Inclusion of Patient's Self-Reported Fatigue into a Standard Laboratory Risk Classification Enhances Survival Prediction in Patients with Advanced Myelodysplastic Syndromes

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1242-1242
Author(s):  
Fabio Efficace ◽  
Pasquale Niscola ◽  
Francesco Cottone ◽  
Gianluca Gaidano ◽  
Amelie Anota ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Prognostic Index ◽  
Risk Groups ◽  
Sensitivity Analyses ◽  
Favorable Prognosis ◽  
High Fatigue ◽  
Eortc Qlq C30 ◽  
Eortc Qlq

Abstract BACKGROUND: Patients with higher risk myelodysplastic syndromes (MDS) according to the International Prognostic Scoring System (IPSS) have poor life expectancy making accurate prediction of overall survival (OS) a critical issue for optimal and personalized patients' management. PURPOSE: The primary objective of this study was to develop a patient-based prognostic index for higher risk-disease, that would include self-reported fatigue into the widely used IPSS classification. A secondary objective was to examine whether this patient-based index would provide more accurate OS prediction than the standard IPSS classification. PATIENTS AND METHODS: Analysis is based on 280 newly diagnosed patients with MDS classified with an intermediate-2 or high-risk score (i.e., higher-risk) according to the IPSS. Patients were recruited in an international prospective cohort observational study involving 37 centers. OS was defined as the date of diagnosis of IPSS intermediate-2 or high risk MDS up to death for any cause. Patients were censored at the date of last follow up if not dead at the time of analysis. Before treatment start, all patients completed the EORTC QLQ-C30 questionnaire and the fatigue scale was a priori selected for possible inclusion into the IPSS. Among all observed values of the fatigue score (range: 0-100) we looked for a threshold defining four risk groups, formed by patients reporting either low or high fatigue respectively in intermediate-2 and high risk IPSS groups. The final prognostic index was developed based on univariate and multivariate Cox models. Differences among Kaplan-Meier OS estimation of new risk categories were assessed by log-rank test. Sensitivity analyses were performed, 1) assessing differences in patients' baseline characteristics among risk groups, by Kruskal-Wallis and Fisher's exact tests 2) accounting for several potential confounding factors (baseline and time-dependent) in a multivariate extended Cox model, including treatment received after baseline assessment and further evolution into acute myeloid leukemia, 3) performing a bootstrap resampling procedure to internally validate the final prognostic index. Discrimination and calibration of the new index were evaluated. For all analyses, α=0.05. RESULTS: With a median follow- up of 15 months (IQR 8-27) we observed 113 deaths. The median OS of the overall population was 17 months (95% CI, 15-19). The majority of patients (N=165, 59%) received treatment with hypomethylating agents. The final cut-off value selected for the EORTC QLQ-C30 fatigue scale was 45 points discriminating between patients with low (<45 points) or high fatigue (≥45 points). A new risk score classification was then developed, namely, the Fatigue(FA)-IPSS(h), enabling to distinguish three risk group categories (i.e., risk-1, risk-2 and risk-3) in contrast to the two categories of the IPSS (intemediate-2 and high-risk). Patients with the most favorable prognosis according to the FA-IPSS(h) (i.e., risk-1) had a median OS of 23 months (95% CI, 19-29), those with risk-2 had a median survival of 16 months (95% CI, 12-17) and those with the least favorable prognosis (risk-3) had median OS of 10 months (95% CI, 4-13). In contrast, median OS was 20 months (95% CI, 17-24 months) and 13 months (95% CI, 9-16 months) for patients with an IPSS intermediate-2 and high risk scores, respectively. Survival rates at 6 months, one and two years were markedly different amongst the three groups of the FA-IPSS(h). For example, one-year OS for patients with the most favorable prognosis (risk-1) was 80.2% (95% CI, 73.4-87.8) and only 37.5% (95% CI, 23.8-59.1) for those with the poorest prognosis (risk-3). Sensitivity analyses supported our findings. The FA-IPSS(h) index showed very good predictive performance (bootstrap-corrected c-index=0.911). CONCLUSION: The FA-IPSS(h) is a new prognostic index that integrates patient's self-reported fatigue into the well established IPSS index. Its use might enhance physicians' ability to more accurately predict OS in higher-risk MDS. Also, implementation of this index into standard practice might have important implications to elicit a more active patient participation during initial consultations. Disclosures Efficace: Seattle Genetics: Consultancy; Bristol Myers Squibb: Consultancy; TEVA: Consultancy, Research Funding; Lundbeck: Research Funding. Gaidano:Gilead: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Karyopharm: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Speakers Bureau; Morphosys: Consultancy, Honoraria. Bonnetain:Roche: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Celgène: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Ipsen: Consultancy, Honoraria; Integragen: Consultancy, Honoraria; Nestle: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Chugai: Consultancy, Honoraria; Merck Serono: Consultancy, Honoraria; Bayer: Consultancy, Honoraria. Fianchi:Novartis: Honoraria; Celgene: Honoraria; Janssen: Honoraria. Breccia:Novartis: Consultancy, Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Platzbecker:Celgene Corporation: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding.

Comparison Of Sequential Vs Alternating Administration Of Bortezomib, Melphalan and Prednisone (VMP) and Lenalidomide Plus Dexamethasone (Rd) In Elderly Patients With Newly Diagnosed Multiple Myeloma (MM) Patients: GEM2010MAS65 Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 403-403 ◽  
Author(s):  
Maria-Victoria Mateos ◽  
Joaquín Martínez-López ◽  
Miguel T. Hernandez ◽  
Rafael Martinez ◽  
Laura Rosiñol ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Research Funding ◽  
Risk Groups ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Sequential Scheme ◽  
To Receive

