Risk Factors for Early Sudden Cardiac Death in Patients with Systemic Light-Chain Amyloidosis on Treatment

Abstract Introduction: Despite advances in therapy for patients with light-chain (AL) amyloidosis, mortality remains high in the first 6 months after diagnosis in those on treatment (Blood 2017;129:2111). The early deaths are usually sudden cardiac deaths (SCD); a prior study showed that troponin I level and lack of response to therapy influenced survival (Br J Haematol 2008;143:369). In January 2021 at the approval of daratumumab with cyclophosphamide, bortezomib and dexamethasone for AL (Dara/CyBorD), the FDA label warned that patients with higher cardiac staging may be at risk for fatal cardiac events. We sought to analyze risk factors for SCD in patients on treatment, defining SCD as a sudden unexpected death caused by loss of cardiovascular function (Arrhythm Electrophysiol Rev 2016;5:177). Methods: From a database of 398 patients with AL amyloidosis collected from 2005-2019, we identified patients who suffered out-patient SCD on treatment within 180 days of diagnosis. We recorded baseline age, gender, systolic BP, presence of syncope, LVEF, FLC, cardiac biomarkers, NYHA class, cycles of treatment with bortezomib, and data on SCD. For comparison we identified an age and gender matched group who achieved complete or very good partial responses (CR or VGPR) based on standard criteria and recorded that group's data (J Clin Oncol 2012;30:4541). We compared these datasets by two-tailed Mann-Whitney and where appropriate by contingency table analysis. We computed the medians of the involved FLC, BNP and troponin for all the cases to determine the frequency with which patients in either group had baseline values above or below those medians. Results: Comparative results are shown in Table 1. We identified 13 SCD and 74 age and gender matched CR/VGPR patients. Compared with the CR/VGPR group, both hypotension and exertional syncope were significantly more common in the SCD group, indicating the presence of autonomic dysfunction. NYHA class 3 or 4 status was also more common in the SCD group (40% and 13% vs 26% and 13% in the CR/VGPR group). In addition, more SCD patients were Mayo cardiac stage III (80% vs 46% in the CR/VGPR group) (Blood 2004;104:1881; J Clin Oncol 2004;22:3751). The SCD patients had significantly lower LVEF and higher iFLC and were significantly more likely to have iFLC values above the median. Similarly they had significantly higher BNP and troponin-I levels and were more likely to have values above the medians. The causes of death were unclear in 9 cases but were described by witnesses as due to syncopal events associated with micturition, climbing stairs, or light exertion. In 4 cases seen in emergency rooms, PEA was documented in 3 and septic shock in 1. The SCD patients had a median of 1 cycle of subcutaneous bortezomib-based therapy (CyBorD) (range, 1-5). Three patients received daratumumab subcutaneously with CyBorD. The median starting dose of bortezomib was 1.3mg/m2 (0.7-1.5) usually on a weekly schedule; 2 patients initiated therapy at 1.5mg/m2 weekly, one of whom had had progression of disease (POD) after 2 cycles of oral melphalan and dexamethasone and then had further progression despite completing 3 cycles of CyBorD (POD=1). Eight patients were inevaluable for hematologic response (NR=8), 2 achieved PR after 2 and 4 cycles of CyBorD (PR=2), and of the 3 who got Dara/CyBorD, 1 was inevaluable, 1 achieved VGPR after C1 and 1 CR in C2 (CR/VGPR=2), before having SCD. Conclusion: These findings indicate the contribution that the presence of autonomic dysfunction makes in this population of AL patients with advanced cardiac disease and high levels of iFLC, key variables in the revised Mayo staging system (J Clin Oncol 2012;30:989). The potential pre-morbid significance of exertional syncope has been identified previously (Am J Cardiol 1997;80:1242). In conclusion, this case series suggests that compared with AL amyloid patients who achieve CR or VGPR with treatment, patients who suffer early SCD on treatment have symptoms indicative of autonomic dysfunction and may benefit from in-patient initiation of treatment and from obtaining insurance approval for Dara/CyBorD but starting therapy with weekly subcutaneous daratumumab and dexamethasone, adding cyclophosphamide and bortezomib at a later timepoint based on hematologic response. Moreover, weekly assessment of FLC response is reasonable in these patients in order to guide therapy and adjust supportive care. Figure 1 Figure 1. Disclosures Comenzo: Sanofi-Aventis: Membership on an entity's Board of Directors or advisory committees; Prothena Biosciences: Consultancy, Research Funding; Caelum: Consultancy, Research Funding; Takeda: Research Funding; Karyopharm: Research Funding; Janssen: Patents & Royalties: WO2016187546A1, Research Funding; Unum: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Updated Results of a Phase 2 Study of Bendamustine in Combination with Dexamethasone (Ben/Dex) in Patients with Previously-Treated Systemic Light-Chain (AL) Amyloidosis

Blood ◽

10.1182/blood.v126.23.3041.3041 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3041-3041 ◽

Cited By ~ 2

Author(s):

Suzanne Lentzsch ◽

Raymond L. Comenzo ◽

Jeffrey A Zonder ◽

Keren Osman ◽

Miao Susanna ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Response Rate ◽

