scholarly journals Antibody Response after Vaccination for Sars-Cov-2 in Patients with AL Amyloidosis and the Impact of Therapy

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 3799-3799
Author(s):  
Efstathios Kastritis ◽  
Evangelos Terpos ◽  
Aimilia D. Sklirou ◽  
Foteini Theodorakakou ◽  
Despina Fotiou ◽  
...  
Keyword(s):  
Serum Albumin ◽  
Plasma Cell ◽  
Research Funding ◽  
Prior Exposure ◽  
Al Amyloidosis ◽  
Viral Inhibition ◽  
Active Therapy ◽  
Factors Associated ◽  
Free Interval ◽  
The Impact

Abstract Patients with lymphoproliferative disorders are at high risk for severe COVID-19. For patients with AL amyloidosis, in which there is also critical organ involvement, this risk may be even higher. Vaccination against SARS-CoV-2 is the best strategy to avoid severe COVID-19, but response to vaccines may be compromised in patients with B-cell lymphoproliferative or plasma cell malignancies, as in AL amyloidosis. Although modest in size, the plasma cell clone in AL may cause immunosuppression while anticlonal therapies further compromise immune responses. To evaluate immunization efficacy, we measured the titers of neutralizing antibodies (NAbs) against SARS-CoV-2 after vaccination with BNT162b2 in patients with AL amyloidosis. As a control group we used volunteers, matched (ratio 1:2) for age and gender, who had no autoimmune or active malignant or infectious disease. Serum was separated within 4 hours from blood collection and stored at -80°C until the day of measurement on (A) day 1 (D1; before the first dose of BNT162b2) (B) day 22 (D22; before the 2nd dose) and (C) day 50 (D50; ie 30 days after the 2nd dose). NAbs against SARS-CoV-2 were measured using FDA approved methodology (cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ, USA). According to the manufacturer of the assay, a titer ≥ 50% is considered a clinically relevant threshold for viral inhibition. The study included 144 patients with AL amyloidosis, of which 120 had NAbs titers assessed on all time points and were included in the final analysis (53% males; median age: 66, IQR: 57-72 years) and 240 matched controls (53% males; median age: 66, IQR: 57-72 years). 66 (55%) AL patients were on active therapy, 17.5% were on daratumumab (DARA)-based therapy, 52 (43%) had discontinued therapy >3 months from the date of the first shot, 19% had prior exposure to DARA and 94 (78%) were in hematologic remission (CR or VGPR). Prior to the 1st dose (D1), NAb titers were similar between patients and controls (median 14.9% (IQR 7.8-23.1%) vs 14% (IQR 6.8-22.9%), p=0.439); 6 AL patients had baseline NAbs >50%, of which 5 reported a history of COVID-19 infection. On D22, there was a significant increase of NAbs titers both in controls and AL patients (both p<0.001); however, median NAb titer was 23.6% (IQR 12.4-37.7%) in AL patients vs 47.5% (IQR 32.1-62.7%) in controls (p<0.001) and 20.5% of AL patients vs 46.7% of controls (p<0.001) developed NAb titers ≥50%. On D50, there was further increase in NAbs titers both in controls and AL patients (both p<0.001) and median NAb titer for AL patients was 83.1% (IQR 41.5-94.9%) vs 95.6% (IQR 91.7-97.2%) in controls (p<0.001); 71% of AL patients vs 98% of matched controls (p<0.001) developed NAb titers ≥50%. Among AL patients, factors associated with NAb titers on D50 included age (p<0.001), lymphocyte counts (p<0.001), serum albumin (p<0.001) and amount of proteinuria at the time of vaccination (p=0.047), renal involvement (p=0.047), use of steroids (p<0.001), active treatment (p<0.001), treatment-free interval (p=0.001), remission status (CR/VGPR) (p=0.018). There was no significant association with gender (p=0.092), BMI (p=0.198), IgG (0.099), IgA (p=0.789) or IgM levels (p=0.687), liver (p=0.521) or heart involvement (p=0.141). Patients on therapy had lower NAb titers at D50 (median 50.1% (IQR 25.3-84.1%) vs 91.6% (IQR 74.5-96.5%) for those not on treatment, p<0.001), so that 51% had a D50 NAb titer ≥50% vs 87% of those not on therapy. Current DARA therapy (median 52.1% vs 46.4% without DARA, p=0.486) or prior exposure to DARA (92.1% vs 91.2%, p=0.966) were not associated with D50 NAb titers. Generalized linear models were used for evaluation of multiple factors associated with D50 NAb titers: at least 3 months since the last dose of anticlonal therapy (p<0.001), lymphocyte counts (p=0.001) and serum albumin levels at the time of vaccination (p=0.020) were independent predictors of NAb titers on D50. When seroconversion was defined as a NAb titer ≥50% at D50, then >3 months of treatment-free interval (HR:7.75, p<0.001,) was the strongest factor associated with seconversion. In conclusion, patients with AL amyloidosis have an attenuated response to vaccination with BNT162b2 especially among those on active therapy or with less than 3 months since the last dose of treatment. For such patients, an anamnestic dosing strategy could be considered, especially after completion of anticlonal therapy. Figure 1 Figure 1. Disclosures Kastritis: Genesis Pharma: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Gavriatopoulou: Sanofi: Honoraria; GSK: Honoraria; Karyopharm: Honoraria; Takeda: Honoraria; Genesis: Honoraria; Janssen: Honoraria; Amgen: Honoraria. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria; Takeda: Honoraria; BeiGene: Honoraria.