Abstract Background VMP and Rd are two of the most efficient and widely accepted regimens in the treatment of elderly newly diagnosed MM patients. In order to further improve the outcome of elderly patients, one possibility would be to use regimens including all these drugs simultaneously, but this may result into high toxicity. Alternatively, the use of these regimens (VMP and Rd) in a sequential or alternating scheme could improve the treatment of elderly patients. We hypothesized the alternating scheme would minimize the emergence of resistant clones, and would reduce the cumulative toxicity. In order to test this hypothesis we decided to compare VMP and RD in a sequential vs an alternating scheme. Patients and methods 241 patients 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 (half of the patients started by VMP and half by Rd) up to 18 cycles). VMP included the iv administration of bortezomib 1.3 mg/m2 twice weekly for 1 six-weeks cycle, followed by once weekly for 8 four-weeks cycles in combination with oral melphalan 9 mg/m2 and prednisone 60 mg/m2 once daily on days 1–4 of each cycle. Rd treatment consisted on lenalidomide 25 mg daily on days 1-21 plus dexamethasone 40 mg weekly. Results 121 patients were allocated to receive the sequential scheme and 120 the alternating regimen. Both arms were well balanced according to the baseline characteristics. 52% patients in the sequential arm and 55% in the alternating and had high risk cytogenetic abnormalities (t(4;14), t(14;16), del17p or 1q gains). After 9 cycles of treatment, in the sequential arm, 35 out of 66 (54%) achieved at least VGPR vs 51 out of 65 patients (78%) in the alternating arm (p=0.002), including sCR/CR rate of 28% vs 38% in the sequential and alternating arms, respectively (p=NS). Seven patients in each arm achieved immunophenotypic CR. Moreover, while four patients progressed in the sequential arm under treatment with VMP, no patients in the alternating scheme developed disease progression during the first 9 cycles, After a median follow up of 12 months, there was a trend for shorter TTP in the sequential as compared with the alternating scheme (18 m-TTP of 83% vs 89% (p=NS)). In terms of OS, 83% of patients in the sequential arm were alive at 18 m versus 93% in the alternating (p=NS). Patients who achieved sCR/CR had a significantly longer 18 m-TTP as compared with patients who didn’t achieve it in both sequential (100% vs 71%; p=0.006) and alternating arms (100% vs 79%; p=0.006) and this translated into a significant benefit in OS. No differences were observed in overall response rates and CR rates in standard and high risk patients. The 18 m-TTP was similar in standard and high risk groups in both sequential (86% vs 81%) and alternating arms (84% vs 94%), noting that 94% of patients receiving the alternating scheme were progression-free at 18 months. Regarding hematologic toxicity, the frequency of G3-4 neutropenia was slightly lower in the sequential than in the alternating arm (16% and 23%) and the same trend was observed for G3-4 thrombocytopenia (16% vs 20%). Concerning non-hematologic toxicity, 5% and 4% of the patients in the sequential and alternating arms developed G3-4 infections, respectively; the rate of G3-4 skin rash was 4% in the sequential and 3% in the alternating arm; 4% of patients in the sequential arm developed G3-4 peripheral neuropathy and 3% in the sequential arm. The rate of grade 3-4 thrombotic events was 2% in both arms. Nevertheless, the detailed evaluation of the toxicity will be done at the completion of the trial when all patients will have received the same amount of drugs in either a sequential or an alternating scheme (at the present time, 42 patients in the sequential arm were not yet at risk for the development of lenalidomide-related side effects). Conclusions The administration of melphalan, bortezomib, lenalidomide and steroids in elderly MM patients in a sequential or alternating scheme is feasible. Although longer follow-up is necessary, the alternating scheme may be superior in terms of response rate and outcome, as result of the early exposure of the plasma cell to different agents. Toxicity profile is acceptable. Aparently both schemes of therapy seems to overcome the poor prognosis of high risk cytogenetic. Disclosures: Mateos: Janssen, Celgene: Honoraria. Off Label Use: Lenalidomide plus dexamethasone is not approved for newly diagnosed MM patients. Ocio:Onyx: Consultancy, Research Funding; Novartis: Consultancy; Array Biopharma: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy; Celgene: Consultancy, Research Funding. San Miguel:Janssen, Celgene: Membership on an entity’s Board of Directors or advisory committees.

Quality-Adjusted Time without Symptoms of Disease and Toxicity (Q-TWiST) Analysis of CPX-351 Versus 7+3 in Older Adults with Newly Diagnosed High-Risk/Secondary Acute Myeloid Leukemia (AML)

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 55-56
Author(s):  
Jorge E. Cortes ◽  
Tara Lin ◽  
Geoffrey L Uy ◽  
Robert J. Ryan ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Sensitivity Analyses ◽  
Base Case ◽  
Newly Diagnosed ◽  
Case Scenario ◽  
Base Case Scenario ◽  
Grade 3 ◽  
Intent To Treat

Introduction: CPX-351 (Vyxeos®; daunorubicin and cytarabine liposome for injection), a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio, has been approved by the US FDA and the EMA for the treatment of adults with newly diagnosed, therapy-related AML or AML with myelodysplasia-related changes. The primary analysis of the pivotal phase 3 study (NCT01696084) that formed the basis for these approvals evaluated patients aged 60 to 75 years with newly diagnosed high-risk/secondary AML and found that, with a median follow-up of 20.7 months, CPX-351 significantly improved median overall survival (OS) versus conventional 7+3, with a comparable safety profile. Final 5-year follow-up results recently reported demonstrated that the OS benefit was maintained. To evaluate both quality and quantity of life, we conducted a Q-TWiST analysis of the phase 3 study to compare survival between patients receiving CPX-351 versus 7+3. Methods: Q-TWiST is used to evaluate outcomes in oncology trials by measuring how much of the survival improvement time is spent with toxicities, how much after disease progression or relapse, and how much is valuable time (ie, Time Without Symptoms of Disease and Toxicity [TWiST]). For this analysis, the OS for each patient from the 5-year follow-up analysis was partitioned into 3 health states: TOX (time before response plus any additional time with a grade 3 or 4 toxicity), TWiST (time without relapse or grade 3 or 4 toxicity), and REL (time after relapse). Q-TWiST gain was assessed as the mean time spent in each state weighted by its respective quality of life, represented by health utility (U; scale of 0.0 [indicates death] to 1.0 [indicates "perfect" health]). Q-TWiST gain was calculated as follows: Q-TWiST = (UTWiST × TWiST) + (UTOX × TOX) + (UREL × REL). The base case scenario used the intent-to-treat population, any grade 3 or 4 toxicities, TOX and REL utility weights of 0.5, and a TWiST utility weight of 1.0. Sensitivity analyses were performed for all treated patients (CPX-351: n = 153; 7+3: n = 151) and the intent-to-treat population, any and treatment-related grade 3 or 4 toxicities, and TOX and REL utility weights of 0, 0.5, and 1.0. A variation of the base case scenario was also performed for the subset of patients who achieved complete remission (CR) or CR with incomplete neutrophil or platelet recovery (CR+CRi; CPX-351: n = 73; 7+3: n = 52). When comparing across populations or studies, reporting relative Q-TWiST gains is an effective measure for evaluating clinical benefit (ie, Q-TWiST gains compared to a control; Solem CT, et al. Expert Rev Pharm Out 2018). A relative Q-TWiST gain of 15% or greater is considered a clinically important difference (CID) in oncology studies (Revicki DA, et al. Qual Life Res 2006). The relative Q-TWiST gain was calculated using the following equation: Q-TWiST difference ÷ mean OS of control arm × 100. Results: In total, 309 patients were randomized to CPX-351 (n = 153) or 7+3 (n = 156). In the base case scenario, the means difference (95% CI) for CPX-351 versus 7+3 was 183 days (60, 306) for the TWiST state, 7 days (−63, 78) for the TOX state, and 22 days (5, 38) for the REL states. The resulting means difference (95% CI) for Q-TWiST gain was 197 days (76, 319) for CPX-351 versus 7+3, and the relative Q-TWiST gain was 53.6%. Among patients who achieved CR or CRi, the means difference (95% CI) for Q-TWiST gain was 248 days (−1, 496) for CPX-351 versus 7+3, and the relative Q-TWiST gain was 39.8%. Both relative Q-TWiST gains were considerably above the standard CID of 15% for oncology. Across the various sensitivity analyses, the relative Q-TWiST gains for CPX-351 versus 7+3 varied from 48.0% to 57.6%, remaining all well above the standard CID threshold (Table). Conclusions: Results of this post hoc analysis suggest the survival benefit with CPX-351 for patients with high-risk/secondary AML are mostly from valuable time (TWiST), thus supporting the clinical benefit for patients. The relative Q-TWiST gains were well above what is considered CID (15%) in the cancer literature and were maintained across various sensitivity analyses, supporting the robustness of the benefit. In the absence of direct measures of quality of life, these results can be used together with the antileukemia effect when considering treatment options for this patient population. Disclosures Cortes: Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sun Pharma: Research Funding; Pfizer: Consultancy, Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding; Merus: Research Funding; Immunogen: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Lin:Aptevo: Research Funding; Abbvie: Research Funding; Gilead Sciences: Research Funding; Genetech-Roche: Research Funding; Incyte: Research Funding; Celyad: Research Funding; Celgene: Research Funding; Jazz: Research Funding; Mateon Therapeutics: Research Funding; Ono Pharmaceutical: Research Funding; Bio-Path Holdings: Research Funding; Astellas Pharma: Research Funding; Prescient Therapeutics: Research Funding; Pfizer: Research Funding; Trovagene: Research Funding; Tolero Pharmaceuticals: Research Funding; Seattle Genetics: Research Funding. Uy:Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Agios: Consultancy; Genentech: Consultancy; Jazz Pharmaceuticals: Consultancy; Astellas Pharma: Honoraria. Ryan:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Faderl:Jazz Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Lancet:Abbvie: Consultancy; Agios Pharmaceuticals: Consultancy, Honoraria; Astellas Pharma: Consultancy; Celgene: Consultancy, Research Funding; Daiichi Sankyo: Consultancy; ElevateBio Management: Consultancy; Jazz Pharmaceuticals: Consultancy; Pfizer: Consultancy.

