Updated Results of Pivotal Phase 2 Trials of Olverembatinib (HQP1351) in Patients (Pts) with Tyrosine Kinase Inhibitor (TKI)-Resistant BCR-ABL1 T315I-Mutated Chronic- and Accelerated-Phase Chronic Myeloid Leukemia (CML-CP and CML-AP)

Abstract Background: Management of CML with TKIs is constrained by treatment resistance, which portends a poor prognosis particularly in pts failing 2 nd-generation TKIs. Cells with BCR-ABL1 T315I mutations are insensitive to 1 st- and 2 nd -generation TKIs, and compound BCR-ABL1 mutations complicate management with all TKIs (including 3 rd-generation ponatinib). Olverembatinib is a novel, potent, 3 rd-generation, orally active BCR-ABL1 TKI with promising activity against CML , largely irrespective of genotype and has a preliminary favorable safety profile. Methods: HQP1351-CC201 and HQP1351-CC202 are Chinese open, single-arm, multicenter phase 2 trials evaluating the safety and efficacy of olverembatinib in adults with TKI-resistant (BCR-ABL1 T351-mutated) CML-CP and CML-CP, respectively. Olverembatinib was administered at 40 mg orally on alternate days for 28-day cycles. The primary outcome measure is major cytogenetic response (MCyR) and major hematologic response (MaHR) by the end of Cycle 12 in CML-CP and CML-AP, respectively. Secondary study endpoints include : complete CyR (CCyR), complete hematologic response (CHR), major molecular response (MMR), progression-free survival (PFS), overall survival (OS), and safety, including treatment-related adverse events (TRAEs) and serious AEs (SAEs). Results: Baseline characteristics Study CC201 （CML-CP ） On the study cutoff date of August 25,2020, 41 pts were enrolled, of whom 32 (78%) completed ≥ 12 cycles and 21 (51.2%) were male. The median (range) follow-up was 13 (3.1-16.3) months, age was 47 (22-70) years, and interval from CML diagnosis to first olverembatinib dose was 5.31 (0.6-23.2) years. In all, 32 (78.1%) pts had received ≥ 2 prior TKIs and 9 pts withdrew because of progressive disease (PD), intolerance, or consent withdrawal before Cycle 12. Study CC202 （CML-AP ） On the cut-off date of July 27, 2020, 23 pts were enrolled, of whom 14 (61%) had completed ≥ 12 cycles and 18 (78.3%) were male. The median (range) follow-up was 13.5 (1.4-15.2) months, age was 41 (21-74) years, and interval from CML diagnosis to first olverembatinib dose was 4.96 (0.4-10.2) years. In all, 18 (78.3%) pts had received ≥ 2 prior TKIs, and 11 pts withdrew because of PD or intolerance before Cycle 12. Efficacy Study CC201 （CML-CP ） After ≥ 12 treatment cycles in pts without responses at baseline, all 31 (100%) experienced CHR (10 other pts had CHR at baseline); 31/41 (75.6%) MCyR; 28/41 (68.3%) CCyR; and 23/41 (56.1%) MMR (Figure 1). The median time to CHR was 1 (95% CI = 1.0-1.9) month, the median time to MCyR was 2.8 (95% CI = 2.8-5.6) months, and the median time to MMR was 6.5 (95% CI = 2.8 to not reached [NR]) months. At 12 months, the PFS rate was 89.3% (95% CI = 73.9%-95.8%), and the OS was 100% (95% CI = 100%-100%). Study CC202 （CML-AP ） After ≥ 12 treatment cycles in pts without responses at baseline, 17/23 (73.9%) experienced MaHR (65.2% CHR and 8.7% no evidence of leukemia [NEL]); 12/23 (52.2%) MCyR; 11/23 (47.8%) CCyR; and 9/23 (39.1%) MMR (Figure 1). The median time to MaHR was 2.8 (95% CI = 1.0-4.7) months, the median time to MCyR was 5.6 (95% CI = 2.00-NR) months, and the median time to MMR was 13.1 (95% CI = 5.6-NR) months. At 12 months, the PFS rate was 74.1% (95% CI = 48.2%-88.4%), and the OS was 91.3% (95% CI = 69.5%-97.8%). Safety Study CC201 （CML-CP ） Frequent TRAEs (all grades; grade 3-4; SAEs) included thrombocytopenia (70.7%; 48.8%; 7.3%), followed by anemia (61%; 26.8%; 2.4%), leukopenia (43.9%; 17.1%; 0), and neutropenia (36.6%; 19.5%; 0). Common nonhematologic TRAEs (all grades; G3-4) included skin pigmentation (56.1%, 0%) and elevations in creatine kinase (51.2%, 14.6%), ALT (39%, 2.4%) and AST (34.1%, 0) (Table 1). No deaths occurred. Study CC202 （CML-AP ） Common TRAEs (all grades; G3-4; SAEs) included thrombocytopenia (73.9%; 56.5%; 17.4%), anemia (60.9%; 34.8%; 13.0%), leukopenia (56.5%; 30.4%; 0), and neutropenia (26.1%; 21.7%; 0). Common nonhematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (47.8%), hypertriglyceridemia (56.5%), hyperphosphatemia (47.8%), hyperuricemia (21.7%), and arthralgia (34.8%), of which most were grade 1-2 (Table 2). Conclusions: Olverembatinib was efficacious and well tolerated when administered as monotherapy in pts with TKI-resistant CP-CML and AP-CML and the BCR-ABL1 T315Imutation. Internal study identifiers: HQP1351-CC201-CC202. ClinicalTrials.gov identifiers: NCT03883087 and NCT03883100. Figure 1 Figure 1. Disclosures Chen: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Niu: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company. Men: Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company. Yang: Ascentage Pharma (Suzhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding. Zhai: Ascentage Pharma Group Inc.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding; Ascentage Pharma (Suzhou) Co., Ltd.: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests, Patents & Royalties, Research Funding.

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Novel BCR-ABL1 Tyrosine Kinase Inhibitor (TKI) HQP1351 (Olverembatinib) Is Efficacious and Well Tolerated in Patients with T315I-Mutated Chronic Myeloid Leukemia (CML): Results of Pivotal (Phase II) Trials

Blood ◽

10.1182/blood-2020-142142 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 50-51 ◽

Cited By ~ 1

Author(s):

Qian Jiang ◽

Xiaojun Huang ◽

Zi Chen ◽

Qian Niu ◽

Dayu Shi ◽

...

