Trend towards Improved Day 100 and 2-Year Survival After SCT for AL Amyloidosis: Outcomes Before and After 2006

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3554-3554
Author(s):  
Morie Abraham Gertz ◽  
Martha Lacy ◽  
Angela Dispenzieri ◽  
Shaji Kumar ◽  
Francis Buadi ◽  
...  
Keyword(s):  
Research Funding ◽  
Troponin T ◽  
Safety Margin ◽  
Early Mortality ◽  
Cardiac Biomarkers ◽  
Al Amyloidosis ◽  
Advisory Committees ◽  
Time Period ◽  
Before And After ◽  
Short Term Mortality

Abstract Abstract 3554 Introduction: The role of SCT in the management of Ig light chain (AL) amyloidosis remains undefined. Patients: We report 422 patients (Table 1) who received SCT for AL amyloidosis to compare outcomes of patients treated before January 2006 with those of patients treated from January 2006 until December 1, 2009. Results: Day 100 all-cause mortality decreased over this time period from 12% to 7% (P=.09) figure 1. Survival at 2 years increased from 78% to 82%. Figure 2 The major determinants of early mortality (before day 100) were the presence of cardiac involvement with amyloid and increased levels of cardiac biomarkers, lower serum albumin, higher serum creatinine, and a higher number of organs involved. (Table 2) On multivariate survival analysis, higher levels of serum troponin T and N-terminal pro–brain natriuretic peptide were the only predictors of early mortality after SCT. Conclusion: Improved supportive care and refined patient selection has improved the safety margin for patients undergoing SCT; short-term mortality showed a more than 40% decrease after 2005. Recognition of this decrease in mortality is important for physicians caring for these patients as they weigh the pros and cons of SCT vs novel agent-based treatment in management of amyloidosis. Disclosures: Gertz: Celgene: Honoraria; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lacy:Celgene: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding.

Higher Plasma Cell Burden Predicts for Early Death In Patients with AL Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1893-1893 ◽  
Author(s):  
Cheng E. Chee ◽  
S. Vincent Rajkumar ◽  
Morie Abraham A Gertz ◽  
Martha Lacy ◽  
Steven Zeldenrust ◽  
...  
Keyword(s):  
Research Funding ◽  
Plasma Cells ◽  
Troponin T ◽  
Early Death ◽  
Organ Damage ◽  
Early Mortality ◽  
Al Amyloidosis ◽  
End Organ Damage ◽  
M Spike ◽  
Beta 2 Microglobulin

Abstract Abstract 1893 Background: Recent data has shown that the level of immunoglobulin free light chain (FLC) is a prognostic factor for patients with AL amyloidosis. Approximately 25% of patients with AL amyloidosis have coexistent multiple myeloma (MM) with myeloma-related end-organ damage and patients may also present with 310% plasma cells (PC) in the bone marrow (BM) in the absence of any MM features. The goal of this study was to determine the effect of increased BM plasmacytosis in the absence of MM end-organ damage on early mortality. Methods: We performed a retrospective study of 263 consecutive patients with AL amyloidosis seen at Mayo Clinic within 30 days of diagnosis from July 2002 – April 2009, to compare the effect of PC burden among those who died within 90 days of diagnosis (n=88) and those who survived more than 90 days after diagnosis (n=175). Only those patients with documented BM PC were included in this study. MM end-organ damage was defined according to the CRAB criteria. Results: In those who died <90 days after diagnosis and patients who lived beyond 90 days, the proportion of patients with 310% BM PC were 57% and 55%, respectively. Overall survival (OS) was significantly shorter in the early mortality group when there was 310% BM PC present at diagnosis (25 vs. 54 days, p=0.006), but this was not observed in the group who survived beyond 90 days (Figure 1). In patients with 310% BM PC, troponin-T, ejection fraction (EF), and hemoglobin (Hgb) were significantly worse in the early mortality cohort but patients who survived beyond 90 days had significant increase in intraventricular septal (IVS) thickness and beta-2 microglobulin (Table 1). As expected, patients with 310% BM PC in both cohorts had significantly higher serum M-spike and involved FLC (Table). The same cohort of patients were analyzed substituting MM-related end-organ damage for 310% BM PC and similar results were observed with the exception of uric acid and calcium being significantly higher in the early mortality cohort with MM (results not shown). Conclusion: This study demonstrated that an excess of early—but not late—deaths occur in AL amyloidosis patients with 310% BM PC at diagnosis. In our cohort, this finding can be attributed to higher troponin-T levels, indicating more severe cardiac involvement as observed by worse cardiac function. These findings warrant additional investigation. 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.