Comparison of the international prognostic factors index (IPI) with the absolute monocyte and lymphocyte prognostic index (AMLPI) for patients (Pts) with diffuse large b-cell lymphoma (DLBCL) receiving R-CHOP.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8067-8067
Author(s):  
Nicolas Batty ◽  
Elham Ghonimi ◽  
Lei Feng ◽  
Luis Fayad ◽  
Anas Younes ◽  
...  
Keyword(s):  
High Risk ◽  
Cell Lymphoma ◽  
Univariate Analysis ◽  
Prognostic Index ◽  
B Cell Lymphoma ◽  
Risk Groups ◽  
Prognostic Effect ◽  
Large B Cell Lymphoma ◽  
High Risk Disease

8067 Background: We studied the value of a proposed prognostic index (PI) generated by baseline absolute monocyte (AMC) and lymphocyte (ALC) counts for pts with DLBCL, using values as previously reported (Leukemia 25:1502-9, 2011). Methods: From 03/07 to 01/09, 245 consecutive pts with untreated DLBCL receiving standard R-CHOP from the MDACC database were evaluated. Baseline AMC and ALC were retrospectively recorded. High AMC (≥610/uL) and a low ALC (≤1000/uL) were examined as dichotomized variables for progression-free (PFS) and overall survival (OS). An AMLPI was generated, stratifying pts into 3 risk groups (RGs): low-(AMC <610/uL and ALC >1000/uL), intermediate-(AMC ≥610/uL or ALC ≤1000/uL), and high-risk(AMC ≥610/uL and ALC ≤1000/uL). The prognostic effect of the AMLPI and the IPI were examined by multivariate analysis (MVA). Results: Ninety (37%) had high AMC and 71 (29%) had low ALC. By univariate analysis, a high AMC was associated with inferior PFS (p=0.01) and OS (p=0.03). The frequencies of AMLPI RGs were: low-105 pts (43%), intermediate-119 (48%), and high risk-21 (9%). With a median follow-up of 22 months (range <1-42), 3-year PFS and OS rates for these RGs were 80%, 61%, and 46% (p=0.007) and 92%, 76%, and 60% (p=0.006), respectively. Three-year PFS rates for IPI 0-2 and 3-5 RGs were 73% and 58%, respectively (p=0.0004); comparable OS rates were 88% and 68%(p<0.0001). For pts with IPI 0-2, 1-year PFS rates for AMLPI low, intermediate, and high RGs were 92%, 89% and 80% (p=0.022); comparable 1-year OS rates were 96%, 95% and 80% (p=0.049). By MVA, AMLPI effect (low vs. high RGs) on PFS was significant (p=0.046) as was IPI effect (0-2 vs 3-5, p=0.005); similar results were observed for OS (p=0.052 and p=0.003, respectively). Conclusions: Baseline AMC and AMLPI are significant variables for PFS and OS for pts with DLBCL receiving R-CHOP. AMLPI can identify pts with low, intermediate, and high-risk disease for PFS and OS, particularly for those with IPI 0-2. AMLPI may also add prognostic value beyond that of the IPI.

scholarly journals A New Prognostic Index for Waldenström Macroglobulinemia Based on a Multicenter Retrospective Study of the Japanese Society of Myeloma

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5320-5320
Author(s):  
Akio Saito ◽  
Atsushi Isoda ◽  
Takeshi Odajima ◽  
Mitsuhiro Itagaki ◽  
Go Yamamoto ◽  
...  
Keyword(s):  
Platelet Count ◽  
High Risk ◽  
Research Funding ◽  
Pharmaceutical Research ◽  
Prognostic Index ◽  
Risk Groups ◽  
Poor Risk ◽  
Ecog Ps ◽  
Pleural Involvement ◽  
Good Risk