Nyha Class ◽

Al Amyloidosis ◽

Phase 2 ◽

Cardiac Events ◽

Advisory Committees ◽

Hematologic Response ◽

Phase 2 Study

Abstract Background: Melphalan in combination with dexamethasone is an active and the standard regimen in AL amyloidosis. Unfortunately very often patients relapse and other drugs are needed. Bendamustine is a bifunctional alkylating agent approved for the treatment of CLL, NHL, and MM in Europe and the US. But its safety and efficacy in AL amyloidosis is not known. In an effort to investigate the activity of Ben/Dex and improve the outcome of patients with relapsed AL we conduct a multi-center, Phase 2 study of Ben/Dex in AL (NCT01222260) and report data of an updated unplanned interim analysis. First data were reported at ASH 2014 (Abstr.3480). Methods: All patients had relapsed AL after a median of 2 prior therapies (range 1-4). Patients with very advanced cardiac involvement (NYHA Class IIIB/IV) were excluded. Patients with NYHA Class IIIA, NT-proBNP ≥ 1800 ng/L or BNP ≥ 400 ng/L, abnormal cTnT or cTnI could be included after evaluation by cardiology to determine the risk associated with the treatment. Patients with a CrCl ³ 15 mL/min were considered for the trial if they were not in active renal failure. This Phase IIa clinical trial uses a two-stage optimal Simon design enrolling 13 patients in the first stage. Since at least three patients experienced hematologic PR or better, the trial proceeded to the second stage treating an additional 16 patients. If 9 or more patients out of the total of 29 patients evaluable for response experience a hematologic PR or better, the treatment will be considered worthy of further development. The primary objective is to determine the partial hematologic response rate (PR). Secondary objectives included overall hematologic response (OHR) rate, organ response rate (OrRR) (Palladini et al., JCO 2012), time to failure (TTF), toxicities (adverse events at least possibly related to treatment), overall survival (OS) and the assessment of expression of genes associated with ER stress. Patients were assigned to bendamustine according to CrCl: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle, CrCl 59-15 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle. The option to dose escalate was available to qualifying subjects including escalating to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) and 100 mg/m2 (if CrCl 59 - 15 mL/min at the time of inclusion into the study). Dexamethasone was started at 20-40mg weekly according to the performance status of the patient. The duration of each cycle was 28 days. Results: As of 7/15/15, 26 patients have received treatment and 28 patients have been enrolled. Median age of enrolled patients was 66 (range 44-77). Enrolled patients received a median of 1.5 prior regimens (range 1-4). Twelve of the enrolled patients received prior autologous stem cell transplant. Median number of cycles for treated patients is 3.5 (range is 1-12), with 4 patients still receiving treatment. Of note, only 2 patients discontinued treatment due to disease progression. Only 9 patients discontinued treatment due to AE. Most common drug-related AEs (all grades, >25%) included fatigue (39%), nausea (35%) and Anemia (27%),. No grade ≥3 drug-related AE occured in >20% of patients. Of note, no cardiac events were observed, including any increase in NT-proBNP.Of 24 patients eligible for response evaluation, 11 (46%) have responded hematologically, including (≥PR 42%, CR 4%). The median time to best response of treatment (partial response or better) was 1.57 months (range 0.97 to 15.1 months). The CR occurred in a patient after 5 cycles suggesting that this heavily pretreated patient population needs longer treatment to achieve response. Better responses were especially observed in less heavily treated patients. With a median follow-up of 13.4 months (range 1.5 to 30.3 months) the median OS has not been reached yet (Figure 1). The median PFS is 11.5 months (95% CI,1.5-29.1months) (Figure 2). Conclusions: In our updated unplanned interim analysis we found that Bendamustine in combination with dexamethasone is feasible and effective in pretreated AL amyloidosis with impaired organ function (NYHA IIIB and creatinine clearance of 30-15 mL/min were allowed). Cardiac events related to Bendamustine were not observed. Preliminary hematologic response rates are promising in this pretreated patient population, and organ assessments are ongoing. Further study of this approach is warranted. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Lentzsch: Axiom: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Will discuss the use of Bendamustine and Dexamethasone under clinical trial NCT01222260. Comenzo:Takeda Millennium: Research Funding; Prothena: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Karyopharm: Research Funding. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support; Prothena: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Osman:Millennium / Takeda: Research Funding.

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Comorbidities and Complications in Adults with Pyruvate Kinase Deficiency

Blood ◽

10.1182/blood-2019-123069 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 2175-2175

Author(s):

Audra N. Boscoe ◽

Yan Yan ◽

Elizabeth Hedgeman ◽

Eduard J. van Beers ◽

Hanny Al-Samkari ◽

...

Keyword(s):

