Rampal, Raajit K.

Abstract Purpose: Myelofibrosis (MF) is a clonal myeloproliferative neoplasm characterized by systemic symptoms, cytopenias, organomegaly, and bone marrow fibrosis. JAK2 inhibitors afford symptom and spleen burden reduction but do not alter the disease course and frequently lead to thrombocytopenia. TGFβ, a pleiotropic cytokine elaborated by the MF clone, negatively regulates normal hematopoiesis, downregulates antitumor immunity, and promotes bone marrow fibrosis. Our group previously showed that AVID200, a potent and selective TGFβ 1/3 trap, reduced TGFβ1-induced proliferation of human mesenchymal stromal cells, phosphorylation of SMAD2, and collagen expression. Moreover, treatment of MF mononuclear cells with AVID200 led to increased numbers of progenitor cells (PC) with wild-type JAK2 rather than JAK2V617F. Patients and Methods: We conducted an investigator-initiated, multicenter, phase Ib trial of AVID200 monotherapy in 21 patients with advanced MF. Results: No dose-limiting toxicity was identified at the three dose levels tested, and grade 3/4 anemia and thrombocytopenia occurred in 28.6% and 19.0% of treated patients, respectively. After six cycles of therapy, two patients attained a clinical benefit by IWG-MRT criteria. Spleen and symptom benefits were observed across treatment cycles. Unlike other MF-directed therapies, increases in platelet counts were noted in 81% of treated patients with three patients achieving normalization. Treatment with AVID200 resulted in potent suppression of plasma TGFβ1 levels and pSMAD2 in MF cells. Conclusions: AVID200 is a well-tolerated, rational, therapeutic agent for the treatment of patients with MF and should be evaluated further in patients with thrombocytopenic MF in combination with agents that target aberrant MF intracellular signaling pathways.

7019 Background: High-risk essential thrombocythemia (HR ET) is characterized by thrombocytosis, thrombohemorrhagic events and systemic symptoms. Pts can experience intolerance, inadequate response or loss of response to first-line cytoreductive therapies (hydroxyurea [HU] or interferon alfa-2a). BET protein inhibition is a novel therapeutic strategy that downregulates inflammatory cytokines and may inhibit differentiation and proliferation of abnormal megakaryocytes involved in ET pathogenesis. Results from the Phase 2 MANIFEST study (NCT02158858) suggested potentially encouraging clinical efficacy in pts with myelofibrosis treated with Pelabresib (PELA), an oral, small-molecule, investigational BET inhibitor. Here we present preliminary results from MANIFEST Arm 4 investigating PELA monotherapy in HR ET refractory or intolerant to HU. Methods: Eligible pts had platelets > 600 x 109/L and ≥ 2 symptoms (average score ≥3/ TSS≥15). Pts received PELA monotherapy 225 mg QD. The primary endpoint was complete hematologic response (CHR; normalization of platelet count (≤400 x 109/L), WBC count (≤10 x 109/L) confirmed after one cycle [after 3 weeks]) and normal spleen size. Secondary endpoints included partial HR (PHR; platelets 400–600 x 109/L and WBC ≤10 x 109/L), symptom improvement (≥50% TSS reduction) and safety. Results: As of July 2022, 20 pts with HR ET were treated: median age 64 yrs (42–83), median Hgb 13 (10–16) g/dL, median platelet count 772 (418–1255) x 109/L and median TSS 32.7 (6.9–123). The majority of pts had a hematologic response (90% [18/20] unconfirmed CHR or PHR); confirmed CHR was observed in 40% (8/20) (Table). Median platelet and WBC count at Wk 12 was 446 x109/L and 8.2 x 109/L, respectively. TSS reduction was reported in 86% (12/14 pts); median TSS reduction at Wk 12 was –31%. Hgb levels remained stable through Wk 24. The most common nonhematologic AEs were nausea (60%; 10% Gr 3), diarrhea (35%; 5% Gr 3) and dysgeusia (35%; no Gr 3). Hemorrhagic or thromboembolic events were reported in 30% pts (15% Gr 3). No events of thrombocytopenia and no Gr 4 events or higher were reported. Conclusions: Preliminary results from Arm 4 of the MANIFEST study suggest potential clinical benefit with PELA monotherapy in pts with HR ET refractory or intolerant to HU as supported by hematologic responses and symptom improvement. Safety results are consistent with the known safety profile of PELA and as expected in the underlying study population. Clinical trial information: NCT02158858 . [Table: see text]

