scholarly journals Organ responses with daratumumab therapy in previously treated AL amyloidosis

2020 ◽  
Vol 4 (3) ◽  
pp. 458-466 ◽  
Author(s):  
Alfred Chung ◽  
Gregory P. Kaufman ◽  
Surbhi Sidana ◽  
Erik Eckhert ◽  
Stanley L. Schrier ◽  
...  
Keyword(s):  
Response Time ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Median Response ◽  
Median Response Time ◽  
Hematologic Response ◽  
Cardiac Responses ◽  
Wide Range ◽  
Significant Difference ◽  
Previously Treated

Abstract Immunoglobulin light chain amyloidosis (AL amyloidosis) involves deposition of abnormally folded light chains into a wide range of tissues causing organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously treated disease. However, data on survival outcomes and organ responses to daratumumab are lacking. Seventy-two patients with previously treated AL amyloidosis who received daratumumab monotherapy with dexamethasone were retrospectively evaluated. With a median follow-up of 27 months, 2-year overall survival (OS) was 86.9% (median OS, not reached) and 2-year time-to-next treatment or death (TTNT)–free survival was 62% (median TTNT, not reached). Forty of 52 evaluable patients achieved a hematologic response (77%), with >60% of patients achieving a very good partial response or better; median time-to-hematologic response was 1 month. Fifty-seven patients (79%) had cardiac involvement, and 55% of evaluable patients achieved a cardiac response, with a median response time of 3.2 months among responders. Cardiac responses were associated with an improvement in OS, with landmark analysis for cardiac responses at 3 months trending toward statistical significance (100% vs 55% at 30 months, P = .051). Forty-seven patients (65%) had renal involvement, and 52% of evaluable patients achieved a renal response, with a median response time of 6 months among responders; there was no significant difference in OS between renal responders and nonresponders. This study demonstrates that daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve deep hematologic responses, as well as improvements in organ function.

scholarly journals Long-Term Outcomes and Organ Responses with Daratumumab Therapy in Previously Treated Patients with AL Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1828-1828
Author(s):  
Alfred Chung ◽  
Gregory P. Kaufman ◽  
Surbhi Sidana ◽  
Erik Eckhert ◽  
Stanley Schrier ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Long Term Outcomes ◽  
Advisory Committees ◽  
Renal Response ◽  
Cardiac Responses ◽  
Previously Treated

Introduction: AL amyloidosis involves deposition of abnormally folded light chains into a wide range of tissues causing end-organ dysfunction, including in the heart and kidney. Daratumumab, a CD38-targeted antibody, has recently demonstrated efficacy in producing hematologic responses in previously relapsed/refractory disease. However, data on long-term outcomes to daratumumab, including organ responses, are lacking. Here we present the largest retrospective study to date on patients with previously treated AL amyloidosis treated with daratumumab. Methods: We conducted a retrospective analysis of relapsed/refractory AL amyloidosis patients treated at Stanford University from January 2016 to January 2019. Patients treated with daratumumab, either as monotherapy with dexamethasone (DMT) or in combination with other plasma-cell directed therapies (DCT) were included. Hematologic and organ responses were assessed by consensus guidelines. Hematologic responses were based on the maximal change in the difference between involved and uninvolved free light chains (dFLC). For cardiac response, a >30% and >300 pg/mL decrease in NT-proBNP for patients with initial baseline NT-proBNP ≥650 pg/mL was considered a response. A graded cardiac response metric was also explored with partial response (PR) representing 30-59% reduction, very good partial response (VGPR) ≥60% reduction, and complete response (CR) NT-proBNP <450 pg/mL as previously reported. For renal response, a >30% decrease (by at least 0.5 g/day) in 24-hour urine protein without worsening in creatinine or creatinine clearance by more than 25% in patients with at least 0.5 g/day pretreatment was considered a response. A graded renal response metric was also explored with PR representing 30-59% reduction in proteinuria, VGPR ≥60%, and CR ≤ 200 mg per 24-hour period. Survival data was analyzed using the Kaplan-Meier method. All time-to-event outcomes, including survival and organ responses, were determined from initiation of daratumumab. Results: Eighty-four patients were identified with baseline characteristics at start of daratumumab shown in Table 1. Median duration of follow-up was 16 months. Two-year overall survival (OS) was 83% and median OS was not reached. Median time-to-next-treatment or death was 31 months. Sixty-seven out of 80 evaluable patients (84%) achieved a hematologic response, with 47 patients (59%) achieving a VGPR or better (Figure 1). Sixty-eight patients (81%) had cardiac involvement, and among the 34 evaluable patients, 18 (53%) of evaluable patients achieved a cardiac response with a median response time of 2 months among responders. In terms of a graded cardiac response, 6 patients (18%) were able to achieve cardiac CR, 5 patients (15%) cardiac VGPR, and 7 patients (21%) PR (Figure 2). The median NT-proBNP percent reduction was 64.5% (IQR: 48.3 - 81.1%) and the median absolute reduction was 2395 pg/mL (IQR 1279.5 - 4089.5 pg/mL). Cardiac responses were associated with an improvement in OS (p<0.001, Figure 3), with landmark analysis for cardiac responses at 6-month trending towards statistical significance (100% vs. 51% at 30 months, p=0.052). Fifty-three patients (63%) had renal involvement, and among the 26 evaluable patients, 12 patients (46%) achieved a renal response with a median initial response time of 6 months among responders. Using graded response, 1 patient (4%) achieved renal CR, 7 patients (27%) renal VGPR, 4 patients (15%) renal PR, and 14 patients had no response, worsening creatinine, or were subsequently started on hemodialysis (54%) (Figure 4). The median percent reduction in proteinuria was 74.1% (IQR: 49.2 - 83.1%) and the median absolute reduction in proteinuria was 3.1 g/24 hours (IQR 2.1 - 4.9 g) among responders. There were no significant differences in OS between renal responders and non-responders. Conclusion: Daratumumab is highly effective in the treatment of previously treated AL amyloidosis, and a significant proportion of patients can achieve durable hematologic responses as well as improvements in organ function. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; IQVIA/Jazz: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech/Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celator: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; BlueBirdBio: Research Funding; Amgen/Onyx: Consultancy, Honoraria, Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees; Agios: Research Funding. OffLabel Disclosure: Daratumumab in AL amyloidosis

