Safety Profile of Bortezomib Impacts Survival in Light Chain Amyloidosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5664-5664
Author(s):  
Zoé Van de Wyngaert ◽  
Greg Vanoutryve ◽  
Guillemette Fouquet ◽  
Stéphanie Guidez ◽  
Charles Herbaux ◽  
...  
Keyword(s):  
Overall Survival ◽  
Dose Reduction ◽  
Safety Profile ◽  
Cardiac Involvement ◽  
Hematological Toxicity ◽  
Al Amyloidosis ◽  
Kidney Involvement ◽  
The Impact ◽  
To Receive

Abstract Background. Bortezomib has improved overall survival (OS) in light chain (AL) amyloidosis; however, data on its activity in severe cardiac AL are sparse. Furthermore, the impact of the safety profile of Bortezomib on overall survival in severe cardiac AL amyloidosis remains unknown given the fragile population. We sought to outline the activity and safety profile of Bortezomib in severe cardiac AL amyloidosis. Methods. Twenty-seven patients diagnosed with AL amyloidosis and treated with Bortezomib were included, mean age was 63 years (36-85), with a sex ratio of 18/9. Eighteen patients had cardiac involvement, among which all had Mayo-Clinic stage III staging but 3, and 9 had kidney involvement only. Seventy percent of patients received Bortezomib as a 1st-line therapy, once (19%) or twice weekly (81%), given IV at the starting dose of 1.3g/m2 in combination to Dexamethasone. Thirteen (48%) patients also received an alkylating agent. Results. Overall hematological response rate was 75% in patients who received at least 1 cycle of Bortezomib, and 83% and 62.5% in patients with and without cardiac involvement, respectively. Complete response was obtained in 45%, and 42% and 50% in the 2 groups, respectively. 44% patients with cardiac involvement had an organ response. An hematological toxicity occurred in 26% of patients, similarly in the 2 groups, consisting mainly of thrombocytopenia with no need for treatment modification. Non-hematological toxicity (grade ≥2) rate was 62% in patients with cardiac involvement and 38% in patients with kidney involvement (p=ns), consisting mostly of fatigue, peripheral neuropathy, infection and gastro-intestinal adverse effects, and leading to 25% of dose reduction, and 33% of Bortezomib interruption before cycle 4, similarly in both groups. The median follow-up was 41 months from start of Bortezomib. Seven patients died during the first cycle of treatment, all of them but one had severe stage III cardiac involvement with LVEF <40%. Importantly, the patients with cardiac involvement who were treated past the first cycle had an estimated 3-year OS similar to those with kidney involvement only (50 vs. 62%, p=ns). All patients with cardiac AL who completed at least 3 cycles of treatment and survived beyond 3 months remained alive at follow-up date. In univariate analysis for the cohort as a whole, occurrence of non-hematological toxicity grade ≥2 was associated with a lower OS (20% if present vs. 67% when absent; p=0.001), as for the consequence of Bortezomib dose reduction (54% vs. 71%, respectively; p=0.036), and decrease of the total dose received to less than 50% of the initial dose (12% vs. 92% respectively, p=0.009). Bortezomib interruption (36% vs. 78%, respectively; p=0.004), or inability to receive at least 3 cycles of Bortezomib also impacted OS (36% vs. 78%, respectively; p=0,004). The impact on OS appeared even more dramatic in patients with cardiac involvement. In multivariate analysis, independent variables that were associated with poor OS were the number of Bortezomib cycles (inability to receive at least 3 cycles) (OR=34.7; p=0.001), occurrence of a non-hematological toxicity (OR=5.1; p=0.011), and absence of hematological response (OR=3.6; p=0.05). Conclusion. Bortezomib is an effective treatment of AL amyloidosis, and significantly improves the most adverse patients characterized with severe cardiac presentation. However, the safety profile is of particular concern in severe cardiac AL, particularly the non hematological ≥grade 2 incidence rate; patients often characterized with dose reduction or interruption, inability to receive sufficient dose concentration or number of cycles. This study confirms that alteration of the safety profile of Bortezomib may hamper the benefits seen particularly in severe cardiac AL, questioning on the use of weekly and sub-cutaneous Bortezomib for very fragile AL, as optimized in fragile patients with Myeloma. Disclosures No relevant conflicts of interest to declare.

