scholarly journals Access to Initial Treatment Was Not the Driving Force of the Survival Disparity By Insurance Status in Follicular Lymphoma — an Analysis of the National Cancer Database (NCDB)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4155-4155
Author(s):  
Ning Dong ◽  
Tatyana A. Feldman ◽  
Lori A. Leslie ◽  
Malik Faheem ◽  
Shanthi Srinivas ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Follicular Lymphoma ◽  
Waiting Time ◽  
Initial Treatment ◽  
Research Funding ◽  
Treatment Modalities ◽  
Categorical Variables ◽  
Low Grade ◽  
Insurance Status ◽  
National Cancer Database

Abstract Background: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma. The initial management varies from watchful waiting to a combination of chemoimmunotherapy (CT) and radiation therapy (RT). Goldstein et al. recently reported (Blood, pre-published online, July 24 2018) that FL patients with no insurance or Medicaid had worse OS. We examined whether the survival discrepancy was caused by access to initial treatment using the National Cancer Database (NCDB). Methods: FL cases diagnosed from year 2004-2015 in NCDB were included. Demographic characteristics were compared using Chi-square test for categorical variables and ANOVA for continuous variables. Use of CT and RT was analyzed in multivariate logistic regression including the following variables: age, gender, race, Hispanic ethnicity, stage, grade, primary site extranodal, facility type, urban/rural location, distance to facility, year period of diagnosis (2004-2010 vs 2011-2015), education, income and insurance status. Overall survival (OS) was analyzed using Cox proportional hazard model including the same covariates with addition of CT and RT. After Jan 2013, rituximab was captured as immunotherapy. To assess the use of rituximab, we compared immunotherapy in years 2014 and 2015 to avoid possible data entry error in 2013. The treatment modalities and OS were similar for uninsured and Medicaid patients, and for Private and Medicare patients after adjusting for covariates. We combined "uninsured" and "Medicaid" into "Less" insurance and "Private" and "Medicare" into "Increased" insurance. Results: A total of 94057 FL cases were included in the analysis with the following insurance status: Uninsured 2723 (2.9%), Medicaid 3804 (4.0%), Private insurance 43354 (46.1%), and Medicare 44176 (47.0%). Patients with no insurance or Medicaid were more likely to present at an advanced stage (Table 1). In the multivariate model, less insurance was associated with less initial use of radiation therapy (OR=0.87, p=0.003) and more use of CT (OR=1.28 p<0.0001). For patients diagnosed in years 2014 and 2015, initial use of immunotherapy (most likely rituximab) and the waiting time before starting immunotherapy did not differ by insurance status. Both less insurance and not-receiving radiation therapy were associated with worse OS after adjusting for covariates (HR=1.96 and 1.30, respectively, p<0.0001 for both, Table 3, Figure 1). Chemoimmunotherapy was not associated with OS. Lower education and income were both associated with worse OS after adjusting for insurance (Table 3). RT is recommended as frontline treatment for suitable patients with early stage (stage I/II) low grade (grade 1/2) FL. We analyzed the use of RT and survival outcome in this patient group. The results were similar to results for the entire patient set. Patients with less insurance received RT less often (21.7% vs 24.7%, p=0.02), and when they did receive radiation therapy, the waiting time before starting treatment was longer (89 days vs 79 days, respectively, p=0.02). Both less insurance and not-receiving RT were associated with worse OS (p<0.0001 for both, Table 4). Conclusion: Follicular lymphoma patients with no insurance or Medicaid had worse OS. Less insurance was associated with decreased access to initial radiation therapy but not chemoimmunotherapy. However the survival discrepancy cannot be solely explained by access to radiation therapy given the magnitude of difference. Moreover, insurance remains a significant predictor of survival after adjusting for initial treatment. The key drivers of the survival discrepancy by insurance status in FL patients need to be further defined. Disclosures Feldman: Portola: Research Funding; KITE: Speakers Bureau; Celgene: Speakers Bureau; Pharmacyclics: Speakers Bureau; Janssen: Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau; Johnson and Johnson: Speakers Bureau. Chang:Incyte: Research Funding.

Initial Treatment Vs Watch and Wait in Advanced-Stage Follicular Lymphoma in the Rituximab Era - an Analysis of the National Cancer Database (NCDB)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-44
Author(s):  
Ning Dong ◽  
Hayder Saeed ◽  
Leidy Isenalumhe ◽  
Franco Castillo Tokumori ◽  
Bijal Shah ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Initial Treatment ◽  
Research Funding ◽  
Stage Iii ◽  
National Cancer Database ◽  
Advanced Stage ◽  
Watch And Wait ◽  
Advisory Committees ◽  
Grade 3