A Randomized Trial Comparing Telephone Tree, Text Messaging, and Instant Messaging App for Emergency Department Staff Recall for Disaster Response

2018 ◽  
Vol 33 (5) ◽  
pp. 471-477 ◽  
Author(s):  
Valerie Homier ◽  
Raphael Hamad ◽  
Josée Larocque ◽  
Pierre Chassé ◽  
Elene Khalil ◽  
...  
Keyword(s):  
Emergency Department ◽  
Response Time ◽  
Disaster Response ◽  
Text Messaging ◽  
Instant Messaging ◽  
Median Response ◽  
Median Response Time ◽  
Staff Members ◽  
Emergency Department Staff ◽  
Significant Difference

AbstractIntroductionA crucial component of a hospital’s disaster plan is an efficient staff recall communication method. Many hospitals use a “calling tree” protocol to contact staff members and recall them to work. Alternative staff recall methods have been proposed and explored.MethodsAn unannounced, multidisciplinary, randomized emergency department (ED) staff recall drill was conducted at night - when there is the greatest need for back-up personnel and staff is most difficult to reach. The drill was performed on December 14, 2017 at 4:00am and involved ED staff members from three hospitals which are all part of the McGill University Health Centre (MUHC; Montreal, Quebec, Canada). Three tools were compared: manual phone tree, instant messaging application (IMA), and custom-made hospital Short Message Service (SMS) system. The key outcome measures were proportion of responses at 45 minutes and median response time.ResultsOne-hundred thirty-two participants were recruited. There were 44 participants in each group after randomization. In the manual phone tree group, 18 (41%) responded within 45 minutes. In the IMA group, 11 participants (25%) responded in the first 45 minutes. In the SMS group, seven participants responded in the first 45 minutes (16%). Manual phone tree was significantly better than SMS with an effect size of 25% (95% confidence interval for effect: 4.6% to 45.0%; P=.018). Conversely, there was no significant difference between manual phone tree and IMA with an effect size of 16% (95% confidence interval for effect: −5.7% to 38.0%; P=.17) There was a statistically significant difference in the median response time between the three groups with the phone tree group presenting the lowest median response time (8.5 minutes; range: 2.0 to 8.5 minutes; P=.000006).Conclusion:Both the phone tree and IMA groups had a significantly higher response rate than the SMS group. There was no significant difference between the proportion of responses at 45 minutes in the phone tree and the IMA arms. This study suggests that an IMA may be a viable alternative to the traditional phone tree method. Limitations of the study include volunteer bias and the fact that there was only one communication drill, which did not allow staff members randomized to the IMA and SMS groups to fully get familiar with the new staff recall methods.HomierV, HamadR, LarocqueJ, ChasséP, KhalilE, FrancJM.A randomized trial comparing telephone tree, text messaging, and instant messaging app for emergency department staff recall for disaster response. Prehosp Disaster Med. 2018;33(5):471–477.

scholarly journals P064: A randomized trial comparing telephone tree, text messaging, and instant messaging app for emergency department staff recall for disaster response

