scholarly journals A Clinical Practice Comparison of Overall Survival, Time-to-Next-Treatment, and Time-to-Treatment-Discontinuation Among CLL/SLL Patients Receiving First-Line Ibrutinib with and without a Del(17p) Mutation

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-3
Author(s):  
Anthony Mato ◽  
Boxiong Tang ◽  
Soraya Azmi ◽  
Keri Yang ◽  
Jennifer C Stern ◽  
...  
Keyword(s):  
Research Funding ◽  
Index Date ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Front Line ◽  
Publicly Traded ◽  
First Line ◽  
Treatment Naïve ◽  
Line Setting ◽  
Present Group

Introduction: Genetic risk factors play an important role in the prognosis of a patient with Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Lymphoma (SLL). One of the strongest negative prognostic factors is the presence of a 17p deletion (del(17p)). While ibrutinib monotherapy has shown efficacy in the relapsed/refractory and treatment-naïve settings (Burger et al., 2015; Munir et al., 2019), evidence from clinical trials specifically concerning its use in patients with del(17p) is limited in the front line setting. The available limited evidence does suggest that its use in patients with del(17p) may result in shorter PFS and OS compared to patients without the deletion (Mato et al., 2018; O'Brien et al., 2018; Brown et al., 2018). Using real world data we addressed two objectives: (1) comparing baseline demographic and clinical characteristics of ibrutinib-treated patients with and without del(17p), and (2) assessing outcomes of overall survival (OS), time-to-next-treatment (TTNT), and time-to-treatment discontinuation (TTD) among CLL/SLL patients with and without del(17p) in the first-line setting. Methods: Data from the nationwide Flatiron Health EHR-derived de-identified database were abstracted. Patients included were those aged ≥18 years, diagnosed with CLL/SLL (ICD-9 codes: 204.1x or ICD-10: C91.1x, C83.0x), and who had at least two clinic encounters in the Flatiron Health network and received ibrutinib as first CLL directed therapy on or after January 1, 2011. Patients had documented CLL/SLL and a documented cytogenetic test performed prior to ibrutinib start date confirming the presence or absence of del(17p). The start of first-line ibrutinib was defined as the index date for all comparative analyses. Baseline characteristics between present or absent del(17p) groups were compared. OS, TTNT, TTD were estimated using Kaplan Meier method and survival outcomes were compared between the two groups using the Cox proportional hazards model. Adjustment for covariates was performed for gender, age at index date, practice type (academic or community), Rai stage at diagnosis, ECOG status year of index date, status of deletion 11q, 13q, Trisomy 12 and IgHV mutation status. Reasons for discontinuation of ibrutinib are being explored. Presence or absence of TP53 mutations were not captured. Results: There were 1,037 first-line ibrutinib treated patients included based on the above inclusion criteria, 24% of patients had del(17p) present. The majority (95%) of patients were treated in community practices and the median follow up period was 18 months. The two groups differed in their Rai stage distribution at diagnosis, with del(17p) present patients tending to be later stage at diagnosis than del(17p) absent. Del(17p) patients also started first-line therapy sooner after diagnosis.Median OS was shorter in the del(17p) present group at 57.54 months from initiation of treatment (p<0.001), compared to the del(17p) absent group where median OS was not reached [Table 1, Figure 1].The Cox proportional hazards models were consistent with this finding, where HR for OS was 1.72 times greater in the del(17p) present group, and this difference was statistically significant in both the unadjusted (p<0.001) [Table 1] and adjusted analyses (p=0.009) [Not shown].In parallel with OS findings, the del(17p) present group tended to have shorter median TTNT (50.23 months vs. NR, p=0.063). The TTD for all patients was 48.62 months, while the TTD was shorter in the del(17p) group (35.80 months vs. NR, p=0.117). These results were confirmed in the Cox proportional hazards models and similarly the difference between groups was not statistically significant [Table 1, Figure 2]. Conclusions: We present the largest study addressing outcomes of patients with del(17p) treated with ibrutinib monotherapy in the front line setting to address an important data gap that current clinical trials have not directly addressed. Since ibrutinib is now a standard of care for such high-risk patients, a deeper understanding if the presence of del(17p) impacts survival outcomes in patients treated with ibrutinib in the front line setting is needed. Based on the significant impact shown on OS, and to a lesser degree TTNT and TTD, these data confirm that del(17p) is a negative predictive factor in this setting. This reflects an ongoing unmet need among treatment naïve CLL/SLL patients with del(17p) status. Disclosures Mato: Janssen: Consultancy, Research Funding; Loxo: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding. Tang:BeiGene, Ltd.: Current Employment, Current equity holder in publicly-traded company. Azmi:BeiGene, Ltd.: Current Employment, Current equity holder in publicly-traded company. Yang:BeiGene, Ltd.: Current Employment, Current equity holder in publicly-traded company. Stern:BeiGene, Ltd.: Current Employment, Current equity holder in publicly-traded company. Hedrick:BeiGene, Ltd: Current Employment, Current equity holder in publicly-traded company. Huang:BeiGene: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company). Sharman:AbbVie: Consultancy, Research Funding; Bristol Meyers Squibb: Consultancy, Research Funding; BeiGene: Research Funding; Pfizer: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; TG Therapeutics: Consultancy, Research Funding; Acerta: Consultancy, Research Funding; Roche: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Does the Achievement of MR4.5 Improve the Outcome of Patients with Chronic Phase Chronic Myeloid Leukemia (CP-CML) Treated with Front Line Tyrosine Kinase Inhibitors (TKI)?

