Frontline Therapy For Patients Research Articles

ABCL-283: A Phase I/II Trial of Brentuximab Vedotin (BV) Plus Rituximab (R) as Frontline Therapy for Patients with Immunosuppression-Associated CD30+ and/or EBV+ Lymphomas

Background: Chronic immunosuppression significantly increases the risk of developing a variety of lymphoid malignancies. Up to 80% of cases are driven by EBV-associated mechanisms of tumorigenesis. Approximately 70% will express CD30 and over 80% will express CD20. Standard-of-care rituximab (R) monotherapy followed by a response-stratified treatment approach shows poor response, with ∼75% patients requiring subsequent chemotherapy exposure; 2-year OS for the population as a whole was ∼70%. We hypothesized that a combination of brentuximab vedotin (BV) and R would yield improved breadth and depth of response compared with R monotherapy, would spare patients subsequent exposure to CIT, and result in favorable OS. Methods: Induction consisted of R 375 mg/m2 given days 1, 8, 15, and 22 and BV 1.2 mg/kg given days 1, 8, and 15 of a 28-day cycle, followed by restaging. Those with progression were removed from the study. Patients with stable disease were offered discontinuation or completion of one consolidation cycle followed by repeat assessment; consolidation was identical to induction. Patients with partial response or complete response could receive either consolidation followed by maintenance therapy (MT) or move directly to MT, which consisted of BV 1.8 mg/kg every 3 weeks and R 375 mg/m2 every 6 weeks for up to 1 year of therapy. Toxicity was defined using CTCAE 4.0, and response was assessed at the end of induction, consolidation (if given), and after cycles 4 and 7 of BV. Results: Toxicity and response data are available for 20 patients. Overall response rate was 70%, including a CR rate of 60%. Median follow-up of 26.1 months; 2-year PFS was 75%, and 2-year OS was 90%. Median time to best response was 28 days. Eighteen patients (92%) experienced toxicity at any grade with the most frequent grade 3/4 toxicities being peripheral neuropathy, neutropenia, infection, and pancreatitis. Conclusions: The combination of BV + R is effective in achieving rapid early remissions as frontline therapy for immunosuppression-related lymphomas. High toxicity rates suggest poor long-term tolerance and a different schedule or shorter treatment courses may be warranted. Further studies are needed to confirm these efficacy results and to determine optimal BV+R dosing regimens and duration.

Evaluating Daratumumab in the Treatment of Multiple Myeloma: Safety, Efficacy and Place in Therapy.

Despite the tremendous advances in the treatment of multiple myeloma, mortality remains significant, highlighting the need for new effective strategies. In recent years, daratumumab, a novel human monoclonal antibody, binding CD38, has dramatically improved outcomes either as monotherapy or in combination with traditional regimens. Originally approved for relapsed/refractory multiple myeloma, this breakthrough medication is now being used as frontline therapy in patients with newly diagnosed multiple myeloma regardless of transplant eligibility, with trials showing promising results. Its tolerable side-effect profile and enhanced efficacy have led to its widespread incorporation into the management of multiple myeloma and further exploration about its use in other entities such as smoldering myeloma, MGUS, MGRS and amyloidosis. This comprehensive review will discuss daratumumab’s mechanism of action and safety profile, as well as research which has defined its current approved indications, and ongoing clinical investigation that will define its future.

A phase II study of pazopanib as front-line therapy in patients with non-resectable or metastatic soft-tissue sarcomas who are not candidates for chemotherapy

BackgroundCytotoxic chemotherapy remains the standard of care first-line treatment for advanced and metastatic soft-tissue sarcomas (STSs). Certain patients may not be chemotherapy candidates based upon age or co-morbidities, leaving limited treatment options. Pazopanib is a multi-targeted tyrosine kinase inhibitor that is FDA-approved for metastatic STS after the first line. We proposed a phase II study evaluating pazopanib as a first-line agent in patients with advanced disease who are deemed not to be candidates for chemotherapy. MethodsEligible patients were at least 18 years old, not candidates for chemotherapyand were treatment naive. Pazopanib was titrated from 200 mg twice daily to a goal of 800 mg daily. The primary end point was the clinical benefit rate (CBR) (CBR = completed response + partial response + stable disease per Response Evaluation Criteria in Solid Tumours [RECIST 1.1]) at 16 weeks. The sample size of 56 evaluable patients was calculated to provide 80% power to test a hypothesised CBR of ≥35% against an unfavourable CBR of ≤20%. If ≥ 17 patients achieved benefit, the null CBR of 20% would be rejected at a nominal 5% alpha level. Secondary end points included progression-free survival (PFS), overall survival (OS), quality of life and serum biomarkers. FindingsFifty-six patients were enrolled from May 2015 to February 2019 and are included in the intention-to-treat analysis. Median PFS was 3.67 (2.62–7.25) months. Median OS was 14.16 (95% confidence interval [CI]: 8.4-NR) months, CBR = 39.29% (22/56) (CI = 0.265–0.533, p = 0.0007). No new or unexpected adverse events were seen. The most common grade I–II events were diarrhoea, nausea and fatigue. The most common grade III–IV events were hypertension and liver function test abnormalities. InterpretationThese data suggest that there is a benefit to front-line pazopanib in patients with STS who are not candidates for cytotoxic chemotherapy.

Frontline treatments in extremely elderly patients with diffuse large B-cell lymphoma: a population-based study in Taiwan, 2010\u20132015

BackgroundThe standard frontline therapy for patients with diffuse large B cell lymphoma (DLBCL) is R-CHOP. However, patients older than 80 years are excluded from clinical trials. The importance of rituximab and anthracycline remains unknown in extremely elderly DLBCL patients. Here, we incorporated data from the Taiwan Cancer Registry Database (TCRD), National Health Insurance Research Database (NHIRD), and National Death Registry to evaluate the clinical benefits of rituximab and anthracycline in elderly patients. From the TCRD and NHIRD, we included DLBCL patients aged older than 60 years who received R-CHOP, R-CVP, CHOP, or CVP between 2010 and 2015.ResultsOf the 3228 eligible patients, 2559 were between 60 and 79 years (the 60–79 group), and 669 were older than 80 years (the 80+ group). The proportions of patients in the different Ann Arbor stages and the practice settings were similar in both groups. The male-to-female ratio and the Charlson comorbidity index (CCI) scores in the 80+ group were higher than those in the 60–79 group. Patients in the 60–79 group received R-CHOP more frequently than those in the 80+ group. In the 60–79 group, the median age of the patients receiving R-CVP or CVP was older than those receiving R-CHOP or CHOP. In the analysis of overall survival (OS) and time to treatment failure (TTF), R-CHOP, female sex, younger age, lower Ann Arbor stage, lower CCI score, and care at a medical center predicted a favorable prognosis in the 60–79 group. However, only R-CHOP, younger age, and lower Ann Arbor stage remained independent favorable prognostic factors in the 80+ group.ConclusionsOur population-based study demonstrated the clinical benefits of rituximab and anthracycline in extremely elderly Asian patients with DLBCL.