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

Neuropathy and Efficacy Of Weekly Subcutaneous Bortezomib In Myeloma and AL Amyloidosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1975-1975 ◽  
Author(s):  
Surbhi Sidana ◽  
Beth Faiman ◽  
Paul Elson ◽  
Mitchell R Smith ◽  
Robert M Dean ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Treatment Duration ◽  
Research Funding ◽  
Proportional Hazards ◽  
Al Amyloidosis ◽  
Logrank Test ◽  
Administration Schedule ◽  
Al Amyloid ◽  
The Impact ◽  
Administration Schedules

Abstract Background Information is limited on the efficacy and long-term tolerability of weekly ubcutaneous (SC) bortezomib (BTZ), especially when given alone or combined only with glucocorticoids. We implemented use of SC BTZ in 12/2010 and based on equal AUC and efficacy with twice a week SC as IV BTZ (Moreau et al. Lancet Oncology 2011) at reduced but still significant neurotoxicity allowed weekly SC, maintaining the BTZ starting dose at 1.3mg/m2. Methods Multiple myeloma (MM) and AL amyloidosis (ALA) patients (pts) who had received SC BTZ by February 2013 were identified from our plasma cell disorder registry. After IRB approval, their electronic medical records were reviewed for occurrence, severity, and evolution of PNP with each BTZ containing regimen, administration schedule of BTZ, presence of underlying PNP and neuropathy risk factors (diabetes mellitus, ESRD, spinal cord compression/disease, vitamin B12 deficiency, alcoholism, chronic liver disease, hyperlipidemia, hypothyroidism), concurrently used antineoplastic agents, physician assigned responses, and reasons for BTZ dose reductions or discontinuation. To compare first BTZ regimen administration schedules Fisher’s exact test and chi-square tests were used for categorical data, Kruskal-Wallis and Wilcoxon rank sum test for age and interval from diagnosis to treatment, and logrank test for treatment duration. Proportional hazards models were used to assess the impact of BTZ administration schedule on neuropathy and response. The impact of prior regimens before first BTZ administration on response was estimated by logistic regression models. Results 136 patients were identified, 12 were excluded due to insufficient data (not followed at our Center). The remaining 124 pts began their first BTZ regimen between 02/2005 and 02/2013. 81% had MM, 12 % ALA, and 7% both MM and amyloidosis. Patients received a median of 2 BTZ containing regimens (range 1-9); overall 312 BTZ regimens were analyzed. In 114 SC weekly, 32 SC twice a week, 59 IV weekly, 62 IV twice a week, and 11 twice a week SC/IV followed by weekly BTZ regimens, neuropathy led to BTZ discontinuation in 7.9% (n=9), 9.4% (n=3), 13.6% (n=8), 22.6% (n=14), 9.1% (n=1), respectively, and to dose reduction in 5.3% (n=6), 3.2% (n=1), 6.8% (n=4), 6.5% (n=4), 9.1% (n=1), respectively. Patients who received weekly SC BTZ as their first BTZ containing regimen (n=37) had received a median of 0 prior regimens (range 0-10), 27% (n=10) had mild (n=8) or severe (n=2) underlying neuropathy, and most (68%) received BTZ with only glucocorticoids (n=23) or alone (n=2), while lenalidomide (n=8) or other agents (n=4) were added to 32%. After a median treatment duration of 4.3 months (0.2-23.3+), 26 of these 37 pts (70%) developed no neuropathy (n=20) or no worsening of pre-existing neuropathy (n=6), but 7 (19%) required BTZ dose reduction (n=2) or supportive medications (n=5) for neuropathy and in 4 (11%) BTZ was discontinued because of neuropathy. In multivariable analyses for neurotoxicity and lack of response, use of schedules other than weekly SC as the first BTZ administration schedule caused more neuropathy (HR 2.3, 95% C.I. 1.0-5.3, p=0.05), while age and underlying disease associated with neuropathy had no impact (p=0.57 and 0.61, respectively); lack of response tended to be more common with schedules other than weekly SC (HR 2.0, 95% C.I. 0.9-4.5, p=0.09) but age and disease (MM vs. AL amyloid) did not affect response (p=0.33 and 0.32, respectively). A response rate of 71% (n=22) to the first SC weekly bortezomib containing regimen in 37 pts who had received a median of 0 (range 0-10) previous regimens was within the expected range for standard administration schedules; of 8 pts who received weekly SC BTZ with not more than a total of 40mg dexamethasone per week as upfront therapy for myeloma, 5 achieved VGPR, 1 PR, and one MR; in 6 evaluable AL amyloid patients this upfront treatment led to VGPR in 3 and PR in 1 patient. Conclusions Weekly SC BTZ, even if administered only with glucocorticoids, is effective and better tolerated than other BTZ administration schedules. However, neuropathy continues to impact therapy, affecting about a third of patients in our series who received BTZ for the first time. Disclosures: Off Label Use: Upfront weekly SC bortezomib. Faiman:Onyx: Consultancy, Speakers Bureau; Millennium: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Valent:Millennium: Speakers Bureau; Clegene: Speakers Bureau. Duong:Celgene: Honoraria, Research Funding. Reu:Onyx: Speakers Bureau; Celgene: Research Funding.