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.

Soluble ST2 (sST2) Is a Novel Valuable Prognostic Marker Among Patients With Immunoglobulin Light Chain (AL) Amyloidosis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3095-3095 ◽  
Author(s):  
Angela Dispenzieri ◽  
Amy K. Saenger ◽  
Shaji K. Kumar ◽  
Morie A. Gertz ◽  
Martha Q Lacy ◽  
...  
Keyword(s):  
Heart Failure ◽  
Research Funding ◽  
Troponin T ◽  
High Sensitivity ◽  
Staging System ◽  
Cardiac Biomarkers ◽  
Al Amyloidosis ◽  
Prognostic Information ◽  
Soluble St2 ◽  
Staging Systems

Abstract The use of soluble cardiac biomarkers such as NT-proBNP and troponin has revolutionized prognostication for patients with AL amyloidosis and led to their use in the Mayo 2004 and 2012 staging systems. Novel soluble markers with different phenotypic targets may further improve this approach. Soluble ST2 (sST2), which is the circulating form of the IL-33 receptor, has been shown to be a marker of cardiac remodelling and fibrosis, is predictive of mortality in patients with congestive heart failure, and is predictive of risk of GVHD and GVHD mortality. Samples of blood of patients with AL amyloidosis collected and frozen at -20C under a biobank IRB protocol were retrieved and sST2 measured. Patients were eligible for present study if they had a research sample collected within 90 days of their AL amyloidosis diagnosis. We have validated that values do not change significantly with storage at -20C over a 90 day period. Concentrations of sST2 were determined using a novel high-sensitivity sandwich immunoassay (Presagew ST2; Critical Diagnostics, San Diego, CA, USA). The sST2 assay had within-run and total coefficients of variation of <7.5% and 13.0% across its measurement range. Samples from 273 consecutive patients meeting diagnostic criteria for AL amyloidosis seen at our institution from 1/9/2010 to 12/22/2011 were evaluated. Median age was 63. 58% were male. One hundred and thirty have died over 33.9 months. Correlation between sST2 and the other biomarkers was modest with correlation coefficients of 0.48 and 0.20 for NT-proBNP and Troponin T, respectively. Patients with sST2 above and below the median of 27.2 ng/mL (6.3-596) had significant differences in 2 year overall survival: 71.2% to 39% (figure). In multivariate modeling sST2’s prognostic value was independent of the Mayo 2004 and the Mayo 2012 cardiac biomarker staging systems, the latter of which also includes prognostic information relating to plasma cell burden. In these multivariate models, sST2 median had a RR of 2.4, (95%CI 1.6, 3.6 p<0.001) with the Mayo 2004 Staging system (RR of 2.9, 95%CI 2.1, 4.1p<0.001); and sST2 median had a RR of 2.2 (95%CI 1.5, 3.4, p<0.001) with the Mayo 2012 staging system (RR 1.9, 95%CI 1.6, 2.3, p<0.001). A larger cohort including patients with longer follow up will be presented at the meeting as will gender specific cut off values and a comparison of our values with those previously used to prognosticate in patients with heart failure. sST2 appears to be a novel powerful prognostic factor for patients with AL amyloidosis. Because sST2 functions as a decoy receptor, which neutralizes the benefits of IL-33, it may play a role in the deleterious phenotype seen in patients with AL, i.e. myocardial hypertrophy and reduction of contractility. Disclosures: Saenger: Critical Diagnostics : Research Funding; Roche: Research Funding. Jaffe:Critical Diagnostics: Consultancy, Research Funding; Roche: Consultancy.

