Examining the Outcomes of Watchful Waiting (WW) Among US Patients with Advanced Stage Follicular Lymphoma (FL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 775-775 ◽  
Author(s):  
Rajni Sinha ◽  
Michelle Byrtek ◽  
Nutan J. DeJoubner ◽  
Ajay K. Nooka ◽  
Michael Taylor ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Research Funding ◽  
Cox Regression ◽  
Single Agent ◽  
Advanced Stage ◽  
Free Survival ◽  
Multivariable Logistic Regression ◽  
Starting Point ◽  
Significant Difference

Abstract Abstract 775 Introduction: WW has been an initial strategy for advanced stage FL because randomized trials showed no clear benefit for immediate initiation of therapy with single agent alkylators when compared to deferring therapy (Brice, JCO 1997; Ardeshna, Lancet 2003), although a recent trial raises questions about WW in the era of rituximab (R) based frontline therapies (Ardeshna, ASH Meeting 2010). Methods: The NLCS is a prospective, multicenter, observational study collecting data on 2,738 newly diagnosed pts with FL diagnosed from 2004–2007 at 265 US sites (80% non-academic). Initial management decisions were made by the treating physician and were categorized as WW (for pts who did not receive therapy in the 90 period following diagnoses and were coded by physicians as WW) or active therapy (AT) including: R alone, R-chemotherapy (RChemo), or other. Baseline clinical factors and treatment setting were compared for WW and AT pts using multivariable logistic regression. Kaplan-Meier (KM) estimation and Cox models were used to evaluate progression-free survival (PFS), time to 2nd and 3rd line management strategy (TT2, TT3), transformation-free survival (TFS), PFS following 1st AT, and overall survival (OS). Due to differences between WW and AT groups, adjusted Cox regression models are presented for the primary analysis of study endpoints controlling for sex, community vs. academic practice site, FL grade, and FLIPI. All time to event analyses were calculated from the 90 day period following diagnosis to allow enrollment in WW, and PFS was calculated from the starting point to the clinician's recording of progressive disease (PD) or death. Results: Among 1,737 pts presenting with stage III/IV FL in the analysis population, 237 underwent WW and 1,500 received AT immediately following diagnosis including: 241 pts treated with R, 1046 with RChemo, 26 with radiation, and 187 other therapies. Multivariable logistic regression demonstrated that the following pt characteristics were predictive of selection of WW rather than initial AT: age > 60 years, no B-symptoms, FL grade 1 or 2, ECOG PS = 0, ≤1 extranodal sites involved, and LDH ≤ULN (all p < 0.05). Median PFS and TT2 were 27 and 35 months for WW, and 64 months and not reached for AT. With a median follow-up of 55 months, 17% of WW pts and 19% of AT pts have died, with no significant difference in OS between WW and AT (p = 0.31). Compared with WW, RChemo improved PFS: adjusted Hazard Ratio (HR) = 0.36, TFS: HR=0.65, TT2: HR=0.48, and TT3: HR=0.53, all p<0.01. For most of the 145 WW pts that later initiated an AT, PD was recorded as the reason for treatment (83%). ATs following WW were: R (51, 35%), RCVP (21, 14%), RCHOP (16, 11%), R + other chemo (23, 16%), investigational (15, 10%), chemo alone (9, 6%), radiation (8, 6%), BMT (1, 1%), or other therapy (1, 1%). The median PFS for R was 42 months when given at diagnosis and 55 months when given following WW. The median PFS for RChemo was 71 months when given at diagnosis and 37 months when given following WW. After adjustment for FLIPI, FL grade, sex, practice setting, and type of treatment, WW adversely affected PFS following 1st AT, H=2.02, p <0.0001. Conclusions: FL pts in the US who undergo initial WW are treated at a median of nearly 3 years. Median PFS following RChemo, but not R is shorter when utilized after period of WW than at diagnosis – albeit in different clinical circumstances. Additional follow-up is needed to assess the tradeoff of this time without therapy with as yet no observable differences in OS. Disclosures: Sinha: CELGENE: Research Funding. Friedberg:Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees. Link:Genentech: Consultancy. Flowers:Spectrum: Consultancy, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Genentech/Roche (unpaid): Consultancy; Novartis: Research Funding; Seattle Genetics: Consultancy.

scholarly journals Head and neck cutaneous melanoma: 5-year survival analysis in a Serbian university center

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Aleksandar Višnjić ◽  
Predrag Kovačević ◽  
Asen Veličkov ◽  
Mariola Stojanović ◽  
Stefan Mladenović
Keyword(s):  
Survival Analysis ◽  
Head And Neck ◽  
Cutaneous Melanoma ◽  
Cox Regression ◽  
Total Sample ◽  
Advanced Stage ◽  
Cross Sectional ◽  
Cox Regression Analysis ◽  
Significant Difference

