Abstract: This observational, retrospective study investigates the frequency and reasons for ruxolitinib rechallenge, its therapeutic effects, and its impact on overall survival in a cohort of 219 patients with myelofibrosis discontinuing ruxolitinib for ≥14 days and surviving for ≥30 days. In comparison with 159 patients discontinuing ruxolitinib permanently, discontinuation due to a lack/loss of spleen response is lower ( P = .004) in 60 patients in whom ruxolitinib is rechallenged for ≥14 days (RUX‐again patients): there is a significant increase in the number of patients with large splenomegaly and a high Total Symptom Score ( P 〈 .001) between the first ruxolitinib stop and restart, and there is a significant increase in the number of patients with a Total Symptom Score reduction ( P = .01) during the rechallenge. The use of a ruxolitinib dose 〉 10 mg twice daily is associated with spleen improvements ( P = .05) and symptom improvements ( P = .02), and overall survival is significantly longer in RUX‐again patients ( P = .004).

Abstract: Ruxolitinib (RUX), the first JAK1/JAK2 inhibitor approved for myelofibrosis (MF) therapy, has recently been associated with the occurrence of second primary malignancies (SPMs), mainly lymphomas and non‐melanoma skin cancers (NMSCs). We analyzed the incidence, risk factors and outcome of SPMs in 700 MF patients treated with RUX in a real‐world context. Median follow‐up from starting RUX was 2·9 years. Overall, 80 (11·4%) patients developed 87 SPMs after RUX start. NMSCs were the most common SPMs (50·6% of the cases). Multivariate analysis demonstrated that male sex [hazard ratio (HR): 2·37, 95% confidence interval (95%CI): 1·22–4·60, P  = 0·01] and thrombocytosis 〉  400 × 10 9 /l at RUX start (HR:1·98, 95%CI: 1·10–4·60, P  = 0·02) were associated with increased risk for SPMs. Risk factors for NMSC alone were male sex (HR: 3·14, 95%CI: 1·24–7·92, P  = 0·02) and duration of hydroxycarbamide and RUX therapy  〉  5 years (HR: 3·20, 95%CI: 1·17–8·75, P  = 0·02 and HR: 2·93, 95%CI: 1·39–6·17, P  = 0·005 respectively). In SPMs excluding NMSCs, male sex (HR: 2·41, 95%CI: 1·11–5·25, P  = 0·03), platelet  〉  400 × 10 9 /l (HR: 3·30, 95%CI: 1·67–6·50, P  = 0·001) and previous arterial thromboses (HR: 3·47, 95%CI: 1·48–8·14, P  = 0·004) were shown to be associated with higher risk of SPMs. While it is reassuring that no aggressive lymphoma was documented, active skin surveillance is recommended in all patients and particularly after prolonged hydroxycaramide therapy; oncological screening should be triggered by thrombocytosis and arterial thrombosis, particularly in males.

Abstract: Introduction: The outcome of patients (pts) with myelofibrosis (MF) who discontinue ruxolitinib (RUX) is poor with scarce therapeutic possibilities (Palandri et al, 2020). However, some evidences suggest that pts may respond to a rechallenge of RUX after drug stop (Gerds et al, 2018). Aims: To investigate in a real-world context: 1) frequency and reasons for rechallenge; 2) therapeutic effects of rechallenge; 3) impact of rechallenge on overall survival (OS) Methods: After IRB approval, a clinical database was created in 20 European Hematology Centers including now retrospective data of 703 MF pts who started RUX from Jan 2011 to Nov 2019. Only chronic phase (CP) pts who stopped RUX for ≥14 days and survived ≥30 days after discontinuation were included. A specific survey collected clinical/laboratory data at RUX stop and at rechallenge, reasons for discontinuation and treatments before rechallenge. OS was estimated from the date of the first/only RUX discontinuation to last contact (log-rank test). Results: A total of 219 CP pts was evaluable for this study. In 60 (27.4%) pts, RUX was re-challenged for ≥14 days after the first discontinuation (RUX-again), while 159 (72.6%) pts discontinued RUX permanently (RUX-stop). The median time from RUX start to stop was of 16.5 and 12.3 mos for RUX-again and RUX-stop pts, respectively (p=0.41). At RUX start, characteristics of RUX-again were: median age 67y (24-88); males 61.7%; PMF 53.3%; median Hb 10.2 g/dl; median PLT/WBC: 249/12.6 x109/l; median RUX starting dose: 15mg BID. Baseline characteristics of RUX-again and RUX-stop pts were comparable. In the 60 RUX-again pts, reasons for discontinuation included loss of/inadequate response (18 pts, 30%) and toxicity (42 pts, 70%). Toxicity included G3-4 thrombocytopenia (38.1%), anemia (26.2%), infections (21.4%), other (14.3%). Conversely, RUX-stop pts discontinued RUX mainly due to loss of/inadequate response (75 pts, 47.2%), while intolerable toxicity occurred in 69 pts (43.4%) (p=0.004) and other causes in 9.4%. At first RUX discontinuation, 35.7% of RUX-again pts presented with large ( & gt;10 cm) splenomegaly; median Total Symptoms Score (TSS) was 10 (TSS & gt;20 in 30.4% of pts). The median duration of temporary RUX discontinuation was 2 mos (range 0.5-71.1). During RUX stop, 65% of RUX-again pts did not receive any therapy, 15% received