Efficacy and Safety of Ruxolitinib in the Treatment of Elderly Patients with Policythemia Vera Resistant/Intolerant to Hydroxyurea

Abstract Introduction: Ruxolitinib (Rux) has been recently approved as second-line therapy in patients (pts) with Polycythemia Vera (PV) resistant/intolerant to hydroxyurea (HU). Median age of PV pts enrolled in the pivotal Response trials was around 60 yrs; at present, no data is reported on the use of Rux in elderly pts. Aims: In a real-world cohort of PV pts treated with Rux, we investigated whether the efficacy and safety of Rux were comparable in pts who initiated therapy when aged ≥75 years compared with younger pts. Methods: After IRB approval, clinical/laboratory data of 934 WHO2016-defined PV pts followed in 29 Hematology Centers were retrospectively collected. Of them, 168 (17.9%) were considered resistant/intolerant to HU at any time during follow-up by responsible physician and shifted to Rux as second-line therapy. Results: Among the 168 pts treated with Rux, 42 (25%, median age 78.2 years) were aged ≥75 yrs at Rux start, 74 (44%, median age 67.7) were aged 60-74 and 52 (31%, median age 53) were <60 at Rux start. No significant differences were observed between the 3 groups, apart from a lower need for phlebotomies in pts aged ≥75 yrs and lower presence of palpable spleen in older pts (age ≥60), that more frequently switched to Rux due to HU intolerance (Table 1). Median duration of HU treatment was 41.0 months (IQR 14.6 - 85.8), with a trend for a longer median treatment duration in pts aged ≥75 [61.0 months (IQR 21.5 - 89.6) vs 35.9 months (IQR 13.4 - 79.6), p=0.04]. Rux starting dose was similar across age groups; however, more elderly pts underwent Rux dose reductions during follow-up (45.2% in pts aged ≥75 vs 28.6% in younger pts, p=0.04). Responses during Rux therapy are reported in Table 2, with no significant differences between the 3 groups at any time. In the overall cohort, response on PV-related symptoms at 6 and 12 months was significantly higher in pts who switched to Rux because of HU intolerance; however, this difference was not observed in pts aged ≥75 yrs. As to the most common hematologic Rux-related toxicities, grade 3-4 anemia and thrombocytopenia were observed in only 2 (1.2%) and 5 (3%) pts, with no difference across age groups (p=0.45 and p=0.18). However, any grade anemia and thrombocytopenia during Rux were more frequently observed in pts aged ≥75 (68.3% vs 51.7% of anemia, p=0.06 and 12.2% vs 3.5% of thrombocytopenia in younger pts, p=0.04). Nineteen and 4 pts experienced infectious and thrombotic complications during Rux with incidence rates of 0.59 and 0.12 per 100 patient-months, respectively, comparably in younger and older (≥75) pts (p=0.75 and p=0.29, respectively). Notably, 6 infections were herpes simplex/zoster virus, comparably distributed between the 3 groups (p=0.60). Permanent Rux discontinuation was needed in 14 pts (8.3%) after a median Rux exposure of 7.8 months (IQR 4.6 - 17.6) (incidence: 0.41 per 100 pts/months). Discontinuation was comparable between age groups, with Rux stop in 4 pts aged ≥75 yrs and 10 younger pts (2.4% vs 5.2% at 8 months, log-rank p=0.75). At last follow-up, 2 pts had died (1 from 2 nd neoplasia after 19.1 months from Rux start and 1 from acute leukemia after 3.3 years), both pts aged 60-74 yrs. Conclusions. In this real-world analysis, use of Rux in HU resistant/intolerant elderly PV pts was effective and safe despite the more frequent need for dose reductions. Older age should not discourage Rux therapy, but stricter hematological monitoring may be suggested. Figure 1 Figure 1. Disclosures Latagliata: BMS Cellgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria; Novartis: Honoraria. Bonifacio: Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cavo: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Palandri: AOP: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Second Line Therapy with Second Generation TKI After Intolerance to Imatinib Based Treatments Showed High Overall Survival in Contrast to Second Line Therapy After Resistance; Results of the Randomized CML Study IV

Blood ◽

10.1182/blood.v118.21.781.781 ◽

2011 ◽

Vol 118 (21) ◽

pp. 781-781

Author(s):

Susanne Saussele ◽

Michael Lauseker ◽

Ulrike Proetel ◽

Martin C. Müller ◽

Benjamin Hanfstein ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Second Generation ◽

Chronic Phase ◽

Imatinib Therapy ◽

Second Line ◽

Second Line Therapy ◽

Advisory Committees ◽

Line Therapy

Abstract Abstract 781FN2 Introduction: Data on second line therapy with second generation tyrosine kinase inhibitors (TKI) in CML treatment were generated mainly from phase II/III industry initiated trials (Review Hehlmann Exp Op. 2011). 24-month overall survival (OS) varies between 88% and 94% after intolerance and/or resistance to imatinib for chronic phase (CP) and between 67% and 72% for accelerated phase (AP) or blast crisis (BC). Intention to treat analyses including outcome of patients after discontinuation of first line therapies have not been available as yet. We thought to evaluate overall and progression-free survival (OS and PFS) of imatinib intolerant vs. resistant patients under second line TKI with long-term follow-up within an investigator initiated trial. Methods: We analyzed data of the German CML study IV, a randomized 5-arm trial to optimize imatinib therapy on an intention to treat basis. According to protocol, follow-up of patients on and after second generation TKI after imatinib intolerance and/or resistance was continued for OS and PFS. Analysis of PFS was only relevant, if intolerance and resistance to imatinib therapy occurred while a patient was still in chronic phase (CP). Patients were censored at the time of allogeneic stem cell transplantation (allo-SCT). Results: From July 2002 to December 2010, 1,502 patients with Philadelphia chromosome and /or BCR-ABL positive CML in CP were randomized. 129 patients of the “imatinib after interferon arm” and 36 other patients had to be excluded (14 due to incorrect randomization or withdrawal of consent, 22 with missing baseline information). 1337 were randomized to primary imatinib treatment (imatinib 400 mg vs. imatinib 800 mg vs. imatinib in combination with either interferon alpha or araC). Of these, 234 (17%) discontinued imatinib therapy. 156 patients were treated with 2nd generation TKI, 61 were directly referred to allo-SCT, 17 patients received other regimens (including interferon alpha only or hydroxyurea). 120 of 156 patients started second generation TKI therapy (nilotinib, n=41, dasatinib, n=75, bosutinib, n=2, nilotinib and dasatinib, n=2) within 3 months after stopping imatinib, received treatment for at least one week and were evaluable for PFS and OS. 36 patients received second TKI later (median 10 months, range 3.5–61.4). Median age was 50 years (range 16–78), 42.5% were female. 48 patients were intolerant, 48 failed imatinib within CP and 24 after loss of CP (accelerated phase, n=10, blast crisis, n=14). Median time to second generation TKI was 17 months (range 1.4–97 months) and median follow-up after start of second-line TKI 31 months (range 0.2–71 months). Risk stratification according to the EUTOS Score was high in 20 patients (17%) and low in 94 patients (78%) and unknown in 6 patients (5%). OS for all 120 patients 3 years after start of second generation TKI was 73%, 96% for intolerant and 80% for resistant patients in CP and 19% for resistant patients in advanced disease (s. Fig. 1). According to EUTOS score, 3-year OS was 78% for low and 56% for high risk patients. Probability of PFS of the 96 patients in 1st CP after 3 years was 96% for intolerant and 76% for resistant patients. After 2nd generation TKI, 18 patients received an allo-SCT: all were in CP, 2 patients after imatinib intolerance, 16 patients after imatinib resistance. Conclusion: Survival on second generation TKI is high for imatinib intolerant patients in first CP but much lower for resistant patients in first CP or for patients with advanced disease phases. Alternative treatment strategies are warranted for these patient groups. Disclosures: Krause: Micromet: Research Funding. Kneba:Hoffmann La Roche: Honoraria. Hochhaus:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. German CML Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; BMBF: Research Funding; EU: Research Funding; Roche: Research Funding; Essex: Research Funding.