Abstract Background Head and neck melanoma (HNM) is specific from the anatomical and etiopathogenetic aspects. In addition to morphopathological parameters, rich vascularization and lymphatic drainage of the head and neck affect the occurrence of lymphogenic and hematogenous metastases, as well as the metastases on both sides of the neck. Methods A retrospective cross-sectional study included cutaneous melanoma patients who underwent surgery at a clinical center over a 10-year period. The clinical follow-up was at least 60 months. The Kaplan-Meier method was used for the survival analysis. The predictor effect of certain independent variables on a given dichotomous dependent variable (survival) was measured by the Cox regression analysis. Results The analysis of demographic and clinical characteristics of 116 patients with HNM revealed that there was no statistically significant difference in age and gender in the total sample. Thirty-three (28.45%) patients were already in stage III or IV of the disease at the first examination, which affected the overall survival rate. The overall 5-year survival was 30.2%. No statistically significant difference in 5-year survival was found in relation to age and location. The period without melanoma progression decreased progressively in the advanced stage. Forty-nine patients (42%) underwent surgery for lymphogenic metastases in the parotid region and/or neck during the follow-up. Conclusions Patients with HNM included in this study frequently presented an advanced stage of the disease at the first examination, which is reflected in a low rate of 5-year survival. Early diagnosis and adequate primary treatment can ensure longer survival.

ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1565-1565 ◽  
Author(s):  
Patrizia Mondello ◽  
Irene Dogliotti ◽  
Jan-Paul Bohn ◽  
Federica Cavallo ◽  
Simone Ferrero ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advanced Stage ◽  
Advisory Committees ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with &gt;90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= &lt;0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS &lt;3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Long-Term Follow-Up Analysis of HD9601 Trial Comparing ABVD Versus Stanford V Versus MOPP/EBV/CAD in Patients With Newly Diagnosed Advanced-Stage Hodgkin's Lymphoma: A Study From the Intergruppo Italiano Linfomi

2011 ◽  
Vol 29 (32) ◽  
pp. 4227-4233 ◽  
Author(s):  
Teodoro Chisesi ◽  
Monica Bellei ◽  
Stefano Luminari ◽  
Antonella Montanini ◽  
Luigi Marcheselli ◽  
...  
Keyword(s):  
Hodgkin’S Lymphoma ◽  
Disease Free Survival ◽  
Hodgkin's Lymphoma ◽  
Advanced Stage ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Free Survival ◽  
Significant Difference

Purpose The Intergruppo Italiano Linfomi HD9601 trial compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus doxorubicin, vinblastine, mechloretamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V [StV]) versus the combination of mechlorethamine, vincristine, procarbazine, prednisone (MOPP) with epidoxorubicin, bleomycin, vinblastine (EBV), lomustine, doxorubicin, and vindesine (CAD) (MOPP/EBV/CAD [MEC]) for the initial treatment of advanced-stage Hodgkin's lymphoma to select which regimen would best support a reduced radiotherapy program (limited to two or fewer sites of either previous bulky or partially remitting disease). Superiority of ABVD and MEC to StV was demonstrated. We report analysis of long-term outcome and toxicity. Patients and Methods Patients with stage IIB, III, or IV were randomly assigned among six cycles of ABVD, three cycles of StV, and six cycles of MEC; radiotherapy was administered in 76, 71, and 50 patients in the three arms, respectively. Results Currently, the median follow-up is 86 months; in the prolonged observation period, eight additional failures, including two relapses, both in the StV arm, and six additional deaths in complete response were recorded. The 10-year overall survival rates were 87%, 80%, and 78% for ABVD, MEC, and StV, respectively (P = .4). The 10-year failure-free survival was 75%, 74%, and 49% in the ABVD, MEC, and StV arms, respectively (P < .001). The 10-year disease-free survival of patients treated or not with radiotherapy (RT) showed no difference for ABVD or MEC (85% v 80% and 93% v 68%), and a statistically significant difference for StV (76% v 33%; P = .004). No significant long-term toxicity was recorded. Conclusion The long-term analysis confirmed ABVD and MEC superiority to StV. The use of RT after StV was established as mandatory. ABVD is still to be considered as the standard treatment with a good balance between efficacy and toxicity.

scholarly journals Follow-up Analysis of Ixazomib, Lenalidomide and Dexamethasone Versus Lenalidomide and Dexamethasone in Routine Clinical Practice

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2716-2716
Author(s):  
Jiri Minarik ◽  
Jakub Radocha ◽  
Alexandra Jungova ◽  
Jan Straub ◽  
Tomas Jelinek ◽  
...  
Keyword(s):  
Clinical Practice ◽  
Research Funding ◽  
Previous Analysis ◽  
Progression Free Survival ◽  
Routine Clinical Practice ◽  
Toxicity Profile ◽  
Advisory Committees ◽  
Free Survival ◽  
Significant Difference

