Frank Bridoux 1, Arnaud Jaccard 2, Jean-Paul Fermand 3, Guy Touchard

Transcription

1 Recent therapeutic advances in AL amyloidosis and myeloma cast nephropathy Frank Bridoux 1, Arnaud Jaccard 2, Jean-Paul Fermand 3, Guy Touchard 1 1 CHU Poitiers, 2 CHU Limoges, 3 Hôpital Saint Louis, Paris, France Centre de référence des amyloses primitives et autres maladies de dépôts d immunoglobulines monoclonales Actualités Néphrologiques Jean Hamburger Hôpital Necker 23 avril 2013

2 Cubilin Megalin Light chains filtered (MW ~ 22 kda) AL amyloidosis LCDD Tamm-Horsfall protein Fanconi syndrome Myeloma mtal cast nephropathy

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4 AL amyloidosis Clonal plasma cells (MGUS/stage I myeloma) Monoclonal light chains (lambda > kappa) Slow spontaneous tissue catabolism (SAP binding) Progressive alteration of organ structure and function Amyloid deposits Amyloid fibrils

5 AL amyloidosis: diagnosis Anti-lambda x 200 Anti-kappa x 200

6 DNA screening in 350 patients with apparent AL amyloidosis 34 (9.7%) had amyloidogenic mutations, confirmed to be the cause of their disease 18 Fibrinogen A alpha chain Val Variants of TTR, including 4 new ones 2 Apolipoprotein A1 (Pro175 and Arg26) 1 Lysozyme His67 Of those, 8 had evidence of monoclonal gammopathy Incomplete penetrance family history sometimes lacking Lachmann HJ et al., NEJM 2002;346:1786

7 Fibrinogen A α-chain amyloidosis Lachmann HJ et al., NEJM 2002;346:1786

8 Diagnosis of amyloidosis Unsuccessful typing after IF/IHC? Molecular biology : amyloidogenic mutation? glomerular deposits only AαFib Tubulo-interstitial deposits only AapoA1 (Leu175Pro) Laser capture-microdissection (paraffin-embedded samples) and tandem mass spectrometry and proteomic analysis : sensitivity ~ 100%, specificity? Sehti S et al. Kidney Int 2012 Immuno-electron microscopy : correct typing in > 90% of cases Arbustini E, et al. Amyloid 2002; 9:108 Herrera GA. Ultrastruct Pathol 2010; 34:161

9 AL amyloidosis : prognostic markers , ,0 Abnormal FLCs in 98% of AL patients 1000,0 100,0 10,0 1,0 0,1 0,1 1,0 10,0 100,0 1000, , ,0 Kappa FLC mg/l Lachmann et al. Br J Haematol 2003; 348: 2583

10 Validation of response criteria in AL amyloidosis XII International Symposium on Amyloidosis, Rome, April 18-21, 2010 Gertz MA, Merlini G. Amyloid 2010; 17(Suppl 1): 48-49

11 AL amyloid cardiomyopathy Heart involvement : 60 % of patients at diagnosis Major prognostic factor Main causes of death : conduction blocks /arrhythmia Median survival = 5 months Kyle RA N Engl J Med 1997; 336: 1202 Kapoor P, et al. Am J Med 2011; 124: 1006

12 Serum markers of heart involvement The Mayo Clinic staging system Threshold values: Troponin T (ctnt) : mg/l NT-proBNP : 332 ng/l Stage 1 : 2 normal values Stage 2 : 1 abnormal value Stage 3 : 2 abnormal values High sensitive ctnt : Threshold 50 ng/l?

13 Amyloidosis : treatment strategies Native protein Reversion to native fold + Amyloid deposits Reduce supply of amyloid precursor protein - Fibrillogenesis Stabilise precursor cccccproteins Inhibit GAG ccccbinding - β sheet breakers Immunotherapy Destabilise by SAP depletion - Courtesy of PN Hawkins and JD Gillmore, National Amyloidosis Centre, London

14 AL amyloidosis : enhance tissue catabolism Depletion of serum SAP : CPHPC 100 Percentage of baseline SAP mg/l Time after starting CPHPC infusion Pepys MB et al. Nature 2002; 417: 254

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16 Standard dose chemotherapy in AL amyloidosis Oral Melphalan + Prednisone (MP): - Median survival : 18 months - Hematological response rate <30% - Delayed response (6-12 mo) insufficient in patients with heart disease Kyle et al. N Engl J Med, 1997; 336: 1202

17 AL amyloidosis : improving clonal response rates High-dose melphalan and autologous stem cell transplant (HDM/SCT) High-dose dexamethasonebased regimens : VAD, M-Dex High hematological response rate (~ 60%) Improved survival (median ~ 5 ys), but Selected patients High treatment-related mortality outside reference centres Hematological response rate > 60% (CR ~ 33%)

18 A French randomized controlled trial HDT/ASCT vs Mdex Inclusion criteria: previously untreated patients, aged ys, biopsy-proven AL, no symptomatic myeloma, ECOG 2 Peripheral blood stem cell Oral Melphalan 10 mg/m 2 /d collection after G-CSF + Dex 40 mg/d HD Melphalan 200 mg/m 2 IV + SCT HDM 140 mg/m 2 if : - age > 65 ys - Heart / kidney / hepatic failure - D1 to D4 - monthly cycles - Up to 18 months