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5158-5158
Author(s):  
Lorenzo Falchi ◽  
Hagop M. Kantarjian ◽  
Xuemei Wang ◽  
Elias Jabbour ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Research Funding ◽  
Proportional Hazards ◽  
Cytogenetic Response ◽  
Cox Proportional Hazards ◽  
P Value ◽  
Front Line ◽  
Molecular Responses ◽  
Free Survival ◽  
Cumulative Rate ◽  
Time Point

Abstract Background: Aside from the possibility of treatment discontinuation, the prognostic significance of deep molecular responses regarding survival endpoints in pts with CP-CML treated with TKI remains controversial. Achievement of complete cytogenetic response (CCyR) correlates with improved overall survival (OS). Among pts with CCyR, achievement of major molecular response (MMR) correlates with improved event-free survival (EFS). We have previously shown that among pts in sustained CCyR, those who achieve deeper molecular responses at 18 or 24 months may have longer EFS and failure-free survival (FFS) but not transformation-free survival (TFS) or OS. In this analysis, we sought to determine whether the achievement of a MR4.5 might correlate with improved long-term outcome in CP-CML pts who achieve CCyR after frontline TKI therapy. Methods: Pts with CP-CML treated with front line TKI, including imatinib 400 mg daily (IM400), imatinib 800 mg daily (IM800), nilotinib (NILO), or dasatinib (DASA), were included in the analysis. Landmark analyses were conducted at various time points to identify the association between achieving MR4.5 and various survival outcomes. Since the benefit of achieving CCyR is well established, only pts who were in CCyR were considered at each time point. The probabilities of OS, EFS, FFS and TFS were estimated using the Kaplan-Meier method and Cox proportional hazards regression models were fit to assess the association between OS, EFS, FFS, TFS and response. All outcomes were measured from the date treatment was started. OS was measured until death from any cause; TFS until death or transformation to accelerated (AP) or blast phase (BP) during study; EFS until loss of complete hematologic response or major cytogenetic response, transformation to AP or BP, or death from any cause; FFS until any event (as per EFS definition), failure (as defined by the ELN criteria), loss of CCyR, discontinuation or change of therapy for any reason. Results: The study population consisted of 478 pts. 59% of them were males and 9% had high Sokal score at diagnosis. 71 pts received IM400, 204 IM800, 105 NILO, and 98 DASA. Median follow-up is 106 (4-177) months (163 for IM400, 133 for IM800, 61 for NILO and 71 for DASA). The overall cumulative rate of CCyR was 92% (85% for IM400, 90% for IM800, 99% for NILO, and 97% for DASA). The overall cumulative rate of MR4.5 was 73% (56%, 74%, 80% and 78%, respectively for the 4 treatment cohorts). Among pts with CCyR, corresponding rates of MR4.5 were 79% overall and 66%, 81%, 83% and 80%, respectively, for the 4 treatment cohorts. For the entire population, the 5-year OS was 92.7%, TFS 86.0%, EFS 80.7%, and FFS 69.1%. In pts who were in CCyR at 12, 18, 24, 30, 36 or 48 months after initiation of TKI therapy there was no significant difference in terms of EFS, FFS, TFS or OS between pts who achieved a MR4.5 and those who did not (Table). Conclusion: Our analysis suggests that the achievement of MR4.5 does not provide a meaningful improvement in EFS, FFS, TFS, or OS for CP-CML pts who have achieved CCyR after being treated with frontline TKI. While obtaining a MR4.5 may enable the option of TKI discontinuation, our results suggest that failure to do so should not be considered failure or suboptimal response and thus should not prompt a change in TKI in pts who are in CCyR. Change of therapy to achieve MR4.5 with the goal of treatment discontinuation should be considered only within clinical trials. Table 1. Cox proportional hazards models for EFS, FFS, TFS, and OS at various time points. Time point EFS FFS TFS OS HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value HR 95% CI p-value 12 months 0.82 0.42-1.61 0.57 0.94 0.58-1.53 0.81 0.99 0.46-2.12 0.98 1.06 0.47-2.39 0.89 18 months 0.96 0.51-1.82 0.9 0.75 0.45-1.25 0.27 1.34 0.69-2.81 0.36 1.41 0.68-2.94 0.35 24 months 0.85 0.44-1.65 0.63 0.8 0.49-1.33 0.39 0.9 0.41-2.01 0.8 0.99 0.43-2.25 0.97 30 months 0.75 0.35-1.62 0.47 0.64 0.36-1.15 0.14 0.82 0.34-1.96 0.65 0.98 0.40-2.39 0.97 36 months 0.98 0.46-2.09 0.96 0.55 0.30-1.02 0.06 1.11 0.47-2.65 0.81 1.24 0.52-2.95 0.63 48 months 0.86 0.35-2.10 0.73 0.7 0.35-1.40 0.31 0.84 0.29-2.43 0.75 0.86 0.30-2.48 0.78 Disclosures Pemmaraju: Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Teva: Consultancy, Research Funding.

