ASCIMINIB PROVIDES DURABLE MOLECULAR RESPONSES IN PATIENTS (PTS) WITH CHRONIC MYELOID LEUKEMIA IN CHRONIC PHASE (CML-CP) WITH THE T315I MUTATION: UPDATED EFFICACY AND SAFETY DATA FROM A PHASE I TRIAL

Background: In pts with CML, the BCR::ABL1 T315I mutation is associated with poor clinical outcomes and confers resistance to previously approved ATP-competitive tyrosine kinase inhibitors (TKIs). Until recently, ponatinib (PON) was the only TKI available for these pts, but its use may be limited by associated cardiovascular events. In the primary analysis of the phase I trial X2101, asciminib-the 1st BCR::ABL1 inhibitor to Specifically Target the ABL Myristoyl Pocket (STAMP)-demonstrated efficacy and a favorable safety profile in heavily pretreated pts with CML with T315I. These results supported the FDA approval of asciminib as a new treatment option for pts with CML-CP with T315I (NCCN 2021). We report updated efficacy and safety data in these pts (data cutoff: January 6, 2021). Aims: Provide updated safety and efficacy data for pts with CML-CP with T315I treated with asciminib monotherapy 200 mg twice daily (BID) after added exposure. Methods: Pts with CML-CP with T315I were enrolled if treated with ≥1 prior TKI and no other effective therapy was available, provided informed consent, and received asciminib 200 mg BID. Results: 48 pts with T315I were included;2 (4.2%) pts had additional BCR::ABL1 mutations at baseline. Eight (16.7%), 15 (31.3%) and 25 (52.1%) pts received 1,2, and ≥3 prior TKIs, respectively. At data cutoff, treatment was ongoing in more than half (27 [56.3%]) of pts;the predominant reason for treatment discontinuation was physician's decision (11 [22.9%]), mainly due to lack of efficacy. Of the 48 pts, 45 were evaluable (BCR::ABL1IS >0.1% at baseline) for major molecular response (MMR);3 were excluded for BCR::ABL1 atypical transcripts. Among evaluable pts, 19 (42.2%) achieved MMR by wk 24 and 22 (48.9%) by wk 96;19 were still in MMR at the cutoff date. Evaluable pts included 26 PON-pretreated and 19 PONnaive pts;34.6% and 68.4%, respectively, achieved MMR by the cutoff date (Table). The probability of pts maintaining MMR for ≥96 wks was 84% (95% CI, 68.1-100.0). Thirteen (28.9%) and 11 (24.4%) pts achieved MR4 and MR4.5, respectively. Twenty (54.1%) and 23 (62.2%) of 37 pts with BCR::ABL1IS >1% at baseline achieved BCR::ABL1IS ≤1% by wk 48 and 96, respectively. The median duration of exposure was 2.08 (range, 0.04-4.13) yrs with more than half (27 [56.3%]) of pts receiving treatment for ≥96 wks;the median daily dose intensity was 398.3 (range, 179-400) mg/day. The safety/tolerability profile of asciminib remained favorable after ≈9 months of added follow-up (Table). The most common (≥5%) grade ≥3 adverse events (AEs) were lipase increase (18.8%, all asymptomatic elevations), thrombocytopenia (14.6%), and vomiting, ALT increase, abdominal pain, hypertension, anemia, neutropenia, and neutrophil count decrease (6.3% each). Arterial occlusive events occurred in 4 (8.3%) pts;none led to dose adjustment/interruption/discontinuation. AEs leading to discontinuation were reported in 2 new pts since the previous data cutoff;both pts discontinued and died due to COVID-19. These were the only study deaths reported in this pt population. Image: Summary/Conclusion: Asciminib monotherapy 200 mg BID exhibited a sustained, favorable safety profile after added exposure with no new safety signals in pts with CML-CP with T315I-a population with high unmet medical need. The clinical efficacy of asciminib is demonstrated by the high proportion of pts achieving durable MMR and BCR::ABL1IS ≤ 1%. The updated analysis confirms asciminib as a treatment option for pts with CML-CP with T315I, including those for whom treatment with PON has failed.

