Mary McMullin - Academia.edu (original) (raw)

Papers by Mary McMullin

Journal of Clinical Pathology, Aug 1, 1995

Cancer Chemotherapy and Pharmacology, Mar 9, 2023

Purpose Gemtuzumab ozogamicin (GO) is indicated for treatment of relapsed/refractory (R/R) acute ... more Purpose Gemtuzumab ozogamicin (GO) is indicated for treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). The QT interval, pharmacokinetics (PK), and immunogenicity following the fractionated GO dosing regimen have not been previously assessed. This phase IV study was designed to obtain this information in patients with R/R AML. Methods Patients aged ≥ 18 years with R/R AML received the fractionated dosing regimen of GO 3 mg/m 2 on Days 1, 4, and 7 of each cycle, up to 2 cycles. The primary endpoint was mean change from baseline in QT interval corrected for heart rate (QTc). Results Fifty patients received ≥ 1 dose of GO during Cycle 1. The upper limit of the 2-sided 90% confidence interval for least squares mean differences in QTc using Fridericia's formula (QTcF) was < 10 ms for all time points during Cycle 1. No patients had a post-baseline QTcF > 480 ms or a change from baseline > 60 ms. Treatment-emergent adverse events (TEAEs) occurred in 98% of patients; 54% were grade 3-4. The most common grade 3-4 TEAEs were febrile neutropenia (36%) and thrombocytopenia (18%). The PK profiles of both conjugated and unconjugated calicheamicin mirror that of total hP67.6 antibody. The incidence of antidrug antibodies (ADAs) and neutralizing antibodies was 12% and 2%, respectively. Conclusion Fractionated GO dosing regimen (3 mg/m 2 /dose) is not predicted to pose a clinically significant safety risk for QT interval prolongation in patients with R/R AML. TEAEs are consistent with GO's known safety profile, and ADA presence appears unassociated with potential safety issues. Trial registry Clinicaltrials.gov ID: NCT03727750 (November 1, 2018).

Haematologica, Jun 24, 2017

Irish Journal of Medical Science, Jun 7, 2022

Background Calreticulin (CALR) mutations are commonly identified in patients with essential throm... more Background Calreticulin (CALR) mutations are commonly identified in patients with essential thrombocythaemia or myelofibrosis. CALR type 1 mutations are known to have a higher overall incidence in males but little is known about the risks of mutation subtypes on myelofibrotic change across patient age and sex. Aims To identify differences in the incidence of myelofibrotic change within subgroups of patients with CALR type 1 mutations. Methods All patients with a positive CALR exon 9 mutation identified within our unit between February 2016 and September 2020 were reviewed with note taken of patient sex, age at diagnosis, initial MPN diagnosis, and subsequent disease transformation. Results In our cohort, young male patients with CALR type 1 mutations were shown to be at significantly increased risk of myelofibrosis compared to age matched female patients. Conclusions Male patients have a worse myeloproliferative neoplasm phenotype than female patients with it occurring at a younger age and being more myelofibrotic in nature. Further investigation is needed into the reasons for this variability.

Journal of Hematopathology, Nov 4, 2016

Chronic myeloid leukaemia (CML) is consistently associated with the BCR-ABL1 fusion gene located ... more Chronic myeloid leukaemia (CML) is consistently associated with the BCR-ABL1 fusion gene located on the derivative chromosome 22 (Philadelphia chromosome, Ph + ve) as a result of a t(9;22)(q34;q11.2) translocation. We describe a 36-year-old male in blast phase CML presenting with acute myelomonocytic leukaemia and eosinophilia. Five months after initial disease diagnosis and despite being treated with standard imatinib therapy (400 mg daily) conventional cytogenetic analysis (CCA) demonstrated the evolution of a chromosome 16 pericentric inversion (inv(16)(p13q22)) within the already Ph + ve cells. Bone marrow aspiration and biopsy revealed 60% blasts, positive for CD34, HLADR, CD33 and CD13. Fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR) confirmed presence of a CBFβ-MHY11 rearrangement whilst next generation sequencing (NGS) detected an E255K point mutation within the BCR-ABL1 tyrosine kinase domain. Neither the CBFβ-MHY11 rearrangement nor the E225K point mutation were present at diagnosis. The patient received a combination of daunorubicin (60 mg/m 2) and cytarabine (100 mg/m 2) and had his tyrosine kinase inhibitor (TKI) changed to nilotinib before undergoing a male unrelated donor (MUD) stem cell transplant (SCT). The t(9;22) and inv(16) rearrangements persisted at day 100 post MUD SCT and his TKI was further switched to dasatinib. The patient presented with pleural effusions and had subsequent CNS relapse and passed away from relapsed disease and infective complications, 19-month post MUD allograft.

