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 ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1786-1786 ◽  
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.

scholarly journals Multiple Myeloma Oligosecretory Relapse, a Non-Negligible Phenomenon. Frequency, Clinical Characteristics and Outcomes in a Single Center

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3772-3772
Author(s):  
Itai Zamir ◽  
Tamir Shragai ◽  
Svetlana Trestman ◽  
Tomer Ziv Baran ◽  
Efrat Luttwak ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Clinical Characteristics ◽  
M Protein ◽  
Advisory Committees ◽  
Monoclonal Protein ◽  
Disease Characteristics ◽  
Comparator Group ◽  
Measurable Disease

Abstract Introduction: Multiple myeloma (MM) is malignancy of plasma cells, which secrete monoclonal antibodies that are detectable in the patient's (pt) serum and/or urine. Infrequently, MM may present as an oligosecretory disease, where monoclonal protein (M-protein) and involved free light chain (iFLC) are either not detected (=non-secretory) or are both below the threshold for measurable disease (=oligosecretory) as defined by International Myeloma Working Group (IMWG). The incidence of non-secretory MM at presentation has been estimated at 1-2% [Chawla, Eur J Haematol 2015], yet data regarding the frequency and clinical phenotype of oligosecretory relapse is lacking. These pts are typically excluded from most clinical trials. Methods: Pt's MM was classified as oligo-secretory, in the absence of measurable disease according to the IMWG criteria (M-protein≥1 gr/dL, or U-PEP &gt; 200 mg/24 hrs or involved free light chain≥ 100 mg/L). Relapse was defined according to IMWG criteria, based on changes in monoclonal protein in the serum or urine, bone or extramedullary lesions on imaging, bone-marrow plasmacytosis, serum hemoglobin, creatinine and calcium levels. Pts treated at our center for MM, who had secretory (i.e., measurable disease) MM at diagnosis, and relapsed (secretory or non-secretory relapse) between January 2016 to July 2020, were included. MM baseline pt and disease characteristics, disease characteristics at relapse, treatment regimens and outcomes were documented. The first oligosecretory relapse (OSR) that any given pt experienced was defined as the index OSR for that pt. For each pt with an OSR, we identified the first 4 pts with a secretory relapse (SR) in the dataset, who matched the pt by the relapse index number and calendar year of relapse, to form a SR comparator group. We compared pt and disease characteristics, therapy patterns and outcomes between the OSR and SR groups. Results: One hundred and seventy-seven pts with relapse were identified; 8 (4.5%) had oligo-secretory disease at MM diagnosis and were excluded; 152 of the 169 pts who were secretory at presentation (89.9%) had secretory MM at all relapses; 17 (10.0%) had an OSR (4 non-secretory and 13 oligosecretory), the SR comparator group included 67 pts. Pts with OSR had similar characteristics compared to SR pts at MM presentation, in terms of demographics, FISH cytogenetics, ISS, levels of M-protein and involved FLC, frequency of extramedullary disease, target organ involvement; Treatment pattern and response to upfront therapy were comparable (Fig1 A). Oligosecretory disease was more frequent at relapse compared to newly diagnosed MM (10% vs 4.5%), proportion of OSR among pts with previously secretory MM increased in later relapses. The proportion of OSR from total 3 rd or 4 th relapses, was high as 20% and 17.6%, respectively (Fig 1B). OSR pts had a higher rate of new plasmacytoma (53% vs 9%, p&lt;0.001) as the criteria for relapse, and a trended towards increase in LDH, and higher rate of extramedullary disease (17% vs 4.4%, p=0.09) whereas increase in monoclonal protein was more frequent in the SR group as a criterion for relapse. Overall response rate to therapy of the index relapse was similar between groups among evaluable pts (58% vs 64%), however, in 5/17 (29%) of the OSR, response was non evaluable from available documentation. Median follow up was 10.2 months [Q1 4.1- Q3 16.7]. Twelve-months progression free survival was 82.4% vs 73.8% (p=0.76), and 12-months overall survival was 60.2% vs 64.75% (p=0.60) in RS and OSR, respectively. Conclusions: Oligosecretory disease was more frequent in relapsed MM, compared to its rate at MM presentation, reaching 10% of the pts with relapsed MM and increasing in more advanced relapses. Pts with OSR and those with SR had similar clinical characteristics of their MM at presentation as well as comparable outcomes, but pts with OSR had higher rates of new skeletal and extramedullary lesions. As identification of the OSR may be challenging in the absence of serum and urine biomarkers, awareness and clinical alertness are warranted to avoid end organ damage. We suggest inclusion of OSR pts in clinical trials should be considered, despite some challenges in following their therapy response, as they comprise a non-negligible proportion of pts, in particular in the advanced relapse setting. Figure 1 Figure 1. Disclosures Avivi: Kite, a Gilead Company: Speakers Bureau; Novartis: Speakers Bureau. Cohen: Neopharm / promedico: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karophram: 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; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: 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.

scholarly journals Organ Damage at Initial Presentation across the Spectrum of Advanced Systemic Mastocytosis Variants

