Arsenic Trioxide (ATO) In the Consolidation Treatment of Newly Diagnosed APL - First Interim Analysis of a Randomized Trial (APL 2006) by the French Belgian Swiss APL Group

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 505-505 ◽  
Author(s):  
Lionel Ades ◽  
Emmanuel Raffoux ◽  
Sylvie Chevret ◽  
Arnaud Pigneux ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
High Risk ◽  
Interim Analysis ◽  
Standard Group ◽  
Newly Diagnosed ◽  
Consolidation Treatment ◽  
Duration Of Hospitalization ◽  
Risk Patients ◽  
Group A ◽  
Standard Risk

Abstract Abstract 505 Background: ATRA combined to anthracycline based chemotherapy (CT) is the reference treatment of newly diagnosed APL, but this treatment is myelosuppressive and may be associated with long term cardiac toxicity. The use of ATO may allow reduction of the amount of CT (and in particular avoid ara C), and further diminish the relapse risk, especially when used in consolidation treatment (US intergroup study, Powell, ASCO 2008). In a randomized trial, we used ATO for consolidation treatment instead of ara C in standard risk APL (baseline WBC < 10G/L), and in addition to AraC in high risk patients (baseline WBC > 10G/L). ATRA, suggested to reduce the relapse risk when used during consolidation (Sanz, Blood 2008, 112: 3130-4) was also tested in standard risk pts. Methods: In APL 2006 trial (started in Nov, 2006) newly diagnosed APL patients (pts) < 70 years with WBC < 10 G/L were randomized between: group A1( standard group) (induction: ATRA 45mg/m2/d until CR with Ida 12 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3; first consolidation with the same CT course, second consolidation with Ida 12 mg/m2/dx3 and AraC 1g/m2/12h x4d; maintenance during two years: intermittent ATRA 15d/3 months and continuous 6 MP + MTX,); Group A2: same treatment as group A1, but AraC replaced by ATO 0.15 mg/Kg/D D1 to 25 days of both consolidation courses; Group A3: same treatment as group A1, but AraC replaced by ATRA 45 mg/m2 d1 to 15 of both consolidation courses. Pts aged < 70 with WBC > 10G/L (Group C) were randomized between: group C1 (standard group): same treatment as Group A1; group C2: same as C1, but with addition of ATO 0.15 mg/Kg/d d1 to 25 of both consolidation courses, at d1. Pts with WBC > 10 G/L all received intrathecal CT for CNS prophylaxis. This first interim analysis was made at the reference date of 1 Jan 2010, in 186 pts aged < 70 years included in 78 centers before 2009 (141 pts in group A (45/45/51 pts in A1/A2/A3 arms), 45 pts in group C (24/21 pts in C1/21 arms)). Results: In standard risk patients (group A) 140 (99.3 %) patients achieved CR, and 1 (2%) had early death. After a median follow up of 22.1 months, 1, 0, and 1 pts had relapsed in the A1, A2 and A3 consolidation groups, resp. (18 months cumulative incidence of relapse- CIR-of 0%, 0% and 2%). 2, 2, and 0 pts had died in CR in the A1, A2 and A3 consolidation groups, resp. The median duration of neutropenia and thrombocytopenia during consolidation courses was 43.5 and 44 days, 40 and 35 days, 20 and 25 days after consolidation cycles in groups A1 (AraC), A2 (ATO) and A3 (ATRA), resp (p<0.01). The median overall duration of hospitalization was 51, 59 and 26 days in A1,A2 and A3 groups, respectively. In high risk pts (group C) 45 (100 %) patients achieved CR. After a median follow up of 23.7 months, 1 and 1 pt had relapsed in the C1 and C2 consolidation groups, resp (18 months CIR of 2% and 2%). One and 3 had died in CR in the C1 and C2 consolidation groups, resp. Median duration of neutropenia and thrombocytopenia was 45.5 and 43.5 days, 51.5 and 48 days, after consolidation cycles in groups C1(AraC) and C2 (AraC+ATO), resp. The median overall duration of hospitalization was 53.5, and 65 days in C1 and C2 groups, respectively. Conclusion: Results of this first interim analysis show that very high CR rates (>95%) can be observed in very multicenter trials in APL, by combining ATRA and anthracycline based CT, while the relapse rate with consolidation and maintenance was very low in all treatments arms, including in pts with WBC > 10G/L. Nevertheless ATO, when combined to high dose CT during consolidation cycles, increased myelosuppression. An amendment further reducing CT in pts receiving ATO is thus being implemented in the trial. Disclosures: Off Label Use: ATO as 1st line treatment in APL. Fenaux:CELGENE, JANSSEN CILAG, AMGEN, ROCHE, GSK, NOVARTIS, MERCK, CEPHALON: Honoraria, Research Funding.