Keyword(s):

Kinase Inhibitor ◽

Skin Pigmentation ◽

Chronic Phase ◽

Prolonged Treatment ◽

Molecular Response ◽

Phase Ii Trials ◽

Publicly Traded ◽

Hematologic Response ◽

T315i Mutation

INTRODUCTION HQP1351 (olverembatinib) is an orally active third-generation BCR-ABL TKI designed for treatment of the patients with CML, harboring T315I mutation, which confers resistance against all first- and second-generation TKIs. METHODS The TKI resistant CML patients harboring T315I mutations either in chronic-phase (CP), or in accelerated-phase (AP), were enrolled into two single-arm, multicenter, open-label pivotal studies: HQP1351-CC201 in and HQP1351-CC202, respectively. The HQP1351 was administered at 40 mg once every other day (QOD) for 28 consecutive days per cycle over 24 months. The primary objective was to evaluate efficacy by major cytogenetic response (MCyR) in patients with CML-CP and major hematologic response (MaHR) in CML-AP. Secondary objectives included safety, tolerability, and pharmacokinetics (PK). RESULTS Baseline characteristics Study CC201 (CML-CP) As of the study cut-off date of March 23, 2020, total 41 patients were enrolled, of whom 38 (92.7%) completed ≥ 6 cycles and 21 (51.2%) were male. Median (range) follow-up was 7.9 (3.1-11.1) months, median age was 47 (22-70) years old. Median (range) interval from CML diagnosis to first HQP1351 treatment was 5.31 (0.6-23.2) years, and 32 (78.1%) patients received ≥ 2 prior lines of TKI. Three patients withdrew from the study-due to progressive disease (PD), intolerance, or consent withdrawal. Study CC202 (CML-AP) As of the cut-off date of February 11, 2020, total 23 patients were enrolled, of whom 18 (78.3%) completed ≥ 6 cycles and 18 (78.3%) were male. Follow-up duration was 8.2 (1.4-9.6) months, median age was 41 (21-74) years old. Median interval from CML diagnosis to first dose of HQP1351 was 4.96 (0.4-10.2) years, and 18 (78.3%) patients received ≥ 2 prior TKIs. Five patients withdrew because of PD or intolerance before Cycle 6. Efficacy Study CC201 (CML-CP) Across a median follow-up of 7.9 months, the mean (95% CI) 3-month progression-free survival (PFS) was 100% (100-100%) and 6-month PFS 96.7% (78.6-99.5%) because of 1 PD. In 31 evaluable patients who did not have a complete hematologic response (CHR) at baseline, 30 (96.8%) achieved CHR. In 41 evaluable patients who did not have a complete CyR (CCyR) at baseline, 31 (75.6%) achieved MCyR, including 27 (65.9%) CCyR and 4 (9.8%) partial CyR (PCyR). Total 20 out of 41 (48.8%) evaluable patients achieved major molecular response (MMR; Figure 1). Study CC202 (CML-AP) Across a median follow-up of 8.2 months, the 3-month PFS was 100% (100-100%) and the 6- month PFS 95.5% (71.9-99.3%) because of 2 PDs. A total of 18 (78.3%) of 23 evaluable patients without MaHR at baseline achieved MaHR, including 14 (60.9%) with CHR. In the 23 evaluable patients without MCyR at baseline, 12 (52.2%) patients achieved MCyR, including 9 (39.1%) CCyR and 3 (13.1%) PCyR. A total of 6 out of 23 (26.1%) evaluable patients achieved MMR (Figure 1). HQP1351 was highly and durably efficacious in the CML patients with T315I mutation; the probability and depth of clinical response may increase with prolonged treatment period. Safety/tolerability Study CC201 Frequent treatment-related adverse events (TRAEs; all grades; G3-4) included thrombocytopenia (65.9%; 48.8%), followed by anemia (48.8%; 24.4%), leukopenia (46.3%; 12.2%), and neutropenia (36.6%; 19.5%). Common non-hematologic TRAEs of any grade included skin pigmentation (53.7%) as well as elevations in creatine kinase (48.8%), ALT (31.7%) and AST (26.8% which most were grade 1 - 2. No death occurred. Study CC202 Common TRAEs (all grades; G3-4; serious AE [SAE]) included thrombocytopenia (73.9%; 52.2%; 17.4%), anemia (65.2%; 39.1%; 13.0%), leukopenia (56.5%; 30.4%; 0%), and neutropenia (26.1%; 21.7%; 0%;). Common non-hematologic AEs included skin pigmentation (69.6%), hypocalcemia (52.2%), proteinuria (52.2%), hypertriglyceridemia (47.8%), hyperphosphatemia (43.5%), arthralgia (34.8%), and fatigue (26.1%), of which most were grade 1- 2. CONCLUSIONS HQP1351 has been shown highly efficacious in heavily TKI-pretreated patients with T315I-mutated CML-CP or CML-AP and was well tolerated. Registration: Clinicaltrials.gov identifier NCT03883087 (Study HQP1351-CC201) NCT03883100 (Study HQP1351-CC202). Disclosures Chen: Ascentage Pharma Group: Current Employment. Niu:Ascentage Pharma Group: Current Employment. Zeng:Ascentage Pharma Group: Current Employment. Men:Ascentage Pharma Group: Current Employment. Lu:Ascentage Pharma Group: Current Employment, Current equity holder in publicly-traded company. Wang:Ascentage Pharma Group: Current Employment. JI:Ascentage Pharma Group: Current Employment. Yue:Ascentage Pharma Group: Current Employment. Yang:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests. Zhai:Ascentage Pharma (SuZhou) Co., Ltd: Current Employment, Current equity holder in publicly-traded company, Other: Leadership and other ownership interests.

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Belumosudil for Chronic Graft-Versus-Host Disease (cGVHD) after 2 or More Prior Lines of Therapy: The Rockstar Study (KD025-213)

Blood ◽

10.1182/blood-2020-139445 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 45-46

Author(s):

Corey Cutler ◽

Stephanie J. Lee ◽

Sally Arai ◽

Marcello Rotta ◽

Behyar Zoghi ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Response Rate ◽