scholarly journals The Effect of Cytogenetic Abnormalities on Organ Involvement and Survival in Patients with AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1833-1833
Author(s):  
Michael Ozga ◽  
Qiuhong Zhao ◽  
Don M. Benson ◽  
Patrick Elder ◽  
Nita Williams ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Plasma Cell ◽  
Cardiac Involvement ◽  
Response To Therapy ◽  
Al Amyloidosis ◽  
Prognostic Impact ◽  
Cytogenetic Abnormalities ◽  
Kidney Involvement ◽  
The Impact

Introduction: Systemic light chain amyloidosis (AL) is a clonal plasma-cell neoplasm that carries a poor prognosis. Efforts are being made at recognizing this disease earlier and developing better prognostic tools as AL is frequently diagnosed at an advanced stage. Cytogenetic analysis and its prognostic relevance have been well studied in multiple myeloma (MM), a related disorder, but remain relatively unknown and less widely reported in AL literature. Previous studies have demonstrated that AL amyloidosis exhibits an increased incidence of translocation t(11;14). However, with an extensive array of fluorescence-in-situ hybridization (FISH) probes now available, multiple other cytogenetic abnormalities are being identified in AL at diagnosis. In addition, it is well known that cardiac involvement in AL is an independent negative prognostic factor for these patients; however, the implications of cytogenetics for these high-risk patients remains largely unexplored. Finally, with the advent of novel non-transplant therapy options for AL patients, we look to evaluate the relevance of daratumumab in this setting. As such, the present study aims to a) determine the most relevant FISH abnormalities in AL patients and establish their importance as independent prognostic factors for response to therapy and in survival, b) assess the impact of cytogenetics on the survival of cardiac AL patients, and c) determine the effect of daratumumab on the survival of patients with AL. Methods: A retrospective chart review was performed on 140 consecutive AL patients treated at The Ohio State University. This cohort included 20 patients who received daratumumab. Patients were divided into subgroups based on FISH data obtained within 90 days of diagnosis. Hyperdiploidy was defined as trisomies of at least 2 chromosomal loci. Primary endpoints were progression free survival (PFS) and overall survival (OS), and Kaplan Meier curves were used to calculate PFS and OS. Results: The median age at diagnosis was 62 years (range: 33-88) and 55% were male. Median number of organs involved was 2, and 49% and 65% had cardiac and kidney involvement, respectively. Chromosomal abnormalities were detected in 86 (61%) patients. Translocation t(11;14) was the most prevalent (44%) aberration followed by hyperdiploidy (43%). We observed a statistically significant relationship between several FISH abnormalities and increased plasma cell burden (PC) (≥10%), including gain (+) 5p/5q (p=0.025), del13q (0.009), +11q (p<0.001), and hyperdiploidy (p<0.001). In addition, hyperdiploidy was associated with worsening of PFS (p=0.019) and OS (p=0.032) (Figure 1A). In multivariable analysis, hyperdiploidy was confirmed to be a poor prognostic marker after adjusting for other confounding variables. In patients with cardiac involvement, hyperdiploidy was also associated with worsening of PFS (p=0.0497) and OS (p=0.006) (Figure 1B). Del 13q was found to be associated with cardiac involvement (p=0.01) but showed no prognostic impact on survival. Conversely, survival benefit was seen among these patients with cardiac involvement who had no FISH abnormalities at diagnosis, both in terms of OS and PFS (p=0.019 and p=0.042, respectively). In addition, the overall presence of t(11;14) did not have any prognostic impact on OS (p=0.76) or PFS (p=0.41). However, on further stratification, we did observe a marginal difference in PFS (p=0.09) among four groups (Figure 1C), and more specifically, patients with presence of only t(11;14) did worse compared to those patients with normal FISH in terms of PFS (p=0.021). This potentially suggests that patients with t(11;14) only are at risk for earlier progression. Finally, we evaluated the efficacy of daratumumab, and observed a median OS of 6.1 years and median PFS 2.6 years. Of note, presence of gain 1q was associated with a trend toward better response to daratumumab. 100% of patients (5/5) with gain 1q achieved a hematologic partial response (PR) or better versus only 60% of patients without +1q. Conclusion: Our findings reveal the effect of hyperdiploidy on PC tumor burden, overall survival, and its importance within the high-risk cardiac AL patient population. The results with daratumumab in our patient subset with gain 1q is intriguing in its own right but identification of the mechanism by which the effect of this mutation is abrogated merits further exploration as its use only continues to grow. Disclosures Rosko: Vyxeos: Other: Travel support. Efebera:Takeda: Honoraria; Akcea: Other: Advisory board, Speakers Bureau; Janssen: Speakers Bureau.