7018 Background: MF is a life-limiting malignancy characterized by marrow fibrosis, splenomegaly, and progressive cytopenias. JAK2 inhibitors can reduce spleen volume, which is considered a surrogate for disease response. For example, ≥10% SVR on ruxolitinib (RUX) is associated with improved OS among patients with platelet (PLT) counts ≥100×109/L. RUX cannot be administered at full dose in patients with lower PLTs, and it is not known whether the association between SVR and OS persists in such patients. PAC is a JAK1-sparing inhibitor of JAK2/IRAK1/ACVR1 that demonstrated SVR benefit vs BAT (including RUX) in PERSIST-2, which enrolled MF patients with PLTs ≤100×109/L. Here we present a retrospective landmark OS analysis of the relationship between SVR and OS on PERSIST-2. Methods: This analysis includes PERSIST-2 patients who were alive and on study at the start of the 12-week SVR window (study week 10) on PAC 200 mg BID or BAT. Spleen volume was assessed radiographically (MRI or CT). OS was evaluated among SVR responders vs non-responders within each treatment arm using different SVR thresholds (≥35%, ≥20%, ≥10%, > 0%) and a landmark analysis methodology. OS was compared using the log-rank test. Results: Among patients on PAC (n = 89), any SVR ( > 0%) at 12 weeks was significantly associated with improved survival (HR = 0.08 [95% CI: 0.01, 0.51], P = 0.0007). Among all SVR response thresholds, SVR ≥10% demonstrated the greatest separation in OS curves between responders vs. non-responders on PAC, with no deaths on study among 65 responders compared to 5 deaths among 24 non-responders (HR = 0.0 [95% CI: 0.0, 0.14], P < 0.0001). By contrast, SVR did not predict OS benefit on BAT (n = 84), including RUX (n = 39). For example, 11% (3/28) of patients on BAT who achieved SVR ≥10% died compared to a similar number (14%, 8/56) of non-responders (HR = 0.63 [95% CI: 0.17, 2.37], P = 0.49). Of the 28 patients on BAT who achieved SVR ≥10%, 23 (82%) were treated with RUX. Among these 23 patients, most patients were receiving low-dose RUX at the time of the landmark: 78% were on ≤10 mg BID and 43% were on £5 mg BID. By contrast, the median relative dose intensity on PAC was 100% (200 mg BID) through week 12 among both SVR ≥10% responders and non-responders. Conclusions: In MF patients with PLTs ≤100×109/L, achieving SVR on full-dose PAC was associated with significant OS benefit. By contrast, this association was not found with BAT, even though most responders were on RUX, albeit at low doses. As PAC can be given at full dose regardless of PLT count, it is possible that PAC may offer a unique survival advantage for MF patients with moderate or severe thrombocytopenia who achieve spleen reduction. Clinical trial information: NCT02055781 .

Abstract Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy with historically poor outcomes and no worldwide consensus treatment approach. Unique among most hematologic malignancies for its frequent cutaneous involvement, BPDCN can also invade other extramedullary compartments, including the central nervous system. Generally affecting older adults, many patients are unfit to receive intensive chemotherapy, and although hematopoietic stem cell transplantation is preferred for younger, fit individuals, not all are eligible. One recent therapeutic breakthrough is that all BPDCNs express CD123 (IL3Rα) and that this accessible surface marker can be pharmacologically targeted. The first-in-class agent for BPDCN, tagraxofusp, which targets CD123, was approved in December 2018 in the United States for patients with BPDCN aged ≥2 years. Despite favorable response rates in the frontline setting, many patients still relapse in the setting of monotherapy, and outcomes in patients with relapsed/refractory BPDCN remain dismal. Therefore, novel approaches targeting both CD123 and other targets are actively being investigated. To begin to formally address the state of the field, we formed a new collaborative initiative, the North American BPDCN Consortium (NABC). This group of experts, which includes a multidisciplinary panel of hematologists/oncologists, hematopoietic stem cell transplant physicians, pathologists, dermatologists, and pediatric oncologists, was tasked with defining the current standard of care in the field and identifying the most important research questions and future directions in BPDCN. The position findings of the NABC’s inaugural meetings are presented herein.