scholarly journals Prolonged lymphocytosis during ibrutinib therapy is associated with distinct molecular characteristics and does not indicate a suboptimal response to therapy

Blood ◽  
2014 ◽  
Vol 123 (12) ◽  
pp. 1810-1817 ◽  
Author(s):  
Jennifer A. Woyach ◽  
Kelly Smucker ◽  
Lisa L. Smith ◽  
Arletta Lozanski ◽  
Yiming Zhong ◽  
...  

Key Points Persistent CLL cells during ibrutinib therapy show evidence of biochemical activation, but inhibited BCR and no proliferation. Long lymphocytosis during ibrutinib therapy is not associated with adverse progression-free survival.

2019 ◽  
Vol 3 (19) ◽  
pp. 2800-2803 ◽  
Author(s):  
Joshua N. Gustine ◽  
Lian Xu ◽  
Nicholas Tsakmaklis ◽  
Maria G. Demos ◽  
Amanda Kofides ◽  
...  

Key Points CXCR4 S338X clonality ≥25% is associated with lower very good partial response and shorter progression-free survival to ibrutinib. CXCR4 S338X clonality assessment represents a novel biomarker to predict outcomes to ibrutinib in Waldenström macroglobulinemia patients.


2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 379-379
Author(s):  
L. Riesenbeck ◽  
S. Bierer ◽  
I. Hoffmeister ◽  
T. Koepke ◽  
L. Hertle ◽  
...  

379 Background: To investigate prognostic markers in patients with metastatic renal cell carcinoma (mRCC) undergoing treatment with the tyrosine kinase inhibitors (TKIs) sorafenib (So) or sunitinib (Su). Methods: Eighty-three patients with mRCC, who were treated at our institution between 2006 and 2009, were evaluated prospectively. Clinical and laboratory parameters were investigated, as well as, treatment-related adverse events. Subclinical hypothyroidism was characterized by serum TSH above the upper limit of normal and both total triiodtyronine (T3) and thyroxine (T4) within normal limits. Clinical hypothyroidism was defined as low serum T3 and T4 together with elevated TSH. Results: Thirty-one (37.3%) patients received So, and 52 (62.7%) were treated with Su. In univariate analyses, a poor ECOG status was associated with an unfavorable progression-free survival (PFS) (p<0.0001); similarly high risk MSKCC criteria correlated with a worse PFS (p=0.003). Furthermore, response to therapy was a surrogate parameter (p<0.0001). Twenty-one of 66 (31.8%) patients developed hypothyroidism during treatment, which was associated with a positive prognosis (p=0.032). In multivariate analyses, only the ECOG status (ECOG 0/1 vs. ECOG 2, p=0.018) and hypothyroidism (p=0.01) were independent prognostic parameters. Conclusions: The development of hypothyroidism during treatment might be useful as a clinical predictor of PFS for mRCC patients undergoing treatment with targeted agents. No significant financial relationships to disclose.


2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 735-735
Author(s):  
Emanuel Petricoin ◽  
Michael J. Pishvaian ◽  
Patricia DeArbeloa ◽  
Daniel Barg ◽  
Dzung Thach ◽  
...  

735 Background: Molecular profiling (MP) for PDAC has gained increased acceptance and we previously demonstrated that targeting actionable mutations can improve patient (pt) outcomes. However, the correlations of diverse patterns of molecular alterations with outcomes following SOC Tx are largely unknown. Methods: We analyzed longitudinal outcomes of 1355 PDAC pts who underwent MP and received SOC Tx. “Persona” types were established based on the molecular characteristics of each pt using unsupervised clustering, as well as a supervised review defined by our molecular tumor board, following classifications reported in previous studies. Progression-free survival (PFS) for each type was assessed based on the choice of first-line Tx (i.e. FOLFIRINOX [FFX] vs. gemcitabine + nab-paclitaxel [GA]). Statistical comparisons were made against all other types within a specific Tx group. Results: The prognostic/predictive value of the persona types for 1st-line Tx revealed distinct differences in outcomes (Table). As expected, the DDR deficiency type was associated with a significantly improved PFS for pts treated with FFX but not for GA. In addition, pts in the cell cycle type had a worse PFS compared to other persona types for both FFX and GA. Using this platform, we will further subdivide the persona types into molecular subtypes and associate these with pt outcomes. Conclusions: Our analyses demonstrate that specific molecular persona types exist in PDAC pts and can be linked to Tx outcomes. Ultimately, knowing the persona type/subtype early in a pt’s Tx course may help personalize Tx to improve outcomes. [Table: see text]


Blood ◽  
2014 ◽  
Vol 123 (4) ◽  
pp. 494-500 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Giuseppe Saglio ◽  
Juan Luis Steegmann ◽  
Neil P. Shah ◽  
...  