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Real-World Outcomes for Transplant-Ineligible Patients with Newly Diagnosed Multiple Myeloma Treated with Lenalidomide, Bortezomib, and Dexamethasone, or Bortezomib and Dexamethasone: An Enhanced Electronic Health Records Database Analysis

Blood ◽

10.1182/blood-2018-99-111121 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 2243-2243

Author(s):

Ajai Chari ◽

Brian Ung ◽

Marc Tian ◽

Amit Agarwal ◽

Kejal Parikh

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Second Line ◽

Second Line Therapy ◽

Employment Equity ◽

Advisory Committees ◽

Line Therapy ◽

Equity Ownership

Abstract Background: For transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM), the only category 1 regimens recommended by the National Comprehensive Cancer Network (NCCN) are lenalidomide and dexamethasone (Rd)-based, including triplet therapy with lenalidomide, bortezomib, and dexamethasone (RVd) (NCCN Myeloma v4.2018). Other doublet regimens, such as bortezomib and dexamethasone (Vd), are still a first-line option for patients with NDMM, especially for those who are elderly and/or frail. However, the latter population is either excluded or markedly underrepresented in clinical trials. Using an electronic health records (EHRs) database, we compared outcomes when either RVd or Vd were used in the treatment of transplant-ineligible patients with NDMM in a real-world practice setting, after adjusting for baseline demographic and clinical differences between the two cohorts. Methods: A retrospective observational study of patients with NDMM was conducted using EHRs from a nationally representative database (Flatiron Health). The Flatiron Network database is an enhanced oncology EHR database of patients treated at 265 clinics throughout the USA. Patients diagnosed with multiple myeloma, ICD-9 (203.0x) or ICD-10 (C90.xx), between January 2011 and May 2018 who were treated with RVd or Vd and did not undergo stem cell transplantation were included in the analysis. The primary comparison was time to next therapy (TTNT) in the overall population and in a subset of frail patients, as determined by a composite score based on age, Eastern Cooperative Oncology Group performance status (ECOG PS) score, and Charlson Comorbidity Index (CCI). Data regarding overall and progression-free survival (PFS) were limited as patient data prior to adoption of the Flatiron Network database were incomplete. Treatment-free interval (TFI) for patients who initiated a second-line therapy was defined as time from start of first-line to start of second-line therapy minus the duration of therapy (DOT). The Kaplan-Meier and Cox proportional hazard methods were used to calculate TTNT after adjusting for differences in patient baseline demographic and clinical characteristics. Results: Of the 8,470 transplant-ineligible patients with NDMM in the database, 2,369 were treated with either RVd (n = 1,309) or Vd (n = 1,060) and met the criteria for inclusion in this analysis. Patients treated with Vd were more likely to be older (median age 75 vs 70 years; P < 0.0001), frail (76.3% vs 65.4%; P = 0.0002), have creatinine clearance < 30 mL/min (23.9% vs 10.7%, P < 0.0001), have a higher ECOG PS score (P = 0.0031), and have International Staging System stage III disease (45.1% vs 28.8%; P < 0.0001). There were no significant differences in baseline neutropenia, anemia, or thrombocytopenia, or in median CCI. The proportion of patients with high-risk cytogenetics was lower in the Vd group (19.7% vs 26.0%; P < 0.0001). The mean DOT was longer for RVd (11.4 ± standard deviation [SD] 13.3 months) than for Vd (7.7 ± SD 9.7 months). However, the median adjusted TTNT was significantly longer with RVd than Vd (40.9 vs 14.8 months; hazard ratio [HR] 0.43; 95% confidence interval [CI] 0.33-0.55; P < 0.0001). The proportion of patients initiating a new treatment was lower in the RVd group (24.8% vs 40.6%; P < 0.0001). Among those who initiated a second-line therapy, the mean TFI for RVd compared with Vd was 42.6 versus 39.3 days, respectively (P = 0.2214). Among the 735 frail patients (416 RVd and 319 Vd), the median TTNT was significantly longer with RVd (32.6 vs 17.1 months; HR 0.40; 95% CI 0.29-0.54; P < 0.0001; Figure). Similar to the overall population, there were no significant differences in TFI (54.9 vs 29.6 days, P = 0.2598) and a significantly higher proportion of Vd patients initiated a new treatment (22.1% vs 36.4%; P < 0.001). Conclusions: In this real-world practice setting where PFS cannot be measured directly, triplet therapy with RVd significantly prolonged TTNT compared with Vd by 26.1 months in the overall patient population, and by 15.5 months in frail transplant-ineligible patients with NDMM. Disclosures Chari: Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; The Binding Site: Consultancy; Array Biopharma: Research Funding; Bristol Myers Squibb: Consultancy. Ung:Celgene Corporation: Employment, Equity Ownership. Tian:Celgene Corporation: Employment. Agarwal:Celgene Corporation: Employment, Equity Ownership. Parikh:Celgene Corporation: Employment, Equity Ownership.