Phase 2 ◽

Publicly Traded ◽

Advisory Committees ◽

Meaningful Improvement ◽

Fund Research

Introduction: Belumosudil (KD025) is a novel oral selective rho-associated coiled-coil kinase 2 (ROCK2) inhibitor specifically designed for the treatment of cGVHD, an immune-mediated inflammatory and fibrotic disorder. In a previous dose-finding study (KD025-208, N=54), two-thirds of patients, including those with fibrotic and inflammatory manifestations, achieved a partial or complete response with belumosudil. Herein, we report on the top-line results (6 months after the last patient in) from the pivotal phase 2 trial (ROCKstar [KD025-213], N=132). Methods: This phase 2, open-label, randomized, multicenter study evaluated belumosudil 200 mg QD (n=66) and BID (n=66) in patients with cGVHD who received 2 to 5 prior lines of therapy (LOT). Treatment continued until clinically significant progression of cGVHD. The primary end point was overall response rate (ORR), defined per the 2014 National Institutes of Health Consensus Criteria. Additional end points included duration of response (DOR), Lee Symptom Scale (LSS) score, failure-free survival (FFS), corticosteroid (CS) dose reductions and overall survival. The study was powered such that the lower bound of the 95% confidence interval (CI) excludes 30%, with appropriate multiplicity adjustment. Results: At enrollment, the median age was 56 years, the median time from cGVHD diagnosis to enrollment was 29 months, 67% of patients had severe cGVHD, 52% had ≥4 organs involved, 72% had received ≥3 prior LOT (including ibrutinib [n=46] or ruxolitinib [n=38]) and 73% were refractory to their last LOT. The baseline characteristics of both arms were well balanced. With a median follow-up of 8 months, the ORR (95% CI) with belumosudil 200 mg QD and BID was 73% (60%-83%) and 74% (62%-84%), respectively (Table 1). In patients who previously received ruxolitinib (29%), the ORR with belumosudil 200 mg QD and BID was 65% (41%-85%) and 72% (47%-90%), respectively. In patients who previously received ibrutinib (35%), the ORR with belumosudil 200 mg QD and BID was 73% (50%-89%) and 71% (49%-87%), respectively. High ORRs were seen in all patient subgroups, regardless of length of time from diagnosis to treatment, including those with severe cGVHD, involvement of ≥4 organs and a refractory response to prior LOT (Figure 1). The response rate was similar across all affected organs. The median time to response was 4 weeks. Of responders, 49% have maintained response for ≥20 weeks. The median DOR has not yet been reached. Clinically meaningful improvement (≥7-point reduction) in LSS score on consecutive assessments was observed in 39% and 33% of patients in the QD and BID groups, respectively. Both responders (43%) and nonresponders (17%) experienced a clinically meaningful improvement in LSS score. FFS was 77% (69%-84%) at 6 months. CS and calcineurin inhibitor discontinuations were seen in 18% and 13% of patients, respectively. Belumosudil was well tolerated, with >95% relative dose intensity in 83% of patients. Drug discontinuation occurred in 10% of patients due to possible drug-related adverse events (AEs), 3% due to progression of underlying disease and 12% due to progression of cGVHD. AEs were consistent with those expected in patients with cGVHD receiving CS and other immunosuppressants (Table 2). Common AEs included fatigue (32%), diarrhea (29%), nausea (26%), cough (24%), dyspnea (24%), upper respiratory tract infection (23%), peripheral edema (21%) and headache (20%). At least 1 serious AE occurred in 34% of patients. Twenty-three percent of patients had at least 1 liver-related investigation; the most common was increased gamma-glutamyltransferase (11%), and only 1 patient showed an increase in bilirubin. Eight patients died during the study; 5 due to AEs (1 possibly related to belumosudil) and 3 during long-term follow-up (>28 days after last dose). There were no reports of cytomegalovirus reactivation or infection. Conclusion: Treatment with belumosudil at both doses resulted in high ORRs across key subgroups, meeting the primary end point of this pivotal randomized trial in cGVHD. Responses were durable and clinically meaningful, irrespective of patient and cGVHD characteristics, and were seen in patients who previously received ruxolitinib and ibrutinib. Belumosudil was well tolerated, with limited and manageable AEs. Further studies will evaluate its use earlier in disease management. The 12-month data analysis will be presented at ASH 2020. Disclosures Cutler: Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kadmon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Medsenic: Consultancy, Membership on an entity's Board of Directors or advisory committees; Generon: Consultancy, Membership on an entity's Board of Directors or advisory committees; Mesoblast: Consultancy, Membership on an entity's Board of Directors or advisory committees. Lee:Pfizer: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Amgen: Research Funding; Kadmon: Research Funding; AstraZeneca: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Syndax: Research Funding. Rotta:Merck: Speakers Bureau; Jazz Pharma: Speakers Bureau. Ramakrishnan:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Cigna: Honoraria. Eiznhamer:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Schueller:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Yang:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Green:Kadmon Corporation, LLC: Current Employment, Current equity holder in publicly-traded company. Aggarwal:Kadmon Corporation, LLC: Consultancy; Angiocrine Bioscience, Inc: Current Employment, Other: stock options. Blazar:BlueRock Therapeutics: Research Funding; BlueRock Therapeuetic: Consultancy; Fate Therapeutics Inc.: Research Funding; Magenta Therapeutics: Consultancy; Childrens' Cancer Research Fund: Research Funding; KidsFirst Fund: Research Funding; Tmunity: Other: Co-founder. Jagasia:Ocugen: Other; Mallinckrodt: Research Funding; Janssen: Research Funding.

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Treatment-Free Remission (TFR) in Patients with Chronic Phase Chronic Myeloid Leukemia (CML-CP) and in Stable Deep Molecular Response (DMR) to Dasatinib - the Dasfree Study

Blood ◽

10.1182/blood.v128.22.1895.1895 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1895-1895 ◽

Cited By ~ 20

Author(s):

Neil P. Shah ◽

Ronald Paquette ◽

Martin C. Müller ◽

Susanne Saussele ◽

Valentin Garcìa-Gutiérrez ◽

...

Keyword(s):