Frontiers in Oncology

The myeloproliferative neoplasms (MPNs) are a group of acquired clonal disorders where mutations ... more The myeloproliferative neoplasms (MPNs) are a group of acquired clonal disorders where mutations drive proliferative disease resulting in increased blood counts and in some cases end-stage myelofibrosis. Epigenetic changes are the reversible modifications to DNA- and RNA-associated proteins that impact gene activity without changing the DNA sequence. This review summarizes mechanisms of epigenetic changes and the nucleosome. The drivers and epigenetic regulators in MPNs are outlined. In MPNs, distinct patterns of epigenetic dysregulation have been seen in chronic and in advanced phases. Methylation age and histone modification are altered in MPNs and by further treatment. The alterations found in methylation age in MPNs and with treatment are discussed, and the changes in histone modification with Janus kinase (JAK) inhibition are evaluated. Currently available therapeutic areas where the epigenome can be altered are outlined. Thus, we review the current knowledge and understanding ...

Table S1. Details for NGS amplicons

Table S3. Variants detected by NGS targeted re-sequencing

Table S2. Details of Exons covered Table S4. Details of antibodies/ streptavidin used Table S5. S... more Table S2. Details of Exons covered Table S4. Details of antibodies/ streptavidin used Table S5. Summary of longitudinal progenitor LSC quantitation by FACS Table S6. Overview of toxicities Figure S1. Progenitor LSC FACS gating strategy Figure S2. Kaplan-Meier plot for duration of response Figure S3. Forest plot of sub group analysis in overall response rate and overall survival.

Background Myeloid malignancies are a group of blood disorders characterized by the proliferation... more Background Myeloid malignancies are a group of blood disorders characterized by the proliferation of one or more haematopoietic myeloid cell lineages, predominantly in the bone marrow and are often caused by aberrant protein tyrosine kinase activity. The protein tyrosine phosphatase CD45 is a transmembrane molecule expressed on all haemopoietic blood cells except that of platelets and red cells. CD45 regulates various cellular physiological processes including proliferation, apoptosis, and lymphocyte activation. The aim of this study was to investigate the role of CD45 in myeloid malignancies in terms of cellular growth, apoptosis, and response to chemotherapy to investigate alternative therapies with less toxicity and more efficacy. Methods The expression profile of CD45 was established in a panel of myeloid leukaemia cell lines and in peripheral blood cells from normal individuals, AML and MPN patients using western blot, flow cytometry, and PCR. CD45 KD was performed by using siR...

Clinical Lymphoma Myeloma and Leukemia

The Lancet Haematology, 2022

Background Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 ... more Background Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia. Methods This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m² on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617.

Blood, 2011

3460 HOX genes are master regulators of hematopoietic stem and progenitor cell (HSPC) development... more 3460 HOX genes are master regulators of hematopoietic stem and progenitor cell (HSPC) development. HOX interaction with TALE (PBX or MEIS) proteins is pivotal to their function. The prevailing hypothesis is that HOX/TALE expression underlies HSPC self-renewal while dysregulated HOX/TALE expression underpins maintenance of the leukemia initiating cell. Expression profiling studies support this hypothesis and highlight the importance of the HOXA cluster and TALE genes in hematopoiesis and leukemogenesis. The aim of this study was to identify and target clinically relevant HOX and TALE genes in AML cells representative of the particular disease subtype. HOXA cluster and leukemia-associated TALE gene expression was evaluated in 166 favourable and intermediate AML patient samples by Affymetrix microarray and expression of the significantly different genes was confirmed by RQ-PCR assays in an independent patient cohort. HOXA1-A2, A4-A10, PBX3 and MEIS1 displayed significant differential e...

