Safety and Efficacy of JAK Inhibitor Therapy in BCR-ABL Negative MPN Patients with Underlying Portal Hypertension

Background The BCR-ABL-negative Myeloproliferative neoplasms (MPNs) are clonal stem cell disorders characterized by constitutive activation of the JAK-STAT pathway that include Polycythemia Vera, Essential Thrombocytosis, Primary (PMF) and Secondary Myelofibrosis (SMF). Splenomegaly is a characteristic feature of MPNs that can be ameliorated by JAK inhibitors (JAKi). Up-to one-third of MPN patients also experience portal hypertension (PH). Thrombosis of the splanchnic circulation is the most widely recognized etiology of PH in MPNs, however PH also occurs in the absence of intra-abdominal thrombosis. The influence of PH on outcomes of JAKi therapy in MPN patients has not been characterized. To this end, we aimed to determine the safety and efficacy of JAKi therapy in MPN patients complicated by PH with and without underlying splanchnic circulation thrombosis (ST). Methods All patients with MPNs assessed at Princess Margaret Hospital between 01/1998 and 01/2021 were identified from the MPN program's database. Patients who had undergone esophagogastroduodenoscopy (EGD) and had endoscopic evidence of PH, namely esophageal or gastric varices or portal hypertensive gastropathy were included. The study population was further limited to patients who started JAKi therapy following diagnosis of PH. Outcomes were compared between patients with and without underlying ST. The primary endpoint was palpable spleen reduction at 24 weeks. Secondary endpoints included best palpable spleen reduction within one year of starting JAKi, improvement in PH severity as determined by serial EGD assessments during JAKi therapy, overall survival, and ≥grade 3treatment emergent adverse events. Statistical differences in the frequencies of baseline characteristics were assessed using the Wilcoxon rank sum and Chi-Square tests. Overall-survival (OS) estimates were calculated by the Kaplan-Meier method using STATA/IC 16.1 software. Results All MPN patients with evidence of PH on endoscopy who started JAKi therapy after diagnosis of PH were included (n=33). Thirteen patients experienced ST prior to the start of JAKi. The proportion of younger patients and those with PH-related complications (i.e., variceal bleeding and/or ascites) was higher in patients with underlying ST (5/20 [25%] vs 9/13 [69%], p=0.01). The median palpable spleen change at approximately 24 weeks of therapy and the best palpable spleen reduction within the first year of therapy was -40.5% ([-100%[ -[+100%]) and -50% ([-100%]-0%) in the entire cohort, respectively. Better spleen responses with JAKi therapy were observed in PH patients without prior ST compared to those with underlying ST (median palpable spleen change at approximately 24 weeks was -58% (-24%-(-100%)] (n=13) vs -26.5% ([-100%]-[+100%]) (n=9), p=0.062; median best palpable spleen change at any time within 1 year of JAKi therapy start was -71% ([-14%]) -[-100%]) (n=17) vs -35% ([0%-[-100%]) (n=9), p=0.045). Of 21 patients with serial EGDs during JAKi treatment, improvement in PH severity as observed in 8 (38%). There were no differences in survival between patients with and without prior ST. Grade 3 treatment-emergent adverse events included anemia (5/33 [15%]), thrombocytopenia (5/33 [15%]), neutropenia (1/33 [3%]), and suspected Wernicke encephalopathy associated with Momelotinib (1/33 [3%]). Conclusion: In this observational study, JAK inhibitor therapy appears to be safe and effective in MPN patients complicated by PH, with a trend towards improved spleen responses among portal hypertensive patients without splanchnic circulation thrombosis. Disclosures Maze: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria; Takeda: Research Funding; PharmaEssentia: Research Funding; Kronos Bio: Research Funding. Gupta: AbbVie: Consultancy, Honoraria; Incyte: Honoraria, Research Funding; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Constellation Pharma: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy; Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Clinical Features and Long-Term Outcomes in a Molecularly-Annotated Cohort of Adolescents and Young Adults with Myeloproliferative Neoplasms