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Updated 6 Year Follow-Up Of The PRIMA Study Confirms The Benefit Of 2-Year Rituximab Maintenance In Follicular Lymphoma Patients Responding To Frontline Immunochemotherapy

Blood ◽

10.1182/blood.v122.21.509.509 ◽

2013 ◽

Vol 122 (21) ◽

pp. 509-509 ◽

Cited By ~ 56

Author(s):

Gilles Andre Salles ◽

John Francis Seymour ◽

Pierre Feugier ◽

Fritz Offner ◽

Armando Lopez-Guillermo ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Second Line ◽

Second Line Therapy ◽

Advisory Committees ◽

Free Survival ◽

Rituximab Maintenance ◽

Line Therapy

Abstract The intergroup PRIMA Phase III study was designed to investigate the potential benefit of 2-years of rituximab maintenance in patients with follicular lymphoma (FL) responding to one of three non-randomised first line immunochemotherapy treatments. The results of the final analysis with 36 months follow-up (Salles et al., Lancet 2011) demonstrated a significant reduction of the risk of progression or death with a hazard ratio (HR) of 0.55 in favour of patients randomized to rituximab maintenance. We present here the updated results with 3 additional years of follow-up. From December 2004 until April 2007, 1217 patients were enrolled from 223 centres and complete data were available for 1193 patients who had the following pre-induction treatment characteristics: median age 56 years [range 22–87]; 52% male; 90% Ann Arbor stage III-IV; 33% B symptoms; 56% bone marrow involvement; 4% ECOG performance status >1; 34% elevated LDH; 32% β2-microglobulin >3mg/L; FLIPI score 0-1 (21%), FLIPI 2 (36%), FLIPI 3-5 (43%). Most patients (75%) received R-CHOP induction (22% R-CVP, 3% R-FCM). Patients responding to induction therapy were stratified based on their immunochemotherapy regimen and response [CR/CRu versus PR] and randomized to observation or rituximab maintenance, 1 infusion (375 mg/m2) every 8 weeks for 2 years. A total of 1018 randomised patients were analyzed according to the ITT principle (513 observation / 505 rituximab maintenance). All initial pre-treatment characteristics were well balanced between arms and the response status at time of randomization was CR=39%; CRu=32% and PR=28% (others 1%). With a median follow-up of 73 months from randomization, 6-year progression free survival estimate was 42.7% (95% CI 38 – 46.9%) in the observation arm (284 events, median=48 months) and 59.2% (95% CI 54.7 – 63.7%) in the rituximab maintenance arm (194 events, median not reached), respectively (stratified Log-Rank, P<. 0001; HR = 0.58 ; 95% CI 0.48 - 0.69). In pre-planned analyses of patients subgroups categorized by age, sex, FLIPI score category, induction chemotherapy and response to induction, the effect of rituximab maintenance was examined and found to be consistent among these different subgroups. In a Cox regression multivariate analysis, rituximab maintenance (HR=0.57; P<.0001) as well as older age (HR=0.79; P=.015), female sex (HR=0.72; P=.0003) and low or intermediate FLIPI groups (HR=0.67; P<.0001) were all significant variables associated with superior progression free survival. A significant reduction in the risk of starting a new anti-lymphoma treatment (HR=0.63, 95% CI 0.52 - 0.76) or starting a new chemotherapy (HR=0.70, 95% CI 0.57 - 0.86) were also observed for rituximab maintenance. The rate of histological transformation did not appear to differ between the 2 treatment arms: in the observation arm, transformation was documented in 24 patients (114 cases with morphological documentation out of 278 progressions) versus 16 patients in the rituximab maintenance arm (80 out of 186) respectively. Overall response rate to second-line therapy was reported by investigators to be 180/227 (79%) in patients from the observation arm (CR/CRu=61%; PR=19%) versus 109/144 (76%) in patients from the rituximab maintenance arm (CR/CRu =51%; PR=22%) (P=NS). At the time of the data cut-off, overall survival (OS) remains favourable in both study arms: 58 patients (11.3%) have died in the observation arm (6-years OS estimate 88.7%) compared to 59 patients (11.7%) in the rituximab maintenance arm (6-year OS estimate 87,4%). Main causes documented for death in the observation and rituximab maintenance arm respectively were lymphoma (28 ; 28), other malignancy (19 ; 5) and infections (4 ; 7). No new significant safety data were captured with this additional follow-up period. In conclusion, with 3 additional years of follow-up, these data demonstrate a sustained and persistent benefit of 2 years of rituximab maintenance therapy after immunochemotherapy, resulting in improved progression free survival. No additional or unexpected long term toxicities were observed and second line therapy efficacy results did not significantly differ between the 2 study arms. Overall survival appears very favourable for these randomized patients. Disclosures: Salles: Roche: Consultancy, Honoraria, Research Funding. Seymour:Roche: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau, Travel support Other; Genetech: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Feugier:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Offner:Lilly: Membership on an entity’s Board of Directors or advisory committees. Lopez-Guillermo:Roche: Membership on an entity’s Board of Directors or advisory committees. Belada:Roche: Consultancy. Catalano:Roche: Membership on an entity’s Board of Directors or advisory committees. Haioun:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Simpson:Janssen Research & Development: Honoraria. Leppa:Roche: Consultancy, Honoraria, Research Funding, Travel support Other. Soubeyran:Roche: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Hagenbeek:Takeda/Millennium: Consultancy. Casasnovas:ROCHE: Consultancy, Honoraria, Research Funding. Coiffier:Millennium Pharmaceuticals : Consultancy. Tilly:Roche: Honoraria; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity’s Board of Directors or advisory committees; Pfizer: Honoraria; Janssen: Honoraria; Amgen: Research Funding.

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Bortezomib-Thalidomide-Dexamethasone Incorporated Into Autotransplantation Is Associated with More Favorable Outcomes After Relapse in Comparison with Thalidomide-Dexamethasone Plus Autotransplantation in Multiple Myeloma

Blood ◽

10.1182/blood.v120.21.4210.4210 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4210-4210 ◽

Cited By ~ 1

Author(s):

Michele Cavo ◽

Monica Galli ◽

Lucia Pantani ◽

Francesco Di Raimondo ◽

Claudia Crippa ◽

...