A phase Ib/III randomized, double-blind, placebo-controlled study of tazemetostat plus doxorubicin as frontline therapy for patients with advanced epithelioid sarcoma.

TPS11573 Background: Epithelioid sarcoma (ES) is characterized by loss of inhibitor of integrase 1 (INI1), allowing enhancer of zeste homologue 2 (EZH2) to repress cell differentiation and promote tumorigenesis. Tazemetostat (TAZ) is an EZH2 inhibitor approved by the FDA as monotherapy for the treatment of patients (pts) aged ≥16 years with metastatic or locally advanced ES ineligible for complete resection. The most common ( > 20%) adverse events include pain, fatigue, nausea, decreased appetite, vomiting, and constipation. TAZ demonstrated anti-cancer activity in ES pts who previously received doxorubicin (dox), a commonly used front line FDA approved therapy for soft tissue sarcomas (STS), including ES. Preclinical studies have demonstrated synergy between TAZ and dox. This phase 1b/3 study (NCT04204941) is assessing the safety and efficacy of TAZ + dox in pts with advanced ES. Methods: This study is enrolling treatment-naïve adult pts with histologically confirmed STS (phase 1b) or INI1-deficient ES pts (phase 3) with ECOG performance status of 0-2 and life expectancy of ≥3 months. The open-label phase 1b portion is currently enrolling up to 24 patients with STS. The primary objectives are to evaluate the safety and tolerability of TAZ + dox, and to identify the recommended phase 3 dose (RP3D). Using a standard 3 + 3 design, TAZ will be evaluated at 3 dose levels (400 mg, 600 mg, and 800 mg orally BID) with standard fixed dose of dox (75 mg/m2 on day 1 of 21-day cycles for up to 6 cycles). After completion of dox, pts will continue to receive TAZ monotherapy until disease progression or intolerable toxicity. Up to 12 additional pts will be enrolled at the maximum tolerated dose for collection of additional safety and pharmacokinetic (PK) data. The double-blind phase 3 study will randomize (1:1) up to 140 pts to receive either TAZ (RP3D) + dox (75 mg/m2) or placebo + dox. The adaptive study design will allow sample size re-estimation (at interim analysis) to up to 200 pts. Pts may continue TAZ or placebo monotherapy after completing 6 cycles of TAZ + dox. Tumor assessments will be performed at screening and every 6 weeks from the start of dosing. The primary objective of phase 3 will be to evaluate the progression-free survival (PFS) by independent review committee. Secondary objectives will include assessment of PFS by investigators, overall survival, safety, disease control rate, overall response rate, duration of response, time to subsequent anticancer therapy, PFS on next treatment, quality of life, and PK. Clinical trial information: NCT04204941 .

Comparative effectiveness of immune-checkpoint inhibitors as first-line treatment for advanced nonsquamous non-small cell lung cancer patients: A network meta-analysis and a systematic review.

e21731 Background: Over the last decade six different immune-checkpoint inhibitors (ICI) have obtained approval in 42 tumor types, several of them are indeed competing for the same indication and there is a lack of direct comparative data to guide the medical oncologist. Network meta-analysis (NMA) is a technique developed as an extension of pairwise meta-analysis to allow comparisons of multiple treatments, using both direct and indirect evidence. This NMA evaluates the effectiveness of several ICIs, either in combination or as single agents, as frontline therapy for patients with advanced non-squamous non-small cell lung cancer (NSCLC). Methods: We conducted a systematic review of randomized controlled trials (RCT) through Pubmed, Embase, Cochrane Central register of Controlled trial databases, Clinicaltrial.gov database and ASCO abstracts (up to June 2019), to identify phase III RCTs on advanced non-squamous NSCLC in the first-line setting. Both the search and study screening were performed for two independent reviewers. NMA of survival outcomes in different subsets of PD-L1 expression groups was performed and ICIs indirect comparisons were performed. Results: 6 RCTs with 5860 patients were included for the NMA. ICIs were evaluated in combination with several chemotherapy regimens and in the case of Nivolumab in combination with ipilimumab. Atezolizumab was evaluated in one of the RCTs in combination with chemotherapy and bevacizumab. Both Pembrolizumab and Nivolumab were evaluated as monotherapy, either in a separate treatment arms within a trial or in a separate trial. Overall ICI in combination improved survival across PD-L1 expression level subgroups compared with chemotherapy (platinum doublets +/- bevacizumab). Indirect comparisons of ICIs in combination therapy for first-line treatment in advanced non-squamous NSCLC showed little evidence of differences between pembrolizumab or atezolizumab in combination with chemotherapy and nivolumab/ipilimumab. Evaluated as monotherapy pembrolizumab seems to have more evidence of effectiveness than nivolumab. Conclusions: ICIs in combination therapy improve survival in previously untreated advanced NSCLC across PD-L1 expression levels compared with standard first line chemotherapy regimens. There is little evidence of survival difference between pembrolizumab and atezolizumab in combination, and nivolumab requires a combination with ipilimumab to reach similar levels of effectiveness.

Brentuximab Vedotin in the Treatment of Peripheral T Cell Lymphoma and Cutaneous T Cell Lymphoma

The recent development of brentuximab vedotin (BV), an antibody-drug conjugate targeting CD30-positive cells, has led to therapeutic advances in the treatment of T cell lymphomas. In this review, we discuss key studies of BV in peripheral T cell lymphoma (PTCL) and cutaneous T cell lymphoma (CTCL) and highlight important questions for further investigation. Monotherapy with BV has proven to be effective and well tolerated in patients with relapsed/refractory (R/R) CD30-positive CTCL. BV has shown significant activity in R/R PTCL as well, with particularly durable responses in patients with anaplastic large cell lymphoma (ALCL). In a landmark phase III study (ECHELON-2), BV + CHP demonstrated superior progression-free and overall survival relative to CHOP as frontline therapy for patients with CD30-expressing PTCL, representing the first randomized trial demonstrating an overall survival benefit in PTCL. Though BV is overall well tolerated, peripheral neuropathy remains a clinically significant adverse effect. BV is a major therapeutic advance in the treatment of patients with R/R CTCL and of those with PTCL in both the R/R and frontline settings. Key ongoing areas of investigation include optimization of CD30 expression as a predictive biomarker as well as the role of BV in consolidation therapy.