Short Daratumumab Consolidation in Patients with AL Amyloidosis or Lcdd Improves Complete Response Rates and Modifies Bone Marrow Microenvironment

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 25-25
Author(s):  
Efstathios Kastritis ◽  
Pantelis Roussakis ◽  
Ioannis V Kostopoulos ◽  
Foteini Theodorakakou ◽  
Despina Fotiou ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Board Of Directors ◽  
Research Funding ◽  
Plasma Cells ◽  
Al Amyloidosis ◽  
Primary Therapy ◽  
Advisory Committees ◽  
Hematologic Response ◽  
Short Course ◽  
Before And After

A deep and profound hematologic response is associated with substantial improvement in the probability of improvement in organ function and survival in patients with AL amyloidosis or LCDD. Bortezomib-based therapy is the mainstay of anti-clonal therapy for AL amyloidosis and LCDD, however, hemCR is achieved in only 20% of patients. Daratumumab has shown to be active and able to induce rapid responses in patients with AL amyloidosis. Plasma cell clones in AL are small and indolent and further improvement of hematologic response could be achieved by consolidation strategies. Given the activity of daratumumab and the rapid induction of deep responses in AL amyloidosis, we treated patients with AL amyloidosis or LCDD , who had not achieved a hemCR after standard therapy, with a short course of daratumumab. In consenting patients, we evaluated MRD in the bone marrow (BM), before and after consolidation, by means of next generation multiparametric flow cytometry (NGF-MFC), using the Euroflow protocol. Thus, beyond the presence of MRD , we were able to evaluate also other components of the BM microenvironment and their changes before and after daratumumab. All patients were treated in the Department of Clinical Therapeutics, Athens, Greece. The study included patients who had achieved either PR or VGPR after completing standard bortezomib-based primary therapy. Consolidation included 4 weekly infusions of daratumumab 16 mg/kg. Pre-emptive therapy for IRR was given starting two days before the first infusion of daratumumab that included low dose steroids (equivalent of 16 mg of methylprednisolone), H1 & H2 inhibitors and montelukast. Twenty-five patients (20 with AL and 5 with LCDD) received daratumumab consolidation. Among patients with AL amyloidosis, median age is 65, kidneys and heart were involved in 70% and 75% respectively, baseline Mayo stage was 20%, 70% and 10% for stage 1,2 & 3 respectively. Baseline immunofixation in serum or urine was positive in all patients, median baseline dFLC at diagnosis was 125 mg/L (range 60-7228). Median time from start of first line therapy to daratumumab consolidation was 7 months and all patients had completed their planned therapy. At the time of initiation of daratumumab, 24 patients were in VGPR and one in PR and the median dFLC level was 12 mg/L; all had positive serum or urine immunofixation and in all patients MRD was detectable by NGF-MFC. Except for one patient, all the others received the planned 4 daratumumab infusion. Mild IRRs occurred in 3 patients (grade 1 in 2 and grade 2 in one patient); no IRRs occurred after the first infusion. One month after completion of consolidation with daratumumab, median dFLC dropped to 5 mg/L and 10 (40%) of the patients improved their response: 36% from VGPR to hemCR and one patient with PR to VGPR. Among those that achieved a hemCR, 5 (50%) became MRD negative by NGF-MFC. However, even among those that remained MRD-positive there was a decrease in the number of aberrant plasma cells (APCs) by a median of one log. In MRD-positive patients a change in the composition of the remaining phenotypic subclones of APCs was also observed. Regarding the other BM cell populations, we observed statistically significant changes in B-cell precursors (increased from 14.32%+/-11.75% to 34.76% +/-24.11%, p=0.0004), naïve B-cells (decreased from 65.58%+/-17.56% to 47.37%+/-22.66%, p=0.0003), T cells (increased from 6.44% +/- 2.78% to 10.86%+/- 6.407%, p=0.0007), CD27+ NK & NKT cells (increased from 15.65% +/-13.5% to 36.34%+/- 24.43%, p=0.0002), mast cells (increased from 0.0092%+/-0.0123% to 0.011%+/-0.012%, p=0.002) and erythroblasts (increased from 1.82%+/-0.97% to 2.41%+/- 1.03%, p=0.076). Due to the small numbers it was not possible to make meaningful comparison between MRD positive and negative patients. However, the above results indicate that even a short course of daratumumab was able to cause significant changes in the BM microenvironment of these patients. From this small prospective study we conclude that consolidation with a short course of daratumumab can improve the depth of response in patients with AL or LCDD that have not achieved a hemCR after primary therapy, even to the depth of undetected MRD. In addition, daratumumab causes significant changes in the BM environment, which need further investigation in order to understand their implications. Disclosures Kastritis: Genesis Pharma: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Gavriatopoulou:Genesis Pharma: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:BMS: Honoraria; Celgene: Honoraria; Takeda: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Genesis pharma SA: Honoraria, Other: travel expenses , Research Funding; Sanofi: Honoraria. Dimopoulos:Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Personal fees, Research Funding, Speakers Bureau. OffLabel Disclosure: daratumumab for AL amyloidosis