Abstract Background: The addition of ixazomib to the doublet lenalidomide and dexamethasone (RD) in relapsed and refractory multiple myeloma (RRMM) has shown significant benefit in progression free survival (PFS) in the TOURMALINE-MM1 study. Several real-world data including our previous analysis confirmed that the combination IRD is feasible and with fair outcomes even outside the clinical trial. Here we report an updated analysis which is aimed at overall survival (OS) and the PFS2 interval which is defined as the time from the date of treatment initiation to the date of first documentation of progressive disease after initiation of further anti-myeloma treatment or death from any cause. Methods: We analyzed a cohort of 344 patients with RRMM, 127 being treated by IRD and 217 by RD combination. The group characteristics and study design are described elsewhere. 1 The median follow-up of the whole cohort was 28.5 months. The primary endpoint was OS, OS in patients with relapse 1-3, progression free survival (PFS), and PFS2. Secondary endpoints were response rates and toxicity profile. For statistical analysis we used Fisher's exact test or Mann-Whitney U test. Survival measures were assessed using the Kaplan-Meier methodology, and statistical significance was assessed using the log-rank test at a significance level of α = 0.05 (all tests two-sided). Results: The outcomes of OS in the whole cohort were already published before, with significantly longer median OS in the IRD vs RD cohort (mOS 36.6 months vs 26.0 months, p = 0.008).1 In the follow-up analysis, the medians were slightly improved, maintaining a significant difference (mOS 40.9 vs 27.1 months, p = 0.001). In patients treated within relapse 1-3, the results outcomes were even more pronounced (mOS 51.7 vs 27.8 months, p ˂ 0.001). The median PFS was also better in the IRD cohort (mPFS 17.5 vs 12.5 months, p = 0.013) but the results did not substantially differ from our previous analysis. The median PFS2 in the IRD vs RD cohort was significantly longer in the IRD cohort (mPFS2 29.8 vs 21.6 months, p = 0.016). The subsequent therapy included mostly pomalidomide (27.5% vs 30.8%), bortezomib (28.8% vs 28.2%) or thalidomide (10.0% vs 16.2%). Monoclonal antibodies (daratumumab, isatuximab) were more frequently used after IRD combination (21.3% vs 4.3%). The response rates in the IRD vs RD cohort were similar as in our primary analysis: overall response rate (ORR) 73.0% vs 66.8%, with significant difference in very good partial response and better (VGPR+) 38.1% vs 26.3%. The toxicity profile did not reveal any additional safety concerns. Majority of grade 3+ toxicities included hematological toxicity (anemia, neutropenia, thrombocytopenia) and infections, with similar distribution in the cohorts. Conclusion: The treatment of RRMM using the full oral IRD regimen in routine clinical practice is easy, safe and with significantly improved outcomes in comparison to RD doublet. Our follow-up analysis confirmed the impact on OS in patients in the whole cohort including relapse 1-3. The median PFS2 was also longer in the IRD cohort, possibly affected by more frequent use of monoclonal antibodies in the next treatment. With support of AZV 17-29343A, NV18-03-00500, MH CZ - DRO (FNOl, 00098892), IGA-LF-2021-001. 1) Minarik J, Pika T, Radocha J. et al. Survival benefit of ixazomib, lenalidomide and dexamethasone (IRD) over lenalidomide and dexamethasone (Rd) in relapsed and refractory multiple myeloma patients in routine clinical practice. BMC Cancer 2021; 21: https://doi.org/10.1186/s12885-020-07732-1 Disclosures Minarik: Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Hajek: Novartis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Pharma MAR: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Clinical and Genomic Factors Are Predictive of Response and Prognostic of Progression-Free Survival in Patients with Waldenström Macroglobulinemia Treated with Ibrutinib

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 2823-2823
Author(s):  
Jorge J. Castillo ◽  
Joshua Gustine ◽  
Maria Demos ◽  
Andrew Keezer ◽  
Kirsten Meid ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Serum Albumin ◽  
Research Funding ◽  
Regression Models ◽  
Progression Free Survival ◽  
Regression Analyses ◽  
Multivariate Logistic Regression ◽  
Free Survival ◽  
Lower Odds

