COVID-19 IN PATIENTS WITH CHRONIC MYELOID LEUKEMIA IN TREATMENT-FREE REMISSION: DISEASE SEVERITY AND IMPACT ON TFR STATUS

Background: Severe SARS-CoV-2 infections associated with high mortality rates are reported in a higher percentage of patients (pts) with hematologic malignancies compared to general population. In chronic myeloid leukemia (CML), pts with uncontrolled disease have a higher mortality risk. The impact of SARS-CoV-2 infection on CML pts in treatment-free remission (TFR) has not been studied so far. In particular, as immune control of residual disease may be important for TFR, the concern is that the infection could induce loss of TFR. Aims: To evaluate the outcome of SARS-CoV-2 infection in CML pts in TFR and assess any impact on maintenance of TFR. Methods: From March 2020 to December 2021, the CANDID study organized by the international CML Foundation has collected data on COVID-19 positive CML pts worldwide. Details on the registry were presented recently (Pagano ASH 2021). For this sub-analysis on pts in TFR additional information were collected including;molecular remission status (BCR::ABL1 ratios) before, during and after SARS-CoV-2 infection covering at least 6 months. For molecular analyses, BCR::ABL1 ratios were classified according to Cross et al (Leukemia 2015). In addition, ratios of 0% without indication of sensitivity were allocated as MR4 i.e. 0.01%IS. PCR outlier results were identified using the ROUT method by nonlinear regression with a maximum false discovery rate (FDR) of 1% (Motulsky et al 2006). Time to molecular relapse (MR) was measured from the date of COVID-19 diagnosis to the date of MR defined as loss of major molecular remission (MMR, BCR::ABL1 >0.1%IS) or the date of last molecular test. Molecular relapse-free survival (MRFS) and overall survival (OS) were estimated with the Kaplan-Meier method. The statistical difference between groups was performed using log-rank test. Results: By December 2021, 1050 COVID-19 positive CML pts were registered. 95 pts were in TFR at the time point of SARS-CoV-2 infection of which 89 (93.68%) recovered and 6 deceased (6.32%). Median age of TFR pts was 57 years, male were 51 (53.68%). Median time from CML diagnosis to reporting date was 13 years (range 3.7-27.0 years). TFR duration was 2.83 years in median (range 0.5 months - 10.1 years) including 19 pts with a duration < 1 year. From the 89 recovered TFR pts, 74 pts completed the 6-month follow up (83%), a further 6 pts with molecular follow-up of 3-5 months after COVID-19 diagnosis were still in TFR, 9 pts were lost to follow-up. Of 74 pts with complete reports, 69 pts remained in TFR (93%) and 5 pts lost TFR. For 71 pts, PCR results were obtained before, during and after infection. With the ROUT method 10 pts demonstrated outlier PCR tests, 61 pts demonstrated stable PCR results. There was no statistically significant difference in PCR results before and during/after infection (p>0.2). MRFS for these 71 pts 15 months after COVID-19 diagnosis was 86%. Probability of TFR loss was higher in pts with a TFR duration < 6 months compared to pts with TFR duration >6 months (27% vs 10%, Fig 1A). Additionally, there were no statistically differences in hospitalization rate (16% vs 23%, p=0.12) and severity of COVID-19 symptoms (12.6% vs 12%, p=0.87) comparing TFR and TKI treated pts. OS of COVID-19 positive TFR pts did not differ from COVID-19 positive pts on TKI therapy (HR 1.1, CI 0.47-2.54) (Fig 1B). Summary/Conclusion: In this sub-analysis of the CANDID study, CML pts in TFR had similar severity and survival to CML pts who were on TKI therapy and there was no evidence of an increased risk of TFR loss after SARS-CoV-2 infection.

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.

Magnitude and Dynamics of the T-Cell Response to SARS-CoV-2 Infection and Vaccination

