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The search for novel targets in chronic myeloid leukaemia (CML) is ongoing, to improve treatment efficacy in refractory disease and increase eligibility for tyrosine kinase inhibitor (TKI) discontinuation. Increased frequency of Tregs and effector Tregs was evident at diagnosis, together with increased expression of T-cell exhaustion markers, including in regulatory T cells at diagnosis and in patients with refractory disease. Plasma analysis revealed significantly increased levels of cytokines including tumour necrosis factor (TNF)-a and interleukin (IL)-6 at diagnosis, in keeping with a pro-inflammatory state prior to treatment. We hence demonstrate T-cell exhaustion and a pro-inflammatory state at diagnosis in CML, likely secondary to leukaemia-associated antigenic overload associated with increased disease burden.

Background: \ud Outcomes for patients with blast-phase chronic myeloid leukaemia are poor. Long-term survival depends on reaching a second chronic phase, followed by allogeneic haematopoietic stem-cell transplantation (HSCT). We investigated whether the novel combination of the tyrosine-kinase inhibitor ponatinib with fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) could improve response and optimise allogeneic HSCT outcomes in patients with blast-phase chronic myeloid leukaemia. The aim was to identify a dose of ponatinib, which combined with FLAG-IDA, showed clinically meaningful activity and tolerability.\ud \ud Methods: \ud MATCHPOINT was a seamless, phase 1/2, multicentre trial done in eight UK Trials Acceleration Programme-funded centres. Eligible participants were adults (aged ≥16 years) with Philadelphia chromosome-positive or BCR-ABL1-positive blast-phase chronic myeloid leukaemia, suitable for intensive chemotherapy. Participants received up to two cycles of ponatinib with FLAG-IDA. Experimental doses of oral ponatinib (given from day 1 to day 28 of FLAG-IDA) were between 15 mg alternate days and 45 mg once daily and the starting dose was 30 mg once daily. Intravenous fludarabine (30 mg/m2 for 5 days), cytarabine (2 g/m2 for 5 days), and idarubicin (8 mg/m2 for 3 days), and subcutaneous granulocyte colony-stimulating factor (if used), were delivered according to local protocols. We used an innovative EffTox design to investigate the activity and tolerability of ponatinib–FLAG-IDA; the primary endpoints were the optimal ponatinib dose meeting prespecified thresholds of activity (inducement of second chronic phase defined as either haematological or minor cytogenetic response) and tolerability (dose-limiting toxicties). Analyses were planned on an intention-to-treat basis. MATCHPOINT was registered as an International Standard Randomised Controlled Trial, ISRCTN98986889, and has completed recruitment; the final results are presented.\ud \ud Findings: \ud Between March 19, 2015, and April 26, 2018, 17 patients (12 men, five women) were recruited, 16 of whom were evaluable for the coprimary outcomes. Median follow-up was 41 months (IQR 36–48). The EffTox model simultaneously considered clinical responses and dose-limiting toxicities, and determined the optimal ponatinib dose as 30 mg daily, combined with FLAG-IDA. 11 (69%) of 16 patients were in the second chronic phase after one cycle of treatment. Four (25%) patients had a dose-limiting toxicity (comprising cardiomyopathy and grade 4 increased alanine aminotransferase, cerebral venous sinus thrombosis, grade 3 increased amylase, and grade 4 increased alanine aminotransferase), fulfilling the criteria for clinically relevant activity and toxicity. 12 (71%) of 17 patients proceeded to allogeneic HSCT. The most common grade 3–4 non-haematological adverse events were lung infection (n=4 [24%]), fever (n=3 [18%]), and hypocalcaemia (n=3 [18%]). There were 12 serious adverse events in 11 (65%) patients. Three (18%) patients died due to treatment-related events (due to cardiomyopathy, pulmonary haemorrhage, and bone marrow aplasia).\ud \ud Interpretation: \ud Ponatinib–FLAG-IDA can induce second chronic phase in patients with blast-phase chronic myeloid leukaemia, representing an active salvage therapy to bridge to allogeneic HSCT. The number of treatment-related deaths is not in excess of what would be expected in this very high-risk group of patients receiving intensive chemotherapy. The efficient EffTox method is a model for investigating novel therapies in ultra-orphan cancers.\ud \ud Funding: \ud Blood Cancer UK and Incyte.

Summary Patients receiving targeted cancer treatments such as tyrosine kinase inhibitors (TKIs) have been classified in the clinically extremely vulnerable group to develop severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), including patients with chronic myeloid leukaemia (CML) taking TKIs. In addition, concerns that immunocompromised individuals with solid and haematological malignancies may not mount an adequate immune response to a single dose of SARS‐CoV‐2 BNT162b2 (Pfizer‐BioNTech) vaccine have been raised. In the present study, we evaluated humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 patients with CML. Seroconversion and cellular immune response before and after vaccination were assessed. By day 21 after vaccination, anti‐Spike immunoglobulin G was detected in 14/16 (87·5%) of the patients with CML and all developed a neutralising antibody response [serum dilution that inhibits 50% infection (ID50) >50], including medium (ID50 of 200–500) or high (ID50 of 501–2000) neutralising antibodies titres in nine of the 16 (56·25%) patients. T‐cell response was seen in 14/15 (93·3%) evaluable patients, with polyfunctional responses seen in 12/15 (80%) patients (polyfunctional CD4+ response nine of 15, polyfunctional CD8+ T‐cell response nine of 15). These data demonstrate the immunogenicity of a single dose of SARS‐CoV‐2 BNT162b2 vaccine in most patients with CML, with both neutralising antibodies and polyfunctional T‐cell responses seen in contrast to patients with solid tumour or lymphoid haematological malignancies.

Classical veno-occlusive disease/sinusoidal obstruction syndrome (VOD/SOS) is a serious complication post allogeneic hematopoietic stem cell transplantation (HSCT). Before the recently revised EBMT criteria, the Baltimore and modified Seattle criteria failed to recognize the syndrome of late-onset VOD. We present real-world experience from a large UK transplant center reporting on VOD/SOS in consecutive HSCT adult patients (n = 530), transplanted for hematological cancers. We identified 27 patients treated with Defibrotide for VOD/SOS diagnosis, where detailed data were available for final analysis. Using standard definitions including EBMT criteria, around 30% (n = 8/27) of cases classified as late-onset VOD presenting at median of 46 (22-93) days but with D100 survival (63% vs 58%, Log-rank; P = 0.81) comparable to classical VOD. Hazard ratio for D100 mortality was 2.82 (95% CI: 1.74-4.56, P < .001, Gray test) with all VOD/SOS events. Twenty percent (n = 2/8) of late-onset VOD patients were anicteric and 42% (n = 8) classical VOD patients presented with refractory thrombocytopenia, while less than half met EBMT criteria for classical VOD in adults, highlighting gaps in real-world diagnostic limitations using EBMT criteria. However, challenges remain about underrecognition and difficulties related to early defibrotide access for treatment of late-onset VOD in current treatment guidelines. Our report strongly supports early Defibrotide for the treatment of severe VOD/SOS in adults regardless of time of onset.