Role of NT-ProBNP to Assess the Adequacy of Treatment Response in AL Amyloidosis.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1689-1689 ◽  
Author(s):  
Ashutosh Wechalekar ◽  
Giampaolo Merlini ◽  
Julian D Gillmore ◽  
P. Russo ◽  
Helen J Lachmann ◽  
...  
Keyword(s):  
Overall Survival ◽  
Cardiac Involvement ◽  
Cox Regression ◽  
Time Lag ◽  
Response To Treatment ◽  
Al Amyloidosis ◽  
International Consensus ◽  
Randomised Study ◽  
Response To Chemotherapy ◽  
The Impact

Abstract We report the use of NT-ProBNP (N-terminal fragment of brain natriuretic peptide) as an independent marker to identify patients with AL amyloidosis whose clonal response to chemotherapy is inadequate. The aim of chemotherapy is to allow improvement in amyloidotic organ function but the significant time lag often means that patients are either over or under treated. Use of biomarkers (such as BNP and NT-ProBNP) for risk stratification is an area of increasing interest. 200 patients with AL amyloidosis diagnosed between 2004–2007, who had completed one line of treatment and had a complete results available prior to and six month from the start of treatment, were identified from the databases of the Amyloidosis centres in Pavia, Italy and London, UK. Organ involvement and response was assessed according to the international consensus criteria (Gertz et al 2005). NT-ProBNP change was deemed significant if there was a rise or fall of both 30% and &gt;300 ng/L over the starting value. Kaplan-Meier and Cox regression were used for survival analysis as appropriate. The median age was 63 yrs (range 38–83) and the median number of organs involved was 2. 132 (66%) had cardiac involvement, 150 (75%) had renal and 42 (21%) had liver involvement at presentation. 115 (56%) responded to chemotherapy with a complete response (CR) in 34 (17%) and a partial response in 81 (40%). At baseline, median NT-ProBNP was 1865 ng/L (range 50–70144) and was &gt;332 ng/L (the cut-off reported as significant by Dispenzieri et al, J Clin Oncol 2004) in 159 patients (80%). The median follow-up was 23 months. The median overall survival (OS) has not been reached with an estimated 2 yr survival of 71%. Patients with cardiac involvement had worse outcomes (OS 29 mo vs. not reached; p =0.001) whereas renal, liver, neuropathy, soft tissue involvement, the light chain type or presence of a measurable M protein did not significantly impact survival. Haematologic responders had a significantly better overall survival (median not reached) than non-responders (median 22 months; p&lt;0.0001) with those achieving CR having significantly better survival than PR (estimated 4 year survival of 94% and 65% respectively; p=0.005). The NT-proBNP increased and decreased significantly in 45 (22%) and 92 (46%) respectively - with the latter group achieving lower FLC concentration after treatment (27.6 vs. 96.4 mg/L, p&lt;0.0001).16 of the 22 (73%) patients with heart involvement who obtained CR also has decreases in NT-ProBNP. Patients without significant NT-ProBNP decrease (median OS 29 months vs. not reached) or with significant increase (median OS 20 months vs. not reached) had significantly poorer outcome (p&lt;0.0001). The impact of this was most marked in patients achieving a PR – in this group, the estimated 3 year survival was 48% for patients in whom there was an increase in NT-ProBNP (not significantly different from the non-responders) vs. 86% for patient in whom there was a decrease (not significantly different from those who achieved CR) (log rank p&lt;0.0001, see figure). On multivariate analysis, cardiac involvement and change NT-ProBNP were highly significant independent prognostic factors. In summary, patients who have a fall in NT-ProBNP have excellent outcomes irrespective of the degree of haematological response. Conversely, the failure to see a fall or to see an increase in NT-ProBNP clearly identifies a group of patients with AL amyloidosis, who despite a haematologic response to treatment, have significantly poorer outcomes. A prospective randomised study to see the effects of rapidly changing to alternative treatment in the latter groups is being planned. Figure Figure

