Real-world efficacy and safety outcomes of imatinib treatment in patients with chronic myeloid leukemia: an Australian experience

Background: Tyrosine kinase inhibitors (TKI) have revolutionised the treatment of chronic myeloid leukaemia (CML), but patients still experience treatment-limiting toxicities or therapeutic failure. Aims: To investigate real-world use and outcomes of imatinib in patients with CML in Australia. Methods: A retrospective cohort study of patients with CML commencing imatinib (2001-2018) was conducted across two sites. Prescribing patterns, tolerability outcomes, survival and molecular response were evaluated. Results: 86 patients received 89 imatinib treatments. Dose modifications were frequently observed (12-month rate of 58%). At last follow-up, 62 patients (5-year rate of 55%) had permanently discontinued imatinib treatment, of which 44 switched to another TKI (5-year rate of 46%). Within 3 months of starting imatinib, 43% (95% CI, 32–53%) of patients experienced imatinib-related grade ≥3 adverse drug reactions (ADRs). Higher comorbidity score, lower body weight, higher imatinib starting dose, and Middle Eastern or North African ancestry were associated with a higher risk of grade ≥ 3 ADR occurrence on multivariable analysis (MVA). Estimated overall survival and event-free survival rates at 3 years were 97% (95% CI, 92–100%) and 81% (95% CI, 72–92%), respectively. Cumulative incidence of major molecular response (MMR) at 3 years was 63% (95% CI, 50–73%). On MVA, imatinib starting dose, ELTS score, BCR-ABL1 transcript type, pre-existing pulmonary disease, and potential drug-drug interactions were predictive of MMR. Conclusion: Imatinib induced deep molecular responses that translated to good survival outcomes in a real-world setting, but was associated with a higher incidence of ADRs, dose modifications and treatment discontinuations than in clinical trials.

Ruxolitinib Re-Treatment in Patients with Myelofibrosis: Real-World Evidence on Patient Characteristics and Outcomes

Ruxolitinib is an FDA-approved treatment of intermediate- and high-risk myelofibrosis. In the phase 3 COMFORT studies, ruxolitinib reduced spleen volume in patients with myelofibrosis, with a median time to response of 3 months. However, nearly 20% of patients discontinued by month 4 with few treatment options available following discontinuation of ruxolitinib treatment. In this study, 2 independent patient care data sources were queried (Cardinal Health Oncology Provider Extended Network [OPEN] and HealthCore Integrated Research Environment [HIRE®]), and a retrospective review of medical charts was conducted. Patients aged ≥18 years with a diagnosis of myelofibrosis (primary or secondary), use of ruxolitinib for myelofibrosis, and documented physician-directed ruxolitinib interruption were included. Among 26 included patients, pre-interruption median (interquartile range [IQR]) ruxolitinib treatment duration was 123 (57–391, OPEN) and 110 (37–148, HIRE) days. Half the patients interrupted treatment within 3 months, commonly for adverse events (42% and 71%, respectively). After restarting ruxolitinib, median (IQR) re-treatment duration was 196 (54–553) and 166 (108–262) days, respectively. Consistent with previous reports, symptoms and spleen size improved in (OPEN/HIRE) 45%/43% and 40%/33% of evaluable patients, respectively. Further studies investigating the management of dose modifications and interruptions are needed to optimize benefit from ruxolitinib therapy.

Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients

Background Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM). Methods The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m2) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib. Results Thirty-two patients, median prior therapies 4 (range, 1–8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months. Conclusions Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.

