Updated results from MOMENTUM: Momelotinib vs. Danazol in JAK inhibitor-experienced, symptomatic, and anaemic myelofibrosis patients

The phase 3 MOMENTUM study (NCT04173494) of the ACVR1/JAK1/JAK2 inhibitor momelotinib (MMB) vs. danazol (DAN) in patients with myelofibrosis (MF) previously treated with a JAK inhibitor (JAKi) met the primary endpoint and all key secondary endpoints at week 24 (W24). We provide updated results from week 48 assessments. Eligible patients had primary or post-ET/ PV MF;DIPSS high, Int-2, or Int-1 risk;Total Symptom Score (TSS) >=10;haemoglobin (Hb) <10 g/dL;platelets >=25 x 109/L;prior JAKi for >=90 days (>=28 days if red blood cell [RBC] transfusions >=4 units in 8 weeks or grade 3/4 thrombocytopenia/anaemia/ hematoma);and palpable spleen >=5 cm. Randomisation was 2:1 to MMB 200 mg/day or DAN 600 mg/day for 24 weeks, followed by open-label (OL) MMB. Week 48 endpoints included durations of response (TSS, transfusion independence [TI], splenic) and overall and leukaemia-free survival (OS, LFS). As of 17 May 2022, 93/130 (72%) MMB -> MMB and 41/65 (63%) DAN -> MMB patients received OL MMB;mean MMB durations were 48 weeks and 24 weeks, respectively. Analyses for W24 responders showed the following: of TSS responders, 31/32 (97%) MMB -> MMB and 6/6 DAN -> MMB patients had TSS < baseline;of TI responders, 36/40 (90%) and 10/13 (77%) had no RBC transfusions or Hb <8 g/dL;and of spleen responders, all patients had splenic volume < baseline. In the OL phase, the most common grade >=3 treatment-emergent adverse events (TEAEs) were thrombocytopenia (MMB -> MMB, 9%;DAN -> MMB, 15%) and anaemia (MMB -> MMB, 9%;DAN -> MMB, 2%). Grade >=3 infections occurred in 19% of MMB -> MMB and 10% of DAN -> MMB patients, including grade >=3 (nonfatal) COVID-19. Peripheral neuropathy (PN) occurred in 2% of patients in each arm, and none discontinued MMB due to PN. TEAEs led to MMB discontinuation in 18% (MMB -> MMB) vs. 10% (DAN -> MMB). A trend towards improved OS up to W24 was previously observed with MMB vs. DAN (hazard ratio [HR], 0.506;p = 0.0719);after all patients crossed over to OL MMB, OS and LFS curves for both arms converged (HR, 0.945, 95% CI, 0.528-1.693;HR, 0.830, 95% CI, 0.473-1.4555). Sixty of 81 (74%) MMB -> MMB and 29 of 43 (67%) DAN -> MMB patients with baseline platelets <=150 x 109/L entered the OL phase. Efficacy and safety results in thrombocytopenic subgroups in the OL period were consistent with the intent-to- treat (ITT) population. OL MMB maintained symptom, TI, and spleen responses with continued good survival and safety in the ITT and low platelet populations. MMB may address an unmet need in anaemic patients with MF.