Keyword(s):

Board Of Directors ◽

Salvage Therapy ◽

Treated Group ◽

Second Line ◽

Front Line ◽

Second Line Therapy ◽

Advisory Committees ◽

Free Interval ◽

Line Therapy

Abstract Abstract 4210 In a previous analysis performed with a median follow-up of 36 months (mos), superior CR/nCR rates and extended PFS were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) vs thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autotransplantation (ASCT) for newly diagnosed myeloma (MM). Here we report an updated analysis of that study, including a detailed analysis of outcomes after relapse or progression (R/P), an important issue for patients (pts) who received up-front a triplet novel agent-based therapy incorporated into ASCT. After a median follow-up of 52 mos, continued TTP and PFS benefits with VTD vs TD were demonstrated, while no difference in OS was seen between the two arms. Median PFS for pts randomized to the VTD arm was 56 mos vs 42 mos for those assigned to TD (HR=0.64, p=0.001). Similarly to PFS, median TTP for pts in the VTD group was longer than in the TD group (57 vs 45 mos, HR=0.63, p=0.0006), reflecting a 37% reduction in the risk of R/P with VTD. The probabilities of R/P in the VTD and TD arms were 41% vs 55% (p=0.002). In comparison with the VTD-treated group, a higher percentage of pts in the TD arm required the immediate start of salvage therapy after symptomatic R/P was documented (67% vs 82.5%). By the opposite, the fraction of pts with asymptomatic R/P that did not require any antimyeloma therapy until the cut-off date for the analysis was higher in the VTD arm compared with the TD-treated group (33% vs 17.5%, p=0.016). In these pts, the median interval from the date of R/P to the cut-off date for the analysis was 7 mos for the TD-treated group vs 17 mos for the VTD-treated group. Median time to subsequent antimyelomatherapy (defined as the interval between start of induction therapy and administration of the first dose of second-line therapy) was significantly longer for pts who experienced R/P in the VTD arm in comparison with pts who progressed in the TD arm (35 vs 29 mos, p=0.018). The associated interval between last administration of front-line therapy (e.g. consolidation for pts who received the entire treatment program or every other treatment before consolidation for those who discontinued earlier) and first administration of second-line therapy (salvage therapy-free interval) was 22.5 mos for the VTD-treated group vs 15 mos for the TD-treated group (p=0.009). Both bortezomib and lenalidomide were the most frequently used agents at the time of R/P (82% of all cases), while only 18% of pts were treated with conventional cytotoxic drugs. As expected, the majority of pts in the TD arm received a second-line therapy that included bortezomib (70%), while lenalidomide-dexamethasone was received by 10% of pts. By the opposite, in the VTD arm both bortezomib- and lenalidomide-based salvage therapies were equally distributed (41% vs 39%). The probability to achieve at least a partial response after second-line therapy including bortezomib was 60% for pts with prior exposure to VTD vs 63% for those randomized to TD. No difference in post-R/P OS was demonstrated between VTD-treated and TD-treated subgroups of pts who received bortezomib-based salvage therapy after R/P (2-yr estimates: 48% vs 53%, p=0.59). In the overall population, post-R/P OS was significantly shorter for pts who received salvage therapy with conventional cytotoxic drugs (2-yr estimate: 41%) in comparison with pts treated with novel agents, including bortezomib or lenalidomide (2-yr estimates: 52% and 53%, respectively) (p=0.0001). In conclusion, front-line therapy with VTD incorporated into ASCT was superior in comparison with TD plus ASCT in terms of extended TTP, PFS, time to subsequent antimyeloma therapy and salvage therapy-free interval. VTD-treated pts had a higher probability than TD-treated pts to experience long-lasting asymptomatic R/P not requiring second-line therapy. VTD-treated and TD-treated pts who subsequently received bortezomib-based salvage therapies had similar rates of response and post-R/P OS. This finding suggests that short-term exposure to VTD, as planned in our study, did not favor the selection of bortezomib-resistant clones, thus allowing to rechallenge bortezomib as (part of) second-line therapy after symptomatic R/P. Disclosures: Cavo: Janssen, Celgene, Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria. Di Raimondo:Celgene, Janssen: Honoraria, Speakers Bureau. Offidani:Janssen, Celgene: Honoraria. Caravita:Celgene, Janssen, Novartis, Genzyme: Honoraria. Boccadoro:Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.

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Genes Influencing the Development and Severity of Chronic ITP Identified through Whole Exome Sequencing

Blood ◽

10.1182/blood.v126.23.73.73 ◽

2015 ◽

Vol 126 (23) ◽

pp. 73-73 ◽

Cited By ~ 3

Author(s):

Jenny M. Despotovic ◽

Linda M. Polfus ◽

Jonathan M. Flanagan ◽

Carolyn M. Bennett ◽

Michele P Lambert ◽

...

Keyword(s):