Background: Randomized trials in the pre-rituximab era showed that watch and wait (WW) when compared to initial treatment (IT) for asymptomatic advanced-stage follicular lymphoma (FL) did not impact overall survival (OS). In the rituximab era, a randomized trial showed patients with advanced-stage, asymptomatic, low-burden FL were less likely to need chemotherapy at 3 years when treated with rituximab only at diagnosis compared to WW, however with no difference in OS (Ardeshna et al., 2014). In another analysis, there was no impact of WW compared to IT on the time to next anti-lymphoma therapy (Solal-Celigny et al., 2012). However, the existing studies were limited by sample sizes and not powered by survival. In addition, few patients with grade 3a FL were included, thus it is not clear if pathological grades (other than grade 3b) should be taken into consideration when choosing WW vs IT. Here we studied the outcomes of WW vs IT for patients with advanced-stage (stage III/IV) FL using the National Cancer Database (NCDB) and compared the outcomes by FL pathological grades. Methods: Patients diagnosed between 2011-2016 were included. We only included patients diagnosed after 2011 (when rituximab was FDA approved for FL as maintenance) so our results reflect the current management of FL. To ensure accurate reporting of IT, only patients who were diagnosed and initially managed at the reporting facility were included. Demographic characteristics were compared using Chi-square test for categorical variables and ANOVA for continuous variables. Univariate comparison of OS was conducted using Logrank test. Multivariate survival analysis was conducted using Cox proportional hazard model with the following covariates: age, gender, race, Hispanic ethnicity, stage, grade, existence of previous malignancies, comorbidity score, facility type, facility lymphoma patient volume, urban/rural location, education, income and insurance status. Results: A total of 14417 patients with stage III/IV FL were included. Among them, 10755 received IT (74.6%) and 3662 (25.4%) were managed by WW at diagnosis. For those who received IT, the median time to treatment was 35 days (IQR 22-56 days). Preliminary analyses showed that patients with grade 1 FL and grade 2 FL were managed similarly and had similar OS, therefore we combined grade 1 and grade 2 into grade 1-2 FL as opposed to grade 3 FL. A total of 13050 patients had grade 1-2 FL and 4286 patients had grade 3 FL. Patients with grade 1-2 FL were more likely to be managed by WW than those with grade 3 FL (29.8% vs 12.5%, respectively; p&lt;0.01). Patients on WW were older, more likely to be female, more likely to have previous malignancies, had higher education and income, and more likely to have private insurance or Medicare than Medicaid or no insurance (Table 1). Patients with grade 1-2 FL had similar OS when managed by WW compared to IT (5-year OS rate: 76.3% vs 76.2%, respectively; p=0.32; Figure 1). In contrast, patients with grade 3 FL had worse OS when managed by WW compared to IT (5-year OS rate: 65.3% vs 73.5%; p&lt;0.001; Figure 2). In multivariate analysis, the interaction term between grade and management was significant (p=0.005), confirming that initial management affected OS in different ways for grade 1-2 FL and grade 3 FL after adjusting for the covariates. Consistent with the results of the univariate analysis, after adjusting for covariates, grade 1-2 FL had similar survival when managed by WW compared to IT (HR=0.93, 95% CI: 0.82-1.05; p=0.25) but grade 3 FL had worse survival when managed by WW (HR=1.43, 95% CI: 1.14-1.82; p=0.002). Other factors associated with OS are listed in Table 2. Conclusion: Our study confirms the findings of lack of OS benefits in patients with advanced stage, grade 1-2 FL when treated with WW versus IT. In contrast, patients with advanced stage, grade 3 FL had worse OS with WW approach. While the NCDB does not separate grade 3 FL into 3a and 3b, it is assumed that FL 3b is universally managed as DLBCL and receive IT given its more aggressive course. Under this assumption, all grade 3 FL patients on WW were likely grade 3a. Thus, our results suggest that grade 3a FL patients on WW had worse OS compared to grade 3 FL patients who received IT (see Figure 2 and its footnote for illustration). Although a definitive conclusion cannot be made regarding grade 3a FL, further studies to compare the outcome of WW vs IT with special focus on stage 3a FL are warranted. Disclosures Shah: NCCN: Vice-Chair, Acute Lymphoblastic Leukemia Working Group: Membership on an entity's Board of Directors or advisory committees; Kite/Gilead, Precision Biosciences, Novartis, AstraZeneca: Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Kite/Gilead, Celgene/Juno/BMS, Novartis, Pfizer, Amgen, Spectrum/Acrotech, Precision Biosciences, Beigene, AstraZeneca, Pharmacyclics/Jansen, Adaptive: Honoraria; Moffitt Cancer Center: Current Employment; Kite/Gilead, Jazz, Incyte: Research Funding. Bello:Seattle Genetics: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau. Sokol:EUSA Pharma: Consultancy, Honoraria, Speakers Bureau; Kymera Therapeutics: Membership on an entity's Board of Directors or advisory committees; Kyowa/Kirin Inc.: Membership on an entity's Board of Directors or advisory committees. Pinilla Ibarz:Pharmacyclics: Consultancy, Speakers Bureau; Novartis: Consultancy; Sanofi: Consultancy; TG Therapeutics: Consultancy; Janssen: Consultancy, Speakers Bureau; Sunesis Pharmaceuticals: Consultancy; AstraZeneca: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Abbvie: Consultancy, Speakers Bureau. Chavez:Karyopharm: Consultancy; BeiGene: Speakers Bureau; Bayer: Consultancy; Merck: Research Funding; Morphosys: Consultancy, Speakers Bureau; AstraZeneca: Speakers Bureau; Celgene: Consultancy; Novartis: Consultancy; AbbVie: Consultancy; Genentech: Speakers Bureau; Epizyme: Speakers Bureau; Gilead: Consultancy; Kite, a Gilead Company: Consultancy, Speakers Bureau; Verastem: Consultancy; Pfizer: Consultancy.