Second versus first wave of covid-19 in patients with mpn

Introduction. MPN-COVID is a European LeukemiaNet cohort study, launched in March 2020 in patients with myeloproliferative neoplasms (MPN) with COVID-19. The first cohort of 175 cases was analyzed at the end of first wave (July 2020) and results provided estimates and risk factors of overall mortality (Barbui T. Leukemia, 2021), thrombosis incidence (Barbui T. Blood Cancer J, 2021), and post-COVID outcomes (Barbui T. Blood Cancer J, 2021). In the second wave of pandemic (June 2020 to June 2021), case-fatality risk in the general population has been found variable across different countries, and no information is available in MPN patients with COVID-19 diagnosed during the second wave in comparison with those of the first wave. Methods. In an electronic case report form, we registered a total of 479 cases of ET (n=161, 34%), PV (n=135, 28%), pre-PMF (n=49, 10%) and overt MF (n=134, 28%), from 39 European hematology units (Italy, Spain, Germany, France, UK, Poland, Croatia). Of these, 304 were diagnosed COVID-19 during the second wave. Results. Patients in the second wave were significantly different from those in the first wave, including parameters such as age (median: 63 vs. 71 years, p<.001), sex (females: 52% vs. 42%, p=0.037), MPN category (MF 24% vs. 34%, p=0.020), comorbidity (at least one comorbidity 63% vs. 74%, p=0.012), disposition (home: 68% vs. 23%, regular ward: 29% vs. 66%, ICU: 3% vs. 11%, p<.001), need of respiratory support (28% vs. 59%, p<.001) and degree of systemic inflammation (C-Reactive Protein: 51% vs. 74%, p=0.008;Neutrophil to Lymphocyte Ratio: 4.1 vs. 5.4, p=0.038). In regard to COVID-19-directed therapy, in the second wave steroids were more frequently prescribed (28% vs. 40%, p=0.007), while the use of antibiotics, antivirals, hydroxychloroquine and experimental therapies was significantly less frequent (p<.001 for all the differences). Interestingly, only 4 out of 46 patients (8.7%) discontinued Ruxolitinib during second-wave acute COVID (all MF admitted to regular ward). In the two waves, distribution probability of COVID-19 incidence by Kernel method showed a substantially similar shape, whereas the two incidence peaks were associated with very different mortality, as reported in Fig. 1A. The difference between the probability of death was highly significant during the first (n=175) vs. second (n=304): 31% vs. 9% at 60 days from COVID-19 diagnosis, respectively (p<.001) (Fig. 1B). Of note, among 26 deaths, 4 (15%) occurred at home, 19 (73%) on regular wards and 3 (12%) in the ICU, and death more frequently afflicted patients with (n=17, 65%) than ET (n=5, 19%) and PV (n=4. 15%) (p<.001). Independent risk factors for death in a multivariate Cox regression model fitted on the whole cohort and adjusted for the wave to which patients belonged, were age over 70 years (HR=5.2, 95% CI 1.8-15.1, p=0.002), male sex (HR=1.9, 95% CI 1.1-3.1, p=0.016), COVID-19 severity revealed by the need for respiratory support (HR=4.5, 95% CI 1.9-10.7, p=0.001), and Ruxolitinib discontinuation (HR=3.0, 95% CI 1.3-6.9, p=0.011). Conversely, in patients who continued this drug, no risk was documented (HR=1.21, p=0.566). Taking into account death as competing event, the second outcome of interest was the incidence of thrombosis, wich occurred in a significantly lower proportion of patients in the second wave compared to the first one (n=5 [1.6%] vs. n=14 [8.0%] at +60 days, respectively, SHR=0.20, p=0.002) (Fig. 1C). All the events, but one (n=4/5) were venous and were reported in patients with ET (SHR=4.4, 95% CI 1.8-10.7, p=0.001). Conclusions. This is the largest series of MPN patients who incurred COVID-19 from June 2020 onward, namely during the 'second COVID-19 wave'. Compared to the first wave, the second one recorded a lower overall COVID-19 severity, but Ruxolitinib discontinuation still remained a risk factor for a dismal outcome. Greater vulnerability of ET than PV in developing venous thrombosis was confirmed also during the second wave. This finding suggests that ET warrants a specific antithrombo ic prophylaxis in addition to heparin.

First Interim Analysis of the Italian Dante Study: De-Escalation before Treatment-Free Remission in Patients with Chronic Myeloid Leukemia Treated with First-Line Nilotinib