T Cell ◽

Board Of Directors ◽

Research Funding ◽

Second Line ◽

Second Line Therapy ◽

Advisory Committees ◽

Chronic Itp ◽

Line Therapy ◽

Whole Exome ◽

Phenotype Data

Abstract Background: Chronic immune thrombocytopenia (ITP) is a complex autoimmune disease characterized by antibody mediated platelet destruction and impaired production. Sustained autoimmunity in chronic ITP appears to be due to generalized immune dysregulation including altered T cell balance with a shift toward immune activation (increased Th1/Th2 ratio) as well as decreased number and impaired function of regulatory T cells (Treg). The cause of these abnormalities has not been fully elucidated and is likely multifactorial, but genetic factors may be involved in ITP pathogenesis. Improved understanding of genetic influences could lead to novel therapeutic approaches. Aim: To identify genetic variants that may be involved in chronic ITP susceptibility and severity. Methods: Whole exome sequencing (WES) was performed on 262 samples with robust phenotype data on children with chronic ITP from the North American Chronic ITP Registry (NACIR, n= 173) and the Platelet Disorders Center at the Weill-Cornell Medical Center (n=89). All but three patients were ≤19 years old at diagnosis; 83% had primary ITP, 10% had Evans syndrome, 7% had other autoimmune disorders. Sequencing data for ITP cases of European American (EA) ancestry were compared to EA controls with platelets >150 x 109/L sequenced in the Atherosclerosis Risk in Communities (ARIC) Study (N=5664) to identify candidate genes associated with ITP susceptibility. Analyses filtered variants on a minor allele frequency (MAF) <0.01 as well as functionality of nonsynonymous, stop gain, splicing, stop loss, and indel variants. Both Fisher-Exact tests of single variants and Firth logistic regression for gene-based tests, accounting for an unequal proportion of cases compared to controls, were used. A Bonferroni corrected threshold based on 16,532 genes was calculated at 3.0x10-6. In a separate analysis, phenotype data for ITP cases were reviewed and cases stratified by disease severity according to second line treatment needed (Yes =139, No=113) and compared to ARIC EA controls with platelet count >150 x 109/L (N=5664). Results: Several damaging variants identified in genes involved in cellular immunity had a significantly increased frequency in the EA ITP cohort (Table). The most significant associations were detected in the IFNA17 gene, which is involved in TGF-β secretion and could affect number and function of the Treg compartment. IFNA17 rs9298814 (9:21227622 A>C) was identified in 26% of cases in the EA ITP cohort compared to <0.01% of EA controls, and other low frequency but presumed deleterious variants were also identified in IFNA17. IFNA17 gene variants remained significant in the most severely affected patients, specifically those requiring second line therapy, providing further evidence for this gene's functional relevance in the pathogenesis and pathophysiology of ITP. Other genes with known impact on T cell number or function, including DGCR14, SMAD2 and CD83 also contained variants with increased frequency in the EA ITP cohort. IFNLR1 and REL genes were also significantly associated with need for second line ITP therapy. Analysis of this large cohort did not validate any of over 20 variants that have been previously published as candidates for ITP susceptibility or evolution to chronic ITP. Conclusion: Damaging variants in genes associated with cellular immunity have an increased frequency in children with chronic ITP compared to controls, providing further evidence for the role of T cell abnormalities in the pathophysiology of ITP. The IFNA17 and IFNLR1 genes maintained significance when the ITP cohort was stratified according to disease severity, and may be important candidate genes involved in immune regulation and sustained autoimmunity associated with chronic ITP. Table. Genes identified through WES analysis of children with chronic ITP. Gene Function Relevant to ITP Pathophysiology Minor Allele Count (MAC)Cases Controls p value EA Chronic ITP vs. EA ARIC (non-ITP) controls N=172 N=5664 IFNA17 Treg, TGF-β signaling 91 17 3.97x10-13 DGCR14 IL-17 induction 14 3 1.27x10-10 SMAD2 TGF-β signaling 1 0 5.62x10-22 CD83 Th17/Treg balance 2 3 1.67x10-6 EA Chronic ITP requiring Second Line Therapy vs. EA ARIC (non-ITP) controls N=139 N=5664 IFNLR1 Class II cytokine receptor 2 1 3.95x10-15 IFNA17 Treg, TGF-β signaling 75 17 3.40x10-7 REL T and B cell function, inflammation 2 0 1.39x10-14 Disclosures Off Label Use: Off-label use of CliniMACS purified CD34+ cells. Lambert:GSK: Consultancy; NovoNordisk: Honoraria; Hardin Kundla McKeon & Poletto: Consultancy. Recht:Baxalta: Research Funding; Kedrion: Consultancy. Bussel:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; protalex: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; rigel: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Practice Patterns of Re-Initiation of Therapy at Time of Relapse or Progression Post- Autologous Stem Cell Transplant (ASCT) Among Patients with AL Amyloidosis

Blood ◽

10.1182/blood.v128.22.3444.3444 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3444-3444 ◽

Cited By ~ 1

Author(s):

Yi L. Hwa ◽

Rahma Warsame ◽

Morie A. Gertz ◽

Francis K Buadi ◽

Martha Q. Lacy ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Practice Patterns ◽

Autologous Stem Cell Transplant ◽

Al Amyloidosis ◽

Cell Transplant ◽

Second Line ◽

Second Line Therapy ◽

Advisory Committees ◽

Line Therapy

Abstract Background: Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur (Milani and Dispenzieri, International Society of Amyloidosis 2016). AL amyloidosis patients who are treated with high dose chemotherapy followed by autologous stem cell transplant (ASCT) are a relatively low-risk and homogenous population, making them an ideal group to study practice patterns. Methods: We conducted a retrospective study to evaluate the patterns of relapse or progression and the timing of re-initiation of therapy among 146 patients who were initially treated with ASCT at Mayo Clinic between 1996 and 2009 and who received second-line therapy between 7/9/1997 and 4/12/2012. Results: The median time from ASCT to second-line therapy was 23.6 months and the median follow up post ASCT was 57.5 months. The indications for second-line treatment were: 1) both hematologic and organ progression 24.7% (36 patients); 2) organ progression only 41.1% (60); 3) hematologic relapse only 34.2% (50). The median dFLC at the time of starting second-line therapy was 10.5 mg/dL (1.6 - 59.5 mg/dL), which was 44.9% (13.8-167.2%) of dFLC level at diagnosis. Increase in proteinuria by > 50% from nadir (that was also at least 1g/24 hours, i.e. renal progression) was present in 35.8%. Increase in NT proBNP by >30% from nadir and minimum of 300 pg/mL was present in 48.9% of patients. The respective 4 years overall survival rates from the time of ASCT were 87.8%, 63.9%, and 56.7% (p=0.0016) for patients who had hematologic relapse, organ progression only and both organ and hematologic progression. Comparisons of laboratory markers at diagnosis, nadir of post ASCT and initiation of second-line therapy are listed in the table. Conclusions: Our study investigated the patterns of relapse / progression following upfront ASCT. This provides some insights on practice patterns of when physicians re-initiate therapy. Table Table. Disclosures Gertz: NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Novartis: Research Funding; Prothena Therapeutics: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria; Ionis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding. Kumar:Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Kesios: Consultancy. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Real-World Outcomes for Pediatric and Young Adult Patients with Relapsed or Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (ALL) Treated with Tisagenlecleucel: Update from the Center for International Blood and Marrow Transplant Research (CIBMTR) Registry

Blood ◽

10.1182/blood-2021-146393 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 428-428

Author(s):

Samuel John ◽

Michael A. Pulsipher ◽

Amy Moskop ◽

Zhen-Huan Hu ◽

Christine L. Phillips ◽

...