Retrospective Analysis of Lymphomas in the Setting of Autoimmune Disease and the Impact of Immunosuppression

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2737-2737
Author(s):  
Adam M. Petrich ◽  
Stefan Klaus Barta ◽  
Frederick Lansigan ◽  
Trent Wang ◽  
Ananta Bhatt ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Retrospective Analysis ◽  
Clinical Features ◽  
Research Funding ◽  
Cytotoxic Chemotherapy ◽  
Prior Exposure ◽  
Primary Therapy ◽  
Histologic Subtype ◽  
The Impact

Abstract Introduction: Post-transplant lymphoproliferative disease (PTLD) encompasses a heterogeneous array of cases of lymphoma/lymphoma-like conditions arising in the setting of immunosuppression (IS) for prior organ or marrow transplant. Such pts face heightened risk of toxicity from exposure to cytotoxic chemotherapy, and may be best treated in the frontline with reduction of IS (RI) and anti-CD20 monoclonal antibody treatment (Trappe, 2012). Autoimmune (AI) disease has been associated with an increased risk of developing lymphoma; however, the relative impact of baseline clinical features, including prior IS, is unknown. Methods: We conducted a multicenter, retrospective analysis of adult pts with pre-existing AI conditions who were diagnosed with lymphoma since 1997. Baseline clinical features at diagnosis of lymphoid malignancy, including International Prognostic Index (IPI) risk factors; underlying AI disease; duration and type of IS; EBV status (by EBER in-situ hybridization); and primary therapy received (RI, rituximab [R] monotherapy, chemotherapy [+/- R]); were collected. Survival analyses were performed using Kaplan-Meier method. We then focused on those who had A) received IS other than corticosteroids (CS) alone; and B) those diagnosed with DLBCL. Those variables found to have significant correlation with OS by univariate analyses (UVA) were used to construct Cox proportional hazards model (multivariate analysis [MVA]) in order to determine which might have the strongest association with OS. Lastly, we sought to evaluate a potential role for RI and/or R as frontline therapy for those with DLBCL. Results: A total of 130 pts were included (Table 1). The most frequent AI disease was rheumatoid arthritis and for all cases, 76% had documented exposure to IS, for a median duration of 4.5 years (range 0.17-57 years) prior to diagnosis of lymphoma. The most common histologic subtype was DLBCL (52%). EBV status was reported for only 34% of pts, but was positive in 68% (25/37), all of whom had received prior exposure to IS beyond CS, and 80% of whom (20/25) were diagnosed with DLBCL. EBV status was infrequently tested in pts not previously exposed to IS (3/31). At a median follow-up of 61 months for the entire cohort, 2-year PFS and OS were 79% and 91%, respectively (Figure 1, Panel A). By UVA, age>60; PS>1; LDH> upper limit of normal (ULN); DLBCL (vs all other histologies); underlying rheumatoid arthritis (RA; vs all other AI diseases); and prior exposure to IS, each correlated with inferior OS (Table 1). By MVA, PS>1 and prior IS maintained significance (p<0.05). If those receiving only CS are grouped with those not previously exposed to IS, the correlation of this factor with OS was strengthened (p 0.008), and by MVA, PS>1 (p 0.002) and prior IS (p 0.010) maintain significance (data not shown). Among 67 pts with DLBCL, median age was 61 (range 26-90), 60% had advanced stage disease, and 32% had IPI of 4 or 5. At a median follow-up of 32 months, the 2-year PFS and OS were 82% and 84%, respectively. There were no differences in frequency of any IPI factors between patients exposed to prior IS (n=53) and those who were naïve to prior IS (n=14). For those not exposed to prior IS, the 2-year OS was 100%, compared to 80% in those who received prior IS (p 0.24); corresponding 2-year PFS were 92% and 79%, respectively (p 0.41). Age>60 and PS>1 were associated with an inferior OS but use of IS was not associated with outcome (Table 2). The 2 year OS for those treated with R plus CHOP(like) chemotherapy, CHOP(like) chemotherapy (without R), R alone (+/- RI), and with RI alone were 92%, 75%, 90%, and 67%, respectively (Figure 1, Panel B; log-rank p value 0.55). Patients who received CHOP-like therapy +/- R, as compared to R and/or RI were more likely to be naïve to IS therapy (15/46 vs 0/22, p = 0.003) and have 2 or more EN sites of disease (15/46 vs 2/22, =0.041). These differences notwithstanding, the 2-year PFS for the two groups were 86% and 74% (p 0.16), and 2-year OS for the two groups were 88% and 82%, respectively (Figure 1, Panel C; p 0.91). Conclusions: Pts with immunosuppression-related lymphoma have high rates of 2-year OS and in DLBCL, IS does not appear to be associated with an inferior outcome. Similar to evolving treatment paradigms in PTLD, rituximab monotherapy and other cytotoxic chemotherapy-free regimens as well as risk-adapted approaches may warrant further evaluation in IS-related DLBCL. Disclosures Petrich: Seattle Genetics: Consultancy, Honoraria, Research Funding. Barta:Seattle Genetics: Research Funding. Feldman:Celgene: Honoraria, Speakers Bureau; Pharmacyclics/JNJ: Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau. Savage:Seattle Genetics: Honoraria, Speakers Bureau; BMS: Honoraria; Infinity: Honoraria; Roche: Other: Institutional research funding.