Introduction: The Bruton tyrosine kinase inhibitor ibrutinib is the only FDA approved therapy for the treatment of symptomatic Waldenstrom macroglobulinemia (WM), and has been associated with high response rates and durable progression-free survival (PFS). Factors associated with depth of response and PFS duration are not well established. We performed a retrospective study aimed at identifying predictive and prognostic factors in WM patients treated with ibrutinib. Methods: We included consecutive patients with a diagnosis of WM treated with ibrutinib monotherapy evaluated at the Dana-Farber Cancer Institute since January 2012 through March 2019. Patients with Bing-Neel syndrome (WM involving the central nervous system) were excluded. Baseline clinical and laboratory characteristics were gathered. MYD88 and CXCR4 mutations were assessed using polymerase chain reaction assays and Sanger sequencing. Responses at 6 months were assessed using criteria from IWWM3. PFS was defined as the time from ibrutinib initiation until last follow-up, death or progression. Univariate and multivariate logistic regression models were fitted for partial response (PR) and very good partial response (VGPR) at 6 months, and Cox proportional-hazard regression models were fitted for PFS. Results: A total of 252 patients were included in our analysis. Selected baseline characteristics include: age ≥65 years (60%), hemoglobin <11.5 g/dl (68%), platelet count <100 K/uL (12%), albumin <3.5 g/dl (39%), b2-microglobulin ≥3 mg/l (70%), serum IgM level ≥7,000 mg/dl (6%), bone marrow involvement ≥60% (54%), previously untreated for WM (33%), time to ibrutinib <3 years (46%). MYD88 L265P and CXCR4 mutations were detected in 98% and 38% of patients, respectively. At 6 months, 71% of patients obtained PR, and 17% VGPR. Multivariate logistic regression analyses showed higher odds of PR at 6 months for hemoglobin <11.5 g/dl (78% vs. 56%; OR 2.8, 95% CI 1.1-6.9; p=0.03) and serum albumin <3.5 g/dl (90% vs. 66%; OR 3.2, 95% CI 1.0-10; p=0.045), while CXCR4 mutations associated with lower odds (44% vs. 82%; OR 0.15, 95% CI 0.06-0.37; p<0.001). Multivariate logistic regression analyses showed higher odds of VGPR at 6 months for b2-microglobulin ≥3 mg/l (21% vs. 3%; OR 3.3, 95% CI 1.1-10; p=0.04) and lower odds for serum IgM level ≥4,000 mg/dl (9% vs. 23%; OR 0.3, 95% CI 0.1-0.8; p=0.02). The median follow-up was 30 months, and the median PFS has not yet been reached. The 5-year PFS rate was 60% (95% CI 48-69%). In the multivariate Cox regression analysis, worse outcomes were seen with CXCR4 mutations (5-year PFS: 45% vs. 71%; HR 2.8, 95% CI 1.4-5.8; p=0.004) and serum albumin <3.5 g/dl (5-year PFS: 36% vs. 68%; HR 2.7, 95% CI 1.3-5.5; p=0.007). A novel PFS risk score was designed using CXCR4 mutational status and serum albumin (Figure), which divided patients into 3 distinct groups: low risk (no risk factors: 43%; 5-year PFS 81%), intermediate risk (1 risk factor: 46%; 5-year PFS 51%) and high risk (2 risk factors: 11%; median PFS 25 months). The PFS difference between groups was statistically significant (p<0.001). The PFS risk score showed consistent results when evaluating previously treated and untreated patients, as well as patients on and off clinical trials. Conclusion: Serum albumin and CXCR4 mutations emerge as important factors predictive of PR at 6 months and also prognostic of PFS in WM patients treated with ibrutinib. A novel PFS stratification tool that separates patients into 3 risk groups was established and would need further validation. Figure Disclosures Castillo: Abbvie: Research Funding; Janssen: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; TG Therapeutics: Research Funding. Hunter:Janssen: Consultancy. Treon:Pharmacyclics: Research Funding; BMS: Research Funding; Janssen: Consultancy.

Radius: A Phase 2 Randomized Trial Investigating Standard of Care ± Midostaurin after Allogeneic Stem Cell Transplant in FLT3-ITD-Mutated AML

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 662-662 ◽  
Author(s):  
Richard Thomas T. Maziarz ◽  
Mrinal M. Patnaik ◽  
Bart L Scott ◽  
Sanjay R. Mohan ◽  
Abhinav Deol ◽  
...  
Keyword(s):  
Research Funding ◽  
Stem Cell Transplant ◽  
Single Agent ◽  
Standard Of Care ◽  
Cell Transplant ◽  
Phase 2 ◽  
Free Survival ◽  
Relapse Rates ◽  
Risk Of Relapse