Arsenic Trioxide (ATO) Or ATRA For Consolidation Treatment Of Standard Risk Non Elderly Newly Diagnosed APL– Second Interim Analysis Of a Randomized Trial (APL 2006) By The French Belgian Swiss APL Group

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 495-495
Author(s):  
Lionel Ades ◽  
Sylvie Chevret ◽  
Emmanuel Raffoux ◽  
Arnaud Pigneux ◽  
Xavier Thomas ◽  
...  
Keyword(s):  
Randomized Trial ◽  
Interim Analysis ◽  
Early Death ◽  
Standard Group ◽  
Newly Diagnosed ◽  
Relapse Risk ◽  
Consolidation Treatment ◽  
Duration Of Hospitalization ◽  
The Difference ◽  
Standard Risk

Abstract Background ATRA combined to anthracycline-based chemotherapy (CT) remains the classical treatment of newly diagnosed APL, but it is myelosuppressive and may be associated with long-term cardiac toxicity. Both ATO (Powell, Blood 2010) and ATRA (Sanz , Blood 2004) may allow to reduce the amount of CT and further diminish the relapse risk. In a randomized trial (APL 2006 trial), we compared for consolidation treatment ATO, ATRA and Ara C in standard risk APL ( ie with baseline WBC < 10G/L). Methods In this trial (started in Nov, 2006) newly diagnosed APL patients (pts) < 70 years with WBC < 10 G/L were randomized for consolidation between AraC, ATO and ATRA. The AraC group (standard group) received for induction: ATRA 45mg/m2/d until CR with Idarubicin (Ida) 12 mg/m2/dx3 and AraC 200mg/m2/dx7 started on day 3; first consolidation with the same CT course, second consolidation with Ida 9 mg/m2/dx3 and AraC 1g/m2/12h x4d ; maintenance during two years with intermittent ATRA 15d/ 3 months and continuous 6 MP + MTX,). The ATO and ATRA groups received the same treatment as the AraC group , but AraC was replaced respectively by ATO 0.15 mg/Kg/d d1 to 25 and ATRA 45 mg/m2/d d1 to 15 for both consolidation courses. We present here results of the second interim analysis, made at the reference date of 1st Jan 2012, in 349 pts aged < 70 years included in 78 centers before 2012. The primary endpoint was event free survival (EFS) at 2 years from CR achievement. Relapse, survival, side effects of the treatment and duration of hospitalization were secondary endpoints. Results Pre-treatment characteristics were well balanced between the 3 consolidation groups. 347 pts (99.4 %) achieved CR, and 2 (0.5%) had early death. Overall, 3, 0, and 4 pts had relapsed and 5, 2, and 2 pts had died in CR in the AraC, ATO and ATRA consolidation groups, respectively. Two year EFS was 95%, 97.4% and 96.8% (p=NS) and 2 year OS was 96.6%, 97.4% and 99% (p=NS), in the AraC, ATO and ATRA consolidation groups, respectively. Median time to ANC >1 G/L and platelets > 50G/L after the first consolidation course was 24 and 25 days, 24 and 23 days, 17 and 20 days in the AraC, ATO and ATRA group, respectively (p<0.01). Similarly, time to ANC >1 G/L and platelets > 50G/L after the second consolidation course was 23 and 27 days, 19 and 18 days, 13 and 19 days in the AraC, ATO and ATRA group (p<0.01). The overall duration of hospitalization was 60.9, 63.1 and 33 days in in the AraC, ATO and ATRA groups, respectively (p<0.01). Conclusion Very high CR rates (close to 98-99%) are now obtained in standard risk APL on a very large multicenter basis using classical ATRA and anthracycline based CT combinations, with very few relapses. ATO or ATRA can replace AraC during consolidation cycles without increasing the relapse risk, and can possibly reduce the rate of deaths in CR (2 and 2 patients versus 5 patients, although the difference was NS). However Ida and ATO, when used concomitantly for consolidation cycles, proved as myelosuppressive as Ida-AraC cycles, while myelosuppression was reduced with Ida-ATRA consolidation courses. Disclosures: Off Label Use: ATO in the treatment of 1st Line APL.

