scholarly journals Trial-in-Progress: Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma (NCT#03269669): SWOG S1608

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2425-2425
Author(s):  
Paul M. Barr ◽  
Hongli Li ◽  
Brian K. Link ◽  
Christopher R. Flowers ◽  
Richard Burack ◽  
...  
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Clinical Factors ◽  
High Risk Patients ◽  
Cytotoxic Treatment ◽  
Additional Chemotherapy ◽  
Risk Patients ◽  
The Impact

Abstract While the majority of follicular lymphoma (FL) patients have an overall survival of nearly 2 decades, a subset of patients has a markedly inferior survival. Across randomized studies, 20% of patients will respond poorly to first-line chemoimmunotherapy and account largely for the early deaths in the larger FL population. This group represents the largest unmet need in FL, for which a precision approach to therapy must be developed. With the development of newer monoclonal antibodies, immunomodulatory agents, therapies targeting molecules downstream of the B-cell receptor and novel cellular strategies, non-cytotoxic treatment has the potential to improve outcomes for patients with early progressing FL. There are several validated clinical factors known to correlate with disease outcome in newly diagnosed FL including age, lactate dehydrogenase, β2-microglobulin and disease extent that have been incorporated in prognostic systems such as FLIPI and FLIPI2. More recently, genetic biomarkers have been identified, including MLL2, EZH2, IRF4, CREPPB, and EPHA7 which reflect the disease biology as well as the impact of the lymphoma microenvironment. The addition of these molecular aberrations to clinical factors has led to the development of the M7-FLIPI as well as a 23-gene score, improving risk prognostication for newly diagnosed FL patients. However, such systems have shown a limited ability to predict progression or relapse within 2 years of chemotherapy. As such, identification of these patients at diagnosis or prior to therapy is currently not possible. S1608 was developed to 1) enable identification of high-risk patients using clinical and molecular markers by validating the m7-FLIPI prognostic system and to 2) identify the novel therapeutic approaches most active in this population. This study is enrolling high-risk patients, refractory to chemoimmunotherapy, and in randomized fashion, comparing novel regimens against additional chemotherapy to identify the most active non-chemotherapeutic strategies for this population. Eligible patients must be 18 years or older with grade 1, 2 or 3a FL and have relapsed or progressed with 2 years of finishing their first course of chemoimmunotherapy. Previous chemotherapy must have been CHOP or bendamustine based. Patients are eligible regardless of anti-CD20 therapy used, whether radiation therapy had been administered and whether or not maintenance therapy was utilized. Note that patients are required to have evidence of progressive disease within 2 years but do not have to be registered within 2 years. These high-risk patients are randomized to 12 months of lenalidomide, umbralisib or additional chemotherapy (for 6 months), all combined with 12 months of obinutuzumab. The primary clinical endpoint is CR rate after 6 cycles, allowing responding patient to proceed with consolidative cellular therapies if desired by the treating physician. Biopsies from diagnosis and at the time of relapse as well as circulating tumor DNA are being collected to prospectively evaluate the m7-FLIPI and to identify additional predictive markers. S1608 is a collaborative effort amongst the SWOG, Alliance and ECOG-ACRIN cooperative groups. The study represents one of the only prospective efforts to characterize early progressing FL and the only randomized trial comparing treatment strategies for this group of follicular lymphoma patients most in need of alternative therapies. Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819, U10CA180820, U10CA180821; and TG Therapeutics, Inc. Figure 1 Figure 1. Disclosures Barr: Genentech: Consultancy; AstraZeneca: Consultancy; Morphosys: Consultancy; TG Therapeutics: Consultancy; Beigene: Consultancy; Abbvie/Pharmacyclics: Consultancy; Bristol Meyers Squibb: Consultancy; Seattle Genetics: Consultancy; Janssen: Consultancy; Gilead: Consultancy. Link: Novartis, Jannsen: Research Funding; MEI: Consultancy; Genentech/Roche: Consultancy, Research Funding. Flowers: Cellectis: Research Funding; Nektar: Research Funding; Takeda: Research Funding; TG Therapeutics: Research Funding; BeiGene: Consultancy; 4D: Research Funding; Karyopharm: Consultancy; Morphosys: Research Funding; Guardant: Research Funding; Bayer: Consultancy, Research Funding; Genmab: Consultancy; Eastern Cooperative Oncology Group: Research Funding; SeaGen: Consultancy; Genentech/Roche: Consultancy, Research Funding; Pharmacyclics/Janssen: Consultancy; Burroughs Wellcome Fund: Research Funding; AbbVie: Consultancy, Research Funding; Adaptimmune: Research Funding; Janssen: Research Funding; Iovance: Research Funding; Acerta: Research Funding; Kite: Research Funding; Allogene: Research Funding; EMD: Research Funding; Amgen: Research Funding; Celgene: Consultancy, Research Funding; Ziopharm: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Sanofi: Research Funding; National Cancer Institute: Research Funding; Xencor: Research Funding; Spectrum: Consultancy; Gilead: Consultancy, Research Funding; Epizyme, Inc.: Consultancy; Biopharma: Consultancy; Denovo: Consultancy; Cancer Prevention and Research Institute of Texas: CPRIT Scholar in Cancer Research: Research Funding; Pharmacyclics: Research Funding. Weigert: Janssen: Speakers Bureau; Epizyme: Membership on an entity's Board of Directors or advisory committees; Roche: Research Funding. Herrera: ADC Therapeutics: Consultancy, Research Funding; Tubulis: Consultancy; Karyopharm: Consultancy; Kite, a Gilead Company: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Gilead Sciences: Research Funding; Merck: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Takeda: Consultancy; Seagen: Consultancy, Research Funding; AstraZeneca: Consultancy, Research Funding. Weinstock: SecuraBio: Consultancy; ASELL: Consultancy; Bantam: Consultancy; Abcuro: Research Funding; Verastem: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; AstraZeneca: Consultancy; Travera: Other: Founder/Equity; Ajax: Other: Founder/Equity. Leonard: ADC Therapeutics, AstraZeneca, Bayer, BMS/Celgene, Epizyme, Inc., Genmab, Gilead/Kite, Karyopharm, BMS/Celgene, Regeneron, MEI Pharma, Miltenyi, Roche/Genentech, Sutro: Consultancy; Roche/Genentech: Consultancy. Kahl: Abbvie, BeiGene, AstraZeneca, Acerta: Research Funding; Research to Practice: Speakers Bureau; Abbvie, ADCT, AstraZeneca, Beigene, Celgene, Teva, Janssen, MTEM, Bayer, InCyte, Adaptive, Genentech, Roche, MEI, KITE, TG Therapeutics, Epizyme, Takeda: Consultancy. Smith: Celgene, Genetech, AbbVie: Consultancy; Alexion, AstraZeneca Rare Disease: Other: Study investigator. Friedberg: Novartis: Other: DSMC ; Acerta: Other: DSMC ; Bayer: Other: DSMC .