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2567-2567
Author(s):  
Emily C. Liang ◽  
Cecelia Perkins ◽  
Rong Lu ◽  
Justin Abuel ◽  
Cheryl Langford ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Mast Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Systemic Mastocytosis ◽  
Organ Damage ◽  
Initial Presentation ◽  
Pleural Effusions ◽  
Advisory Committees ◽  
Significant Difference

Abstract BACKGROUND: Systemic mastocytosis (SM) is characterized by the accumulation of neoplastic mast cells in various organs, including the bone marrow, liver, spleen, and gastrointestinal tract. Advanced SM (AdvSM) comprises 3 subtypes: aggressive SM (ASM), SM with an associated hematologic neoplasm (SM-AHN), and mast cell leukemia (MCL). Individuals with AdvSM often exhibit hematologic and/or non-hematologic organ damage (C-findings), which contributes to the poor prognosis of these patients (pts). To date, the presenting patterns of organ damage across the spectrum of AdvSM subtypes have not been well characterized. In addition, the definition of hematologic and non-hematologic organ damage has evolved from the initial characterization of C-findings used by the World Health Organization (WHO) to define ASM, to more clinically relevant and quantifiable organ damage criteria that are used to assess eligibility for clinical trials in AdvSM. These include the International Working Group-Myeloproliferative Neoplasms Research and Treatment and European Competence Network on Mastocytosis (IWG) criteria and a modified version of these criteria (mIWG), which differ slightly regarding splenomegaly (IWG: symptomatic splenomegaly &gt;5 cm; mIWG: spleen &gt;5 cm). In this retrospective analysis, we describe the distribution and frequency of organ damage at the time of initial presentation among the 3 subtypes of AdvSM as defined by WHO, IWG, and mIWG criteria. METHODS: Among 251 pts with mast cell disorders in our Stanford IRB-approved MPN registry, we identified 87 AdvSM pts between October 1999 and September 2020. Thirteen pts (15%) had ASM, 63 (72%) had SM-AHN, and 11 (13%) had MCL. Comparisons between continuous and categorial variables were performed using the Kruskal-Wallis test and the Fisher's exact test, respectively. We defined IWG/mIWG liver-associated organ damage as a composite of ascites/pleural effusions requiring diuretics or drainage, liver function abnormalities, and/or hypoalbuminemia. RESULTS: Median age at diagnosis was 64 years (range 24-88) and 55 pts (63%) were male. The median number of prior treatments was 1 (range, 0-4). Forty-six pts (53%) were enrolled on clinical trials, and they had a median of 2 organ damage findings by WHO or IWG/mIWG criteria. ASM, MCL, and SM-AHN pts had significantly different WBC, ANC, and monocyte counts; pts with SM-AHN had the highest median white blood cell count (11.4 x 10 9/L), absolute neutrophil count (5.69 x 10 9/L), and monocytosis (1.58 x 10 9/L). Pts with SM-AHN exhibited a trend towards a higher absolute eosinophil count compared to ASM pts (p = 0.06). There was a significant difference in IWG/mIWG-defined RBC and platelet transfusion dependence in the 12 weeks prior to initial presentation. Pts with MCL had the highest transfusion requirement, with 55% and 27% of pts requiring red blood cell and platelet transfusions, respectively. There were no differences in median hemoglobin, platelet count, liver function tests, serum albumin, pleural effusions/ascites, and liver or spleen size by palpation or volumetric imaging. Across the 3 AdvSM subtypes, a significant difference was observed between the # of pts fulfilling IWG/mIWG criteria for liver-related organ damage (p = 0.044). Pts with SM-AHN (p = 0.071) and MCL (p = 0.013) fulfilled more IWG/mIWG liver criteria compared to ASM pts. While the absolute number of IWG/mIWG non-hematologic organ damage findings was not different across the 3 subtypes, a pairwise comparison revealed a statistically higher number of IWG non-hematologic organ damage findings in MCL vs. ASM. Irrespective of the criteria, there were no significant differences in organ damage between pts receiving 0, 1, or ≥2 prior therapies. CONCLUSION: We provide a preliminary snapshot of the patterns of WHO and IWG/mIWG-defined organ damage at initial presentation across a spectrum of AdvSM pts. Pts with MCL had the highest transfusion requirements, and liver-associated organ damage appears to be more frequent in SM-AHN and MCL pts compared to ASM. We next plan to study the profile of organ damage using WHO, IWG, and mIWG criteria in AdvSM patients who enrolled on the phase I (NCT02561988) and phase II (NCT03580655) studies of avapritinib. These analyses will include clinicopathologic and genetic correlates of organ damage, including # prior therapies, KIT D816V variant allele frequency, and myeloid mutation profile. Disclosures Shomali: Incyte: Consultancy, Research Funding; Blueprint Medicines: Consultancy. Gotlib: Kartos: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Honoraria, Membership on an entity's Board of Directors or advisory committees; Cogent Biosciences: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Chair for the Eligibility and Central Response Review Committee, Research Funding; Allakos: Consultancy; BMS: Research Funding; Abbvie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Deciphera: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Blueprint Medicines: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Using Current Clinical Markers to Define High Risk Smoldering Multiple Myeloma: Agree to Disagree