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

scholarly journals Long-Term Follow-Up Results of Lenalidomide, Bortezomib, and Dexamethasone Induction Therapy and Risk-Adapted Maintenance Approach in Newly Diagnosed Multiple Myeloma

2020 ◽  
Vol 38 (17) ◽  
pp. 1928-1937 ◽  
Author(s):  
Nisha S. Joseph ◽  
Jonathan L. Kaufman ◽  
Madhav V. Dhodapkar ◽  
Craig C. Hofmeister ◽  
Dhwani K. Almaula ◽  
...  
Keyword(s):  
High Risk ◽  
Induction Therapy ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Entire Cohort ◽  
Induction Regimen ◽  
Risk Patients ◽  
Standard Risk

PURPOSE The combination of lenalidomide, bortezomib, and dexamethasone (RVD) is a highly effective and convenient induction regimen for both transplantation-eligible and -ineligible patients with myeloma. Here, we present the largest cohort of patients consecutively treated with RVD induction therapy followed by risk-adapted maintenance therapy with the longest follow-up and important information on long-term outcomes. PATIENTS AND METHODS We describe 1,000 consecutive patients with newly diagnosed myeloma treated with RVD induction therapy from January 2007 until August 2016. Demographic and clinical characteristics and outcomes data were obtained from our institutional review board–approved myeloma database. Responses and progression were evaluated per International Myeloma Working Group Uniform Response Criteria. RESULTS The overall response rate was 97.1% after induction therapy and 98.5% after transplantation, with 89.9% of patients achieving a very good partial response (VGPR) or better and 33.3% achieving stringent complete response after transplantation at a median follow-up time of 67 months. The estimated median progression-free survival time was 65 months (95% CI, 58.7 to 71.3 months) for the entire cohort, 40.3 months (95% CI, 33.5 to 47 months) for high-risk patients, and 76.5 months (95% CI, 66.9 to 86.2 months) for standard-risk patients. The median overall survival (OS) time for the entire cohort was 126.6 months (95% CI, 113.3 to 139.8 months). The median OS for high-risk patients was 78.2 months (95% CI, 62.2 to 94.2 months), whereas it has not been reached for standard-risk patients. Five-year OS rates for high-risk and standard-risk patients were 57% and 81%, respectively, and the 10-year OS rates were 29% and 58%, respectively. CONCLUSION RVD is an induction regimen that delivers high response rates (VGPR or better) in close to 90% of patients after transplantation, and risk-adapted maintenance can deliver unprecedented long-term outcomes. This study includes the largest cohort of patients treated with RVD reported to date with long follow-up and demonstrates the ability of 3-drug induction regimens in patients with newly diagnosed multiple myeloma to result in a substantial survival benefit.

scholarly journals Uptake and detection rate of a stepwise cardiometabolic disease detection program in primary care—a cohort study

2019 ◽  
Vol 30 (3) ◽  
pp. 402-407
Author(s):  
Daphne M Stol ◽  
Monika Hollander ◽  
Ilse F Badenbroek ◽  
Mark M J Nielen ◽  
François G Schellevis ◽  
...  
Keyword(s):  
Risk Factors ◽  
Primary Care ◽  
Cohort Study ◽  
High Risk ◽  
Newly Diagnosed ◽  
Additional Risk ◽  
High Risk Patients ◽  
Detection Program ◽  
Risk Patients

Abstract Background Early detection and treatment of cardiometabolic diseases (CMD) in high-risk patients is a promising preventive strategy to anticipate the increasing burden of CMD. The Dutch guideline ‘the prevention consultation’ provides a framework for stepwise CMD risk assessment and detection in primary care. The aim of this study was to assess the outcome of this program in terms of newly diagnosed CMD. Methods A cohort study among 30 934 patients, aged 45–70 years without known CMD or CMD risk factors, who were invited for the CMD detection program within 37 general practices. Patients filled out a CMD risk score (step 1), were referred for additional risk profiling in case of high risk (step 2) and received lifestyle advice and (pharmacological) treatment if indicated (step 3). During 1-year follow-up newly diagnosed CMD, prescriptions and abnormal diagnostic tests were assessed. Results Twelve thousand seven hundred and thirty-eight patients filled out the risk score of which 865, 6665 and 5208 had a low, intermediate and high CMD risk, respectively. One thousand seven hundred and fifty-five high-risk patients consulted the general practitioner, in 346 of whom a new CMD was diagnosed. In an additional 422 patients a new prescription and/or abnormal diagnostic test were found. Conclusions Implementation of the CMD detection program resulted in a new CMD diagnosis in one-fifth of high-risk patients who attended the practice for completion of their risk profile. However, the potential yield of the program could be higher given the considerable number of additional risk factors—such as elevated glucose, blood pressure and cholesterol levels—found, requiring active follow-up and presumably treatment in the future.