This position statement from the Heart Failure Association of the European Society of Cardiology Cardio-Oncology Study Group in collaboration with the International Cardio-Oncology Society presents practical, easy-to-use and evidence-based risk stratification tools for oncologists, haemato-oncologists and cardiologists to use in their clinical practice to risk stratify oncology patients prior to receiving cancer therapies known to cause heart failure or other serious cardiovascular toxicities. Baseline risk stratification proformas are presented for oncology patients prior to receiving the following cancer therapies: anthracycline chemotherapy, HER2-targeted therapies such as trastuzumab, vascular endothelial growth factor inhibitors, second and third generation multi-targeted kinase inhibitors for chronic myeloid leukaemia targeting BCR-ABL, multiple myeloma therapies (proteasome inhibitors and immunomodulatory drugs), RAF and MEK inhibitors or androgen deprivation therapies. Applying these risk stratification proformas will allow clinicians to stratify cancer patients into low, medium, high and very high risk of cardiovascular complications prior to starting treatment, with the aim of improving personalised approaches to minimise the risk of cardiovascular toxicity from cancer therapies.

Introduction: The outlook for patients with chronic myeloid leukemia (CML) has changed dramatically with the development of tyrosine kinase inhibitors (TKIs) with the current treatment goal for many patients being to obtain a durable deep molecular remission, discontinue TKI therapy, and remain treatment free.Areas covered: In this article, the authors review the data from the major TKI discontinuation studies, explore potential predictors of discontinuation outcome and look at possible mechanisms to explain the variable outcomes following TKI discontinuation including immune surveillance and leukemic stem cell (LSC) depletion following TKI treatment. Data from relevant articles published on the Pubmed database between January 2007 and January 2020 have been included.Expert opinion: The results from the majority of TKI discontinuation studies show a consistent picture with approximately half of eligible patients achieving treatment free remission (TFR). However, reliable clinical predictors or biomarkers for the outcome of TKI discontinuation remain elusive and the mechanisms to explain the diversity of discontinuation success are not completely understood. Future studies will need to focus on attempts to increase the number of patients eligible for treatment discontinuation and will likely involve drug combinations including novel agents aimed at targeting the residual LSC population and enhancement of immune surveillance mechanisms.

Patients with haematological malignancies (HM) face high rates of intensive care unit (ICU) admission and mortality. High-flow nasal cannula oxygen (HFNCO) is increasingly used to support HM patients in ward settings, but there is limited evidence on the safety and efficacy of HFNCO in this group. We retrospectively reviewed all HM patients receiving ward-based HFNCO, supervised by a critical care outreach service (CCOS), from January 2014 to January 2019. We included 130 consecutive patients. Forty-three (33.1%) were weaned off HFNCO without ICU admission. Eighty-seven (66.9%) were admitted to ICU, 20 (23.3%) required non-invasive and 34 (39.5%) invasive mechanical ventilation. ICU and hospital mortality were 42% and 55% respectively. Initial FiO

Pre-emptive DLI (pDLI) is an effective strategy in lowering the risk of relapse without significantly increasing the risk of graft-versus-host disease (GVHD) in the case of T cell lineage mixed chimerism (MC) post allogeneic transplant in hematological malignancies. Many patients, however, fail to receive timely pDLI and have dismal outcomes, which are not taken into consideration. We compared long-term outcomes of 106 patients having T cell MC after day 60 and undergoing allogeneic stem cell allograft for acute leukemia from an unrelated donor (UD), with 111 patients having complete chimerism (CC). Fifty-three (56%) patients received prophylactic pDLI. Thirty-six patients (67%) had a response (RR), 17 (33%) had no response (NR), and fifty-two (54%) did not receive any pDLI (ND). OS was better in MC group as compared to CC (54% vs 43%, p = 0.04), mainly due to reduction in NRM (14% vs 25%, p = 0.05), and all grade acute and chronic GVHD. Within the MC group, response to pDLI was the only significant factor predicting OS, DFS, and relapses with NR and ND having unfavorable outcomes as compared to RR (p = 0.001). T cell MC in patients undergoing UD allografts with alemtuzumab is no longer an adverse prognostic factor, as compared to patients having CC, after timely implementation of pDLI.