Survival in Patients with Newly Diagnosed Myeloma Undergoing Therapy with Lenalidomide and Dexamethasone: Impact of High-Risk Cytogenetic Risk Status on Outcome

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 95-95 ◽  
Author(s):  
Prashant Kapoor ◽  
Shaji Kumar ◽  
Rafael Fonseca ◽  
Martha Q. Lacy ◽  
Thomas E Witzig ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Plasma Cell ◽  
Risk Groups ◽  
Newly Diagnosed ◽  
High Risk Patients ◽  
Risk Patients ◽  
The Impact ◽  
Standard Risk

Abstract Background: Multiple myeloma (MM) is a heterogeneous disease with very divergent outcomes that are dictated in a large part by specific cytogenetic abnormalities, as well as other prognostic factors such as the proliferative rate of marrow plasma cells. Prognostic systems incorporating these factors have shown clinical utility in identifying high-risk patients, and are increasingly being utilized for treatment decision-making. However, the prognostic relevance of these factors may change with the application of novel therapies. The objective of this study was to determine the impact of risk-stratification (incorporating plasma cell metaphase cytogenetics, interphase fluorescent in-situ hybridization (FISH) and the slide-based plasma cell labeling index (PCLI)) in a cohort of patients with newly diagnosed MM treated initially with lenalidomide + dexamethasone (Rev-Dex). Methods: From March 2004 to November 2007, 100 consecutive patients treated with Rev (25mg/day) on days 1 through 21 of a 4-week cycle in combination with dexamethasone as initial therapy for newly diagnosed myeloma, were identified. High-risk MM was defined as presence of any one or more of the following: hypodiploidy, monoallelic loss of chromosome 13 or its long arm (by metaphase cytogenetics only), deletion of p53 (locus 17p13) or PCLI ≥ 3% or immunoglobulin heavy chain (IgH) translocations, t(4;14) (p16.3;q32) or t(14;16)(q32;q23) on FISH. PFS and OS survival estimates were created using the Kaplan Meier method, and compared by log-rank tests. Results: The median estimated follow-up of the entire cohort (N=100) was 36 months. The median PFS was 31 months; the median OS has not been reached. The 2- and 3-year OS estimates were 93% and 83%, respectively. 16% patients were deemed high-risk by at least one of the 3 tests (cytogenetics, FISH or PCLI). Response rates (PR or better) were 81% versus 89% in the high-risk and standard risk groups, respectively, P=NS; corresponding values for CR plus VGPR rates were 38% and 45% respectively. The median PFS was 18.5 months in high-risk patients compared to 37 months in the standard-risk patients (n=84), P<0.001(Figure). Corresponding values for TTP were 18.5 months and 36.5 months, respectively, P=<0.001. OS was not statistically significant between the two groups; 92% 2-year OS was noted in both the groups. Overall, 95 patients had at least one of the 3 tests to determine risk, while 55 patients could be adequately stratified based on the availability of all the 3 tests, or at least one test result that led to their inclusion in the high-risk category. The significant difference in PFS persisted even when the analysis was restricted to the 55 patients classified using this stringent criterion; 18.5 months vs. 36.5 months in the high-risk and standard- risk groups respectively; P<0.001. In a separate analysis, patients who underwent SCT before the disease progression were censored on the date of SCT to negate its effect, and PFS was still inferior in the high-risk group (p=0.002). Conclusion: The TTP and PFS of high-risk MM patients are inferior to that of the standard-risk patients treated with Rev-Dex, indicating that the current genetic and proliferation-based risk-stratification model remains prognostic with novel therapy. However, the TTP, PFS, and OS obtained in high-risk patients treated with Rev-Dex in this study is comparable to overall results in all myeloma patients reported in recent phase III trials. In addition, no significant impact of high-risk features on OS is apparent so far. Longer follow-up is needed to determine the impact of risk stratification on the OS of patients treated with Rev-Dex. Figure Figure