Background. T cells are central to the early identification and clearance of viral infections and support antibody generation by B cells, making them desirable for assessing the immune response to SARS-CoV-2 infection and vaccines. We combined 2 high-throughput immune profiling methods to create a quantitative picture of the SARS-CoV-2 T-cell response that is highly sensitive, durable, diagnostic, and discriminatory between natural infection and vaccination. Methods. We deeply characterized 116 convalescent COVID-19 subjects by experimentally mapping CD8 and CD4 T-cell responses via antigen stimulation to 545 Human Leukocyte Antigen (HLA) class I and 284 class II viral peptides. We also performed T-cell receptor (TCR) repertoire sequencing on 1815 samples from 1521 PCR-confirmed SARS-CoV-2 cases and 3500 controls to identify shared public TCRs from SARS-CoV-2-associated CD8 and CD4 T cells. Combining these approaches with additional samples from vaccinated individuals, we characterized the response to natural infection as well as vaccination by separating responses to spike protein from other viral targets. Results. We find that T-cell responses are often driven by a few immunodominant, HLA-restricted epitopes. As expected, the SARS-CoV-2 T-cell response peaks about 1-2 weeks after infection and is detectable at least several months after recovery. Applying these data, we trained a classifier to diagnose past SARS-CoV-2 infection based solely on TCR sequencing from blood samples and observed, at 99.8% specificity, high sensitivity soon after diagnosis (Day 3-7 = 85.1%;Day 8-14 = 94.8%) that persists after recovery (Day 29+/convalescent = 95.4%). Finally, by evaluating TCRs binding epitopes targeting all non-spike SARS-CoV-2 proteins, we were able to separate natural infection from vaccination with > 99% specificity. Conclusion. TCR repertoire sequencing from whole blood reliably measures the adaptive immune response to SARS-CoV-2 soon after viral antigenic exposure (before antibodies are typically detectable) as well as at later time points, and distinguishes post-infection vs. vaccine immune responses with high specificity. This approach to characterizing the cellular immune response has applications in clinical diagnostics as well as vaccine development and monitoring.

Phase 1 Trial of Vodobatinib, a Novel Oral BCR-ABL1 Tyrosine Kinase Inhibitor (TKI): Activity in CML Chronic Phase Patients Failing TKI Therapies Including Ponatinib