The Impact of FLT3-ITD and NPM1 Mutational Status on the Outcome of ATRA Therapy in Patients with Non-APL AML: Results of the UK MRC AML12 Trial

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 554-554 ◽  
Author(s):  
Rosemary Gale ◽  
Robert Hills ◽  
Claire Green ◽  
Yashma Patel ◽  
Amanda Gilkes ◽  
...  
Keyword(s):  
Overall Survival ◽  
Normal Karyotype ◽  
Atra Treatment ◽  
Npm1 Mutation ◽  
Mutational Status ◽  
Hazard Ratios ◽  
The Uk ◽  
The Impact ◽  
To Receive

Abstract Background: The prognostic value of mutations in NPM1 and FLT3-ITD is well known. Previously, Schlenk et al. (ASH 2007, Abstract 297) have reported that survival was significantly improved in a group of older patients who were NPM1 mutant/FLT3-ITD Wild Type when treated with ATRA; there was no significant improvement in overall survival in patients who were either NPM1 WT or FLT3-ITD mutant. We report here on a subset of the UK MRC AML12 trial who have been characterised for FLT3-ITD and NPM1 and who were randomised between ATRA in induction and no ATRA. Patients and Methods: A total of 393 patients were identified and characterised. The median age was 46 years (range 16–68); NPM1 and FLT3-ITD status were determined using methods previously reported (Gale et al. Blood 2008). Median follow-up for survival is 7.1 years. The overall results of the ATRA randomisation have previously been reported (Burnett et al. ASH 2002 Abstract 529) and show no benefit for ATRA treatment. All patients were treated with Daunorubicin, Ara-C and Thioguanine (DAT) with a randomisation between two doses of Ara-C, and were randomised to receive, or not, ATRA 45mg/m2/d during courses 1 and 2 of chemotherapy. ATRA was given for a median of 56 days. Results: A total of 143 (36%) patients had an NPM1 mutation and 93 (24%) had a FLT3-ITD mutation. No significant interactions were seen between either NPM1 status, or FLT3-ITD status and ATRA treatment with respect to complete remission, overall survival or relapse free survival (see Table). Estimates of the hazard ratios (HR) for the interaction between FLT3-ITD and ATRA, and NPM1 and ATRA for overall survival were 0.75 (95% CI 0.42–1.32 p=0.3) and 0.66 (95% CI 0.38–1.12 p=0.13), where an HR&lt;1 indicates greater benefit for ATRA in the mutant group. Looking at patients stratified by both FLT3-ITD and NPM1 status (84 NPM1+ITD−, 34 NPM1−ITD+, 59 NPM1+ITD+, 216 NPM1−ITD−) showed no significant interaction (p=0.4 for heterogeneity of ATRA effect between the four groups, p=0.5 for difference in treatment effect between FLT3 WT/NPM1 mutant and others). The results were not significantly different if restricted to patients with a normal karyotype only. Conclusions: In this randomised comparison of ATRA therapy in younger patients with AML there were no significant interactions. Any impact of NPM1 or FLT3-ITD status on treatment with ATRA is likely to be relatively small or non-existent. CR OS at 5years RFS at 5 years ATRA No ATRA OR, 95% CI ATRA No ATRA HR, 95% CI ATRA No ATRA HR, 95% CI NPM1 WT 80% 86% 1.59 (0.82–3.09) 36% 35% 1.07 (0.79–1.45) 33% 29% 1.05 (0.76–1.46) NPM1 Mutant 91% 89% 0.81 (0.27–2.43) 57% 44% 0.70 (0.45–1.11) 49% 39% 0.83 (0.63–1.31) Interaction with ATRA p=0.3 0.1 0.4 FLT3 WT 83% 87% 1.46 (0.77–2.74) 45% 42% 0.97 (0.73–1.30) 42% 35% 0.87 (0.64–1.18) FLT3 ITD 89% 88% 0.89 (0.25–3.17) 40% 25% 0.73 (0.44–1.21) 32% 26% 0.89 (0.53–1.50) Interaction with ATRA p=0.5 0.4 0.9