Deepening of response after completing rituximab-containing therapy in patients with Waldenstrom macroglobulinemia.

Rituximab-containing regimens are commonly used for frontline therapy in patients with symptomatic Waldenström macroglobulinemia (WM). We had observed that a portion of WM patients experienced deepening of response months to years after therapy completion. We carried a retrospective study aimed at describing this phenomenon. We gathered baseline data, and responses at end of induction, end of maintenance and best response. Deepening of response was defined as ≥25% decrease in serum IgM achieved at a later time from therapy completion. Of 178 patients included, 116 (65%) received maintenance therapy and 62 (35%) were observed. In patients who received maintenance, 44 (38%) had ≥25% decrease in serum IgM level after the end of maintenance with a median time from end of maintenance to lowest IgM level of 1.6 years (range 0.1-7.9 years). In patients who were observed, 19 (31%) had ≥25% decrease in serum IgM level after the end of induction with a median time from end of induction to lowest IgM level of 1.6 years (range 0.2-5.1 years). Baseline hemoglobin <11.5 g/dL, bone marrow involvement ≥50%, CXCR4 mutations and serum IgM ≥4000 mg/dL were associated with lower odds of deepening of response after therapy completion. Deepening of response was associated with better progression-free survival (PFS; HR 0.46, 95% CI 0.26-0.80; P = .006) and better survival after frontline treatment initiation (SAFTI; HR 0.21, 95% CI 0.06-0.73; P = .01). In conclusion, deepening of response occurs in one third of WM patients after completing rituximab-containing regimens and was associated with better PFS and SAFTI.

Ixazomib-Based Frontline Therapy in Patients with Newly Diagnosed Multiple Myeloma in Real-Life Practice Showed Comparable Efficacy and Safety Profile with Those Reported in Randomized Clinical Trials: A Multi-Center Study in China

Jing Li, Li Bao and Zhong-jun Xia contributed equally to this study. Background: Ixazomib (ixa) is the first oral proteasome inhibitor that approved for the use in patients with relapsed/refractory multiple myeloma (RRMM) in &gt; 60 countries. In a recently reported long-term result of a phase 1/2 study (NCT01217957), the all-oral triplet regimen of ixazomib plus Rd (IRd) demonstrated favorable efficacy with acceptable toxicity in patients with newly diagnosed MM (NDMM). Meanwhile, a large phase 3 trial (TOURMALINE-MM2, NCT01850524) evaluating IRd in stem-cell transplantation (SCT) ineligible NDMM patients is ongoing. However, outcomes and toxicity profiles of novel-agent-based MM therapies in real world practice often differ from data reported in clinical trials and data of the efficacy of ixa-based treatment in NDMM in routine practice is currently missing. Aims and Methods: To assess the efficacy and safety profile of ixa-based frontline therapy in NDMM patients in routine practice, we performed a large national, multi-center, observational study enrolling ixa-treated (at least one cycle completed) NDMM patients from 14 China centers. Clinical records on demographics, disease characteristics, treatment regimen and duration, response rate, adverse events (AEs), and treatment discontinuations and survival were collected and analyzed. Results: A total of 60 NDMM patients treated with ixa-based regimens were included. Ixa-based regimens included IRd in 23 (38.3%) patients, the ixa and dexamethaxone (Id) in 17 (28.3%) patients and Id plus chemotherapeutics/other agents (Adriamycin in 12 patients, cyclophosphamide in 5 patients, and thalidomide in 3 patients) in 20 (33.3%). None of the patients included received SCT during follow-up. Median age was 69 years (range 35 - 85) with 33 (55.0%) ≥65 years. At initial diagnosis, ISS stage I/II/III disease were presented in 21.7%/28.3%/50.0% patients at initial diagnosis; high-risk cytogenetic abnormalities (including del 17p, t(4;14), and/or t(14;16) detected by fluorescence in situ hybridization) were detected in 9 patients (19.6%, among 46 patients with FISH results). Twenty-six (43.4%) patients had a ECOG PS ≥2 and 5 patients (8.3%) had extramedullary disease. Eighteen patients were not eligible for ixa phase 1/2 study (NCT01217957) according to its inclusion and exclusion criteria, and even more patients (36, 60%) were not eligible for TOURMALINE-MM2 study. (Table1). The best confirmed ORR (partial response or better) for all 60 patients was 93.3% (56/60), including 63.3% of patients with ≥VGPR and 20.0% with a CR. The median time to response was 41 days. Similar response was observed among different subgroups: the ORR in Ixa phase1/2 study-eligible/ineligible group, MM2 trial- eligible/ineligible group and patients with standard/high-risk cytogenetics was 95.2%, 88.9%, 91.7%, 94.4%, 91.9% and 100.0%, respectively. And no significant difference in response between different ixa-based regimens was observed. After a median follow-up of 137.5 days after the first dose of ixazomib treatment (range, 28 - 372), median overall survival (mOS) and progression-free survival (mPFS) were not reached. (Table2) Adverse events (AEs) of grade 3 or higher were uncommon, reported in 14 (23.3%) patients, including thrombocytopenia (4 patients, 6.7%), diarrhea (5 patients, 8.3%), pneumonia (3 patients, 5.0%) and hypokalemia (1, 1.7%). No drug-related grade 3/4 peripheral neuropathy was recorded. Median cycles of ixa received were 4 cycles (range 1-11); 50 (83.3%) were still on treatment at data cut-off; 6 (10.0%) patients discontinued ixa due to intolerable AEs and 4 (6.7%) stop treatment for other reasons (mostly economic concerns). Discussion and conclusion: Here we reported the first real world, multi-center data on the efficacy and safety profile of ixa-based frontline therapy in patients with NDMM. Our results show that the ixa-based frontline therapy in real-life clinical practice is highly effective and fast in response, with an efficacy data (ORR 93.3%, ≥VGPR rate 63.3%) even better than that reported in NCT01217957 trial (ORR 88.0%, ≥VGPR rate 58.8%). Given the fact that no patients received SCT during follow-up in our cohort, our results maybe more comparable to the ongoing MM2 trial assessing SCT-ineligible NDMM. Ixa-based frontline therapy is well tolerated in NDMM patients treated in routine clinical practice. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Ixazomib is an oral proteasome inhibitor that approved for the use in patients with relapsed/refractory multiple myeloma (RRMM). Here in this abstract, I will present data on real-life practice of the use of ixazomib in newly diagnosed multiple myeloma.