Keyword(s):

Clinical Trial ◽

T Cell ◽

Board Of Directors ◽

Real World ◽

Research Funding ◽

Ad Hoc ◽

Age Groups ◽

Advisory Committees ◽

Advisory Boards

Abstract Background: Tisagenlecleucel is an autologous CD19-directed T-cell immunotherapy indicated in the USA for treatment of patients up to 25 years (y) of age with B-cell ALL that is refractory or in second or later relapse. Overall response rate was 82% with 24 months' (mo) follow-up in the registrational ELIANA trial [Grupp et al. Blood 2018]; pooled data from ELIANA and ENSIGN revealed similar outcomes upon stratification by age (<18y and ≥18y) [Rives et al. HemaSphere 2018]. Early real-world data for tisagenlecleucel from the CIBMTR registry reported similar efficacy to ELIANA with no new safety signals [Pasquini et al. Blood Adv 2020]. Outcomes are reported here for patients who received tisagenlecleucel in the real-world setting, stratified by age (<18y and ≥18y). Methods: This noninterventional prospective study used data from the CIBMTR registry and included patients aged ≤25y with R/R ALL. Eligible patients received commercial tisagenlecleucel after August 30, 2017, in the USA or Canada. Age-specific analyses were conducted in patients aged <18y and ≥18y at the time of infusion. Efficacy was assessed in patients with ≥12mo follow-up at each reporting center and included best overall response (BOR) of complete remission (CR), duration of response (DOR), event-free survival (EFS), relapse-free survival (RFS) and overall survival (OS). Safety was evaluated in all patients who completed the first (100-day) assessment. Adverse events (AEs) of interest - including cytokine release syndrome (CRS) and neurotoxicity - were monitored throughout the reporting period. CRS and neurotoxicity were graded using the ASTCT criteria. Results: As of October 30, 2020, data from 451 patients were collected, all of whom received tisagenlecleucel. The median time from receipt of leukapheresis product at the manufacturing site to shipment was 27 days (interquartile range: 25-34). Patients aged ≥18y appeared to have greater disease burden at baseline than those aged <18y, indicated by lower rates of morphologic CR and minimal residual disease (MRD) negativity prior to infusion. Older patients were also more heavily pre-treated before infusion. All other patient characteristics at baseline were comparable between the two groups (Table 1). In the efficacy set (median follow-up 21.5mo; range 11.9-37.2; N=322), BOR of CR was 87.3% (95% CI 83.1-90.7); MRD status was available for 150 patients, of whom 98.7% were MRD negative. Median DOR was 23.9mo (95% CI 12.3-not estimable [NE]), median EFS was 14.0mo (9.8-24.8) and median RFS was 23.9mo (13.0-NE); 12mo EFS and RFS were 54.3% and 62.3%, respectively. For OS, the median was not reached. Efficacy outcomes were generally similar across age groups (Table 1). In the safety set (median follow-up 20.0mo; range 2.6-37.2; N=400), most AEs of interest occurred within 100 days of infusion. Any-grade CRS was observed in 58.0% of patients; Grade ≥3 in 17.8%. Treatment for CRS included tocilizumab (n=113; 28.3% of all patients) and corticosteroids (n=31; 7.8%). Neurotoxicity was observed in 27.3% of patients; Grade ≥3 in 10.0%. Treatment for neurotoxicity included tocilizumab (n=17; 4.3% of all patients) and corticosteroids (n=28; 7.0%). During the reporting period, 82 (20.5%) patients died; the most common cause of death was recurrence/persistence/progression of primary disease. CRS and chimeric antigen receptor (CAR)-T cell-related encephalopathy syndrome were the primary cause of death in 2 patients and 1 patient, respectively. Overall, safety data were similar across age groups, although more patients aged ≥18y experienced any-grade CRS or neurotoxicity and were subsequently treated (Table 1). Conclusions: Updated registry data for pediatric and young adult patients with R/R ALL treated with tisagenlecleucel revealed that patients aged ≥18y had a greater disease burden and were more heavily pre-treated at baseline than patients aged <18y. The overall efficacy and safety profiles of commercial tisagenlecleucel reflected those observed in the clinical trial setting [Grupp et al. Blood 2018; Rives et al. HemaSphere 2018] and were broadly consistent across age groups. Some important differences between the <18y and ≥18y groups were identified, which may point to challenges in timely identification and/or referral of older patients for CAR-T cell therapy. Figure 1 Figure 1. Disclosures Pulsipher: Equillium: Membership on an entity's Board of Directors or advisory committees; Adaptive: Research Funding; Jasper Therapeutics: Honoraria. Hu: Kite/Gilead: Research Funding; Novartis: Research Funding; Celgene: Research Funding. Phillips: Novartis: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees. Margossian: Cue Biopharma, Inc.: Current Employment; Novartis: Other: Ad hoc Advisory Boards. Nikiforow: Kite/Gilead: Other: Ad hoc advisory boards; Novartis: Other: Ad hoc advisory boards; Iovance: Other: Ad hoc advisory boards; GlaxoSmithKline (GSK): Other: Ad hoc advisory boards. Martin: Novartis: Other: Local PI for clinical trial; Bluebird Bio: Other: Local PI for clinical trial. Rouce: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Tessa Therapeutics: Research Funding; Pfizer: Consultancy. Tiwari: Novartis Healthcare private limited: Current Employment. Redondo: Novartis: Current Employment. Willert: Novartis: Current Employment. Agarwal: Novartis Pharmaceutical Corporation: Current Employment, Current holder of individual stocks in a privately-held company. Pasquini: Kite Pharma: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Grupp: Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy; Novartis, Kite, Vertex, and Servier: Research Funding; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding.