CJEM ◽  
2019 ◽  
Vol 21 (S1) ◽  
pp. S86
Author(s):  
V. Homier ◽  
R. Hamad ◽  
J. Larocque ◽  
P. Chassé ◽  
E. Khalil ◽  
...  
Keyword(s):  
Emergency Department ◽  
Confidence Interval ◽  
Response Time ◽  
Instant Messaging ◽  
Median Response ◽  
Median Response Time ◽  
Staff Members ◽  
Significant Difference ◽  
Tree Group ◽  
Recall Methods

Introduction: A crucial component of a hospital's disaster plan is an efficient staff recall communication method. Many hospitals use a “calling tree” protocol to contact staff members and recall them to work. Alternative staff recall methods have been proposed and explored. Methods: An unannounced, multidisciplinary, randomized emergency department (ED) staff recall drill was conducted at night - when there is the greatest need for back-up personnel and staff is most difficult to reach. The drill was performed on December 14, 2017 at 4:00AM and involved ED staff members from three hospitals which are all part of the McGill University Health Centre (MUHC; Montreal, Quebec, Canada). Three tools were compared: manual phone tree, instant messaging application (IMA), and custom-made hospital Short Message Service (SMS) system. The key outcome measures were proportion of responses at 45 minutes and median response time. Results: One-hundred thirty-two participants were recruited. There were 44 participants in each group after randomization. In the manual phone tree group, 18 (41%) responded within 45 minutes. In the IMA group, 11 participants (25%) responded in the first 45 minutes. In the SMS group, seven participants responded in the first 45 minutes (16%). Manual phone tree was significantly better than SMS with an effect size of 25% (95% confidence interval for effect: 4.6% to 45.0%; P = .018). Conversely, there was no significant difference between manual phone tree and IMA with an effect size of 16% (95% confidence interval for effect: -5.7% to 38.0%; P = .17) There was a statistically significant difference in the median response time between the three groups with the phone tree group presenting the lowest median response time (8.5 minutes; range: 2.0 to 8.5 minutes; P = .000006). Conclusion: Both the phone tree and IMA groups had a significantly higher response rate than the SMS group. There was no significant difference between the proportion of responses at 45 minutes in the phone tree and the IMA arms. This study suggests that an IMA may be a viable alternative to the traditional phone tree method. Limitations of the study include volunteer bias and the fact that there was only one communication drill, which did not allow staff members randomized to the IMA and SMS groups to fully get familiar with the new staff recall methods.

Bortezomib-Containing Regimens in the Treatment of AL Amyloidosis: A Single Center Experience

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4614-4614
Author(s):  
Alessandro Re ◽  
Gina Gregorini ◽  
Annalisa Peli ◽  
Matilde Nardi ◽  
Claudia Crippa ◽  
...  
Keyword(s):  
Light Chain ◽  
Free Light Chain ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Hematologic Toxicity ◽  
Major Advance ◽  
Single Center ◽  
Hematologic Response ◽  
Single Center Experience ◽  
Grade 3

Abstract Abstract 4614 Treatment of patients (pts) with systemic AL Amyloidosis remains challenging and organ dysfunctions improve in not more than 1/3 of cases with standard treatment. Bortezomib has been reported to have activity in this disease, where the misfolded protein may render the amyloidogenic plasma cells particularly vulnerable to proteasome inhibition. To evaluate the feasibility and efficacy of Bortezomib, we report our single center experience with Bortezomib-containing regimens in pts with AL Amyloidosis. Hematologic responses and functional organ responses were evaluated according to the 2005 International Society of Amyloidosis criteria (Gertz et al, Am J Hematol 2005). Complete hematologic response (CR) was defined as normalization of the free light chain ratio with no evidence of a monoclonal protein by immunofixation and partial response (PR) as a 50% reduction in M-spike or absolute light chain level; moreover, dFLC (difference between involved and uninvolved free light chain) &lt; 40 mg/L defined a very good PR (VGPR). A cardiac response was also defined by NT-proBNP criteria (&gt;30% and &gt;300 mg/L decrease in pts with baseline NT-proBNP &gt; 650 mg/L). Since May 2010, 21 consecutive pts with AL Amyloidosis were treated with Bortezomib-containing regimens at our center: Bortezomib-Dexamethasone (Vel-D), 5 pts; Cyclophosphamide-Bortezomib-Dexamethasone (CyBOR-D), 14 pts; Bortezomib-Melphalan-Prednisone (VMP),2 pts. Median age was 62 years (43-74). Fifteen pts were treated upfront, while 7 had refractory or relapsed disease after several lines of therapy. According to the cardiac staging system based on NT-proBNP and troponin I, 6 (29%) pts were stage 1, 9 (42%) stage 2 and 6 (29%) stage 3. At the time of this report 9 pts, still on treatment, have received less than 4 cycles and are not yet evaluable for response. Twelve pts received a median of 5,5 cycles (range, 4–8) and were analysed for outcome. Five received Vel-D, 5 CyBOR-D and 2 VMP. Eight were treated upfront and 4 after previous treatment (including ASCT in 3). Ten (83%) had renal, 6 (50%) cardiac, 2 (17%) soft tissue, 3 (25%) nerve, 2 (17%) gastrointestinal tract and 1 (8%) liver involvement. Four pts (33%) achieved hematologic CR, 3 (25%) VGPR and 3 (25%) PR (overall hematologic response rate (ORR) 83%), with no difference in ORR between Vel-D and CyBOR-D. One pt had a stable disease and 1, treated for second relapse, had progressive disease and died. Median time to response was 2 months (2-4). One pt underwent HD-MEL after PR with Vel-D and 3 pts had peripheral blood stem cells collected (soon after diagnosis (2) and after initial response (1)) and cryopreserved (to perform ASCT if unsatisfactory response or relapse). Four of eight evaluable pts (50%) had a renal response and 4/6 (66%) had a cardiac response. Hematologic toxicity was negligible; 6 pts had significant extra-hematologic complications, including 3 heart failure, 2 interstitial and 1 bacterial pneumonia, 1 Staph. sepsis, 1 H1N1 virus infection, 1 CMV reactivation, 1 grade 3 neuropathy and 1 grade 3 diarrhoea. No pts died because of toxicity. CyBor-D was apparently better tolerated. In this unselected series of systemic AL Amyloidosis, Bortezomib-containing regimens produced rapid hematologic response in the great majority of pts, with and an high rate of organ response. Bortezomib represents a major advance in the clinical management of this disease. Disclosures: No relevant conflicts of interest to declare.

