-
1.
Safety and Efficacy of Propylene Glycol-Free Melphalan in Patients with AL Amyloidosis Undergoing Autologous Stem Cell Transplantation: Results of a phase II study: Propylene Glycol-Free Melphalan Conditioning for Autologous Stem Cell Transplantation for AL Amyloidosis
Sarosiek, S., Lee, M. H., Doros, G., Edwards, C. V., Quillen, K., Brauneis, D., Shelton, A. C., Sanchorawala, V., Sloan, J. M.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Patients with AL amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) may develop renal and cardiac toxicities potentially exacerbated by the co-solvent propylene glycol in conventional melphalan formulations. We investigated the safety and efficacy of propylene glycol-free melphalan (PGF-Mel) during HDM/SCT in patients with AL amyloidosis (NCT02994784). OBJECTIVES Primary objectives of this phase II, open-label study were evaluation for renal dysfunction, new cardiac arrhythmias, and postural hypotension related to autonomic dysfunction. Secondary objectives included time to neutrophil and platelet engraftment, treatment related mortality, overall hematologic response, organ response, and number of peri-transplant hospitalizations. STUDY DESIGN Twenty-eight patients with AL amyloidosis enrolled and 27 underwent HDM/SCT. PGF-Mel (140-200 mg/m(2)) was administered intravenously as 2 equally divided doses. Patients were monitored for up to 30 days after the last administration of PGF-Mel to assess for treatment-related toxicity. Patients were followed for 12 months from time of treatment with HDM/SCT for evaluation of hematologic and organ responses. Kaplan-Meier analysis was used to estimate progression-free survival. RESULTS Two patients (7%) developed renal dysfunction, 5 (19%) experienced new cardiac arrhythmias, and 3 (11%) developed orthostatic hypotension. All patients achieved neutrophil and platelet engraftment with median times of 10 and 17 days post-HDM/SCT, respectively. Treatment-related mortality on day 100 was 0%. Peri-transplant hospitalization occurred in 23 patients (85%). The most common nonhematologic adverse events were diarrhea (93%), fatigue (82%), and nausea (74%). At 6-months post-HDM/SCT, hematologic complete and very-good-partial response occurred in 66% of patients. At 12-months post-HDM/SCT, renal response occurred in 12 of 23 patients (52%) with renal involvement and cardiac response occurred in 3 of 11 (27%) patients with evaluable cardiac involvement. CONCLUSION PGF-Mel is safe and efficacious as a high-dose conditioning regimen for autologous stem cell transplantation in patients with AL amyloidosis.
-
2.
Modified High-Dose versus High-Dose Melphalan Conditioning in Older Patients Undergoing Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis
Hassan, H., Verma, K., Ferri, G., Brauneis, D., Quillen, K., Sloan, J. M., Sanchorawala, V., Edwards, C. V.
Transplantation and cellular therapy. 2022
Abstract
High dose melphalan and autologous stem cell transplant (HDM/SCT) induces deep hematologic responses (HR) in patients with newly diagnosed systemic immunoglobulin light chain (AL) amyloidosis. Modifying melphalan conditioning dose (mHDM <140 mg/m(2)) is considered in older patients due to concerns regarding tolerability. Age does not predict frailty and dose modification could compromise responses in an era where effective non-transplant regimens are available. We analyzed 43 patients ≥ 65 years with AL amyloidosis who underwent SCT at Boston University Amyloidosis Center between 2011 and 2020. Median age was 66 years (range 65 - 68) versus 69 years (range 65 - 76) in the HDM and mHDM groups, respectively. HR of ≥ VGPR at 12 months was 66.7% versus 42.3% for patients treated with HDM versus mHDM. Median progression free survival (PFS) from day 0 of SCT was not reached versus 12.0 months (p = 0.13); grade ≥ 3 non-hematologic transplant-related toxicities occurred in 87.5% versus 76.9%; and transplant-related mortality was 0% versus 2.3% in HDM versus mHDM group, respectively. In carefully selected older patients with AL amyloidosis, HDM is well tolerated. Use of mHDM results in reduced HR and PFS; an important consideration with the advent of highly effective non-transplant therapies.
-
3.