COVID-19 IN CHRONIC MYELOID LEUKEMIA PATIENTS – BRAZILIAN EXPERIENCE

Aims: To collect data about COVID-19 in CML patients from Brazilian centers and their outcomes. Methods: Observational, multicentric, ongoing register study. Hematologists from private and public CML reference centers from different regions of Brazil were invited to report their cases of COVID-19 in CML patients. Those centers are responsible for the care of approximately 3030 CML patients. Results: Between March 2020 and July 2021, 16 institutions contributed to this analysis, and reported 73 COVID-19 cases in CML patients (pts). Eight-five % were from the South and Southeast regions, 11% from Northeast. The median age was 50 years (22-79), with 33% of the pts older than 60. Male patients were predominant (60%). The median time of CML diagnosis was 9 years (0-29). Most of the pts were in first line therapy (57.5%), 27% in second line and 11% in third line. Current CML treatment at COVID-19 was: imatinib (46,5%), nilotinib (22%), dasatinib (16%), post-transplant (4%), asciminib (1%), ponatinib (1%), treatment-free remission (2%), no treatment (7%). COVID-19 grade: asymptomatic (4%), mild (66%), moderate (12%), severe/critical (16%). CML status at COVID: AP/BC (3%), CP (12,4%), hematologic response (11%), complete cytogenetic response (4%), MMR (34%), MR4.0 (8%), MR4.5 (27%). Eleven patients interrupted treatment temporarily during COVID. COVID-19 was confirmed by RT-PCR of oral and nasal swab collection (68%) or rapid/serologic test (32%). Comorbidities were present in 34 pts, most common were: hypertension (33%), diabetes (14%), chronic renal failure (4%), chronic obstructive pulmonary disease/emphysema (5.5%), pulmonary hypertension (1). Hospitalization occurred in 30% of the cases, 18% in an intensive care unit, 8% with mechanical ventilation. Treatment received for COVID-19: antibiotics (31%), steroids (16%), chloroquine (5.5%), oseltamivir (4%);ivermectin (8%): heparin (3%). Sixty-nine patients recovered, 4 died from COVID-19 (5,4%): one 42 year old newly diagnosed male patient with high leukocytes counts and with a simultaneous bacterial infection, two 70-year old patients treated with imatinib, both in MR4.5, and one 31-year old male patient treated with nilotinib, after imatinib and dasatinib failure, with hematologic response. A fifth patient in the accelerated phase died 2 months after discharge, from disease progression and pulmonary infection. All cases occurred before vaccination. There was one case of re-infection, in a patient treated with imatinib. Discussion: Conclusions: the majority of COVID-19 cases in the CML population was mild, but there were 2 deaths of young patients with active disease and two deaths in elderly patients, one of them with comorbidities. The mortality in CML was lower than observed in other hematologic cancers.

The new HFA/ICOS risk assessment tool to identify patients with chronic myeloid leukaemia at high risk of cardiotoxicity.