Survival and Response Outcomes to Different Treatment Schedules in CML Patients Starting Therapy with Imatinib. Results from the CML Spanish Registry (RELMC)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1237-1237
Author(s):  
Luis Felipe Casado ◽  
Isabel Massague ◽  
Pilar Giraldo ◽  
Manuel Perez-Encinas ◽  
Raquel De Paz ◽  
...  
Keyword(s):  
High Risk ◽  
Cumulative Incidence ◽  
Research Funding ◽  
The Other ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
High Risk Patients ◽  
Advisory Boards ◽  
Best Response ◽  
Risk Patients

Abstract Abstract 1237 Background: The RELMC is a multicentric, 17-hospitals-based cancer registry whose aim is to describe the treatments received by patients with CML, their outcomes, and the variables that influence treatment choices. Aim: To study the response and survival outcomes, in newly diagnosed CML patients treated with Imatinib (Im) as first line treatment. Patients and methods: 249 newly diagnosed CML patients have been included. They are distributed in the following subgroups according to treatments received Im400. 166 patients received only Im400. Result: A summary of response and outcome is included in Table 1. Complete cytogenetic response with regards to the best response, the CCyR rate was lower in patients with Im400-HDIm-2GTKI (60%) and Im400-2GTKI (62%). The rates were 84% in Im400, 83% in Im400-HDIm and 85% in HDIm; P Chi2 8,381(a) p=0,079. The CCyR cumulative incidence was also lower in patients with Im400-HDIm-2GTKI and Im400-2GTKI in comparison to the other groups, although second line response was faster in patients who changed to 2GTKI after Im400. The frequency of CCyR as best response in the Hasford high risk patients was low in all groups (66%,50%,50%,50&55%). Major molecular response MMR as best response was lower in patients with Im400-HDIm-2GTKI (50%) and Im400-2GTKI (47%). The rates were 83%, 81% and 77% in the Im400, Im400-HDIm and HDIm groups respectively; P Chi2 19,4(a)p=0,001. The MMR cumulative incidence was higher in the HDIm group, lower in those treated with Im400-HDIm-2GTKI, and intermediate and similar in the other three groups. MMR as best response in the Hasford high risk patients was also low in all groups (60%, 75%, 50%, 50% & 33%). Complete molecular response regarding best response, the CMR rate was lower in patients with Im400-HDIm-2GTKI (37,5%), Im400-2GTKI (31,6%) and Im400-HDIm (34%). In the other groups, the rate was 48% (Im400), and 72% (HDIm); P Chi2 17,4(a) p=0,002. The CMR cumulative incidence was higher in the HDIm group, and nil in those treated with Im400-HDIm-2GTKI. Salvage therapy after suboptimal response (SR) or Failure (F). Two-thirds of patients with SR or F were able to obtain an optimal response and avoid transformation with a timely therapy change. All but one of the options (Im400-HDIm-2GTKI group) were similarly effective. Survival: 6 patients progressed (2,4%) (4 AP, 2 BC), and died; 6 patients changed to allo BMT and were censored; 6 patients died of non-CML related causes. Conclusion: Disclosures: Palomera: Janssen Cilag: Honoraria. Steegmann:Bristol-Myers Squibb: Honoraria, Participated in advisory boards, Research Funding; Novartis: Participated in advisory boards, Research Funding.

Total Therapies (TT) for Newly Diagnosed Patients with Multiple Myeloma (MM): Significant Benefit in High-Risk Disease with Cytogenetic Abnormalities (CA) over the Course of 17 Years.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3490-3490
Author(s):  
Frits van Rhee ◽  
Vanessa Bolejack ◽  
Elias Anaissie ◽  
Guido Tricot ◽  
Klaus Hollmig ◽  
...  
Keyword(s):  
High Risk ◽  
Male Gender ◽  
Significant Benefit ◽  
Newly Diagnosed ◽  
Cytogenetic Abnormalities ◽  
High Risk Patients ◽  
Risk Patients ◽  
Pre Treatment ◽  
The One ◽  
The Impact