Introduction: Treatment-free remission (TFR) in chronic myeloid leukemia (CML) is demonstrated to be achievable and recommended for patients (pts) in sustained deep molecular response (sDMR) who can discontinue tyrosine kinase inhibitor (TKI) treatment and maintain responses in ~50% of cases. While the feasibility and safety of TKI cessation have been largely demonstrated, the strategies of TFR optimization are yet to be clarified. Studies (eg. DESTINY) investigating de-escalation, mainly after imatinib, suggested that a stepwise approach may favor TFR outcome. We present the interim results of the phase 2, prospective, multicenter DANTE study (NCT03874858) evaluating de-escalation and TFR in Italian pts with CML in chronic phase (CML-CP) treated with nilotinib (NIL). Methods: Adults with CML-CP treated with NIL 300 mg twice daily (bid) in first-line for ≥3 years who achieved sDMR for ≥1 year (≥MR 4.0;BCR-ABL level ≤0.01% IS) were enrolled in 27 centers. The study consisted of 4 phases: screening (week [wk] −4-0), consolidation (wk 0-48), TFR (wk 48-144), and follow-up (until wk 144). Ongoing treatment with ≥400 mg/day dose was allowed at study entry. During consolidation, pts were treated with NIL 300 mg once daily (qd). At the end of consolidation phase, pts with sDMR entered TFR phase and discontinued NIL;indeed, pts with at least major molecular response (MMR;BCR-ABL ≤0.1% IS), but without sDMR, continued NIL 300 mg qd. At any time, pts with loss of MMR returned to NIL 300 mg bid. During TFR phase, BCR-ABL levels were monitored monthly from wk 52-96, and then every 3 months. Pts on half-dose or full-dose NIL were monitored every 3 months. The primary endpoint is the percentage of pts in full treatment-free remission (FTFR) 96 wks after the start of consolidation phase. FTFR is defined as pts with MMR or better, including those who remained in discontinuation during TFR phase and those who are treated with half the standard dose. Key secondary endpoints include percentage of pts with sDMR at wk 48;TFR rate at wk 96 and 144;BCR-ABL kinetics and safety. The predictive role of digital droplet PCR is also evaluated as an exploratory objective. Results: Overall, 113 pts were screened and 107 entered consolidation phase. This interim analysis included 52 pts who reached the end of consolidation phase by data cut-off period (February 8, 2021). Of these 52 pts, 49 (94.2%) were ongoing by data cut-off and 3 (5.8%) discontinued the study (1 patient due to adverse event (AE) and 2 per patient's decision). Median age at study entry was 49.5 years. Median time from diagnosis was 5.6 years and median dose of prior NIL treatment was 600 mg/day for all pts except one who was on NIL 450 mg/day at baseline. Median duration of last sustained MR4 and MR4.5 were 30 and 16.5 months, respectively. Further details are listed in Table 1. At screening, molecular response categories were MR4.0 in 13.7%, MR4.5 in 23.1% and undetectable MR4.5 in 63.5% of pts. During consolidation phase, 5 (9.6%) pts discontinued prematurely: 2 pts restarted NIL full dose (3.8%) for MMR loss, 2 (3.8%) discontinued for AEs and 1 (1.9%) for pt decision. Overall, 47 pts completed consolidation: of them 40 (76.9%) sustained DMR and 7 (13.5%) maintained MMR but not sDMR. Of the 7 pts not sustaining DMR during consolidation, 6 regained DMR after a median of 4.4 months, while 1 pt was still in MMR by data cutoff. The 2 pts who lost MMR after 5 and 8 months regained MMR and 1 regained DMR by data cutoff after increasing NIL to 300 mg bid. Median time spent in consolidation phase was 11.7 months, and the evolution of response categories over time is shown in Figure 1. During consolidation phase, AEs were observed in 16 pts (30.8%), of them 2 (3.8%) pts had serious AEs: 1 patient had skin ulcers and COVID-19 related pneumonia, while 1 patient had unstable angina. No deaths and disease progressions were observed. Conclusions: DANTE is the first study that showed the safety and feasibility of NIL de-escalation before TFR in CML-CP pts with sDMR. Inter m results suggest that loss of MMR during de-escalation is rare. De-escalation strategy may lead to further improvement of TFR outcome and tolerability and may also preemptively support the identification of pts who may not be ready for discontinuation, with a tailored approach. To date, accuracy in predicting TFR outcome is still low, and the de-escalation setting may sharpen biological and clinical predictive factors, including the potential role of digital PCR. [Formula presented] Disclosures: Breccia: Abbvie: Honoraria;Pfizer: Honoraria;Novartis: Honoraria;Incyte: Honoraria;Bristol Myers Squibb/Celgene: Honoraria. Abruzzese: Incyte: Consultancy, Honoraria;Novartis: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria;Bristol Myers Squibb: Consultancy, Honoraria. Stagno: InCyte: Consultancy, Honoraria;Pfizer: Consultancy, Honoraria, Other: Support for attending meetings and/or travel;Novartis: Consultancy, Honoraria, Other: Support for attending meetings and/or travel, Research Funding. Iurlo: Incyte: Speakers Bureau;Novartis: Speakers Bureau;Pfizer: Speakers Bureau;Bristol Myers Squibb: Speakers Bureau. Sportoletti: AstraZeneca: Consultancy, Honoraria;Janssen: Consultancy, Honoraria;AbbVie: Consultancy, Honoraria. Lemoli: Jazz, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;AbbVie, Daiichi Sankyo, Servier: Honoraria, Speakers Bureau;Celgene: Other: Support for attending meetings and/or travel. Siragusa: Novartis, CSL, Behring, Amgen, Novonoridsk, SOBI, Bayer: Consultancy, Honoraria, Speakers Bureau. Chiodi: Novartis: Current Employment.