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1794-1794
Author(s):  
Elizabeth Hill ◽  
Neha Korde ◽  
Sham Mailankody ◽  
Candis Morrison ◽  
Alexander Dew ◽  
...  
Keyword(s):  
Risk Factors ◽  
Multiple Myeloma ◽  
Bone Marrow ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Mayo Clinic ◽  
Research Funding ◽  
M Protein ◽  
Advisory Committees ◽  
Rate Of Progression

Introduction Defining high risk (HR) smoldering multiple myeloma (SMM) is becoming increasingly important as multiple clinical trials are actively investigating the role of early treatment. On average, patients with SMM progress to multiple myeloma (MM) at a rate of 10% per year for the first 5 years (Kyle 2007). Several classification systems have been developed to identify patients with a higher rate of progression, including two commonly used models: the 2008 Mayo Clinic model and the PETHEMA (Programa de Estudio y Tratamiento de las Hemopatias Malignas) model. The 2008 Mayo Clinic model incorporates M-protein (>3 g/dL), bone marrow plasma cell percentage (BMPC%) >10%, and a ratio of involved to uninvolved serum free light chains (sFLCr) >8. Patients with all three characteristics had a 76% risk of progression to MM in 5 years (Dispenzieri 2008). The PETHEMA model uses the proportion of BMPCs with aberrant plasma cell phenotype on flow cytometry (>95%) and reduction in uninvolved immunoglobulins (immunoparesis) to identify HR patients. Patients with both risk factors had a 5-year rate of progression to MM of 72% (Perez-Persona 2007). The 2008 Mayo Clinic model was validated prior to the International Myeloma Working Group reclassification of MM in 2014. Therefore, in 2018, Mayo Clinic proposed a new model to define HR SMM referred to as "2/20/20": M-protein >2 g/dL, BMPC% >20%, and sFLCr >20 (Lakshman 2018). The median time to progression for the HR group (2-3 risk factors) was 29 months, compared to 110 months in the low risk (LR) group (0 risk factors). Previously, a high discordance rate among the 2008 Mayo model and the PETHEMA model was reported (Cherry 2013). In this study, we aim to define the concordance among patients defined as HR SMM by the aforementioned models in an independent sequential patient cohort. Methods The medical records of patients sequentially assigned a diagnosis of SMM by the myeloma program at the NIH Clinical Center between April 2010 to July 2019 were reviewed. Patients with myeloma defining events were excluded (i.e. MM). Each patient was assigned a risk score based on the 2008 Mayo Clinic model, the 2018 Mayo Clinic model, and the PETHEMA model. The distribution of patients in the LR, intermediate (IR), and HR groups were compared between the models. Concordance ratios were calculated between the three models. Results A total of 236 patient records were reviewed and per the 2014 IMWG criteria, 138 patients were identified as having SMM. Two patients did not have bone marrow flow cytometry samples and thus could not be classified by the PETHEMA model. Therefore, 136 patients were stratified by risk based on all three models (Table 1,2). The rate of concordance between the 2008 Mayo Model and the PETHEMA model was 31.6% (95% CI: 24.4-39.8%), similar to previously published results. The concordance between the 2018 Mayo Model and the PETHEMA model was slightly higher at 44.8% (95% CI: 36.7-53.2%; P=0.0337). There was significant discordance between the models in classifying patients as HR versus non-HR (Table 3). However, the 2018 Mayo Clinic model had a higher concordance with the PETHEMA model (27.2%; 95% CI: 20.4-35.3%) than the 2008 Mayo Clinic model (4.4%; 95% CI:1.8-9.5%). Conclusions The accurate identification of SMM patients at highest risk of developing MM remains elusive and no one model has been found to be superior than the other. As this study indicates, a significant number of patients may be classified as "HR" according to the PETHEMA model while simultaneously be defined as "LR" based on the Mayo Clinic models. While the 2018 Mayo Clinic model has a higher concordance rate to the PETHEMA model, it remains significantly discordant. These results indicate that the current clinical variables used to determine risk are not reliable. This is likely due to the fact that they are markers of disease burden rather than biology and risk is subject to increase over time (Landgren 2019). It is time for genomic signatures which signify varying biology to be incorporated into risk models. The treatment of HR SMM is currently being investigated in multiple clinical trials. As the results from these trials are published, the data will need to be scrutinized as to how patients were defined as "HR" in order to compare results. At this time, it remains unclear which patients warrant early intervention and it is imperative that patients with SMM be exclusively treated on clinical trials. Disclosures Mailankody: Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Landgren:Merck: Other: IDMC; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

scholarly journals Phase 2 Trial of Ixazomib, Cyclophosphamide and Dexamethasone for Treatment of Previously Untreated Light Chain Amyloidosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 52-53
Author(s):  
Eli Muchtar ◽  
Morie A Gertz ◽  
Betsy Laplant ◽  
Francis K. Buadi ◽  
Nelson Leung ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Board Of Directors ◽  
Light Chain ◽  
Research Funding ◽  
Advisory Board ◽  
Organ Involvement ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Hematologic Response ◽  
Phase 2 Trial