Abstract Introduction: Midostaurin, a multitargeted tyrosine kinase inhibitor (TKI), plus induction and consolidation chemotherapy followed by single-agent midostaurin maintenance therapy resulted in significant benefits in event-free and overall survival (OS) in adults with newly diagnosed FLT3-mutated acute myeloid leukemia (AML) compared with placebo (RATIFY study; Stone et al, N Engl J Med, 2017). In RATIFY, patients who received allogeneic hematopoietic stem cell transplant (alloSCT) did not receive midostaurin maintenance. Despite alloSCT providing the highest likelihood of sustained remission, relapse rates remain high (30%-59%; Schiller et al, Biol Blood Marrow Transplant, 2016), especially in patients with FLT3-internal tandem duplication-positive (ITD+) AML. Posttransplant maintenance therapy may improve this outcome. Here, we report the primary results from RADIUS, a randomized, open-label, phase 2 exploratory trial (NCT01883362) that investigated whether the addition of midostaurin to standard of care (SOC) after alloSCT could reduce the risk of relapse in patients with FLT3-ITD+ AML. Methods: Adults (aged 18-70 y) who had undergone myeloablative alloSCT in first complete remission (CR1), had achieved hematologic recovery, and were transfusion independent were eligible. Patients enrolled postengraftment and were randomized to receive SOC with or without midostaurin 50 mg twice daily continuously (4-week cycles) for up to 12 cycles. Study treatment started 28 to 60 days post-alloSCT and patients were followed for ≥24 months post-alloSCT. The primary endpoint was relapse-free survival (RFS) at 18 months post-alloSCT. Secondary endpoints included safety and disease-free survival (DFS), OS, and RFS at 24 months post-alloSCT. The study was not adequately powered to detect a statistical difference between the 2 arms; a sample size of 60 was calculated to detect a 50% reduction in the risk of relapse. Results: 60 patients were randomized (30 per arm). Baseline characteristics were generally balanced between the 2 arms. Overall, 30 patients completed 12 cycles of study treatment (14 with SOC; 16 with midostaurin). The median exposure to midostaurin was 10.5 months (range, 0.2 to 12.0 months) and the median dose intensity was 93 mg/day (range, 15-100 mg/day). Early treatment discontinuations were similar between arms (15 in the SOC arm; 13 in the midostaurin arm), frequently due to adverse events (AEs; 3% vs 23%) and consent withdrawal (20% vs 7%). Among 6 patients who withdrew consent in the SOC arm, 2 did so to pursue other TKI therapies. Midostaurin dose modifications occurred in 19 patients (63%), mostly due to AEs (84%); 1 instance was due to receiving a concomitant CYP3A4 inhibitor. With an estimated 18-month RFS (95% CI) of 76% (54%-88%) in the SOC arm and 89% (69%-96%) in the midostaurin arm, estimated relapse rates were 24% and 11%, respectively, which is a 46% relative reduction in the risk of relapse with the addition of midostaurin (Figure 1). At 18 months, the median RFS was not reached in either arm. Longer follow-up at 24 months (data not yet matured) will be presented, including RFS, OS, and DFS. In the SOC and midostaurin arms, AEs were reported in 87% and 100% of patients, respectively (the most common any-grade AE was vomiting: 23% vs 73%; Figure 2); serious AEs were reported in 57% and 30% of patients, respectively, with diarrhea (7% vs 13%), nausea (10% vs 3%), vomiting (10% vs 3%), and pyrexia (7% vs 7%) being the most common. Overall, 8 patients discontinued midostaurin therapy due to AEs (mostly gastrointestinal related) and 12 died on study (all during the follow-up phase; 8 in the SOC arm and 4 in the midostaurin arm [n=4 vs n=2 due to AML disease progression]). Rates of graft-vs-host disease (GVHD) were generally similar between the SOC and midostaurin arms (overall, 70% vs 73%; acute GVHD, 53% vs 57% [grade 2/3 events: 37% vs 30%; no grade 4 events]; chronic GVHD, 47% vs 37% [most events were mild or moderate; severe events: 1 with SOC and 2 with midostaurin]). Conclusions: Adding midostaurin to SOC reduced the risk of relapse at 18 months post-alloSCT by 46% (vs SOC). The safety profile of single-agent midostaurin was consistent with previous reports; no major safety concerns were identified when adding midostaurin to SOC following alloSCT. These data suggest that midostaurin monotherapy can be safely administered for ≤1 year and may improve outcomes in patients who undergo alloSCT in CR1. Disclosures Maziarz: Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria; Juno Therapeutics: Consultancy, Honoraria; Kite Therapeutics: Honoraria; Athersys, Inc.: Patents & Royalties. Scott:Agios: Consultancy; Novartis: Research Funding; Celgene: Consultancy, Research Funding; Alexion: Consultancy. Deol:Kite Pharmaceuticals: Consultancy; Novartis: Consultancy. Kim:Novartis: Consultancy, Honoraria, Research Funding; Briston-Meyers Squibb: Consultancy, Honoraria, Research Funding; Paladin: Consultancy; Pfizer: Consultancy. Haines:Novartis: Employment. Bonifacio:Novartis: Employment. Rine:Novartis: Employment. Purkayastha:Novartis Pharmaceuticals Corporation: Employment.

Ten Year Follow up Analysis of the OSHO Phase III Trial (AML 96) Comparing Different Application Modes of AraC in Patients below 60 Years with Acute Myeloid Leukemia (AML): No Impact of AraCApplication Mode on Remission Rate, Toxicity, Disease-Free Survival or Overall Survival

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2966-2966
Author(s):  
Cornelia Becker ◽  
Rainer Krahl ◽  
Antje Schulze ◽  
Georg Maschmeyer ◽  
Christian Junghanß ◽  
...  
Keyword(s):  
Overall Survival ◽  
Prognostic Factors ◽  
Cox Regression ◽  
Disease Free Survival ◽  
Phase Iii ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Significant Difference