Board Of Directors ◽

Median Time ◽

Interim Analysis ◽

Research Funding ◽

Molecular Response ◽

Phase 2 ◽

Advisory Committees ◽

Free Survival ◽

Kinetics Of

Abstract Background: Prior clinical trials demonstrated that 33-61% of patients with CML maintain disease control following TKI discontinuation in the 1st line and beyond (Thielen, Eur J Cancer. 2013; Mahon, Lancet Oncol. 2010; Hochhaus, ASCO 2016; Hughes, ASCO 2016; Imagawa, Lancet Haematol. 2015). Patients who relapsed after discontinuation regained major molecular response (MMR) upon retreatment. Dasatinib, a 2nd generation TKI, induces fast and deep molecular responses, making it an effective option for patients in view of a possible TFR. Here, we report interim results from the phase 2 DASFREE study, investigating TFR with dasatinib in the 1st and 2nd line settings. Methods: DASFREE (CA180-406/NCT01850004) is a phase 2 open-label, single-arm study in adults with CML-CP who were on dasatinib for ≥2 yr as 1st line or subsequent therapy, had confirmed dasatinib-induced DMR (defined as MR4.5, BCR-ABL1 ≤0.0032% [IS]) for ≥1 yr prior to enrollment, and achieved a 1-log reduction in BCR-ABL1 from baseline within 3-6.5 mo of starting dasatinib. Prescreening for MR4.5 was done at a local lab, with confirmation at a central lab twice over a 3-mo interval prior to dasatinib discontinuation (screening phase). BCR-ABL1 was monitored centrally after treatment discontinuation every mo in the 1st yr, then every 3 mo. If loss of MMR occurred, patients resumed dasatinib at the previous dose. The primary endpoint is MMR rate at 1 yr after dasatinib discontinuation. Secondary endpoints include kinetics of loss of response, event-free survival (EFS; no loss of MMR), relapse-free survival (RFS; no loss of MMR, complete cytogenetic response, or complete hematologic response, or progression to accelerated/blast phase CML), progression-free survival, and overall survival. Exploratory analyses include frequency of adverse events (AEs) after discontinuation and during dasatinib treatment, and molecular response rates after reinitiating dasatinib. All patients will be followed for up to 5 yr. This analysis reflects a planned interim assessment of patients followed for TFR for ≥1 yr. Results: Currently, 71 patients are enrolled out of 79 planned. Thirty patients (14 male; median age 51 yr [range: 29-76]; Sokal scores: 60% low, 27% intermediate, 3% high, 10% unknown) followed for ≥1 yr after dasatinib discontinuation were included in this interim analysis. MMR rate at 1 yr following discontinuation was 63% (95% CI: 46-81). EFS rate at 1 yr following discontinuation was 63% (95% CI: 44-78; Figure). RFS rate at 1 yr following discontinuation will be presented. Eleven of 30 patients lost MMR, with a median time to loss of MMR of 4 mo (range: 1-8). Median time on dasatinib prior to discontinuation was 40 mo (range: 26-114) for patients who lost MMR and 55 mo (range: 31-87) for patients who retained MMR. Eleven patients who lost MMR restarted dasatinib therapy: 10 regained MMR, and 1 patient chose to restart therapy at a nonstudy site, discontinued study, and was lost to follow-up. The kinetics of molecular relapse, the number of patients that regained DMR, and the time to regain MMR or DMR will be presented. No transformation events or deaths were observed at the time of this analysis. After discontinuation, 5 patients had musculoskeletal AEs; in 2 patients (with 3 events) these AEs were attributed to withdrawal from dasatinib by investigators. Additional AEs following discontinuation included hypertension (17%) and skin disorders (13%). For patients who restarted dasatinib, AEs were consistent with the known safety profile, and none of the on-treatment AEs resulted in discontinuation. Conclusions: This interim analysis of the first 30 patients enrolled in DASFREE demonstrated patients with dasatinib-induced DMR treated in the 1st and 2nd line had high rates of success at maintaining remission after treatment was discontinued (63% MMR and EFS at 1 yr), and there was rescue of molecular response in all patients once dasatinib was reinitiated. There is a suggested correlation between time on dasatinib prior to discontinuation and maintaining MMR. Dasatinib withdrawal appears to be tolerable, as there was a low incidence of withdrawal symptoms. These data build upon the growing body of evidence supporting the feasibility of TFR in patients with CML-CP and demonstrate that with frequent monitoring of BCR-ABL1, patients treated with dasatinib in the 1st and 2nd line can successfully discontinue treatment. Longer-term follow-up is ongoing. Figure Figure. Disclosures Shah: Bristol-Myers Squibb, ARIAD, Pfizer, Daiichi-Sankyo, Plexxikon: Research Funding. Paquette:Bristol-Myers Squibb: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Ariad: Research Funding, Speakers Bureau. Müller:Ariad, BMS, Novartis, Pfizer: Honoraria; Ariad, BMS, Novartis, Pfizer: Consultancy; Institute for Hematology and Oncology, IHO GmbH: Employment, Equity Ownership. Saussele:Novartis, BMS, Ariad, Pfizer: Honoraria; Novartis, BMS: Research Funding. Garcìa-Gutiérrez:Novartis, BMS, Ariad and Pfizer: Consultancy; Novartis, BMS, Ariad and Pfizer: Research Funding. Nicolini:Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria. Mauro:ARIAD: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria. Mahon:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria, Research Funding; Ariad: Honoraria. Rea:Novartis: Honoraria; Ariad: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Martin-Regueira:Bristol-Myers Squibb: Employment. Subar:Bristol Myers-Squibb: Employment. Li:Bristol-Myers Squibb: Employment. Lipton:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

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Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽

10.1182/blood.v114.22.1128.1128 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1128-1128 ◽

Cited By ~ 2

Author(s):

Hanna Jean Khoury ◽

Michael J. Mauro ◽

Yousif Matloub ◽

Tai-Tsang Chen ◽

Erkut Bahceci ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Median Duration ◽

Myeloid Leukemia ◽

Research Funding ◽

Kinase Inhibitor ◽

Chronic Phase ◽

Phase Iii ◽

Hematologic Toxicity ◽

Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

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Interim Results of an International, Multicenter, Phase 2 Study of Bruton's Tyrosine Kinase (BTK) Inhibitor, Ibrutinib (PCI-32765), in Relapsed or Refractory Mantle Cell Lymphoma (MCL): Durable Efficacy and Tolerability with Longer Follow-up

Blood ◽

10.1182/blood.v120.21.904.904 ◽

2012 ◽

Vol 120 (21) ◽

pp. 904-904 ◽

Cited By ~ 10

Author(s):

Michael Wang ◽

Simon A. Rule ◽

Peter Martin ◽

Andre Goy ◽

Rebecca Auer ◽

...

Keyword(s):

B Cell ◽

Median Time ◽

Research Funding ◽

Tumor Response ◽

Single Agent ◽

Safety Data ◽

Phase 2 ◽

Employment Equity ◽

Equity Ownership

Abstract Abstract 904 Background Bruton's tyrosine kinase (BTK) is a central mediator of B-cell receptor (BCR) signaling which is essential for normal B-cell development. Ibrutinib is an orally administered inhibitor of BTK that induces apoptosis and inhibits cellular migration and adhesion in malignant B-cells. MCL is an aggressive subtype of NHL, and despite high response rates to initial therapy, patients often relapse with acquired chemotherapy resistance and short response durations to conventional therapy. Preliminary results in 51 evaluable patients from the Phase 2 PCYC-1104 study demonstrated ibrutinib could achieve rapid nodal responses (including complete responses) in relapsed and refractory MCL patients (Wang et al, ASH 2011). Treatment with ibrutinib was associated with a transient increase in peripheral lymphocyte count representing a compartmental shift of cells with the CD19+/CD5+ phenotype from nodal tissues to peripheral blood (Chang et al, ASH 2011). Reported here are interim results of an international study of single-agent ibrutinib in previously treated MCL. Methods Subjects with relapsed or refractory MCL who were either bortezomib-naïve or bortezomib-exposed (prior treatment with at least 2 cycles of bortezomib) were enrolled. Ibrutinib was administered orally at 560mg daily (in continuous 28-day cycles) until disease progression. Bortezomib-naive and bortezomib-exposed cohorts were evaluated separately. Tumor response was assessed every 2 cycles according to the revised International Working Group for NHL criteria. The primary endpoint of the study is overall response rate (ORR). Secondary endpoints include: duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety. Subjects A total of 115 subjects (65 bortezomib-naïve and 50 bortezomib-exposed) were enrolled between February 15, 2011 and July 3, 2012. Of the 111 subjects treated, 109 subjects were evaluable for efficacy (received at least one dose of ibrutinib and underwent ≥ 1 tumor response assessment). Baseline characteristics include median age 68 years (40–84), median time since diagnosis 42 months, median number of prior treatments 3 (1–6), bulky disease (≥ 10 cm) 13%, Ann Arbor stage IV at screening 77.4%, prior stem cell transplant 9.6%, high risk by MIPI score at baseline assessment 48.7%, and refractory disease 44.3%. Results Safety data are available for 111 subjects. Treatment-emergent AEs occurring in ≥ 15% of subjects: diarrhea (35%), fatigue (32%), upper respiratory tract infections (23%), nausea (21%), rash (21%), dyspnea (20%), and oedema peripheral (15%). Grade 3 or higher AEs occurring in ≥ 5% of subjects were neutropenia (11%), anemia (5%), diarrhea (5%), dyspnea (5%), pneumonia (5%), and thrombocytopenia (5%). Grade 4 treatment-related AEs were neutropenia (5%), hyperuricaemia (2%), and pancytopenia (1%). One grade 5 AE, pneumonia, was thought to be treatment-related. In the efficacy evaluable subjects, the ORR (complete + partial responses) is reported in Table 1. The median time on treatment was 6.0 months (0.7-16.6 months); 53% of subjects remain on treatment. Median DOR, PFS and OS have not been reached: 9 month DOR 65%, 12 month estimation of PFS 53% and OS 67%. Responses to ibrutinib increase with longer time on study treatment. Time to PR ranged from 1.4 – 8.3 months (median 1.9) and CR ranged from 1.7 – 11.2 months (median 3.9). This is seen with longer follow-up on the initial 51 subjects reported at ASH 2011: median time on study treatment was 3.8 months and is now 11.3 months; ORR was 69% and is now 74.5%; CR rate was 16% and is now 35.3%. Conclusions Longer follow up demonstrates the durability of responses and confirms the unprecedented single agent activity of ibrutinib in relapsed or refractory MCL in terms of ORR. The treatment- emergent AEs were consistent with safety data previously reported. A pivotal study in relapsed and refractory MCL patients following bortezomib treatment has been initiated. Disclosures: Wang: Pharmacyclic: Research Funding. Off Label Use: Ibrutinib is a novel agent being studied in a clinical trial. Rule:Pharmacyclics: Research Funding. Martin:Pharmacyclics: Research Funding. Goy:Pharmacyclics: Research Funding. Auer:Pharmacyclics: Research Funding. Kahl:Pharmacyclics: Research Funding. Jurczak:Pharmacyclics: Research Funding. Advani:Pharmacyclics: Research Funding. McGreivy:pharmacyclics: Employment, Equity Ownership. Clow:Pharmacyclics: Employment, Equity Ownership. Stevens-Brogan:Pharmacyclics: Employment, Equity Ownership. Kunkel:Pharmacyclics: Employment, Equity Ownership. Blum:Pharmacyclics: Research Funding.