scholarly journals Lines of Therapy in Patients with Relapsed or Refractory Large B-Cell Lymphoma and Stem Cell Transplant-Intended Treatment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 45-46
Author(s):  
Julia Thornton Snider ◽  
Paul Cheng ◽  
Xue Song ◽  
Donna McMorrow ◽  
David Diakun
Keyword(s):  
Research Funding ◽  
Index Date ◽  
Intensive Therapy ◽  
B Cell Lymphoma ◽  
Treatment Patterns ◽  
Cell Transplant ◽  
Front Line ◽  
Publicly Traded ◽  
Line Of Therapy ◽  
To Receive

Introduction: Large B-cell lymphoma (LBCL) is the most common subtype of non-Hodgkin lymphoma. Front line therapy is curative in about 60% of patients; however, about 30% of patients relapse and about 10% are refractory. For patients failing the front line, stem cell transplant (SCT) is currently the only curative option in second line of therapy (LOT2). This study examined real-world treatment patterns with curative intent in patients with relapsed or refractory LBCL to understand the unmet medical need in the United States. Methods: This retrospective study used IBM MarketScan® Commercial and Medicare Supplemental Databases. Patients with ≥2 LBCL diagnoses on different days in 1/1/2012 - 3/31/2019 were identified (index date = date of the earliest LBCL diagnosis). Patients who were ≥18 years of age on the index date, had ≥1 claim for any LBCL treatment on or following the index date, ≥6 months of data prior to (baseline) and ≥12 months of data after (follow up period) the index date, and had no baseline LBCL diagnosis were included. Treatment patterns, including lines of therapy (LOT), treatment regimen, duration of LOT and time from the end of a previous LOT to the subsequent LOT, were examined. All patients were required to receive first LOT (LOT1) of R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone +/- rituximab), EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin hydrochloride +/- rituximab), or regimens with anthracycline. Of those, patients were further required to receive LOT2 with SCT-intended intensive therapy or platinum-based chemotherapy as recommended by the National Comprehensive Cancer Network (NCCN). Patients were intended for SCT if they received an SCT-intended LOT2 regimen or received SCT regardless of LOT2 regimen. SCT was identified from the LOT2 start date to the end of the study period. All analyses were stratified by whether a patient was intended for SCT and by receipt of SCT. Results: A total of 3,443 patients with LBCL received an eligible front-line therapy (mean age 59.2 years, male 56.9%, length of follow up 2.5 years, National Cancer Institute (NCI) adapted Deyo-Charlson comorbidity index 0.83). Top comorbidities were other malignancy (63.3%), diabetes (23.3%), psychiatric disturbance (13.9%), and chronic pulmonary obstructive disease (13.2%). Among the LBCL patients, 564 (16.4%) received LOT2 with 197 (34.9%) patients SCT-intended and 367 (65.1%) not SCT-intended (Figure 1). SCT-intended patients were significantly younger than SCT-non-intended patients (55.9 vs. 60.9 years, p<0.001), and patients who received SCT were younger than those who did not receive SCT (53.6 vs. 59.7 years, p<0.001). Among the 197 patients intended for SCT, only 55.3% (n=109/197) received NCCN recommended LOT2 for intensive therapy: ICE (ifosfamide, carboplatin, etoposide) +/- rituximab (32.5%) and GemOx (gemcitabine, oxaliplatin) +/- rituximab (19.3%) were the most common regimens. SCT-intended patients initiated LOT2 nearly one year (345 days) after and third line of therapy (LOT3) 501 days after their LBCL index diagnosis (Figure 2). Duration of LOT decreased as patients moved on to later LOTs (LOT1=121 [standard deviation (SD)=69], LOT2=89 [SD=145] and LOT3=46 [SD=23] days). Likewise, the time between 2 consecutive LOTs decreased (194 [SD=258] days between end of LOT1 and start of LOT2, 124 [SD=182] days between end of LOT2 and start of LOT3). Steroids were often prescribed during LOT1 (82.2%) and LOT2 (74.6%) as concomitant therapy. Among the 109 patients receiving SCT-intended regimens, only 34 (31.2%) went on to receive SCT. An additional 88 patients received SCT without being observed to receive an SCT-intended regimen. They might have received therapy in the inpatient setting, which could not be captured in claims data. Among the 82 patients with LOT3, 60.1% received SCT and 9.8% received Chimeric antigen receptor (CAR) T cell therapy. Conclusion: The findings provide insight into real-world treatment patterns in patients with LBCL who received SCT-intended therapy. A small proportion of LBCL patients received NCCN recommended SCT-preparative regimens in LOT2 and only 31% of them received SCT. This highlights the magnitude of unmet need for relapsed or refractory LBCL patients. Future studies should examine the impact of new therapies on the management of LBCL. Disclosures Thornton Snider: Kite, A Gilead Company: Current Employment; Gilead Sciences: Current equity holder in publicly-traded company, Research Funding; Precision Medicine Group: Ended employment in the past 24 months, Research Funding. Cheng:Kite, A Gilead Company: Current Employment, Current equity holder in publicly-traded company. Song:IBM Watson Health: Research Funding. McMorrow:IBM Watson Health: Current Employment. Diakun:IBM Watson Health: Current Employment, Research Funding.