Evaluation of Posaconazole Dosing in Children and Young Adults: A Single-Center Review

OBJECTIVE Initial posaconazole dosing regimens in children often do not achieve target concentrations, and data continue to support the need for higher initial dosing regimens. The objective of this study is to contribute to the current data regarding suboptimal posaconazole dosing in pediatric patients by retrospectively observing dosing strategies and subsequent drug concentrations. METHODS This study was conducted at a single institution in 27 patients aged 1 to 21 years. Patients who were initiated on any formulation of posaconazole for prophylaxis or treatment while admitted to the hospital were included. The primary outcome was to determine the percentage of pediatric patients who achieved the targeted trough concentration using their initial posaconazole dosing regimen. Secondary outcomes included percentage of patients who experienced a breakthrough invasive fungal infection (IFI), percentage of patients with elevated liver function tests (LFTs), and discontinuation for any reason. RESULTS There were 15 patients (55.5%) who reached desired trough serum concentration after the initial dosing regimen. The number of dose modifications to achieve the desired trough ranged from 1 to 3. Most patients received delayed-release tablets (n = 17), and the average doses for reaching prophylactic and treatment trough concentrations were 6.1 mg/kg/day and 11 mg/kg/day, respectively. There were 2 patients (7.4%) who experienced breakthrough IFI. Overall, 5 patients developed elevated LFTs and 7 patients discontinued treatment early. CONCLUSIONS The results describe a single population of pediatric patients, of whom 55% were able to achieve target trough concentrations of posaconazole with the initial dosing strategy used.

Exploring Alternative Dosing Regimens of Single-Agent Belantamab Mafodotin on Safety and Efficacy in Patients with Relapsed or Refractory Multiple Myeloma: DREAMM-14

Introduction: Belantamab mafodotin is a first-in-class, monomethyl auristatin F (MMAF)-containing, B-cell maturation antigen (BCMA)-directed antibody-drug conjugate (ADC) that is approved in the United States and European Union for adult patients with relapsed/refractory multiple myeloma (RRMM). In the pivotal Phase II DREAMM-2 study, single-agent belantamab mafodotin (2.5 mg/kg administered intravenously every 3 weeks [Q3W]) demonstrated an objective response rate of 32% with a manageable safety profile in triple-class refractory adult patients with RRMM (Lonial et al. Lancet Oncol. 2020). At 13 months of follow-up, responses were durable, with a median duration of response of 11 months and an overall survival of 13.7 months (Lonial et al. ASH 2020, Poster 1417). Corneal events are common and expected with belantamab mafodotin and other MMAF-containing ADCs. In DREAMM-2, keratopathy (a pathological eye exam finding) presented as superficial punctate keratopathy and/or microcyst-like epithelial changes. Ocular symptoms, such as decline in best-corrected visual acuity or patient-reported adverse events (eg, blurred vision or dry eye), were also common during treatment. Corneal events with or without symptoms were managed with dose modifications (delays and reductions), and clinically meaningful responses were observed even with prolonged treatment-free intervals; this suggests that alternative dosing regimens of belantamab mafodotin may lower rates of corneal events without compromising efficacy. The goal of the DREAMM-14 study is to investigate whether an improved overall benefit/risk profile of single-agent belantamab mafodotin can be achieved by modifying the belantamab mafodotin dose, schedule, or both relative to the approved dosing regimen (2.5 mg/kg