Dasatinib is a multi-kinase inhibitor with inhibitory activity against Src kinases in addition to the BCR-ABL1 oncoprotein. The Src kinase Lck plays a pivotal role in signalling from the T cell receptor (TCR) and Src kinases also play a central role in signalling from NK cell activating receptors, with key downstream signalling molecules including ZAP70 and LAT. The STAT5 pathway is essential for NK cell function via IL-15, and T cell function through IL-2 signalling. Immune effector cells are thought to play a role in chronic myeloid leukaemia (CML) disease response, with correlation between the frequency of effector cells, including NK cells and CD8+ T cells, and improved outcome (Hughes A., Blood, 2017; Mustjoki, Blood, 2009). Standard licensed dose of dasatinib is 100mg OD but a reduced dose of 50mg OD can also be used (Naqvi, Cancer, 2019). Methods: 18 patients with chronic phase CML on TKI therapy (Dasatinib N=14, Imatinib N=2, Nilotinib N=2) and 7 healthy controls were included. Of the patients on dasatinib, 10 were taking a dose of 100mg OD and 4 were taking 50mg OD. A two-phase ex vivo functional analysis of immune cell subsets, including CD4+ and CD8+ T cells, NK cells and T regulatory cells (Tregs) was performed. We analysed expression of the cytokines, TNFa, IFNg and IL-2, after treatment of cells with OKT3. We also analysed signalling within cells after treatment with the phosphatase inhibitor H2O2. The relative fluorescence intensity (RFI) was calculated as MFI H2O2 sample/MFI unstimulated sample. Results: Patients on dasatinib had lower frequency of total Tregs and effector Tregs than controls and patients with CML taking other TKIs. However, there was no difference in the frequency of total Tregs between patients on 50mg and 100mg doses of dasatinib. Dasatinib significantly inhibited signalling from the TCR and of the STAT5 pathway when compared with patients on other TKIs and healthy controls, in CD4+ and CD8+ T cells, Tregs and NK cells. Patients on 50mg dasatinib had significantly higher RFI than patients on 100mg in CD4+ cells for pZAP70, and in CD4+ and CD8+ cells for pLAT. Similarly, patients on 50mg dasatinib had a higher RFI for pSTAT5 than those on 100mg in CD4+ and CD8+ T cells and also NK cells. Of note, the difference in the RFI of pSTAT5 between Tregs, and that of both CD8+ T cells and NK cells, was significantly higher in patients on 50mg dasatinib compared with 100mg, suggesting a relative sparing of effector immune cell inhibition at the lower dose. Expression of TNFa, IFNg and IL-2 were significantly reduced in patients taking dasatinib compared with healthy controls and patients on other TKIs. Patients on a 50mg dose of dasatinib had significantly higher proportional increase in IL-2 expression after OKT3 activation in CD4+ and CD8+ cells compared with patients on 100mg. Five patients on dasatinib 100mg OD with increased CD8+ T cells were confirmed to have clonal CD8+ lymphocytosis by performing TCR gene rearrangement analysis. These patients had a lower proportion of Tregs, compared to patients on dasatinib without CD8+ lymphocytosis. Importantly, a significantly lower RFI for pZAP70 and pLAT, within isolated Tregs, was also seen in this group, when compared with patients on dasatinib without CD8+ lymphocytosis. Discussion: Dasatinib inhibits key signalling pathways in T cells and NK cells and suppresses pro-inflammatory cytokine expression in T cells, compared to healthy controls and patients with CML taking other TKIs. However, patients taking a 50mg dose appear to have significantly less inhibition of effector cell function. In contrast, dasatinib may enhance immune surveillance mechanisms due to inhibition of Treg suppressive function, by reducing T effector IL-2 production, as well as STAT5 signalling within Tregs, required for FOXP3 transcription. Patients on dasatinib with clonal CD8+ lymphocytosis, as well as a lower frequency of Tregs, have an additional functional deficit within Tregs, with reduced signalling from the TCR. The presence of clonal CD8+ lymphocytosis is linked to improved outcomes, and typically occurs at the approved 100mg dosage. The dose of dasatinib strongly affects the activity of different immune cell subsets with the lower dosage allowing improved effector cell function. However greater inhibition of Tregs is seen in patients with clonal lymphocytosis, typically at the higher dosage, demonstrating the complexity of the immunomodulatory effect of dasatinib. Disclosures Harrington: Bristol Myers Squibb: Research Funding; Incyte: Honoraria, Speakers Bureau. Dillon:Jazz Pharmaceuticals: Honoraria; Amgen: Honoraria, Research Funding; Astellas: Honoraria; Pfizer: Honoraria, Research Funding; Menarini: Honoraria; Novartis: Honoraria; Abbvie: Honoraria, Research Funding. Radia:Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Education events; Blueprint Medicines Corporation: Membership on an entity's Board of Directors or advisory committees. McLornan:CELGENE: Honoraria, Speakers Bureau; NOVARTIS: Honoraria, Speakers Bureau; JAZZ PHARMA: Honoraria, Speakers Bureau. Rousselot:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy. Rezvani:GemoAb: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: Licensing agreement; Adicet Bio: Membership on an entity's Board of Directors or advisory committees; Formula Pharma: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Other: Educational grant; Affimed: Other: Educational grant; Virogen: Membership on an entity's Board of Directors or advisory committees. Kordasti:Novartis: Research Funding; Celgene: Research Funding; Alexion: Honoraria. Harrison:Novartis: Honoraria, Research Funding, Speakers Bureau; Incyte Corporation: Speakers Bureau; Gilead Sciences: Honoraria, Speakers Bureau; Shire: Honoraria, Speakers Bureau; AOP Orphan Pharmaceuticals: Honoraria; Promedior: Honoraria; Roche: Honoraria; Celgene: Honoraria, Research Funding, Speakers Bureau; CTI Biopharma Corp: Honoraria, Speakers Bureau; Sierra Oncology: Honoraria; Janssen: Speakers Bureau. de Lavallade:Pfizer: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria, Research Funding.

Survival after allogeneic hematopoietic cell transplantation (HSCT) for severe aplastic anemia (SAA) among older patients remains poor and associated with increased risk for graft-versus-host disease (GVHD). In this retrospective study of 65 consecutive patients with acquired SAA who were transplanted using fludarabine, low-dose cyclophosphamide, and alemtuzumab (FCC), outcomes of 27 patients aged at least 50 years were compared with those of 38 patients younger than 50 years. The median age of the older cohort was 61 years (range, 51-71 years); 21 (78%) patients were transplanted from unrelated donors (3 of 21 from HLA 9/10 mismatch donors) and 6 from matched sibling donors. One-year GVHD-free, relapse-free survival (GRFS) was comparable to that of patients younger than 50 years (84% vs 94%, respectively; P 5 .23). Both groups showed low rates of acute (5% vs 4%) and chronic (18% vs 14%) GVHD, with no cases of severe GVHD among matched donor transplants, and similar 1-year transplant-related mortality (14% vs 5.4%, older vs younger; P 5 .23). HSCT comorbidity index (HTC-CI) scores were similar between the groups, but overall survival with an HCT-CI of at least 3 was lower compared with a score less than 3 (76% vs 98%; P 5 .005). Median donor T-cell chimerism among older patients was 64% and 60% at 1 and 3 years, respectively, and was similar to that of younger patients. Increased B regulatory cells potentially contributed to low alloreactivity and mutual donor-recipient tolerance in older patients. Effect of comorbidities rather than age alone may be a more important determinant of suitability for FCC HSCT in older patients.

Introduction Although improvement in survival from haematological malignancies has been reported, a substantial number of these patients develop life threatening complications. Critical care outreach services (CCOS) aim to avert inappropriate ICU admissions, while ensuring timely patient review. Methods We retrospectively analysed patients with haematological malignancy reviewed by an outreach service between January 2014 and December 2015 at a single institution. The aim of our study was to describe the patient population assessed by a well-established outreach team, identify predictors of ICU admission, as well as ICU and hospital mortality. Results Sixty of 126 patients reviewed (47.6%) were admitted to ICU. ICU and hospital mortality were 25.3% and 45.2%, respectively. The odds of being admitted to ICU was 13 times higher ( p = 0.013) if the patient was referred for hypoxia, 20 times higher ( p = 0.006) if they were referred for sepsis or 14 times higher ( p = 0.027) if they were referred to CCOS for hypotension, compared to when the team was automatically alerted. The odds of not surviving hospital admission increased 1.27 times for every extra day of CCOS review ( p = 0.02). When a patient was referred having a refractory or progressive haematological condition, the odds of not surviving to hospital discharge increased by four or 12 times, respectively, compared to when the referred patient was in remission. Receiving high flow nasal cannula oxygen (HFNCO) was associated with a reduction in ICU admission ( p = 0.03), irrespective of the underlying diagnosis, performance status or location of delivery. The CCOS participated in end-of-life discussions in 29% patients. Conclusions ICU and hospital mortality of patients with haemato-oncological malignancy continue to improve. CCOS are heavily involved in the recognition and management of these patients, as well as in the facilitation of end-of-life discussions. Sepsis was associated with increased risk of ICU admission and mortality. Initiation of HFNCO outside ICU appears to be feasible and safe and was not associated with increasing risk in this single centre study.