Abstract Background: We recently reported that the International Prognostic Scoring System for Waldenström macroglobulinemia (ISSWM), which is widely used to predict the prognosis of WM patients, might not be applicable to Japanese patients, and evidence of pleural effusion might be a novel adverse prognostic factor for symptomatic WM in the rituximab era. Further studies with a large number of patients are deemed to be conducted. Methods: We retrospectively analyzed the clinical data of 498 patients with WM diagnosed between January 2001 and December 2015 from 44 institutes involved with the Japanese Society of Myeloma. The overall survival (OS) was analyzed using Kaplan-Meier methods and compared using log-rank test. Several clinical characteristics at the diagnosis were assessed by Cox regression for univariate and multivariate analyses of the OS. Results: We included 420 cases diagnosed with symptomatic (n=314) and asymptomatic WM (n=106) in accordance with the classification of the Second International Workshop on WM. The median age at the diagnosis was 69 (range, 32-91) years, with 75.5% male, and 16.0% had an Eastern Cooperative Oncology Group performance status (ECOG PS) of 2-4. Oral alkylating agents, purine analogs, cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or CHOP-like regimens ± rituximab, rituximab monotherapy, or dexamethasone, rituximab and cyclophosphamide (DRC) were mainly administered as initial treatment. Rituximab-containing therapy was administered in 76.8% of all patients. The median follow-up was 45 months. The 5-year OS rate for all patients was 77.9%, while the rates for those with symptomatic and asymptomatic WM were 72.9% and 92.2%, respectively. Significant differences in the survival were seen between risk groups of ISSWM in symptomatic WM patients (5-year OS: high, 55.4%; intermediate, 81.2%; low, 90.2%; p<0.0001) (Figure 1). A univariate analysis showed that age >65 years, platelet count ≤10×104/µL, serum β2-microglobulin (β2-MG) >3 mg/L, ECOG PS 2-4, abnormal karyotype, pleural involvement, WBC <4000/µL, amyloidosis, fluid retention, pleural effusion, ascites, serum albumin ≤3.5 g/dL, serum creatinine >1.5 mg/dL, CRP >2.0 mg/dL and sIL-2R >4000 U/mL were significant adverse prognostic factors for the OS. A multivariate analysis revealed that a platelet count ≤10×104/µL (hazard ratio [HR] 5.942; 95% confidence interval [CI] 2.265-14.761), serum β2-MG >3 mg/L (HR 2.748; 95% CI 1.091-7.655), ECOG PS 2-4 (HR 2.899; 95% CI 1.219-6.290), and pleural involvement (HR 11.066; 95% CI 3.672-29.829) were adverse independent risk factors for symptomatic WM. We constructed a prognostic model by combining these prognostic variables as follows: patients with good risk (n=219), no adverse factors or only serum β2-MG >3 mg/L or ECOG PS 2-4; patients with poor risk (n=81), ≥1 adverse factors with a platelet count ≤10×104/µL, pleural involvement, or both serum β2-MG >3 mg/L and ECOG PS 2-4. The 5-year OS rates were 82.3% for good risk and 44.4% for poor risk, and this prognostic model significantly stratified symptomatic WM patients separately by the survival (p<0.0001) (Figure 2). The survival of patients with both poor risk in our model and high risk in ISSWM were extremely poor (5-year OS: poor and high [n=57], 24.7%; poor and intermediate [n=14], 80.0%; poor and low [n=2], not available; p=0.0031). In contrast, no significant differences were observed for the survival for the ISSWM risk groups in patients with good risk in our model (5-year OS: good and high [n=69], 76.0%; good and intermediate [n=83], 81.6%; good and low [n=42], 89.5%; p=0.2045). Conclusion: Although ISSWM may be useful for survival risk stratification in Japanese patients, we found that intermediate- and high-risk patients seemed to have a better prognosis than those in Western studies in the rituximab era (Dimopoulos MA, et al. Haematologica. 2008; 93: 1420-22). Thrombocytopenia and pleural involvement were found to be strong adverse prognostic factors in symptomatic WM, and our new prognostic index including them was easy to use in daily clinical practice and superior to ISSWM for detecting high-risk patients. Further studies are warranted to validate our prognostic index, especially in the era of novel agents. Disclosures Yamamoto: Bristol-Myers Squibb: Honoraria. Hagiwara:Celgene: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Sunami:Celgene: Honoraria, Research Funding; Sanofi: Research Funding; Janssen: Research Funding; Daiichi-Sankyo: Research Funding; Ono: Honoraria, Research Funding; Bristol-Myers Squibb K.K.: Honoraria, Research Funding; AbbVie: Research Funding; Takeda: Research Funding; MSD: Research Funding; GlaxoSmithKline: Research Funding; Novartis: Research Funding. Kurokawa:Teijin Pharma: Research Funding; Eizai: Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Chugai Pharmaceutical: Research Funding; Sumitomo Dainippon Pharma: Research Funding; Pfizer: Research Funding; Takeda Pharmaceutical: Research Funding; MSD: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Nippon Sinyaku: Honoraria, Research Funding; Astellas Pharma: Research Funding; Otsuka Pharmaceutical: Research Funding. Takamatsu:Janssen: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Ono: Research Funding. Ito:Bristol-Myers Squibb, Celgene: Honoraria. Tamura:Bristol-Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria; Takeda Pharmaceutical: Honoraria.

scholarly journals Quality of Life and Karnofsky Performance Status in Patients with Relapse or Refractory Primary Central Nervous System Lymphoma during Phase I/II Study of Tirabrutinib

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4561-4561
Author(s):  
Yasuhito Terui ◽  
Yoshitaka Narita ◽  
Motoo Nagane ◽  
Kazuhiko Mishima ◽  
Yoshiki Arakawa ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Central Nervous System Lymphoma ◽  
Advisory Committees ◽  
Chugai Pharmaceutical ◽  
Eortc Qlq C30 ◽  
Eortc Qlq

Abstract Background: Based on the results of a phase I/II study in Japan (Trial registration: JapicCTI-173646), tirabrutinib (TIR), a second-generation inhibitor of Bruton's tyrosine kinase, was approved in March 2020 for the treatment of relapsed or refractory primary central nervous system lymphoma (r/r PCNSL). We have previously reported overall response rate of 63.6% and manageable safety profile results of this study (Narita et al. Neuro Oncol. 2021;23(1):122-133). Further, one-year follow-up data after the last patient had enrolled showed that the effects of TIR persisted in r/r PCNSL patients (Mishima et al. Poster presented at the Society for Neuro-Oncology virtual conference; November 19-21, 2020). Here, based on this one-year follow-up data, we describe the Quality of Life (QoL) and Karnofsky Performance Status (KPS) in r/r PCNSL patients treated with TIR. Methods: Patients with r/r PCNSL, age ≥20 years, and KPS ≥70 were treated with TIR once daily (QD) at a dose of 320 mg, 480 mg, or 480 mg upon fasting (480 mg fasted QD). TIR was administered in 28-day cycles, and treatment was continued until disease progression or clinically unacceptable toxicity was observed. QoL was assessed using questionnaires issued by the European Organization for Research and Treatment of Cancer (EORTC), namely QLQ-C30 (EORTC QLQ-C30), EORTC QLQ-BN20, and EuroQol 5 dimensions 3-level (EQ-5D-3L). The QoL survey was conducted during the screening period, on Day 28 of Cycle 1, after every 2 cycles (i.e., after Day 1 of Cycle 3), after every 4 cycles (i.e., after Day 1 of Cycle 25), and at the end of treatment. KPS was measured during the screening period, on days 1, 8, 15, and 28 of Cycle 1, on day 1 of every cycle after Cycle 3, and at the end of treatment. Results: Forty-four patients were prospectively enrolled, and 20, 7, and 17 patients were treated with TIR at 320 mg QD, 480 mg QD, and 480 mg fasted QD, respectively. Median patient age was 60 years (range 29-86). Median follow-up period was 14.9 months (range, 1.4-27.7) for the entire cohort but was 19.1 months, 23.5 months, and 12.0 months for the 320 mg QD, 480 mg QD, and 480 mg fasted QD groups, respectively. At the time of data cutoff (February 25, 2020), 11 patients (25%) remained on treatment. Mean (SD) score for the global health status/QoL section of the EORTC QLQ-C30 was 50.9 (23.7) at baseline and remained relatively constant during treatment (Figure 1). This trend was also observed for emotional function, cognitive function, and fatigue sections of the EORTC QLQ-C30, for motor dysfunction, communication deficit, weakness of legs, and bladder control sections of the EORTC QLQ-BN20, and in items pertaining to self-care, usual activities, and anxiety/depression in the EQ-5D-3L. Median KPS was 80.0 (range, 70-100) at baseline, which remained unchanged during TIR treatment (Figure 2). Conclusion: QoL and KPS scores in r/r PCNSL patients were maintained during TIR administration, a new treatment option for r/r PCNSL, which does not lead to the deterioration of QoL and KPS. Figure 1 Figure 1. Disclosures Terui: Ono Pharmaceutical: Speakers Bureau; MSD: Speakers Bureau; Janssen: Speakers Bureau; Esai: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Celgene: Speakers Bureau; AbbVie: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau. Narita: Ono Pharmaceutical co.: Honoraria, Research Funding; Dainippon-Sumitomo: Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Stella-pharma: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Bayer: Research Funding; Ohara: Research Funding; Chugai Pharmaceutical co.: Honoraria; Novocure: Honoraria. Nagane: AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Eisai: Honoraria, Research Funding; Pfizer: Research Funding; MSD: Research Funding; Astellas: Research Funding; Nippon-Kayaku: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; Shionogi: Research Funding; Otsuka: Research Funding; Ono Pharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novocure: Honoraria; Sumitomo Dainippon Pharma: Honoraria; RIEMSER: Membership on an entity's Board of Directors or advisory committees. Mishima: Ono Pharmaceutical Co: Research Funding; Astellas: Research Funding; HOYA Technosurgical Co.: Research Funding; Daiichi-Sankyo: Research Funding; AbbVie: Research Funding; Medical U and A: Research Funding; Teijin Pharma: Research Funding; Eisai: Research Funding; MSD: Research Funding; Chugai: Research Funding. Arakawa: Sanofi: Research Funding; Carl Zeiss: Honoraria, Research Funding; Brainlab: Honoraria, Research Funding; Nihon Medi-Physics: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Philips: Research Funding; Siemens: Research Funding; Tanabe Mitsubishi: Research Funding; Chugai: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Meiji Seika: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; CSL Behring: Honoraria, Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Stryker: Research Funding; Astellas Pharma: Research Funding; Taiho Pharma: Research Funding; Nippon Kayaku: Honoraria; Novocure: Honoraria; UCB Japan: Honoraria; Integra Japan: Honoraria; Otsuka: Honoraria; Abbvie: Honoraria. Yonezawa: Eisai: Speakers Bureau; Ono Pharmaceutical co.: Speakers Bureau; Chugai Pharmaceutical co.: Speakers Bureau. Fukuhara: Celgene: Honoraria, Research Funding; Chugai Pharmaceutical: Honoraria, Research Funding; Eisai: Honoraria; HUYA Bioscience International: Honoraria; Incyte: Research Funding; Janssen: Honoraria; Kyowa Kirin: Honoraria; Nippon Shinyaku: Honoraria; Novartis: Honoraria; Ono Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria; Zenyaku Kogyo: Honoraria; Bayer: Research Funding; AbbVie: Honoraria. Sugiyama: Daichi Sankyo Inc.: Consultancy; Ono Pharmaceutical Inc: Honoraria. Aoi: Ono Pharma USA, Inc.: Current Employment. Nishikawa: Novocure: Consultancy; Chugai: Honoraria, Research Funding; MSD: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Ono: Honoraria; Nihon-Kayaku: Honoraria. OffLabel Disclosure: Tirabrutinib. Clinical trial for PCNSL.