Clinical Trial ◽

General Population ◽

Board Of Directors ◽

Research Funding ◽

Advisory Board ◽

Advisory Committees ◽

Age And Gender ◽

Look Back ◽

And Gender ◽

Transfusion History

Introduction: Pyruvate kinase (PK) deficiency causes a defect in the glycolytic pathway, leading to a hereditary hemolytic anemia. Management is supportive and consists of splenectomy, transfusions, and chelation therapy. Aim: To better understand the comorbidity and complication profile of adults with PK deficiency, and the extent to which transfusion frequency contributes, the objectives of this study were to (1) quantify the prevalence of comorbidities and complications according to transfusion history and (2) compare the types and rates of select comorbidities and complications with the general population. Methods: Data were obtained from the enrollment survey of the PK Deficiency Natural History Study (NHS), a longitudinal, retrospective and prospective cohort study in which clinical, laboratory, transfusion, and radiologic data were collected; all participants were confirmed to have 2 mutations in the PKLR gene. Patients (n=122) were eligible for this analysis if they were ≥18 years of age and had sufficient data on transfusion history to enable classification into 1 of 3 cohorts: "Ever Regularly Transfused" (ERT, defined as ≥6 transfusions in any 12-month period), "Never Regularly Transfused" (NRT, defined as having ≥1 lifetime transfusion but never having >4 transfusions in any 12-month period), or "Never Transfused" (NT). To contextualize the findings, the frequencies of select conditions were compared with an age- and gender-matched cohort of individuals from the insured, general US population who did not have any hemolytic anemia diagnoses and had ≥5 years of continuous enrollment in the Truven MarketScan administrative claims database. The NHS reported lifetime prevalence rates, whereas rates obtained from the MarketScan data were based on diagnosis and procedure codes over varying look-back periods; therefore, to minimize bias, we limited PK deficiency vs. general population comparisons to (1) chronic conditions that require lifetime management and would thus still be recorded in claims data years after initial diagnosis, and/or (2) conditions for which a diagnosis/procedure date was available in the NHS and could be matched in time to the average 8-year look-back period for the general population. Frequencies were compared across mutually exclusive cohorts using Fisher's exact 2-tailed tests of significance. Results: ERT (n=65), NRT (n=30), and NT patients (n=27) had a mean age of 34.2, 39.5, and 37.2 years at enrollment, respectively (not significant [ns]), with 46.2%, 56.7%, and 59.3%, respectively, being male (ns). ERT patients trended toward being more likely than NT patients to be Amish and have the homozygous R479H splice variant (30.8% vs 11.1% [p=0.064]) but were significantly less likely to have a missense/missense PKLR genotype (32.3% vs 70.4% [p=0.001]). Compared with the general population, patients with PK deficiency had significantly higher rates of splenectomy, cholecystectomy, osteoporosis, liver cirrhosis, pulmonary hypertension, and current prophylactic antibiotic and anticoagulant use (Table). Rates of splenectomy, cholecystectomy, and osteoporosis were significantly higher in patients with PK deficiency, regardless of transfusion cohort, and both ERT and NRT patients had significantly higher rates of liver cirrhosis than individuals from the general population. A gradient was seen across transfusion cohorts for other conditions. Notably, 83.1% of ERT patients, 50.0% of NRT patients, and 25.9% of NT patients had a history of liver iron overload. ERT patients were also significantly more likely than NRT and NT patients to have had a splenectomy, cholecystectomy, and/or thrombosis, and to currently use prophylactic antibiotics. Findings were consistent when the analysis was restricted to non-Amish patients with PK deficiency. Conclusions: Patients with PK deficiency have higher rates of select comorbidities and complications than age- and gender-matched individuals who do not have PK deficiency. Even patients with PK deficiency who have never been transfused are at increased risk of complications of the disease and its treatment. Disclosures Boscoe: Agios Pharmaceuticals, Inc.: Employment, Equity Ownership. Yan:Agios Pharmaceuticals, Inc.: Consultancy. Hedgeman:IBM Watson Health: Employment. van Beers:Agios Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; RR Mechatronics: Research Funding. Al-Samkari:Agios: Consultancy, Research Funding; Dova: Consultancy, Research Funding; Moderna: Consultancy. Barcellini:Incyte: Consultancy; Alexion: Consultancy, Speakers Bureau; Agios Pharmaceuticals, Inc.: Consultancy; Novartis: Speakers Bureau; Apellis: Consultancy; bioverativ: Consultancy. Eber:Agios Pharmaceuticals, Inc.: Consultancy. Glader:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Chonat:Alexion: Other: advisory board; Agios Pharmaceuticals, Inc.: Other: advisory board. Rothman:Agios: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding. Kuo:Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy. Kwiatkowski:Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding; Celgene: Consultancy; Terumo: Research Funding. Ravindranath:Agios Pharmaceuticals, Inc.: Other: I am site PI on several Agios-sponsored studies, Research Funding. Neufeld:Octapharma, Shire Pharmaceuticals (Baxalta), Novo Nordisk, Celgene, NHLBI/NIH: Research Funding; Octapharma, Agios, Acceleron, Grifols, Pfizer, CSL Behring, Shire Pharmaceuticals (Baxalta), Novo Nordisk, ApoPharma, Genentech, Novartis, Bayer Healthcare: Consultancy; Octapharma: Other: study investigator, NuProtect study (Octapharma-sponsored). Holzhauer:Agios Pharmaceuticals, Inc.: Consultancy. Verhovsek:Sickle Cell Disease Association of Canada: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Haemoglobinopathy Association: Membership on an entity's Board of Directors or advisory committees; Vertex: Consultancy; Sickle Cell Awareness Group of Ontario: Membership on an entity's Board of Directors or advisory committees. Kunz:Novartis: Membership on an entity's Board of Directors or advisory committees. Sheth:Apopharma: Other: Clinical trial DSMB; Celgene: Consultancy; CRSPR/Vertex: Other: Clinical Trial Steering committee. Despotovic:Novartis: Research Funding; Dova: Honoraria. Grace:Agios Pharmaceuticals, Inc: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding.

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Development of Autoimmune Diseases in Women with HPA-1a Alloimmunization and Fetal-Neonatal Alloimmune Thrombocytopenia (FNAIT)

Blood ◽

10.1182/blood.v128.22.2556.2556 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2556-2556

Author(s):

Ramanjot S. Kang ◽

Peter J. Keefe ◽

James B. Bussel

Keyword(s):

Autoimmune Disease ◽

General Population ◽

Autoimmune Diseases ◽

Board Of Directors ◽

Research Funding ◽

Immune Response Gene ◽

Advisory Committees ◽

Age And Gender ◽

And Gender ◽

Hla Dr3

Abstract Introduction: Fetal-NeonatalAlloimmune Thrombocytopenia (FNAIT) is the result of an incompatibility between maternal and fetal human platelet alloantigens (HPA). Affecting 1 in 1000 births, it is one of the most common causes of thrombocytopenia in the neonate. Prospective studies reveal that only 5-10% of pregnancies with HPA-1a incompatibilities result in maternalalloimmunization. The association of HPA-1a incompatibility andalloimmunization is largely based on an immune response gene: the Human Leukocyte Antigen (HLA) class II DRB3*0101 haplotype. Clinical studies have shown that >90% of women that produce HPA-1a antibodies express HLA-DRB3*0101. The HLA-DRB3*0101 haplotype is found on the HLA-DR3 locus of HLA-A1-B8-DR3 - amultigene haplotype which has been implicated in the development of a number of autoimmune diseases. The presence of HLA-A1-B8-DR3 has been shown to impact susceptibility to, the age of onset, and severity of autoimmune diseases. In this study we seek to investigate whether the HPA-1aalloimmunization that results in FNAIT, which is linked to the autoimmune haplotype, is also associated with an increased incidence of maternal autoimmune diseases following pregnancy. Methods: A retrospective review was conducted to identify patients with HPA-1a cases of FNAIT associated pregnancies. Patients with serologically confirmed anti-HPA-1a FNAIT completed a general health status survey developed by our laboratory in 2013 (n = 51; mean age = 30.6 years). In addition to questions about their health, patients described the course of their pregnancy, complications, and any health problems that followed their pregnancy. A follow-up survey was conducted in 2015 (n = 49, mean age = 33.4 years) with additional questions focusing on the development of autoimmune diseases. The incidence of autoimmune disease in our sample population was compared with that in the general population controlled for age and gender (Centers for Disease Control; Table 1). Results: Analysis revealed that of the 49 patients contacted in 2015, 25 patients (51%) had a confirmed diagnosis of an autoimmune disease. Patients reported Rheumatoid Arthritis (RA) (34.6%), Systemic LupusErythematosus (SLE)(10.2%),Sjogren's Syndrome (SS) (4%), and Type 2 Diabetes Mellitus (T2DM) (2%). When compared with the general population, controlled for age and gender, there was an increased incidence of both RA and SLE in the study population. Conclusions: Our results reveal that patients with HPA-1aalloimmunization have indeed developed autoimmune diseases or symptoms that may suggest an autoimmune disease since initial contact in 2013. Specifically, of the 49 patients that were contacted in 2015 and completed the autoimmune disease questionnaire, 25 had confirmed diagnoses of an autoimmune disease. Given the role of the HLA-DR3*0101 haplotype in HLA-1aalloimmunization and that of HLA-A1-B8-DR3 in the development of autoimmune disease, this data suggests that women who do not encode for HPA-1a (i.e., those that express HPA-1b1b) and develop HPA-1aalloimmunization may be susceptible to the development of autoimmune disease(s) later in life. These findings will be compared with women who do not encode for HPA-1a (i.e., those that express HPA-1b1b) but do not make anti-HPA-1a antibodies.Future studies can be aimed at investigating not only the frequency with which autoimmune diseases occur followingalloimmunization but also if they can be prevented. Disclosures Bussel: Protalex: Membership on an entity's Board of Directors or advisory committees, Research Funding; Immunomedics: Research Funding; Symphogen: Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim: Research Funding; BiologicTx: Research Funding; Rigel Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; UpToDate: Patents & Royalties; Prophylix Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding; Physicians Education Resource: Speakers Bureau; Eisai: Membership on an entity's Board of Directors or advisory committees, Research Funding; Momenta Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Genzyme: Research Funding; Ligand: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cangene: Research Funding; Shionogi: Membership on an entity's Board of Directors or advisory committees; Sysmex: Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Favorable Long-Term Outcomes after Daratumumab Discontinuation in AL Amyloidosis Patients Achieving Deep Responses