Procarbazine-Free Escalated Beacopdac in Frontline Therapy of Advanced Hodgkin Lymphoma Reduces Red Cell Transfusion Requirements and May Shorten Time to Menstrual Period Recovery Compared to Escalated Beacopp and Appears to be As Efficacious

Introduction Since interim results from the EuroNet-PHL-C1 study1were published in 2013 showing that the gonadotoxic drug procarbazine in COPP can be safely replaced with dacarbazine (COPDac) it is increasingly common practice to modify escalated BEACOPP (eBPP) by removing oral procarbazine and replacing it with intravenous dacarbazine (250mg/m2 D2-3), hoping to reduce haematopoietic stem cell and gonadal toxicity. However, published data of 'escalated BEACOPDac (eBPDac)' regimen are very limited. Methods We collected retrospective data from 15 centres in the UK, Ireland and France, that offer eBPDac therapy for first line advanced stage Hodgkin Lymphoma, and compared outcomes with matched patients treated with eBPP at 4 UK centres. Most patients were treated as per HD15 or HD18 protocol. The 24 patients treated in Paris followed the AHL2011 protocol with two courses of eBPDac given upfront and if iPET2 negative were deescalated to 4 cycles of ABVD. Results From 2009, 141 patients were managed first line with either eBPP (n=52) or eBPDac (n=89) with median follow-up 40 months for eBPP and 12.7 months for eBPDac patients. Patients were well matched with no significant differences in age (median: 28), sex, stage (stage 3/4: 82%) and international prognostic score (IPS3+:65%). More patients treated with eBPDac received only 4 cycles of treatment (43% vs 12%; p&amp;lt;0.001) reflecting recent publication of HD18 trial data2. In total, 74% patients achieved iPET2 Deauville score 2 or 3 and 96% patients achieved PET negative remission by end of treatment. Of eBPDac patients, 77% achieved iPET Deauville 2 or 3 which was statistically similar to the eBPP cohort (69%; p=0.391) and matched the 76% iPET D2/3 reported in HD181. Of 141 patients, 139 are alive and 136 continue in first remission. Two eBPP patients have relapsed at 13 and 41 months and the latter died of refractory disease. One eBPDac patient had primary refractory disease, another relapsed seven months after treatment, and one 56-year-old eBPDac patient with high IPS died with bowel perforation during cycle 1. Toxicity was compared over the first 4 cycles. There was no difference in day 8 ALT between the two regimens although the mean day 8 neutrophil count was lower in eBPDac than eBPP patients (1.84 vs 2.35; p=0.043; G-CSF given day 9). There was a trend to fewer non-elective days of in-patient care for eBPDac compared with eBPP (mean: 2.78 vs 6.00; p=0.0846), and eBPDac patients received fewer red cell transfusions during cycles 1 to 4 compared with eBPP patients (Mean 1.87 units vs 4.33 units; p&amp;lt;0.001). Women aged &amp;lt; 35, who completed ≥4 cycles of eBPDac/eBPP with &amp;gt; 6 months post chemotherapy follow-up had a similar rate of return of menstrual cycles (eBPP: 20/21; eBPDac: 13/16), although eBPDac patients appeared to restart menstruation earlier post chemotherapy completion (mean: 3.85 months vs 8.65 months, p=0.0018). However, this could also reflect the higher mean chemotherapy cycle number completed by the eBPP women (5.86 vs 4.67; p&amp;lt;0.001). The use of monthly Goserelin to suppress ovulation varied between centres. Conclusions Accepting the limitations of a retrospective study, we suggest that substituting dacarbazine for procarbazine is unlikely to compromise the efficacy of eBPP in frontline therapy of patients with advanced Hodgkin Lymphoma and may have some toxicity benefits. As it is highly unlikely that this single drug substitution will ever be tested in a prospective trial, publishing real-world data from eBPDac patients is important.

Patterns of Care and Predictors of Survival in Adolescents and Young Adults with Hodgkin Lymphoma: A Population-Based Study

Introduction: Hodgkin lymphoma (HL) is one of the most treatable cancers affecting adolescent and young adult (AYA) patients (15 - 39 years), however optimal therapy for de novo disease in this population remains a subject of debate. Population-based studies in HL consistently report a survival disadvantage for AYAs when compared with younger patients. Though the etiology of these disparities is unclear, analyses of clinical trials data suggest that observed survival differences may relate to treatment, rather than to age. Because registry analyses are often limited by lack of information about clinical characteristics and therapeutic exposures, the independent effect of age on HL-outcome outside of the cooperative group setting is unknown. To address this gap in the literature, we: (1) examined initial treatment regimen and patterns of care in a population-based cohort of AYAs compared to children with de novo HL, and (2) examined the impact of sociodemographic and clinical variables on overall survival (OS) and disease-specific survival (DSS) by age, after adjusting for therapy. Methods: Data for 4,426 patients aged 0 - 39 years diagnosed with classical HL between 2007 and 2016 were obtained from the California Cancer Registry (CCR). Detailed treatment information for each patient was extracted from unstructured free-text fields in the CCR database. Chemotherapy regimens were classified based on standard treatment approaches for adult and pediatric HL (Table). Multivariable cox proportional hazards regression models were used to examine the influence of sociodemographic and clinical variables on OS and DSS, overall and by age group, and are presented as adjusted hazard ratios (aHR) with 95% confidence intervals (CI). Models were adjusted for race/ethnicity, sex, insurance, neighborhood socioeconomic status, histology, stage, B symptoms, treatment location at a NCI (National Cancer Institute)-designated cancer center, and radiation therapy (RT). Results: Of the 4,426 patients in this cohort, 33% were &lt;21 years (y) (N= 1,479) and 67% were 22 - 39y (N= 2,947). At median follow-up of 4.4 years, 3-year OS in the full cohort was 95%. Front-line therapy for patients with HL differed significantly across age groups (Table). Approximately 42% of patients &lt;21y received ABVD vs. 69% of older patients. Compared with older patients, a higher proportion of younger patients received ABVE-PC (younger: 8.8% vs. &lt;1%) and modified treatment regimens (younger: 24% vs. 9.6%). Regimens were considered modified if they omitted one drug from a standard protocol but were otherwise administered according to expected dosing schedules; the most common were ABV (18%) and AVD (15%). A higher proportion of patients with private (vs. public/no) insurance received STANFORD V chemotherapy. In total, 40% of patients aged &lt;21y received RT as part of initial therapy vs. 27% of patients 22 - 39y. In survival models, increasing age was associated with a higher risk of death. Compared with patients &lt;14y, the hazard of death from HL was over three-fold higher in patients 22 - 29y (aHR=3.1, CI: 1.1, 9.1) and 30 - 39y (aHR=3.8, CI: 1.3, 11.2). In multivariable models stratified by age, race/ethnicity, insurance, B-symptoms and stage were each significantly associated with survival. In patients &lt;21y, NHBs (aHR: 7.1, CI: 2.4, 20.6) and Hispanics (aHR: 2.5, CI: 1.0, 6.4) experienced worse DSS than NHWs. Having public or no insurance also conferred worse OS (aHR: 1.9, CI: 1.1, 3.5), but initial therapy did not significantly impact OS or DSS. Among those aged 22 - 39y, NHB patients had worse OS (aHR: 1.7, CI: 1.0, 2.8) as did patients with public or no insurance (aHR: 1.7, CI: 1.2, 2.3). Stage IV disease was associated with inferior OS (aHR: 2.9, CI: 1.3, 6.8) and DSS (aHR: 3.3, CI: 1.1, 9.6). Finally, modified treatment regimens (vs. ABVD) were associated with worse OS (aHR: 1.6, CI: 1.0, 2.5), but did not significantly impact DSS in AYAs. Conclusion: In this large, population-based cohort of children and AYAs with HL, we observed that initial therapy varies, but that the majority of AYAs receive ABVD. Variation in therapy was largely insufficient to explain observed survival disparities, as older age, NHB and Hispanic race/ethnicity, and public or no insurance each conferred increased risk of death, even after adjustment for chemotherapy regimen. Further analyses examining comorbidities, treatment-related toxicities, and cause of death are ongoing. Disclosures No relevant conflicts of interest to declare.