Phase I/II Study of IPH1101, γσ T Cell Agonist, Combined with Rituximab, in Low Grade Follicular Lymphoma Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1649-1649 ◽  
Author(s):  
Guy Laurent ◽  
Sylvie Lafaye de Micheaux ◽  
Philippe Solal-Celigny ◽  
Pierre Soubeyran ◽  
Vincent Delwail ◽  
...  
Keyword(s):  
T Cells ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Low Grade ◽  
Low Doses ◽  
Open Label ◽  
Independent Panel ◽  
Pharmacodynamic Profile ◽  
Previously Treated Patients ◽  
Previously Treated

Abstract Abstract 1649 Poster Board I-675 Non-conventional γσ T lymphocytes are innate immunity effectors bearing potent anti-tumoral activity, particularly against malignant B cells. IPH1101 is an agonist of γσ T cells, which in the presence of low doses of IL-2 potentiates their direct cytotoxic activity. ADCC is a major molecular mechanism underlying rituximab's efficacy. Increasing the number and the activation state of killer lymphocytes mediating ADCC is therefore believed to be beneficial for therapeutic potency. Since γσ T cells have been found to be capable of mediating ADCC, modulating γσ T cells in the context of rituximab is worth being tested in a clinical trial. The main purpose is to assess the clinical efficacy of IPH1101 with low doses of IL-2, combined with a standard rituximab treatment, in patients (pts) with follicular lymphoma. This is an open label, multinational study consisting of a dose escalation Phase (ph) I-like part followed by a ph II part. The ph I part has shown a good safety and immuno-biological efficacy profile for the highest dose of IL-2. Consequently, the pts of the phase II part were treated with the combination of rituximab (375 mg/m2) administered 4 times weekly, IPH1101 (750 mg/m2) administered i.v. 3 times (every 3 weeks) and IL-2 (8 MIU) administered daily s.c. for 5 days starting on the day of each IPH1101 administration. All pts presented low grade FL which had relapsed after 1 to 4 lines of previous therapy including at least one rituximab-containing line. Inclusion criteria set forth that pts should have no lesion > 7 cm. Results We report here the end of recruitment and updated data on 45 patients and more than 100 cycles of IPH1101. Overall safety was good, and most of the drug-related adverse events were, as expected, flu like symptoms of grade 1 or 2. The SAEs reported were 2 hypotensions, 1 bronchospasm, 1 allergic reaction (back pain), 1 glomerular filtration decrease, 1 ALAT elevation, 1 hypertension and 1 asthenia. The immuno-biological follow up demonstrated the very good pharmacodynamic profile of IPH1101 in these patients and these data are presented in details in another abstract from Lucas et al. To date, in the first set of evaluable patients (12 pts) and after at least 3 months post treatment, investigators reported about 75% of response and 50% of CR. Most of the responses are already confirmed by an independent panel. Conclusion These observations confirm the good safety and the biological rationale of this approach. Furthermore, the response rate in this first set of pts is encouraging in the context of previously treated patients. Updated results will be presented at the meeting. Disclosures Laurent: Innate pharma: Honoraria. Lafaye de Micheaux:Innate Pharma: Employment. Solal-Celigny:Innate Pharma: Research Funding. Soubeyran:Innate Pharma: Research Funding. Delwail:Innate Pharma: Honoraria. Ghesquières:innate pharma: Honoraria. Thieblemont:Innate Pharma: Honoraria. Jourdan:Innate Pharma: Honoraria. Beautier:Innate Pharma: Employment. Squiban:Innate pharma: Employment. Rossi:Innate Pharma: Honoraria.

Bortezomib Added to CVP-R Is Safe and Effective for Previously Untreated Advanced Stage Follicular Lymphoma: A Phase II Study by the NCIC Clinical Trials Group.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 407-407
Author(s):  
Laurie H. Sehn ◽  
David A Macdonald ◽  
Sheldon H. Rubin ◽  
Guy Cantin ◽  
Morel Rubinger ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Phase Ii ◽  
Research Funding ◽  
Standard Dose ◽  
Phase Iii ◽  
High Risk Population ◽  
Low Grade ◽  
Grade 3 ◽  
To Receive ◽  
Experienced Grade