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For Patients with Sustained MR4-MR4.5, Less Frequent Molecular Monitoring during the First 12 Months after Tyrosine Kinase Inhibitor Cessation Is Viable for Timely Detection of Loss of MMR

Blood ◽

10.1182/blood.v128.22.1890.1890 ◽

2016 ◽

Vol 128 (22) ◽

pp. 1890-1890

Author(s):

Naranie Shanmuganathan ◽

Susan Branford ◽

Jodi Braley ◽

Devendra Hiwase ◽

David T. Yeung ◽

...

Keyword(s):

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitor ◽

Board Of Directors ◽

Median Time ◽

Research Funding ◽

Kinase Inhibitor ◽

Molecular Response ◽

Monitoring Strategy ◽

Molecular Monitoring ◽

Advisory Committees

Abstract Background: Discontinuation of tyrosine kinase inhibitor (TKI) treatment for chronic myeloid leukaemia (CML) patients in stable deep molecular response leads to treatment-free remission (TFR) in approximately 50% of cases. In most studies, monthly PCRs was performed for 12 months followed by 2-3 monthly testing thereafter. Around 80% of molecular relapses occur within the first 6 months after TKI cessation. The current recommendation for TKI recommencement is a single BCR-ABL1 value ≥0.1% IS (International scale), indicating loss of major molecular response (MMR). Not all institutions can offer monthly PCR monitoring due to financial constraints, particularly relevant in developing countries. For some patients, remaining on TKI is a cheaper alternative. Aim: To assess the safety of less frequent BCR-ABL1 monitoring for detection of loss of MMR for CML patients attempting TFR. Methods: We monitored 85 patients who ceased TKI with the aim of achieving TFR. Patients had a minimum of 24 months of sustained MR4 (n=3) or MR4.5 (n=82) prior to TKI cessation. At the time of TKI cessation, 64 patients were on imatinib (75%), 17 on nilotinib (20%) and 4 on dasatinib (5%). Forty of the patients were enrolled in the TWISTER study where the criteria for TKI recommencement was loss of MMR or 2 consecutively rising BCR-ABL1 positive values. The remaining patients were on a registry study and the trigger for TKI recommencement was loss of MMR. Results: TKI recommencement occurred in 49 of 85 patients. Median time to TKI recommencement was 4 months (range 2-28 months) at a median BCR-ABL1 value of 0.27% on the International Scale (IS), range 0.002-24% IS. Thirty-six of the 49 patients (73%) lost MMR prior to TKI recommencement; the median time to loss of MMR was 3 months (range 1 to 10 months). One patient lost MMR within the first month. Figure A demonstrates the time to loss of MMR in the 36 patients with PCR values ≥ 0.1%. Eighteen of the 36 patients (50%) lost MMR by the 3 month BCR-ABL1 assessment and 35 of 36 patients (97%) lost MMR by 6 months. The latest loss of MMR was at 10 months. Fourteen patients recommenced TKI at a BCR-ABL1 value of >1% and 1 recommenced at a value >10%. Clinician delay in TKI recommencement of 1 month resulted in a BCR-ABL1 rise from 0.84% to 24% with associated loss of complete hematological response. We propose monthly BCR-ABL1 testing between 2 and 6 months post TKI cessation followed by 2 monthly testing. Detection of a BCR-ABL1 value of ≥0.1% would trigger TKI recommencement. In the presence of a rising BCR-ABL1, which remains ≤0.1%, monthly monitoring should ensue in order to avoid hematological relapse. If this strategy were employed in this cohort of patients, only 1 patient would have had the trigger for TKI recommencement delayed by 1 month (estimated BCR-ABL1 at recommencement ~2.5%). This patient had loss of MMR in the first month post TKI cessation. If this molecular monitoring strategy was applied to patients in our cohort who had not lost MMR at TKI recommencement, we estimate that 1 other patient would have had TKI recommencement delayed by 1 month based on the average BCR-ABL1 doubling time of 1 log per month. A proportion of patients maintain low levels of BCR-ABL1 after TKI cessation and do not lose MMR. There were 2 such patients in our cohort. Conclusion: The critical time for molecular monitoring to trigger TKI recommencement is the first 6 months. A monthly monitoring strategy beginning 2 months after cessation would capture the majority of patients at loss of MMR. The data suggest that after 6 months, 2-monthly monitoring could follow. Monthly BCR-ABL1 testing can be re-introduced in the event of a positive result in those that ceased TKI with undetectable BCR-ABL1 or if there is a BCR-ABL1 result higher than the cessation value. This approach would reduce BCR-ABL1 testing by approximately 33% in the majority of cases while minimizing hematological relapse. Therefore this strategy would reduce the cost and inconvenience of molecular monitoring for a trial of TKI cessation, making the option of TFR available to some patients for whom it is otherwise not feasible. Disclosures Branford: Qiagen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cepheid: Consultancy; Ariad: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Yeung:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Research Funding. Ross:Novartis Pharmaceuticals: Honoraria, Research Funding; BMS: Honoraria. Hughes:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group.