Background: Bortezomib, a proteasome inhibitor, has shown efficacy in the treatment of newly diagnosed and relapsed light chain (AL) amyloidosis, and the combination of bortezomib, cyclophosphamide and dexamethasone is a commonly used regimen in AL. Ixazomib is the first oral proteasome inhibitor to be approved, and the combination of ixazomib with cyclophosphamide and dexamethasone is an all oral effective regimen for the treatment of multiple myeloma. This phase 2 trial was designed to evaluate the efficacy of this regimen in patients with AL, who have not received any therapy. Patients and methods: Newly diagnosed patients with biopsy proven AL amyloidosis, with organ involvement requiring therapy, were enrolled if they had measurable disease (Serum immunoglobulin free light chain ≥5 mg/dL AND abnormal serum free light chain ratio) and adequate organ function. Patients with severe organ involvement were excluded (Alkaline phosphatase &gt;750 U/L, creatinine clearance &lt;30 mL/min or NT-ProBNP ≥ 7500 ng/dL). Treatment consisted of ixazomib 4 mg days 1, 8, 15; cyclophosphamide 500 mg PO weekly and dexamethasone 40 mg, weekly for twelve 28-day cycles, followed by ixazomib maintenance (days 1, 8, 15) at the last tolerated dose till progression. The primary objective was to determine the hematologic response rate of ixazomib, used in combination with cyclophosphamide and dexamethasone in patients with previously untreated AL. A one-stage binomial design was utilized to test the null hypothesis that the hematologic response rate is at most 30% against the alternative hypothesis that it is at least 50%, with 85% power and 9% type I error. Results: Thirty-five patients were enrolled, median age was 67 (range 38-78) years; 69% were male. Organ involvement included cardiac in 23 (65.7%), renal in 19 (54.3%), and nervous system involvement in 5 (14.3%). At data cutoff 8 patients still remain on study with a median follow up of 4.4 months for those who are alive. Across the trial a median of 4 cycles (range 0-23) of treatment have been completed; the most common reason for going off study was institution of alternate therapy in 17 patients (63%). The overall hematologic response was 57% (20/35) and included amyloid CR in 5 (14%), VGPR in 9 (26%) and a PR in 6 (17%) patients. Confirmed organ responses have been observed in 5 patients so far, 2 each for cardiac and renal and 1 hepatic. The median PFS and OS have not been reached; 4 patients had hematological progression; 6 patients (17%) have died. Across 193 cycles of treatment administered, dose modification was required in 5, 3, and 10 patients, respectively, for ixazomib, cyclophosphamide and dexamethasone. A grade 3 or higher adverse event (AE), at least possibly attributed to the study drugs, was observed in 41% of patients. The figure shows the maximum grade of adverse events for individual patients seen in more than one patient across the study. Conclusions: The all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone is active in patients with previously untreated AL amyloidosis with hematologic responses observed in 57% of patients, including complete responses. Organ response has been observed but will likely need longer follow up for accurate assessment, given the delay in organ responses in this disease. Further evaluation of this combination is warranted. Disclosures Gertz: Alnylam: Consultancy; Ionis/Akcea: Consultancy; Amgen: Consultancy; Medscape: Consultancy, Speakers Bureau; Physicians Education Resource: Consultancy; Data Safety Monitoring board from Abbvie: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Johnson and Johnson: Speakers Bureau; DAVA oncology: Speakers Bureau; Advisory Board for Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Advisory Board for Proclara: Membership on an entity's Board of Directors or advisory committees; i3Health: Consultancy; Springer Publishing: Patents & Royalties; Amyloidosis Foundation: Research Funding; International Waldenstrom Foundation: Research Funding; NCI SPORE MM: Research Funding; Prothena: Consultancy; Sanofi: Consultancy; Janssen: Consultancy; Spectrum: Consultancy, Research Funding; Annexon: Consultancy; Appellis: Consultancy. Kapoor:Celgene: Honoraria; GlaxoSmithKline: Research Funding; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy. Larsen:Janssen Oncology: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Dingli:Apellis: Consultancy; Janssen: Consultancy; Sanofi-Genzyme: Consultancy; Rigel: Consultancy; Bristol Myers Squibb: Research Funding; Karyopharm Therapeutics: Research Funding; Alexion: Consultancy; Millenium: Consultancy. Dispenzieri:Janssen: Research Funding; Intellia: Research Funding; Alnylam: Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Takeda: Research Funding. Kumar:Adaptive Biotechnologies: Consultancy; Carsgen: Other, Research Funding; AbbVie: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Janssen Oncology: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Genecentrix: Consultancy; Dr. Reddy's Laboratories: Honoraria; Tenebio: Other, Research Funding; Takeda: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; BMS: Consultancy, Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Kite Pharma: Consultancy, Research Funding; Karyopharm: Consultancy; Oncopeptides: Consultancy, Other: Independent Review Committee; IRC member; Merck: Consultancy, Research Funding; Amgen: Consultancy, Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments, Research Funding; Genentech/Roche: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Celgene/BMS: Other: Research funding for clinical trials to the institution, Consulting/Advisory Board participation with no personal payments; Cellectar: Other; MedImmune: Research Funding.