Clinical and Laboratory Haematology, 1999

Bone Marrow Transplantation, 2013

Journal of Clinical Pathology, Nov 3, 2020

, M. A. (2020). Mutational profiling in suspected triple-negative essential thrombocythaemia usin... more , M. A. (2020). Mutational profiling in suspected triple-negative essential thrombocythaemia using targeted next-generation sequencing in a real-world cohort.

Blood Advances

Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data ... more Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were...

Journal of Clinical Oncology

7015 Background: Ruxolitinib (RUX), a Janus kinase (JAK) 1/2 inhibitor, is the current standard o... more 7015 Background: Ruxolitinib (RUX), a Janus kinase (JAK) 1/2 inhibitor, is the current standard of care for patients (pts) with myelofibrosis (MF) that improves splenomegaly and disease symptoms with limited impact on disease biology. Many pts lose response over time, highlighting an unmet need for novel therapies. Navitoclax (NAV) is an oral, small-molecule inhibitor of BCL-XL and BCL-2 that has a synergistic effect when used in combination with JAK inhibitors to enhance apoptosis. This ongoing, open-label, multicenter, phase 2 trial (NCT03222609) is evaluating the efficacy and safety of NAV with/without RUX in pts with MF. Here, we report results from JAK inhibitor-naïve pts treated with NAV+RUX. Methods: Enrolled pts had primary or secondary MF with splenomegaly (DIPSS ≥INT-1) and did not receive prior JAK-2 therapy or bromodomain and extraterminal motif (BET) inhibitors. Pts initiated NAV at 100 mg QD or 200 mg QD if baseline (BL) platelet count was ≤150 × 109/L or >150 × 109...

Journal of Clinical Oncology

7058 Background: PAC is a novel JAK2/IRAK1 inhibitor that has shown significant activity in pts w... more 7058 Background: PAC is a novel JAK2/IRAK1 inhibitor that has shown significant activity in pts with MF, including those with platelet (plt) counts <50×109/L. Recently, JAK inhibitors have come under increased scrutiny due to specific, emerging toxicities with drugs in this class. This safety analysis focuses on these toxicities of interest for pts treated with PAC 200 mg BID and best available therapy (BAT), including ruxolitinib (RUX), on the Phase 3 PERSIST-2 and Phase 2 PAC203 studies. Data are presented as risk-adjusted incidences to account for differential time at risk for adverse events (AEs) between arms due to cross-over. Methods: Pts treated with PAC 200 mg BID on PERSIST-2 and PAC203, and those treated with BAT on PERSIST-2, were included. Risk-adjusted AEs, representing event rate per 100 patient-years (pt-yrs), were calculated for overall and fatal AEs, bleeding AEs (determined by Standardized Medical Dictionary for Regulatory Activities Query [SMQ]), cardiac AEs (b...

Journal of Clinical Pathology, Aug 1, 1995

Cancer Chemotherapy and Pharmacology, Mar 9, 2023

Purpose Gemtuzumab ozogamicin (GO) is indicated for treatment of relapsed/refractory (R/R) acute ... more Purpose Gemtuzumab ozogamicin (GO) is indicated for treatment of relapsed/refractory (R/R) acute myeloid leukemia (AML). The QT interval, pharmacokinetics (PK), and immunogenicity following the fractionated GO dosing regimen have not been previously assessed. This phase IV study was designed to obtain this information in patients with R/R AML. Methods Patients aged ≥ 18 years with R/R AML received the fractionated dosing regimen of GO 3 mg/m 2 on Days 1, 4, and 7 of each cycle, up to 2 cycles. The primary endpoint was mean change from baseline in QT interval corrected for heart rate (QTc). Results Fifty patients received ≥ 1 dose of GO during Cycle 1. The upper limit of the 2-sided 90% confidence interval for least squares mean differences in QTc using Fridericia's formula (QTcF) was < 10 ms for all time points during Cycle 1. No patients had a post-baseline QTcF > 480 ms or a change from baseline > 60 ms. Treatment-emergent adverse events (TEAEs) occurred in 98% of patients; 54% were grade 3-4. The most common grade 3-4 TEAEs were febrile neutropenia (36%) and thrombocytopenia (18%). The PK profiles of both conjugated and unconjugated calicheamicin mirror that of total hP67.6 antibody. The incidence of antidrug antibodies (ADAs) and neutralizing antibodies was 12% and 2%, respectively. Conclusion Fractionated GO dosing regimen (3 mg/m 2 /dose) is not predicted to pose a clinically significant safety risk for QT interval prolongation in patients with R/R AML. TEAEs are consistent with GO's known safety profile, and ADA presence appears unassociated with potential safety issues. Trial registry Clinicaltrials.gov ID: NCT03727750 (November 1, 2018).