Key Points In a 3-year follow-up of the DASatinib versus Imatinib Study In treatment-Naive CML patients trial, first-line dasatinib resulted in faster and deeper responses compared with imatinib. Deeper responses at 3, 6, and 12 months were associated with better 3-year progression-free survival and overall survival.


2021 ◽  
Author(s):  
Han Liang ◽  
Jianlian Deng ◽  
Tian Luo ◽  
Huijuan Luo ◽  
Xuan Wu ◽  
...  

Abstract Considerable differences in molecular characteristics have been defined between non-smoker and smokers in patients with lung adenocarcinoma (LUAD), yet studies of open chromatin patterns associated with LUAD progression caused by smoking are still lacking. Here, we constructed a novel network based on correlations between each ATAC-seq peak from TCGA data using our previously developed algorithm. Subsequently, principal component analysis was performed on LUAD samples with retained peaks filtered by the correlation network and pathway analysis was conducted for potential pathways identification. We identified a set of peaks that discriminated smokers in LUAD patients according to levels of exposure to tobacco quantified in pack-years, and also significantly associated with progression-free survival and overall survival of these patients. We then investigated the gene set related to those peaks and found that the comprising genes are strongly associated with LUAD development, such as B3GNT3, ACTN4 and CLDN3. They are consistent with the important roles for the associated pathways in LUAD oncogenesis induced by smoking, including glycosphingolipid biosynthesis and tight junction pathways. In summary, our study may provide valuable insights on exploration of ATAC-seq peaks and on smoking-related LUAD carcinogenesis from a perspective of open chromatin changes.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14088-14088
Author(s):  
J. Feisthammel ◽  
K. Schoppmeyer ◽  
M. Wiedmann ◽  
J. Mossner ◽  
M. Schulze ◽  
...  

14088 Background: The majority of patients with biliary tract cancer present with advanced, unresectable tumors. Irinotecan and 5-Fluorouracil/folinic acid (FOLFIRI) have synergistic activity in gastrointestinal cancers. The aim of this study was to determine the tolerability and activity of systemic chemotherapy with FOLFIRI in patients with intrahepatic cholangiocarcinoma (CCC) or gallbladder cancer (GBC). Methods: This was a prospective, multicenter, non-randomised, open-label, phase II trial. Eligibility criteria: Inoperable adenocarcinoma of the biliary tract, measurable disease, age 18–80 years, ECOG PS 0–2. Patients received irinotecan 80 mg/m2 as a 30 min infusion, followed by folinic acid 500 mg/m2 over 2 h and 5-FU 2000 mg/m2 over 24h weekly × 6 followed by a 2 week rest. Treatment was continued until progression or limiting toxicity. Response to therapy was assessed after every other cycle according to RECIST criteria. Primary end point was response rate, secondary end points were overall survival, progression free survival and toxicity. Results: 30 pts (CCC 17, GBC 13) were enrolled. A total of 387 doses (Median 12.9; 1 to 36) were administered with an overall relative dose intensity of 98%. 30 patients are evaluable for safety. WHO grade 3/4 drug related adverse events occured in 7 patients (23%): Leukopenias in 2, anemia in 1, and diarrhea in 4 patients. 14 patients completed 2 cycles and were evaluable for response. Response rates: CR 0/30, PR 3/30 (10%) and SD 3/30 (10%). 8 patients presented with disease progression at restaging. Median overall survival: CCC 166 days, GBC 327 days. Progression-free-survival: CCC 84 days, GBC 159 days. Conclusions: FOLFIRI is a well tolerated regimen in patients with biliary cancer that can be safely administered on an outpatient basis. FOLFIRI has no substantial activity in CCC and moderate activity in GBC. Further studies are required to define a standard palliative chemotherapy for treatment of biliary cancer. No significant financial relationships to disclose.


2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 425-425 ◽  
Author(s):  
Li-Tzong Chen ◽  
Jens T Siveke ◽  
Andrea Wang-Gillam ◽  
Richard Hubner ◽  
Shubham Pant ◽  
...  