Abstract Abstract 407 Background: Bortezomib, the first-in-class proteasome inhibitor has demonstrated promising efficacy as a single agent in heavily pretreated patients (pts) with follicular lymphoma (FL). This is the first study to evaluate the safety and efficacy of the addition of bortezomib to cyclophosphamide, vincristine, prednisone and rituximab (CVP-R), one of the most commonly used regimens in untreated patients. Methods: This is a phase II multi-centre open-label trial adding bortezomib (1.3 mg/m2 day 1&8) to standard dose cyclophosphamide (750 mg/m2), vincristine (1.4 mg/m2, capped at 2 mg), prednisone (40 mg/m2 × 5) and rituximab (375 mg/m2) for up to 8 cycles in pts with newly diagnosed stage III/IV FL requiring therapy. Response was assessed following 4 and 8 cycles. The two co-primary endpoints were complete response rate (CR/CRu) and incidence of grade 3/4 neurotoxicity. Following the final response assessment, patients were permitted to receive maintenance rituximab at the discretion of the treating physician according to local practice. Results: Between March 2007 and February 2009, 95 patients were enrolled. Median age was 56.6 years (range 29.5 – 83.6 years). 48% percent were male and 63% had stage IV disease. FLIPI score at study entry: low 11%, intermediate 43%, high 46%. Safety data was availabel on all patients. Overall, the combination of bortezomib and CVP-R was extremely well tolerated. No pts have developed grade 4 neurotoxicity and only 6/95 (6.3%) have developed grade 3 neurotoxicity (five sensory neuropathy and one neuropathic pain). The incidence of grade I and II neuropathy was 65.3% and 36.8% respectively. Neurotoxicity was largely reversible. Five pts discontinued therapy prematurely (three refused further treatment, one pt was found to have Hodgkin lymphoma as well as FL and one pt was removed from study for non-compliance). 84% of planned bortezomib treatments and 85% of vincristine treatments were administered without dose reduction. Five pts experienced grade 3/4 anemia and 3 pts experienced grade 3/4 thrombocytopenia. Only 4 episodes of febrile neutropenia occurred and 2 grade 3 infections were noted. No grade 4 infections were reported. No serious adverse events were reported. One patient died due to progressive disease. At present, 78/95 patients are evaluable for response. 37/78 (47%) achieved a CR/CRu (95% CI 36.4, 58.5), and 29/78 (37%) achieved a PR with an ORR of 84.6% (95% CI 76.6, 96.6). An additional 5/78 pts had stable disease, while 7/78 progressed on therapy. Complete efficacy data as well as information on quality of life will be availabel within the next few months. Forty-one of 70 pts (58.6%) with availabel follow-up information went on to receive maintenance rituximab. Conclusions: The addition of bortezomib to standard dose CVP-R is feasible and well tolerated with minimal associated toxicity. Neurotoxicity is primarily low grade and reversible and does not limit delivery of either bortezomib or vincristine. The complete remission rate in this high risk population compares favorably to historical results of patients receiving CVP-R. Based on these encouraging results, a phase III trial of CVP-R with or without bortezomib is currently being planned. Disclosures: Sehn: Johnson and Johnson Ortho Biotec: Honoraria. Off Label Use: Velcade for is not yet approved for follicular lymphoma. Chen:Johnson and Johnson Ortho Biotec: Research Funding. Djurfeldt:Johnson and Johnson Ortho Biotec: Research Funding. Shepherd:Johnson and Johnson Ortho Biotec: Research Funding. Crump:Johnson and Johnson Ortho Biotec: Honoraria.

Rituximab Overcomes Sex as a Strong Adverse Prognostic Factor for Treatment Outcome in Patients with Follicular Lymphoma: Analysis of Patients Treated with Rituximab/CHOP or CHOP in Randomized Trials of the German Low Grade Lymphoma Study Group (GLSG).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3706-3706 ◽  
Author(s):  
Christian Buske ◽  
Eva Hoster ◽  
Martin H. Dreyling ◽  
Roswitha Forstpointner ◽  
Michael Kneba ◽  
...  
Keyword(s):  
Treatment Outcome ◽  
Prognostic Factor ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Low Grade ◽  
Study Group ◽  
Female Patients ◽  
Male Patients ◽  
Male Sex ◽  
Lymphoma Study Group

Abstract Abstract 3706 Poster Board III-642 Sex has been recognized as an important prognostic factor for the treatment outcome of patients with lymphoma. Thus, several retrospective analyses have shown that male sex is associated with an inferior outcome in advanced stage follicular lymphoma. This was confirmed in a retrospective analyses of 1795 patients with follicular lymphoma using Cox regression analysis, in which male sex was independently associated with inferior survival (Solal-Celigny et al., Blood 2004). We now analyzed the prognostic impact of sex on treatment outcome of 1172 patients with follicular lymphoma treated first line with CHOP or R-CHOP in prospectively randomized clinical trials of the German Low-Grade Lymphoma Study Group (GLSG). From these, 616 pts were treated with CHOP, 556 pts with R-CHOP. FLIPI was equally distributed between the two treatment arms (low risk 14% vs. 14%, intermediate risk 42% vs. 41% and high risk 44% vs. 45 %, respectively). 48% of the patients were male (50% in the CHOP and 46% in the R-CHOP arm). For all patients there was a significantly inferior time to treatment failure (TTF) for male patients with a median of 43 months compared to 61 months for female patients (p=0.0035). In the patient group treated with CHOP alone the median TTF was 30 months for male vs. 40 months for female patients (p=0.0041). The observation that male sex was associated with inferior treatment outcome was seen both in the elderly (above 60 yrs of age) as well as the younger patient group (below 60 yrs of age). However, after treatment with R-CHOP sex did not affect treatment outcome anymore with virtually the same results in male vs. female patients (for the total group and for patients < 60yrs TTF median not reached in both arms, p = n.s.; for pts > 60 yrs TTF 81 vs. 84 months, respectively, p=n.s.). In multivariate analysis, also adjusting for FLIPI risk factors, male sex showed up as an independent prognostic factor for patients treated with CHOP alone (HR 1.82; 1.32 – 2.5; p=0.0002), but not for patients treated with R-CHOP (HR 1.06; 0.68 - 1.66, p = 0.79; p=0.0476 for the interaction term of sex with Rituximab). Based on this, male patients had the highest benefit when rituximab was added to CHOP (R-CHOP vs. CHOP: male pts HR 0.31,0.21 - 0.46, p<0.0001 and female pts. HR 0.53, 0.37 - 0.76, p = 0.0005). These data demonstrate that Rituximab functions as an equalizer with regard to sex as a prognostic factor and underlines that well established prognostic factors may lose their predictive power with the emergence of novel effective treatment approaches. Disclosures: Buske: Roche: Honoraria. Hoster:Roche: travel support. Dreyling:Roche: Honoraria, Research Funding. Hallek:BayerScheringAG: Honoraria, Research Funding. Hiddemann:Roche: Honoraria, Research Funding. Unterhalt:Roche: .