Long-Term Safety and Efficacy of Hyper-CVAD Plus Ponatinib As Frontline Therapy for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Long-Term Safety and Efficacy of Hyper-CVAD Plus Ponatinib As Frontline Therapy for Adults with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Upfront Ixazomib Plus Dexamethasone Induce Promptly Hematological Response in Patients with Light-Chain Amyloidosis

Background: CyBorD (bortezomib, cyclophosphamide, and dexamethasone) is considered as an effective induction regimen in newly diagnosed light chain amyloidosis (AL) patients. Although a full dose of dexamethasone (Dex) leads to a higher response rate, the dose is strictly limited, usually because of fluid retention. Additionally, supervised administration of bortezomib weekly, if applied, increases the cost and inconvenience of treatment for service providers and patients.Ixazomib(IXA), an oral proteasome inhibitor, was reported highly effective as a single agent in relapsed or refractory AL amyloidosis. The objective of this observation is to evaluate the feasibility and efficiency of adding a lower dose of Dex to IXA (Id) as an upfront regimen in AL pts. Patients and Methods: Between 9/29/2018-4/1/2019, twenty-five newly diagnosed (ND) AL pts were sequentially enrolled. All AL pts had positive Congo Red staining in biopsy specimens confirmed by immunoelectron microscopy(IEM). Ixazomib 4mg D1,8,15 and Dexamethasone 10mg D1,8,15,22 were given for a 28-day schedule until disease progression or intolerance. Efficiency and safety profiles were assessed at the beginning of each cycle. Patients who had not achieved PR after 3 cycles received additional oral cyclophosphamide (50mg daily). The patients not achieving PR after 3 more cycles would switch to salvage therapies such as lenalidomide-base regimens or melphalan-based regimens. Upfront Id regimen can be prolonged for 2 cycles after a best hematological response (CR) has been achieved. The primary objective was to determine the response rate of this regimen and to evaluate the safety and tolerability of Upfront Id. Secondary objectives included PFS and OS. Results: Patients(n=25) received a median of 4 cycles (1-8) of Id regimen. Most patients were at late stage (20 pts in MAYO stage III, 4 pts in stage I and 1 pts in stage II). The interphase FISH analysis in BM plasma cells finds translocation t(11,14) in 8 pts.(Table 1) All patients were evaluable for toxicity and twenty-four for the response. The ORR was 66.7%(16/24) post cycle 1 and 70.8%(17/24) post cycle 4. Best hematological response achieved to date of this study is CR in 10pts, VGPR in 5 pts. 5 of the 7 pts did not reach their hematological remission have a t(11,14) translocation. With a median of 197 days (34-281) follow-up, 68%(17/25) of the patients were still alive, and 41.7%(10/24) with their best hematological response. 4 of the patients died of sudden and the rest due to the progression of heart failure. (Figure 1) According to CTC AE 5.0, Grade III/IV AEs (no. of pts) included: diarrhea 16%(4), thrombocytopenia 12%(3), general edema 8%(2), hypokalemia 8%(2), AST increased 4%(1), hyperuricemia 4%(1), and pneumonitis 4%(1). All the 4 patients with serious diarrhea quit therapy because of intolerance. (Table 2) Conclusions: Adding low dose dexamethasone to Ixazomib can induce rapid and profound hematological remission in newly diagnosed AL pts, especially in patients without t(11,14). This entirely oral, chemotherapy-free combination regimen ensures patients' compliance. The relatively low incidence of Grade III/IV AEs also makes the regimen seemingly a broad usage in MAYO stage III pts. However, diarrhea and thrombocytopenia in these patients still need awareness. OffLabel Disclosure: Ixazomib (Ixa) is the first oral proteasome inhibitor that approved for the use in patients with relapsed/refractory multiple myeloma (RRMM) in &gt; 60 countries including US and China. In this single-center real-world study, we present the efficacy and safety profile of Ixazomib-based therapy as frontline therapy in patients with AL amyloidosis.

