Current status of hematopoietic cell transplantation in the treatment of systemic amyloid light-chain amyloidosis

Schönland, Stefan; Dreger, Peter; Witte, T.J.M. de; Hegenbart, Ute

doi:10.1038/bmt.2011.152

Cited by 39 publications

(32 citation statements)

References 98 publications

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“…This compares favorably with the 1-year PFS of 72.2%-74.6% seen in the recent phase prospective 1/2 trial of bortezomib. 4 Consistent with data published previously, 1,11,18,20,21,23 attaining a CR was correlated with a significant improvement in median PFS (not reached for patients in CR vs 17.5 months for those not in CR; 95% confidence interval, 8.5-26.5; P ϭ .002; Figure 1A) and for a VGPR-dFLC (not reached for VGPR-dFLC vs 9.1 months for non-VGPR patients; 95% CI, 6.0-12.2; P ϭ .026; Figure 1B). There was no significant difference in the median PFS between those attaining a CR and those with a VGPR-dFLC but not a CR (P ϭ .22), but small numbers and the retrospective nature of the study limit interpretation.…”

supporting

confidence: 80%

“…These results compare favorably to those from other studies, including those on autologous stem cell transplant (RR ϭ 44%-83% and CR ϭ 22%-41%). 20 A significantly higher CR rate was seen in patients treated upfront versus those at relapse (65.0% vs 21.7%; P ϭ .003). This appears superior to other studies in upfront-treated patients (for bortezomib and dexamethasone, RR ϭ 81% and CR ϭ 47%; for CTD, RR ϭ 70% and CR ϭ 27%) 11,21 or even autologous stem cell transplant, and is similar to previously documented experience with bortezomib-alkylator combinations (RR ϭ 90% and CR ϭ 62%).…”

Section: Resultsmentioning

confidence: 93%

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Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival

Venner

Lane

Foard

et al. 2012

Blood

253

156

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Bortezomib has shown great promise in the treatment of amyloid light-chain (AL) amyloidosis. We present our experience of 43 patients with AL amyloidosis who received cyclophosphamide, bortezomib, and dexamethasone (CVD) upfront or at relapse. Of these, 74% had cardiac involvement and 46% were Mayo Cardiac Stage III. The overall hematologic response rate was 81.4%, including complete response (CR) in 41.9% and very good partial response with > 90% decrease in difference between involved/ uninvolved light chain (VGPR-dFLC) in 51.4%. Patients treated upfront had higher rates of CR (65.0%) and VGPR-dFLC (66.7%). The estimated 2-year progressionfree survival was 66.5% for patients treated upfront and 41.4% for relapsed patients. Those attaining a CR or VGPR-dFLC had a significantly better progression-free survival (P ‫؍‬ .002 and P ‫؍‬ .026, respectively IntroductionBortezomib has been shown to be effective in the treatment of amyloid light-chain (AL) amyloidosis. [1][2][3][4][5][6][7][8] Although the efficacy of proteosome inhibitors is based several different mechanisms, of particular relevance to AL amyloidosis is "proteostasis" because of both the excess light-chain production and accumulation of the misfolded proteins. 9,10 Based on the success of bortezomib in myeloma treatment regimens, initial retrospective series showing efficacy with bortezomib with or without dexamethasone 1,7,11 in AL amyloidosis have laid the groundwork for recent prospective clinical trials showing high response rates but have also raised questions about response durability. 4,5 Given the excellent outcomes in myeloma using a steroid/ alkylator backbone in combination with bortezomib, 12,13 similar strategies have been explored in AL amyloidosis. 3,8 In the present study, we describe our experience with the combination of bortezomib, cyclophosphamide, and dexamethasone (CVD) in patients with AL amyloidosis treated in both the upfront and relapsed setting, reporting response and progression-free survival (PFS). Study designThe primary cohort is a retrospective series of 43 patients from the National Amyloidosis Center in London from January 2006 to March 2011 who underwent detailed prospective evaluation as per standard protocol. The median age of these patients was 54 years and 58% were male. Organ involvement and hematologic and organ responses were defined according to international amyloidosis consensus criteria from 2005 14 and were as follows: cardiac, 74%; renal, 79%; liver, 23%; peripheral neuropathy, 18%; autonomic neuropathy, 21%; and other organs, 35%. Complete information for staging by the Mayo Clinic criteria 15 was available in 39 patients and 46% were stage III based on values obtained before the initiation of CVD (22% of upfront patients and 62% of relapsed patients). The CVD regimen was as follows: bortezomib 1.0 mg/m 2 IV on days 1, 4, 8, 11 (increased to 1.3 mg/m 2 if well tolerated); cyclophosphamide 350 mg/m 2 orally on days 1, 8, and 15; and dexamethasone 20 mg orally on days 1, 4, 8, and 11 (increased to 20 mg f...