scholarly journals In Vitro and inVivo Activity of Melflufen in Amyloidosis

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 3100-3100 ◽  
Author(s):  
Ken Flanagan ◽  
Muntasir M Majumder ◽  
Romika Kumari ◽  
Juho Miettinen ◽  
Ana Slipicevic ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cell Lines ◽  
Plasma Cell ◽  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Al Amyloidosis ◽  
Advisory Committees

Background: Immunoglobulin light-chain (AL) amyloidosis is a rare disease caused by plasma cell secretion of misfolded light chains that assemble as amyloid fibrils and deposit on vital organs including the heart and kidneys, causing organ dysfunction. Plasma cell directed therapeutics, aimed at preferentially eliminating the clonal population of amyloidogenic cells in bone marrow are expected to reduce production of toxic light chain and alleviate deposition of amyloid thereby restoring healthy organ function. Melphalan flufenamide ethyl ester, melflufen, is a peptidase potentiated alkylating agent with potent toxicity in myeloma cells. Melflufen is highly lipophilic, permitting rapid cellular uptake, and is subsequently enzymatically cleaved by aminopeptidases within cells resulting in augmented intracellular concentrations of toxic molecules, providing a more targeted and localized treatment. Previous data demonstrating multiple myeloma plasma cell sensitivity for melflufen suggests that the drug might be useful to directly eliminate amyloidogenic plasma cells, thereby reducing the amyloid load in patients. Furthermore, the increased intracellular concentrations of melflufen in myeloma cells indicates a potential reduction in systemic toxicity in patients, an important factor in the fragile amyloidosis patient population. To assess potential efficacy in amyloidosis patients and to explore the mechanism of action, we examined effects of melflufen on amyloidogenic plasma cells invitro and invivo. Methods: Cellular toxicity and apoptosis were measured in response to either melflufen or melphalan in multiple malignant human plasma cell lines, including the amyloidosis patient derived light chain secreting ALMC-1 and ALMC-2 cells, as well as primary bone marrow cells from AL amyloidosis patients, using annexin V and live/dead cell staining by multicolor flow cytometry, and measurement of cleaved caspases. Lambda light chain was measured in supernatant by ELISA, and intracellular levels were detected by flow cytometry. To assess efficacy of melflufen in vivo, the light chain secreting human myeloma cell line, JJN3, was transduced with luciferase and adoptively transferred into NSG mice. Cell death in response to melflufen or melphalan was measured by in vivo bioluminescence, and serum light chain was monitored. Results: Melflufen demonstrated increased potency against multiple myeloma cell lines compared to melphalan, inducing malignant plasma cell death at lower doses on established light chain secreting plasma cell lines. While ALMC-1 cells were sensitive to both melphalan and melflufen, the IC50 for melphalan at 960 nM was approximately 3-fold higher than melflufen (334 nM). However, ALMC-2 cells were relatively insensitive to melphalan (12600 nM), but maintained a 100-fold increase in sensitivity to melflufen (121 nM). Furthermore, while 40% of primary CD138+ plasma cells from patients with diagnosed AL amyloidosis responded to melflufen treatment in vitro, only 20% responded to melphalan with consistently superior IC50 values for melflufen (Figure 1). Light chain secreting cell lines and AL amyloidosis patient samples were further analyzed by single cell sequencing. We further examined differential effects on apoptosis and the unfolded protein response in vitro in response to either melflufen or melphalan. This is of particular interest in amyloidosis, where malignant antibody producing plasma cells possess an increased requirement for mechanisms to cope with the amplified load of unfolded protein and associated ER stress. As AL amyloidosis is ultimately a disease mediated by secretion of toxic immunoglobulin, we assessed the effects of melflufen on the production of light chain invitro, measuring a decrease in production of light chain in response to melflufen treatment. Finally, we took advantage of a recently described adoptive transfer mouse model of amyloidosis to assess the efficacy of melflufen and melphalan in eliminating amyloidogenic clones and reducing the levels of toxic serum light chain in vivo. Conclusions: These findings provide evidence that melflufen mediated toxicity, previously described in myeloma cells, extends to amyloidogenic plasma cells and further affects the ability of these cells to produce and secrete toxic light chain. This data supports the rationale for the evaluation of melflufen in patients with AL amyloidosis. Figure 1 Disclosures Flanagan: Oncopeptides AB: Employment. Slipicevic:Oncopeptides AB: Employment. Holstein:Celgene: Consultancy; Takeda: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy; Genentech: Membership on an entity's Board of Directors or advisory committees; Sorrento: Consultancy. Lehmann:Oncopeptides AB: Employment. Nupponen:Oncopeptides AB: Employment. Heckman:Celgene: Research Funding; Novartis: Research Funding; Oncopeptides: Research Funding; Orion Pharma: Research Funding.