Outcomes Of Chronic Lymphocytic Leukemia Patients With Richter Syndrome

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4179-4179 ◽  
Author(s):  
Sameer A. Parikh ◽  
Ruchi G. Sharma ◽  
Timothy G. Call ◽  
Thomas M Habermann ◽  
Wei Ding ◽  
...  
Keyword(s):  
High Risk ◽  
B Cell ◽  
Median Survival ◽  
Research Funding ◽  
Risk Groups ◽  
Lymphocytic Leukemia ◽  
B Cell Receptors ◽  
Intermediate Risk ◽  
Richter Syndrome

Abstract Introduction Approximately 2-8% chronic lymphocytic leukemia (CLL) patients develop diffuse large B-cell lymphoma (DLBCL, so-called Richter syndrome [RS]) over long-term follow-up. The outcomes of patients with RS are variable and poorly understood. Methods CLL patients seen at Mayo Clinic from January 1995 to April 2013 who developed biopsy-proven DLBCL during follow-up were included in this analysis. Clinical characteristics, therapy and overall survival (OS) of all patients with RS were analyzed. Results One hundred and twenty patients with biopsy-proven RS were identified in the Mayo Clinic database. The median age at diagnosis of RS was 67 years (range, 29-88 years), 87 (73%) were male, and 83 (69%) had received prior CLL therapy. The median duration between diagnosis of CLL and development of RS was 3.8 years (range, 0-34.5 years). Stereotyped B-cell receptors were found in 9/30 (30%) RS patients compared to 219/1294 (17%) non-RS patients (OR=2.1, p=0.07). IGHV4-39 gene usage was present in 2/26 (8%) RS patients compared to 57/1354 (4%) non-RS patients (p=0.3). Of the 30 RS biopsy samples in which Epstein Barr virus (EBV) in-situ hybridization studies were performed, EBV was detected in 7 (23%) patients. After a median follow-up of 5.2 years, 86 (72%) patients have died. Causes of death were as follows: progressive DLBCL (n=46, 53%), progressive CLL (n=2, 2%), infection (n=8, 9%), unknown (n=20, 23%) and other (n=10, 12%). The median OS of the entire cohort was 0.9 years (95% CI, 0.5-1.3 years). Tsimberidou and colleagues proposed a prognosis score (RS score) based on the following variables at the time of RS diagnosis: Eastern Co-operative Group performance status of 2-4, lactate dehydrogenase >1.5 x normal, platelets<100 x 109/L, tumour size >5 cm and >1 prior therapy for CLL. Each parameter was assigned one point, and patients were then assigned to one of four risk groups based on their calculated RS score: 0 or 1, low risk; 2, low-intermediate risk; 3, high-intermediate risk; 4 or 5, high risk. The OS according to the RS score for our group of patients is shown in Figure 1. Median survival in the low, intermediate-1, intermediate-2 and high-risk groups were 2.4 years, 0.7 years, 0.3 years and 0.2 years, respectively (p<0.001). Fifteen (12%) patients received cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) as initial therapy for RS, and 68 (57%) received rituximab in addition to CHOP (R-CHOP). There was no difference in survival among patients who received CHOP compared to R-CHOP (median, 1.8 years. vs. 1.2 years, p=0.5). Twenty-four patients (20%) received non-CHOP-based chemotherapy, and treatment was unknown in 4 (3%) patients. Nine patients (7%) died before definitive therapy could be instituted. Thirteen (11%) patients were able to proceed to stem cell transplantation (SCT): 10 (8%) autologous SCT, 2 (2%) allogeneic SCT and 1 (1%) autologous SCT followed by an allogeneic SCT. Although RS patients who underwent SCT were younger compared to those who did not undergo SCT (median, 59 years. vs. 69 years, p=0.001), no differences in prior CLL therapy or receipt of R-CHOP therapy for DLBCL was noted between the two groups. The median survival of patients who proceeded to SCT was superior compared to those who did not (5.2 years vs. 0.7 years; p=0.005). Conclusion Stereotyped B-cell receptors but not VH4-39 had a suggested evidence of an increased risk of RS in our cohort. Although 90% RS patients received intensive chemotherapy, only 11% patients were able to proceed to SCT. Median survival of RS patients remains dismal at 1 year, and newer therapies are needed to improve outcomes. Disclosures: Shanafelt: Genentech: Research Funding; Glaxo-Smith-Kline: Research Funding; Cephalon: Research Funding; Hospira: Research Funding; Celgene: Research Funding; Polyphenon E International: Research Funding.

scholarly journals Association Between the Multidimensional Prognostic Index and Mortality During 15 Years of Follow-up in the InCHIANTI Study