Q3W). Methods: This Phase II, 5-arm, randomized, parallel, open-label multicenter study will include patients with RRMM who have received at least 3 prior lines of therapy including an anti-CD38 monoclonal antibody (mAb), an immunomodulatory agent, and a proteasome inhibitor. Patients aged ≥18 years with Eastern Cooperative Oncology Group Performance Status ≤2 and who provide informed consent will be eligible. Patients with corneal epithelial disease (except mild punctate keratopathy) or prior exposure to BCMA-targeted therapies or ADCs will be excluded. Patients will be randomized into Arms A to D (n=40 each) and arm E (n=20) in parallel and stratified by the International Staging System (ISS) for MM (I vs II vs III) and prior lines of therapy (3 vs ≥4). Single-agent belantamab mafodotin will be administered at doses and schedules as follows-Arm A: 2.5 mg/kg Q3W (control); Arm B: 1.9 mg/kg Q3W; Arm C: 2.5 mg/kg Q6W; Arm D: 1.9 mg/kg Q6W; Arm E: 1.9 mg/kg Q6W with dose modifications based on oncology staff assessment of ocular symptoms (patient-reported symptoms using the Ocular Surface Disease Index) and visual acuity. Participants in all arms will have Q3W response assessments and Q3W ophthalmic examinations and monitoring by qualified eye care specialists. Ocular event-related dose modifications for all arms except Arm E will be guided by the Keratopathy and Visual Acuity (KVA) scale. Participants in all arms will be treated until progressive disease, unacceptable toxicity, or death. The primary endpoint will be incidence of Grade ≥2 ocular adverse events according to the KVA scale. Key secondary endpoints include ocular safety and tolerability, pharmacokinetics, and efficacy outcomes of belantamab mafodotin in all arms. Follow-up for progression-free survival will be Q3W until progressive disease, start of new anticancer therapy, withdrawal of consent, end of study, or death. Follow-up for overall survival will be Q12W from treatment discontinuation. The duration of this study will be approximately 22 months. The study is planned to start in the first quarter of 2022. Funding: GSK (Study 209628); drug linker technology licensed from Seagen; mAb produced using POTELLIGENT Technology licensed from BioWa. Disclosures Hultcrantz: GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Intellisphere LLC: Consultancy; Amgen: Research Funding; Daiichi Sankyo: Research Funding. Kleinman: Calm Water Therapeutics LLC: Current Employment; GlaxoSmithKline: Consultancy; Eyeon Therapeutics Inc.: Current holder of individual stocks in a privately-held company; ONL Therapeutics: Consultancy, Current holder of individual stocks in a privately-held company; Triphase Accelerator: Consultancy; Helixmith Co., Ltd: Consultancy; Aprea Therapeutics: Consultancy; Editas Medicine, Inc.: Consultancy; Olema Pharmaceuticals, Inc.: Consultancy. Ghataorhe: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. McKeown: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company; AstraZeneca: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. He: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Ling: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Jewell: Alcon: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company; GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Brunner: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Byrne: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company; Adaptimmune: Current equity holder in publicly-traded company; Novartis: Current equity holder in publicly-traded company. Eliason: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Scott: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company. Opalinska: GlaxoSmithKline: Current Employment, Current equity holder in publicly-traded company.