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Patient Profile and Treatment Patterns in a Commercially Insured Population with Follicular Lymphoma

Blood ◽

10.1182/blood-2019-127237 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5880-5880

Author(s):

Nathan H Fowler ◽

Yanni Hao ◽

Stephen Lim ◽

Guifang Chen ◽

Frank Li ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Second Line ◽

First Line ◽

Advisory Committees ◽

First Line Therapy ◽

Line Therapy ◽

Third Line ◽

Line Of Therapy

Introduction: Follicular lymphoma (FL) is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. Patient characteristics and burden of FL are incomplete and vary from previous studies. This study evaluated patient profile, including patient characteristics, treatment patterns, and duration using real-world data. Methods: Using the Truven MarketScan® databases, patients with FL who were newly initiated with FL indicated regimens were identified from 1/1/2010-12/31/2013 (initial treatment identification period). Patients were selected if they were ≥18 years old, had 1 FL ICD-9 code (202.0) as primary or secondary diagnosis, at least 1 FL commonly prescribed systemic anti-cancer therapy after the diagnosis, and did not use any FL indicated regimen in the past 6 months prior to first agent included in the initial treatment identification period. These patents were followed ≥3 months or to June 30, 2018. Primary outcomes were the distribution of regimens by line, the number of patients who switched from first- to second-line therapies, and from second- to third-line therapies. The treatment duration by line of therapy and regimen were also analyzed. Discontinuation was defined as 3 months without receiving a regimen after treatment. Results: This study identified 4,970 patients who initiated treatment for FL. Of these patients, 48.1% were female (n=2,390), with a mean age of 62.0 (SD: 14.0) years. The average follow-up time was approximately 2 years (median: 733 days). In this analysis, 4,970 patients with FL received first-line therapy for 153 days (median: 94 days), 1,985 received second-line therapy (39.9% of patients who received first-line therapy) for 208 days (median: 80 days), and 664 received third-line therapy (13.4% of patients who received first-line therapy) for 117 days (median: 43 days). Of the 4,970 patients on first-line therapy, 453 (9.1%) remained on first-line therapy, 2,532 (51.0%) discontinued treatment, and 1,985 (39.9%) patients switched to the next line of therapy during the follow-up period. Of the 1,985 patients who switched to second-line therapy, 328 (16.5%) remained by the end of follow-up period, 993 (50.0%) discontinued, and 664 (33.4%) switched to the next line of therapy during the follow-up period. Of the 664 patients who switched to third-line therapy, 125 (18.8%) remained, 269 (40.5%) discontinued, and 270 (40.7%) switched to the next line of therapy. The most common first-line regimens in descending order received by patients were rituximab (n=1,478, 29.7%), R-CHOP (n=1,368, 27.5%), BR (n=1,050, 21.1%), R-CVP (n=371, 7.5%), and FCR (n=63, 1.3%). Second-line treatment regimens were (N=1,985) rituximab (n=992, 50.0%), BR (n=202, 10.2%), R-CHOP (n=138, 7.0%), and R-CVP (n=120, 6.1%). Third-line treatment regimens were (N=664) rituximab (n=228, 34.3%), BR (n=91, 13.7%), R-CHOP (n=75, 11.3%), cyclophosphamide (n=35, 5.3%) and R-CVP (n=31, 4.7%). Conclusion: This data set describes the percentage of patients that transition from first- to second-line and second- to third-line treatment for FL. The primary regimens used across the treatment lines conform to those recommended by the NCCN guidelines. In addition, smaller numbers of non-recommended regimens were reported. Disclosures Fowler: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; ABBVIE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis Pharmaceuticals Corporation: Consultancy; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding. Hao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Lim:Novartis Pharmaceuticals Corporation: Employment. Chen:Novartis Pharmaceuticals Corporation: Consultancy, Employment. Li:Novartis Pharmaceuticals Corporation: Employment. Arcona:Novartis Pharmaceuticals Corporation: Employment.

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Improved Progression-Free Survival (PFS) of Alemtuzumab (Campath®, MabCampath®) Plus Fludarabine (Fludara®) Versus Fludarabine Alone as Second-Line Treatment of Patients with B-Cell Chronic Lymphocytic Leukemia: Preliminary Results From a Phase III Randomized Trial.

Blood ◽

10.1182/blood.v114.22.537.537 ◽

2009 ◽

Vol 114 (22) ◽

pp. 537-537 ◽

Cited By ~ 2

Author(s):

Andreas Engert ◽

Liana Gercheva ◽

Tadeusz Robak ◽

Pilipenko Galina ◽

Jingyang Wu ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Progression Free Survival ◽

Lymphocytic Leukemia ◽

Phase Iii ◽

Second Line ◽

Second Line Therapy ◽

Advisory Committees ◽

Free Survival ◽

Line Therapy

Abstract Abstract 537 Introduction: Single-arm pilot and Phase II trial data suggested that the combination of fludarabine and alemtuzumab (FluCam) may improve outcome for patients (pts) with relapsed or refractory chronic lymphocytic leukemia (CLL). To validate these observations, a Phase III, multicenter, open-label, randomized study was conducted to compare the efficacy and safety of FluCam vs. fludarabine (Flu) alone as second-line therapy for pts with relapsed or refractory CLL. Methods: Patients with Rai Stages I-IV were randomized to FluCam or Flu using the minimization method to ensure a balance between treatment arms by study center, Rai stage, disease status, age, sex, prior Flu therapy, and maximum lymph node (LN) size. FluCam was administered in Phases A and B. Patients received escalating doses of intravenous (IV) alemtuzumab alone (Phase A). Once alemtuzumab 30 mg IV was tolerated, pts received FluCam as Flu 30 mg/m2 IV followed immediately by alemtuzumab 30 mg IV on days 1-3 of a 28 day cycle (Phase B). In the Flu arm, pts received 25 mg/m2IV on days 1-5 of a 28 day cycle. For both arms, all pts could receive up to six cycles depending on response and toxicity. All pts received prophylaxis with trimethoprim/sulfamethoxazole DS and famciclovir until CD4+ counts were ≥200 cells/μL. The primary endpoint was progression-free survival (PFS). Secondary endpoints were overall response (OR), complete response (CR), overall and 3 year survival, and safety. The primary analysis was based on the independent response review panel's (IRRP) assessment of response and date of progression for each patient. Two interim analyses were prospectively planned and conducted by the data and safety monitoring board (DSMB) with the final analysis planned after a total of 190 events. The 2nd interim analysis included 139 PFS events and met the pre-specified criteria; the DSMB recommended early study termination. Results: 335 pts were randomized (FluCam n=168 and Flu n=167); Rai Stage III-IV: 37%; median age: 60 years; prior Flu therapy: 20% and maximum LN size ≥5 cm: 14%. The median treatment cycles received were 6 for both arms. 60% of FluCam and 64% of Flu pts received 6 cycles of treatment. The median IRRP determined PFS for FluCam was significantly prolonged compared to Flu (29.6 months vs. 20.7 months, respectively; p=0.005; HR 1.63 [95% CI: 1.16, 2.28]; Figure 1). Median PFS by Rai Stage was: Stage I-II - 27.4 months for FluCam (n = 105) vs. 21.3 months for Flu (n = 103), p=0.215; Stage III-IV - 26.1 months for FluCam (n = 61) vs. 12.1 months for Flu (n = 62), p=0.003. Per investigator response assessment, FluCam resulted in significantly higher OR and CR rates (OR: FluCam 84.8% vs. Flu 67.9%, p<0.001; and CR: FluCam 30.4% vs. Flu 16.4%, p=0.002). The IRRP assessment of response was not completed for all pts and is not availabel for the 2nd interim analysis. No differences in survival have been observed (FluCam 37 deaths and Flu 41 deaths) with a median follow up of 17 months. Adverse events (AEs) occurring in >10% of the pts included pyrexia, neutropenia, leukopenia, thrombocytopenia, anemia, chills, lymphopenia, rash, infusion related reactions, nausea and urticaria in the FluCam arm; and, neutropenia, thrombocytopenia, anemia and leukopenia in the Flu arm. Treatment-emergent grade 3/4 thrombocytopenia (18% vs. 22%), neutropenia (60% vs. 66%) and anemia (13% vs. 22%) were comparable in FluCam vs. Flu arms. Overall, 33% (n=54) of pts in the FluCam arm experienced a SAE vs. 26% (n=42) in the Flu arm. Reported SAEs for neutropenia were 4.9% in the FluCam arm and 1.8% in the Flu arm; however, febrile neutropenia was similarly reported in the two arms 3.7% vs 3.6% of pts, respectively. Infections including CMV occurred in 47% and 35% of the FluCam and Flu pts, respectively. Symptomatic CMV infection occurred only in the FluCam arm in 8% of pts, of which 1% were SAEs and 0% classified as grade 4 or higher. Deaths occurring on therapy or within 30 days after last dose were 2% on the FluCam arm vs. 5% on the Flu arm. Conclusions: The 2ndinterim analysis indicates that the combination of FluCam is superior to Flu as second-line therapy for pts with relapsed or refractory CLL, including those with advanced disease stage. With significantly longer PFS, higher OR and CR rates, an acceptable safety profile and a convenient administration regimen, FluCam may be an additional second-line treatment option for pts with relapsed or refractory CLL. Disclosures: Engert: Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Alemtuzumab (Campath, MabCampath) is indicated for the treatment of CLL. This trial examined the use of alemtuzumab in combination with fludarabine monophospate.. Gercheva:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Robak:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Galina:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Wu:Genzyme Corporation: Employment. Sirard:Genzyme Corporation: Employment. Elter:Genzyme Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Real-World Treatment Patterns and Outcomes Among Patients with Hairy Cell Leukemia