Brentuximab Vedotin in Front-Line Therapy of Hodgkin Lymphoma (HL) and CD30-Expressing Peripheral T-Cell Lymphoma (PTCL) in Adults Age 60 and Above

Background Despite the advances in therapy of classical Hodgkin lymphoma (cHL) and CD30-expressing peripheral T-cell lymphoma (PTCL) over the years, the outcomes seen in younger patients with the disease have not been attained in patients ≥60 years of age. Studies cite 5-year progression-free survival (PFS) and freedom from treatment failure rates of 30%-45% in older patients with HL, as compared to rates of 75%-80% expected in younger patients (Evens 2008; Proctor 2009). In a recent retrospective study of patients &gt;60 years of age diagnosed with PTCL between 2008-2014, a multivariate analysis demonstrated that a Charlson Comorbidity Index (CCI) ≥2 and high IPI score (3-5) were independent risk factors for worse overall survival (OS) and PFS (Zhao 2016). Similarly, multivariate analysis of registry data from Sweden shows that a CCI ≥2, when adjusted for age, is independently associated with worse OS and PFS outcomes (Ellin 2018). There is no standard treatment regimen for elderly patients with cHL and PTCL, and co-morbidities including depressed cardiac and renal function limit the ability to use combination chemotherapy, and represent a high unmet need. Brentuximab vedotin (BV, ADCETRIS®) is a CD30-directed antibody-drug conjugate (ADC) consisting of the chimeric IgG1 antibody cAC10, specific for human CD30; the microtubule-disrupting agent monomethyl auristatin E (MMAE); and a protease-cleavable linker that covalently attaches MMAE to cAC10. Following the binding of BV to CD30-expressing cells, the ADC-CD30 complex is internalized, and MMAE released via proteolytic cleavage. Binding of MMAE to tubulin disrupts the microtubule network within the cell, subsequently inducing cell cycle arrest and apoptosis. Single-agent BV has demonstrated robust activity in patients with HL refractory to several lines of chemotherapy and the ECHELON-1 study (Connors 2017) established its efficacy in combination with chemotherapy for the front line treatment of HL. In a phase 2 study of single-agent BV in 27 patients aged ≥ 60 years with HL, there was an objective response rate of 92%, with 73% achieving complete remission (Forero-Torres, 2015). For CD30-expressing PTCL, single-agent BV is an active and well-tolerated treatment for patients with relapsed or refractory disease (Horwitz 2014) and the ECHELON-2 study showed that the addition of BV to combination chemotherapy in the frontline treatment improves both PFS and OS (Horwitz 2018). In the elderly patient populations who are not candidates for multi-agent chemotherapy, frontline treatment with single-agent BV may have the potential to be an active and well-tolerated treatment. Study Design Two additional cohorts have been added to the SGN35-015 phase 2 open-label study (NCT01716806) to evaluate the efficacy and tolerability of BV as monotherapy in treatment-naive patients with cHL, which excludes nodular lymphocyte-predominant HL (Part E) or treatment-naive patients with CD30-expressing PTCL (Part F). The primary objective of these cohorts is to assess objective response rates of single-agent BV as frontline therapy in patients ≥60 years of age and ineligible for conventional chemotherapy for HL (Part E) or CD30-expressing PTCL (Part F). Eligible patients in Parts E and F must be ≥75 years or ≥60 years of age and have one of the following: confirmed ejection fraction &lt;45% or estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 and &lt;50 mL/min/1.73 m2, as determined by the Modification of Diet in Renal Disease study equation. Approximately 30 evaluable patients will be enrolled in Parts E and F of the study and administered BV 1.8 mg/kg as a single intravenous infusion on Day 1 of each 21-day cycle. Patients achieving a complete remission, partial remission, or stable disease will receive up to 16 cycles of treatment. Treatment response will be assessed by spiral CT scans of the chest, abdomen, and pelvis and PET scans at Cycles 2, 6, and 11. Response assessment will be determined by blinded independent central review. Disclosures Yasenchak: BMS: Consultancy; Seattle Genetics: Consultancy. Bordoni:Phillips &amp; Gilmore: Honoraria; Genentech: Speakers Bureau; Merck: Speakers Bureau; Seattle Genetics, Inc.: Research Funding; Practice Point Communication: Honoraria; Deciphera: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Honoraria; AstraZeneca: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Yazbeck:Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Gilead Sciences: Research Funding. Patel-Donnelly:Seattle Genetics, Inc.: Research Funding. Larson:Seattle Genetics, Inc.: Research Funding. Newhook:Seattle Genetics, Inc.: Employment. Ho:Seattle Genetics, Inc.: Employment, Equity Ownership. Mei:Seattle Genetics, Inc.: Research Funding.

Pre-treatment maximum standardized uptake value predicts outcome after frontline therapy in patients with advanced stage follicular lymphoma.

The impact of pre-treatment maximum standardized uptake value (SUVmax) on the outcome of follicular lymphoma (FL) following specific frontline regimens has not been explored. We performed a retrospective analysis of 346 patients with advanced stage follicular lymphoma (FL) without histological evidence of transformation, and analyzed the impact of SUVmax on outcome after frontline therapy. Fifty-two (15%) patients had a SUVmax >18, and a large lymph node ≥6 cm was the only factor associating with SUVmax >18 on multivariate analysis (odds ratio 2.7, 95% confidence interval [CI]: 1.3-5.3, P=0.006). The complete response rate was significantly lower among patients treated with non-anthracycline-based regimens if SUVmax was >18 (45% vs. 92%, P<0.001), but not among patients treated with R-CHOP (P=1). SUVmax >18 was associated with significantly shorter progression-free survival among patients treated with non-anthracycline-based regimens (77 months vs. not reached, P=0.02), but not among patients treated with R-CHOP (P=0.73). SUVmax >18 associated with shorter overall survival (OS) both in patients treated with R-CHOP (8-year OS 70% vs. 90%, P=0.02) and non-anthracycline-based frontline regimens (8-year OS 50% vs. 85%, P=0.001). In conclusion, pre-treatment PET scan has prognostic and predictive value in patients with advanced stage FL receiving frontline treatment.

MS09.02 Clincal and Molecular Biomarkers for Selection of Sclc Patients Candidate to Immunecheckpoint Blockade