Patients with haematological malignancies are at high risk of infection because of various mechanisms of humoral and cell-mediated immune deficiencies, which mainly depend on underlying disease and specific therapies. Some of these infections are vaccine preventable. However, these malignancies are different from each other, and the treatment approaches are diverse and rapidly evolving, so it is difficult to have a common programme for vaccination in a haematology ward. Additionally, because of insufficient training about the topic, vaccination is an area often neglected by haematologists, and influenced by cultural differences, even among health-care workers, in compliance to vaccines. Several issues are encountered when addressing vaccination in haematology: the small size of the cohorts that makes it difficult to show the clinical benefits of vaccination, the subsequent need to rely on biological parameters, their clinical pertinence not being established in immunocompromised patients, scarcity of clarity on the optimal timing of vaccination in complex treatment schedules, and the scarcity of data on long-term protection in patients receiving treatments. Moreover, the risk of vaccine-induced disease with live-attenuated vaccines strongly limits their use. Here we summarise guidelines for patients without transplantations, and address the issue by the haematological group-myeloid and lymphoid-of diseases, with a special consideration for children with acute leukaemia.

Kinase domain mutations in BCR-ABL1 are associated with resistance to tyrosine kinase inhibitors in patients with chronic myeloid leukaemia. Next-generation sequencing (NGS) allows detection of low-level kinase domain mutations, but its relevance in clinical practice remains debated. We aimed to examine the clinical effects of low-level kinase domain mutations identified using NGS in patients with chronic myeloid leukaemia.In this population-based study, we included consecutive patients newly diagnosed with chronic myeloid leukaemia treated with first-line tyrosine kinase inhibitors, and patients identified at the time of resistance to first-line treatment with imatinib at six institutions (teaching hospitals and district hospitals) in southeast England. We screened patients for BCR-ABL1 kinase domain mutations using NGS, irrespective of patient response to tyrosine kinase inhibitor therapy. When we detected a mutation with NGS, we retrospectively analysed all previous samples to establish the date of first occurrence and subsequent kinetics of the mutant subclone (or subclones). The primary endpoints of this study were progression-free and event-free survival at 5 years.Between Feb 1, 2007, and Dec 31, 2014, we screened 121 patients with chronic myeloid leukaemia for BCR-ABL1 kinase domain mutation. 99 consecutive patients were newly diagnosed, with available sequential RNA stored. The remaining 22 patients were diagnosed between June 1, 1999, and June 30, 2006, and were screened at the time of resistance to first-line treatment with imatinib. Imatinib was the first-line treatment for 111 patients, nilotinib for seven patients, and dasatinib for three patients. We detected a kinase domain mutation in 25 (21%) of 121 patients. Low-level kinase domain mutations were first identified in 17 (68%) of 25 patients with mutation. For patients with a complete cytogenetic response, 13 (14%) of 93 patients screened had a mutation. Five (71%) of the seven patients with a clinically relevant mutation lost complete cytogenetic response compared with 15 (17%) of 86 patients without a clinically relevant mutation (80 patients without mutation and six patients with a tyrosine kinase inhibitor-sensitive mutation, p=0·0031). Patients harbouring a mutant clone had poorer 5-year progression-free survival (65·3% [95% CI 40·5-81·8] vs 86·9% [75·8-93·2]; p=0·0161) and poorer 5-year event-free survival (22·2% [CI 5·6-45·9] vs 62·0% [50·4-71·6]; p0·0001) than did patients without a mutation. We identified a kinase domain mutation in four (10%) of 41 patients with samples available at 3 months after starting first-line tyrosine kinase inhibitor treatment; all four subsequently progressed to accelerated phase disease compared with only three (8%) of 37 without a mutation (p0·0001).NGS reliably and consistently detected early appearance of kinase domain mutations that would not otherwise be detected by Sanger sequencing. For the first time, to our knowledge, we report the presence of kinase domain mutations after only 3 months of therapy, which could have substantial clinical implications. NGS will allow early clinical intervention and our findings will contribute to the establishment of new recommendations on the frequency of kinase domain mutation analysis to improve patient clinical care.None.

Encouraging results have been observed from initial studies evaluating vaccines targeting the novel beta coronavirus which causes severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, concerns have been raised around the efficacy of these vaccines in immunosuppressed populations, including patients with haematological malignancy. Myeloproliferative neoplasms (MPN), in particular myelofibrosis (MF), are associated with heterogenous immune defects which are influenced by patient age, disease subtype and the use of cytoreductive therapies. Patients with a WHO defined diagnosis of an MPN presenting to our clinic were recruited following first injection of 30μg BNT162b2. A positive anti-S IgG ELISA was seen in 76.1% (16) of patients following vaccination with positive neutralising antibodies detected in 85.7% (18) of patients. A memory T cell response was observed in 80% (16) of patients, with a CD4+ T cell response in 75% (15) and a CD8+ T cell response in 35% (7). These results, for the first time, provide some reassurance regarding the initial immune response to the BNT162b2 vaccine amongst patients with MPN, with response rates similar to that observed in the general population.

Patients receiving targeted cancer treatments such as tyrosine kinase inhibitors (TKIs) have been classified in the clinically extremely vulnerable group to develop severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), including patients with Chronic Myeloid Leukaemia (CML) taking TKIs. In addition, concerns that immunocompromised individuals with solid and haematological malignancies may not mount an adequate immune response to a single dose of SARS-CoV-2 BNT162b2 (Pfizer-BioNTech) vaccine have been raised.We evaluated humoral and cellular immune responses after a first injection of BNT162b2 vaccine in 16 CML patients. Seroconversion and cellular immune response prior and after vaccination were assessed.By day 21 post-vaccination, anti-Spike IgG were detected in 14/16 (87.5%) of CML patients and all developed a neutralizing antibody response (ID50>50), including medium (ID50 of 200-500) or high (501-2000) neutralising antibodies titres in 9/16 (56.25%) patients. T cell response was seen in 14/15 (93.3%) evaluable patients, with polyfunctional responses seen in 12/15 (80%) patients (polyfunctional CD4+ response 9/15, polyfunctional CD8+ T cell response 9/15).These data demonstrate the immunogenicity of a single dose of SARS-CoV-2 BNT162b2 vaccine in most CML patients with both neutralizing antibodies and polyfunctional T-cell responses seen, in contrast to patients with solid tumour or lymphoid haematological malignancies.FundingKing’s Together Rapid COVID-19 Call awards to MHM, KJD; A Huo Family Foundation Award to MHM, KJD; Chronic Disease Research Foundation award CDRF-22/2020 to KJD, MHM; Wellcome Trust Investigator Award 106223/Z/14/Z to MHM; CG was supported by the MRC-KCL Doctoral Training Partnership in Biomedical Sciences (MR/N013700/1); Fondation Dormeur, Vaduz for funding equipment to KJD

BackgroundPatients with haematological malignancies (HM) face high rates of Intensive Care Unit (ICU) admission and mortality. High flow nasal cannula oxygen (HFNCO) is increasingly used to support HM patients in ward settings, but there is limited evidence on the safety and efficacy of HFNCO in this group. MethodsWe retrospectively reviewed all HM patients receiving ward-based HFNCO, supervised by a critical care outreach service (CCOS), from January 2014 - January 2019. ResultsWe included 130 consecutive patients. Forty-three (33.1%) were weaned off HFNCO without ICU admission. Eighty-seven (66.9%) were admitted to ICU, 20 (23.3%) required non-invasive and 34 (39.5%) invasive mechanical ventilation. ICU and hospital mortality were 42% and 55% respectively. Initial FiO2 1 day (OR 0.16, 95% CI 0.04, 0.59, p=0.006) were associated with reduced likelihood for ICU admission. Invasive ventilation was associated with reduced survival (OR 0.27, 95%CI 0.1-0.7, p=0.007). No significant adverse events were reported.ConclusionHM patients receiving ward-based HFNCO have higher rates of ICU admission, but comparable hospital mortality to those requiring CCOS review without respiratory support. Results should be interpreted cautiously, as the model proposed depends on the existence of CCOS.