Blood ◽

10.1182/blood.v126.23.2125.2125 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2125-2125

Author(s):

Sudeep Karve ◽

Victoria Divino ◽

Andrew Gaughan ◽

Mitch DeKoven ◽

Guozhi Gao ◽

...

Keyword(s):

Health Plan ◽

Real World ◽

Index Date ◽

Treatment Patterns ◽

Second Line ◽

First Line ◽

Second Line Therapy ◽

First Line Therapy ◽

Line Therapy

Abstract Background and Objective : Hairy cell leukemia (HCL) is a rare condition and accounts for ~2% of all leukemia cases in the US. NCCN guidelines recommend first-line agents including pentostatin and cladribine among patients with HCL. However, a paucity of data exists with regard to real-world treatment patterns among patients with HCL. Current study evaluates treatment patterns and associated clinical outcomes among patients with HCL using a large US administrative claims database. Methods : This retrospective observational study was conducted using the IMS Health PharMetrics Plus Health Plan Claims Database (2006-2014), which includes over 150 million unique health plan members across the US and is nationally representative of the commercially-insured US population. Data includes date stamped medical and pharmacy records along with information on health plan enrollment. Individuals with at least 2 medical claims with a diagnosis for HCL (identified using ICD-9-CM cod: 202.4x) were selected and the first observed claim defined the "index date." Patients <18 years of age at index date or with other malignancies during 6 months (the "pre-index period") prior to index date were excluded. Patients were required at least 90 days of continuous enrollment (the variable "follow-up period") in the health plan post index date with exception of patients who died within 3 months of diagnosis. Patients were followed until death (recorded on inpatient discharge disposition), end of enrollment or end of database, whichever occurred earlier. Study measures including patient demographic and baseline clinical characteristics, line of therapy (LOT), treatment patterns, relapse (receipt of same or new regimen in subsequent LOT following a gap of 365 days) and refractory disease (receipt of same or new regimen where the gap of two adjacent LOTs was <365 days) and post-treatment complications were assessed during the follow-up period. All analyses were descriptive in nature. Results : The study cohort included 749 patients after applying the selection criteria (mean follow-up from diagnosis 32 months). At diagnosis, the mean age (standard deviation) of the study cohort was 56 (10) years and majority of patients were male (77%). Mean baseline comorbidity burden (assessed using Charlson Comorbidity Index score) was 0.8 (1.1) with hypertension (24%) and aplastic anemia (22%) being the two most common co-morbidities. Only 38% (n=282) of patients received first-line chemotherapy post diagnosis. Majority initiated first-line cladribine (76%) as a single agent, while 9% had evidence of single agent pentostatin. Mean time to initiation of first-line therapy from diagnosis was 132 (294) days and average time on first-line therapy was 34 (104) days. Among patients with first-line therapy 14% received second-line therapy and rituximab (53%) and cladribine (21%) were frequently observed second-line agents. Post first-line therapy, mean time to initiation of second-line therapy was 303 (406) days. Among second-line initiators, 76% had refractory disease and 24% had relapsed following first-line. Neutropenia and fever were frequently reported complications while on chemotherapy. Conclusion : The real-world chemotherapy utilization patterns observed in this study are consistent with the NCCN guidelines with cladribine and pentostatin being the agents of choice for first-line therapy. Following diagnosis, more than one-third of patients initiated chemotherapy and only a small proportion of these received second-line chemotherapy suggesting durable response with first-line therapy. Limited follow-up post first-line therapy may have impacted the proportion of patients initiating second-line therapy as well as categorization of refractory and relapse disease. Disclosures Karve: AstraZeneca: Employment. Divino:IMS Health: Employment, Other: IMS Health received funding from AstraZeneca for this study. Gaughan:AstraZeneca: Employment. DeKoven:IMS Health: Employment, Other: IMS Health received funding from AstraZeneca for this study. Gao:MedImmune: Employment. Lanasa:MedImmune: Employment.

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