425 Background: CA19-9 has been shown to correlate with response to therapy and OS in patients with mPAC. NAPOLI-1, a randomized phase 3 study evaluated nal-IRI, a nanoliposomal formulation of irinotecan, with or without 5-FU/LV vs 5-FU/LV in patients with mPAC previously treated with gemcitabine-based therapy. Nal-IRI+5-FU/LV significantly improved OS (primary endpoint) vs 5-FU/LV (6.1 mo vs 4.2 mo; unstratified hazard ratio [HR] = 0.67; P = 0.012). CA19-9 response (≥50% decline from baseline) was superior with nal-IRI+5FU/LV compared with 5-FU/LV (29% vs 9%; P=0.0006). Nal-IRI alone did not show a statistical improvement in survival. Methods: Patients with a recorded baseline CA19-9 measurement were divided into quartiles to evaluate the treatment effect pattern of CA19-9 from nal-IRI+5-FU/LV and 5-FU/LV arms. Quartile ranges were based on 404 available CA19-9 values from randomized patients (N=417). Unstratified Cox proportional hazards regression was used to estimate HRs and corresponding 95% CIs. Effect of baseline CA19-9 on time to response, progression-free survival, and response will be presented. Results: Of patients randomized to receive nal-IRI+5-FU/LV (n = 117) or 5-FU/LV enrolled contemporaneously (n = 119), 218 received study drug and had a baseline CA19-9 measurement. Results show a greater treatment effect on OS with higher CA19-9 level relative to 5-FU/LV. Conclusions: In patients with mPAC previously treated with gemcitabine-based therapy, nal-IRI+5-FU/LV significantly improved OS supported by progression free survival and objective response rate. The CA19-9 serum level can provide important information with regards to overall survival. Clinical trial information: NCT01494506. [Table: see text]


2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19513-e19513
Author(s):  
Alexandre Tungesvik ◽  
Praneeth Reddy Sudalagunta ◽  
Jessica Huang ◽  
Elizabeth Dimaggio ◽  
Gabe De Avila ◽  
...  

e19513 Background: Although there is much to be optimistic about in the multiple myeloma community as the approval of new therapies and regimen-combinations for relapsed refractory disease continues to grow, determining the best option for a patient can be complicated. Both carfilzomib- (C) and daratumumab- (D) based regimens have demonstrated superior efficacy in this setting, but there is a paucity of data supporting which should be selected first, and if regimen sequence influences outcomes. The aim of this study is to describe sequencing patterns in the era of these newer agents and to determine if there is a difference in outcomes for patients with RRMM who received one of the following treatment sequences: C-regimen with a D-regimen given immediately prior (DC); C-regimen without any prior D (C only); D-regimen with a C-regimen given immediately prior (CD); or D-regimen without any prior C (D only). Methods: This is a retrospective analysis of patients with RRMM consecutively treated at Moffitt Cancer Center between 1/1/2015 and 6/25/18. Response to therapy was assessed using the International Myeloma Working Group (IMWG) criteria. Progression-free survival (PFS) was measured in days from the start of therapy to progression. Time to response (TTR) was measured in days from the start of therapy to first response. Results: 132 patients with RRMM who received 1-3 prior lines of therapy with at least one line of therapy containing either C or D were identified. Overall, the majority of patients were treated with C only (n = 101), 10 received DC, 31 received D only, and 35 received CD. In patients that received C only, partial response (PR) was achieved in 38%, very good partial response (VGPR) was 20%, and stringent complete response (sCR) was 2%. In patients that received DC, PR was 20% and VGPR was 10%; no patient achieved a sCR. Of the patients that received D only, PR was 29%, VGPR was 10%, and sCR was 3%. In patients that received CD, PR was 31% and VGPR was 26%; no patient achieved sCR. Median PFS in patients who received C only, DC, D only, and CD was 117 days, 126 days, 104 days, and 190 days, respectively. TTR in patients who received C only, DC, D only, and CD was 82 days, 39 days, 98 days, and 88 days, respectively. Conclusions: The data suggests that RRMM patients who receive either CD or DC appear to have a PFS advantage over those patients who did not. Notably, an early TTR was found in patients that received DC. Further analysis is ongoing.


2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 240-240
Author(s):  
Suleyman Yasin Goksu ◽  
Rodrigo Alterio ◽  
Elizabeth McGehee ◽  
Muhammad Shaalan Beg ◽  
Syed Mohammad Ali Kazmi ◽  
...  