AL Amyloidosis and Concomitant Myeloma: Time to Reconsider Assumptions

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4044-4044
Author(s):  
Wesley Witteles ◽  
Ronald Witteles ◽  
Michaela Liedtke ◽  
Sally Arai ◽  
Richard Lafayette ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Overall Survival ◽  
Plasma Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Renal Involvement ◽  
World Health ◽  
Bone Lesions ◽  
Al Amyloidosis ◽  
Bone Marrow Biopsies

Abstract Abstract 4044 Background: Conventionally, multiple myeloma is believed to coexist in approximately 10% of AL amyloidosis patients. However, it is unclear whether this figure is too low based on current World Health Organization criteria. These criteria, mainly created to differentiate myeloma from monoclonal gammopathy of undetermined significance, include the presence of ≥ 10% plasma cells on a bone marrow biopsy or aspirate as being diagnostic of myeloma. Aims: To define the frequency and relevance of a concomitant diagnosis of myeloma in patients with AL amyloidosis. Methods: Records from consecutive patients with biopsy-proven AL amyloidosis treated at the Stanford University Amyloid Center were reviewed. Plasma cell percentages were determined by manual counts from bone marrow aspirate smears and by CD138 immunohistochemistry (IHC) performed on bone marrow core biopsies. Results: A total of 41 patients (median age 61 years, 32% female) were evaluated. The median number of organs involved with amyloidosis was 2 (range 1–4), with 28 patients (68%) having cardiac involvement, 22 patients (54%) having renal involvement, 15 patients (37%) having gastrointestinal involvement, 12 patients (29%) having soft tissue involvement, and 10 patients (24%) having nervous system involvement. All patients had bone marrow biopsies and aspirates performed at the time of amyloid diagnosis, with most undergoing both manual counts of plasma cells from aspirates and IHC from core biopsies. Based on conventional criteria, manual aspirate counts defined 15/28 (54%) patients as having myeloma, and IHC defined 26/31 (84%) patients as having myeloma (p=0.01). Only nine patients had a detectable serum paraprotein on immunofixation (median 1.1 g/dl, range 0.4–2.6). 81% of patients had an elevated serum free light chain (85% lambda), with a median level of 37.3 mg/dl (range 8.6–256 mg/dl). Compared to the frequency of elevated plasma cells, the prevalence of anemia (29%), hypercalcemia (14%), impaired kidney function (21%), and lytic lesions (7%) was low. After a median follow-up of 13 months (range 1–127 months), the one-year overall survival (74% vs. 58%) and three-year overall survival (50% vs. 50%) was not significantly different between patients with ≥10% plasma cells and patients with <10% plasma cells (p=NS). Discussion: As defined by bone marrow plasma cell involvement, a strikingly high percentage (84%) of AL amyloidosis patients would be considered to have concurrent myeloma. This figure is much higher than has been traditionally quoted in the literature, likely due to the utilization of newer methods of counting plasma cells. There was a low prevalence of myeloma-associated end-organ effects (hypercalcemia, anemia, renal insufficiency, lytic bone lesions), and a myeloma diagnosis had no impact on survival. Conclusion: In this cohort of AL amyloid patients, concomitant myeloma was present in the vast majority of patients using modern diagnostic techniques. The significance of this diagnosis appears to be minimal – calling into question whether the diagnostic criteria for myeloma should be redefined in this population. Disclosures: Witteles: Celgene: Research Funding. Liedtke:Celgene: Lecture fee, Research Funding. Schrier:Celgene: Research Funding.

Unraveling Early Mortality In Patients with AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4990-4990
Author(s):  
Cheng E. Chee ◽  
Vincent Rajkumar ◽  
Morie Gertz ◽  
Martha Lacy ◽  
Steven Zeldenrust ◽  
...  
Keyword(s):  
Organ Failure ◽  
Plasma Cell ◽  
Research Funding ◽  
Troponin T ◽  
Early Mortality ◽  
Cell Labeling ◽  
Al Amyloidosis ◽  
Renal Nerve ◽  
Treatment Information ◽  
Number Of Patients

Abstract Abstract 4990 Background: Although there have been improvements in 5-year overall survival (OS) rates among patients with AL amyloidosis over the past decades, OS is still poor, and death rates within the first 3–6 months after diagnosis have not changed significantly. This retrospective study was performed to identify risk factors for and causes of death during the first 90 days following diagnosis of AL amyloidosis. Method: From July 2002 to April 2009, 301 patients with a diagnosis of AL amyloidosis who were seen at Mayo Clinic within 30 days of diagnosis were identified from the dysproteinemia database. The 100 who died within 90 days were the focus of our study. The other 201 who were alive beyond 90 days were used as a comparator group. Outside physician offices were contacted to obtain further information pertaining to treatment and cause of death for our study group. Results: Of the 100 patients with early death, median age at diagnosis was 63.7 years (range: 34.7–89.4). 25 patients were diagnosed with concurrent multiple myeloma (MM) based on MM-specific end-organ damage. Overall, the number of patients with 2, 3 and 4 organs (cardiac, renal, nerve or liver) involved with amyloidosis was 37, 15 and 4, respectively. Using the cardiac biomarker staging system, 78% of 46 evaluable patients were stage III at diagnosis followed by 22% stage II and no stage I. Table 1 describes the characteristics of the studied population. Amyloid-related deaths were identified in 61 patients with the most common cause being cardiac arrest or sudden death (33%) followed by end-organ failure (24%). Treatment was started in 50% of patients; 34% received no treatment; and no treatment information was available for the remainder. OS was 54.5 days in patients who received treatment as compared to 7.5 days in those who received no treatment (p<0.0001); outcomes were similar in the group in whom no treatment information was available and those patients who were known to have received treatment. Melphalan with dexamethasone was the most common treatment (21%) and was associated with improved OS compared to other treatments including novel agents (57 vs. 26 days, p=0.003). Outcomes were no different if the patients had received novel therapies, but numbers were small. When compared to patients who lived for more than 90 days from their diagnosis, patients with early mortality had higher median intraventricular septum (IVS) (15 vs. 13 mm, p<0.0001), lower ejection fraction (EF) (50 vs. 64%, p<0.0001), and higher troponin-T (0.125 vs. 0.01 ng/ml, p<0.0001) and NT-proBNP (9020 vs. 1292 pg/ml, p<0.0001). We also found that patients who died within 90 days of their diagnosis had significantly higher plasma cell labeling index (PCLI), uric acid, beta-2 microglobulin, involved free light chain (FLC) and creatinine. Conclusion: This study highlights the characteristics of patients who died within 90 days of diagnosis of AL amyloidosis. The majority of patients died from arrhythmia and organ failure. This implies that other interventions aside from treatment of the underlying plasma cell (PC) disorder will likely be required to change the early outcomes of this disease. Disclosures: Lacy: Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