Bortezomib Plus Melphalan and Prednisone (VMP) Followed By Lenalidomide and Dexamethasone (Rd) in Newly Diagnosed Elderly Myeloma Patients Overcome the Poor Prognosis of High-Risk Cytogenetic Abnormalities (CA) Detected By Fluorescence in Situ Hibridization (FISH)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4243-4243 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Norma C Gutierrez ◽  
María-Luisa Martín ◽  
Joaquín Martínez-López ◽  
Miguel T Hernandez ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Poor Prognosis ◽  
Plasma Cells ◽  
Risk Group ◽  
Fish Analysis ◽  
Newly Diagnosed ◽  
The Poor ◽  
Risk Patients ◽  
Standard Risk

Abstract Background: Novel insights into the biology of myeloma cells have led to the identification of relevant prognosis factors. CA has become one of the most important prognostic factors, and the presence of t(4;14), t(14;16) or del(17p) are associated with poor prognosis. Although there are some reports indicating that 1q gains may be considered as a poor-risk feature, the information is not uniform. Furthermore, there are important controversies about whether or not novel agents-based combinations are able to overcome the poor prognosis of CA. Bortezomib-based combinations have shown to improve the outcome of patients with high-risk CA but they do not completely overcome their adverse prognosis. Here we report a preplanned analysis, in a series of elderly newly diagnosed myeloma patients included in the Spanish GEM2010 trial and receiving VMP and Rd, in a sequential or alternating approach, in order to evaluate the influence of CA by FISH on the response rate and outcome. Patients and methods: 242 pts were randomized to receive a sequential scheme consisting on 9 cycles of VMP followed by 9 cycles of Rd or the same regimens in an alternating approach (one cycle of VMP alternating with one Rd, up to 18 cycles. VMP included the iv administration of weekly bortezomib (except in the first cycle that was given twice weekly) at 1.3 mg/m2 in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1-4. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. FISH analysis for t(4;14), t(14;16), del(17p) and 1q gains was performed at diagnosis according to standard procedures using purified plasma cells. Results: In 174 out of the 233 patients evaluable for efficacy and safety, FISH analysis at diagnosis were available and two groups were identified: high-risk group (n= 32 patients with t(4;14) and/or t(14;16) and/or del(17p)) and standard-risk group (n=142 patients without high-risk CA). There weren't differences in the rates of CA according to the treatment arm. Response Rates (RR) were no different in the high-risk vs standard-risk groups, both in the sequential (74% vs 79% RR and 42% vs 39% CR) and alternating arms (69% vs 86% RR and 39% vs 38% CR). After a median follow-up of 37 months, high-risk patients showed shorter PFS as compared to standard risk in the alternating arm (24 versus 36 months, p=0.01, HR 2.2, 95% IC 1.1-4.2) and this also translated into a significantly shorter 4-years OS (27% vs 72%, p=0.006, HR 3.3, 95% IC 1.4-7.7). However, in the sequential arm, high-risk and standard-risk patients showed similar PFS (32 months vs 30 months) and 4-years OS (64% vs 60%). This effect was observed only in the sequential arm applied to either t(4;14) or del(17p). As far as 1q gains is concerned, 151 patients had 1q information and 76 of them had 1q gains (50.3%), defined as the presence of more than 3 copies in at least 10% of plasma cells. The rate of 1q gains was well balanced in both sequential and alternating arms. The ORR was similar in patients with or without 1q gains (83% vs 80%) as well as the CR rate (45% vs 31%), and no differences were observed between sequential and alternating arms. Patients with or without 1q gains had a similar PFS (33 months vs 30 months) and 4-years OS (58% vs 65%) in the whole series and no differences were observed in the sequential and alternating arms. This effect has been observed in patients with 1q gains as isolated CA and the outcome was slightly but not significantly worse when 1q gains were present plus either t(4;14) and/or del17p. Conclusions: The total therapy approach including VMP and Rd administered in a sequential approach is able to overcome the poor prognosis of the presence of high-risk CA in elderly patients with newly diagnosed MM. The presence of 1q gains has no impact in the PFS and OS of elderly patients treated with VMP and Rd. Disclosures Mateos: Celgene: Consultancy, Honoraria; Onyx: Consultancy; Janssen-Cilag: Consultancy, Honoraria; Takeda: Consultancy. Gironella:Celgene Corporation: Consultancy, Honoraria. Paiva:BD Bioscience: Consultancy; Binding Site: Consultancy; Sanofi: Consultancy; EngMab AG: Research Funding; Onyx: Consultancy; Millenium: Consultancy; Janssen: Consultancy; Celgene: Consultancy. Puig:Janssen: Consultancy; The Binding Site: Consultancy. San Miguel:Millennium: Honoraria; Janssen-Cilag: Honoraria; Novartis: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Onyx: Honoraria; Sanofi-Aventis: Honoraria.