Background: Myeloproliferative neoplasms (MPNs) are a heterogenous group of chronic hematologic malignancies that lead to morbidity and early mortality primarily due to thrombotic complications and progression to acute leukemia. Clinical and mutational risk factors have been demonstrated to predict outcomes in patients with MPNs, and are used commonly to guide therapeutic decisions (including allogenic stem cell transplant) in myelofibrosis. Adolescents and young adults (AYA, age ≤45 years) comprise less than 10% of all MPN patients, and have unique clinical and therapeutic considerations. The prevalence and clinical impact of somatic mutations implicated in myeloid disease has not been extensively reported in this population. Methods: We conducted a retrospective review of patients evaluated at the Princess Margaret Cancer Centre (PMCC) between 1/1/2000 and 30/6/2021 for an MPN diagnosed at ≤45 years of age. Diagnoses were defined per 2016 WHO criteria using available information on chart review. Targeted mutational profiling of clinically relevant myeloid genes (49- or 54-gene panel) was previously performed on peripheral blood or bone marrow samples. Pathologic variants in ASXL1, EZH2, IDH1/2, SRSF2, and U2AF1 Q157 were categorized as high-molecular risk (HMR). Categorical variables were compared using the χ2 test. Kaplan-Meier method was used for overall survival (OS) and time-to-event analysis; and were compared using the log-rank test. Results: A total of 237 patients with initial MPN diagnosis ≤45 years were included in the study, with median age of diagnosis 35 (range 12-45) years. MPN diagnosis included: essential thrombocythemia (ET, n=100), polycythemia vera (PV, n=75), prefibrotic primary myelofibrosis (Pre-PMF, N=29), overt PMF (n=24), and MPN-unclassifiable (MPN-u, n=9). Driver mutation data, available for 230 (97%) patients, were: JAK2 in 134 (56%), CALR in 70 (30%), MPL in 6 (2.5%), and triple-negative in 20 (8.4%) patients. Median follow-up was 10.2 (range 0.3-45.3) years, and median OS was the shortest for those with overt PMF (21.4 years, P=0.001) compared with PV (33.0 years), ET (31.4 years), and Pre-PMF (median OS not reached). No difference in OS based on driver mutation was observed. Progression to a secondary MF (SMF) was observed in 84 patients (47% of ET, 48% of PV) after median time of 19.7 years; with no difference in time to progression due to diagnosis or driver mutation. Progression to an accelerated/blast phase (AP/BP) was observed in 26 patients and was associated with diagnosis of overt PMF (P=0.04) and triple-negative for driver mutation (P=0.04). Thrombosis was observed in 61 (26%) patients: 34 (14%) patients with thrombosis prior to/concurrent with MPN diagnosis, and 34 (14%) patients with thrombosis after diagnosis. Splanchnic circulation thrombosis was found in 29 (12%) patients and 12 (5%) patients had Budd-Chiari syndrome. Portal hypertension was reported in 37 (16%) patients. CALR type-2 mutations were associated with the lowest frequency of total thrombosis (4%, P=0.02); while JAK2 had the greatest frequency of splanchnic circulation clot (17%, P=0.03). Targeted mutational profile was obtained for 202 (85%) of patients: 135 samples obtained during the initial disease phase, 51 samples during a secondary MF phase, and 16 during an AP/BP. For the patients with mutation analysis in the initial phase, 24 pathogenic mutations were observed in 16 (12%) patients including 3 patients with HMR mutations. The most frequent mutations observed were in TET2 (n=12, 9%), and ASXL1 (n=3, 2%). Presence of additional mutations did not predict OS, AP/BP progression, or thrombosis; though TET2 mutation was associated with shorter time to SMF progression in patients with PV/ET (P=0.002). Additional mutations were found in 34/51 (67%) patients in whom mutational analysis was first performed during a SMF disease phase. Conclusions: A long-term follow-up study of a large molecularly annotated cohort of AYA patients with MPN demonstrated excellent long-term survival for these patients. Overt PMF is associated with the lower OS and higher risk of AP/BP transformation. Thrombotic complications including splanchnic circulation thrombosis are frequent complications. Mutations aside from JAK2/MPL/CALR are uncommon and HMR mutations rare in the initial phase of MPN in the AYA population. Figure 1 Figure 1. Disclosures Gupta: Roche: Consultancy; Pfizer: Consultancy; AbbVie: Consultancy, Honoraria; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Research Funding; Constellation Pharma: Consultancy, Honoraria. Maze: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene-BMS: Honoraria; Takeda: Research Funding; PharmaEssentia: Research Funding; Kronos Bio: Research Funding.