Bortezomib-Based Induction Is Associated with Superior Outcomes in Light Chain Amyloidosis Patients Treated with Autologous Hematopoietic Cell Transplantation Regardless of Plasma Cell Burden
Cornell, R. F., Fraser, R., Costa, L., Goodman, S., Estrada-Merly, N., Lee, C., Hildebrandt, G., Gergis, U., Farhadfar, N., Freytes, C. O., et al
Transplantation and cellular therapy. 2021;27(3):264.e1-264.e7
-
-
-
Free full text
Abstract
The benefits of pre-transplant induction chemotherapy in light chain (AL) amyloidosis, a low burden plasma cell (PC) neoplasm associated with multiorgan dysfunction, is debatable, although with the availability of bortezomib, this approach is being increasingly pursued. We analyzed the outcomes of AL amyloidosis patients undergoing autologous hematopoietic cell transplant between 2014 and 2018 that were reported to the Center for International Blood and Marrow Transplant Research database. Of 440 patients, 294 received bortezomib-based induction, and 146 received no induction. Patients receiving induction had greater PC burden compared to no induction (PC 10% or more, 39% versus 11%; P < .01). At 2 years, the induction group compared to no induction had lower relapse/progression: 13% (9% to 18%) versus 23% (16% to 32%) (P = .02); better progression-free survival (PFS): 82% (77% to 87%) versus 69% (61% to 77%) (P < .01); and similar overall survival (OS): 92% (88% to 95%) versus 89% (84% to 94%) (P = .22), findings that were confirmed on multivariate analysis. A subset analysis limited to patients with <10% PC also showed superior relapse/progression (hazard ratio [HR], .43; 95% confidence interval [CI], .24 to .78; P < .01) and PFS (HR, .43; 95% CI, .26 to .72; P < .01) for induction compared to no induction. Thus, we conclude that pre-transplant bortezomib-based induction was associated with improved relapse/progression and PFS in AL amyloidosis. Longer survival follow-up is warranted, as OS was excellent in both cohorts at 2 years.
Clinical Commentary
What is known?
NIHMS1664451
What did this paper set out to examine?
What did they show?
What are the implications for practice and for future work?
-
4.
Early serum free light chain response after high-dose melphalan and stem cell transplantation predicts hematologic response in AL amyloidosis
Furtado, V. F., Brauneis, D., Weinberg, J., Elhassan, N., Sloan, J. M., Sanchorawala, V.
Bone marrow transplantation. 2021
-
5.
Sequential response-driven bortezomib-based therapy followed by autologous stem cell transplant in AL amyloidosis
Basset, M., Milani, P., Nuvolone, M., Benigna, F., Rodigari, L., Foli, A., Merlini, G., Palladini, G.
Blood advances. 2020;4(17):4175-4179
-
-
Free full text
-
Abstract
Autologous stem cell transplant (ASCT) is highly effective in selected patients with light chain (AL) amyloidosis. Bortezomib, preceding or following ASCT, improves responses. Satisfactory responses, including at least a partial response, very good partial response (VGPR) with organ response, or complete response, can be observed after induction therapy alone. We report 139 patients treated upfront with cyclophosphamide/bortezomib/dexamethasone (CyBorD), followed by ASCT only if response was unsatisfactory. Only 1 treatment-related death was observed. After CyBorD, hematologic response (HR) rate was 68% (VGPR or better, 51%), with 45% satisfactory responses. Transplant was performed in 55 (40%) subjects and resulted in an 80% HR rate (65% = VGPR). Five-year survival was 86% and 84% in patients treated with ASCT or CyBorD alone, respectively (P = .438). Also, 6- and 12- month landmark analyses did not show differences in survival. Duration of response was not different in the 2 groups (60 vs 49 months; P = .670). Twenty-one (15%) patients with an unsatisfactory response to CyBorD could not undergo ASCT because of ineligibility or refusal; instead, they received rescue chemotherapy, with HR in 38% of cases and 51% 5-year survival. This sequential response-driven approach, offering ASCT to patients who do not attain satisfactory response to upfront CyBorD, is very safe and effective in AL amyloidosis.
-
6.
Comparing measures of hematologic response after high-dose melphalan and stem cell transplantation in AL amyloidosis
Sarosiek, S., Zheng, L., Sloan, J. M., Quillen, K., Brauneis, D., Sanchorawala, V.