Abstract Clinical trials on different cytarabine doses for treatment of AML provide evidence of a dose response effect, but also for increase toxicity after high dose AraC (HDAC). Pharmacokinetic measurements of cytarabine-triphosphate (AraC-CTP), which is the most relevant cytotoxic metabolite of AraC, have revealed its formation in leukemic cells to be saturated with infusion rates above 250 mg/m2/h, this being significantly lower than used in HDAC schedules. Methods: Based on a pharmacological model and encouraging results of a phase II study we conducted a prospective randomized multicenter clinical trial comparing the effects of two different application modes of AraC in patients up to 60 years with untreated newly diagnosed AML. Patients were randomized to receive AraC at two different infusion rates (IR) during induction and consolidation treatment: arm A/experimental: 1 × 2 g/m2/d AraC over 8 hours (IR 250 mg/m2/h) arm B/standard: 2 × 1 g/m2/d AraC over 3 hours (IR 333 mg/m2/h). Induction and first consolidation consisted of AraC (days 1, 3, 5, 7) in combination with an anthracycline (Idarubicine 12 mg/m2 or Mitoxantrone 10 mg/m2, days 1–3). The final dosage points (AraC day 7 and anthracycline day 3) were excluded from the second consolidation. The third consolidation consisted of either allogeneic or autologous stem cell transplantation or of chemotherapy identical to second consolidation. Results: From 02/97 to 04/02 419 patients were enrolled in the study. The present analysis is based on 361 eligible and evaluable patients with a median follow up of 7 years. CR was reached in 249/361 (69%; 95%CI: 65%–74%) patients. No statistically significant differences were detected between arms A and B with regard to CR-rate (69% vs 69%) or early death rate (11% vs 8%). Hematological recovery of median white blood cell count (WBC) &gt; 109/l and median platelets (plt) &gt; 50 × 109/l revealed no difference between arms A and B after induction (WBC day 22 vs 22, p=0,68; plt day 25 vs 26, p=0,41) and consolidation (WBC day 28 vs 27, p=0,07; plt day 42 vs 40, p= 0,58). The event free survival (EFS) after 5 years is 0,25 ± 0,03 % for all patients with an overall survival of 0,31 ± 0,03 % after 5 years. For the purposes of analysis, the 83 transplant patients (23 allogeneic MRD, 14 allogeneic MUD and 46 autologous) were censored at time of transplant. No statistically significant difference between arms A and B in regard to EFS (0,25 ± 0,04 vs 0,25 ± 0,04, p=0,99), relapse incidence (0,63 ± 0,06 vs 0,60 ± 0,06, p=0,89), overall survival (0,32 ± 0,04 vs 0,30 ± 0,04, p=0,44) and therapy associated mortality (0,18 ± 0,04 vs 0,17 ± 0,03, p=0,95) were detectable after adjustment of prognostic factors. An analysis of risk factors by multivariate cox regression model confirmed cytogenetics at diagnosis to be the most important risk factor for CR rate (p&lt;10−6) and for EFS (p&lt;10−6). Other significant prognostic factors for EFS evaluated in the multivariate analysis were de novo vs secondary AML (p=0,0001), WBC (continuous) (p=0,001), LDH (&gt;1–4 × vs other ULN) (p=0,008) and FAB classification (FAB M0,6,7 vs FAB M1,2,4,5) (p=0,0005). EFS after 5 years shows a significant correlation to cytogenetics (p&lt;10−6) with 0,71±0,1, 0,27±0,05, 0,20±0,06 and 0,03±0,03 for favorable, normal, other and unfavorable cytogenetic karyotype, respectively. Conclusion: We conclude that the application of AraC at the presumptive saturating infusion rate of 250 mg/m2/h results in comparable remission rates, toxicity, event free survival and overall survival as compared to the standard IR with 333 mg/m2/h.

Patterns of Hypomethylating Agent and Transfusion Use in Myelodysplastic Syndrome: a Claims Database Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2490-2490
Author(s):  
Hind T Hatoum ◽  
Swu-Jane Lin ◽  
Deborah Buchner ◽  
Edward Kim
Keyword(s):  
Logistic Regression ◽  
Myelodysplastic Syndrome ◽  
Poisson Regression ◽  
Research Funding ◽  
Myelogenous Leukemia ◽  
Transfusion Rate ◽  
Inclusion Criteria ◽  
Significant Difference ◽  
To Receive

Abstract Abstract 2490 Poster Board II-467 Introduction: Myelodysplastic syndrome (MDS) is characterized by ineffective hematopoiesis, multilineage dysplasia, peripheral cytopenias, and susceptibility to leukemic transformation. Supportive treatments include red blood cell (RBC) and platelet (PLT) transfusions as well as erythrocyte stimulating agents (ESAs) to correct disease-induced cytopenias. Active treatment with hypomethylating agents (HMAs) have been shown in clinical trials to reduce transfusion dependence and leukemic progression among patients with MDS. The purpose of this study is to describe the patterns of care among patients with MDS, and outcomes associated with HMA treatment options. Methods: Data were obtained from the MarketScan® database, which contains pharmacy, medical, hospital, and laboratory claims for several million members, from January 2002 through June 2008. Inclusion criteria included: age 18 or older; at least 2 claims with an ICD-9 diagnosis of MDS in 2006 or later; at least 6 months of pre-diagnosis health plan enrollment; at least 4 months of enrollment after initial HMA treatment; at least 1 complete cycle of decitabine (DAC; 5 treatments) or azacitidine (AZA, 7 treatments). Patients were excluded if they were treated with lenalidomide, had a prior cancer diagnosis, prior treatment with DAC or AZA, or had other isolated cytopenia or myeloproliferative diagnoses. Patients with a diagnosis of acute myelogenous leukemia within the first 28 days of treatment were also excluded. Descriptive statistics characterized patient demographics, including time between diagnosis and treatment, days per cycle, use of ESA, and number of treatment cycles. Logistic regression assessed predictors of HMA treatment using age at MDS diagnosis, gender, Charlson Comorbidity Index (CCI), and calendar year as predictors. Poisson regression compared the risk of RBC or PLT transfusion between DAC and AZA, controlling for age, gender, CCI, treatment cycles, time to initiating treatment, and follow-up duration. Results: 2525 patients met full inclusion criteria (51% female), of whom 95.4% received no HMA treatment. Logistic regression revealed that females were less likely to receive HMA therapy (OR 0.486, p<0.001). There was no significant difference in follow-up duration between the DAC and AZA groups. Over 50% of HMA-treated patients received 4 or more treatment cycles, with no significant difference between DAC (n=37) and AZA (n=60). Mean (SD) days from MDS diagnosis to first treatment was 93.7 (101.4) for DAC vs. 50.8 (73.4) for AZA (p=0.03). Median treatment days per cycle were 4.86 for DAC and 5.00 for AZA (p>0.05). Mean (SD) days to discontinuation of RBC/PLT transfusion was 15.8 (48.3) for DAC and 70.1 (136.1) for AZA (p<0.05). The RBC/PLT transfusion rate was lower for DAC than for AZA (0.06 vs 0.17 per month, p<0.05). Poisson regression found a significantly lower likelihood of RBC/PLT transfusion in the DAC group (OR=0.206, p<0.05). Use of ESA did not differ between treatments (p>0.05). Discussion: Only a small portion of MDS patients receive HMA treatments, with females less likely to receive drug therapy. Initiation of decitabine occurs later than azacitadine after MDS diagnosis for unclear reasons. Decitabine is associated with lower rates of RBC/PLT transfusion and shorter time to discontinuation of transfusions, consistent with a prompt time to clinical response. Further research is needed to clarify optimal initiation timing for HMA treatment to maximize therapeutic benefits. Disclosures: Hatoum: Eisai Inc.: Research Funding. Lin:Eisai Inc.: Research Funding. Buchner:Eisai Inc.: Employment. Kim:Eisai Inc.: Employment.