Phase I Study of BT062 Given as Repeated Single Dose Once Every 3 Weeks in Patients with Relapsed or Relapsed/Refractory Multiple Myeloma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1862-1862 ◽  
Author(s):  
Asher A. Chanan-Khan ◽  
Sundar Jagannath ◽  
Leonard T. Heffner ◽  
David Avigan ◽  
Kelvin P. Lee ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Phase I Study ◽  
M Protein ◽  
Advisory Committees ◽  
Elimination Phase ◽  
Protein Levels ◽  
Dose Levels

Abstract Abstract 1862 Poster Board I-887 Background: Biotest AG (Dreieich, Germany) is developing the immunoconjugate BT062, which comprises the anti-CD138 chimerized MAb (nBT062) and the cytotoxic agent maytansinoid (DM4). Once bound to CD138 on a target cell, the conjugate is internalized and releases DM4. At present, CD138 represents one of the most reliable target antigens for identification of multiple myeloma (MM) cells and has been reported to be a highly sensitive and specific diagnostic marker of MM. Preclinical investigations demonstrated significant in vitro and in vivo anti-MM activity of BT062, providing the rationale for the conduct of clinical trials (Ikeda et al., 2009). Objectives: To determine the maximum tolerated dose (MTD), the dose-limiting toxicities (DLTs), pharmacokinetics (PK) and anti-MM activity of increasing doses of BT062 on a repeated single dose schedule once every three weeks in relapsed or relapsed/refractory MM. Clinical response was assessed as per the international working group criteria (Durie et al., 2006). Methods: This is a prospective, open label, dose-escalation multicenter study. Patients aged ≥ 18 years with relapsed or relapsed/refractory MM who have failed previous treatments including an immunomodulating agent and a proteasome inhibitor were eligible to participate. Patients with clinical response (or no evidence of progressive disease) and without unacceptable toxicities were eligible for further treatment cycles. Patients are enrolled in cohorts of 3 at each dose level, with DLT in the first cycle triggering cohort expansion. Results: To date 20 patients have been treated with BT062 at 7 dose levels ranging from 10 mg/m2 to 200 mg/m2. Maximum administered dose has not been defined to date with continued enrollment at 200 mg/m2 dose. None of the patients treated experienced serious hypersensitivity reactions or humoral responses (HAHA) against BT062. The most frequently reported adverse events to date cover primarily events expected for the underlying disease. Nevertheless, a few adverse events have also been observed involving skin and mucosa (tissues of epithelial origin with CD138 expressing cells). No grade 4 toxicity has been reported. Preliminary PK results indicate an unusual rapid clearance from plasma in the early elimination phase, followed by a generally normal terminal elimination phase at dose levels up to 120 mg/m2, whereas a more typical clearance profile was observed for all 3 patients at the 160 mg/m2 dose. Interestingly, even in phase I study decreased urine M-Protein or serum FLC levels have been observed in 2 patients. One of these patients showed a decrease in urine M-Protein by more than 50% after administration of 8 repeated low doses. At a high dose level another patient without detectable M-Protein levels, showed a decrease of serum FLC by more than 50% after having received the second dose of BT062. Furthermore, evidence of clinical benefit has been observed in at least 6 patients with early stabilization of M-protein levels (and light-chain burden) in serum and /or urine. Conclusion: Development of a monoclonal antibody in MM remains an important therapeutic option and BT062 is an exciting possibility. Preliminary data from this phase I study, demonstrate an acceptable toxicity profile of BT062 in the clinics. Even in phase I study, evidence of clinical activity is observed. These encouraging results and the unique PK observed support investigation of a more frequent dosing regimen for optimizing anti-MM responses. Updated data on safety, PK and efficacy of BT062 from this clinical trial will be presented at the meeting. Disclosures: Jagannath: Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Avigan:Genzyme: Consultancy, Research Funding; Celgene: Research Funding. Lutz:Immunogen, Inc.: Employment. Haeder:Biotest AG: Employment. Ruehle:Biotest AG: Employment. Uherek:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Munshi:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Anderson:Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Biotest AG: Consultancy, Research Funding.