Abstract Background: In 1989, TT with tandem autotransplants (AT) was developed - in analogy to St. Jude’s TT program for childhood ALL - to advance the treatment outcome of MM patients. New agents and treatment principles were introduced as we moved from TT1 to T2 to TT3, mainly to address the inferior outcome in high-risk patients, introducing post-AT consolidation chemotherapy and thalidomide in TT2 and treatment in between chemotherapy cycles/transplants plus bortezomib in TT3. The consistently high-risk associated with the presence of metaphase cytogenetic abnormalities (CA) had been recognized in TT1. We now examine the benefit of intensifying therapy over time in patients with and without CA. Patients and Methods: According to our MM data base, 979 newly diagnosed patients had at least 1 AT; 181 patients were enrolled prior to 1999 and 798 patients thereafter (566 on TT2 and 232 on TT3). Univariate and multivariate analyses were performed to examine the impact on overall survival (OS) of time of protocol enrollment in the context of pre-treatment laboratory parameters Results: Pre-treatment features of the 2 cohorts were comparable in terms of frequencies of CA and serum levels of B2M, CRP and creatinine. The recent cohort (after 1999) had higher percentages of patients aged >65yr (22% vs 8%) and with LDH>190U/L (32% vs 7%, p<.001) but lower proportions with albumin<3.5g/dL (2% vs 9%, p<.001) and Hb<10g/dL (19% vs 50%, p<.001). Median OS was superior in the 798 patients enrolled after 1999 compared to the 181 prior to 1999 (not reached vs 72mo, p=.007). Other univariately significant adverse features included CA, B2M>=3mg/L, CRP>=6mg/L (all p<.001); age >=65yr (p=.002), creatinine>1.5mg/dL (p=.007), albumin<3.0g/dL (p=.018) and male gender (p=.049). On multivariate analysis, the following adverse variables entered the model: CA (HR=2.19, p<.001), B2M>=3mg/L (HR=1.79, p<.001), CRP>=6mg/L (HR=1.48, p=.002), age >=65yr (HR=1.44, p=.015), enrollment pre-1999 (HR=1.38, p=.026) and male gender (HR=1.27, p=.047). Importantly, a significant benefit was apparent for the one-third of patients with CA who received TT post-1999 (median not reached versus 4yr, p=.02), whereas there was a trend apparent for those without CA (Figure). Conclusion: Pursuit of the TT approach has indeed improved the outcome of the one-third of high-risk patients with CA, with a 5-yr OS rate of ~55% post-1999 versus 35% pre-1999. OS By Enrollment Periods
 Total Therapies 1/2/3 OS By Enrollment Periods
 Total Therapies 1/2/3

Long Term Outcome of Patients with Acute Promyelocytic Leukemia Treated with All-Trans Retinoic Acid, Arsenic Trioxide with or without Gemtuzumab Ozogamicin

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3776-3776
Author(s):  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
Guillermo Garcia-Manero ◽  
Elihu Estey ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Gemtuzumab Ozogamicin ◽  
Low Risk ◽  
Newly Diagnosed ◽  
Term Outcome ◽  
Long Term Outcome ◽  
High Risk Patients ◽  
Risk Patients

Abstract Background - Combination of all-trans retinoic acid (ATRA) and arsenic trioxide (ATO) for the initial treatment of patients with low and intermediate risk acute promyelocytic leukemia (APL) has been shown to be superior to ATRA plus chemotherapy but there is limited available long-term follow up on the "chemotherapy-free" combinations. Methods - We examined the long-term outcome of patients with newly diagnosed APL treated at our institution on three consecutive prospective clinical trials of the combination of ATRA and ATO with or without gemtuzumab ozogamicin (GO) (ID01-014; NCT01409161; NCT00413166). Initially patients received ATRA 45 mg/m2 in two divided doses daily and beginning 10 days later, ATO 0.15 mg/kg daily. With subsequent studies, the schedule was modified for all patients to receive concomitant therapy with ATRA and ATO from day 1. Patients with WBC > 10 x 109/L and patients whose WBC rose to greater than 10 x 109/L during therapy also received a dose of GO 9 mg/m2. Standard supportive care as well as steroids for prophylaxis for differentiation syndrome were administered to all patients. A bone marrow exam to assess response was performed between days 21 and 28 and, if necessary, repeated weekly. Once in CR, patients received consolidation with ATO 0.15 mg/kg daily 5 days/week for 4 weeks every 8 weeks for a total of 4 cycles and ATRA 45 mg/m2 daily for 2 weeks every 4 weeks for a total of 8 months. Bone marrow assessment was performed every 3 months for 1 year and if PCR for PML-RARA was confirmed positive, a dose of GO would be administered. Results - From July 2002 to May 2015, 183 patients have been enrolled into the three trials. During the same period a total of 235 patients with newly diagnosed APL were seen at our institution. Reasons for not being enrolled in the studies were: insurance/socio-economic in 39 (75%) and died within 48 hours of presentation in 13 (25%). Median age of the study patients was 50 years (range, 14-84). 52 (28%) were older than 60 years. Median WBC at presentation was 2.2 x 109/L (range, 0.3-187.9). 52 (28%) had high risk disease with WBC > 10 x 109/L and 131 (72%) had low risk disease with a WBC ≤ 10 x 109/L. Cytogenetics were t(15;17) alone in 117 (64%), t(15;17) plus other in 48 (26%), other, not done, or insufficient in 18 (10%). PCR was positive for PML-RARA in all patients (100%) with the long isoform in 104 (57%), short in 78 (43%), and both in 1 (<1%). Overall 176 (96%) achieved CR with CR rate of 96% for low risk patients and 96% for high risk patients. Early death (occurring within 1 month of study entry) occurred in 7 (4%) and was due to 1 infection/multi-organ failure (MOF), 3 hemorrhage, 3 MOF/hemorrhage/infection. Differentiation syndrome was diagnosed in 21 (11.5%) Other toxicities included QT prolongation in 14 (7.7%), infections in 44 (24.0%), and hemorrhagic events in 10 (5.5%). The median duration of follow-up is 39.6 months (range, 0.8 - 138.8). Six patients (3%) have relapsed including 2 (1%) with extramedullary (both CNS) relapse. The median event-free (EFS), disease-free (DFS) and overall survival (OS) have not yet been reached. The 5-year EFS is 85%, DFS is 96%, and OS is 87% (Figures 1). The 5-year DFS and OS for low risk patients is 99% and 88%, respectively and for the high risk patients 87% and 85%, respectively (figure 2). Conclusion - The combination of ATRA and ATO, with and without GO is effective and associated with excellent long-term DFS and OS in both low and high risk patients with newly diagnosed APL. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Cortes: Teva: Research Funding; BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Jabbour:Pfizer: Consultancy, Research Funding. Faderl:Celator: Research Funding; Astellas: Research Funding; Seattle Genetics, Inc.: Research Funding; Karyopharm: Consultancy, Research Funding; Onyx: Speakers Bureau; Ambit: Research Funding; BMS: Research Funding; JW Pharma: Consultancy; Celgene: Consultancy, Research Funding, Speakers Bureau; Pfizer: Research Funding. Wierda:Glaxo-Smith-Kline Inc.: Research Funding; Celgene Corp.: Consultancy. DiNardo:Novartis: Research Funding. Konopleva:Novartis: Research Funding; AbbVie: Research Funding; Stemline: Research Funding; Calithera: Research Funding; Threshold: Research Funding.

