The frequency of chromosomal abnormalities in AL amyloidosis and their impact on treatment response.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e19539-e19539
Author(s):  
Hassan Yameen ◽  
Shayna Sarosiek ◽  
Vaishali Sanchorawala
Keyword(s):  
Plasma Cells ◽  
Response Rate ◽  
Chromosomal Abnormalities ◽  
Complete Response ◽  
High Dose ◽  
Al Amyloidosis ◽  
Response Data ◽  
Hematologic Response ◽  
Number Of Patients ◽  
High Dose Melphalan

e19539 Background: Chromosomal abnormalities (CA) found in AL amyloidosis (AL) are similar to those found in multiple myeloma (MM.) However, t(11;14) has been reported more frequently in AL, anywhere from 30% - 50% in studies. It has been reported that the presence of t(11;14) confers a lower hematologic response rate with bortezomib-based therapy (BBT) and a better hematologic response rate with high dose melphalan and autologous stem cell transplantation (HDM/SCT). Methods: We performed a retrospective review of 307 newly diagnosed patients seen at our center between January 2013 and December 2017, for whom interphase fluorescent in-situ hybridization (iFISH) data, performed on bone marrow aspirate using standard MM FISH probes on enriched plasma cells after magnetic separation, were available. Patients who already had iFISH performed prior to their visit with us were also included. We collected data on the incidence of CA, first line treatment, and hematologic response to this treatment. Results: Of the 307 patients, CA were not detected in 37%. 21% had t(11;14), 25% had 13q deletion, 21% had IgH rearrangements with an undetermined partner chromosome, and 11% had 1q21 gain. In those for whom initial treatment and hematologic response data were available, in patients with t(11;14), hematologic complete response (CR) was achieved by 18% following HDM/SCT and 27% following BBT. For those with 1q21 gain, CR was achieved by 33% following HDM/SCT and 19% following BBT. In contrast, hematologic CR was achieved by 47% following HDM/SCT and 40% following BBT for those who had no detectable CA with iFISH. Conclusions: Our study shows a lower incidence of t(11;14) in AL compared to other studies. This may be partly explained by the high number of patients with IgH rearrangements with undetermined partner chromosomes, some of whom may indeed harbor t(11;14). Our study also did not show a better hematologic response rate with HDM/SCT in t(11;14) patients compared with BBT. Hematologic response rates were much better both with HDM/SCT and BBT for those with no detected CA compared to patients who had t(11;14) or 1q21 gain.

High Dose Melphalan with Autologous Stem Cell Transplantation Overcomes Poor Prognosis of Primary Amyloidosis

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1350-1350
Author(s):  
Simrit Parmar ◽  
Mubeen Khan ◽  
Gabriela Rondon ◽  
Nina Shah ◽  
Qaiser Bashir ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Plasma Cells ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Bone Marrow Plasma ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Abstract 1350 Background: Systemic Primary AL Amyloidosis is a rare but potentially fatal disease resulting from tissue deposits of amyloid fibrils derived from monoclonal immunoglobulin light chains. High-dose melphalan followed by autologous hematopoietic stem cell transplant (auto HCT) is associated with hematologic and organ responses and improved survival. Methods: In this retrospective analysis we identified 46 patients with primary AL amyloidosis who received auto HCT between 01/1998 to 05/2010 at MDACC. Organ responses were determined using Amyloidosis Consensus Criteria. Results: The median age at auto HSCT was 56 years (34-74) where 61% were males and 35% were older than 60 years of age. 61% had lambda light chain restriction and only 4% had cytogenetic abnormalities. Disease characteristics are summarized in Table 1. The median time from diagnosis to auto HCT was 6.6 months (2.2-29.4 months). 22 pts (47.8%) had one organ, 19 pts (41.3%) had 2 organ and 4 pts (8.7%) had 3 organ involvement. 11 pts (23.9%) had heart and 35 pts (76.1%) had kidney involvement. The median follow up from the time of diagnosis was 22.4 months and from time of auto HCT was 16.7 months. High dose Melphalan dose was 200mg/m2 in 24 pts (52%) and 140mg/m2 in 22 (47.8%). There were 4 early deaths and 4 pts whose follow up was less than 3 months and their response was not assessed. Out of the 38 evaluable patients, the post-transplant organ responses were as follows ≥PR 25(66%), ≥stable disease 35(92%) (Table2). The hematologic responses were: CR=5 (13%), ≥VGPR=10(26%), ≥PR=26 (68%), ≥SD=37(97%). One patient had progressive disease. There was a correlation between organ response and hematologic response (chi square;p<10-3). The day-100 treatment related mortality (TRM) was 8.7% and 1-yr TRM was 13%. The median progression-free (PFS) and overall survival (OS) from auto HCT was 73.8 months and not reached (from transplant). The median PFS and OS from diagnosis were 93 months and 59.8 months respectively. In multivariate analysis, heart involvement (p=0.01), female sex (p=0.011), age ≥60 years (p=0.002), bone marrow plasma cells≥10% (p=0.043) and Beta-2 microglobulin>3.5mg/l (p=0.02) were associated with poor OS. Improved OS correlated with organ response (52.6 vs 11.4 months; p=0.01) and hematologic response (52.6 vs.6.1months; p=0.002). Hemoglobin <10 g/dl (p=0.047), bone marrow plasma cells≥10% (p=0.043) and age≥60 years (p=0.075) were associated with shorter PFS. Hematologc response (p=0.48) and organ response (p=0.12) were not associated with improved PFS. Conclusion: In this analysis the outcome of patients with primary systemic AL amyloidosis was durable with auto HCT with acceptable mortality risk and improved survival. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Calreticulin expression in the clonal plasma cells of patients with systemic light-chain (AL-) amyloidosis is associated with response to high-dose melphalan