Association of early bone metastases and outcomes of the bone predominant metastatic urothelial carcinoma (BP mUC) phenotype.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e16016-e16016
Author(s):  
Ariel Ann Nelson ◽  
Matthew David Wright ◽  
Ali Raza Khaki ◽  
Leonidas Nikolaos Diamantopoulos ◽  
Ravi Kumar Kyasaram ◽  
...  
Keyword(s):  
Bone Metastases ◽  
Proportional Hazards ◽  
De Novo ◽  
Progression Free Survival ◽  
Cox Proportional Hazards ◽  
First Line ◽  
Kaplan Meier ◽  
Platinum Based Chemotherapy ◽  
Metastatic Setting ◽  
Line Setting

e16016 Background: Prior analyses demonstrated worse outcomes with the BP mUC clinical phenotype. UC molecular subtypes that may correlate with the BP phenotype have been defined, however molecular subtyping is not a readily available standard practice. We hypothesized that BP mUC has worse prognosis vs. non-BP (NBP) mUC and evaluated patient (pt) characteristics associated with the mUC subtype, responses and outcomes. Methods: We searched the electronic medical record (EMR) to identify pts with mUC who received systemic therapy in the metastatic setting. Demographic, clinicopathologic, treatment (trt), response, progression-free survival (PFS), overall survival (OS ) from start of first line trt. Imaging was reviewed to identify NBP or BP disease. Logistic regression, Cox proportional-hazards and Kaplan-Meier analyses were performed. Results: 149 mUC pts were identified (64% male, 68% smokers ), median age at 1st line trt was 68 years. 70% had de-novo mets, 46% to lung and 27% to liver. 22% of pts were BP, of these, 36% were de-novo metastatic. In non- de-novo metastatic pts (70% of pts), first progression of disease to bone was associated with development of the BP phenotype (OR = 30.46, 95% CI 6.37 to 145.61; p < 0.0001). BP pts had higher rate of death (HR = 2.28, 95% CI 1.45 to 3.58, p = 0.0004), shorter PFS from 1st line trt, (11.7 vs 14.9 weeks, p = 0.032) as well as shorter OS from 1st line trt (24.6 vs 56.6 weeks, p = 0.002) compared to NBP pts. There was no difference in PFS between BP and NBP groups for pts treated with 1st line platinum-based chemotherapy (11.8 vs 18.3 weeks, p = 0.091) or for BP pts treated with 1st line immunotherapy vs platinum-based chemotherapy (11.71 vs 11.86 weeks, p = 0.135). Conclusions: Early bone metastases are associated with the development of the BP metastatic phenotype. BP pts have worse PFS and OS from 1st line trt compared to NBP pts. PFS remains poor when BP pts are treated with either platinum-based chemotherapy or immunotherapy in the first line setting. Imaging to determine the presence of bone metastases may routinely be pursued and careful attention paid on follow up imaging. Clinical trials and prospective registries focusing on efficacy endpoints for BP mUC are needed.

Overall survival (OS) in men with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC) receiving bicalutamide (BIC) followed by enzalutamide (ENZA) or abiraterone (ABI).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 40-40
Author(s):  
Daniel J. George ◽  
Scott T. Tagawa ◽  
Stanislav Lechpammer ◽  
Dave Russell ◽  
Agnes Hong ◽  
...  
Keyword(s):  
Real World ◽  
Index Date ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Veterans Health ◽  
Health Administration ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Cox Analysis ◽  
The Impact

40 Background: The objective of this study was to evaluate real-world OS in men with chemotherapy-naïve mCRPC treated with first-line ENZA or ABI or sequencing to these agents after treatment with BIC ( > 90 d). Methods: A retrospective analysis was performed using the Veterans Health Administration (VA) database. Men with mCRPC and ≥ 1 pharmacy claim for ABI or ENZA (1st claim date = index date) following surgical or medical castration and with no chemotherapy treatment 12 months pre-index date were identified from 01APR2014 to 31MAR2017. Men had continuous VA enrollment for ≥ 12 months pre- index date and were followed until death or study end. Cox proportional hazards regression models examined the impact of treatment on OS, and the impact of first using BIC ( > 90 d) vs first-line use of ABI and ENZA on OS. Adjusted Kaplan-Meier analysis was conducted to graphically describe OS. Results: This study included 1229 ENZA- and 1945 ABI-treated men with mCRPC with mean ages of 74 and 73 y, respectively. Median follow‐up was 548 and 572 d, and median OS was 892 and 786 d, respectively. ENZA and ABI were first-line treatment in 1068 and 1628 men, but BIC ( > 90 d) was first used before sequencing to ENZA or ABI in 161 and 317 men, respectively. Median duration of BIC treatment was similar in men subsequently treated with ENZA or ABI (251 v 246 d, respectively). Compared with first-line ABI, use of ABI following BIC led to shorter OS (hazard ratio [HR] = 1.30; 95% CI 1.11 -1.52). Compared with first-line ENZA, use of ENZA following BIC resulted in a nonsignificant effect on OS (HR = 0.92; 95% CI 0.72-1.19). In the Cox analysis, ENZA-treated men had longer OS compared with ABI-treated men (HR = 0.84; 95% CI 0.76-0.94). Conclusions: Use of BIC ( > 90 d) before sequencing to ENZA did not negatively effect OS, however BIC before ABI impacted OS adversely in men with chemotherapy-naïve mCRPC. There are significant differences in OS favoring ENZA compared with ABI regardless of prior BIC. Real-world observational data are nonrandomized, and markers for disease severity/volume are not available in the claims database. Further research is required to confirm these findings.