2020 ◽  
Author(s):  
Alberto Pilotto ◽  
Nicola Veronese ◽  
Giacomo Siri ◽  
Stefania Bandinelli ◽  
Toshiko Tanaka ◽  
...  
Keyword(s):  
High Risk ◽  
Age Groups ◽  
Area Under The Curve ◽  
Prognostic Index ◽  
Risk Groups ◽  
Community Dwelling ◽  
Low Risk ◽  
Using Data ◽  
Dose Response Effect

Abstract Background Multidimensional Prognostic Index (MPI) is recognized as a prognostic tool in hospitalized patients, but data on the value of MPI in community-dwelling older persons are limited. Using data from a representative cohort of community-dwelling persons, we tested the hypothesis that MPI explains mortality during 15 years of follow-up. Methods A standardized comprehensive geriatric assessment was used to calculate the MPI and to categorize participants in low-, moderate-, and high-risk classes. The results were reported as hazard ratios (HRs) and the accuracy was evaluated with the area under the curve (AUC), with 95% confidence intervals (CIs) and the C-index. We also reported the median survival time by standard age groups. Results All 1453 participants (mean age 68.9 years, women = 55.8%) enrolled in the InCHIANTI study at baseline were included. Compared to low-risk group, participants in moderate (HR = 2.10; 95% CI: 1.73–2.55) and high-risk MPI group (HR = 4.94; 95% CI: 3.91–6.24) had significantly higher mortality risk. The C-index of the model containing age, sex, and MPI was 82.1, indicating a very good accuracy of this model in explaining mortality. Additionally, the time-dependent AUC indicated that the accuracy of the model incorporating MPI to age and sex was excellent (&gt;85.0) during the whole follow-up period. Compared to participants in the low-risk MPI group across different age groups, those in moderate- and high-risk groups survived 2.9–7.0 years less and 4.3–8.9 years less, respectively. Conclusions In community-dwelling individuals, higher MPI values are associated with higher risk of all-cause mortality with a dose–response effect.

scholarly journals Possibility of a Risk-Adapted Treatment Strategy for Untreated Aggressive Adult T-Cell Leukemia-Lymphoma (ATL) Based on the ATL Prognostic Index: A Supplementary Analysis of the JCOG9801 Study

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1645-1645
Author(s):  
Kosuke Toyoda ◽  
Kunihiro Tsukasaki ◽  
Ryunosuke Machida ◽  
Tomohiro Kadota ◽  
Takuya Fukushima ◽  
...  
Keyword(s):  
High Risk ◽  
Research Funding ◽  
Risk Group ◽  
Prognostic Index ◽  
Risk Groups ◽  
Low Risk ◽  
Intermediate Risk ◽  
Adult T Cell Leukemia ◽  
Ann Arbor ◽  
Ecog Ps

Abstract Introduction The JCOG9801 study, a randomized phase III trial of the Japan Clinical Oncology Group (JCOG), compared CHOP every two weeks (CHOP-14) with VCAP-AMP-VECP (mLSG15) for patients with untreated aggressive adult T-cell leukemia-lymphoma (ATL) [J Clin Oncol 2007;25:5458-64]. Based on a higher complete response (CR) rate and marginally better overall survival (OS), we concluded that mLSG15 could be a sufficiently effective regimen at the expense of higher toxicity profiles. However, there was an insufficient mLSG15 effect among patients with an Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 or those aged ≥56 years, suggesting that mLSG15 is not always a definitive treatment for all patients with aggressive ATL. Thus, identifying patients who should receive mLSG15 is essential. We aimed to conduct a supplementary analysis of patients enrolled in the JCOG9801 study using the ATL prognostic index (ATL-PI) that has been recently advocated for acute- and lymphoma-types of ATL [J Clin Oncol 2012;30:1635-40]. Methods We adopted the "age-adjusted" ATL-PI that was established for ATL patients aged ≤70 years as patients aged between 15 and 69 years were eligible in the JCOG9801 study. Having eliminated "age", this index comprised 4 factors, namely Ann Arbor stage (III or IV), ECOG PS (>1), serum albumin (<3.5 g/dL), and soluble interleukin-2 receptor (sIL-2R; >20,000 U/mL). We excluded patients lacking any factors of the age-adjusted ATL-PI and those with unfavorable chronic type based on the age-adjusted ATL-PI model from patients enrolled in JCOG9801. Subsequently, we categorized the remaining patients into three groups, namely low, intermediate, and high risk, and compared mLSG15 and CHOP-14 in terms of OS, treatment CR rate, and toxicity in each risk group. Results Of 118 enrolled JCOG9801 patients, we included 105 patients in this supplementary analysis based on the above criteria, of which 51 and 54 were treated with mLSG15 and CHOP-14, respectively. According to the age-adjusted ATL-PI, these patients were classified as follows: low (n=44, 41.9%), intermediate (n=54, 51.4%), and high (n=7, 6.7%) risks. Regarding patient characteristics, between the two treatment arms, there were no remarkable differences in age, sex, ECOG PS, ATL subtypes, Ann Arbor stage, presence of B symptoms, presence of bulky mass (≥5 cm), and serum albumin, serum calcium, and sIL-2R levels. The mLSG15 arm included 21 (41.2%), 25 (49.0%), and 5 (9.8%) patients in the low-, intermediate-, and high-risk groups, respectively, whereas the CHOP-14 arm included 23 (42.6%), 29 (53.7%), and 2 (3.7%) patients, respectively. We excluded the high-risk group from our analysis due to the small number of patients. mLSG15 did not show any superior trend for OS compared to CHOP-14 in the low-risk group (hazard ratio [HR]: 0.957; 95% confidence interval [CI]: 0.491-1.868) (Figure A). In contrast, in the intermediate-risk group, better prognosis for OS was observed with mLSG15 (HR: 1.538; 95% CI: 0.841-2.811) than with CHOP-14 (Figure B). Similarly, the CR rate, including the unconfirmed CR rate, did not differ between both arms of the low-risk group (mLSG15 vs. CHOP-14, 47.6% vs. 43.5%), while in the intermediate-risk group, mLSG15 showed a higher CR rate than CHOP-14 (44.0% vs. 13.8%). Regarding toxicity profiles, grade 4 thrombocytopenia was more frequently observed in the mLSG15 arm of both risk groups than in the CHOP-14 arm (66.7% vs. 4.5% in the low-risk group; 68.0% vs. 24.1% in the intermediate-risk group only). There was a higher incidence of grade 4 neutropenia in the mLSG15 arm than in the CHOP-14 arm (100.0% vs. 75.9%) only in the intermediate-risk group. All three treatment-related deaths were documented in the mLSG15 arm of the intermediate-risk group. Conclusions Given the very poor prognosis of ATL, our findings suggest that despite higher toxicities, mLSG15 is more suitable for the intermediate-risk group of age-adjusted ATL-PI, whereas its benefits appear modest in the low-risk group. This supplementary analysis is exploratory; therefore, a further prospective study of aggressive ATL is necessary to confirm these results. Disclosures Tsukasaki: Daiich-Sankyo: Consultancy; Ono Pharma: Consultancy; HUYA: Consultancy, Research Funding; Chugai Pharma: Honoraria, Research Funding; Eisai: Research Funding; Celgene: Honoraria; Mundy Pharma: Honoraria; Kyowa-hakko/Kirin: Honoraria; Seattle Genetics: Research Funding. Fukushima:NEC corporation: Research Funding. Maruyama:Bristol-Myers Squibb: Honoraria; Solasia Pharma: Research Funding; Pfizer: Research Funding; Nippon Boehringer Ingelheim: Research Funding; Novartis: Research Funding; Otsuka: Research Funding; Astellas Pharma: Research Funding; Abbvie: Research Funding; Mundipharma International: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Eisai: Honoraria, Research Funding; Biomedis International: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Kyowa Hakko Kirin: Honoraria, Research Funding; Fujifilm: Honoraria, Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; MSD: Honoraria, Research Funding; Chugai Pharma: Honoraria, Research Funding; Dai-ichi-Sankyo: Honoraria; Dai-Nippon-Sumitomo: Honoraria; Asahi Kasei Pharma: Honoraria; AstraZeneca: Research Funding; Amgen Astellas BioPharma: Research Funding; Zenyaku Kogyo: Honoraria, Research Funding; GlaxoSmithKline: Research Funding. Nagai:SymBio Pharmaceuticals Limited: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Honoraria, Research Funding; Janssen Pharmaceutical K.K.: Honoraria, Research Funding; Chugai Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Solasia Pharma K.K.: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Bayer Yakuhin Ltd.: Research Funding; Abbvie G. K.: Research Funding; Celgene Corporation: Honoraria, Research Funding; Takeda Pharmaceutical Co., Ltd.: Honoraria, Research Funding; AstraZeneca plc.: Research Funding; Roche Ltd.: Honoraria; Esai Co., Ltd.: Honoraria, Research Funding; HUYA Bioscience International: Research Funding; Ono Pharmaceutical Co., Ltd.: Honoraria, Research Funding; Sanofi K. K.: Honoraria; Zenyaku Kogyo Co., Ltd.: Honoraria, Research Funding; Mundipharma K.K.: Honoraria, Research Funding; Gilead Sciences Inc.: Honoraria, Research Funding.

