete molecular remission of KIT D816V?

• What is the clinical impact of KIT inhibitors on the natural history of the AHN component?

• Does the presence of an AHN or multimutated molecular profile abrogate the potential benefits of molecular remission of KIT D816V or negative MRD?

• How do we sequence KIT inhibitors and AHN-directed therapy in patients with SM-AHN?

• What is the optimal role and timing of allogeneic HSCT in the era of KIT inhibitors and who are most appropriate candidates for transplant?

• How do we use KIT inhibitors as a cytoreduction strategy before transplant?

• Should KIT inhibitors be continued after transplant only in patients with detectable KIT D816V?

• Will KIT inhibitors with less CNS penetration (eg, BLU-263, bezuclastinib) permit their use with therapy for high-risk AHN (eg, HMA ± venetoclax) or with intensive induction chemotherapy in KIT D816V-positive AML?

• Is there a role for cladribine + selective KIT inhibitors in patients with AdvSM with refractory/relapsed or rapidly progressive disease?

CNS, central nervous system; HMA, hypomethylating agent; MRD, measurable residual disease.