Phase I Study of Novel SYK Inhibitor TAK-659 in Combination with R-CHOP for Front-Line Treatment of High Risk Diffuse Large B-Cell Lymphoma

Background: DLBCL is highly heterogeneous in underlying biology and clinical behavior. Several high-risk disease features and poor prognostic factors are associated with a higher propensity for refractory disease or relapse after standard R-CHOP therapy; these subset patients require novel strategies to improve upon outcomes. Single-agent TAK-659, a novel oral SYK inhibitor, has demonstrated efficacy in heavily pre-treated DLBCL (Gordon et al., Clin Cancer Res, 2020). We report results of a phase I single institution, single arm dose escalation study that assessed safety of 1 st line treatment with R-CHOP and adjunctive TAK-659 for treatment naïve high-risk DLBCL. Methods: Patients aged ≥18 years, ECOG 0-2 with untreated stage I-IV DLBCL with high-risk features defined as, ABC/non-GCB subtype, high-intermediate or high-risk NCCN-IPI (score ≥4), MYC gene rearranged by FISH including double hit lymphoma (DHL), double expressing DLBCL (DEL; overexpression of MYC ≥40% AND BCL2 ≥50% by IHC respectively), or previously treated transformed low-grade lymphoma without prior exposure to anthracycline, were eligible. Patients were treated with R-CHOP for 1 cycle on or off study followed by combined treatment with R-CHOP and TAK-659 for an additional 5 cycles on study. TAK-659 was dosed daily with dosing escalated from 60mg (dose level 1), to 80mg (dose level 2) to 100mg (dose level 3) based on a 3+3 design. The primary objective was to determine the safety and establish the maximum tolerated dose of TAK-659 when combined with R-CHOP in the front-line treatment of high-risk DLBCL. Secondary objectives were to assess preliminary efficacy of this combination as determined by overall response rate (ORR) by PET-CT (Lugano 2014 criteria), progression free survival (PFS), overall survival (OS) and establish the pharmacokinetics of TAK-659 according to dose. Results: 12 pts were enrolled from Dec 2019 to Nov 2021. The median age was 64 yrs (range 25-75); 8 (67%) had stage III/IV disease, 4 (33%) with high risk NCCN-IPI ≥ 4. Histology included 7 (58%) with de novo DLBCL (4 GCB, 3 non-GCB subtype DLBCL) including 7 (58%) with DEL, 3 (25%) with transformed FL, 1 (8%) with Richter's and 1 (8%) with DHL. Dose level 3 (100 mg) was established as the MTD. PKs were measured pre- and post-dose D1 and D15 of cycle 2; Cuzick's test signaled an increase in AUC by dose level on D1 (p = 0.01) but not on D15 (Fig 1). ORR was 100% (CR 92%; Fig 2). With a median follow-up of 14.2 months, 1 pt had primary refractory disease (ABC and DEL), 2 pts with CR subsequently progressed (1 non-GC DLBCL, 1 Richter's) and 1 died of cardiogenic shock unrelated to study drug. The 12-month PFS and OS rates were 82% and 90% respectively with estimated 18-month PFS and OS rates of 68% and 90% respectively. The most common treatment related adverse events (TRAEs) attributed to TAK-659 were lymphopenia (n=12, 100%), infection (6=, 50%), AST elevation (n = 12, 100%) and ALT elevation (n = 10, 83%) (Table). Incidence and severity of transaminitis was consistent with prior reports for this agent. Most common grade 3/4 toxicities were hematologic. Median number of cycles of TAK-659 delivered was 5 (range 3-5). TRAEs led to TAK-659 dose modifications in 8 (67%) pts, though none at dose level 1: 2 (17%) required permanent dose reductions (both for lung infections), while 5 (42%) required discontinuation (4 for infection, and 1 for febrile neutropenia). R-CHOP administration was delayed in 2 pts because of TAK-659 related TRAEs. Aside from dose modifications of vincristine for peripheral neuropathy, no additional dose modifications for R-CHOP were needed. Infections encountered included bacterial and opportunistic infections (1 each for PJP, CMV and aspergillosis) and 1 case of COVID. Growth factor prophylaxis and anti-fungal therapy were not mandated; PJP prophylaxis was advised for CD4 counts < 200 at initial diagnosis. Conclusion: TAK-659, a novel SYK inhibitor combined with R-CHOP in pts with newly diagnosed high-risk DLBCL including DLBCL transformed from follicular lymphoma and DEL produces high CR rates; survival at 12 months appears promising. A dose of 60 mg was well tolerated, did not require dose modifications and maintained a similar AUC to the MTD of 100 mg with ongoing treatment. Opportunistic infections were noted with this treatment combination suggesting that patients should receive aggressive anti-microbial prophylaxis with future evaluation of this combination. Figure 1 Figure 1. Disclosures Karmali: BeiGene: Consultancy, Speakers Bureau; Morphosys: Consultancy, Speakers Bureau; Kite, a Gilead Company: Consultancy, Research Funding, Speakers Bureau; Takeda: Research Funding; Karyopharm: Consultancy; EUSA: Consultancy; Janssen/Pharmacyclics: Consultancy; AstraZeneca: Speakers Bureau; BMS/Celgene/Juno: Consultancy, Research Funding; Genentech: Consultancy; Epizyme: Consultancy; Roche: Consultancy. Ma: Beigene: Research Funding, Speakers Bureau; Juno: Research Funding; AstraZeneca: Honoraria, Research Funding, Speakers Bureau; Loxo: Research Funding; Janssen: Research Funding, Speakers Bureau; Abbvie: Honoraria, Research Funding; TG Therapeutics: Research Funding; Pharmacyclics: Research Funding, Speakers Bureau. Winter: BMS: Other: Husband: Data and Safety Monitoring Board; Agios: Other: Husband: Consultancy; Actinium Pharma: Consultancy; Janssen: Other: Husband: Consultancy; Epizyme: Other: Husband: Data and Safety Monitoring Board; Gilead: Other: Husband: Consultancy; Ariad/Takeda: Other: Husband: Data and Safety Monitoring Board; Karyopharm (Curio Science): Honoraria; Merck: Consultancy, Honoraria, Research Funding; Novartis: Other: Husband: Consultancy, Data and Safety Monitoring Board. Gordon: Zylem Biosciences: Patents & Royalties: Patents, No royalties; Bristol Myers Squibb: Honoraria, Research Funding. OffLabel Disclosure: TAK-659 will be discussed for the treatment of DLBCL (not FDA approved for this indication)