Blood ◽

10.1182/blood-2019-124981 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1884-1884 ◽

Cited By ~ 1

Author(s):

Alfred Chung ◽

Gregory P. Kaufman ◽

Surbhi Sidana ◽

David Iberri ◽

Erik Eckhert ◽

...

Keyword(s):

Disease Progression ◽

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Control Group ◽

Al Amyloidosis ◽

Cell Transplant ◽

Advisory Committees ◽

Free Interval ◽

Significant Difference

Daratumumab (DARA) is a CD38-targeted antibody FDA-approved for the treatment of multiple myeloma (MM) and its efficacy has recently been demonstrated in the treatment of AL amyloidosis. DARA is conventionally given indefinitely until evidence of disease progression or intolerance for the treatment of MM. In AL amyloidosis, the optimal duration of therapy is not known, and patients may be treated indefinitely on maintenance, extrapolating from MM data. However, the plasma cell burden observed in AL amyloidosis is often lower than in MM, and thus certain patients achieving deep responses may have durable responses with time-limited treatment. Outcomes for patients who are observed after DARA discontinuation are not known. We report the outcomes of patients at our institution who received time-limited DARA. A retrospective analysis of AL amyloidosis patients treated at Stanford University from 2016 to 2019 with DARA monotherapy and dexamethasone for at least 2 months was performed, and patients who subsequently had DARA discontinued for reasons other than disease progression or lack of response were selected for the study. Hematologic responses were assessed by consensus guidelines. Duration on and off therapy were explored, along with time-to-next treatment or death (TTNT), defined as the time from DARA initiation to restarting/switching therapy or death. An exploratory analysis comparing TTNT between the study population and a control cohort who achieved hematologic CR and were maintained on DARA was conducted with the Kaplan-Meier method and log-rank testing. 67 patients received at least 2 months of DARA monotherapy and dexamethasone; among these, 15 patients discontinued therapy for reasons other than disease progression and were included. Median age was 66 years old and median lines of prior therapies was 4 (range: 1 - 6). Baseline difference between involved and uninvolved free light chains (dFLC) prior to DARA initiation was 2.6 mg/dL (range: 0 - 16.8 mg/dL). 10 of 15 patients had cardiac involvement with median NT-proBNP of 1982 pg/mL and 9 of 15 patients had renal involvement with median 24-hour proteinuria of 6.2 g and eGFR of 32 mL/min/1.73m2 at DARA initiation. Median duration from starting to stopping DARA was 7.8 months (range: 2 - 21 months). Median duration from achieving best hematologic response to stopping DARA was 3 months (range: 0 - 17 months). Reasons for discontinuation included: patient preference (5), fatigue/body aches (4), infection (2), other active medical comorbidities (3), and lack of perceived further benefit (1). At DARA discontinuation, median dFLC was 0.1 mg/dL (range: 0 - 2.2 mg/dL) and there were 12 hematologic CR, 1 VGPR, 1 PR, and 1 not assessable for response. Outcomes for all 15 patients are shown in Figure 1. The median treatment-free interval was 17.5 months (range: 5 - 34 months); estimated 2-year TTNT-free survival was 83% (95% CI: 61 - 100%). All 14 evaluable patients eventually achieved CR. 3 patients restarted DARA for rising dFLC, and all 3 patients demonstrated response to retreatment (2 achieving CR and 1 near PR with ongoing follow-up). There were 2 deaths. One patient with severe baseline cardiac amyloidosis developed sudden rise in dFLC after treatment-free interval of 21 months; although he rapidly achieved hematologic CR on retreatment, he died of heart failure within 2 months of restarting DARA. The other patient developed therapy-related AML while off therapy and underwent allogenic stem cell transplant but died of leukemia (censored for AL amyloidosis outcomes at transplant). There was no significant difference in the TTNT between the study group and a control group of 16 patients who achieved CR and were on continuous maintenance (Figure 2; p=0.807). AL amyloidosis patients achieving deep responses with DARA can have favorable outcomes after treatment discontinuation, including a long treatment-free interval. Although our sample size is small, the outcomes of these patients appeared comparable to those achieving CR on continuous DARA maintenance, and patients were able to regain responses when retreatment was necessary. These results suggest that DARA may be safely discontinued in patents achieving deep hematologic responses, which has significant implications for quality of life and financial burden of treatment. Future studies evaluating time-limited versus continuous DARA maintenance after achievement of deep responses are warranted. Disclosures Kaufman: Janssen: Other: travel/lodging, Research Funding. Liedtke:Janssen: 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; 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; 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; 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; Agios: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Daratumumab for treatment of AL amyloidosis

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

Blood ◽

10.1182/blood-2019-122152 ◽

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

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Melphalan and Dexamethasone Plus Bortezomib Induces Hematologic and Organ Responses in AL-Amyloidosis with Tolerable Neurotoxicity.