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Thrombosis and Risk of Mortality in Newly Diagnosed High-Risk Polycythemia Vera: An Analysis of the Medicare Claims Database in the United States

Blood ◽

10.1182/blood-2020-141370 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 9-10

Author(s):

Naveen Pemmaraju ◽

Aaron T. Gerds ◽

Shreekant Parasuraman ◽

Jingbo Yu ◽

Anne Shah ◽

...

Keyword(s):

High Risk ◽

Median Time ◽

Research Funding ◽

Index Date ◽

Newly Diagnosed ◽

Publicly Traded ◽

Risk Of Mortality ◽

Increased Risk ◽

History Of

Background Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with an increased risk of thrombotic events (TEs), a major cause of morbidity and mortality. Patients aged ≥60 years and/or with a history of thrombosis are considered to have high-risk PV. There is limited contemporary, real-world evidence exploring the effect of TEs on mortality in patients with PV. The aim of this analysis was to compare the risk of mortality in patients newly diagnosed with high-risk PV who experienced a TE vs those who did not experience a TE. Study Design and Methods All data from the Medicare Fee-for-Service (FFS) claims database (Parts A/B/D) from January 2010-December 2017 were used to identify patients with a PV diagnosis (all high risk based on cohort being ≥65 years of age) with ≥1 inpatient or ≥2 outpatient claims. The index date was the date of the first qualifying PV claim. Patients with a PV diagnosis or use of cytoreductive therapy within 12 months before the index date (pre-index period) were excluded; ≥12-months continuous medical and pharmacy enrollment pre-index dates was required. The study sample was categorized into TE and non-TE groups based on the occurrence of any of the following events during follow-up: deep vein thrombosis, pulmonary embolism, ischemic stroke, acute myocardial infarction, transient ischemic attack, peripheral arterial thrombosis, or superficial thrombophlebitis. TEs were evaluated from the index date to the end of follow-up. Cox regression analyses with time-varying effects were used to assess mortality risk among patients with PV, with post-index TE as a time-dependent variable, stratified by pre-index TE, and adjusting for patient demographic characteristics and comorbid conditions. Results A total of 56,176 Medicare FFS beneficiaries with PV diagnoses met inclusion criteria. The median age was 73 years, 51.9% were men, and 90.7% were white; 10,110 patients (18.0%) had a history of TE before diagnosis (ie, pre-index). In the follow-up period, 20,105 patients (35.8%) had a TE and 36,071 patients (64.2%) did not have a TE. In the comparison between the TE vs non-TE groups, the median (range) age (75.0 [65-104] vs 73.0 [65-106] years, respectively), mean (SD) Charlson comorbidity index score (3.1 [2.6] vs 2.2 [2.3]), and percentage of patients with a history of cardiovascular events (34.1% vs 23.8%), bleeding (13.3% vs 10.4%), or anemia (28.6% vs 23.4%) were higher (Table 1). Among all patients with PV, the median time from diagnosis to first post-index TE was 7.5 months. Among those with pre-index TE (n=10,093), median time from index to first post-index TE was 0.6 months, whereas patients without pre-index TE (n=46,083) had a median time to first post-index TE of 14.2 months. Among all patients with TE during follow-up, the most common TEs were ischemic stroke (47.5%), transient ischemic attack (30.9%), and acute myocardial infarction (30.5%). The risk of mortality was increased for patients who experienced a TE compared with those who did not (hazard ratio [HR; 95% CI], 9.3 [8.4-10.2]; P<0.0001). For patients who experienced a pre-index TE, the risk of mortality was increased for patients who experienced a subsequent TE during follow-up compared with patients who did not (HR [95% CI], 6.7 [5.8-7.8]; P<0.0001). Likewise, for patients who did not experience a pre-index TE, the risk of mortality was increased for patients who experienced a TE during follow-up compared with patients who did not (HR [95% CI], 13.1 [11.4-15.0]; P<0.0001). Conclusions In this real-world study, approximately one-third of patients with newly diagnosed high-risk PV experienced a TE during follow-up and had a 9-fold increased risk of mortality vs those who did not experience a TE. TE risk mitigation remains an important management goal in patients with PV, particularly in those with prior TE. Disclosures Pemmaraju: Samus Therapeutics: Research Funding; Celgene: Honoraria; SagerStrong Foundation: Other: Grant Support; Affymetrix: Other: Grant Support, Research Funding; MustangBio: Honoraria; Blueprint Medicines: Honoraria; LFB Biotechnologies: Honoraria; Plexxikon: Research Funding; Novartis: Honoraria, Research Funding; AbbVie: Honoraria, Research Funding; Stemline Therapeutics: Honoraria, Research Funding; Pacylex Pharmaceuticals: Consultancy; Daiichi Sankyo: Research Funding; Incyte Corporation: Honoraria; Roche Diagnostics: Honoraria; Cellectis: Research Funding; DAVA Oncology: Honoraria. Gerds:Sierra Oncology: Research Funding; Celgene: Consultancy, Research Funding; Gilead Sciences: Research Funding; Imago Biosciences: Research Funding; Pfizer: Research Funding; CTI Biopharma: Consultancy, Research Funding; Roche/Genentech: Research Funding; Apexx Oncology: Consultancy; AstraZeneca/MedImmune: Consultancy; Incyte Corporation: Consultancy, Research Funding. Parasuraman:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Yu:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Shah:Avalere Health: Current Employment. Xi:Incyte Corporation: Other: Avalere Health is a paid consultant of Incyte Corporation; Avalere Health: Current Employment. Kumar:Avalere Health: Current Employment; Incyte Corporation: Other: Avalere Health is a paid consultant of Incyte Corporation. Scherber:Incyte Corporation: Current Employment, Current equity holder in publicly-traded company. Verstovsek:Gilead: Research Funding; Incyte Corporation: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; CTI Biopharma Corp: Research Funding; Promedior: Research Funding; Roche: Research Funding; AstraZeneca: Research Funding; Blueprint Medicines Corp: Research Funding; Genentech: Research Funding; Sierra Oncology: Consultancy, Research Funding; Protagonist Therapeutics: Research Funding; ItalPharma: Research Funding; PharmaEssentia: Research Funding; NS Pharma: Research Funding; Celgene: Consultancy, Research Funding.

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Dasatinib (SPRYCEL®) in Patients (pts) with Chronic Myelogenous Leukemia in Accelerated Phase (AP-CML) That Is Imatinib-Resistant (im-r) or -Intolerant (im-i): Updated Results of the CA180–005 ’START-A’ Phase II Study.

Blood ◽

10.1182/blood.v108.11.2160.2160 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2160-2160 ◽

Cited By ~ 11

Author(s):

Jorge Cortes ◽

D.W. Kim ◽

F. Guilhot ◽

G. Rosti ◽

R.T. Silver ◽

...