Feasibility of tele-chemotherapy administration to improve access to rural cancer patients.

112 Background: Telehealth improves access to cancer care for patients with cancer in rural communities. It allows qualified infusion nurses to administer chemotherapy in smaller rural towns under supervision by health professionals from larger tertiary sites. Here we would like to share our institutional experience in tele-chemotherapy administration to patients in rural Utah. Methods: We collected patient data including treatment regimens administered at our tele health sites from March 2019 to February 2021. Results: A total of 133 unique patients received 1073 cycles of low to intermediate risk treatment regimens. 42 unique regimens including intravenous and oral chemotherapy drugs, immune therapy and targeted drugs were administered at four rural facilities including Cassia Regional Center, Sanpete Valley Hospital, Severe Valley Hospital and Heber Valley Hospital in Utah. 52 physicians located at tertiary sites were involved in tele-chemotherapy administration. In addition to Medicare, Medicaid, the tele chemotherapy was covered by four commercial payers including Blue Cross Blue Shield, Select Health, Tricare and United Healthcare. Conclusions: Tele chemotherapy administration is feasible and allows improved access to cancer patients in rural communities. We aim to expand current project to capture the patient satisfaction and clinical outcomes including treatment delays, dose modifications, infusion reactions, hospitalizations or emergency visits.

Temporal characteristics of treatment-emergent adverse events and dose modifications with tivozanib and sorafenib in the phase 3 TIVO-3 study of relapsed or refractory mRCC.

4567 Background: The randomized phase 3 TIVO-3 study met the primary endpoint of improved PFS with tivozanib (TIVO) vs sorafenib (SOR) in patients with relapsed/refractory mRCC with fewer dose reductions, interruptions and discontinuations despite a longer time on therapy. Greater insight into temporal characteristics of treatment-emergent adverse events (TEAEs) may enable proactive supportive care strategies and improve patient experience. Methods: Updated safety from the previously reported TIVO-3 study with a data cutoff August 15, 2019, was analyzed by treatment arm for time-to-onset (TTO, days [d]) of the most commonly reported TEAEs, and TTO of first dose reduction, interruption, and discontinuation occurring with TIVO and SOR. Duration of TEAE (median d and IQ range), and rate of dose reduction, interruption, or discontinuation due to the TEAE was calculated for each arm. Results: Patients in the safety analysis randomly assigned to TIVO (n = 173) or SOR (n = 170) received 11.9 and 6.7 cycles, or 336 and 192 mean days of treatment exposure, respectively. Incidence of any Gr, Gr >3, and TTO of any Gr TEAE of special interest occurring with >20% frequency in either arm is shown in Table 1. While TIVO was associated with less Gr>3 diarrhea, rash and PPE and more HTN than SOR, there were few differences in the TTO or duration of these TEAEs. Overall, dose reductions, interruptions, and discontinuations due to TEAEs were less frequent with TIVO than SOR, and TTO of first dose reduction (85 vs 45 d), interruption (81 vs 50 d), and discontinuation (114 vs 49 d) was longer for TIVO than SOR. Among those experiencing the same TEAE in either arm, resulting dose modifications were less frequent with TIVO than SOR. Conclusions: TIVO-3 demonstrated improved PFS with TIVO compared to SOR in mRCC, with longer duration of TIVO exposure, but fewer all Gr and Gr >3 TEAEs. Temporal characteristics of TEAEs were similar, but time to dose modifications was longer with TIVO than SOR. Among those with the same TEAEs, unmodified treatment was continued more often with TIVO than SOR. Clinical trial information: NCT02627963. [Table: see text]