Blood cancer journal. 2020;10(8):88
Abstract
Hematologic complete response (hemCR) in AL amyloidosis requires absence of monoclonal protein by immunofixation electrophoreses (IFE) and normal serum free light chain ratio (FLCR). Recent literature suggests that an involved free light chain (iFLC) <20?mg/L or difference in free light chains (dFLC) <10?mg/L may more accurately predict outcomes after treatment. We evaluated overall survival in 340 patients treated with high-dose melphalan and stem cell transplantation (SCT). Of 305 patients evaluable 6 months after SCT, 90 (30%) achieved hemCR, 132 (43%) dFLC <10?mg/L, 118 (39%) iFLC <20?mg/L, and 176 (58%) normal FLCR. Of 215 patients without hemCR, 65 (30%) had dFLC <10?mg/L and 86 (40%) had normal FLCR. Overall survival (OS) in those achieving dFLC <10?mg/L or normal FLCR without hemCR was inferior to those achieving hemCR (p?=?0.013 and p?=?0.001). OS was not significantly different in patients achieving iFLC <20?mg/L without hemCR compared with hemCR (p?=?0.243). Of those with hemCR, OS was not significantly improved if dFLC <10?mg/L was also achieved (p?=?0.852), but OS was improved for those with hemCR who also attained iFLC <20?mg/L (p?=?0.009). Multivariate analysis demonstrated absence of monoclonal protein in IFE and iFLC <20?mg/L as independent predictors of survival. Attainment of hemCR remains a treatment goal, although achieving iFLC <20?mg/L may also predict improved OS.
-
7.
The role of induction therapy before autologous stem cell transplantation in low disease burden AL amyloidosis patients
Huang, X., Ren, G., Chen, W., Guo, J., Zhao, L., Zeng, C., Ge, Y., Liu, Z.
Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis. 2020;:1-9
Abstract
BACKGROUND Induction therapy is recommended before autologous stem cell transplantation (ASCT) for AL amyloidosis patients with high disease burden [bone marrow plasma cells (BMPCs) > 10%], but the role of induction therapy before ASCT in patients with low disease burden (BMPCs ≤ 10%) is still unknown. METHODS A total of 227 patients with AL amyloidosis were included in this study. Among 227 patients, 124 patients received bortezomib-based induction prior to ASCT and were defined as group A, 35 patients received other chemotherapeutic induction and were defined as group B, and the other 68 patients without induction were defined as group C. We compared the differences of efficacy and prognosis between the three groups. RESULTS The haematological overall response rates (ORR) of groups A, B and C were 91%, 67% and 75%, respectively. The complete response rates (CR) of groups A, B and C were 50%, 25% and 20%, respectively. Both the ORR and CR rates of group A were significantly higher than those of groups B and C. The renal response rates of groups A, B and C were 64%, 46% and 47%, respectively. The cardiac response rates of groups A, B and C were 74%, 45% and 40%, respectively. The renal and cardiac responses rates of group A were also significantly higher than those of the other two groups. After a median follow-up of 44 months, the median OS was not reached. The 5-year estimated overall survival (OS) rates of groups A, B and C were 81%, 57% and 67%, respectively. The median progression-free survival (PFS) was 83 months for all patients. The 5-year estimated PFS rates of groups A, B and C were 61%, 38% and 49%, respectively. Both the OS and PFS of group A were higher than those of both group B and group C. On multivariate analysis, baseline dFLC > 50 mg/L was associated with worse survival, but induction with bortezomib was associated with better survival. CONCLUSION Our study demonstrated that low disease burden AL patients who are eligible for ASCT may benefit from bortezomib-based induction therapy.
-
8.
Induction Therapy with Bortezomib and Dexamethasone and Conditioning with High-Dose Melphalan and Bortezomib Followed by Autologous Stem Cell Transplantation for AL Amyloidosis: Long Term Follow-Up Analysis
Gupta, V. K., Brauneis, D., Shelton, A. C., Quillen, K., Sarosiek, S., Sloan, J. M., Sanchorawala, V.
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2019
Abstract
In light-chain (AL) amyloidosis, the depth of hematologic response to treatment is associated with improved survival and organ responses. We conducted a clinical trial utilizing bortezomib in induction and in conditioning with melphalan prior to stem cell transplantation (SCT) for AL amyloidosis. The results of this clinical trial with a median follow-up of 36 months have been reported previously. Here we report the long-term results of this clinical trial with a median follow-up of 77 months. The objectives of this follow-up report are to describe survival, durability of hematologic and organ responses, and relapse rates. Thirty-five patients were enrolled from 2010 to 2013. Hematologic complete responses (CR) and very good partial responses (VGPR) were noted in 27/27 (100%) of assessable patients at 6 months following SCT. Four patients (15%) had hematologic relapse at a median of 42 months and 1 patient (3.7%) had organ progression despite maintaining a VGPR at 37 months. The median overall and progression-free survivals have not yet been reached. Renal and cardiac responses occurred in 65% and 88% at 5 years post SCT, respectively. Median time to renal and cardiac response was 12 months and 6 months, respectively. In conclusion, incorporating bortezomib into induction and conditioning yielded durable hematologic responses of AL amyloidosis with corresponding organ responses and prolonged survival.