only palliation (steroids, hydroxyurea), while 11.7% switched to investigational agents, 3.3% underwent splenectomy and 5% allogeneic transplantation. Compared to disease status at first RUX stop, at RUX restart there was a significant increase of pts with large splenomegaly and high TSS, while the PLT count was higher and RUX dose significantly lower (Table 1). The median duration of RUX rechallenge was 7.5 mos (0.5-72.7). During the rechallenge, 44.6% and 48.3% pts improved spleen and symptoms, and there was a significant increase in pts with TSS reduction (p=0.01); 8 pts (13.3%) continued RUX with stable/worsening spleen size and improvement in TSS. Conversely, 26.8% and 20% of pts had increase in spleen size and in symptoms, respectively. While Hb levels remained stable, PLT count significantly decreased during rechallenge (p & lt;0.001). At last contact, 51.7% of RUX-again pts had permanently discontinued RUX. The reasons for temporary discontinuation had no impact on the reduction of spleen/symptoms during rechallenge and on OS. However, comparing RUX-again and RUX-stop pts, RUX-again pts showed a better OS, with a median survival of 41.1 mos and 23.7, respectively in the 2 cohorts (Fig. 1). Conclusions: This real-world study highlights that RUX rechallenge is quite common in CP-MF pts, involving almost 30% of treated pts, particularly when the discontinuation is due to toxicity. The temporary discontinuation, while improving PLT count, generally caused a significant increase in disease burden. After rechallenge, almost 50% of pts achieved clinical responses regardless of reason of first discontinuation. This residual disease control activity, that correlated with improved OS, should be weighed up also given the new therapeutic possibilities available in these pts. Disclosures Palandri: Novartis: Consultancy, Honoraria. Breccia:Abbvie: Consultancy; Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Cavazzini:Incyte: Honoraria; Pfize: Honoraria; Novartis: Honoraria. Crugnola:Janssen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Celgene: Honoraria. Heidel:CTI: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Research Funding. Pane:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Daiichi Sankyo: Consultancy, Other: Travel Expenses; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Janssen: Other: Travel Expenses; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Cuneo:janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Semenzato:Takeda: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Lemoli:AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BerGenBio ASA: Research Funding. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Palumbo:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract: Introduction: Hydroxyurea (HU) is the most used cytoreductive therapy (tx) for patients (pts) with polycythemia vera (PV). However, many pts may have suboptimal responses (SubOR) and/or toxicity (TOX) to HU. After HU, Ruxolitinib (RUX) may achieve hematocrit (HCT) and spleen reductions, but other tx are also available, mainly busulfan (BUS) and interferons (IFN). Aims: In a large cohort of PV pts, we investigated if: 1) type of SubOR to HU influenced subsequent tx strategy; 2) differential tx had an impact on overall survival (OS). Methods: After IRB approval, clinical/laboratory data of 2016 WHO-defined PV pts from 21 European Hematology Centers were retrospectively collected. SubOR included ≥1 of the following criteria after ≥3 mos of HU: WBC/PLT count & gt;10/400 x109/l, need for phlebotomies (PHL); splenomegaly and/or symptoms persistence/occurrence (Barosi G et al, Blood 2009). Only pts with stable SubOR were included in this analysis. Since a complete response was never achieved, the index date (ID) was set at 3 mos from HU start in all pts (Barosi G et al, BJH 2009). OS was calculated from the ID by Cox analysis with age & gt;80, adjusted with left truncation from PV diagnosis. Results: At data cut-off date (June 2020), 808 PV pts were collected; 688 received HU. Among the 452 (65.7%) pts who presented a stable SubOR to HU, 41 did not receive any tx for PV due to early death or progression to BP/MF and were excluded from this analysis. Baseline characteristics of the 411 evaluable pts were: median age: 65 yrs (21- 87); males: 54%; median (range) WBC/PLT count, x109/l: 10 (1.1-38)/465 (139-1209); median Hb (g/dl)/HCT (%): 18.6/56 (males); 17.6/54 (females); palpable splenomegaly: 38%; symptoms: 80.5%; pruritus: 42%. A previous thrombosis occurred in 104 (25.3%) pts. At least one cardiovascular risk factor (CVRF: smoke, diabetes, hypertension, dyslipidemia and overweight) was present in 325 pts (79.1%). After a median follow-up of 4.8 yrs (0.5-27.6) from HU start, 104 (25.3%) switched to RUX (HU-RUX), 18 (4.4%) switched to another agent (HU-other, including IFN, BUS, PHL only), and 289 (70.3%) continued HU (HU-alone). Pts with baseline palpable spleen (p & lt;0.001) and pruritus (p=0.01) more frequently switched to