Rebound thrombocytosis is associated with response in AML patients treated with venetoclax and hypomethylating agents
Authors: Tamer A. Othman, Matthew Mei, Jianying Zhang, Ibrahim Aldoss, Anthony Stein, Stephen J. Forman, Guido Marcucci, Vinod Pullarkat
Journal: American Journal of Hematology (2021)

Combination therapy with the selective Bcl-2 inhibitor venetoclax and a hypomethylating agent (VEN-HMA) represents a significant step forward in the therapy of acute myeloid leukemia (AML), with high efficacy across multiple biological subtypes of AML, both in the frontline and relapsed/refractory settings, while being much less toxic than intensive conventional chemotherapy. While the overwhelming majority of AML cases are associated with thrombocytopenia at time of initiation of induction, rebound thrombocytosis is a well-described phenomenon in patients who achieve complete remission (CR) after intensive induction therapy and is correlated with favorable risk disease by European Leukemia Net (ELN) criteria as well as superior long-term outcomes.1 However, literature regarding the incidence and biological correlates of thrombocytosis in AML patients treated with VEN-HMA is lacking. We performed a single-center retrospective study of newly-diagnosed patients with AML who were treated with VEN-HMA to look for the incidence and biological correlates of rebound thrombocytosis. We found a significant relationship between rebound thrombocytosis and response rate as well as a trend towards overall survival; rebound thrombocytosis was also correlated with the presence of an IDH1/2 mutation. A total of 123 adult patients with newly-diagnosed AML who were treated with VEN-HMA for at least one cycle and had at least 1 month of follow-up were identified. The median age was 73 years (range: 30–86), and 57% were male (n = 71). Sixty-seven percent (n = 83) of patients had high risk disease by the ELN criteria,2 whereas 26% of patients were intermediate risk (n = 32), and only 7% had favorable risk disease (n = 8). A complex karyotype was present in 34% (n = 43) of patients. Baseline demographic and disease data are described in Table 1. Overall, 27 out of 123 patients (22%) experienced rebound thrombocytosis (defined as a platelet count of over 400 × 109/L after a period of prior thrombocytopenia) while receiving VEN-HMA. This threshold was chosen because it is the upper limit of normal for our institutional assay and has supporting literature as well.3 The only disease-related factors correlating with thrombocytosis included de novo AML as opposed to secondary AML evolving from antecedent MDS or MPN or therapy-related AML (p = .005). Notably, gender, age, and ELN risk group were all not associated with the development of thrombocytosis. The development of thrombocytosis was significantly correlated with a complete remission rate (CR/CRi) (92% vs 71%, p = .004), and there was also a trend towards improved overall survival (594 days vs 378 days, p = .073). Thrombocytosis occurred after a median of two cycles (range: 1–3). The median peak platelet count in patients who developed thrombocytosis was 706 × 109/L (range: 409–1265), and of the 29 patients with thrombocytosis, four experienced a second episode of thrombocytosis after normalization of the platelet count. Treatment outcomes are also included in Table 1. .763 (F vs Int vs High) .599 (Int vs High) We also examined the correlation of common somatic mutations (FLT3-ITD/TKD, IDH1/2, TP53, NPM1, CEBPA, DNMT3A, RUNX1, TET2, KRAS/NRAS, PTPN11, BCOR,ASXL1, U2AF1, and SRSF2) with thrombocytosis. The only mutation correlated with thrombocytosis was an IDH1/2 mutation (31% of patients with thrombocytosis had an IDH1/2 mutation vs 7% of patients without thrombocytosis, p = .005). No other mutation had a significant interaction with thrombocytosis, although no patient with a KRAS/NRAS mutation developed thrombocytosis (0% vs 12% prevalence in the entire cohort, p = .063). As this was largely an older population with predominantly adverse disease by ELN criteria, the overall cohort was enhanced for deleterious TP53 mutations (overall prevalence 30%), which showed no correlation with thrombocytosis. Rebound thrombocytosis has been described in patients with AML treated with intensive induction chemotherapy and is correlated with favorable outcomes.1 Schnell et al. reported on a cohort of 291 AML patients who received intensive induction therapy with cytarabine and idarubicin, of whom 41% experienced rebound thrombocytosis.1 However, this was predominantly driven by patients with ELN favorable risk disease, as only 11% of patients with ELN adverse risk disease in their study experienced thrombocytosis after intensive induction therapy. In contrast, 20% of the patients with ELN adverse risk disease treated with VEN-HMA in our cohort developed rebound thrombocytosis. In fact, more than two thirds of the patients in our cohort had adverse risk disease, which reflects both the generally older age of patients who are induced with VEN-HMA (as older patients tend to have biological worse risk disease) as well as the preference for intensive induction chemotherapy with curative intent for patients with favorable risk disease. As such, rebound thrombocytosis may be more common with HMA-VEN than with conventional chemotherapy. Moreover, it also appears that rebound thrombocytosis is a useful biomarker for response and in our cohort was strongly associated with achievement of CR/CRi. Nonetheless, while rebound thrombocytosis correlated with marrow response, it did not appear to be significantly correlated with either 1-year or 2-year OS. This is likely due to the relatively short duration of follow-up as well as deaths in remission, both of which would dilute the survival impact. Although VEN-HMA is active across the various AML genetic subgroups, it appears to be particularly active for patients whose disease carries an IDH1/2 mutation.4, 5 Of interest, this was the only mutation in our cohort that was significantly correlated with rebound thrombocytosis, which further supports the notion that rebound thrombocytosis is a biomarker for disease sensitivity to venetoclax-based therapy. The mechanism underlying rebound thrombocytosis is unclear but may have its basis in thrombopoietin (TPO) biology. Leukemic blasts in AML have been shown to scavenge TPO via increased expression of the TPO receptor MPL, with the level of MPL receptor expression correlating with the degree of thrombocytopenia6 as TPO production is not increased in response to the platelet count. Therefore, one can postulate that elimination of the leukemic blasts with initiation of VEN-HMA therapy would make more TPO available in bone marrow for thrombopoiesis, and would in turn lead to rebound thrombocytosis. In summary, development of rebound thrombocytosis was significantly correlated with response in patients with AML treated with VEN-HMA and appears to be an early biomarker of disease response. Larger studies will be needed to determine if rebound thrombocytosis is also correlated with durability of response and survival. IA: Advisory board and research support form AbBvIE. VP: advisory board for AbbVie and Jazz Pharmaceuticals, speakers bureau for Jazz, Amgen, Novartis, AbbVie. AS: speaker bureau for Stemline, Amgen, Celgene, advisory board for Stemline and Amgen. GM: speakers' bureau for AbbVie and Novartis, advisory board with Janssen. The data that support the findings of this study are available from the corresponding author upon reasonable request.