Busulfan Induces Hematologic and Molecular Responses in Polycythemia Vera (PV) Refractory to Multiple Drugs

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 5068-5068
Author(s):  
Emil Tom Kuriakose ◽  
Stefani Gjoni ◽  
Y. Lynn Wang ◽  
Amy Jones ◽  
Nicholas C.P. Cross ◽  
...  
Keyword(s):  
Response Time ◽  
Polycythemia Vera ◽  
Phase Iii ◽  
Molecular Response ◽  
Low Doses ◽  
Molecular Responses ◽  
Hematologic Response ◽  
Significant Difference ◽  
Multiple Drugs

Abstract Abstract 5068 Busulfan, a highly effective and established drug in polycythemia vera (PV), produces lasting clinical and hematologic responses. Its use as a first and second line therapy for PV recently diminished owing to largely unsubstantiated concerns of increased leukemogenicity. However, in a pivotal phase III trial of busulfan vs. P32 conducted by the EORTC in patients with PV, busulfan sustained long term clinical and hematologic responses as well as superior 10 year overall survival (70% vs. 55%). Toxicity was minimal and a low incidence of acute leukemia was reported (1% at 8 years). Accordingly, we treated 5 PV patients with busulfan, 4 of whom were refractory to multiple drugs including hydroxyurea (HU), pegylated interferon alfa-2a (pIFN), imatinib, dasatinib, and anagrelide. Clinical and hematologic response was graded according to PVSG criteria and molecular response according to ELN criteria. JAK2V617F allele burdens were determined by pyrosequencing, which quantifies mutant alleles more than 5%. If negative by pyrosequencing, we used an ARMS-PCR assay with a sensitivity of 0. 1%. Phlebotomy was performed to maintain the hematocrit (Hct) less than 45% for men and 42% for women. Treatment with busulfan was discontinued if patients experienced adverse side effects and/or had platelet counts less than 100, 000/mL while in clinical remission. All 5 patients had complete hematologic responses (CHR) within 3 months of starting busulfan (table 1). Molecular responses (MR) were: 1 complete (CMR) after 6 months, 1 partial (PMR) after 6 months, and 3 with no response (NMR) after 3, 7, and 60 months of treatment respectively. The 2 patients who had MR were homozygous for JAK2V617F, and the 3 who did not were heterozygous. Treatment was discontinued in the patient with CHR and CMR after 7 months due to thrombocytopenia; the patient has since maintained CHR and CMR for 3 years off treatment. The remaining 4 patients have maintained CHR on low doses of busulfan (table 1). No adverse events were observed over a median treatment duration of 15 months (range: 3–60 months). The significant difference in molecular response between patients with homozygous and heterozygous JAK2 mutations receiving similar doses of busulfan is noteworthy. This suggests a susceptibility of homozygous JAK2V617F clones to busulfan, but not to other drugs including HU, IFNa, and anagrelide. In summary, our 5 patients with multidrug refractory PV had rapid and sustained hematologic responses to busulfan at low doses, with favorable short and long term toxicity profiles. Two JAK2V617F homozygous patients had the best MR. Our findings indicate the effectiveness of a safe, relatively inexpensive drug in inducing clinical outcomes not significantly different from that of costly drugs, such as JAK2 inhibitors. In addition, the high rates of MR we observed in patients with homozygous JAK2 mutations warrant further study of busulfan with respect to this parameter. Table 1: Demographics and treatment results of 5 patients treated with busulfan for PV Patient Age (yr)-Sex (M/F) Prior treatments-duration (yr) Busulfan dose Adverse effects Duration of tx (months) Hematologic response/time to response (months) Molecular response/time to response (months) Pre-busulfan JAK2 allele burden 1 75-F HU-2 yr 4mg daily thrombocytopenia 7 CHR/3 CMR/6 100% 2 70-F HU+anagrelide-1yr Imatinib-2yr Dasatinib-3 yr IFNa-1 yr 2mg 3 times a week None 15 CHR/1 PMR/6 85% 3 84-F HU-2 yr Dasatinib- 3yr Imatinib-1yr 2mg 4 times a week None 18 CHR/3 None 27% 4 81-M HU-5 yr 2mg daily None 3 CHR/2 None 23% 5 81-F None 2mg 3 times a week None 60 CHR/3 None 45% Disclosures: No relevant conflicts of interest to declare.