Blood ◽  
2008 ◽  
Vol 111 (2) ◽  
pp. 549-557 ◽  
Author(s):  
Ping Zhou ◽  
Julie Teruya-Feldstein ◽  
Ping Lu ◽  
Martin Fleisher ◽  
Adam Olshen ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Calcium Binding ◽  
Plasma Cells ◽  
Complete Response ◽  
High Dose ◽  
Al Amyloidosis ◽  
Embryonic Fibroblasts ◽  
Knock Out ◽  
High Dose Melphalan

In high doses with stem-cell transplantation, melphalan is an effective but toxic therapy for patients with systemic light-chain (AL-) amyloidosis, a protein deposition and monoclonal plasma cell disease. Melphalan can eliminate the indolent clonal plasma cells that cause the disease, an achievement called a complete response. Such a response is usually associated with extended survival, while no response (a less than 50% reduction) is not. Gene-expression studies and a stringently supervised analysis identified calreticulin as having significantly higher expression in the pretreatment plasma cells of patients with systemic AL-amyloidosis who then had a complete response to high-dose melphalan. Calreticulin is a pleiotropic calcium-binding protein found in the endoplasmic reticulum and the nucleus whose overexpression is associated with increased sensitivity to apoptotic stimuli. Real-time PCR and immunohistochemical staining also showed that expression of calreticulin was higher in the plasma cells of those with a complete response. Furthermore, wild-type murine embryonic fibroblasts were significantly more sensitive to melphalan than calreticulin knock-out murine embryonic fibroblasts. These data have important implications for understanding the activity of melphalan in plasma-cell diseases and support further investigation of calreticulin and its modulation in patients with systemic AL-amyloidosis receiving high-dose melphalan.

Outcome of Patients with AL Amyloidosis Who Do Not Achieve Hematologic Complete Response After Treatment with High Dose Melphalan and Autologous Transplantation: Results In a Series of 421 Patients

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2394-2394
Author(s):  
M. Teresa Cibeira ◽  
Vaishali Sanchorawala ◽  
David C Seldin ◽  
Karen Quillen ◽  
Nancy Andrea ◽  
...  
Keyword(s):  
Response Rate ◽  
Medical Center ◽  
Autologous Transplantation ◽  
Complete Response ◽  
High Dose ◽  
Al Amyloidosis ◽  
Entire Cohort ◽  
Organ Response ◽  
High Dose Melphalan ◽  
Related Mortality