COVID-19 Infection in chronic myeloid leukemia after 1 year of the pandemic in Italy. A campus CML analysis

Background: An outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) started in December 2019 in the province of Hubei in China. Italy was one of the most affected countries with many cases diagnosed already in February 2020 and a lockdown was declared on March 9th. Limited information has been reported with regard to the impact of the pandemic on chronic myeloid leukemia (CML) patients. Aims: To observe the temporal course of Covid-19 infection and the characteristics of positive patients. Methods: The Campus CML Italian group carried out a first survey on the management of CML patients during the lockdown. We launched a second survey during the pandemic phases 2 and 3, between May 2020 and January 2021. Results: We collected retrospective information on 8665 CML patients followed at 46 centers throughout the country. Within this cohort, we recorded 217 Covid-19-positive symptomatic patients (2.5%). Most patients (57%) were diagnosed as having Covid-19 infection between September 2020 and January 2021;30% were diagnosed in phase 1 (March-April 2020) and only 13% between May and August. Most of the positive patients were between 50 and 65 years (35%), while 26% had less than 50 years, 18.8% were between 65 and 75 years, and 11% had more than 75 years. A male prevalence was observed (73%). The median time from CML diagnosis to Covid-19 infection was 6 years (3 months-18 years). Fifty-six percent of patients presented concomitant comorbidities at the time of infection. When Covid-19 was diagnosed, 27% of patients were receiving imatinib, 26% nilotinib, 18% dasatinib, 8% ponatinib, 8% bosutinib, 2% asciminib, while 11% were not receive treatment. At the time of the infection, 74% of patients were in molecular remission, 6% in complete cytogenetic remission, 3% in partial cytogenetic remission, 6% in complete hematological response and 11% in treatment-free remission. At diagnosis, 28% of patients presented fever and respiratory symptoms, 13% cough, 10% isolated fever, 13% ageusia, 12% anosmia, 4% had more than 1 symptom, while 20% were completely asymptomatic. Twenty-one patients (9.6%) required hospitalization without the need of respiratory assistance, 18 (8.2%) were hospitalized for respiratory assistance, 8 (3.6%) were admitted to an ICU, while 150 patients (69%) were only quarantined. Twenty-three percent of patients discontinued TKI therapy during the infection. The source of contagion was familiar in 49% of patients, 18% due to work, 3% in healthcare professionals, whereas in 30% was not known. Twelve patients died due to Covid-19 infection with a mortality rate of 5.5% in the positive cohort and of 0.13% in the whole cohort. Five patients reported consequences post-infection: 1 patient reported a Guillan-Barrè syndrome, 1 patient a maculopapular rash, 1 patient a pulmonary fibrosis, 1 patient a bacterial endocarditis and 1 patient was diagnosed as having alterations of the microcirculation. Summary/Conclusion: This study reports the 1-year of data on the Covid- 19 infection in a specific hematological malignancy in the European country first hit by the pandemic. A longer follow-up is needed to further define the impact of Covid-19 infection sequelae in CML patients.

Long-term follow-up of recovered mpn patients with covid-19

To our knowledge, there is no information on long-term follow-up of recovered patients with chronic myeloproliferative neoplasms (MPN) with COVID-19. It can be hypothesized that cytokine storm of the acute phase and the post-COVID persistence of a residual inflammatory state may contribute to elicit hematopoietic stem cell insults and continuous vascular endothelial damage, leading to MPN disease progression and persistent high risk of thrombosis. Aims: To describe sequelae of COVID-19 in surviving patients with MPN following COVID-19. Methods: MPN-COVID study involved 38 European blood centers, and accrued 180 patients with MPN diagnosed with COVID-19 from Feb to Jun 2020, assessing mortality and incidence of thrombosis and bleeding during the acute phase of the pandemic [Barbui T et al. Leukemia. 2021;35(2):485-493. Barbui T et al. Blood Cancer J. 2021;11(2):21]. One-hundred-twenty-five (69%) of these patients survived and were followed up for at least 6 months. Centers were asked to update symptoms, treatments, hematological changes, major outcomes (i.e., thrombosis, disease evolution and death). Results: Among the 125 surviving patients, all eligible for the follow-up update, with a median age 70 years (IQR: 58-79), the following phenotypes were registered: PV (n=38, 30%), ET (n=37, 30%), early PMF (n=14, 11%) and MF (n=36, 29%). During the acute phase of infection, 38 (30%) were managed at home, 80 (64%) in a regular ward and 7 (6%) in ICU. Symptoms (i)The 3 prevalent symptoms during the acute phase of the disease were fever (79%), cough (56%) and dyspnea (53%), while gastrointestinal, neurological, musculoskeletal symptoms, as well as fatigue and anosmia/ dysgeusia, were present in a minor proportion, ranging from 1.6% to 17%. (ii) In the post-acute COVID-19 phase, 36 of 125 patients (32%) declared the persistence of some of these symptoms, fatigue being the most frequent (19%), while none presented persistence of fever and only 10% of dyspnea. Major outcomes (i) Major thrombosis was documented in 5 patients and involved 3 patients with MF (one fatal intestinal ischemia, two non-fatal events: splenic infarction and peripheral artery thrombosis), one case in PV (acute myocardial infarction) and one with ET (DVT of the legs with pulmonary embolism). Age varied from 61 to 80 years. The first event occurred five months after COVID-19 recovery and the Kaplan Meier thrombosis-free survival probability after 9 months was 82%. (ii) Acute myelogenous leukemia (AML) was ascertained in 3 patients (1 in MF, 1 in early-PMF, 1 in ET);one was fatal and occurred in a 49-yearold patient, the other 2 in 78- and 82-year-old patients, respectively. One non-Hodgkin′s lymphoma (in ET) and one progression of a previous parotid carcinoma (in MF) were seen in two patients aged 60 and 77 years, respectively. (iii) Deaths were reported in 8 patients (6.4%), due to AML (n=1), thrombosis (n=1), progression to prior carcinoma (n=2, 1 suspected), multi organ failure (n=1) and heart failure (n=2);the cause was unknown in a single patient. Five deaths (63%) occurred in MF patients. (iv) Overall, the event-free survival pooling together thrombosis, disease evolution and death reached 66% after 9 months from COVID- 19 recovery, indicating that, during this time of observation, 1 out of 3 patients died or have experienced at least one of the other two severe events. Summary/Conclusion: These results indicate that MPN patients who have survived SARS-CoV-2 infection continue to experience severe events suggesting an increased vigilance in the post-COVID period.