Introduction: Vodobatinib, a novel 3rd generation (3G) TKI effective against wild-type and mutated BCR-ABL1 with limited off-target activity, was evaluated in a Phase I multicentre dose-escalation study in chronic myeloid leukemia (CML) patients (pts) who failed ≥ 3 TKIs or less (if not eligible for other approved 3G TKIs) (NCT02629692). The activity and safety of vodobatinib was evaluated in ponatinib treated (PT) and ponatinib naïve (PN) chronic phase (CP)-CML subjects in an exploratory analysis. Methods: Multiple escalating doses of vodobatinib (once daily) in 28-day cycles were evaluated in a 3+3 study design. The primary objective was determination of the maximal tolerated dose (MTD) or recommended phase 2 dose (RP2D) along with safety and a secondary objective was to evaluate anti-leukemic activity. Dose escalation involved dose doubling until 2 pts in a cohort experienced Grade 2 toxicity, or 1 pt experienced Grade 3 or 4 toxicity, after which dose escalation was reduced to 40% increments. Treatment continued until unacceptable toxicity, disease progression (PD), consent withdrawal, or death. Results: As of 15 Jul 2020, 31 CP-CML pts received vodobatinib at doses of 12 to 240 mg;16 pts (9 males) in ponatinib treated (PT) cohort [7 (44%) ponatinib was the immediate prior TKI] and 15 pts (7 males) in the ponatinib naïve (PN) cohort. The baseline demographics and disease history are represented in Table 1. Efficacy: Median duration of treatment was 17.3 (0.6-36) and 14.8 (0.5- 42) months in the Ponatinib treated and naive groups, respectively;11 pts in the PT group [2 in Deep molecular response (DMR), 3 in MMR;5 in MCyR (2 in CCyR and 3 in PCyR);1 in stable disease] and 10 pts in the PN group (2 in DMR, 4 in MMR and 3 in CCyR, 1 in stable disease) are continuing on treatment. Overall efficacy outcomes are included in Tables 2 and 3. Of 16 PT pts, 2 (13%) pts, both with double mutations, had disease progression. Of 15 PN pts, 4 (26%) pts (with baseline mutation of T315I at 48 mg, Y253H at 66 mg, F317L and E255V mutation at 174 mg) progressed. Safety: In ponatinib treated pts, the most commonly reported treatment emergent adverse events (TEAEs), (all grades) included nausea (4, 25%) and diarrhea (3, 25%). Other commonly reported TEAEs included thrombocytopenia (3, 19%), rash (3, 19%), non-cardiac chest pain (3, 19%), increased amylase (3, 19%), and fall (3, 19%). Grade ≥ 3 TEAEs were reported in 10 (63%) pts included 1 pt each with anemia, lymphopenia, fall, skull fracture, spinal fracture, lipase increase, fluid overload, syncope, dyspnea, and hypertension. Vodobatinib related AEs included amylase increase, lipase increase, dyspnea, fluid overload, thrombocytopenia and neutropenia. Grade ≥ 3 TEAEs reported in more than one pt included neutropenia (2, 13%) amylase increase (2, 13%) and thrombocytopenia (2, 13%). In PN pts, the most commonly reported TEAEs (all grades) included myalgia (5, 33%) and back pain (4, 27%). Other commonly reported TEAEs were thrombocytopenia (4, 27%), and nasopharyngitis (3, 20%).Grade ≥ 3 TEAEs were reported in 7 (47%) pts (1 pt with anemia, 1 pt with pneumonia, 1 pt with neutropenia, 1 pt with gout, hypokalemia, thrombocytopenia, 1 pt with increased liver and pancreatic enzymes and 1 pt each with dementia and amnesia. Vodobatinib related AEs included alanine aminotransferase increase, blood bilirubin increased, amnesia, neutropenia and thrombocytopenia. No grade ≥ 3 event was reported in more than 1 pt. Overall, three cardiovascular TEAEs were reported, in 2 pts (1 each in PT and PN), all deemed unrelated to vodobatinib. Three pts died on study: 1 due to disease progression in the PT group;1 due to pneumonia (suspected COVID-19) and 1 due to intracranial hemorrhage in the PN group. The intracranial hemorrhage event (Grade 5 AE) was considered possibly related and was confounded by disease progression to blast phase that included extra-medullary sites. At the highest dose of 240 mg, two dose limiting toxicities were reported. The next lower dose level of 204 mg was est blished as MTD with a favorable safety profile in heavily pre-treated CP-CML pts. Conclusion: Vodobatinib was evaluated over 9 escalating doses. Comparable and promising efficacy was noted in both PT (50% CCyR) and PN (67% CCyR) groups, meriting further study of vodobatinib as a potential new agent for treatment of previously treated CP-CML. [Formula presented] Disclosures: Cortes: Daiichi Sankyo: Consultancy, Research Funding;Jazz Pharmaceuticals: Consultancy, Research Funding;Immunogen: Research Funding;Merus: Research Funding;Bristol-Myers Squibb: Research Funding;Takeda: Consultancy, Research Funding;Sun Pharma: Research Funding;BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Telios: Research Funding;Astellas: Research Funding;Amphivena Therapeutics: Research Funding;Arog: Research Funding;BiolineRx: Consultancy, Research Funding;Pfizer: Consultancy, Research Funding;Novartis: Consultancy, Research Funding. Kim: Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Takeda: Research Funding;BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau;Sun Pharma.: Research Funding;Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau;ILYANG: Consultancy, Honoraria, Research Funding. Alvarado: BerGenBio ASA: Research Funding;MEI Pharma: Research Funding;Astex Pharmaceuticals: Research Funding;Sun Pharma: Research Funding;FibroGen: Research Funding;Tolero Pharmaceuticals: Research Funding;Jazz Pharmaceuticals: Research Funding;Daiichi-Sankyo: Research Funding. Nicolini: Sun Pharma Ltd: Consultancy;Incyte: Research Funding, Speakers Bureau;Novartis: Research Funding, Speakers Bureau. Apperley: Bristol Myers Squibb: Honoraria, Speakers Bureau;Incyte: Honoraria, Research Funding, Speakers Bureau;Novartis: Honoraria, Speakers Bureau;Pfizer: Honoraria, Research Funding, Speakers Bureau. Deininger: DisperSol: Consultancy;Pfizer: Honoraria, Other, Research Funding;Leukemia & Lymphoma Society: Research Funding;Ariad: Consultancy, Honoraria, Other;Medscape: Consultancy;Novartis: Consultancy, Other, Research Funding;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Fusion Pharma: Consultancy;Blueprint Medicines Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: part of a study management committee, Research Funding;Incyte: Consultancy, Honoraria, Other, Research Funding;Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees;SPARC: Research Funding;Gilead Sciences: Research Funding;Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding;Galena: Consultancy, Honoraria, Other;Celgene: Research Funding. de Lavallade: Incyte: Honoraria, Research Funding;Bristol Myers Squibb: Honoraria, Research Funding;Novartis: Honoraria;Pfizer: Honoraria. Charbonnier: Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau;Novartts: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gambacorti-Passerini: Pfizer: Honoraria, Research Funding;Bristol-Myers Squibb: Consultancy. Lucchesi: Pfizer: Honoraria;Incyte: Honoraria;Novartis: Honoraria. Mauro: Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding;Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding;Sun Pharma/SPARC: Research Funding;Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding;Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Whiteley: Novartis: Consultancy;Dova: Consultancy;Jazz: Speakers Bureau;Seattle Genetics: Consultancy Speakers Bureau;GlaxoSmithKline: Speakers Bureau;Epizyme: Current equity holder in publicly-traded company, Speakers Bureau;Karyopharm: Current equity holder in publicly-traded company;Aprea: Current equity holder in publicly-traded company;MorphoSys: Consultancy;Agios: Consultancy, Speakers Bureau;Pfizer: Consultancy;Rigel: Consultancy. Yao: Sun Pharma Industries Incorporated: Current Employment. Kothekar: Sun Pharma Advanced Research Company Limited: Current Employment. Sreenivasan: Sun Pharma Advanced Research Company Limited: Current Employment. HV: Sun Pharma Advanced Research Company Limited: Current Employment. Chimote: Sun Pharma Advanced Research Company Limited: Current Employment.