Haematologica, Jun 24, 2017

Irish Journal of Medical Science, Jun 7, 2022

Background Calreticulin (CALR) mutations are commonly identified in patients with essential throm... more Background Calreticulin (CALR) mutations are commonly identified in patients with essential thrombocythaemia or myelofibrosis. CALR type 1 mutations are known to have a higher overall incidence in males but little is known about the risks of mutation subtypes on myelofibrotic change across patient age and sex. Aims To identify differences in the incidence of myelofibrotic change within subgroups of patients with CALR type 1 mutations. Methods All patients with a positive CALR exon 9 mutation identified within our unit between February 2016 and September 2020 were reviewed with note taken of patient sex, age at diagnosis, initial MPN diagnosis, and subsequent disease transformation. Results In our cohort, young male patients with CALR type 1 mutations were shown to be at significantly increased risk of myelofibrosis compared to age matched female patients. Conclusions Male patients have a worse myeloproliferative neoplasm phenotype than female patients with it occurring at a younger age and being more myelofibrotic in nature. Further investigation is needed into the reasons for this variability.

Journal of Hematopathology, Nov 4, 2016

Chronic myeloid leukaemia (CML) is consistently associated with the BCR-ABL1 fusion gene located ... more Chronic myeloid leukaemia (CML) is consistently associated with the BCR-ABL1 fusion gene located on the derivative chromosome 22 (Philadelphia chromosome, Ph + ve) as a result of a t(9;22)(q34;q11.2) translocation. We describe a 36-year-old male in blast phase CML presenting with acute myelomonocytic leukaemia and eosinophilia. Five months after initial disease diagnosis and despite being treated with standard imatinib therapy (400 mg daily) conventional cytogenetic analysis (CCA) demonstrated the evolution of a chromosome 16 pericentric inversion (inv(16)(p13q22)) within the already Ph + ve cells. Bone marrow aspiration and biopsy revealed 60% blasts, positive for CD34, HLADR, CD33 and CD13. Fluorescence in situ hybridization (FISH) and reverse transcription-polymerase chain reaction (RT-PCR) confirmed presence of a CBFβ-MHY11 rearrangement whilst next generation sequencing (NGS) detected an E255K point mutation within the BCR-ABL1 tyrosine kinase domain. Neither the CBFβ-MHY11 rearrangement nor the E225K point mutation were present at diagnosis. The patient received a combination of daunorubicin (60 mg/m 2) and cytarabine (100 mg/m 2) and had his tyrosine kinase inhibitor (TKI) changed to nilotinib before undergoing a male unrelated donor (MUD) stem cell transplant (SCT). The t(9;22) and inv(16) rearrangements persisted at day 100 post MUD SCT and his TKI was further switched to dasatinib. The patient presented with pleural effusions and had subsequent CNS relapse and passed away from relapsed disease and infective complications, 19-month post MUD allograft.