scholarly journals Imatinib as Second-Line Therapy, Ameliorates or Maintains Molecular Responses Obtained with Ponatinib First-Line in Chronic Phase CML Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1894-1894
Author(s):  
Franck E. Nicolini ◽  
Gaelle Fossard ◽  
Valerie Coiteux ◽  
Viviane Dubruille ◽  
Vincent Alcazer ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Front Line ◽  
First Line ◽  
Advisory Committees ◽  
Line Therapy ◽  
Line Setting

Abstract Background & aims The third generation tyrosine kinase inhibitor (TKI) Ponatinib demonstrates extremely potent BCR-ABL inhibitory activity in CML patients in chronic or advanced phase, resistant to 1, 2 or 3 prior TKI (Cortes NEJM, 2013) and it seemed interesting to test this agent in the front-line setting of chronic phase patients. The EPIC trial was a phase III trial set up to compare the molecular outcomes of Imatinib 400 (IM400) versus Ponatinib 45 mg daily at one year. However, this trial has been abrogated at early stages by the FDA despite the impressive molecular efficacy of Ponatinib (Lipton, Lancet Oncol 2016) because of unexpected and unacceptable rates of arterial thrombotic events that occurred in another trial (PACE). A majority of patients in the Ponatinib arm were switched towards IM400, but their outcome is not known. The aim of this study was to analyse the general and molecular outcomes of such patients in our country. Methods This is an observational study following the rules and regulations of these studies in our country. Data were monitored and retrospectively collected in the 5 centers involved in the EPIC trial. Molecular analyses were performed locally during ponatinib exposure (in parallel with centralised assessments) and during IM treatment thereafter. Only local results, expressed in % BCR-ABL (IS), were used in this analysis, and all respective molecular biology laboratories have been involved in the Eutos/ELN BCR-ABL accreditation system. Results Thirteen patients were analysed, 9 males and 4 females, with a median age of 58.5 (range 19.5-69) years at chronic phase CML diagnosis. Sokal scores were low for 4, intermediate for 7, high for 2 patients, Euro score was low for 7, intermediate for 5 and high for 1, Eutos LTS score was low for 10, intermediate for 2 and high for 1. Patients were harbouring a "conventional" Philadelphia chromosome without clonal evolution (20-28 metaphases analysed/patient) at diagnosis. All patients were harbouring a Major BCR-ABL transcript. The median BCR-ABL transcript level was 109 (range 35-440) % at diagnosis. Blood pressure was normal in all patients at diagnosis except one. Ponatinib was initiated in all patients at 45 mg daily after a median of 1.5 (range 0.8-2.75) months after diagnosis. Median Ponatinib duration was 4 (range 0.5-6.3) months. Complete Hematologic Response was obtained in 0.98 (range 0.5-1) month in all patients. At 3 months, median BCR-ABL ratio was 0.19 (range 0.008-2.74) %, all patients being in early molecular response (EMR) and 4 patients being already in major molecular response (MMR). Median Ponatinib dose at cessation was 45 (range 0-45) mg daily. IM was started at 400 mg daily in all patients after a median of 1 (range 1-35) day after Ponatinib cessation and after a median of 4 (range 0.54-6.54) months after Ponatinib initiation. The median BCR-ABL transcripts at 3, 6, 12, 18, 24, 30, 36 and 42 months of Ponatinib (i.e. after a median time of 7, 10, 16, 22, 28, 34, 40 and 46 months of IM) were 0.22 (range 0.01-27)%, 0.08 (0.005-8.99)%, 0.08 (0.01-2.01)%, 0.1 (0.003-1.9)%, 0.03 (0.001-1.61)%, 0.01 (<0.001-0.21)%, 0.01 (0.001-0.21) and 0.01 (0.001-0.02) respectively (see figure 1). On the 10 evaluable patients for molecular analyses, at Ponatinib cessation 40% of patients were >MMR, 40% of patients in MMR, 20% in MR4. At last follow-up, on IM400 10% of patients were in >MMR, 40% in MMR, 20% in MR4, 10% in MR4.5 and 20% in MR5, i. e. 50% in deep molecular response. At last follow-up, all patients were alive, still on IM400 daily for 32 (27.75-37.4) months, except 4 [1 grade 3 asthenia (now on Dasatinib), 2 molecular failure (now on Dasatinib and Bosutinib)], 1 free of treatment]. None of the patients progressed towards advanced phases to date. No thrombotic events occurred in any of the patients on Ponatinib. Three patients developed hypertension on Ponatinib requiring treatment, still ongoing at last follow-up in all. Conclusion The use of Imatinib after Ponatinib first-line therapy for chronic phase CML patients is safe. Despite a significant tyrosine kinase inhibition inferior activity in vitro, it allows the maintenance or the improvement of molecular responses throughout time and serves as a consolidation therapy. These data might pave the way for the design of future clinical trials using Ponatinib in the front-line setting in conjunction with Ponatinib dose reduction. Figure 1 Figure 1. Disclosures Nicolini: Ariad, BMS: Consultancy, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Coiteux:Novartis, BMS, ARIAD: Speakers Bureau. Mouchel:Ariad/Incyte: Employment. Mahon:BMS: Honoraria; Pfizer: Honoraria; Novartis: Honoraria, Research Funding; Ariad: Honoraria. Etienne:novartis: Consultancy, Speakers Bureau; BMS: Speakers Bureau; ARIAD: Speakers Bureau; Pfizer: Speakers Bureau. Guerci:Pfizer: Consultancy; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; ARIAD: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