Difference of Treatment Outcomes in AL Amyloidosis and Multiple Myeloma with / without Translocation (11;14)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4224-4224 ◽  
Author(s):  
Kenshi Suzuki ◽  
Miho Kasuga ◽  
Kanji Miyazaki ◽  
Sohsuke Meshitsuka ◽  
Yu ABE ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Chromosome Aberration ◽  
The Other ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Positive Group ◽  
Other Hand ◽  
Significant Difference ◽  
Organ Response

Abstract Introduction AL amyloidosis (AL) is characterized by the deposition of immunoglobulin light chains as amyloid fibrils accumulated in different organs. Translocation (11;14) (t(11;14)) is seen in about half of AL patients, but the clinical significance is still unknown. So our study has focused on the chromosome aberration of t(11;14). We report the relationship between the chromosome aberration and the organ response, the organ involvement which greatly influence prognosis of AL patients. Furthermore, we examined the prognosis and treatment response to compare t(11;14) influences of AL with t(11;14) influences of multiple myeloma (MM). Patients and Methods We analyzed in AL and symptomatic MM patients have t(11;14) using fluorescence in situ hybridization from January 2010 to December 2014 in Japanese Red Cross Medical Center. We examined the overall survival and the therapy response rate. In addition, we compared t(11;14)-positive and negative in AL and MM respectively. Besides, we investigated the involved organ parts and the organ response with melphalan and dexamethasone (MD) therapy in AL. Outcome was assessed based on remission after three months and one year. Remissions were determined according to consensus criteria in 2011 for AL and IMWG uniform criteria for MM. Survival distribution of OS was estimated using the Kaplan-Meier method and compared using the log-rank test. Data between t(11;14)-positive and negative were compared with the Mann-Whitney U test or X2 test. The statistical analysis was performed using IBM SPSS statistics ver.23. Results Among 27 patients with AL, 9 cases were t(11;14)-positive patients (age median, 64yr; range, 37-80), and 13 out of 46 were positive in MM (age median, 64yr; range, 34-86). (excluded complication of both AL and MM cases) In AL cases, the t(11;14)-positive group tended to shorter overall survival (OS) than negative cases. On the other hand, in the patients with MM, positive group tended to superior OS to negative (AL: P=0.442(Fig.1A), MM: P=0.327(Fig.1B)). Compared with t(11;14)-negative AL group, t(11;14) positive group was tended to have much organ involved numbers of amyloid protein (67% v 34%; P=0.109) and much cardiac involvement patients (67% v 39%; P=0.171). On the other hand, there were little cardiac and renal response in both t(11;14)-positive and negative with MD therapy after 3 months (heartF17% v 0% P=0.462/renalF0% v 0%). In MM patients, ORR after 3 months were 67% and 79% in t(11;14)-positive and negative cases respectively (P=0.386). That after 1 year were 78% and 74% respectively (P=0.889). Conclusion t(11;14) is important prognostic factor and showed conflict prognosis between AL and MM. From this investigation, the importance of connecting the chromosome abnormality every disease was shown. In addition, our investigation recognized tendencies that the amyloid involvement rate to the heart was high, and the cardiac response with MD therapy were low in AL t(11;14)-positive group. As these results, we thought that t(11;14)-positive AL patients' OS were shortened. The significant difference did not appear in this examination while these tendencies were clearly accepted in little number of patient cases. Further investigation using rather number of patient samples is needed. In conclusion, the cardiac amyloid involvement is high in the AL t(11;14)-positive group, and the cardiac response by MD therapy is low. We should have doubt eyes of the amyloid involvement to the heart in AL t(11;14)-positive patients, and have the posture that can support cardiac amyloidosis immediately. In addition, breakthrough new treatments are expected urgently for AL patients. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