Abstract Abstract 2394 Background: Treatment of AL amyloidosis with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT) results in hematologic complete response (CR) in 40% of patients and a median survival of about 5 years. Hematologic CR is associated with improved organ function and long survival. Whether patients who fail to achieve CR have any benefit from HDM/SCT has not been examined in a large series of patients. OBJECTIVE: The aim of this study was to investigate the outcome of patients with AL who do not achieve a CR after HDM/SCT and assess the transplant-related mortality (TRM) at a single specialized referral center. DESIGN and PATIENTS: Retrospective analysis of 421 patients with AL amyloidosis treated with HDM/SCT (100 to 200 mg/m2) in the Amyloid Treatment and Research Program at Boston Medical Center between July 1994 and December 2008. The subgroup of patients who did not achieve a CR at 1 year after transplant was analyzed in detail to assess their outcome in terms of organ response, event-free survival (EFS) and overall survival (OS). The median follow-up was 4 years (range, 0 to 15.6) for the entire cohort and 6.3 years (range, 1 to 15.6 years) for surviving patients. RESULTS: Three hundred and forty patients out of 421 included in the study (81%) were evaluable for response at 1 year post-HDM/SCT. The CR rate among the 1-year survivors was 43% while 195 patients (57%) did not achieve a CR, defined as disappearance of all signs of monoclonal gammopathy and bone marrow plasmacytosis. By consensus criteria, organ response rate in the non-CR group was 53.3%, compared to 78.6% for CR-patients (p<0.0001). Hematologic and/or clinical progression was observed in 68% (133/195) of non-CR patients, with a median time to progression of 1.5 years (range, 0.13 to 11.3). More than half of these patients (68/133) received second line therapy with melphalan (4), thalidomide (21), bortezomib (8), lenalidomide (24), dexamethasone (8), a second HDM/SCT (2), and a reduced-intensity allogeneic SCT (1). Fifty (26%) of the non-CR patients are alive and clinically stable, although 12 of them received further treatment due to persistence of clonal disease without evidence of clinical/organ progression. Median EFS in the non-CR population was 2 years (CI95% 1.6–2.7), as compared with 8.3 years for patients in CR (p<0.0001). Outcome of non-CR patients in terms of event rate and EFS was not influenced by the light chain isotype. The OS was significantly longer for evaluable patients who achieved a CR compared with those who did not (13.2 versus 5.9 years, p<0.0001). The estimated probability of survival for patients in CR was 86% (CI95% 79–91%) at 5 years and 67% (CI95% 57–76%) at 10 years, while it was 58% (CI95% 50–65%) and 24% (CI95% 16–32%) at 5 and 10 years, respectively, for those who did not achieve CR. At the time of this analysis, 234 (55.5%) of the 421 patients have died, 81 (19.2%) of them within the first year after HDM/SCT. Transplant-related mortality was 11.4%, decreasing to 5.6% for the 124 patients who received HDM/SCT in the last 5 years, despite the fact that the patients' clinical characteristics were similar in the two time periods. CONCLUSIONS: Treatment of selected AL patients with HDM/SCT resulted in durable hematological responses, high organ response rate and a median OS of almost 6 years even in those who do not achieve a CR after HDM/SCT. Supported by NIH HL-68705 and Instituto de Salud Carlos III (grant CM07/00108). Disclosures: Sanchorawala: Celgene corp: Research Funding.

scholarly journals Safety and Efficacy of Once Weekly Subcutaneous Bortezomib in Advanced Stage AL Amyloidosis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4753-4753 ◽  
Author(s):  
Naresh Bumma ◽  
Frederic J. Reu ◽  
Christy Samaras ◽  
Hien K. Duong ◽  
Mitchell R. Smith ◽  
...  
Keyword(s):  
Cardiac Toxicity ◽  
Cardiac Risk ◽  
High Dose ◽  
Al Amyloidosis ◽  
Hematologic Response ◽  
Staging Systems ◽  
Plasma Cell Disorder ◽  
High Dose Melphalan ◽  
Cell Disorder