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 Increased Early Mortality after Fludarabine and Melphalan Conditioning with Peripheral Blood Grafts in Haploidentical SCT with Post-Transplant Cyclophosphamide

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 4496-4496 ◽  
Author(s):  
Luke Eastburg ◽  
David A. Russler-Germain ◽  
Ramzi Abboud ◽  
Peter Westervelt ◽  
John F. DiPersio ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
T Cell ◽  
Board Of Directors ◽  
Research Funding ◽  
Early Mortality ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Post Transplant ◽  
Equity Ownership

The use of post-transplant cyclophosphamide (PTCy) in the context of haploidentical stem cell transplant (haplo-SCT) has led to drastically reduced rates of Graft-vs-Host (GvH) disease through selective depletion of highly allo-reactive donor T-cells. Early trials utilized a reduced-intensity Flu/Cy/TBI preparative regimen and bone marrow grafts; however, relapse rates remained relatively high (Luznik et al. BBMT. 2008). This led to the increased use of myeloablative (MA) regimens for haplo-SCT, which have been associated with decreased relapse rates (Bashey et al. J Clin Oncol. 2013). Most studies have used a MA total body irradiation (TBI) based regimen for haplo-SCT. Preparative regimens using fludarabine and melphalan (FluMel), with or without thiotepa, ATG, and/or low dose TBI have also been reported using bone marrow grafts. Reports on the safety and toxicity of FluMel in the haplo-SCT setting with PTCy and peripheral blood stem cell (PBSC) grafts are lacking. In this two-center retrospective analysis, the safety/toxicity of FluMel as conditioning for haplo-SCT was evaluated. We report increased early mortality and toxicity using standard FluMel conditioning and PBSC grafts for patients undergoing haplo-SCT with PTCy. 38 patients at the University of Rochester Medical Center and the Washington University School of Medicine underwent haplo-SCT with FluMel conditioning and PBSC grafts between 2015-2019. Outcomes were measured by retrospective chart review through July 2019. 34 patients (89.5%) received FluMel(140 mg/m2). Two patients received FluMel(100 mg/m2) and two patients received FluMel(140 mg/m2) + ATG. The median age at time of haplo-SCT was 60 years (range 21-73). 20 patients were transplanted for AML, eight for MDS, two for PMF, two for NHL, and five for other malignancies. The median Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) score was 4 (≥3 indicates high risk). 11 patients had a history of prior stem cell transplant, and 16 patients had active disease prior to their haplo-SCT. Seven patients had sex mismatch with their stem cell donor. Median donor age was 42 (range 21-71). 20 patient deaths occurred by July 2019 with a median follow up of 244 days for surviving patients. Nine patients died before day +100 (D100, "early mortality"), with a D100 non-relapse mortality (NRM) rate of 24%. Median overall and relapse free survival (OS and RFS, respectively) were 197 days (95% CI 142-not reached) and 180 days (95% CI 141-not reached), respectively, for the entire cohort. The 1 year OS and NRM were 29% and 50%. The incidence of grades 2-4cytokine release syndrome (CRS) was 66%, and 52% of these patients were treated with tocilizumab. CRS was strongly associated with early mortality, with D100 NRM of 36% in patients with grade 2-4 CRS compared to 0% in those with grade 0-1. The incidence of acute kidney injury (AKI) was 64% in patients with grade 2-4 CRS, and 8% in those without (p < 0.001). 28% of patients with AKI required dialysis. Grade 2-4 CRS was seen in 54% of patients in remission prior to haplo-SCT and in 92% of those with active disease (p = 0.02). Of the 9 patients with early mortality, 89% had AKI, 44% needed dialysis, and 100% had grade 2-4 CRS, compared to 31%, 10%, and 55% in those without early mortality (p = 0.002, p = 0.02, p = 0.01). Early mortality was not significantly associated with age, HCT-CI score, second transplant, disease status at transplant, total dose of melphalan, volume overload/diuretic use, or post-transplant infection. In conclusion, we observed a very high rate of NRM with FluMel conditioning and PBSC grafts for haplo-SCT with PTCy. The pattern of toxicity was strongly associated with grade 2-4 CRS, AKI, and need for dialysis. These complications may be mediated by excessive inflammation in the context of allo-reactive donor T-cell over-activation. Consistent with this, multiple groups have shown that FluMel conditioning in haplo-SCT is safe when using bone marrow or T-cell depleted grafts. Based on our institutional experiences, we would discourage the use of FluMel as conditioning for haplo-SCT with PTCy with T-cell replete PBSC grafts. Alternative regimens or variations on melphalan-based regimens, such as fractionated melphalan dosing or inclusion of TBI may improve outcomes but further study and randomized controlled trials are needed. This study is limited in its retrospective design and sample size. Figure Disclosures DiPersio: WUGEN: Equity Ownership, Patents & Royalties, Research Funding; Karyopharm Therapeutics: Consultancy; Magenta Therapeutics: Equity Ownership; Celgene: Consultancy; Cellworks Group, Inc.: Membership on an entity's Board of Directors or advisory committees; NeoImmune Tech: Research Funding; Amphivena Therapeutics: Consultancy, Research Funding; Bioline Rx: Research Funding, Speakers Bureau; Macrogenics: Research Funding, Speakers Bureau; Incyte: Consultancy, Research Funding; RiverVest Venture Partners Arch Oncology: Consultancy, Membership on an entity's Board of Directors or advisory committees. Liesveld:Onconova: Other: Data safety monitoring board; Abbvie: Membership on an entity's Board of Directors or advisory committees.