A Randomized Phase III Trial of Melphalan and Dexamethasone (MDex) Versus Bortezomib, Melphalan and Dexamethasone (BMDex) for Untreated Patients with AL Amyloidosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 646-646 ◽  
Author(s):  
Efstathios Kastritis ◽  
Xavier Leleu ◽  
Bertrand Arnulf ◽  
Elena Zamagni ◽  
María Teresa Cibeira ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Standard Of Care ◽  
Cardiac Response ◽  
Phase Iii ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Phase Iii Trial ◽  
Hematologic Response ◽  
Grade 3

Abstract Background. Current upfront treatment of light chain (AL) amyloidosis is often based on bortezomib in patients. However, data on the safety and efficacy of bortezomib in this setting mostly derive from uncontrolled, retrospective series, that are difficult to compare due to different proportion of patients with advanced disease. Here we report the analysis of a multicenter randomized phase III trial comparing MDex, a current standard of care, and MDex with the addition of bortezomib (BMDex) in newly-diagnosed AL amyloidosis that was performed in Europe and Australia (EMN-03 study, NCT01277016). Patients and Methods. Main eligibility criteria included measurable disease (M-protein >10 g/L or dFLC >50 mg/L), estimated glomerular filtration rate (eGFR) ³30 mL/min, and adequate liver function. Previously treated patients, those who had >30% bone marrow plasma cell or lytic bone lesions, NYHA class >II heart failure, grade 3 sensory or grade 1 painful peripheral neuropathy, or ECOG performance status >2 were excluded. In January 2013 the protocol was amended to include Mayo stage III patients, provided their NT-proBNP was <8500 ng/L (stage IIIa). Patients were randomized to receive either MDex (melphalan at 0.22 mg/kg and dexamethasone at 40 mg daily for 4 consecutive days every 28 days) or BMDex (bortezomib added at 1.3 mg/m2, on days 1, 4, 8, and 11 in cycles 1 and 2, and on days 1, 8, 15, and 22 in the following cycles). The primary endpoint was overall hematologic response at 3 months. Treatment was continued until completion of MDex cycle 9 or BMDex cycle 8, or achievement of CR or of at least partial response (PR) plus organ response after cycle 6, and was discontinued in case PR was not achieved by cycle 3. Enrollment is now completed (110 patients) with the last patient enrolled in February 2016 (database lock: July 25, 2016). Results. Patients' characteristics are reported in the Table. The proportion of patients experiencing at least 1 grade 3-4 severe adverse events (SAE) was similar in the MDex and BMDex arms (49% vs. 60%, P=0.11). The total number of reported adverse events per cycle was lower in the MDex group (10% vs 23%, P<0.01). Most common SAEs (MDex vs. BMDex) were cytopenia (4% vs. 7%, P=0.04), fluid retention (3% vs. 6%, P=0.02), and neuropathy (0 vs. 2%, P<0.01). One patient died within 3 months in the MDex arm and 3 in the BMDex group (P=0.28). Response was evaluated by intent to treat. Hematologic response rates after cycle 3 were 51% and 78% (P=0.001), with 28% and 53% complete response (CR) /very good partial response (VGPR) (P=0.003), in the MDex and BMDex arms, respectively. Overall hematologic response at the end of treatment, after a median of 5 cycles, was 56% and 81% (P=0.001), with 38% and 64% CR/VGPR in the MDex and BMDex arms, respectively (P=0.002). Cardiac response was reached in 8 of 33 evaluable patients treated with MDex (24%) and 10 of 26 (38%) who received BMDex (P=0.119). Renal response was attained in 17 of 35 patients (48%) in both arms. However, there was a higher proportion of cardiac progression in the MDex arm with borderline statistical significance (32% vs. 15%, P=0.054). After a median follow-up of living patients of 25 months, 26 patients (24%) died, 16 in the MDex arm and 10 in the BMDex arm with no significant difference in survival (Figure 1a). Achievement of hematologic and cardiac response at 3 months significantly improved survival (Figures 1b and 1c). Conclusion. This is the first prospective randomized trial of novel agents in AL amyloidosis. The criteria of hematologic and cardiac response are validated in the prospective setting for the first time. The primary endpoint, hematologic response at 3 months has been reached, showing more frequent and more profound hematologic responses with BMDex, preventing progression of cardiac dysfunction, with a modest increase in toxicity. This regimen can be proposed as a new standard of care in AL amyloidosis. We would like to acknowledge the European Myeloma Network, the Australasian Leukaemia and Lymphoma Group and the Leukaemia Foundation of Australia for their ongoing support, and Janssen-Cilag for partially funding the trial and providing the study drug. Disclosures Kastritis: Genesis: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Cibeira:Janssen: Honoraria; Celgene: Honoraria. Mollee:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: 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; Nilelse: Research Funding. Hajek:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Moreau:Janssen: Honoraria, Speakers Bureau; Celgene: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria. Mateos:Janssen, Celgene, Amgen, Takeda, BMS: Honoraria. Wechalekar:Takeda: Honoraria; Janssen: Honoraria; Glaxo Smith Kline: Honoraria; Celgene: Honoraria. Dimopoulos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Palumbo:Janssen Cilag: Honoraria; Takeda: Employment, Honoraria. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria, Research Funding. Merlini:Pfizer: Honoraria, Speakers Bureau; Millennium Takeda: Consultancy; Prothena: Honoraria; GlaxoSmithKline: Consultancy. Palladini:Prothena: Honoraria.