Blood ◽

10.1182/blood.v114.22.746.746 ◽

2009 ◽

Vol 114 (22) ◽

pp. 746-746 ◽

Cited By ~ 2

Author(s):

Jeffrey A Zonder ◽

Vaishali Sanchorawala ◽

Rachel M. Snyder ◽

Jeffrey Matous ◽

Howard Terebelo ◽

...

Keyword(s):

Peripheral Neuropathy ◽

Board Of Directors ◽

Research Funding ◽

Dose Adjustment ◽

Response Rate ◽

Al Amyloidosis ◽

Two Stage ◽

Advisory Committees ◽

Subsequent Dose ◽

Stage 1

Abstract Abstract 746 Introduction: Primary systemic amyloidosis (AL) is a monoclonal plasma cell disorder associated with progressive organ dysfunction and short survival. Standard therapy for patients (pts) not eligible for autologous stem cell transplant (ASCT) is melphalan (Mel; M) + dexamethasone (Dex; D). With non-ASCT therapy, the median overall survival (OS) of high-risk AL pts remains < 1 yr. After the VISTA study showed the addition of bortezomib (Bz) to Mel + Prednisone improved response rate, complete response rate, response duration, and OS in pts with myeloma, we designed this study to determine if adding Bz to MD improves outcomes in AL. Key eligibility criteria: ECOG PS ≤ 3, Cr ≤ 5 mg/dL, T.Bili ≤ 2.5 x IULN, ALT/AST ≤ 3 x IULN, ANC ≥ 1.0 K/mm3, PLT ≥ 80 K/mm3, peripheral neuropathy (PN) ≤ Gr 2 (≤ 1 if painful), no lower limit for LVEF. Study design: Two-stage Phase II study. Stage I: 16 pts with biopsy-proven AL or light chain deposition disease (LCDD). 1° endpoint: complete hematologic responses (cHR). If ≥5 cHRs observed, then 2nd stage with 17 more pts to be opened. The study has a 90% power to detect a true cHR rate of 50%. 2° endpoints include overall HR (cHR + Partial Responses (PR)), organ response (OrR), and OS. Treatment: M (9 mg/m2 PO days 1-4; 6 mg/m2 if Cr > 2.5 mg/dL), Bz (1.3 mg/m2 IV days 1, 8, 15, 22; 1.0 mg/m2 if pt has PN at baseline) and D (40 mg PO/IV days of & days after Bz; 20 mg if ≥ 70 yrs, peripheral edema, or CHF) in 4-6 wk cycles, max of 20 cycles. PN was assessed serially with the FACT/GOG-Ntx survey. Results: To date, 23 pts have been enrolled: 21 with AL; 2 with LCDD. Med age 64 (range: 47-76). Med # prior Rx: 1 (range: 0-2; 7 with ≥1 prior ASCT). Med # organs involved: 4 (range 1-6; 8 pts with ≥ 3). PS 0-1/2-3: 18/1. Response data for the 16 pts comprising stage 1 of this two-stage study are reported here; accrual of all 33 pts is expected to be complete by ASH, and results will be updated. One pt who was not response-evaluable (RE) for HR is included in toxicity data (n=17). Med # cycles MD-Bz: 4+ (range: 2-12+; 9 pts still on treatment). 15 of 16 pts had heme responses: 6 cHRs & 9 PRs. Ten RE pts had OrR (2 cardiac, 3 renal, 6 nerve, 1 lung; total >10 because some pts improved in > 1 organ). Nerve symptom improvement occurred exclusively in pts with cHR. Two pts had progressive disease (PD). Two pts died (4.5 and 9 mos from enrollment, from pneumonia and PD, respectively). Despite baseline dose adjustment for co-morbidities, 12 pts needed subsequent dose-reduction of ≥ 1 of the study meds during therapy (10 Bz, for thrombocytopenia and/or PN in almost all cases). Five pts developed neutropenia (Gr 3-4: 1), 15 pts developed thrombocytopenia (Gr 3-4: 11). Nine pts developed peripheral neuropathy (Gr 3: 2). Other grade 3-4 non-hematologic AEs seen in ≥ 2 pts included edema (5), syncope (3), SVT (2), dehydration (2), fatigue (2), and renal failure (2). One pt developed reversible cardiomyopathy (cycle 8) attributed to Bz. Calculated sensory/dysfunction (S/D) composite scores based on patient responses from the FACT/GOG-Ntx survey improved in 7 of 14 pts between cycles 1 and 4, were stable in 4 pts and worsened in only 3. On average, the S/D score accounted for 43% of each pt's total Ntx score at baseline, whereas it only accounted for 39% of the score after 4 cycles, and 45% after 8 cycles, indicating progressive disability from Bz-related PN was uncommon. As results of nerve conduction studies did not correlate well with reported symptoms or FACT/GOG-Ntx scores in stage 1 of the study, mandatory EMGs were discontinued in stage 2. Conclusions: MD-Bz shows promising activity in the treatment of AL, with 94% of pts in the first stage of this trial achieving HR (38% cHR) and evidence of OrR observed in 63%. Toxicity is manageable, but meds often require baseline or subsequent dose adjustment. A randomized study of MD +/- Bz in AL is planned. Disclosures: Zonder: Cephalon: Consultancy; Pfizer: Consultancy; Amgen: Consultancy; Millennium: Consultancy, Research Funding, Speaking CME Only, No PromotionalTalks; Celgene: Speaking CME only; no Promotional Talks. Off Label Use: Bortezomib is being used in the treatment of AL amyloidosis in this trial; it is currently approved for use as treatment of multiple myeloma.. Matous:Celgene: Honoraria, Speakers Bureau; Cephalon: Speakers Bureau. Janakiraman:Millennium: Honoraria, Research Funding. Mapara:Resolyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Cephalon: Membership on an entity's Board of Directors or advisory committees, My Wife: Suzanne Lentzsch, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, My wife: Suzanne Lentzsch, Research Funding; Sentium: Stocks. Gasparetto:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

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LONG-TERM RESULTS of the GIMEMA VTD Consolidation TRIAL In Autografted MULTIPLE Myeloma PATIENTS (VEL-03-096): IMPACT of Minimal RESIDUAL DISEASE Detection by REAL Time Quantitative PCR On LATE Recurrences and Overall SURVIVAL

Blood ◽

10.1182/blood.v118.21.827.827 ◽

2011 ◽

Vol 118 (21) ◽

pp. 827-827 ◽

Cited By ~ 5

Author(s):

Marco Ladetto ◽

Simone Ferrero ◽

Daniela Drandi ◽

Federica Cavallo ◽

Luigia Monitillo ◽

...