7 Prognostic factors for overall survival in patients with advanced melanoma treated with Anti-PD-1 therapy – the melimmune score

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A7-A7
Author(s):  
Soraia Lobo-Martins ◽  
Diogo Martins-Branco ◽  
Patrícia Miguel Semedo ◽  
Cecília Melo Alvim ◽  
Ana Maria Monteiro ◽  
...  
Keyword(s):  
Risk Factors ◽  
Prognostic Factors ◽  
Poor Prognosis ◽  
Proportional Hazards ◽  
Checkpoint Inhibitors ◽  
Prognostic Score ◽  
Daily Practice ◽  
Cox Proportional Hazards ◽  
Time To Death ◽  
Line Setting

BackgroundImmune checkpoint inhibitors (ICI) have changed the paradigm of advanced malignant melanoma (MM). Several prognostic factors, mostly linked to inflammation, have been under scope to better select patients for such therapies. We aimed to build and apply a prognostic score in this setting.MethodsBaseline characteristics and outcomes on 147 patients with advanced MM treated with an anti-PD1 (nivolumab or pembrolizumab) in monotherapy, between Jan-2016 and Oct-2019, in the 1st, 2nd or 3rd line setting were collected from two centres in Portugal. Data cut-off for follow-up was May-2020. Cox proportional hazards regression was used to identify independent prognostic factors for OS.ResultsWith a median FU of 28.93 months (95% CI [22.52–33.54]), mOS for the whole cohort was 14.75 months (95% CI, [10.80–18.71]). Overall, 43 and 104 patients were treated with nivolumab and pembrolizumab, respectively. We identified four adverse prognostic factors that were independent predictors of bad prognosis: number of metastatic sites >2 (p<0.001), baseline PS-ECOG =1 (p<0.001), presence of baseline lymphopenia (over lower limit of normal) (p=0.002) or very high baseline LDH (>2x upper limit of normal) (p<0.001).Patients were separated into three risk categories according to the number of risk factors present: favourable prognosis (no risk factors; n=34), intermediate prognosis (one risk factor; n=65) and poor prognosis (two or more risk factors; n=48). mOS was 43.41 (95% CI [32.13–54.69], 14.39 (95% CI [6.78–22.01]) and 6.53 months (95% CI [3.61–9.44]), for favourable, intermediate, and poor prognosis group, respectively (p<0.001; figure 1). AUC of ROC curve for OS was 0.737 (95% CI [0.654–0.819], p<0.001).Abstract 7 Figure 1Time to death - Kaplan-Meier survival plotConclusionsUsing easily accessible parameters from our daily practice, we propose the MELImmune prognostic score for advanced MM patients treated with anti-PD1 in monotherapy that could be incorporated to the daily clinical practice and clinical trials. We further aim to validate this score in an independent larger sample.Ethics ApprovalThe study was approved by both institutions’ Ethics Committee.

scholarly journals Rates and Correlates of Short Term Virologic Response among Treatment-Naïve HIV-Infected Children Initiating Antiretroviral Therapy in Ethiopia: A Multi-Center Prospective Cohort Study

Pathogens ◽  
2019 ◽  
Vol 8 (4) ◽  
pp. 161
Author(s):  
Birkneh Tilahun Tadesse ◽  
Adugna Chala ◽  
Jackson Mukonzo ◽  
Tolosssa Eticha Chaka ◽  
Sintayehu Tadesse ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Viral Load ◽  
Plasma Viral Load ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Virological Suppression ◽  
Virologic Suppression ◽  
Hiv Drug Resistance ◽  
Treatment Naïve ◽  
The Impact

There is limited data on virologic outcome and its correlates among HIV-infected children in resource-limited settings. We investigated rate and correlates of virologic outcome among treatment naïve HIV-infected Ethiopian children initiating cART, and were followed prospectively at baseline, 8, 12, 24 and 48 weeks using plasma viral load, clinical examination, laboratory tests and pretreatment HIV drug resistance (PDR) screening. Virologic outcome was assessed using two endpoints–virological suppression defined as having “undetectable” plasma viral load < 150 RNA copies/mL, and rebound defined as viral load ≥150 copies/mL after achieving suppression. Cox Proportional Hazards Regression was employed to assess correlates of outcome. At the end of follow up, virologic outcome was measured for 110 participants. Overall, 94(85.5%) achieved virological suppression, of which 36(38.3%) experienced virologic rebound. At 48 weeks, 9(8.2%) children developed WHO-defined virological treatment failure. Taking tenofovir-containing regimen (Hazard Ratio (HR) 3.1-[95% confidence interval (95%CI) 1.0–9.6], p = 0.049) and absence of pretreatment HIV drug resistance (HR 11.7-[95%CI 1.3–104.2], p = 0.028) were independently associated with earlier virologic suppression. In conclusion, PDR and cART regimen type correlate with rate of virologic suppression which was prominent during the first year of cART initiation. However, the impact of viral rebound in 38.3% of the children needs evaluation.