Dose-Escalated, Intratumoral TLR9 Agonist and Low-Dose Radiation Induce Abscopal Effects in Follicular Lymphoma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3092-3092 ◽  
Author(s):  
Holbrook E Kohrt ◽  
Jaqueline Chu ◽  
Joshua Brody ◽  
Debra K Czerwinski ◽  
Cariad Chester ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
T Cell ◽  
Immune Responses ◽  
Research Funding ◽  
Low Dose ◽  
Low Grade ◽  
Tlr9 Agonist ◽  
Treatment Naïve ◽  
Clinical Responses

Abstract Abscopal effects, systemic tumor regression following localized therapy, are induced by radiation therapy and augmented with intratumoral immunostimulation. Based on a preclinical lymphoma model, we previously investigated low-dose immunostimulation with a Toll-like receptor 9 (TLR9) agonist in combination with fractionated, low-dose radiation therapy in relapsed/refractory NHL (NCT00185965) and Mycosis Fungoides (NCT00226993). In an attempt to improve the potency of the immune responses and the rate of clinical responses, the dose of CpG was increased 3-fold and enrollment broadened to include treatment-naive as well as relapsed/refractory low-grade lymphoma (NCT00880581). We treated 15 treatment-naive patients and 15 relapsed/refractory patients with follicular lymphoma using low-dose radiotherapy to a single tumor site followed by 18mg of the C-G enriched, synthetic oligodeoxynucleotide (CpG) TLR9 agonist, PF-3512676 injected at the same site, with injections repeated 10 times weekly. Clinical responses were assessed at distant, untreated tumor sites. Immune responses were evaluated by measuring T-cell activation after in vitro re-stimulation with autologous tumor cells. The in situ vaccination with escalated-dose CpG was well tolerated with 16 cases of grade 1 to 2 local or systemic reactions including 2 cases of possibly-related autoimmune disease and no treatment-limiting adverse events. Among treatment-naive and relapsed/refractory patients, four and three patients, respectively, had partial responses with median duration of response of 29 and 12 weeks, respectively. Two and four patients, respectively, had stable disease of duration greater than one year with median time to best clinical benefit among patients with a response or stable disease of 31 and 12 weeks. The range of time to best response was broad, from 10 to 184 weeks (see Figure). Median progression-free survival was similar among treatment-naive and relapsed/refractory patients, at 41 and 35 weeks, respectively, and median overall survival was not reached in either cohort with median follow-up of 2.6 and 3.5 years. Importantly, in response to in situ vaccination, all patients made tumor-specific immune responses within 2 to 4 weeks post-vaccination with the most informative markers being the activation marker CD278 (ICOS) for CD4 T cell response among the CD45RO+ memory subset, and perforin and granzyme B for CD8 T cell responses. Based on the anti-lymphoma activity observed we have recently initiated two Phase I/II dose-escalation trials of a second-generation TLR9 agonist and radiation therapy in relapsed/refractory low-grade NHL and relapsed NHL post-allogeneic transplant (NCT01745354). Figure 1 Figure 1. Disclosures Advani: Seattle Genetics, Inc.: Other, Research Funding; Genentech: Research Funding; Janssen Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding.

scholarly journals Tumor-Confirmed Follicular Lymphoma Mutations Are Detectable in Peripheral Blood Years Prior to Clinical Diagnosis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 709-709
Author(s):  
Joseph G Schroers-Martin ◽  
Joanne Soo ◽  
Gabriel Brisou ◽  
Florian Scherer ◽  
David M. Kurtz ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Clinical Diagnosis ◽  
Peripheral Blood ◽  
Stock Options ◽  
Research Funding ◽  
Low Grade ◽  
Pet Ct ◽  
Significant Difference ◽  
Tumor Biopsies ◽  
Privately Held