BiovaxID Vaccine Therapy of Follicular Lymphoma in First Remission: Phase III Blinded Safety Update.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4500-4500 ◽  
Author(s):  
Angelos M. Stergiou ◽  
Sattva S. Neelapu ◽  
Roman Casciano ◽  
Margo A. Jaffee ◽  
Larry W. Kwak
Keyword(s):  
Chest Pain ◽  
Follicular Lymphoma ◽  
Safety Profile ◽  
Safety Data ◽  
Phase Iii ◽  
Phase 2 ◽  
Phase 3 ◽  
The Impact ◽  
To Receive

Abstract Background: A previous single-arm Phase 2 study (Nature Med5:1171–7,1999), evaluated the ability of tumor-specific idiotype (ID) conjugated to keyhole limpet hemocyanin (KLH) administered with granulocyte-monocyte colony-stimulating factor - GM-CSF (BiovaxID vaccine) to induce complete remission (CR) and molecular remission (MR) in follicular NHL patients in first CR after chemotherapy. We reported (ASH 2005, Abstr 2441) that at 9.2 years follow-up, disease free survival (DFS) and overall survival (OS) were 45% and 95%, respectively; median DFS was 8.0 years. To date, there have been no additional reported mortalities in this cohort. Although these data are promising, improvements in the treatments and increasing survival for patients with follicular lymphoma have necessitated additional rigor in the evaluation of overall safety and overall risk-benefit. The ongoing Phase 3 study that opened in 2000 by the NCI is designed to evaluate the impact of this vaccine on DFS in previously untreated subjects who have attained CR/Cru. As of August 2007, 231 subjects have been enrolled to receive chemotherapy and 176 have been randomized to receive vaccine (ID-KLH or KLH-KLH). Methods: Since Phase 3 trial inception in 2000, SAEs have been reported through a pharmacoviligance group and identified according to time period on the study (i.e. during chemotherapy, during vaccine, after vaccine, or unknown), causality, and relatedness to study agent. Results: As of August 2007, 32 SAEs have been reported in the BV301 trial, 7 of which occurred during the vaccination segment of the study. At a blinded interim analysis of the Phase 3 safety data, of the 7 SAEs reported during the vaccine segment of the study, 3 are considered unlikely to be related to the study agent (chest pain, compression fracture, herpes zoster), 2 possibly related (arrhythmia supraventricular, chest pain), 1 unrelated (vomiting), and 1 unknown (febrile neutropenia). The 1 SAE, cerebral ischaemia, that occurred post vaccine is considered unrelated to the study agent. Conclusions: Additional follow-up on the Phase 2 patients is needed, as well as similar analyses in other cohorts. Blinded Phase 3 safety data shows a positive safety profile for BiovaxID. Unblinded safety data will be needed to determine the final efficacy and safety profile.

Safety Profile Of Bortezomib Impacts Survival Of Cardiac AL Amyloidosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5316-5316
Author(s):  
Zoé Van de Wyngaert ◽  
Greg Vanoutryve ◽  
Charles Herbaux ◽  
Guillemette Fouquet ◽  
Helene Demarquette ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Light Chain ◽  
Safety Profile ◽  
Cardiac Involvement ◽  
Response Rate ◽  
Stage Iii ◽  
Hematological Toxicity ◽  
Great Promise ◽  
Prognostic Impact ◽  
Duration Of Response