Impact of proteasome inhibitor vs. IMiD maintenance therapy on outcomes of patients with high-risk multiple myeloma (HRMM).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20557-e20557
Author(s):  
Eric Leon Tam ◽  
David Joseph Iberri ◽  
Michaela Liedtke ◽  
Lori S. Muffly ◽  
Parveen Shiraz ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Maintenance Therapy ◽  
Proteasome Inhibitor ◽  
Post Transplant ◽  
Risk Patients ◽  
To Receive ◽  
Standard Risk

e20557 Background: The ideal choice of maintenance therapy in patients with HRMM high-risk multiple myeloma remains unknown. We analyzed the outcomes of patients with HRMM undergoing transplant receiving different maintenance approaches. Methods: Patients with MM undergoing their first ASCT from 2012-19 within 1 year of diagnosis were identified from the prospectively maintained database of patients undergoing ASCT. HRMM was defined as having t(4;14), t(14;16), t(14;20), del17p13, or gain 1q detected on fluorescent in situ hybridization (FISH). Results: Of the 412 patients undergoing ASCT within 1 year of diagnosis, 333 had FISH data available and of these, 37% (124/333) patients had high-risk cytogenetics. Distribution of HR cytogenetics was as follows: deletion 17p: 37% (n = 46), t(4;14): 27% (n = 34), t(14;16) or t(14;20): 12% (n = 26), gain1q: 31% (n = 41). 9% (n = 12) had more than one HR abnormality. In patients with HRMM, median age at transplant was 59 years (range: 39 to 73), and 61% (n = 103) were males. 64% (n = 107) of high-risk patients received post-transplant maintenance therapy. Maintenance therapy in this group included a proteasome inhibitor (PI) in 34% (n = 29), immunomodulatory drug (IMiD) in 59% (n = 51), or both in 7% (n = 6). There was no difference in baseline characteristics of HRMM patients receiving PI vs. IMiD maintenance, except that patients with del17p were more likely to receive PI maintenance therapy (55% vs 28%, p = 0.01). (Table) After a median follow-up of 3.1 years from diagnosis, patients with HRMM had inferior PFS compared to patients with standard risk disease, with median PFS of 3 vs. 4.8 years, p < 0.001. Amongst the 86 HRMM patients receiving maintenance therapy, median PFS in patients receiving PI vs. IMiD vs. both PI + IMiD maintenance was 3 vs. 3.2 vs. 2.2 years, respectively, log-rank p = 0.7. In the sub-group of patients with 17p deletion, median PFS in the three groups was 3 vs. 2.9 vs. 2.2 years, respectively, log-rank p = 0.7. Conclusions: Patients with HRMM have inferior PFS compared to patients with standard risk disease. We observed similar outcomes in HRMM patients post-transplant regardless of the choice of maintenance therapy. [Table: see text]

scholarly journals Children's Oncology Group (COG) AALL0434: Successful Disease Control without Cranial Radiation in Newly Diagnosed T Lymphoblastic Lymphoma (T-LL)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1000-1000 ◽  
Author(s):  
Robert James Hayashi ◽  
Stuart S. Winter ◽  
Kimberly P. Dunsmore ◽  
Meenakshi Devidas ◽  
Brent Wood ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Partial Response ◽  
Board Of Directors ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Risk Patients ◽  
To Receive ◽  
Standard Risk