-
9.
Bortezomib based induction followed by stem cell transplantation in light chain amyloidosis: results of the multicenter HOVON 104 trial
Minnema, M. C., Nasserinejad, K., Hazenberg, B., Hegenbart, U., Vlummens, P., Ypma, P. F., Kroger, N., Wu, K. L., Kersten, M. J., Schaafsma, M. R., et al
Haematologica. 2019
-
-
-
Free full text
-
Editor's Choice
Abstract
This prospective, multicenter, phase II study investigated the use of 4 cycles of bortezomib-dexamethasone induction treatment, followed by high dose melphalan and autologous stem cell transplantation (SCT) in patients with newly diagnosed light chain (AL) amyloidosis. The aim of the study was to improve the hematologic CR rate 6 months after SCT from 30% to 50%. Fifty patients were enrolled and 72% had 2 or more organs involved. The overall hematologic response rate after induction treatment was 80% including 20% CR and 38% VGPR. Fifteen patients did not proceed to SCT due to various reasons but mostly treatment related toxicity and disease related organ damage and death (2 patients). Thirty-one patients received melphalan 200 mg/m2 and 4 patients a reduced dose because of renal insufficiency. The SCT procedure was without treatment related mortality. Hematologic responses improved at 6 months after SCT to 86% with 46% CR and 26% VGPR. However, due to the high discontinuation rate before SCT the primary endpoint of the study was not met and the CR rate on intention to treat analysis was 32%. Organ responses continued to improve after SCT. We confirm the high efficacy of bortezomib-dexamethasone treatment in AL amyloidosis patients. However, because of both treatment related toxicity and disease characteristics, 30% of the patients could not proceed to SCT after induction treatment.
PICO Summary
Population
Patients with newly diagnosed light chain amyloidosis (n=50)
Intervention
4 cycles of bortezomib-dexamethasone induction treatment, followed by high dose melphalan and autologous stem cell transplantation But 30% of patients could not procede to SCT after induction.
Comparison
None
Outcome
Hematologic responses improved at 6 months after SCT to 86% with 46% CR and 26% VGPR. However, due to the high discontinuation rate before SCT the primary endpoint of the study was not met and the CR rate on intention to treat analysis was 32%. Organ responses continued to improve after SCT.
-
10.
Combination of bortezomib in the induction, conditioning and consolidation with autologous hematopoietic stem cell transplantation in patients with immunoglobulin light chain amyloidosis
Huang, X., Fu, Z., Chen, L., Chen, W., Ren, G., Guo, J., Zhao, L., Zeng, C., Zhang, H., Gong, D., et al
American journal of hematology. 2019
Abstract
Bortezomib and autologous hematopoietic stem cell transplantation (ASCT) are both active regimen in AL amyloidosis. In this study, we assessed safety and efficacy of combination of bortezomib in the induction, conditioning and consolidation with ASCT in patients with newly diagnosed AL amyloidosis. Treatment schedule consisted of two cycles of bortezomib and dexamethasone (BD) induction therapy, ASCT treatment (the conditioning regimen consisted of melphalan and bortezomib), and four additional 21-day cycles of bortezomib treatment after ASCT. Twenty-one patients were enrolled in the study. Nine patients had cardiac involvement. The overall response rate (ORR) was 90% (18/20) at 12 months after ASCT in evaluable patients, including 10 patients (50%) with complete response, 7 patients (35%) with very good partial response. The organ response rate was 72.2%. The renal and cardiac response was 55% and 40% at 12 months after ASCT respectively, and reached to 66.7% and 50% at 24 months. Peripheral neuropathy and infection were the common adverse events during the treatment, and five patients have been discontinued bortezomib for neuropathy. No death occurred in this study. After a median follow-up of 53 months, the overall survival was 100%, and the estimated progression free survival was 79.9% at 60 months. Data from this study demonstrate that incorporating bortezomib into induction, conditioning and consolidation with ASCT yielded a high rate of hematologic response with tolerable toxicity in patients with AL amyloidosis. The overall survival and progression-free survival also improved after long term follow-up in these patients. (ClinicalTrial.gov Identifier: NCT01273844). This article is protected by copyright. All rights reserved.