Keyword(s):

Clin Oncol ◽

Board Of Directors ◽

Research Funding ◽

Residual Disease ◽

Tumor Burden ◽

Long Term Results ◽

Clinical Relapse ◽

Advisory Committees ◽

Tumor Load

Abstract Abstract 827 Background and aims: We have recently shown that a consolidation therapy with bortezomib/thalidomide/dexamethasone (VTD) in multiple myeloma (MM) patients responding to autologous transplantation (ASCT) induces major tumor shrinking assessed by real time-quantitative (RQ)-PCR. Moreover we found that low levels of minimal residual disease (MRD) associated to a better progression-free survival (PFS) [GIMEMA VEL-03-096 trial, EudraCT Number 2004-000531-28: Ladetto et al, J Clin Oncol 2010]. We here present the updated results of this study at a median follow-up of 65 months. In the present analysis the following additional issues have been addressed: a) impact of MRD on PFS over time, with special interest to the role of MRD kinetics on outcome; b) impact of MRD on overall survival (OS). Patients and methods: Inclusion criteria and treatment schedule for this study have been already reported [Ladetto et al., J Clin Oncol 2010] and included: 1) a documented complete or very good partial remission following ASCT delivered as first line treatment; 2) no previous therapy with thalidomide or bortezomib; 3) presence of a molecular marker based on the immunoglobulin heavy chain rearrangement (IGH). MRD was assessed on bone marrow samples at diagnosis, study entry, after two VTD courses, at the end of treatment and then at six months intervals, up to clinical relapse. Patients underwent MRD detection using either qualitative nested PCR and RQ-PCR, employing IGH-derived patient specific primers as already described [Voena et al., Leukemia 1997; Ladetto et al., Biol Bone Marrow Transpl 2000]. For outcome analysis patients were grouped according to following definitions: a) MRD negativity on two consecutive samples by the most sensitive PCR method (nested PCR): full molecular remission (FMR); b) MRD negativity on two consecutive samples by RQ-PCR (less sensitive but currently better standardized, according to European Study Group on MRD detection guidelines [van der Vendel et al., Leukemia 2007]): standard molecular remission (SMR); c) post-treatment tumor load above the median by RQ-PCR: high tumor burden (HTB); d) post-treatment tumor load below the median by RQ-PCR: low tumor burden (LTB); e) recurrence of detectable MRD after FMR/SMR: molecular relapse (M-rel); f) increase of MRD levels of at least one log: active disease (AD). Results: Feasibility, toxicity and clinical outcome of the trial have been already reported [Ladetto et al., J Clin Oncol 2010]. Thirty-nine patients were enrolled and median clinical follow-up from start of first line treatment is 65 months. 270 of the planned samples for MRD monitoring (86%) were actually received by the centralized lab. So far 17 relapses and six deaths have been reported. Following VTD consolidation, 7/38 evaluable patients achieved FMR (18%) and 15/38 achieved SMR (39%). Three M-rel were observed, two of them followed by clinical relapse within six months. Achievement of SMR proved highly predictive for PFS (5-years (y) PFS 82% vs 44%, p=0.009, figure 1A), as well as the presence of HTB and AD (5-y PFS 35% vs 87%, p<0.001, figure 2). Interestingly, patients with LTB and no evidence of M-rel or AD had an excellent outcome with a 5-y PFS of 87%, (even considering that molecular follow-up was incomplete due to lack of samples in the two events observed in the low risk group, figure 2). Most notably, none of the patients achieving FMR or SMR has so far died and both SMR and AD proved to be significant predictors for OS (respectively, 5y-OS 100% vs 74%, p=0.012, figure 1B, and 5y-OS 86% vs 100%, p=0.037, data not shown). Conclusions: Our long-term results indicate that: 1) the achievement of SMR following VTD consolidation in MM patients is associated with a better outcome in terms of PFS and OS; 2) a dynamic increase in molecular tumor burden (AD), detectable by RQ-PCR, predicts late disease relapses several months before clinical recurrence. Taken together these results suggest the importance of developing tailored treatment for patients with high residual burden or showing increasing levels of MRD during follow-up, as already pursued for example in mantle cell lymphoma [Andersen et al., J Clin Oncol 2009]. Disclosures: Ladetto: Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Bayer: Honoraria; Mundipharma: Honoraria; Janssen-Cilag: Research Funding; Italfarmaco: Research Funding. Cavallo:celgene: Honoraria. Guglielmelli:celgene: Honoraria; Janssen-Cilag: Honoraria. Boccadoro:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Palumbo:Merck: Honoraria; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria.

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The Majority of Patients with Relapsing Light Chain (AL) Amyloidosis Are Not Eligible for Enrollment Onto Clinical Trials: Using Screen Failures to Define Major Unmet Medical Needs

Blood ◽

10.1182/blood.v126.23.1786.1786 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1786-1786 ◽

Cited By ~ 1

Author(s):

Heather Landau ◽

Raymond L. Comenzo ◽

Tasneem Balasinorwala ◽

Melissa Warner ◽

Ola Landgren ◽

...