A Phase III Randomized Intergroup Trial (SWOG S0016) of CHOP Chemotherapy Plus Rituximab Vs. CHOP Chemotherapy Plus Iodine-131-Tositumomab for the Treatment of Newly Diagnosed Follicular Non-Hodgkin's Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 98-98 ◽  
Author(s):  
Oliver W. Press ◽  
Joseph M Unger ◽  
Lisa M. Rimsza ◽  
Jonathan Friedberg ◽  
Michael LeBlanc ◽  
...  
Keyword(s):  
Research Funding ◽  
Cox Regression ◽  
Hazard Ratio ◽  
Phase Iii ◽  
Advanced Stage ◽  
Chop Chemotherapy ◽  
Prior Therapy ◽  
Beta 2 ◽  
Beta 2 Microglobulin

Abstract Abstract 98 Background: Advanced follicular lymphomas (FL) are incurable with conventional chemotherapy and there is no consensus on the best treatment approach. The SWOG cancer research cooperative group and Cancer and Leukemia Group B (CALGB) compared the safety and efficacy of two immunochemotherapy regimens for FL in a Phase III randomized intergroup protocol (S0016) that enrolled 554 patients with previously untreated, advanced stage FL between 3/1/2001 and 9/15/2008. Methods: Pts were eligible if they had advanced stage (bulky stage II, III or IV) evaluable FL of any grade (1, 2, or 3) and had not received any prior therapy. In one arm (CHOP-R), patients received 6 cycles of CHOP chemotherapy (750 mg/m2 cyclophosphamide, 50 mg/m2 doxorubicin, 1.4 mg/m2 vincristine, and 100 mg prednisone daily for 5 days) at 3 week intervals with 6 doses of rituximab anti-CD20 antibody (375 mg/m2 on days 1, 6, 48, 90, 134 and 141 according to the schedule described by Czuczman et al.[J.Clin.Oncol 17:268, 1999]). In the second arm of the protocol, patients received 6 cycles of CHOP, followed by a dosimetric infusion of tositumomab/iodine I-131 tositumomab and then 1–2 weeks later a therapeutic infusion of I-131-tositumomab labeled with sufficient I-131 (median 85 mCi) to deliver a total body dose of 75 cGy (CHOP-RIT). The study was designed to have 86% power to detect a hazard ratio (HR) of CHOP-RIT to CHOP-R of 0.67 for 2 yr PFS based on a one-sided.021 level test (accounting for 3 interim analyses). Results: Of the 554 enrolled pts, 532 were eligible and 526 were evaluable for toxicity (263 on each arm of the protocol). Pt characteristics (age, sex, race, stage, beta 2 microglobulin level, tumor bulk, B symptoms) were well-balanced in the two arms of the protocol. In general, both regimens were well-tolerated (Table I). Median follow-up time among patients still alive is 4.9 years. One hundred and six of 267 eligible pts on the CHOP-R arm have progressed or died compared to 86 of 265 eligible pts on the CHOP-RIT arm. The 2 year estimate of PFS was 76% on the CHOP-R arm and 80% on the CHOP-RIT arm (Figure 1). In multivariate Cox regression adjusting for the stratification factor (serum beta-2 microglobulin level), the hazard ratio for CHOP-RIT vs. CHOP-R was 0.79 (95% CI: 0.60–1.05, p=.11 [2-sided] or p=.06 [1-sided]). Twenty-six of 267 pts on the CHOP-R arm have died compared to 40 of 265 eligible pts on the CHOP-RIT arm. The 2-year estimate of overall survival was 97% on the CHOP-R arm and 93% on the CHOP-RIT arm. In multivariate Cox regression adjusting for the stratification factor serum beta-2 microglobulin, the hazard ratio for CHOP-RIT vs. CHOP-R was 1.55 (95% CI: 0.95–2.54, p=.08 [2-sided]). Conclusion: No statistically significant differences in PFS, OS, or serious toxicities are yet demonstrable with either regimen administered in this trial. However, PFS and OS are outstanding with either of the two regimens with median times to progression not yet reached for either treatment. Future studies will be needed to assess whether combining CHOP-R with RIT consolidation and with maintenance rituximab will confer additive benefit, as being evaluated in a follow-up trial (SWOG protocol S0801) that has recently completed accrual. Disclosures: Press: Spectrum: Consultancy, Honoraria; Roche/Genentech: Consultancy, Honoraria, Research Funding. Off Label Use: Front-line use of I-131-tositumomab for consolidation therapy in 1st remission of follicular lymphoma. Friedberg:Genentech: Consultancy, Honoraria. Czuczman:Glaxo Smith Kline: Consultancy, Research Funding; Genentech: Consultancy, Honoraria. Kaminski:Glaxo Smith Kline: Patents & Royalties. Maloney:Genentech/Roche: Consultancy, Honoraria, Speakers Bureau; Glaxo Smith Kline: Consultancy, Honoraria, Speakers Bureau. Cheson:Glaxo Smith Kline: Research Funding. Fisher:Roche: Consultancy, Honoraria.