AIMS: Tyrosine kinase inhibitors (TKIs) used to treat chronic myeloid leukaemia (CML) can cause cardiovascular adverse events. So far, the Systematic Coronary Risk Evaluation (SCORE) charts of the European Society of Cardiology (ESC) have been used to identify cancer patients at increased cardiovascular risk. The primary aim of our study was to evaluate the usefulness of the new cardiovascular risk assessment model proposed by the Cardio-Oncology Study Group of the Heart Failure Association (HFA) of the ESC in collaboration with the International Cardio-Oncology Society (ICOS) to stratify the cardiovascular risk in CML patients, compared with SCORE risk charts. The secondary aim was to establish the incidence of adverse arterial events (AEs) in patients with CML treated with TKIs and the influence of preventive treatment with aspirin. METHODS AND RESULTS: A retrospective single-centre observational study was carried out on 58 patients (32 men and 26 women; mean age ± SD: 59 ± 15 years) with CML treated with TKIs for a median period of 43 ± 31 months. Cardiological evaluation was performed and cardiovascular risk was estimated with SCORE risk charts and with the new risk assessment tool proposed by HFA/ICOS. AEs were recorded. According to SCORE charts and the new HFA/ICOS risk stratification tool, respectively, 46% (Group A1) and 60% (Group A2) of patients were at high-very high risk, and 54% (Group B1) and 40% (Group B2) at low-moderate risk. AEs were significantly more frequent in Group A1 than Group B1 (P value < 0.01) when considered overall; they were significantly more frequent in Group A2 than Group B2 either overall or considered individually. HFA/ICOS risk stratification tool was significantly more sensitive than SCORE (P < 0.01) in identifying patients at higher risk of cardiovascular toxicity. In addition, we did not find AEs in patients pretreated with aspirin. CONCLUSIONS: The new HFA/ICOS risk stratification model allows a more tailored cardiovascular risk stratification in patients with CML and it is more sensitive than SCORE charts.

An update of safety and efficacy results from phase 1 dose-escalation and expansion study of vodobatinib, a novel oral BCR-ABL1 tyrosine kinase inhibitor (TKI), in patients with chronic myeloid leukemia (CML) and philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ All) failing prior tki therapies

Introduction: Vodobatinib is a novel third generation TKI effective against wild-type and mutated BCR-ABL1 (except T315I) with limited off-target activity. We present updated results from the Phase 1 dose-escalation (DEs) and expansion (DEx) study in CML and Ph+ALL patients (pts) failing ≥ 3 prior TKIs (< 3 prior TKIs if approved TKI is not clinically advised or available);patients with T315I are not eligible (NCT02629692). Methods: This is an open-label, phase 1, multicentre, 3+3 study evaluating maximum tolerated dose (MTD), safety and efficacy of vodobatinib administered once daily in 28 day cycles (dose range: 12 to 240 mg). MTD was established at 204 mg. DEx study enrolled chronic phase CML (CP-CML) patients at 174 mg dose of vodobatinib. Treatment continued until unacceptable toxicity, disease progression, consent withdrawal or death. Adverse events were assessed using NCI-CTCAE v4.03. Results: As of 15 Jul 2021, 52 pts are enrolled in DEs and DEx cohorts. Forty one of these pts received doses from 12 to 240 mg in the DEs cohort;32 