Comparison of dose modification strategies to address expected hematologic toxicities in treatment-naïve higher-risk (HR) MDS patients treated with venetoclax + azacitidine.

7041 Background: Venetoclax (Ven) is a selective, potent BCL-2 inhibitor. Ven + azacitidine (Aza) were associated with a combined complete remission (CR)/marrow CR (mCR) rate of 79% in a phase 1b study of patients (pts) with HR-MDS. Here we compared two different dose modification strategies to manage expected hematologic toxicities in two safety expansion cohorts with similar follow-up periods. Methods: Pts ≥18y diagnosed with treatment-naïve IPSS intermediate-2 or high-risk MDS with ECOG ≤2 were enrolled. Aza 75 mg/m2 (iv or subQ daily) was administered for 7 days (d) and Ven was administered at 400 mg for 14d in each 28d cycle. In both cohorts, dose modification during Cycle 1 was not recommended; dose modifications in subsequent cycles were prescribed for AEs. In Safety Expansion Cohort 1 (SE1), either Aza or Ven were initially reduced according to investigator’s choice for significant neutrophil or platelet toxicity. Dose reductions per protocol were 33% for Aza and 50% for Ven (for 14d each cycle). In subsequent cycles, Ven duration could be shortened to 9d of each cycle. In Safety Expansion Cohort 2 (SE2), dose modification guidelines recommended stepwise reductions, first in Aza dose (first to 50 mg/m2, then 36 mg/m2) and subsequently in Ven duration to 7d of each cycle (Ven 400 mg). The impact of each dose modification strategy on safety and efficacy in SE1 vs SE2 was compared. Worsening of treatment-emergent adverse events (TEAE) grades from baseline (BL) was analyzed by cycle. Responses were evaluated using IWG 2006 criteria. Analyses included all pts who received ≥1 dose of study drug. Results: We compared 22 pts in SE1 and 21 pts in SE2 with median (range) follow-up of 7.5 (1.0–8.9) and 7.9 (1.8–10.1) mos, respectively. A similar frequency of ≥ G3 hematologic TEAEs (approx %) were reported in SE1 and SE2, respectively, including anemia (14% and 33%), febrile neutropenia (46% and 48%), leukopenia (36% and 19%), neutropenia (55% and 48%) and thrombocytopenia (32% and 38%). Infections (59% and 38%) were more frequent in SE1 than SE2. In a longitudinal analysis, there were more TEAE grade increases from BL to Cycle 1 in SE2 vs SE1. This could be accounted by pts in SE1 and SE2 having unbalanced susceptibility to AEs at BL, as SE1 and SE2 pts received identical Aza + Ven doses in Cycle 1. Response rates were identical: 86% of pts in both SE1 and SE2 had CR or mCR. For pts with mCR, hematologic improvement occurred in 50% of SE1 and 46% of SE2 pts. Conclusions: No obvious hematologic differences were observed when reducing Aza before Ven (SE2) in MDS compared to investigator’s choice (SE1). Both approaches had a similar acceptable safety profile without compromising efficacy for pts with HR-MDS. Clinical trial information: NCT02942290. [Table: see text]