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

Cardiac Biomarkers Predict for Ability To Tolerate and Complete Therapy with Lenalidomide ± Dexamathosone in AL Amyloidosis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 130-130 ◽  
Author(s):  
Angela Dispenzieri ◽  
Martha Lacy ◽  
Steven Zeldenrust ◽  
Suzanne R. Hayman ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Adverse Events ◽  
Overall Response Rate ◽  
Response Rate ◽  
Troponin T ◽  
Single Agent ◽  
Cardiac Biomarkers ◽  
Al Amyloidosis ◽  
Significant Activity ◽  
Cardiac Biomarker ◽  
Overall Response

Abstract Background: Primary systemic amyloidosis (AL) is an incurable plasma cell disorder. Lenalidomide, especially in conjunction with dexamethasone, has been shown to be highly active in patients with multiple myeloma. Methods: We studied the toxicity and efficacy of lenalidomide in patients with symptomatic AL. Patients received single agent lenalidomide. If progression by 3 months or no evidence of hematologic response after 3 cycles, dexamethasone was added. Originally, twenty-three patients (Cohort 1) were enrolled according to study design. Because of a significant early drop out rate and notable activity of the regimen, the trial was modified to include an additional 15 patients (Cohort 2). Baseline characteristics and adverse events are available for all enrolled patients, but at the time of this writing, response data are available for Cohort 1 patients due to short follow-up of Cohort 2, but will be updated by the time of the meeting. Results: Median age was 64 years, with 69% male. Twenty-three were previously treated. Organ involvement was cardiac (67%), renal (64%), hepatic (17%), nerve (17%). Thirty-three, twenty-two, and forty-four percent of patients were cardiac biomarker stage 1, 2, and, 3 respectively. Of the 37 patients, one was a cancel, and 6 have not yet made it through 3 months of protocol treatment and event monitoring. The respective median follow-ups for Cohorts 1 and 2 are 17 and 3.4 months. Of the remaining, 30 patients, within the first 3 cycles of therapy fifteen patients discontinued treatment: 7 early deaths and 8 adverse events or other causes. Three additional patients died 0.5 to 2 months after stopping treatment. The best predictor for early withdrawal and/or death was baseline NT-proBNP and cardiac biomarker staging system (cut-offs for serum troponin T &lt;0.035 ng/ml and NT-proBNP &lt;332 pg/ml--Stage I neither above cut-off; Stage III, both above cut-off; and Stage II, one above cut-off). Figure1 Figure1. Figure 2 Figure 2. Of the twenty 22 patients assessed for response ten patients responded to treatment for an overall response rate of 45%, including 23% organ responders. Among the patients with organ responses, there were four renal responses, two cardiac responses and two liver responses. All but one of the responders had dexamethasone added to their treatment program. The most common grade 3−4 adverse events at least possibly attributable to lenalidomide were neutropenia (38%), thrombocytopenia (21%), fatigue (15%), and rash (12%). Conclusions: Lenalidomide and dexamethasone has significant activity in patients with AL with an overall response rate of 45%. Baseline NT−proBNP may be an effective eligibility screening strategy for subsequent trials.