RUX. Conversely, pts ≥80y more frequently received HU-alone/other (p=0.03). Notably, Charlson Comorbidity Index and CVRF had no impact on tx strategy. Median HU daily dose was 0.65 g (≥2 g/d: 8.7% of pts) and was higher in HU-RUX pts (1 vs 0.6 g/d in HU-alone/other pts, p=0.004). While 331 (80.5%) pts had a stable SubOR without TOX, 80 (19.5%) had also TOX. Notably, pts with only SubOR more frequently continued HU (p & lt;0.001). Conversely, the co-occurrence of TOX was significantly associated to RUX switch (p & lt;0.001) (Fig. 1a). In 45.5% of pts, the SubOR was related only to uncontrolled WBC/PLT/HCT, while 16.1% of pts had an optimal hematological control but presented spleen/symptoms; the remaining 38.4% of pts had both uncontrolled myeloproliferation and spleen/symptoms. The presence of both uncontrolled myeloproliferation and spleen/symptoms significantly predicted RUX switch (p & lt;0.001). Investigating the SubOR criteria individually among the HU-alone/other and the HU-RUX groups, we found that uncontrolled leukocytosis and/or thrombocytosis (p & lt;0.001), rather than PHL need (p=0.13), was significantly associated with RUX switch. Moreover, the persistence/occurrence of symptoms (p=0.001) or splenomegaly (p=0.005) were significantly associated with RUX use (Fig. 1b). After the ID, 31 pts died. HU-RUX pts presented increased OS compared to HU-alone/other pts (p=0.03). Conclusions. This study revealed a high rate of SubOR to HU, possibly also affected by low HU doses, and a lack of urgency to change the tx in these pts, with & gt;70% of pts continuing HU despite the stable SubOR. Particularly, good tolerance to HU, absence of splenomegaly and pruritus, and older age were the main factors against a tx change. Notably, despite HCT & gt;45% is associated with worse outcome (Marchioli R, NEJM 2013), PHL need did not significantly trigger tx change. The better OS in the HU-RUX group is presumably multifactorial and requires further confirmation. Overall, this analysis points out the need to improve HU management and response evaluations, weighing appropriate tx strategies in case of SubOR. Disclosures Palandri: Novartis: Consultancy, Honoraria. Benevolo:Amgen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Breccia:Bristol-Myers Squibb/Celgene: Consultancy, Honoraria; Abbvie: Consultancy; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Cavazzini:Pfize: Honoraria; Novartis: Honoraria; Incyte: Honoraria. Heidel:Celgene: Consultancy; CTI: Consultancy; Novartis: Consultancy, Research Funding. Crugnola:BMS: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Pane:Daiichi Sankyo: Consultancy, Other: Travel Expenses; Janssen: Other: Travel Expenses; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Other: travel expenses, Speakers Bureau; Novartis pharma SAS: Consultancy, Other: Travel Expenses, Research Funding, Speakers Bureau; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Other: Travel Expenses, Speakers Bureau; AbbVie: Consultancy, Other: Travel Expenses, Speakers Bureau. Cuneo:Gilead: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astra Zeneca: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Krampera:Janssen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Semenzato:Takeda: Honoraria; Roche: Honoraria; Abbvie: Honoraria. Lemoli:Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; BerGenBio ASA: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Cavo:Jannsen, BMS, Celgene, Sanofi, GlaxoSmithKline, Takeda, Amgen, Oncopeptides, AbbVie, Karyopharm, Adaptive: Consultancy, Honoraria. Palumbo:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Abstract: In polycythemia vera (PV), the prognostic relevance of an ELN-defined complete response (CR) to hydroxyurea (HU), the predictors of response, and patients’ triggers for switching to ruxolitinib are uncertain. In a real-world analysis, we evaluated the predictors of response, their impact on the clinical outcomes of CR to HU, and the correlations between partial or no response (PR/NR) and a patient switching to ruxolitinib. Among 563 PV patients receiving HU for ≥12 months, 166 (29.5%) achieved CR, 264 achieved PR, and 133 achieved NR. In a multivariate analysis, the absence of splenomegaly (p = 0.03), pruritus (p = 0.002), and a median HU dose of ≥1 g/day (p 〈 0.001) remained associated with CR. Adverse events were more frequent with a median HU dose of ≥1 g/day. Overall, 283 PR/NR patients (71.3%) continued HU, and 114 switched to ruxolitinib. In the 449 patients receiving only HU, rates of thrombosis, hemorrhages, progression, and overall survival were comparable among the CR, PR, and NR groups. Many PV patients received underdosed HU, leading to lower CR and toxicity rates. In addition, many patients continued HU despite a PR/NR; however, splenomegaly and other symptoms were the main drivers of an early switch. Better HU management, standardization of the criteria for and timing of responses to HU, and adequate intervention in poor responders should be advised.