scholarly journals 1036. Persistence of Guideline-Recommended Antiretroviral Therapy Regimens among Persons Living with HIV Newly Initiating Treatment in the US

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S548-S549
Author(s):  
Joshua P Cohen ◽  
Xingzhi Wang ◽  
Rolin L Wade ◽  
Helena Diaz Cuervo ◽  
Dionne M Dionne
Keyword(s):  
Antiretroviral Therapy ◽  
Proportional Hazards ◽  
Cox Proportional Hazards ◽  
Treatment Discontinuation ◽  
Forest Plot ◽  
Current Guideline ◽  
First Line ◽  
Persons Living With Hiv ◽  
Living With Hiv

Abstract Background Discontinuation of first-line antiretroviral therapy (ART) may lead to poor outcomes for persons living with HIV (PLWH). While single-tablet regimens (STRs) have been associated with greater persistence compared to multi-tablet regimens (MTRs), few real-world studies have assessed persistence with current guideline-recommended ART regimens. The study aims to assess persistence among treatment-naïve PLWH initiating guideline-recommended ART regimens Methods Longitudinal pharmacy claims were extracted from IQVIA’s US LRx database for PLWH initiating ART between Jan 1, 2016 - Jul 31, 2019 (index period), with the observational period up to Jan 31, 2020. Index date was defined as the date of the first ART claim for STRs, or the date of the last filled drug of 1st set of claims for MTRs. Persistence was measured as the number of days until treatment discontinuation (≥ 90-day gap in therapy) and presented via Kaplan-Meier curves. Risk of discontinuation was assessed via Cox proportional hazards models, with BIC/FTC/TAF used as the reference ART regimen. Results Overall, 90,949 PLWH initiated STRs and 20,737 initiated MTRs. Average (SD) age was 43 (14) years, 75% were male, and 75% had commercial insurance. At 6 months of follow-up, 71% of PLWH initiating STRs and 56% initiating MTRs remained on their ART regimen. The proportion remaining on their index regimen at 6 months of follow-up was 79% for BIC/FTC/TAF, 73% for EVG/COBI/FTC/TAF, 71% for DTG/ABC/3TC, 69% for DTG + FTC/TAF, 67% for EFV/FTC/TDF, 62% for EVG/COBI/FTC/TDF, and 38% for DTG + FTC/TDF. Risk of discontinuation was higher for MTRs compared to STRs (hazard ratio [HR]: 1.63, 95% CI: 1.61 - 1.66). Compared to the referent BIC/FTC/TAF, risk of discontinuation was higher for EVG/COBI/FTC/TAF (HR: 1.54, 95% CI: 1.48 - 1.60), DTG/ABC/3TC (HR: 1.58, 95% CI: 1.52, 1.65), DTG + FTC/TAF (HR: 1.83, 95% CI: 1.74 - 1.93), EFV/FTC/TDF (HR: 2.31, 95% CI: 2.21 - 2.41), EVG/COBI/FTC/TDF (HR: 2.58, 95% CI: 2.47 - 2.70), and DTG + FTC/TDF (HR: 6.20, 95% CI: 5.83 - 6.59). Table 1. Persistence with ART by regimen for STR and MTR Figure 1. Forest Plot of Hazard Ratios for Treatment Discontinuation Conclusion Among US adult PLWH, STRs were associated with longer persistence on first-line therapy compared to MTRs. Among STRs, persistence was highest for BIC/FTC/TAF. Disclosures All Authors: No reported disclosures

Impact of KRAS mutational status on outcomes in patients with pancreatic cancer (PDAC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4142-4142
Author(s):  
Lucy Xiaolu Ma ◽  
Gun Ho Jang ◽  
Amy Zhang ◽  
Robert Edward Denroche ◽  
Anna Dodd ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
Advanced Disease ◽  
Cox Proportional Hazards ◽  
Prognostic Impact ◽  
First Line ◽  
Kras Mutations ◽  
Kaplan Meier ◽  
Mutational Status ◽  
Translational Research Program ◽  
The Impact