A Typology of Players: Between Instinctive and Contemplative *

2016 ◽  
Vol 131 (2) ◽  
pp. 859-890 ◽  
Author(s):  
Ariel Rubinstein
Keyword(s):  
Response Time ◽  
The Other ◽  
Spearman Correlation ◽  
Median Response ◽  
Median Response Time ◽  
Shed Light

Abstract A new typology of players is proposed based on the classification of actions as either instinctive or contemplative. A person’s type is the probability of him choosing a contemplative action. To test the typology, results of 10 games are analyzed. Actions in each game were classified depending on whether their response time was more or less, respectively, than the median response time of all subjects who played the game. It is argued that fast actions are more instinctive and slow actions are more contemplative. A subject’s contemplative index (CI) is defined as the proportion of games in which he chose a contemplative action. It is found that for 8 of the 10 games, the CI in the other 9 games is positively correlated with a player’s choice of a contemplative action in that game (average Spearman correlation of 9%). The CI is used to shed light on the nature of choice in five additional games.

scholarly journals Patterns of Relapse after Upfront Therapy in AL Amyloidosis

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2140-2140 ◽  
Author(s):  
Paolo Milani ◽  
Marco Basset ◽  
Francesca Russo ◽  
Andrea Foli ◽  
Giovanni Palladini ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Partial Response ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Second Line ◽  
Second Line Therapy ◽  
Prolonged Time ◽  
Hematologic Response ◽  
Line Therapy ◽  
Upfront Therapy

Abstract Introduction. In the last few years a major international effort allowed establishing baseline staging systems and response criteria in AL amyloidosis. However, we still lack validated progression criteria. This is acutely relevant for reporting progression free survival in clinical trials and because novel agents are first tested in the relapsed/refractory setting. We studied the patterns of relapse and outcome of 259 consecutive patients with AL amyloidosis who attained hematologic response after upfront therapy. Methods. The prospectively maintained database of the Pavia Amyloidosis Research and Treatment Center, including 1069 treatment-naïve patients with AL amyloidosis diagnosed between 2004 and 2015, was searched for patients who achieved at least partial response (PR) after upfront treatment, and did not require second-line therapy for at least 6 months. Relapse was defined as the initiation of second-line therapy. Results. A total of 259 consecutive patients were identified. Their median age was 66 years (range 39-84 years). The heart was involved in 184 patients (71%) and the kidney in 179 (69%) of subjects. Cardiac stage was I in 29% of patients, II in 46%, IIIa in 18%, and IIIb in 7%. Renal stage was I in 48% of patients, II in 39%, and III in 13%. Upfront treatment was melphalan and dexamethasone (MDex) in 129 patients (50%), cyclophosphamide, bortezomib and dexamethasone (CyBorD) in 71 (27%), bortezomib plus MDex (BMDex) in 46 (18%), bortezomib and dexamethasone in 10 (4%) in 3 subjects (1%) with IgM-AL amyloidosis. Best hematologic response after upfront therapy was CR in 82 patients (32%), very good partial response (VGPR) in 134 (52%), and partial response (PR) in 43 (16%). Cardiac response was achieved in 38% of patients and renal response in 27%. All patients in whom treatment was discontinued in PR had also achieved organ response. After a median follow-up of living patients of 41 months, 92 patients (35%) needed second line therapy (relapsed). At time of relapse, dFLC (difference between amyloidogenic - involved - and uninvolved free light chains) increased in 86 patients (93%), reaching a median of 60 mg/L [interquartile (IQR) range 26-108 mg/L], corresponding to 41% (IQR 19-84%) of baseline value, with 44 patients (48%) whose dFLC at relapse remained below the threshold of "measurable disease" (50 mg/L) generally required for enrollment in clinical trials. Progression of NT-proBNP was observed in 20 patients, and was preceded by a dFLC increase (to a median of 50% of baseline value; IQR: 20-83%) in 20 (91%). A >50% increase in proteinuria was observed in 24 patients (26%), 2 of whom maintained VGPR with no increase in dFLC. In 11 patients (12%) estimated glomerular filtration rate decreased by >25%, with dFLC increase in all cases. Overall, 70 patients (76%) had signs of cardiac or renal progression at time of second line therapy initiation. Median time to second line therapy was 57 months. The variables significantly associated with prolonged time to relapse were baseline dFLC <60 mg/L (11% vs 32% relapsing at 3 years, P=0.004), quality of hematologic response (21%, 35%, and 54% relapsing at 3 years, among patients in CR, VGPR, and PR, respectively; CR vs. VGPR: P=0.003, VGPR vs. PR: P=0.028), and treatment with BMDex [27% relapsing at 3 years, compared with 38% with CyBorD (P=0.014), and 39% with MDex (P=0.023)]. A multivariate analysis stratified by achievement of CR showed that treatment with BMDex independently prolonged time to second line therapy (HR=0.28, P=0.016), while dFLC <60 at diagnosis retained borderline significance (HR=0.15, P=0.067). Thirty-two patients died, and median survival after relapse was 58 months. Progression of NT-proBNP was associated with shorter survival (median 17 vs. 62 months, P=0.001). Conclusion. Low dFLC burden at diagnosis and treatment with the combination of bortezomib, melphalan and dexamethasone are associated with more durable responses. An increase in NT-proBNP should not be awaited to start treatment, because it is associated with poorer survival. However, cardiac progression is preceded by a dFLC increase in >90% of cases. Increases in dFLC (>20%) should trigger second-line therapy in patients with cardiac involvement. Disclosures Palladini: Prothena: Honoraria. Merlini:Pfizer: Honoraria, Speakers Bureau; GlaxoSmithKline: Consultancy; Millennium Takeda: Consultancy; Prothena: Honoraria.