Follicular Lymphoma Therapy Based on Biological Insights and Novel Concepts

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. SCI-7-SCI-7
Author(s):  
Sonali M. Smith
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Unmet Needs ◽  
The United States ◽  
Sales Force ◽  
New Drugs ◽  
Early Relapse ◽  
High Risk Patients ◽  
Risk Patients ◽  
The Impact

The majority of patients with follicular lymphoma experience a protracted course with survival estimates measured in decades. However, there are several critical unmet needs, including pre-emptive identification of high-risk patients, management of early relapse, and treatment of patients with multiply relapsed or rituximab-refractory disease. While exact numbers are not known, approximately 15-20% of patients will have early relapse and the bulk of patients will become rituximab-refractory with time; since there are 30,000 newly diagnosed patients with follicular lymphoma annually in The United States, this constitutes a substantial cancer and societal burden. Unfortunately, the overall possibility for widespread cure remains elusive. Clinical prognostic tools including the FLIPI and FLIPI-2 are difficult to apply at an individual level, and, to date, there are no prospectively validated biologic tools capable of identifying the highest risk groups. The M7-FLIPI, which integrates seven gene mutations (EZH2, ARID1A, MEF2B, EP300, FOXO1, CREBBP, CARD11) with performance status and the FLIPI, is prognostic in patients receiving chemoimmunotherapy, and merits further study. There are currently no pathobiologic predictors of outcome in patients treated with monoclonal antibodies or non-cytotoxic therapies. While prognostication in treatment-naïve patients remains elusive, there are now several time-to-event based observations following initial therapy that define a high-risk subset of patients with inferior survival; these include CR30 and EFS24 which will be further described. As discussed by the previous speakers, a provocative emerging theme is that many somatic mutations and epigenetic and genetic changes occur relatively early in the evolution of the disease and could potentially shape the subsequent clinical course. The possibility that early progression (as defined by EFS24, for example) is directly related to these events affords the exciting prospect of identifying high-risk patients before they receive standard treatment; furthermore, if confirmed, these aberrations are ripe targets for new agents. Moving from prognostication to prediction of response to individual agents or regimens is badly needed in this disease, particularly since there are a plethora of new drugs and new targets being identified. An important and poorly understood component of FL biology that is likely to impact clinical behavior is the tumor microenvironment. The non-malignant milieu of follicular lymphoma is comprised of several cell types, and their composition and interaction with the malignant compartment probably evolves with the disease course. The relationship between the microenvironment and the malignant cell is also a valid target, with both immunomodulatory agents and immunotherapy drugs actively being tested. Overall, the incorporation of biologic insights into treatment of follicular lymphoma will drive the next generation of clinical investigations and move to limit the impact of unmet needs in this disease. Disclosures Smith: Amgen: Other: Educational lecture to sales force; TGTX: Consultancy; Portola: Consultancy; Juno: Consultancy; AbbVie: Consultancy; Celgene: Consultancy; Genentech: Consultancy, Other: on a DSMB for two trials ; Pharmacyclics: Consultancy; Gilead: Consultancy.

scholarly journals Molecular Treatment Stratification for Newly Diagnosed High-Risk Myeloma, Including Plasma Cell Leukemia - Feasibility Results of the Ukmra Optimum: MUK9 Trial (NCT03188172)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3162-3162 ◽  
Author(s):  
Matthew Jenner ◽  
Amy L Sherborne ◽  
Andrew Hall ◽  
Vallari Shah ◽  
Katrina Walker ◽  
...  
Keyword(s):  
High Risk ◽  
Plasma Cell ◽  
Primary Endpoint ◽  
Research Funding ◽  
Plasma Cell Leukemia ◽  
Newly Diagnosed ◽  
Cell Leukemia ◽  
High Risk Patients ◽  
High Risk Disease ◽  
Risk Patients