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

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1884-1884 ◽  
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

scholarly journals Northstar-2: Updated Safety and Efficacy Analysis of Lentiglobin Gene Therapy in Patients with Transfusion-Dependent β-Thalassemia and Non-β0/β0 Genotypes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3543-3543 ◽  
Author(s):  
Alexis A. Thompson ◽  
Mark C. Walters ◽  
Janet L. Kwiatkowski ◽  
Suradej Hongeng ◽  
John B. Porter ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Board Of Directors ◽  
Research Funding ◽  
Advisory Board ◽  
Adult Patients ◽  
Employment Equity ◽  
Advisory Committees ◽  
Transfusion Independence ◽  
Equity Ownership

Background Transfusion-dependent β-thalassemia (TDT) is treated with regular, lifelong red blood cell (RBC) transfusions and despite iron-chelating therapy, carries a risk of serious organ damage from iron overload and other complications. Transplantation with autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin for β-thalassemia) is being evaluated in patients with TDT. Interim results are presented here from the ongoing, international, single-arm, phase 3 Northstar-2 study (HGB-207; NCT02906202) of LentiGlobin gene therapy in pediatric, adolescent, and adult patients with TDT (defined by receiving ≥100 mL/kg/yr of RBCs or ≥8 RBC transfusions/yr) and non-β0/β0 genotypes. Methods Patients undergo hematopoietic stem cell (HSC) mobilization with G-CSF and plerixafor. Following apheresis, CD34+ cells are transduced with BB305 lentiviral vector and infused into patients after pharmacokinetic-adjusted, single-agent busulfan myeloablation. The primary efficacy endpoint is transfusion independence (TI; weighted average hemoglobin [Hb] ≥9 g/dL without RBC transfusions for ≥12 months). HSC engraftment, βA-T87Q-globin expression, Hb levels, detection of replication competent lentivirus (RCL), and adverse events (AE) are also assessed. Patients are followed for 2 years and offered participation in a long-term follow-up study. Summary statistics are presented as median (min - max). Results Twenty patients were treated in Northstar-2 as of 13 December 2018 and have been followed for a median of 8.1 (0.5 - 22.2) months. At enrollment, median age was 16 (8 - 34) years; 5 patients were &lt;12 years of age. Median drug product cell dose was 8.0 (5.0 - 19.9) x106 cells/kg and vector copy number was 3.2 (1.9 - 5.6) copies/diploid genome. Time to neutrophil and platelet engraftment in the 18/20 and 15/20 evaluable patients was 22.5 (13 - 32) and 45 (20 - 84) days, respectively. Non-hematologic grade ≥3 AEs in ≥3 patients after LentiGlobin infusion included stomatitis (n=12), febrile neutropenia (n=6), pyrexia (n=4), epistaxis (n=3), and veno-occlusive liver disease (n=3). One serious AE of grade 3 thrombocytopenia was considered possibly related to LentiGlobin. No patient died, had graft failure, or had detection of RCL. No insertional oncogenesis has been observed. Gene therapy-derived HbAT87Q stabilized approximately 6 months after infusion. In adolescent and adult patients treated with LentiGlobin, median HbAT87Q at Months 6, 12 and 18 was 9.5 (n=11), 9.2 (n=8), and 9.5 (n=3) g/dL, respectively. The median total Hb without transfusions at Months 6, 12, and 18 were 11.9 (n=11), 12.4 (n=8), 12.3 (n=2) g/dL, respectively. At Month 6, 91% (10/11) of patients had total Hb of &gt;11 g/dL without transfusions. Five adolescent and adult patients were evaluable for the primary endpoint of transfusion independence, 4 (80%) of whom achieved TI. The median weighted average Hb during TI was 12.4 (11.5 - 12.6) g/dL which compared favorably to pre-transfusion nadir Hb levels before enrollment (median 9.1 g/dL [7.5 - 10.0 g/dL]). At time of analysis, the median duration of TI was 13.6 (12.0 - 18.2) months. One patient who did not achieve TI stopped transfusions for 11.4 months but resumed transfusions due to recurrent anemia. This patient had a 71.4% reduction in RBC transfusion volume from Month 6 to Month 18 compared to baseline. Marrow cellularity and myeloid:erythroid (M:E) ratios were evaluated in 8 adolescent and adult patients with ≥12 months follow-up to assess the effect of LentiGlobin treatment on dyserythropoiesis. Seven of 8 patients had improved marrow M:E ratios at Month 12 (0.63 - 1.90) compared with baseline (0.14 - 0.48). In patients who stopped transfusions, soluble transferrin receptor levels were reduced by a median of 72% (58% - 78%) at Month 12 (n=6). Updated outcomes in adolescents and adults and outcomes in pediatric patients will be reported. Summary In this update of the Northstar-2 study of LentiGlobin gene therapy in patients with TDT and non-β0/β0 genotypes, transfusion independence was observed in 4/5 evaluable adolescent and adults and 10/11 treated patients had total Hb of &gt;11 g/dL without transfusion support 6 months after LentiGlobin infusion. HbAT87Q stabilized approximately 6 months after treatment and patients who stopped RBC transfusions had improved erythropoiesis. A safety profile consistent with busulfan conditioning was observed after LentiGlobin gene therapy. Disclosures Thompson: bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Walters:TruCode: Consultancy; AllCells, Inc: Consultancy; Editas Medicine: Consultancy. Kwiatkowski:bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Celgene: Consultancy; Agios: Consultancy; Imara: Consultancy; Apopharma: Research Funding; Novartis: Research Funding. Porter:Protagonism: Honoraria; Celgene: Consultancy, Honoraria; Bluebird bio: Consultancy, Honoraria; Agios: Consultancy, Honoraria; La Jolla: Honoraria; Vifor: Honoraria; Silence therapeutics: Honoraria. Thrasher:Rocket Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Orchard Therapeutics: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Generation Bio: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; 4BIOCapital: Membership on an entity's Board of Directors or advisory committees. Thuret:BlueBird bio: Other: investigators for clinical trials, participation on scientific/medical advisory board; Celgene: Other: investigators for clinical trials, participation on scientific/medical advisory board; Novartis: Other: investigators for clinical trials, participation on scientific/medical advisory board; Apopharma: Consultancy. Elliot:bluebird bio, Inc.: Employment, Equity Ownership. Tao:bluebird bio, Inc.: Employment, Equity Ownership. Colvin:bluebird bio, Inc.: Employment, Equity Ownership. Locatelli:Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bellicum: Consultancy, Membership on an entity's Board of Directors or advisory committees; bluebird bio: Consultancy; Miltenyi: Honoraria.