Association between hepatic oxygenation on near-infrared spectroscopy and clinical factors in patients undergoing hemodialysis

The hepato-splanchnic circulation directly influences oxygenation of the abdominal organs and plays an important role in compensating for the blood volume reduction that occurs in the central circulation during hemodialysis (HD) with ultrafiltration. However, the hepato-splanchnic circulation and oxygenation cannot be easily evaluated in the clinical setting of HD therapy. We included 185 HD patients and 15 healthy volunteers as the control group in this study. Before HD, hepatic regional oxygen saturation (rSO2), a marker of hepatic oxygenation reflecting the hepato-splanchnic circulation and oxygenation, was monitored using an INVOS 5100c oxygen saturation monitor. Hepatic rSO2 was significantly lower in patients undergoing HD than in healthy controls (56.4 ± 14.9% vs. 76.2 ± 9.6%, p < 0.001). Multivariable regression analysis showed that hepatic rSO2 was independently associated with body mass index (BMI; standardized coefficient: 0.294), hemoglobin (Hb) level (standardized coefficient: 0.294), a history of cardiovascular disease (standardized coefficient: -0.157), mean blood pressure (BP; standardized coefficient: 0.154), and serum albumin concentration (standardized coefficient: 0.150) in Model 1 via a simple linear regression analysis. In Model 2 using the colloid osmotic pressure (COP) in place of serum albumin concentration, the COP (standardized coefficient: 0.134) was also identified as affecting hepatic rSO2. Basal hepatic oxygenation before HD might be affected by BMI, Hb levels, a history of cardiovascular disease, mean BP, serum albumin concentration, and the COP. Further prospective studies are needed to clarify whether changes in these parameters, including during HD, affect the hepato-splanchnic circulation and oxygenation in HD patients.

Blood reservoir function in patients with Fontan circulation and asplenia syndrome

Splanchnic circulation constitutes a major portion of the vasculature capacitance and plays an important role in maintaining blood perfusion. Because patients with asplenia syndrome lack this vascular bed as a blood reservoir, they may have a unique blood volume and distribution, which may be related to their vulnerability to the haemodynamic changes often observed in clinical practice. During cardiac catheterisation, the mean circulatory filling pressure was calculated with the Valsalva manoeuvre in 19 patients with Fontan circulation, including 5 patients with asplenia syndrome. We also measured the cardiac output index and circulatory blood volume by using a dye dilution technique. The blood volume and the mean circulatory filling pressure and the venous capacitance in patients with asplenia syndrome were similar to those in the remaining patients with Fontan circulation (85 ± 14 versus 77 ± 18 ml/kg, p = 0.43, 31 ± 8 versus 27 ± 5 mmHg, p = 0.19, 2.8 ± 0.6 versus 2.9 ± 0.9 ml/kg/mmHg, p = 0.86). Unexpectedly, our data indicated that patients with asplenia syndrome, who lack splanchnic capacitance circulation, have blood volume and venous capacitance comparable to those in patients with splanchnic circulation. These data suggest that (1) there is a blood reservoir other than the spleen even in patients with asplenia; (2) considering the large blood pool of the spleen, the presence of a symmetrical liver may represent the possible organ functioning as a blood reservoir in asplenia syndrome; and (3) if this is indeed the case, there may be a higher risk of hepatic congestion in patients with Fontan circulation with asplenia syndrome than in those without.