Keyword(s):

Kinase Inhibitor ◽

Mutational Analysis ◽

Present Report ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Significant Activity ◽

Hematologic Response ◽

Grade 3

Abstract Dasatinib (SPRYCEL®, formerly BMS-354825) is a novel, oral, multi-targeted kinase inhibitor that induces complete hematologic and cytogenetic remissions in pts in all phases of im-r or im-i CML. START-A is an open-label study of dasatinib in pts with im-r or im-i AP-CML. Preliminary results with early follow-up suggested significant activity. The present report updates the results of this study with a minimum of 9 months of follow-up. Dasatinib was given orally at 70 mg twice daily (BID). Dose escalation to 100 mg BID was allowed for inadequate initial response and reduction to 50 or 40 mg BID for persistent toxicity. Evaluation included weekly blood counts and monthly bone marrow including cytogenetics. Molecular evaluation of BCR-ABL transcript levels by real-time qPCR was performed at baseline and upon documentation of complete cytogenetic response. A total of 174 pts (161 im-r and 13 im-i) were enrolled between December 2004 and July 2005 in 39 centers worldwide. There were 96 (55%) males; median age was 57 years (range 22–86); median time from original diagnosis of CML was 82 months. Prior therapy included im in all pts (>600 mg/day in 91 (52%), im for >3 years in 103 (59%) pts, interferon in 126 (72%) pts, stem cell transplantation in 23 (13%) pts. Major cytogenetic response (MCyR) to prior im had been seen in 57 (33%) pts. The average daily dose (median across all pts) was 130 mg/day (range 44–199). Major hematologic response (MaHR) was documented in 110 (63%) pts with complete hematologic response in 75 (43%) and no evidence of leukemia in 35 (20%). At 9 months, 85% of pts have maintained their MaHR. MCyR was documented in 65 (37%) pts, complete in 49 (28%), partial in 16 (9%). Median progression-free survival (PFS) has not been reached; estimated PFS at 9 months is 70%. In the 94 pts with BCR-ABL mutations at baseline the MaHR rate was 69%. Generally, response rates were similar in the im-i and im-r groups. Cytopenias were significant with grade 3–4 thrombocytopenia and neutropenia in 82% and 76% of pts, respectively. Non-hematologic toxicities were generally mild to moderate. The most frequent (% any grade, % grade 3–4) were diarrhea (51%, 8%), headache (29%, 1%), fatigue (26%, 4%), fever (25%, 3%) and pleural effusion (25%, 3%). Pleural effusions were optimally managed with dose interruption and diuretics and/or pulse steroids. Dasatinib is highly effective in pts with im-r or im-i AP-CML with high rates of durable MaHR and MCyR. An updated analysis with at least 12 months of follow-up, including molecular response data and mutational analysis at time of progression, will be presented.

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Outcomes of Patients with Chronic Phase CML Who Discontinued Ponatinib in the Frontline Setting

Blood ◽

10.1182/blood.v126.23.1580.1580 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1580-1580

Author(s):

Preetesh Jain ◽

Hagop M Kantarjian ◽

Elias Jabbour ◽

Zeev Estrov ◽

Gautam Borthakur ◽

...

Keyword(s):

Clinical Trial ◽

Median Time ◽

Research Funding ◽

Chronic Phase ◽

Cytogenetic Response ◽

The Other ◽

Molecular Response ◽

Vascular Events ◽

Grade 3

Abstract Background: Ponatinib is a novel TKI efficacious in relapsed refractory patients (pts) with CML and in those with T315I mutation. Despite the achievement of deep early responses in most pts observed in the frontline setting, the concern for arterio-thrombotic events led to the discontinuation (DC) of ponatinib frontline clinical trial. In this study, we have assessed the outcomes after DC of ponatinib of pts in a clinical trial of frontline ponatinib in CML-CP. Methods: Fifty one pts with CML-CP were treated with frontline ponatinib in a single-arm, clinical trial between May 2012 and September 2013. Initial dose of ponatinib was 45 mg orally daily in 43 pts and, after amendment, 30 mg in 8 pts. All pts DC ponatinib therapy after June 2014 and were switched to another TKI. Patients were assessed for cause of DC, treatment received after ponatinib DC, response achieved/maintained on subsequent TKI, adverse events (AE) and survival after ponatinib DC. Survival was calculated from the time of ponatinib DC to the time of last follow up. Results: All 51 patients DC ponatinib: 38 per FDA recommendation and 13 due to AE. Median duration of ponatinib therapy was 13.2 months (range-2.1-25.4). At the time of DC, 47/51 (92%) pts were in complete cytogenetic response (CCyR) and 4 (8%) in partial cytogenetic response (PCyR); 1 pt DC before 3-mo evaluation. Forty (78%) pts were in MMR and 26 (51%) in molecular response 4.5-log (MR4.5). Thirty-six (70%) pts were switched to dasatinib, 7 (14%) to imatinib, and 4 (8%) each to nilotinib and bosutinib. After switching to another TKI, with a median of 13 months (range, 0.2 to 26.3) of follow-up, 2 pts have lost their cytogenetic response (both PCyR on ponatinib), 1 pt improved from PCyR to CCyR and one maintained PCyR; all 47 (92%) pts with CCyR on ponatinib maintained this response. Molecular responses improved in some pts: 6 improved from no MMR to MMR; 1 to MR4.5 (median time on ponatinib 4 months; median time on subsequent TKI 17 months); 11 from MMR to MR4.5 (median time on ponatinib 13 months; median time on subsequent TKI 17 months). One pt (treated with imatinib 400) lost MR4.5 to no MMR after 2 months. At last follow-up 37 pts (72%) had MR4.5 and 45 (90%) MMR. Two pts died after ponatinib DC. One pt was treated with imatinib 400 and developed grade-3 edema and recurrent lung cancer; the second was switched to dasatinib and had recurrent progressive peripheral arterial disease (PAD). Four pts had events (2 deaths, 1 secondary MDS with -7 and 1 pt lost major CyR). Median post ponatinib survival (Figure-1) and median post ponatinib event free survival (not shown) was not reached (1-year OS 98% and EFS 95%). Forty five pts continued on their first post-ponatinib TKIs, 5 required 2 post-ponatinib TKI and 1 pt received 3 different TKIs after DC. The most common cause for post-ponatinib TKI switch was toxicity (n=6). Of the 36 pts switched to dasatinib, 5 discontinued: 4 due to pleural effusion and 1 with acute renal failure. 29/36 pts (81%) were in MMR before switch and all maintained MMR; 4 pts achieved MMR after switch to dasatinib. Four pts developed grade 3-4 non hematological vascular AEs (3 among pts with such events while on ponatinib and 1 new vascular event within 3 months of ponatinib DC). Of the 4 pts switched to nilotinib, 1 DC within 3 months due to grade-3 pancreatitis and also developed grade-1 pulmonary hypertension with 1 month of discontinuing ponatinib. This pt was then switched to bosutinib. The other 3 pts maintained MMR and had no vascular events. Of the 4 pts switched to bosutinib, one developed MDS, one was switched back to ponatinib off protocol (patient's choice), 1 lost cytogenetic response and one DC therapy after 1 month and maintains MR4.5 (this pt had TIA while on ponatinib, developed cerebral infarct within 1 month post ponatinib). Seven pts switched to imatinib. One developed a new PAD within 3 months of ponatinib DC (history of MI while on ponatinib). The other 6 pts maintained MMR on imatinib. Overall, 15 pts who had aggravated hypertension on ponatinib were under control after DC of ponatinib. Conclusion: Treatment with 2nd generation TKIs and imatinib was effective and safe in pts who DC ponatinib, and most pts were able to maintain/improve the responses achieved on ponatinib. Ponatinib-associated hypertension was usually reversible after DC and most vascular events with subsequent TKIs occurred in patients with prior such events while on ponatinib. Figure 1. Post ponatinib survival in patients Figure 1. Post ponatinib survival in patients Disclosures Jabbour: pfizer: Research Funding; ariad: Research Funding; teva: Consultancy; teva: Research Funding; pfizer: Consultancy; bms: Consultancy; ariad: Consultancy. Estrov:incyte: Consultancy, Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