Abstract Background: COG AALL0434 evaluated the safety and efficacy of a multi agent chemotherapy backbone containing Capizzi based methotrexate/pegaspargase in newly diagnosed T-LL patients. High-risk patients were randomized to receive the COG augmented BFM (ABFM) regimen with or without Nelarabine. This was part of a larger trial including T-Lymphoblastic Leukemia (T-ALL) patients featuring a 2 x 2 pseudo-factorial randomization at the end of induction using the COG ABFM regimen with a randomization of Capizzi MTX/pegaspargase (C-MTX) verses high dose MTX and a randomization with or without Nelarabine (Nel). Methods: AALL0434 enrolled 277 patients with T-LL (2010-2014). Patients were assigned to two risk categories based upon the degree of bone marrow involvement at diagnosis: (≥1%, High Risk, <1% Standard Risk), and the ability to achieve at least a partial response at the end of induction. Patients with prior steroid treatment were assigned to the high risk group. Both groups were treated using the ABFM C-MTX regimen. High-risk patients were randomized to receive or not receive six, 5-day courses of Nel 650 mg/m2/day. No patients received prophylactic cranial radiation and CNS3 patients were ineligible. Response criteria included, Complete Response (CR): disappearance, Complete Response unconfirmed (CRu): >75% reduction, Partial Response (PR): >50% reduction, of all measurable disease, all without new lesions. Results: At the end of induction, 98.9% of the evaluable patients achieved at least a partial response (30.7% CR, 34.7% CRu, 33.5% PR). For all T-LL patients, the 4-year event free survival (EFS) and overall survival (OS) were 87.0 +/- 2.1% and 90.0+/-1.8%. The 4-year Disease Free Survival (DFS) from end of induction was 90.0+/- 2.1%. There was no difference in DFS observed between the high risk and standard risk groups, (p=0.25) or by treatment regimen (p=0.31). Nel did not show an advantage for high-risk T-LL patients, with 4-year DFS 85.0 +/- 5.6% with Nel (N=60) vs 89.0 +/- 4.7% without Nel (N=58) (p=0.28). Neither stage nor tumor response at the end of four weeks of induction therapy resulted in differences in EFS (p= 0.34 and p= 0.22, respectively). Minimal detectable disease (MDD) of the bone marrow at diagnosis (<0.1%, 0.1-0.99%, >1.0%), used to establish the risk assignment for this trial, failed to demonstrate thresholds at diagnosis that resulted in differences in EFS (p=0.27). Relapse involving the CNS only occurred in 4 patients (1.4%). Overall toxicity and neurotoxicity was acceptable and not significantly different than that experienced from the ALL cohort. There was one observed second malignancy and 5 deaths not from progressive disease. Conclusion: COG AALL0434 produced excellent outcomes in one of the largest trials ever conducted for patients with newly diagnosed T-LL. The COG ABFM regimen with C-MTX provides excellent disease control regardless of stage, or the degree of disease involvement of the bone marrow at diagnosis. Nelarabine did not show an improvement in the outcome, although the trial was underpowered to address this specific question. Disclosures Teachey: Amgen: Consultancy; La Roche: Consultancy. Bollard:Torque: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cellectis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Neximmune: Honoraria, Membership on an entity's Board of Directors or advisory committees.

scholarly journals Real World Assessment of Treatment Patterns and Outcomes Among Multiple Myeloma Patients across Different Risk Stratification Criteria in the United States: A Retrospective Cohort Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1640-1640
Author(s):  
Motiur Rahman ◽  
Christopher Kim ◽  
Jazmine Mateus ◽  
Alissa Keegan
Keyword(s):  
High Risk ◽  
Risk Stratification ◽  
Real World ◽  
Treatment Initiation ◽  
Treatment Patterns ◽  
Community Practice ◽  
Newly Diagnosed ◽  
The Us ◽  
Standard Risk