Abstract Background Light chain amyloidosis (AL) is characterized by a median overall survival (OS) from diagnosis of approximately 3 years, but with clinically overt cardiac involvement this is reduced to 1 year. Bortezomib (B) has shown great promise in the treatment of AL, especially of cardiac involvement. However, efficacy might be hampered by severe safety issues with use of B, primarily of neuropathy type. We sought to study the prognostic impact of the safety profile of B in AL with attention to cardiac involvement. Method This study has included 27 patients with AL, of these 18 had cardiac and 9 kidney but no cardiac involvement. AL was diagnosed as outline in international consensus criteria, as to the hematologic and organ responses. B was given IV twice weekly at the starting dose of 1.3 mg/m², in combination to weekly cyclophosphamide in 13 patients (52%). Results The median age was 63, sex ratio was 18/9, all cardiac AL had Mayo Cardiac Stage III but 3, and none in patients with no cardiac AL. 70% were at diagnostic. Seven patients died during the first month, all of them but one had cardiac AL. We then looked at the safety profile of B in the studied population, and found that 25% and 75% experienced some degree of hematotoxicity in cardiac and in no cardiac AL (p=NS). The non hematology toxicity rate was 62% and 38%, respectively (p=NS). 26% of patients needed dose reduction of B and 33% dose interruption of B in the study before cycle 4, all related to non hematological toxicity of neuropathy, fatigue and GI AEs; and was similar in cardiac as compared to no cardiac AL. The overall hematologic response rate (ORR) was 56% and at least VGPR (with >90% decrease in difference between involved/uninvolved light chain) 41%. The responses were 56% and 39% in cardiac AL, similar to patients with no cardiac involvement (56% and 44%), respectively. The median duration of response was 13 months overall, 10 and 20 months in cardiac and in no cardiac AL, respectively (p=NS). Non hematological toxicity did not impact the response rate or the duration of response. With a median follow-up of 41 months from start of B, 70% relapsed and 59% died in the study as a whole, and 67% and 67% in the cardiac group, respectively. The median time to progression was 20 (95CI 4;35.5) months as a whole, and 13 (9;17) months and 20 (0;43) months in cardiac and in no cardiac AL (p=NS). The median OS was not reached in the cohort as a whole and in patients with no cardiac involvement, but was 5 months in cardiac AL (p=NS); the estimated 4-year OS was 55%, 62% and 50%, respectively. Interestingly, all cardiac AL that survived beyond 6 months remain alive at F-up date. Several variables negatively impacted survival in univariate analysis in the group with cardiac AL, including decreased LVEF (p=0.025), NYHA greater than 2 (p=0.007),Mayo Cardiac Stage III (p=0.028), no hematological (p=0.002) and no organ responses (p=0.05), occurrence of non hematological toxicity (p=0.002) with the consequence of dose reduction of B (p=0.09) and dose interruption of B (p=0.04). In multivariate analysis, independent variables that impacted survival were hematological response (OR = 5.1, 95%CI = 1.5-18; p = 0.011) and non hematological toxicity (OR = 3.6, 95%CI = 0.8-14; p = 0.05). Conclusion Bortezomib is a very rapid and effective therapy for AL particularly of cardiac involvement. However, patients may develop severe side effects with Bortezomib that preclude efficacy of Bortezomib given IV, and consequently impact negatively survival. This data favours use of sub cutaneous Bortezomib in AL although not validated in this indication yet. Disclosures: Leleu: Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Leopharma: Consultancy, Honoraria; Millennium : Honoraria; Amgen: Honoraria; Novartis: Honoraria.

Association of transfusion independence with improved overall survival in myelofibrosis patients receiving momelotinib.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7046-7046
Author(s):  
Ruben A. Mesa ◽  
Stephen T. Oh ◽  
Aaron Thomas Gerds ◽  
Vikas Gupta ◽  
John V. Catalano ◽  
...  
Keyword(s):  
Overall Survival ◽  
Hematological Toxicity ◽  
Clinical Activity ◽  
Published Data ◽  
Open Label ◽  
Double Blind ◽  
Transfusion Independence ◽  
Transfusion Dependency ◽  
Clinical Trial Information