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

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 746-746 ◽  
Author(s):  
Jeffrey A Zonder ◽  
Vaishali Sanchorawala ◽  
Rachel M. Snyder ◽  
Jeffrey Matous ◽  
Howard Terebelo ◽  
...  
Keyword(s):  
Peripheral Neuropathy ◽  
Board Of Directors ◽  
Research Funding ◽  
Dose Adjustment ◽  
Response Rate ◽  
Al Amyloidosis ◽  
Two Stage ◽  
Advisory Committees ◽  
Subsequent Dose ◽  
Stage 1

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

Blood Transfusion and Erythropoiesis Stimulating Agents (ESAs) Use In Patients with Diffuse Large B-Cell Lymphoma (DLBCL)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3357-3357
Author(s):  
Nicolas Batty ◽  
Elham Ghonimi ◽  
Lei Feng ◽  
Anas Younes ◽  
Rodriguez Alma ◽  
...  
Keyword(s):  
Blood Transfusion ◽  
Research Funding ◽  
B Cell Lymphoma ◽  
Continuous Variables ◽  
Chop Chemotherapy ◽  
Chi Square ◽  
Period 2 ◽  
Time Period ◽  
Before And After ◽  
Time Periods

Abstract Abstract 3357 Background: The national coverage decision regarding reimbursement for usage of ESAs for chemotherapy-induced anemia (CIA) from the Centers for Medicare & Medicaid Services (CMS) underwent changes in early 2007. This study examines the rates of packed red blood cell (PRBC) transfusions and usage of ESAs before and after the changes of these health care regulations in patients with DLBCL treated with standard Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (R-CHOP) chemotherapy. Methods: We retrospectively reviewed from records of patients seen at our center from March 2007 to January 2009 with previously untreated DLBCL, identified from a prospective database of the lymphoma registry at UT-MDACC. Eligibility for inclusion in this evaluation required treatment with at least 4 cycles of standard R-CHOP chemotherapy, one cycle given every three weeks, and adequate information regarding ESA and blood transfusion administration. Three time periods were identified based on 3 successive changes in billing coverage guidelines for ESAs. These changes were based upon reimbursement of ESAs for hemoglobin levels of ≤ 12 g/dl (Period 1), ≤ 11 g/dl (Period 2) and ≤ 10 g/dl (Period 3). The number of PRBC transfusions and number, dose, and type of ESA injections were reported per patient. We also evaluated the overall survival (OS) rates for patients in these three time intervals. Chi-square and Kruskal-Wallis tests were used to analyze categorical and continuous variables, respectively. The Kaplan-Meier and log-rank tests were used to estimate OS rates and evaluate the associations of PRBC transfusions and use of ESAs with OS, respectively. Results: 160 records were available for review, and 129 were included in this analysis. There were 77 patients in Period 1, 31 in Period 2, and 21 in Period 3. With a median follow-up time of 24.7 months (range 1 – 38), PRBCs and ESAs were administered to 43 and 34 patients, respectively. PRBC transfusion rates in each time period were: 29 (37.7%) for Period 1, 8 (25.8%) for Period 2, and 6 (28.6%) for Period 3 (p = 0.43). Patients receiving ESAs in each time period were 25 (33.3%), 5 (16.7%), and 4 (19%), respectively (p = 0.16). There were no differences in the rates of PRBC transfusions (p = 0.88) or use of ESAs (p = 0.36) for these patients over these time periods, although the latter observation may be due to small numbers of patients in each period group. The 2-year OS rate was 68% for those 43 who received transfusions compared to 94% for the 86 patients who did not require transfusions (p=0.001), while there was no statistical difference between OS rates for those 34 who did and the 95 patients who did not receive ESAs (87% vs 84%, p=0.97). Conclusions: The changes of CMS reimbursement for ESAs in patients with CIA may have decreased the use of ESAs, but in this study have not made any changes in the rates of PRBC transfusions in patients with DLBCL receiving standard R-CHOP chemotherapy. Furthermore, OS rates were lower in those requiring transfusions than in those who did not, but the use of ESAs appeared to have no effects on these results. Disclosures: Wang: Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Fowler:Millennium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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