Abstract Background: Intravenous bortezomib (BTZ) based therapy is effective for AL amyloidosis, although cardiac toxicity is a concern in advanced stage patients (pts). Survival in AL amyloidosis is dependent on hematologic and cardiac organ response emphasizing the need for safe and effective treatments. Staging systems to identify high cardiac risk pts developed by Dispenzieri et al JCO 22.18 (2004): 3751-3757 and revised by Kumar et al JCO 30.9 (2012): 989-995 can be used to guide therapy. Since January 2011, our institutional preference has been to treat plasma cell disorder patients with subcutaneous (SC) once weekly BTZ and have eliminated requirement for intravenous hydration. Considering the historically poor outcome of high cardiac risk AL amyloid pts with conventional therapy, we did not exclude them from weekly SC bortezomib and report safety and efficacy data here. Methods: After IRB approval, we reviewed our plasma cell disorder registry and identified 40 pts with AL amyloidosis who received weekly SC BTZ as initial therapy between January 2011 and June 2014. Review of the electronic medical record was used to confirm details of BTZ based regimens, response to treatment according to consensus criteria (Palladini et al. JCO (2012): 4541-4549.), and adverse events including neuropathy and cardiac toxicity graded via the NCI CTCAE version 4.0. We ascribed advanced cardiac stage to pts who were stage 3 by the 2004 staging and 3 and 4 by the 2012 staging. Six pts were excluded from hematologic response assessment as the difference between the involved and uninvolved free light chains was less than 50 mg/L at baseline. Results: Out of the 34 evaluable pts, 18 (53%) and 23 (68%) were found to be advanced cardiac stage by the respective staging systems and 1 of these pts died of ventricular tachycardia arrest about 8 hours after initial 1 mg/m2 bortezomib dose with 8 mg of dexamethasone. Additional toxicity included grade 4 ventricular tachycardia in 1 patient after the fifth cycle of BTZ although not in close relation to the BTZ dose. Neurologic toxicity attributed to BTZ was seen in 4 pts (10%) with 3 grade 1 and 1 grade 3. Six deaths occurred in SC BTZ treated pts and all were in advanced cardiac stage pts. Two advanced cardiac stage pts successfully underwent high dose melphalan and autologous stem cell transplant. Hematologic responses are listed in the tables. All patients received corticosteroid. Table 1Hematologic response with weekly SQ BTZ in cardiac risk stage 3 disease (as per 2004 staging) Alkylating agent Hematologic response (median follow up: 13 months)VGPR or betterPartial responseNo response / deathYes ( N=9)33%22%44%No ( N=9)55%22%22% Table 2 Hematologic response with weekly SQ BTZ in stage 3/4 disease (as per 2012 staging) Alkylating agent Hematologic response (median follow up 13 months) VGPR or better Partial response No response / death Yes (N=12) 42% 17% 42% No (N=11) 64% 27% 9% Discussion: Only 2 pts experienced cardiac toxicity and 1 was in close temporal relation to the BTZ dose but resulted in death. The responses seen with weekly SC BTZ in advanced cardiac stage AL amyloidosis are reasonably consistent with those seen with intravenous dosing although small patient numbers limit this comparison. Hematologic response in pts treated with BTZ and corticosteroid alone can support a response adapted therapeutic approach. Two advanced cardiac stage pts were able to undergo high dose melphalan after improvement in their cardiac status with BTZ based therapy. Once weekly SC BTZ based therapy was safe and effective treatment for AL amyloidosis even in high cardiac risk pts. Disclosures No relevant conflicts of interest to declare.

Early Serum Free Light Chain Responses Following High-Dose Melphalan and Stem Cell Transplantation for AL Amyloidosis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4352-4352
Author(s):  
Saulius Girnius ◽  
Frank Tsai ◽  
David C. Seldin ◽  
Karen Quillen ◽  
Lisa Yanarella ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Light Chain ◽  
Predictive Value ◽  
Complete Response ◽  
High Dose ◽  
Al Amyloidosis ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
High Dose Melphalan

Abstract Abstract 4352 AL amyloidosis is a clonal plasma cell dyscrasia which produces insoluble amyloid fibrils from Ig light chains, leading to multiorgan failure. High dose melphalan and autologous stem cell transplantation (HDM/SCT) can induce remission and extend survival, but response is assessed at 6 and 12 months. Serum free light chain (FLC) assays can improve detection of AL amyloidosis, have prognostic significance, and are routinely used to assess response to treatment. Serum half life of FLCs is only 2-6 hours, even with diminished glomerular filtration rates. In a small prospective series, we previously reported that FLC levels 1-3 weeks after HDM/SCT correlate with hematologic response at 1 year. This study was performed to confirm these results on a larger scale. A prospective analysis of patients with AL amyloidosis treated with HDM/SCT was performed to determine the extent to which early FLC responses predict hematologic complete response (CR). Exclusion criteria included initial normal FLC concentrations and ratios and chronic renal insufficiency (Cr>1.2 mg/dL) with a normal FLC ratio. Hematologic responses, as defined by standard traditional criteria, were determined at 6 and 12 months. Traditional criteria define hematologic CR as by normalization of bone marrow exam and absence of monoclonal gammopathy in urine and serum by immunofixation electrophoreses. Serum FLC concentrations were measured by a sensitive nephelometric analysis within 10 days and within 3 weeks of HDM/SCT. Complete response for serum FLC was defined as normalization of FLC concentration and ratio or normalization of the ratio in renal failure (Cr>1.2 mg/dL). Serum FLC levels or k/l FLC ratios were abnormal and informative in 124 patients (87%) prior to HDM/SCT, and these patients were included in subsequent analyses. One week after transplant, sensitivity of FLC to predict hematologic CR was 0.64, specificity was 0.67, positive predictive value (PPV) was 0.49, negative predictive value (NPV) was 0.79, positive likelihood ratio (LR) was 1.92, and negative LR was 0.54. For a >90% reduction in FLC, sensitivity to predict hematologic CR was 0.36, specificity was 0.86, PPV was 0.54, NPV was 0.75, positive LR was 2.59, and negative LR was 0.74. Two to three weeks after transplant, sensitivity of FLC CR to predict hematologic CR was 0.72, specificity was 0.74, PPV was 0.57, NPV was 0.85, positive LR was 2.78, and negative LR was 0.38. For a >90% reduction in FLC, sensitivity to predict hematologic CR was 0.34, specificity was 0.86, PPV was 0.52, NPV was 0.74, positive LR was 2.40, and negative LR was 0.77. Serum FLC concentrations within 3 weeks of HDM/SCT have poor predictive values and should not be used to predict hematologic CR. However, failure to reduce FLC concentrations by 90% has a somewhat higher negative predictive value and could be used to guide additional post-transplant management. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients

Blood ◽  
2011 ◽  
Vol 118 (16) ◽  
pp. 4346-4352 ◽  
Author(s):  
Maria Teresa Cibeira ◽  
Vaishali Sanchorawala ◽  
David C. Seldin ◽  
Karen Quillen ◽  
John L. Berk ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Complete Response ◽  
Long Term Results ◽  
High Dose ◽  
Al Amyloidosis ◽  
Organ Response ◽  
High Dose Melphalan

Abstract Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatment-related mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR.

scholarly journals A randomized phase 3 study of ixazomib–dexamethasone versus physician’s choice in relapsed or refractory AL amyloidosis

Leukemia ◽  
2021 ◽  
Author(s):  
Angela Dispenzieri ◽  
Efstathios Kastritis ◽  
Ashutosh D. Wechalekar ◽  
Stefan O. Schönland ◽  
Kihyun Kim ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Response Rate ◽  
Treatment Options ◽  
Clinical Importance ◽  
Complete Response ◽  
Al Amyloidosis ◽  
Vital Organ ◽  
Phase 3 ◽  
Hematologic Response ◽  
Time To Event Data

AbstractIn the first phase 3 study in relapsed/refractory AL amyloidosis (TOURMALINE-AL1 NCT01659658), 168 patients with relapsed/refractory AL amyloidosis after 1–2 prior lines were randomized to ixazomib (4 mg, days 1, 8, 15) plus dexamethasone (20 mg, days 1, 8, 15, 22; n = 85) or physician’s choice (dexamethasone ± melphalan, cyclophosphamide, thalidomide, or lenalidomide; n = 83) in 28-day cycles until progression or toxicity. Primary endpoints were hematologic response rate and 2-year vital organ deterioration or mortality rate. Only the first primary endpoint was formally tested at this interim analysis. Best hematologic response rate was 53% with ixazomib–dexamethasone vs 51% with physician’s choice (p = 0.76). Complete response rate was 26 vs 18% (p = 0.22). Median time to vital organ deterioration or mortality was 34.8 vs 26.1 months (hazard ratio 0.53; 95% CI, 0.32–0.87; p = 0.01). Median treatment duration was 11.7 vs 5.0 months. Adverse events of clinical importance included diarrhea (34 vs 30%), rash (33 vs 20%), cardiac arrhythmias (26 vs 15%), nausea (24 vs 14%). Despite not meeting the first primary endpoint, all time-to-event data favored ixazomib–dexamethasone. These results are clinically relevant to this relapsed/refractory patient population with no approved treatment options.

scholarly journals Therapeutic Activity of Combining BCL-2 and HMG-CoA Reductase Inhibition in Systemic Light-Chain Amyloidosis

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 23-24
Author(s):  
Ping Zhou ◽  
Hashim Mann ◽  
Xun Ma ◽  
Teresa Fogaren ◽  
Yifei Zhang ◽  
...  
Keyword(s):  
Light Chain ◽  
Research Funding ◽  
Plasma Cells ◽  
Response Rate ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Light Chain Amyloidosis ◽  
Hematologic Response ◽  
Coa Reductase