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supporting

confidence: 80%

Section: Resultsmentioning

confidence: 93%

Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival

Venner

Lane

Foard

et al. 2012

Blood

253

156

View full text Add to dashboard Cite

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“…[10][11][12][13] However, HDM offers the prospect of long-term remission in AL. [14][15][16] Therefore, it remains a therapeutic option for carefully selected AL patients at specialized centers, 15 although controversy regarding its pros and cons persists. 17 In MM, cytogenetic aberrations are established as prognostic markers for risk stratification.…”

Section: Introductionmentioning

confidence: 99%

Prognostic impact of cytogenetic aberrations in AL amyloidosis patients after high-dose melphalan: a long-term follow-up study

Bochtler

Hegenbart

Kunz

et al. 2016

Blood

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Key Points• Translocation t(11;14) confers a favorable prognosis in AL amyloidosis patients treated with HDM.Cytogenetic aberrations detected by interphase fluorescence in situ hybridization (iFISH) of plasma cells are routinely evaluated as prognostic markers in multiple myeloma. This longterm follow-up study aimed to assess the prognosis of systemic light chain amyloidosis (AL) patients treated with high-dose melphalan (HDM) chemotherapy and autologous stem cell transplantation, depending on iFISH results. Therefore, we analyzed a consecutive cohort of 123 AL patients recruited from 2003 to 2014. HDM was safe, with only 1 of 123 patients dying as a result of treatment-related mortality, and effective, with a complete remission (CR) rate of 34%. Translocation t(11;14) as the most prevalent aberration (59%) led to an improved CR rate after high-dose therapy (41.2% vs 20.0%; P 5 .02), translating into a prolonged hematologic event-free survival (hemEFS; median, 46.1 vs 28.1 months; P 5 .05) and a trend for better overall survival (median, not reached vs 93.7 months; P 5 .07). In multivariate analysis, t(11;14) was confirmed as a favorable prognostic factor regarding hemEFS along with lower values for the difference between involved and uninvolved free light chains. Conversely, deletion 13q14, gain of 1q21, and hyperdiploidy had no significant prognostic impact. The high-risk cytogenetic aberrations t(4;14), t(14;16), and del(17p13) conferred an unfavorable prognosis, although statistical significance was reached only for univariate CR analysis in this small group of 9 patients. Thus, t(11;14) positivity in HDM-treated AL patients conferred superior CR rates and hemEFS. In view of the reduced response of t(11;14) to bortezomib, this highlights the impact of therapy on the prognostic role of cytogenetic aberrations. (Blood. 2016;128(4):594-602)

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“…4,5 Remission of AL amyloidosis is defined as a complete hematologic response (ie, no evidence of serum monoclonal free light chains). 2 Remission rates with these treatment modalities vary but have been reported 6 as high as 40%. Here, we describe 2 patients cared for at our institution who, after AHSCT, experienced slowly declining renal function because of massive glomerular AL deposits, as determined by kidney biopsy.…”

mentioning

confidence: 99%

Progressive Renal Light Chain Amyloidosis With the Absence of Detectable Free Monoclonal Light Chains After an Autologous Hematopoietic Stem Cell Transplant for Amyloid Light Chain Amyloidosis

Roth

Benson²,

Hebert³

et al. 2013

Archives of Pathology &Amp; Laboratory Medicine

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Amyloid light chain amyloidosis involving the kidneys is not uncommon in patients with monoclonal gammopathy. The mainstay of treatment of amyloid light chain amyloidosis is autologous hematopoietic stem cell transplantation. Evidence that the autologous hematopoietic stem cell transplantation has been successful is the absence of free monoclonal light chains in serum and urine. Herein, we report 2 cases of progressive renal amyloid light chain amyloidosis after autologous hematopoietic stem cell transplantation, documented by kidney biopsy, despite the absence of monoclonal protein in the serum and urine. Kidney function declined progressively in both patients. During that time, numerous immunofixation and protein electrophoresis test results were negative for monoclonal protein, both in serum and urine, concealing the progression of the amyloidosis. We conclude that close monitoring of kidney function is warranted following autologous hematopoietic stem cell transplantation in patients with amyloid light chain amyloidosis, even with negative results from monoclonal protein testing. Unexplained, worsening renal function warrants a kidney biopsy to assess whether retreatment of the monoclonal gammopathy is indicated.

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Current status of hematopoietic cell transplantation in the treatment of systemic amyloid light-chain amyloidosis

Cited by 39 publications

References 98 publications

Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival

Cyclophosphamide, bortezomib, and dexamethasone therapy in AL amyloidosis is associated with high clonal response rates and prolonged progression-free survival

Prognostic impact of cytogenetic aberrations in AL amyloidosis patients after high-dose melphalan: a long-term follow-up study

Progressive Renal Light Chain Amyloidosis With the Absence of Detectable Free Monoclonal Light Chains After an Autologous Hematopoietic Stem Cell Transplant for Amyloid Light Chain Amyloidosis

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