Venetoclax and Decitabine Show Robust Activity in Advanced Systemic Mastocytosis
Authors: Atieh Tahani , Woodroof Janet , Yacoub Abdulraheem 
Published: November 2020

Systemic mastocytosis (SM) is a heterogeneous group of diseases characterized by the proliferation of abnormal mast cells in the bone marrow or other organs. 1 Activating mutations in KIT are found in the majority of patients, with the KIT D816V mutation being the most common .2 While patients with indolent systemic mastocytosis (ISM) have a life-expectancy similar to the general population, approximately 40-53% of patients with SM have an associated hematologic neoplasm (SM-AHN) with a median overall survival of 2 years. 1-3 Treatment of SM-AHN is primarily directed at the AHN as this determines overall survival, with symptomatic treatment for SM if needed.4 Midostaurin is the only approved agent for SM with KIT K816V mutation and overall response rates in SM-AHN are &lt;60%. 5-6 No agents are approved beyond first line.
We present the unique case of an 81-year-old male who presented with SM and low risk CMML (46 XY with ASXL1, KIT (p.D816V), SRSF2, TET2, RUNX1, MSH2, CBL). He received first line therapy with midostaurin 100 mg twice a day and achieved an early partial response but progressed after 7 months with increasing mastocytosis burden, rising tryptase and transformation of CMML to AML (image 1). He was subsequently treated with combination standard dose decitabine and venetoclax. The best response for the AML was CRi which was achieved after the first cycle and continues to be ongoing over 12 months since initiation of therapy. We also observed objective response of the SM disease burden on BM exams and steady decline in tryptase levels that continues to be ongoing (figure 1 and 2). Best response by IWG-MRT-ECNM is partial remission achieved after 9 months of therapy.
SM-AML is rare and can be diagnosed concomitantly with SM or as a transformation of an SM-AHN. Additional mutations are often present, with the presence of ASXL1 and RUNX1 being associated with a particularly poor prognosis.7-8 Treatment for SM-AML is similar to standard AML treatment with allogenic stem cell transplantation (ASCT) being preferred in those able to tolerate it. While ASCT is the only potential cure for both diseases, SM often persists even with response of the AML.9-11
In a case report of 11 patients with SM-AML, 8 patients received induction chemotherapy with cytarabine and daunorubicin while 3 received induction with cytarabine and idarubicine. Seven patients received ASCT but five relapsed and eventually expired. None of the 3 long-term survivors had a c-KIT D816V mutation and two of them received ASCT. In 7 out of the 10 patients in CR or after ASCT, SM persisted. 9 In 2 case reports of SM-AML with D816V mutation, treatment consisted of induction and consolidation chemotherapy plus dasatinib and chemotherapy with ASCT and dasatinib. Both patients achieved HCR but again had persistent SM.10-11
The activity of hypomethylating agents (HMA) with venetoclax has not previously been reported in patients with SM-AML. Venetoclax plus either HMAs or low-dose cytarabine was approved for the treatment of AML in the elderly and those unable to tolerate induction chemotherapy in 2018. Venetoclax is an oral inhibitor of BCL-2, an antiapoptotic protein important in the pathophysiology of AML. In the initial study, the CR/Cri rate was 68% with a median time to response of 1.2 cycles. Venetoclax has also shown activity in other hematologic malignancies, including chronic lymphocytic leukemia, and non-Hodgkin's lymphoma.12
SM-AML is an aggressive disease with limited treatment options. To our knowledge, this is the first report of sustained response of both SM-AHN and AML using a HMA and venetoclax. Given the difference in response time and dynamics, this treatment combination seems to have activity in both disease clones independently. This case suggests a potential treatment option for this unmet need and demonstrates the importance of research into the utility of venetoclax in mast cell neoplasms.

Disclosures
Yacoub: Ardelyx: Current equity holder in publicly-traded company; Dynavax: Current equity holder in publicly-traded company; Cara Therapeutics: Current equity holder in publicly-traded company; Hylapharm: Current equity holder in private company; Incyte: Speakers Bureau; Agios: Honoraria, Speakers Bureau; Novartis: Speakers Bureau; Roche: Other: Support of parent study and funding of editorial support.