Second-Line Bosutinib in Elderly CML Patients: Final Results of Best Study

Introduction: The median age of CML patients failing a first-line TKI because of resistance or intolerance is higher than 60 years. Bosutinib (BOS), dasatinib (DAS) and nilotinib (NIL) have similar second-line efficacy, but in elderly patients DAS and NIL toxicity is more frequent and more clinically relevant. BOS safety profile may be an added value in this setting, but the approved initial dose of 500 mg OAD may be higher than necessary. Aims: All TKIs have been tested in CML patients at a fixed initial dose, with dose reductions in case of toxicity. On the contrary, the aim of our study was to evaluate the efficacy and the tolerability of low-dose second-line BOS in elderly CML patients, using the molecular response at given timepoints to increase the dose only in selected patients, thus finding the minimum effective dose. Methods: A prospective phase 2 single-arm multicenter study has been designed by the GIMEMA CML Working Party (NCT02810990). Study design: All patients started BOS 200 mg OAD for 2 weeks (ârun-inâ period), then the dose was increased to 300 mg OAD;after 3 months, patients with BCR-ABLIS transcript ≤ 1% continued 300 mg OAD, while in patients with transcript > 1% the dose is furtherly increased to 400 mg OAD, in absence of relevant toxicity. The primary endpoint was the rate of MR3 at 12 months. Key inclusion criteria: > 60 yrs old, chronic phase CML, intolerance or failure of any first-line TKI (2013 ELN criteria), absence of T315I or V299L mutation. Results: Sixty-three patients have been enrolled. Median age: 73 yrs (range 60-90). Reasons for switching to BOS: Intolerance 63%, resistance 37%. First-line TKI: Imatinib 83%, DAS 11%, NIL 6%. All patients reached at least 1-year observation. Due to the emergency situation caused by SARS CoV2 spread in Italy, few data are still missing, but final results will be presented onsite. Maximum BOS dose: 400 mg OAD, 19%;300 mg OAD, 76%;200 mg OAD, 5%. At baseline, 17% of patients were already in MR3;MR3 rates at 3, 6 and 12 months were 44%, 54% and 59%, respectively. The cumulative rate of patients achieving or maintaining a MR3 by 12 months was 67%;patients achieving MR4 or MR4.5 by 12 months were 44% and 24%, respectively. Overall, 30%, 29% and 8% of patients had 1 log, 2 logs or > 3 logs reduction from baseline BCR-ABLIS transcript level (67% of patients had a molecular improvement from baseline). Selected adverse events: Acute coronary syndromes, 4 patients;pericarditis, 2 patients;peripheral arterial thrombosis, 1 patient;no pleural effusions were observed. Events leading to permanent treatment discontinuation: 2 unrelated deaths, 7 adverse events, 4 unsatisfactory responses (without progressions), 1 second neoplasia. Fourty-nine patients are still on BOS at the last contact: 10% of them on 400 mg OAD, 61% on 300 mg OAD, 29% on 200 mg OAD. Conclusions: These results trial showed that in elderly patients intolerant to or failing a first-line TKI BOS may be highly effective and better tolerated at a dose lower than 500 mg OAD, namely at 300 mg OAD.