Response to Frontline Therapy with Second Generation Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia: Analysis of Outcome for b3a2 Vs. b2a2 Fusion Transcripts

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3781-3781 ◽  
Author(s):  
Carlos G. Romo ◽  
Hagop M Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Alfonso Quintás-Cardama ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
Overall Survival ◽  
Tyrosine Kinase ◽  
Research Funding ◽  
Initial Therapy ◽  
Molecular Response ◽  
Exon 2 ◽  
Free Survival ◽  
Significant Difference ◽  
Frontline Therapy

Abstract Abstract 3781 Background: CML is characterized by the reciprocal translocation between chromosomes 9 and 22 [t(9;22)(q34;q11.2)], also known as the Philadelphia chromosome. This results in the formation of the BCR-ABL fusion gene, which is translated to a protein with increased tyrosine kinase activity. The breakpoint in the BCR gene can occur in different sites, most commonly between exons 13 and 15 which fuse to exon 2 of the ABL gene creating the b2a2 and b3a2 junctions. Previous studies have reported a better outcome for patients (pts) having a b2a2 transcript when treated with imatinib. To our knowledge there are no published reports analyzing the outcome of pts treated with a 2ndgeneration TKI as initial therapy for CML according to the fusion transcript. We analyzed the significance of these variations among pts with CML in chronic phase (CP) enrolled in 2 parallel trials of dasatinib and nilotinib as initial therapy. Patients and Methods: A total of 204 pts with CML in CP, treated at our institution between 2005 and 2012 with nilotinib or dasatinib as frontline therapy were included in this analysis. Among them 88 (43%) had the b2a2 transcript (median age of 47 years; range 18–80) at the start of therapy, 74 (36%) showed the b3a2 variant (median age of 47; range 17–82 years), and 42 (21%) presented both (median age 53; range 27–81). One patient had a b3a3 transcript and 2 pts showed an e1a2 transcript. Forty-two (48%) of those with b2a2 were treated with dasatinib and 46 (52%) with nilotinib; of the pts with b3a2 34 (46%) were treated with dasatinib and 40 (54%) with nilotinib, in the group of pts with both transcripts 24 (57%) received dasatinib 24, and 18 (43%) of them nilotinib (Table 1). Results: The Sokal risk group for those with the b2a2 transcript was high in 10%, intermediate in 29%, and low in 61%. For pts with b3a2 the risk classification was 5%, 25, and 70%, respectively. The group with both transcripts had 10%, 31% and 69%, respectively. Significant difference was observed in the time of molecular response and overall outcome between pts with b2a2 and those with b3a2 (CCyR 91% vs. 96%; MMR 75% vs. 91%, respectively). The 3-year probability of overall survival (OS) was 100% for both groups. The 3-year probability of event-free survival (EFS) was 93% and 99%, and the transformation-free survival (TFS) 99% and 98% for the b2a2 and the b3a2 group respectively (Table 2). On the 12 mo. follow-up one of the pts with e1a2 transcript achieved CCyR (treated with nilotinib), and the second patient (pt) major cytogenetic response (receiving dasatinib). The pt presenting with b3a3 was treated with dasatinib and achieved MMR by 3 mo. and CCyR at the 12 months follow-up. Conclusions: Although all pts whether they express b3a2 or b2a2 at diagnosis, have an excellent overall survival, those with b3a2 have a significantly higher rate of molecular responses and a trend for better EFS. These results mirror what we have previously reported for pts treated with imatinib as initial therapy. The biologic characteristics for this difference warrant further investigation. Disclosures: Kantarjian: Novartis: Research Funding; Bristol Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding. Jabbour:Bristol Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document