scholarly journals Impact of Chromosomal Abnormalities in Acute and Lymphoma Types Adult T-Cell Leukemia-Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 4123-4123
Author(s):  
Nobuaki Nakano ◽  
Hiroo Katsuya ◽  
Takahiro Itoyama ◽  
Mototsugu Shimokawa ◽  
Atae Utsunomiya ◽  
...  
Keyword(s):  
Serum Albumin ◽  
Research Funding ◽  
Chromosomal Abnormalities ◽  
Structural Break ◽  
Median Number ◽  
Albumin Level ◽  
Chromosomal Analysis ◽  
Break Points ◽  
Ecog Ps ◽  
The Impact

Abstract Background: Adult T-cell leukemia-lymphoma (ATL), which is a hematological malignancy related to human T-lymphotropic virus type I (HTLV-1), is known as a malignant lymphoid disease with poor prognosis. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is considered a treatment modality to contribute prolonging the survival in some population of patients (Katsuya H et al. 2015 Blood). A small study indicated that ATL cells frequently have chromosomal abnormalities including various numerical aberrations and complex structural abnormalities (Kamada N et al. Cancer Res. 1992). However, there has been no large study to examine the relationship between chromosomal abnormalities and survival. Here we report the impact of chromosomal abnormalities on survival in ATL patients with conventional chemotherapy. Patients and Methods: In this study, we extracted a population of patients from the database of ATL-PI project, which is a nation-wide survey of ATL patients newly diagnosed between January 2000 and May 2009, and the overall results were reported elsewhere (Katsuya H et al. JCO 2012, Blood 2015). Fifteen hundred and twelve patients were registered in this project, and we excluded the patients who received allo-HSCT, and who were diagnosed with smoldering and chronic type ATL. Moreover, patients whose chromosomal analysis with G-banding stain showed normal, multiploid or no mitosis, or no information on chromosomal analysis and on the factors to determine the ATL-PI were also excluded. As a consequence, 210 patients with acute (n=157) and lymphoma (n=53) types were selected for this analysis. Abnormal karyotypes were analyzed from the aspect of numerical and structural break points. To identify the specific abnormalities and to avoid the secondary changes, the stem-line karyotype, which meant the simplest abnormal clone, was used as the representative karyotype for this study. A statistical analysis was performed with 'EZR' (Kanda T. BMT 2013). We examined an overall survival (OS) in relation to chromosomal abnormalities using cox proportional hazard regression model, and p-value of less than 0.05 was considered as statistically significant. Results: Among the 210 patients, 119 and 91 patients were male and female, respectively. The median age of patients was 66 years (40-89). With respect to other factors of ATL-PI, the median level of soluble interleukin-2 receptor (sIL-2R), serum albumin, were 30800 U/mL (620-1,219,000), 3.6 g/dL (1.6-5.3), respectively. Almost all patients were diagnosed with stage II-IV of clinical stage (n=200), and almost half of patients certified 2-4 of ECOG-PS (n=113). Sixty-nine, 106, and 35 patients were classified as high, intermediate and low risk by ATL-PI, respectively. Specimens used for chromosomal analysis were taken from lymph nodes (n=77), bone marrow (n=72), peripheral blood (n=50), pleural fluids (n=4), ascites (n=4) and 1 each of stomach, sinusoidal tumor, and tonsillar lesions. The median number of numerical abnormalities and marker chromosomes were 2 (0-20) and 1 (0-20), and the median number of structural break points was 6 (0-21). The numerical abnormalities were loss of sex chromosomes (31%) followed in decreasing order by -14 (24%), -13 (19%), -9 (12%) and -17 (12%) while the structural break points were located at 1p (30%), 3q (30%), 14q (30%), 6q (26%) and 1q (22%). The median OS was 286 days (1-2565). ECOG-PS, serum albumin level, sIL-2R, and structural break points at 9q or 19p, and the number of structural break points over 4 or 5 points were shown to be the significant factors affecting the survival by univariate analysis. Then, the multivariate analysis indicated that 2-4 of ECOG-PS (HR: 2.021, 95%CI: 1.436-2.791, p<0.001), serum albumin level < 3.5 g/dl (HR: 1.631, 95%CI: 1.282-2.074, P<0.001), and chromosomally structural break points at 9q (HR: 1.584, 95%CI: 1.096-2.289, p<0.001) and 19p (HR: 1.765, 95%CI: 1.038-2.999, p<0.001) were factors that negatively contributed to OS. Discussions and Conclusion: This is the first large study showing the impact of chromosomal abnormality in acute and lymphoma types ATL on OS. It demonstrated that structural break points at 9q and 19p were the independent risk factors for OS in addition to those of ATL-PI. Disclosures Katsuya: The Uehara Memorial Foundation: Research Funding. Utsunomiya:Daiichi Sankyo Co., Ltd.: Speakers Bureau. Tsukasaki:Daiichi Sankyo Co., Ltd.: Consultancy; Takeda: Research Funding. Suzumiya:Takeda: Honoraria; Astellas: Research Funding; Kyowa Hakko kirin: Research Funding; Chugai: Honoraria, Research Funding; Toyama Chemical: Research Funding; Eisai: Honoraria, Research Funding.