Purpose of review Despite unprecedented challenges during the preceding year, there have been a wide range of significant advances in the field of chronic myeloid leukaemia. In this review article we highlight papers reporting on some of the most important developments over the last year, both with regards to the clinical management of patients with chronic myeloid leukaemia, as well as studies that help to increase our understanding of the pathophysiology of the disease. We have performed a PubMed search to identify important papers and abstracts listed over the last year and have included additional papers published prior to this, where relevant, to provide context. Recent findings We comment on novel biomarkers for treatment free remission as well as recent results from second generation Tyrosine Kinase Inhibitor (TKI) discontinuation studies. We discuss new techniques that are being used to assess TKI resistance as well as reviewing novel and emerging approaches to the management of resistant patients, including the use of combination therapies. Summary This review highlights some of the most important research to have been reported over the last year in the field of chronic myeloid leukaemia, encompassing emerging diagnostic techniques, biomarkers and novel therapeutic options.

In PACE (Ponatinib Ph+ ALL and CML Evaluation), a phase 2 trial of ponatinib that included patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant to multiple prior tyrosine kinase inhibitors (TKIs), ponatinib showed deep and durable responses, but arterial occlusive events (AOEs) emerged as notable adverse events. Post hoc analyses indicated that AOEs are dose dependent. We assessed the benefit/risk ratio across 3 ponatinib starting doses in the first prospective study to evaluate a novel, response-based, dose-reduction strategy for TKI treatment. Adults with CP-CML resistant to or intolerant of at least 2 prior BCR-ABL1 TKIs or with a BCR-ABL1 T315I mutation were randomly assigned 1:1:1 to 3 cohorts receiving ponatinib 45, 30, or 15 mg once daily. In patients who received 45 or 30 mg daily the dose was reduced to 15 mg upon response (BCR-ABL1IS transcript levels ≤1%). The primary end point was response at 12 months. From August 2015 through May 2019, 283 patients were randomly assigned to the cohorts: 282 (94 per dose group) received treatment (data cutoff, 31 May 2020). The primary end point (98.3% confidence interval) was achieved in 44.1% (31.7-57.0) in the 45-mg cohort, 29.0% (18.4-41.6) in the 30-mg cohort, and 23.1% (13.4-35.3) in the 15-mg cohort. Independently confirmed grade 3 or above treatment-emergent AOEs occurred in 5, 5, and 3 patients in the 45-, 30-, and 15-mg cohorts, respectively. All cohorts showed benefit in this highly resistant CP-CML population. Optimal benefit/risk outcomes occurred with the 45-mg starting dose, which was decreased to 15 mg upon achievement of a response. This trial is registered on www.clinicaltrials.gov as NCT02467270.

The management of chronic myeloid leukaemia (CML) has seen considerable change in the last several years. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of CML in adults and children.

Severe acute respiratory syndrome coronavirus‐2 (SARS‐CoV‐2), emerged at the end of 2019 and caused an infection named COVID‐19 (Guan, Ni et al. 2020). Patients with compromised immune systems are at increased risk of complications but this risk is not precisely defined (Liang, Guan et al. 2020). Although age, gender, comorbidities and ethnicity are risk factors for adverse outcomes (Huang, Wang et al. 2020), various pre‐existing conditions, including haematological cancers, have also been reported to correlate with poor outcomes (Aries, Davies et al. 2020, He, Chen et al. 2020, Malard, Genthon et al. 2020, Martin‐Moro, Marquet et al. 2020, medRxiv 2020)

Objective Relapse and graft-vs-host disease (GVHD) are still the main complications after allogeneic hematopoietic stem cell transplantation, especially in the setting of reduced intensity regimen (RIC) and unrelated donor. We compared here anti-thymocyte globulin (ATG) or alemtuzumab as GVHD prophylaxis in patients with myeloid disease transplanted after RIC and from an unrelated donor. Method ATG and alemtuzumab patients have been matched by age, gender, HLA matching, comorbidities and cytogenetics risk (119 patients in each group). Results After matching, we found that ATG decreased the risk of relapse (HR: 0.55, P = .0049) and improved relapse-free survival (RFS, HR: 0.70, P = .042). The improved RFS with ATG was more pronounced in CMV-positive patients but was not influenced by disease risk. Regarding overall survival, GVHD-free relapse-free survival and transplant-related mortality, the risk was similar using ATG or alemtuzumab. Conclusion Even if GVHD risk is lowered by alemtuzumab use, it does not translate in better outcome due to higher risk of relapse.

Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to unprecedented healthcare challenges on a global scale. Impressive efforts have led to rapid development of multiple efficacious vaccines against SARS-CoV-2, however concerns remain over the degree of protection vaccination offers to immunocompromised recipients. To answer this question, we have designed a prospective study to evaluate response to vaccination in patients with haematological malignancies (Harrington, Leukaemia 2021; Harrington, BJHaem, 2021). 103 patients were included with samples collected in 60 patients after first dose and 71 patients following second dose. We have analysed humoral and T cell response to a first dose of vaccine against SARS-CoV-2 in patients post allogeneic stem cell transplantation (HSCT) and compared those to patients with CML or MPN. Methods: ELISA plates were coated with antigen Nuclear (N) protein or the S protein. Serial dilutions of plasma were added to wells and incubated for 2 h at room temperature. Control reagents included N-specific monoclonal antibody, S-specific monoclonal antibody, negative control plasma, positive control plasma and blank wells. Secondary antibody was added and incubated for 1h at room temperature. IgG was detected using goat-anti-human-Fc-AP and plates read at 405 nm. Where an EC50 was not reached at 1:25, a plasma was considered seropositive if the OD at 405nm was 4-fold above background and a value of 25 was assigned. T cell functionality was assessed using intracellular cytokine staining after incubation with SARS-CoV-2 specific peptides covering immunogenic domains of the Spike (S) protein. A response was considered positive if there was a 3-fold increase in pro-inflammatory cytokine expression from baseline, and above a threshold of 0.01. Specific peptides (0.25 µg/ml), anti-CD28 and BFA were added to cells. Unstimulated cells were utilised as negative controls. Cells were stained with viability dye, then with antibodies directed against surface markers, and fixed and permeabilised prior to staining for intracellular cytokines TNFa and IFNg. Gating on lymphocytes, single cells, live cells, CD3+ cells, CD4+ cells and CD4- (CD8+) was performed. Results: Of the 103 patients included in this study, post vaccination evaluation on 56 patients have been analysed so far, including 37 patients with chronic myeloid malignancies (MPN n=21 and CML n=16) and 19 patients post HSCT. From the latter group, median time since transplant was 53.9 months (18.7 to 76.8) with 12 participants on extracorporeal photopheresis (ECP) therapy for graft versus host disease (GvHD) with median frequency of 24.5 days (14-42). BNT162b2 vaccine was administered to 48 patients (85.7%). An anti-S IgG response was observed after a first dose in 16/21 (76.1%) of the MPN group and 14/16 (87.5%) of CML patients, but in only 7/19 (36.8%) of post HSCT patients (Fishers Exact Test - p=0.02/0.002, Fig 1a). Of the latter group a low positive value where an EC50 was not reached was observed in 4/19 (21.1%) and a moderate response in 3/19 patients (15.8%). Of the 12 patients with active GvHD on ECP, a positive response was observed in 4 patients (33.3%), however only one patient recorded a response where an EC50 was measurable. A T cell response was observed in 16/20 (80%) of the MPN group and 14/15 (93.3%) of those with CML after a single dose, with a polyfunctional T cell response (>1 cytokine) observed in 65% and 80% respectively. In comparison only 5/19 patients (38.5%) post HSCT mounted a T cell response (p=0.027/p=0.002, Fig 1b), with a CD4+ response in 4 (30.8%) and a CD8+ response in 3 (23.1%). In this group, a polyfunctional T cell response was found in 4/19 patients (30.8%). 33.3% of patients with GVHD requiring ECP had a T cell response, compared with 42.9% in post HSCT without GVHD. Summary: Despite encouraging results of antibody and T cell response to a first vaccination dose in patients with chronic myeloid malignancies, these results raise concerns regarding the humoral and T cell responses to vaccination in patients post HSCT, recognised as a particularly immunosuppressed group. Further longitudinal data is required to determine if these results translate into a reduction in cases and severity of infection in these groups. We are currently analysing the response to a second vaccine injection and responses to sequential doses of vaccination across the whole cohort will be presented. Figure 1 Figure 1. Disclosures Harrington: Bristol Myers Squibb: Research Funding; Incyte: Honoraria. Radia: Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Study steering group member, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Education events; Cogent Biosciences Incorporated: Other: Study Steering Committee; EXPLORER and PATHFINDER studies: Other: Member of the Response Adjudication Committee. Kordasti: Beckman Coulter: Honoraria; Celgene: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Alexion: Honoraria. Dillon: Menarini: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Other: Session chair (paid to institution), Speakers Bureau; Astellas: Consultancy, Other: Educational Events , Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Research Support, Educational Events; Amgen: Other: Research support (paid to institution); Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: educational events; Jazz: Other: Education events; Shattuck Labs: Membership on an entity's Board of Directors or advisory committees. Harrison: Promedior: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AOP Orphan Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Speakers Bureau; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Constellation Pharmaceuticals: Research Funding; Galacteo: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Geron: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sierra Oncology: 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; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keros: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de Lavallade: Bristol Myers Squibb: Research Funding; Incyte: Honoraria, Research Funding; Novartis: Speakers Bureau.

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 CP-CML 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 included 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. Figure 1 Figure 1. Disclosures Cortes: Novartis: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sun Pharma: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kim: Novartis: Research Funding; BMS: Research Funding; Pfizer: Research Funding; ILYANG: Research Funding; Takeda: Research Funding. Alvarado: MEI Pharma: Research Funding; Daiichi-Sankyo: Research Funding; Sun Pharma: Consultancy, Research Funding; CytomX Therapeutics: Consultancy; Jazz Pharmaceuticals: Research Funding; BerGenBio: Research Funding; Astex Pharmaceuticals: Research Funding; FibroGen: Research Funding. Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel, accommodations, expenses, Research Funding; Incyte Biosciences: Honoraria, Other: travel, accommodations, expenses, Research Funding, Speakers Bureau; BMS: Honoraria; Sun Pharma Ltd.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kartos Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Apperley: Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau. Deininger: Fusion Pharma, Medscape, DisperSol: Consultancy; Novartis: Consultancy, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Incyte: Consultancy, Honoraria, Research Funding; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding. de Lavallade: Bristol Myers Squibb: Research Funding; Incyte: Honoraria, Research Funding; Novartis: Speakers Bureau. Charbonnier: Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gambacorti-Passerini: Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy. Mauro: Novartis: Consultancy, Research Funding; Takeda: Consultancy; Pfizer: Consultancy; Sun Pharma / SPARC: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Vandenberghe: Pfizer: Research Funding; Bristol Myers Squibb/Celgene: Consultancy; Miltenyi Biotec: Consultancy; Novartis: Consultancy; Janssen: Consultancy, Research Funding; Kite, a Gilead Company: Consultancy; Gilead Sciences: Consultancy, Other: Travel support. Radhakrishnan: Intas Pharmaceuticals: Research Funding; Emcure Pharmaceuticals: Research Funding; Dr Reddy's Laboratories: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen India: Honoraria; Cipla Pharmaceuticals India: Research Funding; Bristol-Myers-Squibb India: Membership on an entity's Board of Directors or advisory committees, Research Funding; Aurigene: Speakers Bureau; AstraZeneca India: Honoraria, Speakers Bureau; NATCO Pharmaceuticals: Research Funding; Novartis India: Membership on an entity's Board of Directors or advisory committees; Roche India: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yao: Sun Pharma: Current Employment. Inamdar: Sun Pharma Advanced Research Company: Current Employment. Sreenivasan: Sun Pharma Advanced Research Company: Current Employment. Dillu: Sun Pharma Advanced Research Company: Current Employment. Chimote: Sun Pharma Advanced Research Company: Current Employment.