Immunotherapy has dramatically altered the treatment options available to patients with lung cancer. In the past year, small cell lung cancer (SCLC) fully joined the immunotherapy era with approvals by the US Federal Drug Administration (FDA) for three separate immune checkpoint inhibitors – atezolizumab for frontline therapy in patients with extensive stage SCLC (ES-SCLC) (in combination with platinum-etoposide chemotherapy) and nivolumab and pembrolizumab (each as monotherapy) for relapsed SCLC. The combination of nivolumab plus ipilimumab also demonstrated durable activity in a subset of patients treated on the Phase 1/2 CheckMate032 trial, with an overall response rate of 22% and a 2 year overall survival rate of 26%.1 The addition of atezolizumab to carboplatin and etoposide as a new standard of care was based on results from the Phase 3 IMpower133 trial.2 In that randomized trial, the addition of atezolizumab to carboplatin-etoposide, followed by atezolizumab maintenance, led to improvements in both progression free survival (PFS) (4.3 months in the placebo control arm versus 5.2 months in patients receiving atezolizumab) and overall survival (OS) (10.3 months with placebo versus 12.3 months with atezolizumab). Additional randomized trials testing other immune checkpoint inhibitors in combination with standard platinum-etoposide chemotherapy are ongoing, with clinical findings expected in the next several months. This includes the phase 3 trial of durvalumab plus platinum-etoposide (CASPIAN), which has now been reported to show improved overall survival (OS) with the addition of durvalumab at a planned interim analysis (press release). Despite these landmark approvals for immune checkpoint inhibitors in ES-SCLC, a large number of patients with SCLC do not appear to receive clinic benefit with the currently available inhibitors of PD-1/PD-L1 and/or CTLA-4. Furthermore, there are not yet established biomarkers for identifying those patients with SCLC who are likely to respond. As with non-small cell lung cancer, immunohistochemistry (IHC) for PD-L1 levels and tumor mutation burden (TMB) are both candidate biomarkers.3,4 However, neither of these have been prospectively validated to date in SCLC and there may be important differences in their performance depending on how testing is done (e.g., variation between antibodies, scoring methods/cutoffs, or technical differences between molecular platforms). Recently, new combinations of targeted therapies together with immune checkpoint inhibitors (such as inhibitors of DNA damage response (DDR) such as PARP1 or Chk1 to enhance STING pathway activation) have demonstrated promise in preclinical studies of SCLC and are being translated into the clinic for further investigation.5 In addition, other new immunotherapeutic approaches are being tested in ongoing trials. Examples of these include studies of chimeric antigen receptor T-cells (CAR-T) and bi-specific T-cell engagers (BiTE molecules) targeting the notch inhibitor ligand DLL3 for patients with relapsed SCLC. In this context, additional biomarkers related to specific combinations of targeted and immune-therapies and/or new classes of immunotherapy (e.g., SLFN11 levels for PARP inhibitors; cMyc status for Chk1 inhibitors; markers of STING pathway activation; or DLL3 expression levels) may emerge as additional biomarkers relevant to immune responses. Finally, a better understanding of tumor and immune environment heterogeneity between patients – as well as intra-tumoral heterogeneity – will lead to more effective strategies for matching patients to specific immunotherapies and overcoming immunotherapy resistance. REFERENCES 1. Della Corte CM, Gay CM, Byers LA. Beyond chemotherapy: Emerging biomarkers and therapies as small cell lung cancer enters the immune checkpoint era. Cancer 2019;125:496-8. 2. Horn L, Mansfield AS, Szczesna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med 2018;379:2220-9. 3. Antonia SJ, Lopez-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016;17:883-95. 4. Hellmann MD, Callahan MK, Awad MM, et al. Tumor Mutational Burden and Efficacy of Nivolumab Monotherapy and in Combination with Ipilimumab in Small-Cell Lung Cancer. Cancer Cell 2018;33:853-61 e4. 5. Sen T, Rodriguez BL, Chen L, et al. Targeting DNA Damage Response Promotes Antitumor Immunity through STING-Mediated T-cell Activation in Small Cell Lung Cancer. Cancer Discov 2019;9:646-61. Immunotherapy, biomarkers, small cell lung cancer (SCLC)

1677PD - A phase II study of pazopanib as front-line therapy in patients with non-resectable or metastatic soft tissue sarcomas who are not candidates for chemotherapy

BackgroundAnthracycline based chemotherapy remains the standard of care for first-line treatment for advanced and metastatic soft tissue sarcoma. In some instances, patients may not be a candidate for chemotherapy based on age or other comorbidities leaving no viable treatment option. Pazopanib is a multi-targeted tyrosine kinase inhibitor that is FDA approved as a second-line and beyond treatment for metastatic soft tissue sarcoma. We proposed a phase II study to evaluate pazopanib as a first-line agent in patients with non-resectable or metastatic disease who are not candidates for cytotoxic chemotherapy. MethodsEligible patients were at least 18 years old, not a candidate for chemotherapy, and had not received prior systemic therapy for sarcoma. Initial starting dose of pazopanib was 200mg BID titrated to 800mg daily. The primary endpoint was clinical benefit rate (CBR) (CR + PR + SD per RECIST 1.1) at 16 weeks. The sample size of 56 evaluable patients was calculated to provide 80% power to test a hypothesized CBR of≥35% against an unfavorable CBR of≤20%. If≥17 patients achieved benefit, the null CBR of 20% would be rejected would be rejected at a nominal 5% alpha level (actual alpha=0.043). Secondary endpoints included PFS rate, OS, quality of life, and serum biomarkers. Results56 patients are included in the intention-to-treat analysis. Currently 52 patients are evaluable for CBR. Data from the final 4 patients will be added at the time of presentation. Median PFS was 12 (8.29∼24.14) weeks and PFS rate at 16 weeks was 40% (CI 0.2893-0.5617). Median OS was 8.6 months, CBR=36.5% (19/52), 95% CI=0.2362∼0.5104, 2-sided exact binomial test p=0.00507. No new or unexpected adverse events were seen. The most common Grade I-II adverse events were diarrhea, nausea, and anemia. The most common grade III-IV adverse events were hypertension and liver function test (LFT) abnormalities. Longitudinal quality of life analysis will be added at the time of presentation as well. ConclusionsGiven that the primary endpoint was met, these data suggest that there is a benefit to front-line pazopanib in patients who are not candidates for cytotoxic chemotherapy. Clinical trial identificationNCT02300545. Legal entity responsible for the studyWashington University in St Louis. FundingNovartis/GSK. DisclosureM. Agulnik: Advisory / Consultancy: Novartis; Advisory / Consultancy: Lilly; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Bayer; Speaker Bureau / Expert testimony: Janssen; Speaker Bureau / Expert testimony: Eisai; Speaker Bureau / Expert testimony: BMS; Speaker Bureau / Expert testimony: Bayer. M. Varun: Travel / Accommodation / Expenses: Deciphera; Research grant / Funding (institution): Immunocellular; Research grant / Funding (institution): Orbus Therapeutics. M. Milhem: Advisory / Consultancy: Amgen; Advisory / Consultancy: Trieza; Advisory / Consultancy: Biontech; Advisory / Consultancy: Blueprint medicine cooperation; Advisory / Consultancy: Immunocore; Advisory / Consultancy: Array BioPharma, Inc. S. Robinson: Research grant / Funding (institution): TRACON; Honoraria (institution), Advisory / Consultancy: BTG International; Honoraria (institution), Advisory / Consultancy: Society of Interventional Radiology Foundation. S. Attia: Research grant / Funding (institution): AB Science; Research grant / Funding (institution): TRACON Pharma; Research grant / Funding (institution): CytRX Corporation; Research grant / Funding (institution): Bayer; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): Daiichi Sankyo; Research grant / Funding (institution): Lilly; Research grant / Funding (institution): Immune Design; Research grant / Funding (institution): Karyopharm Therapeutics; Research grant / Funding (institution): Epizyme; Research grant / Funding (institution): BluePrint Medicine; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): CBA Pharma; Research grant / Funding (institution): Desmoid Tumor Research Foundation; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Philogen; Research grant / Funding (institution): Laboratories; Research grant / Funding (institution): Bavarian Nordic; Research grant / Funding (institution): BTG; Research grant / Funding (institution): PTC Therapeutics; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): FORMA Therapeutics. B.A. Van Tine: Advisory / Consultancy, Research grant / Funding (self), Travel / Accommodation / Expenses: Lilly; Research grant / Funding (institution): Merck; Research grant / Funding (institution): Tracon; Advisory / Consultancy: CytRX; Advisory / Consultancy, Speaker Bureau / Expert testimony: Janssen; Advisory / Consultancy: Immune Design; Advisory / Consultancy: Daiichi Sankyo; Advisory / Consultancy: Plexxicon; Advisory / Consultancy: Pfizer; Advisory / Consultancy, Speaker Bureau / Expert testimony: Adaptimmune; Speaker Bureau / Expert testimony: Caris; Advisory / Consultancy: Bayer. All other authors have declared no conflicts of interest.