Background High-risk myeloma patients have unsatisfactory outcomes with current treatments and are in urgent need of improved diagnostic and therapeutic strategies. We have recently validated specific markers predicting high-risk disease in newly diagnosed MM (NDMM), in particular double-hit with presence of ≥2 consensus high-risk markers t(4;14), t(14;16), t(14;20), del(1p), gain(1q), del(17p) (Shah V, et al., Leukemia 2018) and diagnostic GEP SKY92 high risk signature (Sherborne A, et al., IMW 2017). Diagnostic tests for these markers were implemented in the UK multi-center OPTIMUM: MUK9 trial to prospectively stratify therapy for high-risk NDMM. Trial design OPTIMUM: MUK9 is a phase 2 trial for transplant eligible NDMM, consisting of two inter-related protocols: a molecular screening protocol (MUK9A) and an interventional trial (MUK9B) for high-risk MM identified in MUK9A. Patients with suspected or confirmed MM fit for intensive therapy enrolled in MUK9A have central molecular profiling at ICR, London, of CD138-selected BM MM cells for translocations, copy number aberrations (qRT-PCR; MLPA P425, MRC Holland) and SKY92 signature status (MMprofiler; SkylineDx). If clinically indicated SOC therapy (VTD, max. 2 cycles) can be given whilst central results are generated. Patients found to have high-risk MM by double-hit and/or SKY92 are offered enrolment into MUK9B. All other patients receive SOC (VTD, HD-MEL+ASCT) for which clinical data is collected. Patients diagnosed with plasma cell leukemia (PCL) can be enrolled directly in MUK9B. MUK9B treatment consists of quintuplet daratumumab, cyclophosphamide, bortezomib, lenalidomide, dexamethasone (Dara-CVRd) induction (up to 6 cycles), bortezomib-augmented single HD-MEL+ASCT, Dara-VRd consolidation 1 (6 cycles), Dara-VR consolidation 2 (12 cycles) and Dara-R maintenance (until PD). Dose adjustments are permitted in order to maximize tolerability of long-term therapy. Patient reported outcomes (PRO) are recorded at baseline and throughout treatment. Response and MRD are centrally assessed (Birmingham, Leeds). Primary endpoint for MUK9A is feasibility of central molecular testing within 56 days turnaround time, which we report on here. Primary endpoint of MUK9B is treatment efficacy, comparing MUK9B PFS to near-concurrent molecularly matched high-risk patient outcomes from UK NCRI Myeloma XI using a Bayesian design. Secondary endpoints include safety, PFS2, MRD and OS and study of molecular evolution in high-risk disease. Results The protocol recruited 29/Sep/17 - 31/Jul/19 at 39 UK sites, achieving the recruitment target of 105 high-risk patients treated on MUK9B ahead of projections. At the time of analysis (12/Jul/19), 430 patients with suspected or confirmed NDMM have been recruited to MUK9A across 39 UK NHS hospitals. Of these, 376 (87%) patients were confirmed to have symptomatic MM (60.9% male; median age 61y (range 29-79)) as per updated IMWG diagnostic criteria (2014), including 9 (2%) PCL patients, with the remainder diagnosed as SMM/MGUS (31; 7%) or other (14; 3%). For 371 of the 376 symptomatic MM patients BM was received by the central laboratory and was of sufficient quality for profiling in 331 (89%) patients. Repeat samples were requested for all others and a sufficient sample received for 20/45 (44%). Central results were successfully reported within the pre-specified 56 day interval for all patients (median 17 days; IQR 13-22). Of 346 patients with a reported result, 128 (37.0%) have high-risk MM, with molecular characteristics mirroring Myeloma XI patients (Figure 1). PCL patients show expected characteristics as listed in Table 1. Basic demographics were not different between high-risk vs. non-high-risk. 101 high-risk patients have or are planning to enter MUK9B, 10 pending decision; 17 high-risk patients did not enter MUK9B, the majority due to ineligibility. 92 patients have started Dara-CVRD therapy. There are currently no safety concerns, the majority of patients are completing induction successfully; 1 patient stopped induction therapy due to adverse events. Updated results will be presented. Discussion Our data demonstrate feasibility of multi-center molecular stratified trial delivery for high-risk NDMM patients. These early trial results strongly support accelerated trial strategies for MM patient groups with high unmet need and rational drug development specifically for high-risk MM. Disclosures Jenner: Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hall:Celgene, Amgen, Janssen, Karyopharm: Other: Research funding to Institution. Walker:Janssen, Celgene: Other: Research funding to Institution. Croft:Celgene: Other: Travel expenses. Jackson:Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Flanagan:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Drayson:Abingdon Health: Consultancy, Equity Ownership. Owen:Celgene, Janssen: Consultancy; Celgene: Research Funding; Janssen: Other: Travel expenses; Celgene, Janssen: Honoraria. Pratt:Binding Site, Amgen, Takeda, Janssen, Gilead: Consultancy, Honoraria, Other: Travel support. Cook:Celgene, Janssen-Cilag, Takeda: Honoraria, Research Funding; Janssen, Takeda, Sanofi, Karyopharm, Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen, Bristol-Myers Squib, GlycoMimetics, Seattle Genetics, Sanofi: Honoraria. Brown:Amgen, Celgene, Janssen, Karyopharm: Other: Research funding to Institution. Kaiser:Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy; Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses.