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

scholarly journals Results of a Phase I Trial of Lenalidomide, Rituximab (R2) and Ixazomib for Frontline Treatment of High Risk Follicular and Indolent Non-Hodgkin Lymphoma

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 1-2
Author(s):  
Brian T. Hill ◽  
Deepa Jagadeesh ◽  
Alex V. Mejia Garcia ◽  
Robert M. Dean ◽  
Omer N. Koc ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Board Of Directors ◽  
Research Funding ◽  
Marginal Zone ◽  
Proteasome Inhibitors ◽  
Marginal Zone Lymphoma ◽  
Aggressive Lymphoma ◽  
Advisory Committees ◽  
Frontline Treatment

INTRODUCTION: Lenalidomide and Rituximab (R2) is an effective frontline treatment regimen for patients (pts) with indolent B-cell lymphoma including follicular lymphoma (FL). Recent phase III data from the RELEVANCE trial comparing R2 to traditional chemoimmunotherapy showed that this regimen is generally well-tolerated and has favorable clinical efficacy [61% overall response, 53% CR rate, 77% 3-year progression free survival (PFS) (Morschhauser, et al)]. Proteasome inhibitors such as bortezomib disrupt NF-KB signaling and have shown clinical activity in indolent NHL. Although randomized trials have failed to demonstrate clinical benefit of adding bortezomib to standard chemoimmunotherapy regimen bendamustine + rituximab (BR) for frontline treatment of FL, the addition of proteasome inhibitors to lenalidomide is a mainstay of treatment for plasma cell neoplasms due to synergistic antitumor effect. The oral proteasome inhibitor ixazomib has less potential for dose-limiting neuropathy than bortezomib, making it an attractive option to incorporate into the R2 regimen. We sought to investigate the safety and efficacy of the addition of ixazomib to R2 for FL and indolent B-cell NHL through a phase I clinical trial of this combination for patients with high risk disease. METHODS: Adult (age ≥ 18) pts with untreated FL or other indolent lymphoma, adequate organ function and performance status were enrolled. To be enrolled, FL patients were required to have stage 2, 3 or 4 disease, with high tumor burden by GELF criteria and/or FLIPI score of 3-5. During 3 x 3 dose escalation, ixazomib was given at a dose of 2 mg (n=3), 3 mg (n=3) or 4 mg (n=12) PO on days 1, 8, and 15 with lenalidomide 20 mg PO on days 1-21 every 28 days. Rituximab was administered at standard dosing on days 1,8,15,21 for cycle 1, once every 28 days for cycles 2-6 and then once every 2 months for cycles 7-12. Treatment was continued for 12 cycles and no maintenance therapy was specified per protocol. All pts received low dose aspirin for venous thromboembolism prophylaxis and acyclovir for prevention of VZV reactivation. Response assessments by CT were performed after cycle 3 and 6 and by PET/CT at the end-of-treatment (cycle 12). RESULTS: 20 pts were enrolled and 18 were eligible for treatment [15 FL (14 grade 1-2, 1 grade 3A), 2 splenic marginal zone lymphoma and 1 nodal marginal zone lymphoma].The median age of treated pts was 61 (range 40-83) years old. 55% of patients were female. Stage at diagnosis was II (n =2), III (n = 4) and IV (n = 12). For FL pts, FLIPI scores at enrollment were low (n=2), intermediate (n = 5) and high risk (n=8) and FLIPI-2 scores were low (n=3), intermediate (n = 2) and high risk (n=10). There were no dose limiting toxicities during 3 x 3 dose escalation. Grade (G) 1/2 and G3/4 treatment-related hematologic adverse events (AEs) included neutropenia (6%, 28%), thrombocytopenia (16.7%, 5.6%) and anemia (16.7%, 0%). The most common treatment-related AEs included nausea/vomiting (44% G1, 11% G2), diarrhea, (50% G1, 22% G2, 5% G3), rash (33% G1, 6% G2, 11%G3), peripheral neuropathy (22% G1, 6% G2), myalgia/arthralgia (17% G1, 17% G2), and infection (33% G2, 17% G3). There was one pulmonary embolism and no cases of febrile neutropenia. As of June, 2020, median follow-up among living pts was 21 months. 4 pts discontinued treatment due to disease progression; 2 with transformation to aggressive lymphoma. Of the transformed cases, one subject died on study due to progression disease and one developed CNS disease on study treatment but proceeded to autologous stem cell transplant. The best overall response rate was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. 18-month Kaplan-Meier estimates of PFS and overall survival were 71% and 94%, respectively (Figure). CONCLUSION: R2 can safely be combined with at the target dose of 4 mg of ixazomib for treatment-naïve indolent NHL patients. Non-hematologic AEs were generally consistent with known toxicity of each component of therapy. CR rate and PFS were was similar to the outcomes reported in the RELEVANCE trial despite enrolling high risk patient. R2 may serve as backbone for future studies of novel treatment combinations for high risk FL after thorough evaluation for occult transformation to aggressive lymphoma. Disclosures Hill: Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Jagadeesh:MEI Pharma: Research Funding; Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Smith:Takeda: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Ixazomib is off-label for treatment of NHL