Frontiers in Oncology

The myeloproliferative neoplasms (MPNs) are a group of acquired clonal disorders where mutations ... more The myeloproliferative neoplasms (MPNs) are a group of acquired clonal disorders where mutations drive proliferative disease resulting in increased blood counts and in some cases end-stage myelofibrosis. Epigenetic changes are the reversible modifications to DNA- and RNA-associated proteins that impact gene activity without changing the DNA sequence. This review summarizes mechanisms of epigenetic changes and the nucleosome. The drivers and epigenetic regulators in MPNs are outlined. In MPNs, distinct patterns of epigenetic dysregulation have been seen in chronic and in advanced phases. Methylation age and histone modification are altered in MPNs and by further treatment. The alterations found in methylation age in MPNs and with treatment are discussed, and the changes in histone modification with Janus kinase (JAK) inhibition are evaluated. Currently available therapeutic areas where the epigenome can be altered are outlined. Thus, we review the current knowledge and understanding ...

Table S1. Details for NGS amplicons

Table S3. Variants detected by NGS targeted re-sequencing

Table S2. Details of Exons covered Table S4. Details of antibodies/ streptavidin used Table S5. S... more Table S2. Details of Exons covered Table S4. Details of antibodies/ streptavidin used Table S5. Summary of longitudinal progenitor LSC quantitation by FACS Table S6. Overview of toxicities Figure S1. Progenitor LSC FACS gating strategy Figure S2. Kaplan-Meier plot for duration of response Figure S3. Forest plot of sub group analysis in overall response rate and overall survival.

Background Myeloid malignancies are a group of blood disorders characterized by the proliferation... more Background Myeloid malignancies are a group of blood disorders characterized by the proliferation of one or more haematopoietic myeloid cell lineages, predominantly in the bone marrow and are often caused by aberrant protein tyrosine kinase activity. The protein tyrosine phosphatase CD45 is a transmembrane molecule expressed on all haemopoietic blood cells except that of platelets and red cells. CD45 regulates various cellular physiological processes including proliferation, apoptosis, and lymphocyte activation. The aim of this study was to investigate the role of CD45 in myeloid malignancies in terms of cellular growth, apoptosis, and response to chemotherapy to investigate alternative therapies with less toxicity and more efficacy. Methods The expression profile of CD45 was established in a panel of myeloid leukaemia cell lines and in peripheral blood cells from normal individuals, AML and MPN patients using western blot, flow cytometry, and PCR. CD45 KD was performed by using siR...

Clinical Lymphoma Myeloma and Leukemia

The Lancet Haematology, 2022

Background Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 ... more Background Treatment for adults with acute lymphoblastic leukaemia requires improvement. UKALL14 was a UK National Cancer Research Institute Adult ALL group study that aimed to determine the benefit of adding the anti-CD20 monoclonal antibody, rituximab, to the therapy of adults with de novo B-precursor acute lymphoblastic leukaemia. Methods This was an investigator-initiated, phase 3, randomised controlled trial done in all UK National Health Service Centres treating patients with acute lymphoblastic leukaemia (65 centres). Patients were aged 25-65 years with de-novo BCR-ABL1-negative acute lymphoblastic leukaemia. Patients with de-novo BCR-ABL1-positive acute lymphoblastic leukaemia were eligible if they were aged 19-65 years. Participants were randomly assigned (1:1) to standard-of-care induction therapy or standard-of-care induction therapy plus four doses of intravenous rituximab (375 mg/m² on days 3, 10, 17, and 24). Randomisation used minimisation and was stratified by sex, age, and white blood cell count. No masking was used for patients, clinicians, or staff (including the trial statistician), although the central laboratory analysing minimal residual disease and CD20 was masked to treatment allocation. The primary endpoint was event-free survival in the intention-to-treat population. Safety was assessed in all participants who started trial treatment. This study is registered with ClincialTrials.gov, NCT01085617.

Blood, 2011

3460 HOX genes are master regulators of hematopoietic stem and progenitor cell (HSPC) development... more 3460 HOX genes are master regulators of hematopoietic stem and progenitor cell (HSPC) development. HOX interaction with TALE (PBX or MEIS) proteins is pivotal to their function. The prevailing hypothesis is that HOX/TALE expression underlies HSPC self-renewal while dysregulated HOX/TALE expression underpins maintenance of the leukemia initiating cell. Expression profiling studies support this hypothesis and highlight the importance of the HOXA cluster and TALE genes in hematopoiesis and leukemogenesis. The aim of this study was to identify and target clinically relevant HOX and TALE genes in AML cells representative of the particular disease subtype. HOXA cluster and leukemia-associated TALE gene expression was evaluated in 166 favourable and intermediate AML patient samples by Affymetrix microarray and expression of the significantly different genes was confirmed by RQ-PCR assays in an independent patient cohort. HOXA1-A2, A4-A10, PBX3 and MEIS1 displayed significant differential e...