Keyword(s):

Clinical Trials ◽

Phase I ◽

Board Of Directors ◽

Research Funding ◽

Organ Damage ◽

M Protein ◽

Al Amyloidosis ◽

Advisory Committees ◽

Medical Needs ◽

Measurable Disease

Abstract Background: Hematologic response criteria in AL amyloidosis are based on reduction of FLCs and correlate with organ improvement and survival in the front-line setting (Palladini 2012). Hematologic progression is defined from complete response (CR) as any detectable monoclonal (m) protein or abnormal FLC ratio (light chain must double); and from partial response (PR) as a 50% increase in serum or urine m-protein to > 0.5g/dl or 200mg/d respectively; or a 50% increase in FLC to > 10mg/dL based on consensus criteria (Gertz 2005); while cardiac and renal progression criteria have recently been validated (Palladini 2012 & 2014). Trials enrolling relapsed pts define measurable disease by a difference in FLC (dFLC) >5mg/dl such that accurate responses (VGPR, PR) can be assessed. However, many pts with hematologic and/or organ progression fail to meet dFLC > 5mg/dL set by inclusion criteria (if progression from CR) or the high bar of FLC > 10mg/dL set by the progression criteria and are ineligible for clinical trials. Composite criteria for progression of disease involving both hematologic measures and biomarkers of organ damage do not exist. The goal of the current study was to characterize pts with AL and evidence of progressive disease who were ineligible for clinical trials in order to determine the magnitude of this problem and define potential AL study populations whose medical needs are not being met. Methods: Previously treated AL pts screened for clinical trials from 5/2013 to 5/2015 at Memorial Sloan Kettering Cancer Center and Tufts Medical Center were reviewed retrospectively. Trials included 1) phase I/II trial of carfilzomib (NCT01789242), 2) phase I trial of ixazomib (NCT01318902) and 3) phase III trial of ixazomib/dexamethasone versus physician's choice (NCT01659658). Inclusion for all 3 required relapsed AL with dFLC >5mg/dl and evidence of organ damage. Pts with progressive hematologic and/or organ disease (by consensus or validated criteria) who were screened for these trials were included in this analysis. Results: Among 36 pts screened, 33% (N=12) enrolled. Yet, 67% (N=24) with hematologic (N=14), cardiac (N =6) and/or renal (N=11) progression were ineligible. Median age was 61 years (range, 41-78); prior lines of therapy were 1 in 38%, 2 in 38% and >2 in 25%. Median BNP, TROP, serum ALB, eGFR and 24hr urine total protein were: 283pg/mL (36-2197), 0ng/mL (0-0.09), 3.4g/dL (1.3-4.8), 66ml/min (7-128) and 1800 mg/24hrs (trace-12,875), respectively. Median involved FLC was 6.48mg/dl (0.93-52.6) and dFLC 4.69mg/dl (0.01-52). 58% (14/24) were ineligible due to dFLC <5mg/dl, which was the most common reason for screen failure despite meeting hematologic and/or organ criteria for progression. Others were excluded for multiple myeloma (N=2), cardiac stage III (N=4), prior malignancy (N=1), number of prior therapies (N=1) and low creatinine clearance (N=2). 92% (22/24) have received therapy: 19 off study, 2 on alternate trials and 1 eventually qualified with dFLC >5mg/dl; 2 are being monitored for FLC progression with unclear clinical implications. One-third of patients ineligible for these trials have died. Conclusions: The finding that only 1/3 of pts with AL amyloidosis and hematologic or organ progression requiring therapy are eligible for clinical trials demonstrates the limitations of the current definitions of progression and "measurable disease" criteria for enrolling relapsed pts on trials. The necessary decision to treat pts with organ progression in advance of their meeting a criterion for FLC progression (to >10mg/dl) indicates that this arbitrarily defined value needs to be revised. Moreover, time to next therapy rather than progression free survival (as currently defined) is a more relevant clinical trial end point. More sensitive, validated hematologic progression and composite criteria defining progression of hematologic and organ disease are critically needed to identify patients whose level of hematologic disease progression and risk of organ damage is at variance with current criteria as defined by FLCs. This will enable novel therapies that have the potential to reduce the risks of end-stage organ failure and death to be tested in this population. Disclosures Landau: Spectrum Pharmaceuticals: Honoraria; Prothena: Consultancy, Honoraria; Onyx: Honoraria, Research Funding; Janssen: Consultancy; Janssen: Consultancy; Takeda: Research Funding. Comenzo:Prothena: Research Funding; Janssen: Research Funding; Karyopharm: Research Funding; Takeda Millennium: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees. Landgren:BMJ Publishing: Honoraria; Bristol-Myers Squibb: Honoraria; Celgene: Honoraria; Medscape: Honoraria; Onyx: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Research Funding; BMJ Publishing: Consultancy; Medscape: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy. Giralt:CELGENE: Consultancy, Honoraria, Research Funding; TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding.

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Predictors of Early Relapse Following Initial Therapy for Systemic Immunoglobulin Light Chain Amyloidosis

Blood ◽

10.1182/blood.v128.22.2082.2082 ◽

2016 ◽

Vol 128 (22) ◽

pp. 2082-2082

Author(s):

Nidhi Tandon ◽

Surbhi Sidana ◽

Morie A. Gertz ◽

Angela Dispenzieri ◽

Martha Q. Lacy ◽

...

Keyword(s):