7046 Background: Momelotinib (MMB) is a potent JAK1, JAK2 and ACVR1 inhibitor with clinical activity against the hallmark features of myelofibrosis (MF), namely anemia, constitutional symptoms and splenomegaly, across the continuum of JAKi naïve or previously JAKi treated intermediate/high risk MF patients as demonstrated in the previously conducted Phase 3 SIMPLIFY-1 & -2 clinical trials (S1, S2). S1 enrolled JAKi-naïve patients with MF (n = 432) double-blind randomized 1:1 to MMB or ruxolitinib (RUX). S2 enrolled patients with MF with hematological toxicity during prior RUX therapy (n = 156) randomized 2:1 to open-label MMB or best available therapy (BAT; consisting of RUX in 88% of patients). In both trials, following the 24-week randomized treatment (RT) period, patients could continue MMB (MMB→MMB) and those randomized to RUX/BAT could cross-over to MMB (RUX/BAT→MMB) for extended treatment (ET). Previously published data from the SIMPLIFY studies demonstrate robust overall survival (OS) for MMB-treated patients in S1 and S2 (median not reached and 34.3 months, respectively) with a maximum follow up of approximately 5 years and median of 2.9 years in S1 and 2.3 years in S2. Methods: OS data for patients receiving MMB in S1 and S2 are reported here for subgroups defined by Week 24 (W24) transfusion independence (TI) responders vs non-responders, and also other efficacy endpoints. Survival was estimated using KM analysis with descriptive log-rank tests for comparison applied (all p-values are descriptive). Results: As previously reported, W24 TI rates were higher in the MMB arms of S1 (67% vs 49%) and S2 (43% vs 21%). In S1, W24 TI responders in the MMB group show an OS advantage, with median OS not reached and 3-year survival of 80% (HR = 0.30; p = 0.0001) compared to MMB TI non-responders. Similarly in S2, W24 TI responders in the MMB group show a trend toward better OS compared to TI non-responders (HR = 0.57; p = 0.0652). The HRs in S1 for MMB responders vs non-responders for W24 SRR and TSS were 0.59 (p = 0.0904) and 0.65 (p = 0.1657), respectively. Alternative analyses using OS defined from W24 demonstrated consistent results. Conclusions: These new analyses suggest JAKi naïve patients receiving MMB who maintain or achieve TI at W24 have favorable OS compared to MMB TI non-responders, with a similar trend observed in S2. These findings are consistent with anemia and transfusion dependency being key predictors of shortened OS in MF and suggest that TI response at W24 may become a surrogate for clinical benefit, supporting the clinical relevance of MMB’s differentiated pro-erythropoietic ACVR1 inhibition. Clinical trial information: NCT01969838.

Efficacy of Melphalan and Prednisone Plus Thalidomide in Patients Older Than 75 Years With Newly Diagnosed Multiple Myeloma: IFM 01/01 Trial

2009 ◽  
Vol 27 (22) ◽  
pp. 3664-3670 ◽  
Author(s):  
Cyrille Hulin ◽  
Thierry Facon ◽  
Philippe Rodon ◽  
Brigitte Pegourie ◽  
Lotfi Benboubker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Elderly Patients ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Standards Of Care ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
To Receive

Purpose Until recently, melphalan and prednisone were the standards of care in elderly patients with multiple myeloma. The addition of thalidomide to this combination demonstrated a survival benefit for patients age 65 to 75 years. This randomized, placebo-controlled, phase III trial investigated the efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed myeloma. Patients and Methods Between April 2002 and December 2006, 232 previously untreated patients with myeloma, age 75 years or older, were enrolled and 229 were randomly assigned to treatment. All patients received melphalan (0.2 mg/kg/d) plus prednisone (2 mg/kg/d) for 12 courses (day 1 to 4) every 6 weeks. Patients were randomly assigned to receive 100 mg/d of oral thalidomide (n = 113) or placebo (n = 116), continuously for 72 weeks. The primary end point was overall survival. Results After a median follow-up of 47.5 months, overall survival was significantly longer in patients who received melphalan and prednisone plus thalidomide compared with those who received melphalan and prednisone plus placebo (median, 44.0 v 29.1 months; P = .028). Progression-free survival was significantly prolonged in the melphalan and prednisone plus thalidomide group (median, 24.1 v 18.5 months; P = .001). Two adverse events were significantly increased in the melphalan and prednisone plus thalidomide group: grade 2 to 4 peripheral neuropathy (20% v 5% in the melphalan and prednisone plus placebo group; P < .001) and grade 3 to 4 neutropenia (23% v 9%; P = .003). Conclusion This trial confirms the superiority of the combination melphalan and prednisone plus thalidomide over melphalan and prednisone alone for prolonging survival in very elderly patients with newly diagnosed myeloma. Toxicity was acceptable.

scholarly journals Sociodemographic Characteristics as Predictors of Outcomes in Hepatocellular Carcinoma: A Retrospective Cohort Study

2020 ◽  
Vol 27 (1) ◽  
pp. 107327482095661
Author(s):  
Bryce D. Beutler ◽  
Mark B. Ulanja ◽  
Rohee Krishan ◽  
Vijay Aluru ◽  
Munachismo L. Ndukwu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Overall Survival ◽  
Cohort Study ◽  
Native American ◽  
Retrospective Cohort Study ◽  
Retrospective Cohort ◽  
Private Insurance ◽  
Insurance Status ◽  
The Impact ◽  
To Receive

