research paper
Lenalidomide and dexamethasone for systemic AL amyloidosis following prior treatment with thalidomide or bortezomib regimens
Shameem Mahmood, Christopher P. Venner, Sajitha Sachchithanantham, Thirusha Lane, Lisa Rannigan, Darren Foard, Jenny H. Pinney, Simon D. J. Gibbs, Carol J. Whelan, Helen J. Lachmann, Julian D. Gillmore, Philip N. Hawkins and Ashutosh D. Wechalekar National Amyloidosis Centre, University College London Medical School, Royal Free Hospital Campus, London, UK Received 16 March 2014; accepted for publication 11 May 2014 Correspondence: Dr Ashutosh Wechalekar, National Amyloidosis Centre, UCL Medical School (Royal Free Campus), Rowland Hill Street, London NW3 2PF, UK. Email: [email protected]
Summary The outcomes and responses to treatment remain poorly studied among patients with systemic AL amyloidosis who require further treatment following prior novel agent-based therapy. We report here treatment with lenalidomide-dexamethasone in 84 AL amyloidosis patients with relapsed/refractory clonal disease following prior treatment with thalidomide (76%) and/or bortezomib (68%). On an intention-to-treat (ITT) basis, the overall haematological response rate was 61%, including 20% complete responses. The median overall survival (OS) has not been reached; 2-year OS and progression-free survival (PFS) was 84% and 73%, respectively. Achieving a free light chain (FLC) response was an independent good prognostic factor for OS in multivariate analysis. There was no impact of prior thalidomide or bortezomib therapy on response rate, OS or PFS. 16% achieved an organ response at 6 months, with a marked improvement in organ responses in patients on long term therapy (median duration 11 months) and 55% achieving renal responses by 18 months. Lenalidomide/dexamethasone therapy achieves good haematological responses in patients with AL amyloidosis with relapsed/refractory clonal disease. The rate of renal responses among patients who received prolonged treatment was unexpectedly high, raising the possibility that immunomodulatory effects of lenalidomide therapy might enhance the otherwise slow natural regression of amyloid deposits. Keywords: Lenalidomide, haematological response, difference in involved and uninvolved free light chains, monoclonal protein response, overall survival.
Amyloidosis is a disorder of protein misfolding, leading to the formation and deposition of amyloid fibrils in different tissues with consequent dysfunction of the affected organs. Systemic immunoglobulin light chain (AL) amyloidosis is the most common type (Merlini & Bellotti, 2003) caused by an underlying plasma cell dyscrasia and treatment is targeted toward suppressing this clone. Treatments have been adapted from those developed for treatment of myeloma. Immunomodulatory drugs (IMiDs) are emerging as an important backbone for the treatment of AL amyloidosis in both the relapsed/refractory (Dispenzieri et al, 2007 Wechalekar et al, 2007; Sanchorawala et al, 2010; Palladini et al, 2012) and upfront settings (Dispenzieri et al, 2007; Wechalekar et al, 2007; Moreau et al, 2010; Sanchorawala et al, 2010). Small phase II studies have reported good clonal responses using First published online 13 June 2014 doi: 10.1111/bjh.12973
lenalidomide-dexamethasone in 67% (Dispenzieri et al, 2007; Sanchorawala et al, 2007) and similar clonal response rates of 50–62% with addition of alkylating agents (Moreau et al, 2010; Kastritis et al, 2012; Kumar et al, 2012; Palladini et al, 2013). Few series have reported organ responses after lenalidomide treatment. It is well recognized that organ responses are usually much delayed in AL amyloidosis with the exception of cardiac responses based on biomarkers, although the latter are difficult to interpret in patients in IMiD-based therapies (Tapan et al, 2010). Premature assessment of organ response may fail to capture the full clinical impact of any treatment in this disease. We report a substantial series of patients treated with lenalidomide in the relapsed/refractory setting, following the use of bortezomib and/or thalidomide with long-term ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 842–848
Lenalidomide and Dexamethasone in Light Chain Amyloidosis follow-up evaluating the impact of previous therapies on haematological responses. We also report an unexpectedly high rate of organ responses on long-term follow-up in patients treated with lenalidomide.