BTK Inhibitors for the Treatment of Chronic Lymphocytic Leukemia

BTK Inhibitors for the Treatment of Chronic Lymphocytic Leukemia

Survival of patients with metastatic HER2 positive gastro-oesophageal cancer treated with second-line chemotherapy plus trastuzumab or ramucirumab after progression on front-line chemotherapy plus trastuzumab

BackgroundThe role of continuing anti-HER2 therapy beyond progression on front-line therapy in patients with metastatic HER2 positive gastro-oesophageal cancer (GEC) is unclear. Continued chemotherapy plus trastuzumab (CT) has never been compared with the current standard second-line treatment, chemotherapy plus ramucirumab (CR).MethodsThe Flatiron Health electronic health record derived database, a nationwide database comprising patient-level structured and unstructured data, curated via technology-enabled abstraction, was reviewed for patients with metastatic HER2 positive GEC who received first-line CT, followed by second-line CT or CR. Survival from second-line therapy (SST) and time to next therapy or death (TTNTD) were compared using Kaplan-Meier curves and logrank analysis.Results133 patients with metastatic HER2 positive GEC who received first-line CT were identified. 32 received second-line CR and 101 received CT. Median SST for patients treated with CT versus CR was 10.2 months (IQR 5.1–20.8) and 6.8 months (IQR 2.4–20.2), respectively (p=0.29). Median TTNTD for second-line CT versus CR was 4.9 months (IQR 2.8–9.8) and 5.1 months (IQR 2.3–7.5), respectively (p=0.65). Patients who received second-line CT were more likely to receive a multiagent chemotherapy backbone (76% vs 3%, p≤0.001).ConclusionsThis analysis showed no significant difference in SST for patients treated with second-line CT versus CR. Further studies are needed to clarify the role of trastuzumab in the second line, especially in patients with confirmed retention of HER2 positivity following progression.

Treatment value of second-generation BCR-ABL1 tyrosine kinase inhibitors compared with imatinib to achieve treatment-free remission in patients with chronic myeloid leukaemia: a modelling study

Treatment-free remission in chronic myeloid leukaemia-ie, achievement of a sustained deep molecular response leading to discontinuation of BCR-ABL1 tyrosine kinase inhibitor (TKI) therapy-has become a potential aim of therapy. Highly priced second-generation TKIs might offer deep molecular response status more quickly and for more patients than imatinib; however, with the availability and lower cost of generic imatinib, the value of second-generation TKIs as frontline therapy for this particular treatment endpoint remains unknown. We aimed to assess the potential value of second-generation TKIs used as frontline therapy in patients with chronic myeloid leukaemia in chronic phase in relation to the probability of achieving sustained deep molecular responses compared with generic imatinib, and the associated cost of each modality. We used a decision analytic model to consider the value of different TKI approaches from the payer's perspective. The proportion of patients achieving sustained deep molecular response after 5 years of treatment in chronic phase was estimated at 26% with imatinib and 44% with second-generation TKIs. We also modelled more favourable scenarios of the proportion of patients achieving such response with second-generation TKIs at 66%, 88%, and a near-perfect response of 99%. For each scenario, we examined the impact of the combination of health utilities for chronic-phase chronic myeloid leukaemia (base case 0·89, range 0-1) and the annual cost of second-generation TKIs (base case US$152 814 [ie, the price of nilotinib in the USA], range 0-240 000) on the cost-effectiveness of second-generation TKIs compared with generic imatinib. We used different price scenarios for generic imatinib in the USA (average price $35 000 per year; lowest price $4400 per year), Europe ($4000 per year), and developing countries ($2100 per year). We calculated incremental cost-effectiveness ratios (ICERs) and assessed cost-effectiveness by considering two societal willingness-to-pay thresholds: $50 000 per quality-adjusted life-year (QALY) in all markets and $200 000 per QALY in the USA. In the base case, we obtained an ICER of $22 765 208, meaning that second-generation TKIs as frontline therapy to achieve sustained deep molecular response was not cost-effective under either of the societal willingness-to-pay thresholds. In our sensitivity analyses, none of the explored scenarios showed potential treatment value for use of second-generation TKIs at the current prices in the USA or at the price of $30 000-40 000 per year elsewhere. For example, considering a scenario in the USA using second-generation TKIs versus imatinib (annual price $4400 per year) with the potential benefit in favour of second-generation TKI (willingness to pay $200 000 per QALY, 66% of patients achieving sustained deep molecular response, and health utility of the chronic phase of 0·1), the cost of second-generation TKIs would need to be less than $25 000 per year to be a cost-effective option. Under the same conditions in developing nations, with a price of generic imatinib of $2100 per year and a willingness to pay of $50 000 per QALY, the annual price of second-generation TKIs should not exceed $10 000 per year of therapy. Considering the current prices of second-generation TKIs and of generic imatinib under different pricing scenarios in the USA, Europe, and developing countries, second-generation TKIs at current prices do not offer good value as frontline therapy in chronic myeloid leukaemia in order to achieve sustained deep molecular response and treatment-free remission. National Cancer Institute.