Introduction: Overexpression of BCL-2 in association with t(11;14) in multiple myeloma (MM) and systemic light-chain amyloidosis (AL) makes it a therapeutic target for the BCL-2 inhibitor venetoclax; response rates of 60-80% in t(11;14) have been reported in MM (Kumar S, Blood 2017 & Vaxman I, Expert Rev Hematol 2018). Addition of HMG-CoA reductase inhibitors (statins) may augment venetoclax activity (Lee JS, Sci Transl Med 2018). We now report ex-vivo functional activity of venetoclax with AL patient CD138-selected plasma cells and provide clinical outcomes of 8 patients with relapsed/refractory AL who were treated with venetoclax and a statin. Methods: To construct a functional assay NCI-H929 and KMS-12-PE cells were used as controls and incubated with venetoclax to assess the IC50. Cell viability was measured with CellTiter-Glo and caspase activity with Caspase-Glo 3/7 (Promega, Madison, WI). H929 cells were the negative and KMS cells the positive control. From patient marrows CD138+ cells were isolated (Miltenyi Biotec, Auburn, CA) as previously described (Ma X, Gene Ther 2016) and incubated with 100 nM of venetoclax for 18 hours with controls. In AL patients, Venetoclax was started at 200 mg daily and escalated to 400 mg daily after 2 weeks if tolerated. Statin (atorvastatin, 10-40 mg daily or simvastatin 40 mg daily) was started concurrently or for lack of response to venetoclax alone. Bone marrow assessment was performed prior to starting venetoclax and response assessment was performed monthly. Results: Venetoclax induced apoptosis in a dose escalated manner with KMS-12-PE cells (t(11;14) positive) when compared with H929 cells (Figure 1A-B). CD138-selected plasma cells from 20 patients (17 AL, 2 MM, 1 MGUS) were incubated with venetoclax (100 nM) for 18 hours and had a median caspase 3/7 activity level that was significantly higher in patients with t(11;14) (Figure 1C). Eight patients were treated with venetoclax in combination with a statin. Baseline characteristics are provided in Table 1. Median age of the cohort was 70 (range, 59 - 77), of which five (63%) were male, and 6 were λ-type (1-kappa, 1-heavy chain). At diagnosis, four (50%) patients had involvement of two or more organ systems (cardiac, renal, gastrointestinal, vascular, and/or neurological). Cardiac involvement was the most common (88%). Seven patients had t(11;14) and/or positive cyclin D1 staining on pre-treatment marrow studies. The median number of prior therapies was 2 (1 - 5), and all except one had been previously treated with daratumumab. Venetoclax-statin combination was started due to hematologic progression (4), organ progression (1), or suboptimal response to prior therapy (3). At a median follow-up of 8 weeks (5 - 25), overall hematologic response rate is 63% (1 CR, 3 VGPR, 1 PR and 1 progression). Cardiac response was seen in 2 patients. One patient who lacked the t(11;14) mutation had early disease progression. One patient with stage-3 cardiac AL amyloidosis experienced cardiac progression without hematologic response on venetoclax alone but responded promptly with both hematologic and cardiac response to addition of simvastatin, 40 mg daily. Statin dose was reduced in 1 patient due to grade 1 myalgia. All responders continue on treatment at their most recent follow-up. Conclusion: In this cohort of 8 patients with AL amyloidosis treated with a combination of venetoclax and statin, hematologic response rate was 63% and &gt;VGPR was seen in 50%. The combination was well tolerated. Consistent with the preclinical activity of venetoclax in MM, functional activity of venetoclax was similarly higher in plasma cells from AL patients harboring t(11;14). As t(11;14) is the most common cytogenetic abnormality in systemic AL amyloidosis, venetoclax and statin combination may provide a potent therapeutic alternative for relapsed/refractory AL patients and requires validation in clinical trials. Disclosures Chaulagain: Sanofi Genzyme: Honoraria. Comenzo:Takeda: Consultancy, Research Funding; Prothena: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Amgen: Consultancy; Karyopharm: Consultancy, Research Funding; Caleum: Consultancy; Unum: Consultancy; Sanofi: Consultancy. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor and currently approved for non-Hodgkin's lymphoma and Acute myeloid leukemia. Venetoclax has shown clinical activity in clinical trials with multiple myeloma, especially patients who harbor t(11;14). Given the preclinical and clinical evidence of its efficacy, we treated 8 relapsed/refractory patients with systemic light-chain amyloidosis with a combination of venetoclax and a statin.

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