Will adding alkylating agent to bortezomib improve survival of newly diagnosed AL amyloidosis patients?

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 8517-8517
Author(s):  
Yumeng Zhang ◽  
Lauren Duncanson ◽  
Taiga Nishihori ◽  
Doris K. Hansen ◽  
Jose L. Ochoa-Bayona ◽  
...  
Keyword(s):  
Alkylating Agent ◽  
Cancer Center ◽  
Al Amyloidosis ◽  
Primary Therapy ◽  
Hematologic Response ◽  
First Line Therapy ◽  
Significant Difference ◽  
Group A ◽  
Initiation Of Therapy ◽  
Group B

8517 Background: The combination of bortezomib (Bort) and alkylating agent (AA) is a frequently used first-line therapy for AL amyloidosis. Kastritis et al. compared melphalan and dexamethasone with or without bortezomib as primary therapy and demonstrated increased hematologic response rate with the bortezomib and melphalan combination. However, the role of AA is unclear. This study aimed to evaluate if adding AA to Bort improved patient outcomes in AL amyloidosis. Methods: We retrospectively reviewed clinical data on 209 patients with systemic AL Amyloidosis at Moffitt Cancer Center between 2008 and 2020. We excluded patients with localized amyloidosis or amyloid other than AL. Patients were divided into two groups based on upfront therapy: A) Bort and B) Bort + AA. All patients also received dexamethasone. The staging was per Mayo 2012. Organ involvement, response, and progression were defined based on the 2005 criteria. Overall survival (OS) was defined as the time from initial diagnosis until death or last contact. Time to next therapy (TTNT) was calculated in patients with the documented hematologic response from the time of initiation of therapy to time of the next therapy/last follow up/death. Results: Of 209 patients, 36% (n=76) received Bort+AA; 30% (n=62) received Bort. No significant difference in clinical characteristics was seen in both groups except for age (which was higher for arm A: median 65 and 62 years, respectively, p=0.043) (table). In addition, Bort+AA became more commonly used as a frontline therapy after 1/1/2014 (p=0.001). Group A and B had similar median OS (69.9 months [95% CI. 44.7-95.2] and 64.4 mo [95% CI 40.5-88.3] respectively, p=0.60). 86% of patients in group B achieved a hematologic response as compared to 74% of patients in group A (p=0.15). Similarly, 47% of patients in group B achieved an organ response as compared to 34% of patients in group A (p=0.22). TTNT was higher in group A than group B (16.9 mo [95% CI, 0-41.5] and 7.8 mo [95% CI, 3.5-12.0], respectively, p=0.08). Conclusions: While Bort+AA is a commonly used regimen for amyloidosis, the addition of AA to Bort did not result in superior OS, TTNT compared to Bort alone in this retrospective study. This finding should be confirmed in prospective studies. Baseline Characteristics. [Table: see text]

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