Background: Race, gender, insurance status, and income play important roles in predicting health care outcomes. However, the impact of these factors has yet to be fully elucidated in the setting of hepatocellular carcinoma (HCC). Methods: We designed a retrospective cohort study utilizing data from the Surveillance, Epidemiology, and End Results (SEER) program to identify patients diagnosed with resectable HCC (N = 28,518). Demographic factors of interest included race (Asian/Pacific Islander [API], African American [AA], Native American/Alaska Native [NA], or White [WH]) and gender (male [M] or female [F]). Insurance classifications included those having Medicare/Private Insurance [ME/PI], Medicaid [MAID], or No Insurance [NI]. Median household income was estimated for all diagnosed with HCC. Endpoints included: (1) overall survival; (2) likelihood of receiving a recommendation for surgery; and (3) specific surgical intervention performed. Multivariate multinomial logistic regression for relative risk ratio (RRR) and Cox regression models were used to identify pertinent associations. Results: Race, gender, insurance status, and income had statistically significant effects on the likelihood of surgical recommendation and overall survival. API were more likely to receive a recommendation for hepatic resection (RRR = 1.45; 95% CI: 1.31-1.61; Reference Race: AA) and exhibited prolonged overall survival (HR = 0.77; 95% CI: 0.73-0.82; Reference Race: AA) as compared to members of any other ethnic group; there was no difference in these endpoints between AA, NA, or WH individuals. Gender also had a significant effect on survival: Females exhibited superior overall survival (HR = 0.89; 95% CI: 0.85-0.93; Reference Gender: M) as compared to males. Patients who had ME/PI were more likely than those with MAID or NI to receive a surgical recommendation. ME/PI was also associated with superior overall survival. Conclusions: Race, gender, insurance status, and income have measurable effects on HCC management and outcomes. The underlying causes of these disparities warrant further investigation.

scholarly journals Final Results of the IELSG-19 Randomized Trial of Mucosa-Associated Lymphoid Tissue Lymphoma: Improved Event-Free and Progression-Free Survival With Rituximab Plus Chlorambucil Versus Either Chlorambucil or Rituximab Monotherapy

2017 ◽  
Vol 35 (17) ◽  
pp. 1905-1912 ◽  
Author(s):  
Emanuele Zucca ◽  
Annarita Conconi ◽  
Giovanni Martinelli ◽  
Reda Bouabdallah ◽  
Alessandra Tucci ◽  
...  
Keyword(s):  
Overall Survival ◽  
Randomized Trial ◽  
Lymphoid Tissue ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Free Survival ◽  
Final Sample ◽  
Phase Iii Study ◽  
To Receive

Purpose There is no consensus on the optimal systemic treatment of patients with extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue. The IELSG-19 phase III study, to our knowledge, was the first such study to address the question of first-line treatment in a randomized trial. Patients and Methods Eligible patients were initially randomly assigned (1:1 ratio) to receive either chlorambucil monotherapy (6 mg/m2/d orally on weeks 1 to 6, 9 to 10, 13 to 14, 17 to 18, and 21 to 22) or a combination of chlorambucil (same schedule as above) and rituximab (375 mg/m2 intravenously on day 1 of weeks 1, 2, 3, 4, 9, 13, 17, and 21). After the planned enrollment of 252 patients, the protocol was amended to continue with a three-arm design (1:1:6 ratio), with a new arm that included rituximab alone (same schedule as the combination arm) and with a final sample size of 454 patients. The main end point was event-free survival (EFS). Analysis of chlorambucil versus the combination arm was performed and reported separately before any analysis of the third arm. Results At a median follow-up of 7.4 years, addition of rituximab to chlorambucil led to significantly better EFS (hazard ratio, 0.54; 95% CI, 0.38 to 0.77). EFS at 5 years was 51% (95% CI, 42 to 60) with chlorambucil alone, 50% (95% CI, 42 to 59) with rituximab alone, and 68% (95% CI, 60 to 76) with the combination ( P = .0009). Progression-free survival was also significantly better with the combination ( P = .0119). Five-year overall survival was approximately 90% in each arm. All treatments were well tolerated. No unexpected toxicities were recorded. Conclusion Rituximab in combination with chlorambucil demonstrated superior efficacy in mucosa-associated lymphoid tissue lymphoma; however, improvements in EFS and progression-free survival did not translate into longer overall survival.

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