240 Background: While gastroesophageal cancers with different primary tumor locations can have distinct molecular characteristics and clinical outcomes, the efficacy of palliative chemotherapy in tumors with different locations is unknown. Using primary tumor location as a surrogate for molecular subtype, we investigated the differential efficacy of first-line doublet chemotherapy in metastatic gastroesophageal adenocarcinomas. Methods: We performed a retrospective review of patients with metastatic gastroesophageal adenocarcinoma who received first-line palliative chemotherapy at the University of Texas Southwestern Medical Center and the Dallas County Safety Net Parkland Hospital diagnosed between 2011-2019. Cases were identified using cancer registries. We categorized the tumor location as proximal or distal based on endoscopy and imaging studies. Disease response was assessed on the first staging scan and classified as ‘disease shrinkage, stability, or progression.’ Overall and progression-free survival were evaluated using Kaplan-Meier and Cox proportional hazards methods. Results: 99 patients were identified; 58.6% had proximal tumors. Patients with proximal tumors were more likely to be white (38% vs. 13%, p = 0.008) and older with age ≥ 50 years (71% vs. 51%, p = 0.04) and less likely to have peritoneal metastasis (48% vs. 78%, p = 0.003) than distal tumors. Patients with proximal tumors had a higher disease shrinkage than patients with distal tumors (53% vs. 21%, p = 0.004). Patients with proximal tumors also had better overall survival (median 12.5 vs. 8.7 months) and progression-free survival in response to 5-FU based chemotherapy (median 5 vs. 4 months) compared to patients with distal tumors, but this was not statistically significant. On multivariable analysis, tumor location was not independently predictive of progression-free survival after adjusting for age, gender, presence of signet rings, diffuse, intestinal histology, and peritoneal metastasis (HR 1.22 95% CI 0.74-2.00), but pretreatment albumin was (HR 0.63 95% CI 0.43-0.94). Conclusions: Proximal gastroesophageal cancers have a better clinical response to first-line 5FU containing chemotherapy than distal cancers. Currently, there is no platform to determine molecular subgroups that is commercially available. Until testing for this becomes available, differences in response rates to palliative chemotherapy in gastroesophageal cancers with different anatomical locations should be recognized and studied further.


Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4238-4238 ◽  
Author(s):  
Ivan M. Borrello ◽  
Kimberly Noonan ◽  
Carol Ann Huff ◽  
Anna Ferguson ◽  
Amy Sidorski ◽  
...  

Abstract Background: The depth of response to therapy in myeloma (MM) correlates with improved progression free survival. We have previously shown that lenalidomide (Len) can augment vaccine efficacy to the pneumococcal conjugate vaccine (PCV), PrevnarÒ. We extend those observations to examine whether vaccinating patients on Len in a near complete remission (nCR) (negative M-spike, IFE positive) could further deepen the clinical response and generate measurable myeloma specific immunity. Design: Patients on a Len-containing regimen (VRD, Rd, BiRD or R) that achieved and maintained a nCR for 4-6 months were eligible for the study. Patients continued only on single agent Len and received 4 GVAX vaccinations consisting of two allogeneic MM lines: H929, U266 admixed with K562 transduced to express GM-CSF as well as PCV. Patients received 3 monthly vaccines and a boost at 6 months. Immune monitoring was performed on BM samples obtained at baseline, 3 months and 1 year Results: To date 32 patients have been screened. 17 patients initially in a nCR were ineligible for vaccination: 3 (18%) had disease progression, 7 (42%) entered into an IFE negative CR, and 7 (42%) maintained a nCRduring the observation period but opted not to enroll. 15 patients have been enrolled and completed their vaccinations. Patient characteristics are shown in the Table. Of note, none possessed high-risk features by ISS or FISH. Median follow-up for the study is 34.0 months. Median progression free survival (PFS) of the cohort of vaccinated patients has not been reached whereas the PFS in the observation arm that remained on the multidrug Len-containing therapy was 17.9 months (p<0.001). Vaccination in the setting of a rising M-spike was less likely to induce a durable remission with a median PFS of 14.3 months (p<0.003). Laboratory analysis showed that the patients achieving a CR had greater expression of PD-1 on CD4 and CD8 cells at baseline in the BM. Furthermore, durable responses were associated with the development and persistence of MM-specific immunity. Conclusions: Vaccination in combination with Len in patients with minimal residual disease generates potent MM-specific immunity and appears to significantly extend the PFS. Vaccination in a nCR with a poly-antigenic approach such as GVAX in combination with Len-induced immunomodulation shows promising early clinical activity that warrants further investigation as an approach to inducing and maintaining durable clinical remissions. Table 1. Vaccination(n=15) Observation(n=16) Age 69 (55-81) 66 (40-83) FISH (high risk) 0% 0% ISS Stage III 2 (13%) 3 (19%) IFE negative 0 (0%) 7 (42%) Prior Therapies 1.8 (1-4) 1.8 (1-3) Disclosures Borrello: Celgene: Research Funding. Noonan:Celgene: Speakers Bureau.


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