scholarly journals A Phase I Trial of Pomalidomide, Bortezomib (Velcade), and Dexamethasone (PVD) As Initial Treatment of AL Amyloidosis and Light Chain Deposition Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4767-4767
Author(s):  
Jeffrey Zonder ◽  
Christiane Houde ◽  
Sascha Tuchman ◽  
Vishal Kukreti ◽  
Vaishali Sanchorawala ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Research Funding ◽  
Median Number ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Light Chain Deposition Disease ◽  
Deposition Disease ◽  
Plasma Cell Dyscrasias ◽  
Light Chain Deposition

Abstract Introduction: AL amyloidosis (AL) and Light Chain Deposition Disease (LCDD) are plasma cell dyscrasias in which misfolded monoclonal light chains form insoluble extracellular protein deposits (fibrillar and amorphous, respectively). In AL particularly, toxic soluble light chain oligomers also play a role in disease pathogenesis. Treatment of AL and LCDD aims at eliminating the abnormal plasma cell clone. Typical agents used include corticosteroids, bortezomib (btz), alkylators, or immunomodulatory drugs (IMiDs) such as lenalidomide (len) or pomalidomide (pom). Len-btz-dexamethasone (dex) is a highly efficacious frontline regimen commonly used for multiple myeloma, a related plasma cell cancer. Despite this, prospective studies using btz-IMiD combos as initial therapy of AL or LCDD are lacking. Here we report our experience with pom-btz-dex(PVD) for pts with AL or LCDD. Methods: This is a prospective Phase I trial using a standard 3+3 dose escalation scheme (described in Table 1). The primary objective is to establish the maximally tolerated dosing (MTD), with assessment for dose limiting toxicity (DLT) extending through cycles 1 and 2 for each pt. Hematologic and organ responses (HR and OR) were assessed using recently updated guidelines. PVD was administered in repeating 28-day cycles until either DLT or progressive disease. Key inclusion/exclusion criteria: biopsy proven AL amyloidosis or LCDD; no more than 1 prior cycle of anti-plasma cell therapy; measurable disease defined as at least a 5 mg/dL difference between the involved (iFLC) and uninvolved (uFLC) serum free light chains, or a serum M-protein of 0.5 g/dL or greater (latter not permissible without measurable sFLCdifference after protocol amendment); ECOG PS of 2 or less; adequate renal, hepatic, and marrow function; no Grade 3 or higher peripheral neuropathy (PN; pts with painful grade 2 PN also excluded). Abnormal left ventricular ejection fraction or cardiac biomarkers allowed, but pts with NYHA class III/IV congestive heart failure or uncontrolled ventricular arrhythmias were excluded. Antithrombotic/antiviral prophylaxis was required for all pts. Results: Six pts have been enrolled thus far (3 each in cohorts 1 and 2, respectively). Three additional pts have already been identified for cohort 3. Five of 6 pts had AL, and 1 had LCDD. Median age was 65.5 yrs (range 49-74 yrs). 5 pts were female. Mayo cardiac stage I/II/III in 1, 2, and 3 pts, respectively. Three pts had one prior cycle of therapy (the others had none). The iFLC was lambda type in all 5 AL pts, and kappa for the pt with LCDD. Median number of organs involved by AL/LCDD was 2 (range, 2-4; 4 with both cardiac and renal, and 1 additional pt with cardiac). The median number of PVD cycles administered was 3 (range 1-6). Two pts are still on therapy. The reasons for stopping PVD in the other 4 pts were: sudden death due to underlying cardiac AL (during cycle 3 of PVD), pt preference after reaching maximal HR (after cycle 6), lack of HR (after cycle 3), and toxicity (after cycle 4). Baseline dex dose adjustment was required for protocol-specified reasons in all pts. One pt required further dex reduction during cycle 4 of PVD. No pts required baseline or subsequent modification of pom or btz. Table 2 summarizes reported adverse events (AEs). No DLTshave been observed. Two pts achieved HR (0 CR, 1 VGPR, 1 PR, 3 SD, 0 PD). Organ responses have not been observed, but the first protocol-specified OR assessment takes place after 4 cycles of PVD and some pts have yet to reach this time point. Conclusions: PVD was well tolerated in this group of pts with AL and LCDD. Importantly, no significant myelosuppression or PN was noted in the first 2 (out of a planned 4) dose cohorts. Most AEs have been related to the ptsÕ underlying AL/LCDD, though dex has posed difficulties for some pts. Hematologic responses have been seen, but organ responses are predictably lagging. Once the MTD is established, an 18-pt expansion cohort dosed at that level willfurther examine the efficacy of PVD as up-front treatment for AL and LCDD. Disclosures Zonder: Celgene: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy. Off Label Use: Pomalidomide and Bortezomib are approved drugs for multiple myeloma; they are used in this trial as treatment for the related plasma cell dyscrasias AL amyloidosis and light chain deposition disease. . Tuchman:Celgene: Honoraria, Research Funding, Speakers Bureau; Millennium: Honoraria, Research Funding, Speakers Bureau. Kukreti:Celgene: Honoraria. Burt:Celgene: Speakers Bureau. Matous:Takeda Pharmaceuticals International Co.: Speakers Bureau; Onyx: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Research Funding, Speakers Bureau.