chronic phase (CP-CML), 3 accelerated phase CML (AP-CML), 4 blast phase CML (BP-CML), 2 Ph+ ALL. Eleven CPCML pts were enrolled in DEx cohort at 174 mg dose. The baseline demographics and disease history are represented in Table 1. Efficacy: Of the 32 CP-CML pts enrolled in DEs: At baseline, 21 (65%) pts had no cytogenetic response, 4 (12.5%) were in PCyR, 7 (22%) were in CCyR. On vodobatinib therapy, 11(34%) pts achieved CCyR, 3 (9%) achieved PCyR and 7 (22%) maintained baseline CCyR. Baseline major molecular response (MMR) was present in 1 (3%) pt;and 14 pts (44%) achieved MMR on study. Of the remaining 11 pts, 5 (16%) had haematologically stable disease (no CyR and molecular response) and 6 (19%) had disease progression (cytogenetic or hematological) as their best response (Table 2 and 3). Seventeen CP-CML pts had prior ponatinib treatment, of which 11 (65%) had MCyR (4 achieved CCyR, 4 maintained CCyR, 3 achieved PCyR);while 8 (47%) achieved MMR. In the remaining 15 pts ponatinib naïve CP-CML: 10 (66%) had CCyR (7 achieved CCyR, 3 maintained CCyR);with 7 (47%) with MMR (6 achieved, 1 maintained). Two of the 3, AP-CML pts had baseline hematological response (CHR) with absence of cytogenetic and molecular response. The 3 pts further deepened their responses with 1 pt achieving CCyR with MMR and 2 pts in PCyR. Of the 4 BP-CML pts, 2 achieved CHR and 2 patients had disease progression as their best response;Of the 2 Ph+ ALL pts, 1 pt maintained CCyR and MMR while the other reported disease progression as the best response. Median duration of treatment overall was 23 (0.5-51) months [CP-CML 23 (0.5-51);AP-CML 36 (9-40);BP-CML 3 (0.5-18) and Ph+ ALL 4 (0.7-7.3) months]. Twenty one pts continue in study. In the DEx cohort, 1 of the 11 CP-CML pts was in PCyR at baseline. No pts had molecular response. Of the 11 patients, 6 (54 %) pts achieved CCyR, 1(10%) pt achieved PCyR. MMR was achieved by 1 pt (10%). Data is maturing for 1 pt. Median duration of treatment is 16 (0.3-19) months and 10 pts continue in study. Safety: Forty nine of 52 pts reported at least 1 TEAE. Most common any grade TEAEs included thrombocytopenia (33%), cough (19%), anaemia & diarrhoea (17% each). Thirty one pts (60%) reported Grade 3 and 4 treatment emergent AEs: most common were thrombocytopenia (15%), neutropenia and anaemia (12%), increased amylase and lipase (8% each). Ten (19%) pts reported cardiovascular TEAEs (Grade 1: angina pectoris, palpitations, ventricular extra-systoles, arteriosclerosis, hot flush, hypotension, intermittent claudication;Grade 2: hypertension, hypotension;Grade 3: cardiac failure congestive, hypertension);with a Grade 2 hypertension being vodobatinib related. Nineteen pts (37%) reported SAEs;vodobatinib related SAEs were reported in 3 pts (fatal intracranial haemorrhage (ICH), Grade 2 back pain and Grade 3 amnesia reported in 1 pt each). There were 5 deaths on study: 1 was related to use of vodobatinib (1 ICH, confounded by disease progression to blast phase that include extra-medullary sites) and the remaining unrelated (1 sudden death, 1 disease progression, 1 pneumonia fungal, 1 suspected COVID-19). Conclusion: Vodobatinib continues to be associated with favourable long term safety and efficacy in heavily pre-treated CML failing ≥ 3 prior TKIs, including ponatinib. Phase 2 study evaluating vodobatinib in pts failing at least 3 prior lines of therapy, including ponatinib, is ongoing.