Introduction: Ponatinib is a third-generation, pan-inhibitory tyrosine kinase inhibitor (TKI) designed to potently inhibit BCR-ABL1 with or without any single resistance mutation, including T315I. Patients (pts) with resistant disease or with T315I BCR-ABL1 mutations respond inadequately to earlier-generation BCR-ABL1 TKIs, leading to poor survival outcomes. OPTIC (Optimizing Ponatinib Treatment in CP-CML, NCT02467270; ongoing) is a phase 2 trial evaluating the safety and efficacy of ponatinib in pts with CP-CML whose disease is resistant to 2 or more TKIs or who have a T315I mutation. Here, we present an in-depth post hoc analysis of OPTIC trial pt responses by baseline disease burden and mutation status. Methods: Pts with CP-CML resistant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to ponatinib starting doses of 45 mg (cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg → 15 mg), and 15 mg (C) once daily. Doses were reduced to 15 mg after achievement of ≤1% BCR-ABL1 IS in cohorts A and B. Pts could re-escalate to their original starting dose for loss of response. The primary endpoint is ≤1% BCR-ABL1 IS at 12 months; secondary endpoints include cytogenetic and molecular responses and safety outcomes. In this analysis, outcomes are analyzed by baseline T315I mutation status and baseline disease burden in the intent-to-treat (ITT) population. BCR-ABL1 mutations were assessed by Sanger sequencing at a central laboratory (MolecularMD, Portland, OR, USA). Results: 283 pts were randomized (A/B/C: n=94/95/94). At baseline, 84.1% of pts had a high (>10% BCR-ABL1 IS) disease burden; 23.8% had T315I mutation, 17.0% had a mutation other than T315I, and 57.8% had no mutation. The 45 mg →15 mg cohort showed the highest ≤1% BCR-ABL1 IS response rates by 36 months (Figure 1). Subanalysis of pts across the 3 dosing arms showed that pts with T315I mutations had the highest ≤1% BCR-ABL1 IS response rates (60%) by 3 years with the 45 mg → 15 mg dose compared with the other cohorts, with a trend toward higher progression-free survival (PFS) in the 45 mg →15 mg arm (Table 1). Across all 3 cohorts, 97 pts without T315I mutations (ie, no mutation or with mutations other than T315I) achieved ≤1% BCR-ABL1 IS. Median duration of response (mDoR) for pts with a T315I mutation at baseline was 27 months for pts (n=15) in the 45 mg → 15 mg cohort and 12 mo for pts (n=5) in the 30 mg → 15 mg cohort. For pts without T315I mutations, the mDoR was not reached. Across all 3 cohorts, 79% of pts who achieved ≤1% BCR-ABL1IS maintained this response during the study. A total of 25 patients lost responses (Table 2). Of those who lost response, 11 had T315I, 10/11 dose re-escalated; of those who re-escalated, 6/10 regained ≤1% BCR-ABL1IS after dose re-escalation (Table 2). The most common nonhematologic treatment-emergent adverse events (TEAEs) in the ITT population for all cohorts combined were arterial hypertension (28%), headache (18%), and lipase increased (17%). The most common hematologic TEAEs were thrombocytopenia (40%), neutropenia (26%), and anemia (19%). Overall, 6.0% of pts experienced a treatment-emergent arterial occlusive event (TE-AOE); 4.6% experienced a Grade ≥3 TE-AOE. Conclusions: Previous analyses established these largely resistant pts achieved high response rates when treated with ponatinib. Consistent with this, the OPTIC post hoc analysis showed clinical benefit across all 3 dosing regimens regardless of T315I mutation status at baseline; the 45 mg →15 mg cohort showed the highest response rates regardless of baseline disease burden (as assessed by BCR-ABL1 IS levels). Regardless of T315I mutation status, most patients were able to maintain their response after dose reduction to 15 mg/day upon achieving BCR-ABL1IS ≤1%. Compared with patients without a T315I mutation, patients with a T315I mutation at baseline were more likely to lose their response upon dose reduction; however, 60% of responses were regained with dose re-escalation. For pts with T315I mutations, PFS was greater with 45 mg → 15 mg dosing compared with the other arms; for pts without T315I mutations, all 3 doses showed robust PFS and OS outcomes. The data presented further support the benefit of using ponatinib post-2nd generation TKI for pts with resistant disease regardless of baseline T315I mutation status. Figure 1 Figure 1. Disclosures Deininger: Incyte: Consultancy, Honoraria, Research Funding; Fusion Pharma, Medscape, DisperSol: Consultancy; Blueprint Medicines Corporation: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; SPARC, DisperSol, Leukemia & Lymphoma Society: Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Part of a Study Management Committee, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Research Funding. Apperley: Incyte, Pfizer: Honoraria, Research Funding, Speakers Bureau; Bristol Myers Squibb, Novartis: Honoraria, Speakers Bureau. Chuah: Steward Cross: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Pfizer: Other: Travel, Research Funding; Novartis, Korea Otsuka Pharmaceutical: Honoraria. Hochhaus: Bristol-Myers Squibb: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Research Funding; Incyte: Research Funding. De Lavallade: Pfizer, Novartis.: Honoraria; Bristol Myers Squibb, Incyte: Honoraria, Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding. Lomaia: Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Pharmstandard: Honoraria. McCloskey: Takeda: Consultancy, Speakers Bureau; Jazz: Consultancy, Speakers Bureau; BMS: Honoraria, Speakers Bureau; COTA: Other: Equity Ownership; Incyte: Speakers Bureau; Amgen: Speakers Bureau; Novartis: Consultancy; Pfizer: Consultancy. Mauro: Bristol Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy; Novartis: Consultancy, Research Funding; Sun Pharma / SPARC: Research Funding; Pfizer: Consultancy. Moiraghi: Novartis, Pfizer, Takeda: Speakers Bureau. Pavlovsky: Novartis, BMS, Pfizer, Takeda: Speakers Bureau. Rosti: Pfizer: Research Funding, Speakers Bureau; Bristol Myers Squibb, Incyte, Novartis: Speakers Bureau. Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Undurraga: AbbVie, Janssen, Novartis, Pfizer, Roche: Other: Advisory Board; Janssen, Novartis, Pfizer: Speakers Bureau. Lu: Takeda: Current Employment. Vorog: Takeda: Current Employment. Cortes: Takeda: Consultancy, Research Funding; Sun Pharma: Consultancy, Research Funding; Bristol Myers Squibb, Daiichi Sankyo, Jazz Pharmaceuticals, Astellas, Novartis, Pfizer, Takeda, BioPath Holdings, Incyte: Consultancy, Research Funding; Bio-Path Holdings, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

Context: PON, a third-generation tyrosine kinase inhibitor (TKI), demonstrated deep, long-lasting responses/survival in patients with chronic-phase chronic myeloid leukemia (CP-CML) resistant/intolerant to second-generation TKI therapy (PACE; NCT01207440); post hoc analysis suggested a relationship between dose and adverse events/response. We present the primary analysis of OPTIC (NCT02467270), an ongoing, randomized, phase 2 trial in resistant/intolerant CP-CML to evaluate safety and efficacy of PON response–based dosing regimens. Methods: Patients with CP-CML resistant/intolerant to ≥2 TKIs or with the BCR-ABL1 T315I mutation were randomized to PON starting doses of 45 mg (cohort A), 30 mg (B), and 15 mg (C) once daily. Doses were reduced to 15 mg with achievement of ≤1% BCR-ABL1IS in cohorts A and B. Primary endpoint is Results: 283 patients were randomized (A/B/C: n=94/95/94) and had the following baseline characteristics: median age 48 y (18–81 y); 98% received ≥2 (55% ≥3) TKIs; 99% had resistant disease; 40% had ≥1 baseline mutations (23% T315I). At 32-mo median follow-up, 134 patients (47%; n=50/41/43) remained on treatment and 204 patients (72%) had PON exposure ≥12 mo. At 12 mo, 44% (41/93) in A, 29% (27/93) in B, and 23% (21/91) in C achieved ≤1% BCR-ABL1IS; cohort A met the primary endpoint. Progression-free survival/overall survival at 36 months was 73/89% (A), 66/89% (B), and 70/92% (C). Most common grade ≥3 treatment-emergent adverse events (TEAEs) were thrombocytopenia, 27%; neutropenia, 17%; and anemia, 7%. Arterial occlusive events (AOEs)/serious AOEs were reported in cohorts A (10%/4%), B (5%/4%), and C (3%/3%). Dose reductions or discontinuations for TEAEs (A/B/C) were 46/35/32% and 19/16/14%, respectively. Conclusions: The OPTIC primary analysis demonstrates the optimal benefit/risk profile for PON was achieved with a response-based dosing regimen starting with 45 mg/d, followed by dose reduction to 15 mg/d upon achieving ≤1% BCR-ABL1IS. Observed ≤1% BCR-ABL1IS responses are supported by robust survival outcomes in patients with and without BCR-ABL1 mutations. The OPTIC study is sponsored by ARIAD Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited, with additional funding from Incyte Corporation (Wilmington, DE).