scholarly journals Lenalidomide Induction and Maintenance Maximizes Outcome for Newly Diagnosed Transplant Eligible Myeloma Patients Irrespective of Risk Status: Long-Term Follow-up of the Myeloma XI Trial

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1910-1910 ◽  
Author(s):  
Graham Jackson ◽  
Charlotte Pawlyn ◽  
David Cairns ◽  
John R Jones ◽  
Bhuvan Kishore ◽  
...  
Keyword(s):  
High Risk ◽  
Financial Support ◽  
Research Funding ◽  
Risk Groups ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Cytogenetic Abnormalities ◽  
Long Term Follow Up

Background: Immunomodulatory (IMiD) compounds are effective therapies for multiple myeloma (MM) acting via modulation of the CUL4 E3-ubiquitin ligase cereblon. Based on their structure individual IMiD compounds have different substrate specificities altering both their efficacy and side effect profile. These mechanistic differences impact the optimum sequencing of these agents as induction and maintenance. Within the UK NCRI Myeloma XI trial we compared triplet induction regimens containing Lenalidomide (Len) or Thalidomide (Thal) and maintenance treatment with Len or observation. With extensive long term follow up data we have explored the interaction of the induction and maintenance use of Thal and Len before and after ASCT. Methods: Myeloma XI is a multicenter, randomized controlled trial for newly diagnosed MM, with pathways for transplant eligible (TE) and non-eligible patients. TE patients were randomized between Len or Thal plus cyclophosphamide and dexamethasone (CRD vs CTD) continued for a minimum of 4 cycles and to max. response. For patients with a suboptimal response there was a subsequent randomization to intensification with a proteasome inhibitor containing triplet or no further therapy prior to ASCT. A maintenance randomization at 3 months post ASCT compared Len till disease progression vs observation (Obs). Analyses by molecular risk strata were pre-specified in the protocol. Adverse cytogenetic abnormalities were defined as gain(1q), t(4;14), t(14;16), t(14;20), or del(17p): standard risk (SR, no adverse cytogenetic abnormalities), high risk (HiR, one adverse cytogenetic abnormality), or ultra-high risk (UHiR, two or more adverse cytogenetic abnormalities). Results: 2042 TE patients were randomized to CRD n=1021 and CTD n=1021. After a median follow up of 68 months (interquartile range 49-83) for the induction randomization, 1378 PFS and 728 OS primary endpoint events had occurred. Patients received a median (range) of 5 (1-18) cycles of CRD and 5 (1-13) cycles of CTD induction therapy. There were higher rates of haematological toxicity with CRD and peripheral neuropathy with CTD. CRD induction was associated with a significantly improved median PFS (hazard ratio (HR) 0.86, 95%CI 0.77, 0.96, CRD 36 months vs CTD 33 months, P=0.005, Figure 1A) and median OS (HR 0.81, 95%CI 0.70, 0.93, CRD 96 months vs CTD 85 months, P=0.004, Figure 1B). Responses were deeper with CRD (>=VGPR 65.3%, PR 24.5%) than CTD (>=VGPR 52.8%, PR 33.2%) and depth of response was associated with outcome. Significant heterogeneity in PFS outcome was identified between molecular risk groups with HiR and UHiR benefiting most from induction with CRD rather than CTD (SR HR 0.99 [95%CI 0.79, 1.24], HiR HR 0.58 [0.44, 0.78], UHiR HR 0.60 [0.38, 0.94], P.het 0.01). 897 TE patients were randomized to Len (n=496) and Obs (n=401). After a median follow up of 68 months (interquartile range 51-84) for the maintenance randomization, 527 PFS primary endpoint events had occurred. Lenalidomide was associated with a significant improvement in PFS compared to observation (median PFS Len 64 [54,76] vs Obs 32 [28,36], HR 0.52 [0.45,0.61], P<0.001). This was consistent across all risk subgroups (SR HR 0.44 [95%CI 0.34, 0.56], HiR HR 0.50 [0.37, 0.67], UHiR HR 0.52 [0.31, 0.87], P. het 0.87). Optimum outcomes were seen in those receiving Len as both induction and maintenance therapy (Figure 1C). Patients receiving CRD induction followed by Len maintenance (CRD-R) had a median PFS of 77 months [56, 86] compared to CTD-R 64 [49, 74], CRD-Obs 37 [33, 42] and CTD-Obs 44 [38, 51]. Conclusions: In this study the use of Len as both induction and maintenance was associated with the best outcomes irrespective of cytogenetic risk group. With long term follow up CRD induction for newly diagnosed transplant eligible myeloma patients was associated with both a PFS and OS benefit compared to CTD and was better tolerated. The PFS impact of CRD was particularly notable in patients with high and ultra-high risk disease. Lenalidomide maintenance was associated with significantly longer PFS than observation across all risk groups. on behalf of the NCRI Haematological Oncology Clinical Studies Group Disclosures Jackson: Celgene, Amgen, Roche, Janssen, Sanofi: Honoraria. Pawlyn:Amgen, Celgene, Janssen, Oncopeptides: Honoraria; Amgen, Celgene, Takeda: Consultancy; Amgen, Janssen, Celgene, Takeda: Other: Travel expenses. Cairns:Celgene, Amgen, Merck, Takeda: Other: Research Funding to Institution. Jones:Celgene: Honoraria, Research Funding. Kishore:Celgene, Takeda, Janssen: Honoraria, Speakers Bureau; Celgene, Jazz, Takeda: Other: Travel expenses. Garg:Janssen, Takeda, Novartis: Other: Travel expenses; Janssen: Honoraria; Novartis, Janssen: Research Funding. Lindsay:Celgene: Other: personal fees and non-financial support ; Takeda: Other: personal fees and non-financial support ; Amgen: Other: non-financial support. Russell:Jazz: Consultancy, Honoraria, Speakers Bureau; Pfizer Inc: Consultancy, Honoraria, Speakers Bureau; DSI: Consultancy, Honoraria, Speakers Bureau; Astellas: Consultancy, Honoraria, Speakers Bureau. Jenner:Abbvie, Amgen, Celgene, Novartis, Janssen, Sanofi Genzyme, Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Cook:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Karyopharm: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau. Drayson:Abingdon Health: Consultancy, Equity Ownership. Owen:Janssen: Other: Travel expenses; Celgene, Janssen: Honoraria; Celgene, Janssen: Consultancy; Celgene: Research Funding. Gregory:Abbvie, Janssen: Honoraria; Celgene: Consultancy, Research Funding; Amgen, Merck: Research Funding. Kaiser:Takeda, Janssen, Celgene, Amgen: Honoraria, Other: Travel Expenses; Celgene, Janssen: Research Funding; Abbvie, Celgene, Takeda, Janssen, Amgen, Abbvie, Karyopharm: Consultancy. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding. Morgan:Bristol-Myers Squibb, Celgene Corporation, Takeda: Consultancy, Honoraria; Amgen, Janssen, Takeda, Celgene Corporation: Other: Travel expenses; Celgene Corporation, Janssen: Research Funding. OffLabel Disclosure: CTD/CRD induction therapy and Lenalidomide maintenance 10mg 21/28 days