Randomized Comparison of Imatinib 800 Mg Vs. Imatinib 400 Mg +/- IFN in Newly Diagnosed BCR/ABL Positive Chronic Phase CML: Analysis of Molecular Remission at 12 Months; The German CML-Study IV.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 339-339 ◽  
Author(s):  
Rudiger Hehlmann ◽  
Susanne Jung-Munkwitz ◽  
Michael Lauseker ◽  
Armin Leitner ◽  
Nadine Pletsch ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Standard Dose ◽  
Chronic Phase ◽  
Study Group ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Molecular Remission ◽  
High Risk Patients ◽  
Risk Patients

Abstract Abstract 339 Initial reports that high dose imatinib results in better responses more rapidly than standard dose imatinib remain controversial. The German CML Study Group therefore compared imatinib 800 mg (IM 800) with standard dose imatinib +/- IFN (IM 400, IM 400 + IFN) in newly diagnosed, not pretreated CML with regard to molecular response at 12 months and survival in a randomized clinical trial. By April 30, 2009, 1026 chronic phase CML patients have been randomized (326 for IM 400, 338 for IM 800, 351 for imatinib + IFN). Comparison was for molecular and cytogenetic remissions, overall (OS) and progression free (PFS) survival and toxicity. 1015 patients were evaluable at baseline, 904 for survival analysis (294 for IM 400, 286 for IM 800, 324 for IM 400+IFN), 790 for cytogenetic (analysis of at least 20 metaphases required) and 823 for molecular response. The three treatment groups were similar regarding median age, sex, median values of Hb, WBC, platelets and distribution according to the EURO score. Median follow-up was 25 months in the imatinib 800 mg arm and 42 months in the imatinib 400 mg +/-IFN arms. The difference is due to the fact that at first the IM 800 arm was designed for high risk patients only and opened up to all risk groups in July 2005. The median daily doses of imatinib were 626 mg (209- 800 mg) in the IM 800 arm and 400 mg (184- 720 mg) in the IM 400 +/- IFN arms. Of 218 patients receiving imatinib 800 mg and evaluable for dosage at 12 months, 100 (45.9%) received more than 700 mg/day, 27 (12.4%) 601-700 mg, 37 (17.0%) 501-600 mg, 48 (22.0%) 401-500 mg and only 6 (2.8%) 400 mg/day or less. The cumulative incidences at 12 months of complete cytogenetic remission (CCR) were 52.3%, 64.9% and 50.6%, and of major molecular remission (MMR) 30.2%, 54.3% and 34.6% with IM 400, IM 800 and IM 400 +IFN, respectively. The cumulative incidences of achieving CCR and MMR with IM 400, IM 800 and IM 400+IFN at 6, 12, 18 and 24 months after start of treatment are summarized in the table. MMR at 12 months was reached faster with IM 800 than with IM 400 (p=0.0003) or IM400+IFN (p=0.0131). Optimal molecular response (OMR=<0.01% BCR-ABL according to the international scale) was reached with IM 800 after a median of 31.3 months vs. 47.5 and 42.5 months with IM 400 +/- IFN. Also CCR was reached faster with IM 800 (p<0.01). The more rapid achievement of MMR with IM 800 was observed in low and intermediate risk patients with little or no difference in high risk patients. In an analysis “as treated” patients receiving more than 600 mg/day reached remissions faster than those receiving lower dosages (CCR after a median of 7.8 vs. 8.9 months, MMR after a median of 10.4 vs. 12.9 months). At the time of this evaluation, OS (92% at 5 years) and PFS (88% at 5 years) showed no difference. Type and severity of adverse events (AE) at 12 months did not differ from those expected (all grades and grades III/IV). Hematologic (thrombocytopenia 7% vs. 4%) and non-hematologic AEs (gastrointestinal 35% vs. 15-24% and edema 29% vs. 16-19%) were more frequent with IM 800, fatigue (14% vs. 7-13%) and neurological problems (15% vs. 6-7%) more frequent with IM 400 + IFN (all grades). These data show a significantly faster achievement of MMR at 12 months with IM 800 as compared to IM 400 +/-IFN. So far, this faster response rate did not translate into better OS or PFS. Hence IM 400 should still be considered as standard of care. With some individual dose adjustments tolerability of IM 800 was good. Longer observation is required to determine whether this more rapid achievement of MMR and CCR will have a long term impact or not. Disclosures: German CML Study Group: Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; European LeukemiaNet: Research Funding; Kompetenznetz Leukämie: Research Funding; Roche: Research Funding; Essex: Research Funding.

Validation of Elevated Blood Soluble PD-L1 As an Independent Prognostic Marker in Newly Diagnosed Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2998-2998 ◽  
Author(s):  
Thierry Fest ◽  
James R Cerhan ◽  
Maher K Gandhi ◽  
Imane Azzaoui ◽  
Pauline Crooks ◽  
...  
Keyword(s):  
High Risk ◽  
Intermediate Risk ◽  
Newly Diagnosed ◽  
Clinical Factors ◽  
High Risk Patients ◽  
The Us ◽  
Risk Patients ◽  
Pre Treatment ◽  
French Cohort ◽  
Large B Cell