4142 Background: KRAS mutations (m) (KRASm) are present in over 90% of pancreatic adenocarcinomas (PDAC) with a predominance of G12 substitutions. KRAS wildtype (WT) PDAC relies on alternate oncogenic drivers, and the prognostic impact of these remains unknown. We evaluated alterations in WT PDAC and explored the impact of specific KRASm and WT status on survival. Methods: WGS and RNAseq were performed on 570 patients (pts) ascertained through our translational research program from 2012-2021, of which 443 were included for overall survival (OS) analyses. This included 176 pts with resected and 267 pts with advanced PDAC enrolled on the COMPASS trial (NCT02750657). The latter cohort underwent biopsies prior to treatment with first line gemcitabine-nab-paclitaxel or mFOLFIRINOX as per physician choice. The Kaplan-Meier and Cox proportional hazards methods were used to estimate OS. Results: KRAS WT PDAC (n = 52) represented 9% of pts, and these cases trended to be younger than pts with KRASm (median age 61 vs 65 years p = 0.1). In resected cases, the most common alterations in WT PDAC (n = 23) included GNASm (n = 6) and BRAFm/fusions (n = 5). In advanced WT PDAC (n = 27), alterations in BRAF (n = 11) and ERBB2/3/4 (n = 6) were most prevalent. Oncogenic fusions (NTRK, NRG1, BRAF/RAF, ROS1, others) were identified in 9 pts. The BRAF in-frame deletion p.486_491del represented the most common single variant in WT PDAC, with organoid profiling revealing sensitivity to both 3rd generation BRAF inhibitors and MEK inhibition. In resected PDAC, multivariable analyses documented higher stage (p = 0.043), lack of adjuvant chemotherapy (p < 0.001), and the KRAS G12D variant (p = 0.004) as poor prognostic variables. In advanced disease, neither WT PDAC nor KRAS specific alleles had an impact on prognosis (median OS WT = 8.5 mths, G12D = 8.2, G12V = 10.0, G12R = 12.0, others = 9.2, p = 0.73); the basal-like RNA subtype conferred inferior OS (p < 0.001). A targeted therapeutic approach following first line chemotherapy was undertaken in 10% of pts with advanced PDAC: MMRd (n = 1), homologous recombination deficiency (HRD) (n = 19), KRASG12C (n = 1), CDK4/6 amplification (n = 3), ERBB family alterations (n = 2), BRAF variants (n = 2). OS in this group was superior (14.7 vs 8.8 mths, p = 0.04), mainly driven by HRD-PDAC where KRASm were present in 89%. Conclusions: In our dataset, KRAS G12D is associated with inferior OS in resected PDAC, however KRAS mutational status was not prognostic in advanced disease. This suggests that improved OS in the WT PDAC population can only be achieved if there is accelerated access to targeted drugs for pts.

Fibroblast growth factor receptor alteration (FGFRa) status and progression outcomes of patients with advanced or metastatic urothelial cancer (mUC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4530-4530
Author(s):  
Sarah Fleming ◽  
Dina Gifkins ◽  
Waleed Shalaby ◽  
Jianjun Gao ◽  
Philip Rosenberg ◽  
...  
Keyword(s):  
Proportional Hazards ◽  
The United States ◽  
Cox Proportional Hazards ◽  
Small Sample ◽  
Prognostic Impact ◽  
Patient Records ◽  
Front Line ◽  
Convenience Sample ◽  
Adjusted Risk ◽  
Metastatic Urothelial Cancer

4530 Background: FGFRa appear in approximately 15% of cases of mUC. Data on whether FGFRa in mUC have a prognostic impact or predictive benefit for particular treatments have been limited by small sample sizes. The objective of this study was to evaluate the association between tumor FGFRa and clinical outcomes of patients with advanced UC or mUC regardless of therapy type and status. Methods: A convenience sample of oncologists and urologists across the United States provided patient level data on 400 patients with stage IIIb or IV UC via a standardized questionnaire over a 1-month period (August 17, 2020 – September 20, 2020). Study design enriched for FGFRa by requiring physicians to provide ≥1 FGFRa patient record. The questionnaire included physician characteristics, patient demographic information, FGFR status, therapy given, response, and clinical and radiographic measures of progression. Patient records were eligible for inclusion if they were identified and treated during July 1, 2017, to June 30, 2019. Cox proportional hazards models were used to estimate adjusted risk of disease progression by FGFR status. Results: A total of 104 physicians (58.7% medical oncologists, 31.7% hematologic oncologists, and 9.6% urologic oncologists) contributed 414 patient records Overall, 73.9% of the patients were male and the average age was 64.5 years (SD ±10.6). Median follow-up was 15 months. Of the 414 patients, 218 (52.7%) had FGFRa and 196 (47.3%) had FGFR wild-type ( FGFRwt) mUC . Of the 218 patients with FGFRa, 47.2% were treated with front-line chemo, 27.5% with a programmed death-ligand 1 inhibitor (PD-L1), 11.5% with chemo + PD-L1, and 13.8% with other treatments. Of the 196 FGFRwt patients, 63.2% were treated with front-line chemo, 21.9% with PD-L1, 12.2% with chemo + PD-L1, and 2.6% with other treatments. There was no difference in response or progression status for those receiving front-line chemo (HR, 1.15; 95% CI, 0.86-1.55). Among 97 patients (55 FGFRa and 42 FGFRwt) who received PD-L1 alone as front-line therapy, those who had FGFRa had an adjusted risk of progression 2 times higher than their FGFRwt counterparts (HR, 2.12; 95% CI, 1.13-4.00). Conclusions: Patients with FGFRa mUC progressed earlier than FGFRwt patients treated with front-line PDL-1 inhibitors; however, there was no difference in progression in patients treated with chemo based upon FGFR status. This real-world study using a survey design efficiently generated a relatively large FGFRa dataset, mitigating a core limitation of other studies assessing the patient population with FGFRa. Further work is warranted to validate these results and determine the optimal strategy for treating the patient with FGFRa mUC. Gene expression profiling of FGFRa mUC samples from clinical trials will help determine the potential impact of subtype or other features that may associate with benefit from therapy.

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