Board Of Directors ◽

Light Chain ◽

Research Funding ◽

Initial Therapy ◽

Al Amyloidosis ◽

Line Treatment ◽

First Line ◽

Advisory Committees ◽

Early Relapse ◽

First Line Treatment

Abstract Introduction Immunoglobulin light chain amyloidosis (AL Amyloidosis) is a monoclonal plasma cell proliferative disorder that is characterized by tissue deposits of misfolded insoluble κ or λ light chain derived amyloid fibrils, leading to organ dysfunction. The prognosis of patients depends on the number and severity of organ involvement, especially cardiac involvement. Autologous stem cell transplant (ASCT), if eligible, alkylator (melphalan) and novel drugs like proteasome inhibitors (PI) and immunomodulators (IMiD) have improved the overall survival (OS) during the past decades. But still, nearly half of the patients die within a year of diagnosis. We analyzed the factors predicting early relapse / progression or death (within 12 months) after first line therapy for systemic AL amyloidosis. Methods Clinical and laboratory data of all consecutive patients with systemic AL amyloidosis seen at Mayo Clinic within 90 days of their diagnosis, between 2006 and 2015, was collected by chart review and analyzed retrospectively. Patients who died within 3 months of starting the first line treatment were excluded from analysis. Early relapse (ER) was defined as relapse / progression requiring treatment change / re-institution or death within 12 months of starting first line treatment. Patients in the cohort with ER were compared with patients with a follow up of more than 12 months who had a relapse / progression beyond 12 months or had continuing response at the time of analysis. Categorical variables were analyzed using chi - square and Fisher's exact test and continuous variables using Kruskal- Wallis test and Wilcoxon rank sum test. Multivariate analysis was done using logistic regression model. Results Seven hundred and eighty six patients with newly diagnosed systemic AL amyloidosis met the study criteria and were included in the analysis. Among these, 230 (29.3%) patients had ER within 12 months of starting initial therapy while 556 (70.7%) patients either relapsed after 1 year or had continuing response at the time of analysis. Baseline demographics, organ involvement and type of first line therapy are presented in Table1. The median estimated follow up for the entire cohort from start of initial therapy was 62.9 months (95% CI; 59.9, 67.3). The variables included in the univariate and multivariate analyses for factors predicting ER were age at diagnosis (≤ vs > 70 years ), revised mayo stage (I and II vs III and IV), bone marrow plasma cell percentage (BMPC; ≤ 10% vs > 10%), presence of any chromosomal abnormalities, trisomies or IgH translocations by fluorescence in situ hybridization (FISH), multiorgan involvement [(>1 vs 1) (heart, liver, kidney, gastrointestinal tract, autonomic neuropathy), incorporation of ASCT in initial therapy. In univariate analysis, mayo stage (p<0.0001), multiorgan involvement (p=0.0008) and inclusion of ASCT as part of initial therapy (p<0.0001) were significantly associated with ER, while age (p=0.06), BMPC(p=0.9), FISH abnormalities (p=0.2) were not. However, in multivariate analysis, only mayo stage (III + IV vs I + II; p=0.01) and non-inclusion of ASCT in first line treatment (p=0.0001) were significantly predictive of ER. Conclusions Despite the introduction of ASCT and novel drugs, the early mortality in systemic AL amyloidosis remains high. This study demonstrates that patients with ER are older with higher prevalence of cardiac involvement and multiorgan involvement and higher Mayo stage (III and IV). Incorporation of ASCT as part of the initial therapy was associated with reduced early relapse, but it is difficult to separate the influence of the eligibility for ASCT from the effect of ASCT itself. This will help us in characterizing these patients to better understand their mechanisms of resistance to therapy and gives an insight to the type of initial therapy that benefits them. Disclosures Dispenzieri: GSK: Membership on an entity's Board of Directors or advisory committees; Jannsen: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Alnylam: Research Funding; pfizer: Research Funding. Kapoor:Takeda: Research Funding; Amgen: Research Funding; Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Kesios: Consultancy; BMS: Consultancy; Sanofi: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; Glycomimetics: Consultancy; Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Onyx: Consultancy, Research Funding; AbbVie: Research Funding; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding.

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Practice Patterns of Re-Initiation of Therapy at Time of Relapse or Progression Post- Autologous Stem Cell Transplant (ASCT) Among Patients with AL Amyloidosis

Blood ◽

10.1182/blood.v128.22.3444.3444 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3444-3444 ◽

Cited By ~ 1

Author(s):

Yi L. Hwa ◽

Rahma Warsame ◽

Morie A. Gertz ◽

Francis K Buadi ◽

Martha Q. Lacy ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Practice Patterns ◽

Autologous Stem Cell Transplant ◽

Al Amyloidosis ◽

Cell Transplant ◽

Second Line ◽

Second Line Therapy ◽

Advisory Committees ◽

Line Therapy

Abstract Background: Among patients with immunoglobulin light chain (AL) amyloidosis, there is little consensus on when reinstitution of chemotherapy should occur (Milani and Dispenzieri, International Society of Amyloidosis 2016). AL amyloidosis patients who are treated with high dose chemotherapy followed by autologous stem cell transplant (ASCT) are a relatively low-risk and homogenous population, making them an ideal group to study practice patterns. Methods: We conducted a retrospective study to evaluate the patterns of relapse or progression and the timing of re-initiation of therapy among 146 patients who were initially treated with ASCT at Mayo Clinic between 1996 and 2009 and who received second-line therapy between 7/9/1997 and 4/12/2012. Results: The median time from ASCT to second-line therapy was 23.6 months and the median follow up post ASCT was 57.5 months. The indications for second-line treatment were: 1) both hematologic and organ progression 24.7% (36 patients); 2) organ progression only 41.1% (60); 3) hematologic relapse only 34.2% (50). The median dFLC at the time of starting second-line therapy was 10.5 mg/dL (1.6 - 59.5 mg/dL), which was 44.9% (13.8-167.2%) of dFLC level at diagnosis. Increase in proteinuria by > 50% from nadir (that was also at least 1g/24 hours, i.e. renal progression) was present in 35.8%. Increase in NT proBNP by >30% from nadir and minimum of 300 pg/mL was present in 48.9% of patients. The respective 4 years overall survival rates from the time of ASCT were 87.8%, 63.9%, and 56.7% (p=0.0016) for patients who had hematologic relapse, organ progression only and both organ and hematologic progression. Comparisons of laboratory markers at diagnosis, nadir of post ASCT and initiation of second-line therapy are listed in the table. Conclusions: Our study investigated the patterns of relapse / progression following upfront ASCT. This provides some insights on practice patterns of when physicians re-initiate therapy. Table Table. Disclosures Gertz: NCI Frederick: Honoraria; Celgene: Honoraria; Med Learning Group: Honoraria, Speakers Bureau; Research to Practice: Honoraria, Speakers Bureau; Novartis: Research Funding; Prothena Therapeutics: Research Funding; GSK: Honoraria; Sandoz Inc: Honoraria; Ionis: Research Funding; Alnylam Pharmaceuticals: Research Funding; Annexon Biosciences: Research Funding. Kumar:Millennium: Consultancy, Research Funding; Array BioPharma: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Noxxon Pharma: Consultancy, Research Funding; AbbVie: Research Funding; Glycomimetics: Consultancy; Janssen: Consultancy, Research Funding; BMS: Consultancy; Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Consultancy, Research Funding; Kesios: Consultancy. Kapoor:Celgene: Research Funding; Amgen: Research Funding; Takeda: Research Funding. Dispenzieri:Prothena: Membership on an entity's Board of Directors or advisory committees; Alnylam: Research Funding; Celgene: Research Funding; Jannsen: Research Funding; pfizer: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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