Abstract Background: Mutations in chromatin modifying genes (CMGs) including KMT2D, CREBBP, EZH2, and EP300 have been inferred as early events in follicular lymphoma (FL) by truncal status in mature tumors and persistence between diagnosis and relapse. We previously reported frequent detection of CREBBP lysine acetyltransferase (KAT) domain mutations in pre-diagnostic blood and tissue specimens from individuals later developing FL (Schroers-Martin et al, ASH Annual Meeting 2017). However, the limited availability of paired tumor biopsies has precluded confirmation of concordance between precursor lesions and subsequent clinical malignancy. Methods: The American Cancer Society (ACS) Cancer Prevention Study-II (CPS-II) LifeLink cohort collected screening blood or saliva samples from over 100,000 cancer-free American participants between 1998 and 2002. To evaluate detection of tumor-confirmed variants in pre-diagnostic specimens, we identified 29 FL patients with available FFPE tumor biopsy and screening sample (Fig A). The median age at screening was 71 years (range 56-83) with a median time to FL diagnosis of 56 months (TTD, range 6-139). Tumor biopsies were sequenced utilizing hybrid capture sequencing for commonly mutated lymphoma genes. DNA extracted from pre-diagnostic blood or saliva cell pellet specimens was sequenced utilizing error-corrected CAPP-Seq (Newman et al Nat Biotech 2016) to a median depth of 5204x. We sequenced to similar depths peripheral blood DNA from control cohorts of individuals with detectable t(14;18) but no subsequent lymphoma diagnosis (n=14) and healthy individuals without detectable t(14;18) by PCR (n=20). Results: Coding mutations were identified from all tumors with a mutational distribution similar to prior FL sequencing studies. Tumor-derived variants were detected in 7 of 29 paired pre-diagnostic specimens (24%) at a median TTD of 44 months (range 11-112 months, Fig B). The statistical significance of detection was assessed using a previously described approach based on Monte Carlo sampling (Newman et al Nat Biotech 2016) and the error distribution of affected loci in control cohorts. While an outlier case contained concordant TNFRSF14, FOXO1, and STAT6 mutations 90 months pre-diagnosis at an elevated allelic fraction (AF) of 1.8%, the mean AF of other detected precursor variants was 0.091%. Individuals with detected variants were not older (Fig C) nor significantly closer to clinical diagnosis (Fig D). The most frequently detected lesions were CREBBP (6/15 cases, 40%) and BCL2 (3/13, 23%) with one case demonstrating a fuller mutational profile including FOXO1 and ARID1A at 44 months before diagnosis. All detected precursor CREBBP variants localized to the KAT domain, reflecting prior observations in pre-diagnostic samples without confirmatory biopsy (Fig E). Of note, saliva cell pellets may contain 30% or more hematopoietic DNA (Kaur et al Chimerism 2012) and we detected tumor-confirmed variants in both saliva and blood screening specimens (Fig F) with no significant difference in AF (Fig G). In an illustrative independent case with available imaging, a patient undergoing radical prostatectomy was found to have involvement of a pelvic lymph node with in situ follicular neoplasia (ISFN). Staging PET/CT showed no evidence of FL (Fig H) and he was followed expectantly for 4 years without emergent disease. Eight years after surgery he presented with inguinal swelling and bilateral FDG-avid adenopathy on PET/CT. Excisional biopsy confirmed low grade FL and sequencing for M7-FLIPI revealed a CREBBP KAT domain variant. Retrospective sequencing of serial peripheral blood specimens from his initial surveillance showed detectable CREBBP R1446C at the earliest collected time point (AF range 0.019-0.046%) rising to AF 0.082% after clinical diagnosis. Conclusions: Precursor FL mutations are detectable in peripheral blood and saliva years prior to clinical diagnosis with a spectrum of variants enriched in CREBBP and BCL2 and concordant with subsequent FL tumors. Such lesions may assist in stratifying individuals at elevated risk of clinical malignancy, including after identification of pathologic precursors such as ISFN. Figure 1 Figure 1. Disclosures Kurtz: Foresight Diagnostics: Consultancy, Current holder of stock options in a privately-held company; Roche: Consultancy; Genentech: Consultancy. Khodadoust: Alexion, AstraZeneca Rare Disease: Other: Study investigator; CRISPR Therapeutics, Nutcracker Therapeutics: Research Funding; Myeloid Therapeutics: Membership on an entity's Board of Directors or advisory committees. Diehn: Roche: Consultancy; AstraZeneca: Consultancy; RefleXion: Consultancy; BioNTech: Consultancy; Varian Medical Systems: Research Funding; Illumina: Research Funding; CiberMed: Current holder of stock options in a privately-held company, Patents & Royalties; Foresight Diagnostics: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Roulland: BMS: Research Funding. Alizadeh: Bristol Myers Squibb: Research Funding; Gilead: Consultancy; CAPP Medical: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Celgene: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Janssen Oncology: Honoraria; Foresight Diagnostics: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Cibermed: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company; Forty Seven: Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company.

scholarly journals Prognosis after Upfront Radiation Therapy in Plasma Cell Myeloma: Analysis of the National Cancer Data Base

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3230-3230
Author(s):  
Xavier Orcutt ◽  
Peter Barth ◽  
Adam J Olszewski
Keyword(s):  
Radiation Therapy ◽  
Systemic Therapy ◽  
Research Funding ◽  
National Cancer Data Base ◽  
Sensitivity Analyses ◽  
Insurance Status ◽  
Plasma Cell Myeloma ◽  
Cancer Data ◽  
Factors Associated ◽  
Skeletal Complications