Patients and methods This cohort consisted of all patients with systemic AL amyloidosis followed at the UK National Amyloidosis Centre from July 2007 to August 2013 who were treated with lenalidomide for relapsed (n = 62) or refractory (n = 22) clonal disease, having received at least one prior line of therapy. The diagnosis of amyloidosis was confirmed on histology by Congo red staining and AL type was confirmed by specific immunostaining of amyloidotic tissue by antibodies to kappa or lambda light chains and exclusion of hereditary amyloidosis by gene sequencing as appropriate. All patients had evidence of either abnormal serum free light chain (FLC) ratio or a monoclonal immunoglobulin component by serum or urinary immunofixation or electrophoresis. Written consent for retrospective publication of data was obtained from all patients in accordance with the Declaration of Helsinki. Organ involvement, haematological and organ responses were classified according to the updated international amyloidosis consensus criteria (Comenzo et al, 2012), with a renal response described as a 50% decrease and at least a decrease of ≥05 g/24 h of 24-h urinary protein in patients with baseline urinary protein >05 g/l, with no worsening of the creatinine/creatinine clearance by 25% over baseline. Patients with no urine or urine quantification
Lenalidomide and dexamethasone for systemic AL amyloidosis following prior treatment with thalidomide or bortezomib regimens
Shameem Mahmood, Christopher P. Venner, Sajitha Sachchithanantham, Thirusha Lane, Lisa Rannigan, Darren Foard, Jenny H. Pinney, Simon D. J. Gibbs, Carol J. Whelan, Helen J. Lachmann, Julian D. Gillmore, Philip N. Hawkins and Ashutosh D. Wechalekar National Amyloidosis Centre, University College London Medical School, Royal Free Hospital Campus, London, UK Received 16 March 2014; accepted for publication 11 May 2014 Correspondence: Dr Ashutosh Wechalekar, National Amyloidosis Centre, UCL Medical School (Royal Free Campus), Rowland Hill Street, London NW3 2PF, UK. Email: [email protected]
Summary The outcomes and responses to treatment remain poorly studied among patients with systemic AL amyloidosis who require further treatment following prior novel agent-based therapy. We report here treatment with lenalidomide-dexamethasone in 84 AL amyloidosis patients with relapsed/refractory clonal disease following prior treatment with thalidomide (76%) and/or bortezomib (68%). On an intention-to-treat (ITT) basis, the overall haematological response rate was 61%, including 20% complete responses. The median overall survival (OS) has not been reached; 2-year OS and progression-free survival (PFS) was 84% and 73%, respectively. Achieving a free light chain (FLC) response was an independent good prognostic factor for OS in multivariate analysis. There was no impact of prior thalidomide or bortezomib therapy on response rate, OS or PFS. 16% achieved an organ response at 6 months, with a marked improvement in organ responses in patients on long term therapy (median duration 11 months) and 55% achieving renal responses by 18 months. Lenalidomide/dexamethasone therapy achieves good haematological responses in patients with AL amyloidosis with relapsed/refractory clonal disease. The rate of renal responses among patients who received prolonged treatment was unexpectedly high, raising the possibility that immunomodulatory effects of lenalidomide therapy might enhance the otherwise slow natural regression of amyloid deposits. Keywords: Lenalidomide, haematological response, difference in involved and uninvolved free light chains, monoclonal protein response, overall survival.
Amyloidosis is a disorder of protein misfolding, leading to the formation and deposition of amyloid fibrils in different tissues with consequent dysfunction of the affected organs. Systemic immunoglobulin light chain (AL) amyloidosis is the most common type (Merlini & Bellotti, 2003) caused by an underlying plasma cell dyscrasia and treatment is targeted toward suppressing this clone. Treatments have been adapted from those developed for treatment of myeloma. Immunomodulatory drugs (IMiDs) are emerging as an important backbone for the treatment of AL amyloidosis in both the relapsed/refractory (Dispenzieri et al, 2007 Wechalekar et al, 2007; Sanchorawala et al, 2010; Palladini et al, 2012) and upfront settings (Dispenzieri et al, 2007; Wechalekar et al, 2007; Moreau et al, 2010; Sanchorawala et al, 2010). Small phase II studies have reported good clonal responses using First published online 13 June 2014 doi: 10.1111/bjh.12973
lenalidomide-dexamethasone in 67% (Dispenzieri et al, 2007; Sanchorawala et al, 2007) and similar clonal response rates of 50–62% with addition of alkylating agents (Moreau et al, 2010; Kastritis et al, 2012; Kumar et al, 2012; Palladini et al, 2013). Few series have reported organ responses after lenalidomide treatment. It is well recognized that organ responses are usually much delayed in AL amyloidosis with the exception of cardiac responses based on biomarkers, although the latter are difficult to interpret in patients in IMiD-based therapies (Tapan et al, 2010). Premature assessment of organ response may fail to capture the full clinical impact of any treatment in this disease. We report a substantial series of patients treated with lenalidomide in the relapsed/refractory setting, following the use of bortezomib and/or thalidomide with long-term ª 2014 John Wiley & Sons Ltd British Journal of Haematology, 2014, 166, 842–848
Lenalidomide and Dexamethasone in Light Chain Amyloidosis follow-up evaluating the impact of previous therapies on haematological responses. We also report an unexpectedly high rate of organ responses on long-term follow-up in patients treated with lenalidomide.
Patients and methods This cohort consisted of all patients with systemic AL amyloidosis followed at the UK National Amyloidosis Centre from July 2007 to August 2013 who were treated with lenalidomide for relapsed (n = 62) or refractory (n = 22) clonal disease, having received at least one prior line of therapy. The diagnosis of amyloidosis was confirmed on histology by Congo red staining and AL type was confirmed by specific immunostaining of amyloidotic tissue by antibodies to kappa or lambda light chains and exclusion of hereditary amyloidosis by gene sequencing as appropriate. All patients had evidence of either abnormal serum free light chain (FLC) ratio or a monoclonal immunoglobulin component by serum or urinary immunofixation or electrophoresis. Written consent for retrospective publication of data was obtained from all patients in accordance with the Declaration of Helsinki. Organ involvement, haematological and organ responses were classified according to the updated international amyloidosis consensus criteria (Comenzo et al, 2012), with a renal response described as a 50% decrease and at least a decrease of ≥05 g/24 h of 24-h urinary protein in patients with baseline urinary protein >05 g/l, with no worsening of the creatinine/creatinine clearance by 25% over baseline. Patients with no urine or urine quantification