scholarly journals A Novel Machine Learning-Derived Dynamic Scoring System Predicts Risk of Thrombosis in Polycythemia Vera (PV) Patients

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3619-3619
Author(s):  
Ghaith Abu-Zeinah ◽  
Spencer Krichevsky ◽  
Richard T. Silver ◽  
Elwood Taylor ◽  
Douglas Tremblay ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Scoring System ◽  
Research Funding ◽  
External Validation ◽  
Risk Groups ◽  
Advisory Committees ◽  
Thrombosis Risk ◽  
Dynamic Scoring

Abstract Introduction: Thrombosis remains a leading cause of morbidity and early mortality in PV. The European LeukemiaNet (ELN) classifies patients (pts) at diagnosis as high-risk according to age ≥60 years (yr) and/ or prior thrombosis, but dynamic models predicting short-term risk of initial or recurrent thrombosis are unavailable. We utilized machine learning (ML) to develop a dynamic scoring system that predicts thrombosis in PV pts using the most important of 60 clinicopathologic features. Methods: A Random Forests ML model was trained to classify instances (3-month follow-up intervals of PV pts) as predictive or non-predictive of thrombosis, arterial or venous, in subsequent 3-6 months based on 60 features: 4 demographic, 11 history & physical, 13 treatments, 18 laboratory, and 14 pathology and molecular. The dataset was derived from Weill Cornell Medicine (WCM) Research Database Repository as previously described (Abu-Zeinah et al. Leukemia 2021) and split into training (75%) and testing (25%) sets. Hyperparameter tuning was performed to optimize model training. Synthetic minority oversampling technique (SMOTE) was implemented to reduce class imbalance since instances predictive of thrombosis were a minority. Missing data were imputed using multiple imputation by chained equations (MICE). The scoring system was developed based on ML-derived features of highest importance and confirmed by logistic regression multivariable analysis (MVA). Cumulative incidence (CI) of thrombosis was compared between risk groups using Fine-Gray model. External validation of the ML model and scoring system is underway using the Mount Sinai School of Medicine (MSSM) PV dataset. Statistical analyses and plots were performed in RStudio software v 1.4.1106. Results: 470 PV pts at WCM were included with baseline features shown in Fig 1A. During follow-up, 159 thromboses (88 venous, 71 arterial) occurred in 115 pts. CI of thrombosis was significantly higher shortly after diagnosis, as previously appreciated (Hulcrantz et al. Ann Intern Med. 2018), and following a thrombotic event (Fig 1B-C). Bilinear fitting to CI curves identified a 2-yr breakpoint that marked the transition from a high to a much lower long-term risk after diagnosis (incidence rate (IR), per year, of 4.4% vs 1%, respectively) and after thrombosis (IR of 9.7% vs 1.8%). Of the ML model's top 10 features, 5 that independently predicted thrombosis in MVA were selected for a clinically convenient scoring system to estimate thrombosis risk (Fig 1D-E). One point was assigned for each of age ≥60 yr, prior thrombosis, WBC ≥12 x 10 9/L, peri-diagnosis (&lt;2 yr from diagnosis), and peri-thrombosis (&lt;2 yr from last thrombosis). Using this scoring system, we found that high-risk (Hi) and intermediate-risk (Int) pts (score ≥2 and =1) were 6.5 and 2.3 times more likely to have thrombosis, respectively, than low-risk (Lo) pts (score = 0) (p&lt;0.001 and p=0.014). Probability of thrombosis was significantly different for Lo, Int, and Hi at 1 yr (0%, 1%, and 6%), 2 yrs (1%, 3%, and 10%), and 5 yr (2%, 9% and 21%) (Fig 1F & 1H). In contrast, ELN high-risk pts were only 2.2 times more likely to have thrombosis than ELN low-risk pts (Fig 1G-H). The concordance (C-index) of the ML-derived model (0.7± se 0.02) was higher than ELN (0.59 ± se 0.03). External validation using the MSSM PV data (Fig 1A) is ongoing. Discussion: We applied ML to our large PV-WCM dataset to identify most important clinicopathologic features predicting thrombosis. In contrast to linear models, ML has little penalty for increasing number of parameters tested and can easily accommodate high-dimensional data to improve predictions. Because "big data" is not routinely available to caregivers, we developed a simple, dynamic scoring system predicting the risk of thrombosis in PV based on 5 most important features identified by ML. This new and dynamic scoring system outperformed ELN stratification and may prove useful in guiding treatment and improving selection of pts for clinical trials aimed at preventing thrombosis in PV pts. Conclusion: The risk of thrombosis in PV pts is temporally non-linear and strongly influenced by proximity to diagnosis and recent thrombosis. A simple ML-derived dynamic scoring system is presented that better classifies pts into distinct Lo, Int, and Hi thrombosis risk groups based on age, prior thrombosis, WBC, peri-diagnosis, and peri-thrombosis. Figure 1 Figure 1. Disclosures Abu-Zeinah: PharmaEssentia: Consultancy. Silver: Abbvie: Consultancy; PharamEssentia: Consultancy, Speakers Bureau. Mascarenhas: Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Galecto: Consultancy; Geron: Consultancy; PharmaEssentia: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees; Prelude: Consultancy; Celgene/BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merus: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Promedior: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kartos: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Consultancy, Membership on an entity's Board of Directors or advisory committees; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees; Forbius: Research Funding; Geron: Consultancy, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Scandura: MPN-RF (Foundation): Research Funding; CR&T (Foudation): Research Funding; European Leukemia net: Honoraria, Other: travel fees ; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Constellation: Research Funding.

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