Covid-19 in patients with chronic myeloid leukemia: Poor outcomes for patients with comorbidities, older age, advanced phase disease, and those from low-income countries: An update of the candid study

Background The iCMLf CANDID study represents the largest global cohort study to date characterizing COVID-19 in CML. This real world data collection, from 157 institutions in 49 countries, is essential to differentiate impact of patient, disease, and therapy specific factors on risk and outcomes, as the pandemic continues. Objective The primary aim of the CANDID study is to collect and analyze information on COVID-19 cases among CML patients (pts) to define risk factors, clinical evolution and outcome. Patients and methods Since March 2020, the iCMLf has collected data, with contributions from physicians treating CML pts and partner organizations. Country income was determined according to the World Bank Data. COVID-19 severity was classified according to the World Health Organization criteria. Univariate analysis was performed using log-rank test or logistic regression. Multivariate analysis was performed using Cox proportional hazards model or multivariate logistic regression. All the statistical analysis was performed using R statistical software (version 4.0.2). Results By April 2021, 642 cases of COVID-19 were reported from 50 countries. COVID-19 was diagnosed by PCR and/or serology in 601 pts (94%) and clinically suspected in 41 pts (6%). These 642 pts were reported by 186 physicians managing an estimated 37,449 CML pts (approximate incidence 0.7%). Most cases reported were from Europe (52%), followed by Asia (18%) and South America (16%). North America reported 10% of the cases and Africa 2.8%. The median age at the time of COVID-19 diagnosis was 53 years (18-94) and 59% of pts were males. Median time from CML diagnosis to COVID-19 was 8.34 years (range: 0-34). CML treatment at the time of COVID-19 diagnosis: hydroxyurea in 4 pts (6%), 38 (6%) bosutinib, 96 (15%) dasatinib, 275 (43%) imatinib, 92 (14%) nilotinib, 18 (3%) ponatinib, 3 (0.5%) other 4th generation TKIs;one alpha interferon. Ninety-nine (15%) pts were not receiving any treatment: 53 (8%) were in treatment free-remission (TFR) and 46 were without treatment (7%) for other reasons: treatment side effects (7), stem cell transplantation (12), pregnancy (3), lack of efficacy (2), unknown (1) and newly diagnosed CML (21). Significant comorbidities were present in 281 pts (44%), most common were: heart conditions, including hypertension (162), diabetes (76), lung diseases (47) obesity (42) and others (84). COVID-19 was asymptomatic in 53 cases (8%), mild in 363 cases (56%), moderate in 119 cases (18%), severe/critical in 86 cases (13%) and of unknown severity in 21 cases (3%). At the data cut-off, from the 606 pts with known outcome, 48 pts died (8%) and 558 (92%) recovered. Age >75y (Fig 1A, p<0.001), comorbidities (Fig 1B, p=0.039), low income country (Fig 1C, p<0.001), advanced phase CML at time of COVID-19 (Fig 1D, p<0.001) had statistically significant association with overall survival (OS) in CML pts with COVID-19. OS was 71% in low or lower middle income countries, 93% in upper middle and 95% in high-income countries (Fig 1C, p<0.001). The mortality rate for pts with cardiovascular disease;heart failure, coronary artery disease, cardiomyopathies, hypertension, stroke or cerebrovascular disease (12%), and chronic lung disease (13%) were higher than those pts with other comorbidities (6%), or without comorbidities (4%;p=0.003;Fig 1E). By multivariate analysis, all these risk factors remained significantly associated with OS. For pts who were hospitalized with severe disease, age >75y (p=0.037), comorbidities (p=0.001), male gender (p=0.01), CML status (AP/BC vs CP in MMR;p=0.049), CML treatment (pre-TKI vs TFR;p=0.02) and length of time with CML (p<0.05) were significant risk factors for mortality. By multivariate analysis, all the risk factors except age remained significant. The risk factors for mortality for pts with moderate, severe, or critical disease were age >75y (p=0.003) and low and lower middle income countries (p<0.001), both confirmed by multivariate analysis. Conclusions We confirmed a higher mortality for CML pts with COVID-19 n older pts (>75y), pts with cardiovascular or pulmonary comorbidities and from low and low-middle income countries, the latter probably related to limitations in supportive care. Additionally, more deaths occurred in pts in advanced phases and in pts not in MMR.

Machine learning identifies molecular regulators and therapeutics for targeting SARS-CoV2-induced cytokine release.

Although 15-20% of COVID-19 patients experience hyper-inflammation induced by massive cytokine production, cellular triggers of this process and strategies to target them remain poorly understood. Here, we show that the N-terminal domain (NTD) of the SARS-CoV-2 spike protein substantially induces multiple inflammatory molecules in myeloid cells and human PBMCs. Using a combination of phenotypic screening with machine learning-based modeling, we identified and experimentally validated several protein kinases, including JAK1, EPHA7, IRAK1, MAPK12, and MAP3K8, as essential downstream mediators of NTD-induced cytokine production, implicating the role of multiple signaling pathways in cytokine release. Further, we found several FDA-approved drugs, including ponatinib, and cobimetinib as potent inhibitors of the NTD-mediated cytokine release. Treatment with ponatinib outperforms other drugs, including dexamethasone and baricitinib, inhibiting all cytokines in response to the NTD from SARS-CoV-2 and emerging variants. Finally, ponatinib treatment inhibits lipopolysaccharide-mediated cytokine release in myeloid cells in vitro and lung inflammation mouse model. Together, we propose that agents targeting multiple kinases required for SARS-CoV-2-mediated cytokine release, such as ponatinib, may represent an attractive therapeutic option for treating moderate to severe COVID-19.