Abstract: The impact of ruxolitinib therapy on evolution to blast phase (BP) in patients with myelofibrosis (MF) is still uncertain. In 589 MF patients treated with ruxolitinib, we investigated incidence and risk factors for BP and we described outcome according to disease characteristics and treatment strategy. After a median follow‐up from ruxolitinib start of 3 years (range 0.1‐7.6), 65 (11%) patients transformed to BP during (93.8%) or after treatment. BP incidence rate was 3.7 per 100 patient‐years, comparably in primary and secondary MF (PMF/SMF) but significantly lower in intermediate‐1 risk patients (2.3 vs 5.6 per 100 patient‐years in intermediate‐2/high‐risk patients, P   〈  .001). In PMF and SMF cohorts, previous interferon therapy seemed to correlate with a lower probability of BP (HR 0.13, P = .001 and HR 0.22, P = .02, respectively). In SMF, also platelet count 〈 150 × 10 9 /l (HR 2.4, P = .03) and peripheral blasts ≥3% (HR 3.3, P = .004) were significantly associated with higher risk of BP. High‐risk category according to dynamic International Prognostic Score System (DIPSS) and myelofibrosis secondary to PV and ET Collaboration Prognostic Model (MYSEC‐PM predicted BP in patients with PMF and SMF, respectively. Median survival after BP was 0.2 (95% CI: 0.1‐0.3) years. Therapy for BP included hypomethylating agents (12.3%), induction chemotherapy (9.2%), allogeneic transplant (6.2%) or supportive care (72.3%). Patients treated with supportive therapy had a median survival of 6 weeks, while 73% of the few transplanted patients were alive at a median follow‐up of 2 years. Progression to BP occurs in a significant fraction of ruxolitinib‐treated patients and is associated with DIPSS and MYSEC‐PM risk in PMF and SMF, respectively.

Abstract: In 816 patients with 2016 World Health Organization‐defined polycythemia vera (PV) enrolled in a multicenter retrospective study, we investigated the predictive value of Charlson comorbidity index (CCI) and body mass index (BMI) on thrombosis, progression to post‐PV myelofibrosis (PPV‐MF) and survival. Patients were subgrouped according to CCI = 0 (58.1%, no comorbidities) or CCI ≥ 1 (41.9%) and according to normal/underweight (BMI  〈  25, 54.5%) or overweight/obesity (BMI ≥ 25, 45.5%) at PV diagnosis. BMI was available for 529 patients. Patients with CCI ≥ 1 were older and more frequently presented cardiovascular risk factors compared to patients with CCI = 0 ( p   〈  0.001), while overweight/obese patients were more frequently males ( p   〈  0.001). Cumulative incidence of thromboses with death as competing risk was 13.3% at 10 years. Multivariable analysis with death as competing risk showed that previous thromboses (subdistribution hazard ratio [SHR]: 2.1, p  = 0.01) and hypertension (SHR: 1.77, p  = 0.04) were significantly associated with a higher thrombotic risk, while BMI ≥ 25 lost statistical significance (SHR: 1.69, p  = 0.05) and CCI ≥ 1 was excluded after evaluation of goodness of fit. After a median follow‐up of 6.1 years, progression to PPV‐MF occurred in 44 patients, and 75 patients died. BMI ≥ 25 was associated with a lower probability of progression to PPV‐MF (SHR: 0.38, CI95%: 0.15–0.94, p  = 0.04) and better survival (hazard ratio [HR] : 0.42, CI95%: 0.18–0.97, p  = 0.04). CCI ≥ 1 did not affect progression to PPV‐MF ( p  = 0.44) or survival ( p  = 0.71).  The evaluation of CCI and BMI may improve the prognostic definition of PV. In patients with hypertension an accurate evaluation of thrombotic risk is warranted.

Abstract: In real‐world data from 524 patients who received ruxolitinib for myelofibrosis, the incidence of and risk factors associated with drug discontinuation were investigated along with how reasons for discontinuation, disease phase at discontinuation, and salvage therapies may influence outcomes. At 3 years, higher risk category, lower platelet count, unfavorable karyotype, and transfusion dependency at the start of ruxolitinib were associated with a greater probability of drug discontinuation; and outcomes were significantly better in patients who discontinued in chronic phase versus blast phase and in those who received investigational agents and/or ruxolitinib rechallenge.