Efficacy Outcomes of Treatments for Double Relapsed/Refractory Follicular Lymphoma (R/R FL): A Systematic Literature Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 42-43
Author(s):  
Brad S. Kahl ◽  
Anik R. Patel ◽  
Omer Zaidi ◽  
Sonya J. Snedecor ◽  
Anna G. Purdum
Keyword(s):  
Clinical Trials ◽  
Follicular Lymphoma ◽  
Board Of Directors ◽  
Clinical Data ◽  
Research Funding ◽  
Treatment Options ◽  
Unmet Need ◽  
Progression Free Survival ◽  
Disease Stage ◽  
Advisory Committees

ABSTRACT Introduction: Patients with indolent non-Hodgkin lymphomas (iNHL), including follicular lymphoma (FL), have high response to first-line treatment. However, retreatment is often required when relapses occur, and those with multiple relapses represent a patient population with an unmet need for effective treatment. Clinical data for several treatment options exist for the general relapsed and refractory (R/R) population; however, there are relatively fewer data specific to FL patients with ≥2 lines of prior treatment. This work systematically identified the available efficacy data in the double R/R FL population. Methods: The MEDLINE and EMBASE databases were searched through February 10, 2020. Studies were limited to interventional clinical trials of R/R FL patients (or mixed histologies with a predominance of FL) and articles published in English. Studies also must have reported one or more efficacy measures, such as overall response rate (ORR), complete response (CR), duration of response (DoR), time to next treatment (TTNT), progression-free survival (PFS), and overall survival (OS). Potential interventions of interest were lenalidomide ± rituximab (R), duvelisib, ibrutinib, venetoclax, polatuzumab vedotin + R, obinutuzumab, copanlisib, umbralisib, idelalisib, and tazemetostat. Results: Of 35 publications examining treatment outcomes in R/R FL patients, only 14 (representing 5 unique clinical trials) were specific to the ≥ 2-line population. These trials were: CHRONOS Part B (copanlisib), DAWN (ibrutinib), DELTA (idelalisib), DYNAMO (duvelisib), and Morschhauser et al. 2019 (tazemetostat) and included a total of 605 participants. All studies used similar inclusion criteria, and patients included were similar in age (median 62-65), disease stage (III/IV), and ECOG score (0-2). Patients in the CHRONOS study had a median number of prior treatments of 2, whereas those in the DELTA study had 5. ORR ranged from 21% (ibrutinib) to 59% (copanlisib) (Table). The DoR ranged from 8.3 months in tazemetostat patients with EZH2 gene mutation to 19.4 months for ibrutinib. PFS ranged from 5.7 months in tazemetostat patients with wild-type EZH2 to 11.2 months for copanlisib. Median TTNT was only reported in the DAWN study (16 months). Conclusions: Very few clinical data exist reporting efficacy outcomes specific to the double R/R FL population. The limited data indicate that current treatments do not produce durable responses for most double R/R FL patients, demonstrating an unmet need. Further research is needed to fully understand the efficacy and safety of other potential interventions for this population. Disclosures Kahl: Genentech:Consultancy;Pharmacyclics LLC:Consultancy;AstraZeneca Pharmaceuticals LP:Consultancy, Membership on an entity's Board of Directors or advisory committees;ADC Therapeutics:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Celgene Corporation:Consultancy;AbbVie:Consultancy;Roche Laboratories Inc:Consultancy;BeiGene:Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding;Janssen:Consultancy, Membership on an entity's Board of Directors or advisory committees;Acerta:Consultancy, Research Funding.Patel:Kite, a Gilead Company:Current Employment.Zaidi:BMS:Consultancy.Snedecor:Pharmerit - an OPEN Health Company:Other: Employment at consultancy paid by Kite Pharma to conduct this work.Purdum:Kite, a Gilead Company:Current Employment.

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