Clinical and Laboratory Haematology, 1999

Bone Marrow Transplantation, 2013

Journal of Clinical Pathology, Nov 3, 2020

, M. A. (2020). Mutational profiling in suspected triple-negative essential thrombocythaemia usin... more , M. A. (2020). Mutational profiling in suspected triple-negative essential thrombocythaemia using targeted next-generation sequencing in a real-world cohort.

Blood Advances

Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data ... more Myeloproliferative neoplasms (MPNs) are uncommon in children/young adults. Here, we present data on unselected patients diagnosed before 25 years of age included from 38 centers in 15 countries. Sequential patients were included. We identified 444 patients, with median follow-up 9.7 years (0-47.8). Forty-nine (11.1%) had a history of thrombosis at diagnosis, 49 new thrombotic events were recorded (1.16% patient per year [pt/y]), perihepatic vein thromboses were most frequent (47.6% venous events), and logistic regression identified JAK2V617F mutation (P = .016) and hyperviscosity symptoms (visual disturbances, dizziness, vertigo, headache) as risk factors (P = .040). New hemorrhagic events occurred in 44 patients (9.9%, 1.04% pt/y). Disease transformation occurred in 48 patients (10.9%, 1.13% pt/y), usually to myelofibrosis (7.5%) with splenomegaly as a novel risk factor for transformation in essential thrombocythemia (ET) (P= .000) in logistical regression. Eight deaths (1.8%) were...

Journal of Clinical Oncology

7015 Background: Ruxolitinib (RUX), a Janus kinase (JAK) 1/2 inhibitor, is the current standard o... more 7015 Background: Ruxolitinib (RUX), a Janus kinase (JAK) 1/2 inhibitor, is the current standard of care for patients (pts) with myelofibrosis (MF) that improves splenomegaly and disease symptoms with limited impact on disease biology. Many pts lose response over time, highlighting an unmet need for novel therapies. Navitoclax (NAV) is an oral, small-molecule inhibitor of BCL-XL and BCL-2 that has a synergistic effect when used in combination with JAK inhibitors to enhance apoptosis. This ongoing, open-label, multicenter, phase 2 trial (NCT03222609) is evaluating the efficacy and safety of NAV with/without RUX in pts with MF. Here, we report results from JAK inhibitor-naïve pts treated with NAV+RUX. Methods: Enrolled pts had primary or secondary MF with splenomegaly (DIPSS ≥INT-1) and did not receive prior JAK-2 therapy or bromodomain and extraterminal motif (BET) inhibitors. Pts initiated NAV at 100 mg QD or 200 mg QD if baseline (BL) platelet count was ≤150 × 109/L or >150 × 109...

Journal of Clinical Oncology

7058 Background: PAC is a novel JAK2/IRAK1 inhibitor that has shown significant activity in pts w... more 7058 Background: PAC is a novel JAK2/IRAK1 inhibitor that has shown significant activity in pts with MF, including those with platelet (plt) counts <50×109/L. Recently, JAK inhibitors have come under increased scrutiny due to specific, emerging toxicities with drugs in this class. This safety analysis focuses on these toxicities of interest for pts treated with PAC 200 mg BID and best available therapy (BAT), including ruxolitinib (RUX), on the Phase 3 PERSIST-2 and Phase 2 PAC203 studies. Data are presented as risk-adjusted incidences to account for differential time at risk for adverse events (AEs) between arms due to cross-over. Methods: Pts treated with PAC 200 mg BID on PERSIST-2 and PAC203, and those treated with BAT on PERSIST-2, were included. Risk-adjusted AEs, representing event rate per 100 patient-years (pt-yrs), were calculated for overall and fatal AEs, bleeding AEs (determined by Standardized Medical Dictionary for Regulatory Activities Query [SMQ]), cardiac AEs (b...