Abstract Background: Despite the development of highly active novel agents, high risk (HR) multiple myeloma (MM) patients continue to demonstrate relatively poor prognosis. Limited data is published on how treatment patterns with risk stratification systems have changed over time. Moreover, real world studies using electronic health records (EHRs) have not evaluated the performance of risk stratification systems with real world outcomes. This study aims to evaluate the ability to implement three different risk stratification systems - international staging system (ISS), revised ISS (R-ISS), and high-risk chromosomal abnormalities (HRCA, defined as presence of del(17)p, t(4;14) and/or t(4;16)) [Palumbo et al. 2015] - to characterize treatment patterns and associated outcomes [real world overall survival (rwOS) and real world progression free survival (rwPFS)] among newly diagnosed MM (NDMM) patients in the US community practice. Methods: This study used Flatiron Enhanced MM EHR de-identified database (New York, NY). Newly diagnosed MM patients (≥ 18 years) were diagnosed from January 2015 through June 2020 (cohort 1 - for studying treatment distribution) with follow-up through December 2020, and from January 2015 through December 2018 (cohort 2 - for rwOS and rwPFS), with follow-up through December 2020. Patients with malignancies other than MM were excluded. Proportion of rwOS was measured from treatment initiation until death, and median rwPFS was measured from treatment initiation until death, progression, or start of new line of therapy using Kaplan-Meier method. Results: A total of 1,979 and 1,382 patients were eligible in cohorts 1 and 2, respectively. In both the cohorts, approximately 18% (cohort 1: N=367, cohort 2: N=248), 41% (cohort 1: N=805, cohort 2: N=566), and 37% (cohort 1: N=738, cohort 2: N=508) were HR patients according to the R-ISS, ISS, and HRCA criteria, respectively. Approximately half of the HR patients were ≥70 years old (52% for R-ISS III and ISS III, and 47% for HRCA), with chronic kidney disease stage ≥3 by eGFR for 54% R-ISS III and ISS III, and 34% high risk CA, and ECOG score ≥2 for 18% R-ISS III, 19% ISS III, and 14% HRCA patients. Triplets were the most frequent treatment regimens (62% for R-ISS III and II, and 66% for R-ISS I; 59% for ISS III, and 65% for ISS II and I; 65% for HRCA and 61% for standard risk CA(SRCA) with proteasome inhibitors (PIs) / immunomodulatory agents (IMiDs) / dexamethasone being most common regimen across all the risk stratification criteria. Quadruplet agent use was higher in R-ISS III and ISS III categories (6.8% vs. 3.3% for R-ISS III vs. I; 6.3% vs. 2.8% for ISS III vs. I). The median rwPFS in HR patients were shorter than the lower risk subgroups (R-ISS III: 8.8 months [95% CI 7.1 - 11.0], R-ISS II: 12.1 months [95% CI 10.7 - 13.6], R-ISS I: 23.5 months [95% CI 13.8 - .]; ISS III: 10.4 months [95% CI 8.5 - 11.5], ISS II: 12.7 months [95% CI 10.7 - 14.3], ISS I: 16 months [95% CI 12.2 - 19.5]; HRCA: 10.1 months [95% CI 8.8 - 12.1], SRCA: 13.1 months [95% CI 11.3 - 14.8]). The 2-year rwOS was lower in the HR subgroups (R-ISS III: 0.65 [95% CI 0.59 - 0.70], R-ISS II: 0.79 [95% CI 0.76 - 0.81], R-ISS I: 0.91 [95% CI 0.85 - 0.95]; ISS III: 0.68 [95% CI 0.64 - 0.72], ISS II: 0.81 [95% CI 0.77 - 0.84], ISS I: 0.89 [95% CI 0.85 - 0.92]; HRCA: 0.75 [95% CI 0.71 - 0.79], SRCA: 0.79 [95% CI 0.76 - 0.81]). Discussion: This study found that median rwPFS and 2-year rwOS proportions were consistently lower among HR patients compared to the standard risk individuals. The majority of the HR patients were older, with decreased levels of physical functioning and worse indicators of end-organ damage including renal function, anemia, and hypercalcemia. Most patients received triplets with frequent use of PIs likely for aggressive disease control among HR patients. Some HR patients received more quads than lower risk patients suggesting treatment intensification, but HR patients also received stem cell transplants at a lower rate. Although a smaller proportion of patients have all the data collected needed for R-ISS classification, the consistent findings across treatment outcomes suggest that R-ISS is implementable in real world studies and has a greater discriminatory ability than ISS or HRCA alone. Overall, this study suggests that HR patients have relatively poor outcomes which calls for the study of risk-adapted implementation of novel therapies among this patient population in the US community practice settings. Figure 1 Figure 1. Disclosures Rahman: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company. Kim: Amgen: Current Employment, Current equity holder in publicly-traded company. Mateus: Amgen Inc.: Current Employment, Other: Work at Amgen as a contract employee through DOCS. Keegan: Amgen Inc.: Current Employment, Current holder of stock options in a privately-held company.

Risk-adapted therapy utilizing upfront brentuximab vedotin (Bv) and rituximab (R) with reduced toxicity chemotherapy in children, adolescents, and young adults with Hodgkin lymphoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 10532-10532
Author(s):  
Jessica Hochberg ◽  
Liana Klejmont ◽  
Lauren Harrison ◽  
Allyson Flower ◽  
Quihu Shi ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
High Risk ◽  
Hodgkin Lymphoma ◽  
Combination Chemotherapy ◽  
Early Response ◽  
Brentuximab Vedotin ◽  
Response To Therapy ◽  
Newly Diagnosed ◽  
Risk Patients