Abstract Introduction Systemic therapy with corticosteroids, immunomodulatory agents and/or proteasome inhibitors is the principal treatment modality for plasma cell myeloma. However, some patients with advanced bone disease may start treatment with radiation therapy (RT) to control pain from lytic lesions, fractures, or spinal cord compression. The degree of bone involvement may correlate with cytogenetic lesions, gene expression profile, and prognosis in myeloma (Zhan et al., Blood 2006; Kumar and Rajkumar, Nat Rev Clin Oncol 2018), yet the prognostic relevance of upfront RT use has not been previously studied. We hypothesized that the need for upfront RT may be associated with worse long-term outcomes, as an indicator of late-stage diagnosis or a biologically aggressive disease with bone destruction. Our objective was to examine patterns of use, factors associated with upfront RT, and survival outcomes among myeloma patients treated with upfront RT. Methods From the National Cancer Data Base (NCDB), a nationwide registry containing records of >70% of incident cancers in the United States, we selected adult patients with histologically confirmed myeloma diagnosed between 2004 and 2015, who received chemotherapy within 12 months of diagnosis. We excluded patients with solitary plasmacytoma, those treated outside of the reporting facility, or those receiving palliative RT as the only therapy. We defined upfront RT as RT delivered before or within 14 days of the start of chemotherapy. We examined factors associated with upfront RT in a multivariable logistic model. We then examined the association between upfront RT and overall survival (OS) in a proportional hazard model adjusting for age, sex, race, income, insurance status, comorbidity index, year of diagnosis, type of treating hospital, and time from diagnosis to start of therapy. Results Of the 88,995 patients with myeloma, 15,223 (18%) received upfront RT, at median 15 days from diagnosis. Median radiation dose was 3000 cGy delivered over median 10 fractions, with the most common targets being spine/skull (59%), hips/pelvis (12%), and other bones (11%). Among patients receiving upfront RT, 73% started it before chemotherapy, while 27% started RT within 14 days of chemotherapy initiation. Use of upfront RT was significantly less common in academic than community hospitals (16% versus 20%, P<.0001). In the multivariable model, patients receiving upfront RT were significantly younger (odds ratio [OR] for a 10-year age increment: 0.92, 95% CI: 0.91-0.94), more likely to be male (OR: 1.11, 95% CI: 1.07-1.15), white non-Hispanic than black (OR: 1.13, 95% CI: 1.08-1.19), uninsured than privately insured (OR: 1.17, 95% CI: 1.06-1.29), and treated at a community rather than an academic hospital (OR: 1.28, 95% CI: 1.24-1.33). Receipt of upfront RT was also inversely associated with median income in the area of residence, distance to the hospital, and number of comorbidities (P<.0001). Median OS for the entire cohort was 4.2 years (95% CI, 4.1-4.2), longer for those treated with upfront systemic therapy (4.3 years, 95% CI, 4.2-4.3) than those receiving upfront RT (3.7 years, 95% CI, 3.6-3.8; Fig. A). After adjusting for baseline patient characteristics, treatment with upfront RT was associated with significantly worse OS (hazard ratio [HR]: 1.09, 95% CI: 1.07-1.12). This association was consistent in sensitivity analyses limited to patients who survived >1 year from diagnosis (HR: 1.15, 95% CI: 1.11-1.19), those who underwent autologous stem cell transplantation (HR: 1.11, 95% CI, 1.02-1.22; Fig. B), or accounting for baseline mortality rate using the endpoint of relative survival rather than OS (HR: 1.10, 95% CI: 1.07-1.14). Conclusions In this large nationwide cohort, nearly 1 in 5 of newly diagnosed myeloma patients received upfront RT. The association between socio-economic variables like income or insurance status and the use of upfront RT suggests that a delay in diagnosis may lead to severe skeletal complications of myeloma requiring RT. Worse survival with upfront RT may similarly correspond to more advanced disease, but persistent association in sensitivity analyses supports the hypothesis that a presentation with skeletal complications reflects a more aggressive myeloma biology. Further research should aim at disentangling the socio-economic, clinical, and molecular reasons underpinning this association. Disclosures Olszewski: Genentech: Research Funding; TG Therapeutics: Research Funding; Spectrum Pharmaceuticals: Consultancy, Research Funding.

A Pilot Phase II Study of C-MOPP-R, Ibritumomab Tiuxetan, and Autologous Transplant for Untreated and Relapsed Follicular Lymphoma: Response, Toxicity, and Feasibility,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4157-4157
Author(s):  
Mark J. Fesler ◽  
Yashaswini Yeragunta ◽  
Sheetal A. Majethia ◽  
Paul J. Petruska
Keyword(s):  
Follicular Lymphoma ◽  
Research Funding ◽  
Autologous Transplantation ◽  
Treatment Protocol ◽  
World Health ◽  
Treatment Modalities ◽  
Ibritumomab Tiuxetan ◽  
Hematopoietic Stem ◽  
Off Label ◽  
Autologous Transplant