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ZUMA-4: A Phase 1/2 Multicenter Study of KTE-X19 in Pediatric and Adolescent Patients With Relapsed/Refractory B Cell Acute Lymphoblastic Leukemia or Non-Hodgkin Lymphoma

Blood ◽

10.1182/blood-2020-137233 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 42-42

Author(s):

Alan S. Wayne ◽

Gerard Michel ◽

Daniel W. Lee ◽

André Baruchel ◽

Sonali Chaudhury ◽

...

Keyword(s):

B Cell ◽

Research Funding ◽

Kinase Inhibitor ◽

Cell Lymphoma ◽

Lymphoblastic Leukemia ◽

Phase 1 ◽

B Cell Lymphoma ◽

Primary Phase ◽

Phase 2 ◽

Publicly Traded

Background: Although approximately 80% - 85% of patients with acute lymphoblastic leukemia (ALL), the most common childhood malignancy, achieve durable complete remissions (CRs) after initial treatment, the remaining 15% - 20% of patients with relapsed or refractory (R/R) ALL have unfavorable outcomes (Leukemia2018;32:2316-25; N Engl J Med 2015;373:1541-52) and could benefit from effective new therapies. KTE-X19 is an autologous, anti-CD19 chimeric antigen receptor (CAR) T cell therapy approved for the treatment of R/R mantle cell lymphoma and under investigation for additional R/R hematologic malignancies including chronic lymphocytic leukemia, adult ALL, and pediatric B cell ALL and non-Hodgkin lymphoma (NHL). KTE-X19 treatment has shown high rates of CRs, with a manageable safety profile for adult patients with R/R B cell ALL in the Phase 1 portion of ZUMA-3, including those with poor risk factors (J Clin Oncol 2019;37[suppl, abstr]:7006). ZUMA-4 is an ongoing Phase 1/2 study evaluating KTE-X19 in pediatric and adolescent patients with R/R B cell ALL or NHL (NCT02625480). End-of-Phase 1 interim analysis of ZUMA-4 showed the feasibility of KTE-X19 therapy with optimized dosing and adverse event (AE) management strategies for the treatment of pediatric patients with R/R ALL (Pediatr Blood Cancer 2019;66[suppl]:S24). The protocol for Phase 2 of ZUMA-4 has been amended to include broader B cell ALL enrollment criteria with a focus on patients with early relapse associated with poorer outcomes, and an NHL cohort was added. Methods: Key B cell ALL enrollment criteria include age ≤ 21 years, weight ≥ 10 kg, and B cell ALL that is primary refractory, relapsed within 18 months of first diagnosis, R/R after ≥ 2 lines of systemic therapy, or R/R after allogeneic stem cell transplantation at least 100 days prior to enrollment. Criteria for disease burden have been amended to also include patients with minimal residual disease-positive disease at enrollment. Patients with Philadelphia chromosome-positive ALL are eligible if intolerant to tyrosine kinase inhibitor therapy or if R/R after ≥ 2 tyrosine kinase inhibitor therapies. Patients with chronic myelogenous leukemia lymphoid blast crisis or clinically significant infections are not eligible. For B cell NHL, key enrollment criteria include age < 18 years, weight ≥ 10 kg, histologically confirmed diffuse large B cell lymphoma not otherwise specified (DLBCL NOS), primary mediastinal large B cell lymphoma, Burkitt lymphoma (BL), Burkitt-like lymphoma or unclassified B cell lymphomas intermediate between DLBCL and BL, with ≥ 1 measurable lesion. For NHL, disease must be primary refractory, R/R after ≥ 2 lines of systemic therapy, or R/R after autologous or allogeneic stem cell transplantation ≥ 100 days prior to enrollment. Patients with acute graft-versus-host disease or chronic graft-versus-host disease requiring treatment within 4 weeks of enrollment are not eligible. Patients with central nervous system-1 disease (no detectable lymphoblasts in cerebrospinal fluid), with central nervous system-2 disease (detectable disease, but white blood cell count < 5/μL in cerebrospinal fluid) without clinically evident neurologic changes, or who had prior blinatumomab treatment can be included in the ALL and NHL cohorts. Patients with prior CD19-directed therapy, except for blinatumomab, are excluded. Patients receive conditioning chemotherapy with fludarabine 25 mg/m2 on Days −4, −3, and −2 and cyclophosphamide 900 mg/m2 on Day −2 followed by a single infusion of KTE-X19 at a target dose of 1 × 106 anti-CD19 CAR T cells/kg on Day 0. The study has completed the Phase 1 portion and is currently enrolling in Phase 2, with a target accrual of approximately 50 additional patients with ALL and 16 with NHL. For ALL, the primary Phase 2 objective is to evaluate KTE-X19 efficacy as assessed by overall CR rate (CR + CR with incomplete hematologic recovery). For NHL, the primary Phase 2 objective is KTE-X19 efficacy assessment by objective response rate (complete response + partial response). Secondary Phase 2 objectives for ALL and NHL cohorts include safety and tolerability, additional efficacy endpoints, and changes in patient-reported outcome scores. ZUMA-4 is currently recruiting at 23 sites in the United States, Canada, France, and the Netherlands. Disclosures Wayne: Servier: Research Funding; Kite, a Gilead Company: Research Funding. Lee:Amgen Oncology: Consultancy; Kite, a Gilead Company: Research Funding; Juno: Consultancy; Harpoon Therapeutics: Consultancy. Baruchel:Bristol-Myers Squibb: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Bellicum: Consultancy. Brown:Novartis: Consultancy; Janssen: Consultancy; Servier: Honoraria; Jazz: Honoraria. Hermiston:Novartis: Membership on an entity's Board of Directors or advisory committees; Sobi: Membership on an entity's Board of Directors or advisory committees. Krueger:Atara: Other: Travel support; Kite, a Gilead Company: Other: Travel support; Novartis: Consultancy, Other: Travel support; no honoraria, Speakers Bureau. Shen:Gilead: Current equity holder in publicly-traded company; Kite, a Gilead Company: Current Employment, Other: Travel support. Tailford:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company. Masouleh:Kite, a Gilead Company: Current Employment, Current equity holder in publicly-traded company.

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