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

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

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

scholarly journals Increased Bone Marrow Plasma Cells at Diagnosis Predicts Overall Mortality in AL Amyloidosis Patients Undergoing Risk-Adapted Stem Cell Transplant

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2522-2522
Author(s):  
Chrystal A. Landry ◽  
Melody Smith ◽  
Joanne F. Chou ◽  
Sean M. Devlin ◽  
Hani Hassoun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Treatment Response ◽  
Plasma Cell ◽  
Stem Cell Transplant ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Cell Disease ◽  
The Impact

Abstract Background: High dose melphalan with autologous stem cell transplant (SCT) is an effective therapy for patients with light chain (AL) amyloidosis. With appropriate patient selection, risk-adapted melphalan dosing (RA-SCT), and post transplant consolidation in patients with <CR, treatment-related mortality is low and overall median survival (OS) in a large series is beyond 6 years and more than a decade for patients who achieve a complete hematologic remission (CR).1,2 However, some patients who achieve CR relapse within 2 years and have inferior OS. A recent study suggested that bone marrow plasmacytosis (BMPC) exceeding 10% at diagnosis is associated with an inferior survival, similar to patients considered to have AL with concurrent symptomatic multiple myeloma (MM) based on the presence of hypercalcemia, renal dysfunction, anemia and bone lesions (CRAB criteria).3 We aimed to confirm the prognostic significance of BMPC at diagnosis in AL patients who underwent RA-SCT +/- consolidation on OS and evaluate the impact on event-free survival (EFS). Methods: We assessed the outcomes of all AL patients who underwent RA-SCT at Memorial Sloan Kettering Cancer Center. Patients with >2 major organs involved, NYHA class III/IV CHF, critical arrhythmias, cardiac syncope or concurrent symptomatic MM based on CRAB criteria were ineligible. Response was assessed at 3 and 12 months after RA-SCT; patients with < CR at 3 months were offered consolidation. EFS and OS were calculated from transplant to next treatment, death or last follow-up and were estimated by Kaplan-Meier methods. A one-year landmark was used to compare survival by treatment response (CR vs <CR). OS and EFS were compared across covariates of interest using the log-rank test. The patients were divided based upon percentage of BMPCs on initial diagnostic bone marrow using the highest estimate from the aspirate or biopsy. Cox proportional hazards model was used to examine the effect of BMPC on OS after adjusting for response at 1 year and cardiac stage. Results: Between 2/2000 and 6/2011, 148 patients with AL amyloidosis underwent RA-SCT and were followed. Five patients without diagnostic bone marrow results available were excluded. Of those included, 63% (N=90) of patients had ≤ to 10% BMPC at diagnosis and 37% (N=53) had more than 10%. With a median follow up among survivors of 7.73 years, the median EFS is 4.82 years, 95% CI (3.84 – 6.23), and the median OS has not been reached. By univariate analysis, melphalan dose (200, 140, or 100mg/m2) (EFS P = 0.002, OS P = 0.002), organ involvement (≤ 1 vs >1) (EFS P = <0.01, OS P = 0.003), and Mayo cardiac stage (I, II, or III) (EFS P = 0.003, OS P = <0.01) were all significantly associated with both EFS and OS. Patients with ≤ 10% BMPCs at diagnosis had a trend toward better EFS (P = 0.08) and statistically significant longer OS (P = 0.008) compared to patients with a higher burden of plasma cell disease at baseline (> 10% BMPCs) (Figure 2). Achieving a CR at 1 year following RA-SCT was associated with superior EFS (P = 0.027) and OS (P = 0.043) (Figure 1) but was independent of whether or not CR was achieved with or without consolidation (EFS P = 0.14; OS P = 0.24). In multivariate analysis, higher burden of plasma cell disease at baseline remained an independent risk factor for OS [HR: 4.7 (95%CI: 1.7-12.9, p<0.01)], after adjusting for treatment response at 1 year and cardiac stage. Conclusion: AL amyloidosis patients who are eligible for RA-SCT have excellent outcomes with OS at 10 years of 58% (95%CI: 47%-66%). Patients who achieve a CR with RA-SCT alone or with RA-SCT plus consolidation do equally well overall. Patients with greater burden of organ disease as indicated by number of organs involved, the requirement for dose reduction, or Mayo cardiac stage have inferior outcomes. This is unlikely to change without earlier diagnosis. The finding that greater plasma cell burden at diagnosis also impacts OS in patients who received RA-SCT independent of cardiac disease, treatment response and/or consolidation suggests that a more proliferative clone may require more MM-like therapy, and that these patients may benefit from more prolonged maintenance therapy. A clinical trial addressing this question in patients with AL amyloidosis is planned. Figure 1 Figure 1. Figure 2 Figure 2. 1. Gertz et al. BMT 2013; 48: 557. 2. Cibieira MT, et al. Blood 2011; 118: 4346. 3. Kourelis TV et al. JCO 2013; 31: 4319. Disclosures No relevant conflicts of interest to declare.

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