Abstract Abstract 4157 Introduction: We initiated an aggressive treatment protocol for newly diagnosed and relapsed follicular lymphoma in March 2006. This is an IRB approved prospective study registered at clinicaltrials.gov as NCT01130194, which sequentially utilizes three treatment modalities: immunochemotherapy, radioimmunotherapy, and autologous transplantation, in an effort to cure the disease. We report preliminary results of the first twenty patients. Methods: Patients' whose diagnosis of follicular lymphoma was confirmed by our hematopathologists in accordance with the 2008 World Health Organization criteria signed informed consent, and were enrolled in our study. Patients must have had an indication for treatment, stage II-IV disease, any grade, ECOG performance status of 0–1, and adequate organ function to participate. PET/CT has been the standard response tool for follicular lymphoma at our institution since study initiation, and responses were assessed by Cheson criteria. Treatment consisted of six cycles of C-MOPP-R every 28 days: cyclophosphamide 650mg/m2 IV day 1 and 8, vincristine 1.4mg/m2 IV day 1 and 8, procarbazine 100mg/m2 PO daily day 1–14, prednisone 40mg/m2 PO daily day 1–14, rituximab 375mg/m2 IV day 1 and 8, and pegylated filgrastim 6mg SC day 9. Prophylaxis consisted of a quinolone, TMP-SMX, acyclovir, and fluconazole. Chemotherapy alterations were made at the discretion of the treating physician. Mobilization and collection of hematopoietic stem cells with growth factor was performed in patients with documented response and no residual bone marrow disease after four to six cycles of C-MOPP-R. After completion of C-MOPP-R and recovery of ANC >1000 cells/mcL and platelets to 100K, patients received ibritumomab tiuxetan at standard dosing. Upon second recovery, patients were admitted for BEAM(C) conditioned autologous transplant. Results: See Table 1 for baseline characteristics. 45% (n=9) of patients received all 3 modalities, 35% (n=7) received C-MOPP-R + radioimmunotherapy, and 20% (n=4) received C-MOPP-R only. The ORR (CR+PR) was 95% (n=19, CR n=18, PR n=1). All responses occurred during C-MOPP-R therapy. The lone non-responder had progressive disease after two cycles of C-MOPP-R. With a median follow-up of 27 months (range 7–54 months), the median event-free survival and overall survival for all 20 patients has not yet been reached. See Figures 1 and 2 for EFS and OS, respectively. See Table 2 for toxicity rates during the treatment. Thirty-five percent of patients required a dose reduction or discontinuation of vincristine for peripheral neuropathy. In addition to our lone non-responder, two patients on protocol have died; one of pulmonary hemorrhage thought to be related to BEAC conditioning, and one due to pulmonary embolism and sepsis. One patient received 2 cycles of C-MOPP-R, refused further therapy, relapsed, and is still alive. The main reason for not completing protocol therapy was insurance denial of ibritumomab tiuxetan or autologous transplantation. Conclusion: Based on our interim analysis of this prospective, ongoing study we propose this therapeutic protocol is an effective and feasible regimen with the possibility of cure for patients with follicular lymphoma. Response rates with C-MOPP-R are excellent and overall, the treatment protocol is well tolerated. Further updates of this cohort and ongoing prospective enrollment on this protocol will help clarify the ultimate role of aggressive therapy in upfront and relapsed follicular lymphoma. Disclosures: Fesler: Spectrum Pharmaceuticals: Research Funding. Off Label Use: Ibritumomab tiuxetan was utilized off-label for some patients on this study prior to FDA approval in untreated patients. Procarbazine was utilized off-label for patients in this study in spite of proven efficacy as a single agent in non-Hodgkin lymphoma. Petruska:Spectrum Pharmaceuticals: Research Funding.

R-Bendamustine Vs R-CHOP As Initial Treatment for Advanced Stage Low Grade Follicular Lymphoma: A Matched-Pair Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3048-3048 ◽  
Author(s):  
Karishma Phansalkar ◽  
Mohamed Amin Ahmed ◽  
Nathan Fowler ◽  
Long Ma ◽  
Mansoor Noorani ◽  
...  
Keyword(s):  
Follicular Lymphoma ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Matched Pair ◽  
Cancer Center ◽  
Low Grade ◽  
Advanced Stage ◽  
First Line ◽  
Matched Pair Analysis ◽  
Pair Analysis

Abstract Introduction: In the randomized phase 3 clinical trial performed by the Study group indolent Lymphoma (STiL) in patients with indolent and mantle cell lymphoma, the complete response (CR) rates and progression-free survival (PFS) were superior with first-line bendamustine plus rituximab (BR) therapy compared with CHOP plus rituximab (R-CHOP) therapy. However, in a second randomized phase 3 clinical trial (the BRIGHT study) also performed in patients with indolent and mantle cell lymphoma, the CR rates were similar between BR and R-CHOP groups and PFS data has not been reported. In both trials, the toxicity profile was better for BR compared with R-CHOP. Here, we report the results of a matched-pair analysis of advanced stage low-grade follicular lymphoma patients treated with first-line BR or R-CHOP at MD Anderson Cancer Center, Houston, Texas. Methods: We reviewed the medical records of all patients (n=74) with stage III or IV grade 1 or 2 follicular lymphoma treated at MD Anderson Cancer Center with first-line BR between January 2009 and December 2013. Each BR patient was paired with a grade 1 or 2 follicular lymphoma patient treated with first-line R-CHOP matched by age, gender, and stage. Patients with histological diagnosis of concurrent diffuse large B-cell lymphoma were excluded. Results: There were no significant differences in most baseline patient characteristics including age, gender, stage, FLIPI 1 and FLIPI 2 risk groups, Ki-67 score, absolute monocyte count, and absolute lymphocyte count (p>0.05). However, more patients in R-CHOP group met GELF criteria compared with BR group (69% vs 47%, p=0.012). Also, more patients in R-CHOP group had SUVmax >10 on baseline FDG PET scan compared with BR group (74% vs 49%, p=0.011). Median number of chemotherapy cycles was 6 for both groups (range, 2-6 for BR and 4-8 for R-CHOP). The CR rates were comparable between the two groups (93% for BR and 91% for R-CHOP, p=0.142). The median follow-up was 24.4 months (range, 2.8-63.2 months) for BR patients and 68.1 months (range, 4.4-149.4 months) for R-CHOP patients. At 24 months, the PFS and overall survival (OS) were comparable between the two groups (PFS and OS of 85% and 94% for BR and 82% and 99% for R-CHOP; log rank p=0.654 for PFS and 0.158 for OS). Conclusions: In this 1:1 matched pair analysis of advanced stage low-grade follicular lymphoma patients treated with first-line BR or R-CHOP, the CR rates, PFS and OS were comparable between the two therapies. However, longer follow-up is required for better comparison of PFS, OS, and long-term toxicities between the two regimens. Disclosures Fanale: Seattle Genetics, Inc.: Consultancy, Honoraria, Other, Research Funding. Wang:Pharmacyclics, Janssen: Honoraria, Research Funding. Westin:Novartis: Research Funding.

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