10532 Background: Cure rates for CAYA patients with Hodgkin Lymphoma remain high, however are limited by significant toxicity of chemoradiotherapy. Brentuximab Vedotin and Rituximab have shown efficacy in relapsed HL. We hypothesize that the addition of both to combination chemotherapy will be safe in newly diagnosed HL preserving current EFS with elimination of more toxic chemoradiotherapy. Objective: To evaluate the safety and overall response and EFS of Brentuximab and Rituximab in combination with risk adapted chemotherapy in CAYA with newly diagnosed HL. Methods: Age 1-30 yrs with newly diagnosed classical HL given 3 to 6 cycles of chemoimmunotherapy: Brentuximab vedotin with Doxorubicin, Vincristine, Prednisone and Darcarbazine (Bv-AVPD) for Low risk patients or Doxorubicin, Vinblastine, Darcarbazine and Rituximab (Bv-AVD-R) for Intermediate/High risk. Early response measured by PET/CT scan following 2 cycles. Slow responders received an additional 2 cycles of Bv-AVD-R for Intermediate Risk or Ifosfamide/Vinorelbine for High Risk patients. Radiation therapy was given ONLY to those patients not in CR. Results: Total = 19 patients. Median age = 15yr (range 4-23yr). Risk = 2 low, 13 intermediate, 4 high. Toxcity = 1 episode of GrIII mucositis, 1 episode of GrIII infusion reaction to Brentuximab. 17 patients have completed therapy. All 17 patients achieved a complete response to therapy for a CR = 100%. Eleven (58%) have achieved a rapid early response. No patient has required radiation therapy. For 17 patients who have completed therapy, the EFS and OS is 100% with a median follow up time of 915 days (30 months). Conclusions: The addition of Brentuximab vedotin and Rituximab to combination chemotherapy for newly diagnosed Hodgkin Lymphoma appears to be safe. Our early results show significant promise with a CR rate of 100% and 58% rapid early response. We have successfully deleted toxic alkylator, topoisomerase inhibitor, bleomycin and radiation from this treatment regimen. The EFS/OS to date is 100% with a median follow up time of 2.5 years. Further follow up and a larger cohort is needed to determine long term outcomes of this approach. Clinical trial information: NCT02398240.

Efficacy of daratumumab + SOC versus SOC in myeloma induction regimens, by risk-stratification: Meta-analysis of phase III randomized control trials.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e20512-e20512
Author(s):  
Nisha Joseph ◽  
Craig C. Hofmeister ◽  
Madhav V. Dhodapkar ◽  
Lawrence Boise ◽  
Sagar Lonial ◽  
...  
Keyword(s):  
High Risk ◽  
Meta Analysis ◽  
Phase 3 ◽  
High Risk Patients ◽  
Hazard Ratios ◽  
Risk Patients ◽  
Q Statistic ◽  
The Impact ◽  
Standard Risk

e20512 Background: Addition of daratumumab, a CD38 monoclonal antibody, to standard of care (SOC) myeloma induction regimens resulted in deeper responses. Phase 3 trials comparing daratumumab + SOC vs SOC consistently favored the daratumumab combinations. The objective of this analysis is to test the hypothesis that high-risk patients benefit from the addition of daratumumab to SOC induction regimens. Methods: We identified four phase 3 clinical trials (RCT) that randomized newly diagnosed myeloma patients to receive daratumumab +SOC vs. SOC. The GRIFFIN trial did not have PFS events and was excluded. A meta-analysis of 3 RCTs with updated data from ASH 2019 (ALCYONE, MAIA, CASSIOPEIA) was performed using the fixed (Mantel-Haenszel) model to calculate the impact of daratumumab + SOC versus SOC. The consistency of results (effect sizes) among studies was investigated by means of two heterogeneity tests, the χ 2-based Cochran's Q test, and the I2 Statistic. We considered that heterogeneity was present when the P value of the Cochran's Q test was < 0.1 and I2 statistic was > 50%. Results: The pooled hazard ratios (HR) for standard risk patients for PFS was HR 0.589 (95% CI 0.502-0.691; P < 0.001) in favor of daratumumab. Q-statistic for PFS ( P= 3.462; df= 2; I2 = 42.23) suggests homogeneity across studies. The pooled hazard ratios (HR) for high risk patients for PFS was HR 0.799 (95% CI 0.609-1.047; P= 0.104) in favor of daratumumab. Q-statistic for PFS ( P= 1.306; df= 2; I2 = 0.00) suggests homogeneity across studies. Conclusions: Our meta-analysis demonstrates that addition of daratumumab to SOC myeloma induction regimens prevented progression in both standard and high-risk patients, though the impact was more pronounced in the standard-risk patients. This benefit seems to improve with longer follow up, as seen both in ALCYONE (Mateos et al ASH 2019) and MAIA trial (Bahlis et al ASH 2019). Focused accrual of high-risk patients in larger daratumumab induction trials and longer follow up of the existing trials are further needed.

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