Introduction: In PACE (NCT01207440), patients with refractory chronic-phase chronic myeloid leukemia (CP-CML) with substantial prior second-generation tyrosine kinase inhibitor (TKI) treatment demonstrated deep, lasting responses to ponatinib. However, long-term follow-up identified rates of arterial occlusive events (AOEs) as a risk. OPTIC (NCT02467270) is a randomized Phase 2 trial evaluating ponatinib at 3 starting doses: 45 mg, 30 mg, and 15 mg daily in patients with CP-CML resistant/intolerant to ≥2 TKIs or with a T315I mutation. The interim analysis showed that the 45-mg (vs 30 mg or 15 mg) starting dose (with reduction to 15 mg upon response) provided the best clinical outcomes and responses were maintained in >75% of patients who dose reduced. Here, we present efficacy and safety outcomes by baseline mutation status and line of treatment for the 3 dose cohorts. Methods: Patients with CP-CML resistant/intolerant to ≥2 TKIs or with T315I mutation were randomized to ponatinib starting doses of 45 mg (Cohort A; 45 mg → 15 mg), 30 mg (B; 30 mg → 15 mg), and 15 mg (C) once daily (qd). Doses were reduced to 15 mg on achievement of ≤1% BCR-ABL1ISin Cohorts A and B. Doses also could be reduced for safety. The primary endpoint is ≤1% BCR-ABL1IS at 12 months. In this analysis, the outcome was analyzed by baseline mutation status (none, any, T315I, and non-T315I) and number of prior TKIs (≤2 or ≥3) in the intent-to-treat (ITT) population. Treatment-emergent adverse events (TEAEs), serious TEAEs, and AOEs by adjudication were summarized by number of prior TKIs (≤2 or ≥3). Interim analysis results are descriptive. Results: Patients (N=283) were randomized: A/B/C n=94/95/94; median age was 48 y (18‒81 y). Seven patients were excluded from the intent-to-treat population (N=276) because they had atypical transcripts. Mutation status was well balanced between cohorts; 59% had no mutation, 41% had ≥1 baseline mutation, 24% had T315I, and 17% had a non-T315I mutation. In all categories of mutation status, the rate of ≤1% BCR-ABL1IS by 12 months was highest in Cohort A, with the most notable differences seen in patients with T315I (A: 60%, B: 25%, C: 6%) (Table 1). Patients with no mutations or other mutations had smaller differences but the outcomes all still favored 45 mg. Patients in all cohorts were treated with multiple TKIs, with 54% (A), 60% (B), and 53% (C) having 3 or more prior TKIs. The rate of ≤1% BCR-ABL1IS by 12 months was highest in Cohort A, both in patients treated with ≤2 or ≥3 prior TKIs (43% and 49%, respectively) (Table 1). Table 2 shows rates of TEAEs and TE-AOEs by cohort and number or prior TKIs. There was a trend toward higher event rates in Cohort A and for patients treated with ≥3 TKIs. Rates of adjudicated AOEs were low (≤6%) in all 3 cohorts irrespective of the number of prior TKIs. Conclusions: At this interim analysis with a median follow-up of ~21 months, the maximum benefit:risk, regardless of mutation status or number of prior TKIs, was observed in patients treated with a 45-mg starting dose, with a reduction to 15 mg upon achievement of response. Patients with the T315I mutation who initiated ponatinib at 45 mg experienced better response rates than those who initiated ponatinib at 30-mg or 15-mg starting doses. Primary analysis will provide a refined understanding of the benefit:risk profile of 3 different starting doses of ponatinib. Disclosures Cortes: BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sun Pharma: Research Funding; Telios: Research Funding; Amphivena Therapeutics: Research Funding; Astellas: Research Funding; Bristol-Myers Squibb: Research Funding; BiolineRx: Consultancy, Research Funding; Arog: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Immunogen: Research Funding; Merus: Research Funding. Apperley:Bristol Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau. Hochhaus:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Honoraria; MSD: Research Funding. Mauro:Sun Pharma/SPARC: Research Funding; Pfizer: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Other: Travel, Accommodation, Expenses, Research Funding. Rousselot:Bristol-Myers Squibb: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Takeda: Consultancy; Incyte: Consultancy, Research Funding. Sacha:Incyte: Consultancy, Honoraria, Speakers Bureau; Bristol-Myers Squibb Company: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau. Talpaz:Novartis: Research Funding; IMAGO: Consultancy; Constellation Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding. Chuah:Korea Otsuka Pharmaceutical: Honoraria; Pfizer: Other: Travel, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding. Lipton:Bristol-Myers Squibb: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Deininger:SPARC: Research Funding; Novartis: Consultancy, Other, Research Funding; Sangamo: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Other, Research Funding; 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; Fusion Pharma: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Medscape: Consultancy; DisperSol: Consultancy; Leukemia & Lymphoma Society: Research Funding; Gilead Sciences: Research Funding; Ariad: Consultancy, Honoraria, Other; Bristol-Myers Squibb: Consultancy, Honoraria, Other, Research Funding; Galena: Consultancy, Honoraria, Other; Celgene: Research Funding; Pfizer: Honoraria, Other, Research Funding. Schiffer:BMS: Consultancy; Novartis: Consultancy; Takeda: Research Funding. García Gutiérrez:Pfizer: Honoraria, Other: travel/accommodations/expenses, Research Funding; Novartis Pharma AG: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding; Incyte: Consultancy, Honoraria, Other: travel/accommodations/expenses, Research Funding. de Lavallade:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria, Research Funding; Incyte: Honoraria, Research Funding. Etienne:Bristol-Myers Squibb: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding, Speakers Bureau; Pfizer: Consultancy, Speakers Bureau; Incyte: Consultancy, Speakers Bureau. Lu:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Srivastava:Takeda: Current Employment. Rosti:Novartis: Speakers Bureau; Incyte: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Pfizer: Research Funding, Speakers Bureau.