Abstract Background. Recent clinical trials based on immunotherapies targeting the PD-1/PD-L1 pathway have shown striking durable responses in a subset of patients with solid cancers. The Programmed death 1 (PD-1) protein is a key immune checkpoint inhibitor expressed by activated T cells. Its ligand, PD-L1, was reported highly expressed by tumor cells in some diffuse large B-cell lymphomas (DLBCL) of non-Germinal Center phenotype. We recently reported on the French multicenter GOELAMS075 trial that pre-treatment soluble PD-L1 (sPD-L1) in plasma was elevated in DLBCL patients compared to controls, and that elevated sPD-L1 was associated with inferior overall survival (OS), independent of the International Prognostic Index (IPI) and other clinical factors (Rossille et al., Leukemia 2014). Here, we replicate and extend these findings in two independent studies from Australia and the US. Methods. The protein expression of sPD-L1 was evaluated using a commercial ELISA kit. The French discovery cohort consisted of 288 adults with newly diagnosed aggressive DLBCL, age 18 to 60 years, and treated with R-CHOP or high dose chemotherapy plus rituximab followed by autologous stem cell support (clinicaltrials.gov: NCT00561379); there were also 60 controls. The Australian study consisted of 51 DLBCL patients age 18 to 71 years, all stages, treated with R-CHOP14, along with 57 controls. The US study was an observational cohort from the Iowa/Mayo Lymphoma SPORE and consisted of 225 DLBCLs, age 19 to 92 years, all stages, treated with immunochemotherapy, along with 98 controls. Plasma samples were collected pre-treatment using EDTA tubes for the Australian and the US cohorts, BDª P100 tubes for the French cohort. sPD-L1 expression was measured in Rennes, France (French & US samples) and in Brisbane, Australia (Australian samples).The Kaplan-Meier method and Cox regression were used to model the association of sPD-L1 with OS. The 95th percentile of the sPD-L1 levels in each matched control group was used as the cutoff point to define elevated sPD-L1 levels. Results. Replicating the French findings, sPD-L1 levels were significantly higher for DLBCL patients compared to controls in both the US (P<0.0001) and Australian (P<0.0001) studies (Figure 1). The odds ratios for elevated sPD-L1 among patients compared to controls were 10.7 (95% CI 3.3-22.0), 8.9 (95% CI 3.1-25.3) and 12.6 (95% CI 2.7-28.0) for the French, US and Australian studies, respectively. In the French cohort, elevated sPD-L1 levels were associated with inferior OS (Hazard Ratio (HR)=2.05; 95% CI 1.18-3.57), and this was replicated in the US cohort (HR=1.71; 95% CI 0.97-3.01) (Figure 2). Due to the similarity of the results, we next pooled the French and US cohorts to increase power for multivariate and subset analyses. The median age at diagnosis of the 513 patients was 54 years; 29% were more than 60 years old; 69% of the patients had stage III-IV disease; 56% were IPI intermediate-risk and 9% were IPI high-risk patients. The median follow-up was 48 months (range, 0.5-126) overall, and 66 months for the patients still alive; there were 102 deaths. Using a cutpoint of 1729 pg/mL from the combined studies, patients with elevated sPD-L1 had inferior OS compared to patients without elevated sPD-L1, with 3-year OS rates estimated at 78% (95% CI 71.8-84.9) vs. 87.8% (95%CI 84.5-91.4) (P<0.01). In multivariate analysis, elevated sPD-L1 (HR=1.75; 95%CI 1.16-2.64), age (HR=1.03; 95%CI 1.02-1.05), high-risk IPI score (HR=3.71; 95%CI 1.91-7.21) and ALC ² 1 G/L (HR=2.19; 95%CI 1.44-3.33) were all significant at P<0.01. In analyses stratified by IPI, the 3-year OS rates among high-risk patients (IPI 4-5) was 40.9% (95% CI 23.6-71.0) for elevated sPD-L1 vs. 82.1% (95% CI 69.1-97.6) for not elevated sPD-L1 (P<0.01). There was no association of sPD-L1 with 3-year OS among low risk (IPI 0-1) or intermediate-risk (IPI 2-3) patients. Conclusion. We confirmed that sPD-L1 levels are higher in pre-treatment plasma samples of newly diagnosed DLBCL patients compared to controls, and that elevated levels of sPD-L1 are associated with inferior OS in DLBCL patients treated with immunochemotherapy, and this is independent of IPI and other clinical factors. Among high risk patients, we identified a subgroup with less than 50% survival. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

scholarly journals Follicular lymphoma: are we ready for a risk-adapted approach?

Hematology ◽  
2017 ◽  
Vol 2017 (1) ◽  
pp. 358-364 ◽  
Author(s):  
Brad S. Kahl
Keyword(s):  
High Risk ◽  
Follicular Lymphoma ◽  
Randomized Clinical Trials ◽  
International Prognostic Index ◽  
Prognostic Index ◽  
Predictive Biomarkers ◽  
Western Hemisphere ◽  
Ongoing Research ◽  
High Risk Patients ◽  
Risk Patients

Abstract Follicular lymphoma is the most common indolent non-Hodgkin lymphoma in the Western hemisphere. The natural history of FL appears to have been favorably impacted by the introduction of rituximab after randomized clinical trials demonstrated that the addition of rituximab to standard chemotherapy induction has improved the overall survival. Yet, the disease is biologically and clinically heterogeneous with wide variations in outcomes for individual patients. The ability to accurately risk-stratify patients and then tailor therapy to the individual is an area of ongoing research. Historically, tumor grade, tumor burden, and the FL international prognostic index (version 1 and version 2) have been used to distinguish low-risk from high-risk patients. Biologic factors such as mutations in key genes can identify patients at high risk for poor outcomes to first-line therapy (mutational status of 7 genes [EZH2, ARID1A, MEF2B, EP300, FOX01, CREBBP, and CARD11] with Follicular Lymphoma International Prognostic Index). More recently, the quality of the response to initial therapy, as measured by either PET imaging or by remission duration, has been show to identify individuals at high risk. However, several unmet needs remain, including a better ability to identify high-risk patients at diagnosis, the development of predictive biomarkers for targeted agents, and strategies to reduce the risk of transformation.

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