19 AL amyloidosis : HDM/SCT vs MDex Patient survival (ITT) 100 Survival % MDex: median 56.9 months (N= 50) (20 deaths) 40 P< HDM/SCT : median 22.2 months (N= 50) (31 deaths) Months Jaccard et al. N Engl J Med 2007; 357: 1083

20 AL amyloidosis : HDM/SCT vs MDex Low risk versus high risk (Mayo Clinic criteria) Low risk: interventricular septum thickness 15 mm, LVEF > 55%, serum creatinine 2.0 mg/dl, total bilirubin 2.0 mg/dl Survival % MDex HDM HDM MDex p = 0.97 p = 0.13 Low risk (N=60) High risk (N= 40) Months

21 HDM/SCT vs MDex : conclusions MDex > HDM/SCT: Most patients eligible, moderate toxicity, oral route Similar response rates Survival : Similar in low-risk patients Equally poor in high-risk patients Mdex: first-line therapy in most European centers since 2007 Jaccard et al. N Engl J Med 2007; 357: 1083

22 Other strategies required in : m. Survival Cu 1,8,6,4,2 Cum m. Survival 1,8,6,4, Months Months High-risk patients (Mayo Clinic stage III) Non-responders

23 Novel anti-myeloma agents in AL amyloidosis Thalidomide Lenalidomide (Revlimid ) + dexamethasone Bortezomib (Velcade ) Combined with alkylating agents : melphalan, cyclophosphamide In development: Bendamustine Pomalidomide Novel proteasome inhibitors (carfilzomib) Monoclonal antibodies targeting plasma cells (daratuzumab, elotuzumab)

24 Standard-dose dose regimens including novel agents in AL HRR(%) Cyclo-Dex + Thalidomide MDex + MDex 50% - Revlimid CR 40% Bortezomib - Dex MDex + Bortezomib ORR100% Cy-Bor-D - Wechalekar, Blood 2009 Kastritis, JCO 2010 Moreau, Blood 2010 Zonder ASH, 2009 Mickael, Blood 2012

25 Improved survival of patients with AL amyloidosis The UK experience: 1.0 Proportion surviving (n=352) Median follow-up 0.6 : 4.8 yrs (n=418) No graft failure due to recurrent amyloid (5/22 and 5/14) p=0.016 Solid organ transplantation = a valid option 5-yr survival = % for kidney recipients (n=22) providing 45% suppression for heart recipients of the underlying (n=14) plasma cell clone and limited disease extension 0.4 The French experience: (n=208) (n=153) 5-yr survival = 87.5% for kidney recipients (n= 12) 63% for heart recipients (n= 18) Median follow-up : 23 months Recurrence : Kidney transplant Time (4/12) (mths) Heart transplant (5/18, 2 deaths) High rate of infections Merlini et al. XIII Intl. Workshop on Myeloma, Paris, 2011 Sattianayagam PT, et al. Am J Transplant 2010; 10: 2124 Pourreau F, Muller C, et al. XIII International Symposium on Amyloidosis, Groningen 2012

26 Conclusions Early diagnosis of AL amyloidosis is crucial M-Dex: current standard of care Already challenged by the novel anti-myeloma agents to be introduced rapidly : - after 1 to 3 courses of M-Dex if no clonal response (Mayo stage 1-2) - VCD (CyBorD) as first-line if Mayo stage 3 International phase III trial M-Dex vs M-Dex + Bortezomib HDM/SCT? limited to highly selected patients, experienced centers Chemotherapy guided by frequent assessment of FLC and cardiac biomarkers

27 Main cause of AKI in MM (30 to >80% in pathological studies) High mass MM (LC MM) No LC over-representation Predominant LC (> 70%) proteinuria Precipitating factors May be associated with other LC nephropathies Renal recovery : 50% (<20% if HD) Myeloma cast nephropathy

28 MCN : impact of ESRD on patient survival N = 85 patients with hematological response PR RR = free of dialysis NR = on dialysis Leung N, Bridoux F, Kumar S, et al. ASH 2011, abstract 3949

29 Myeloma cast nephropathy : pathophysiology Excessive Light LC endocytosis chains filtered in PT : (MW ~ 22 kda) Activation of redox pathways Increased expression of NFκB and MAPK Transcription of IL-6, IL-8, CCL2, TGFβ-1 Morphological changes Apoptosis, epithelial-mesenchymal transition Renal fibrosis Tamm-Horsfall protein LC interaction with THP : 9 amino-acid binding region of THP interacts with LC CDR3 Increased by : dehydration, acidic urine ph, high Ca, infection furosemide, NSAids, contrast media Tubular obstruction Morphological changes Tubular atrophy, interstitial inflammation, giant-cell reaction (tubulorrhexis) Renal fibrosis Sanders PW et al. J Clin Invest 1988 Sengul S et al. Kidney Int 2002 Myeloma mtal cast nephropathy

30 Myeloma cast nephropathy : pathophysiology Binding interaction between LCs and THP - Variable binding affinity depending on key amino-acids in CDR3 Mutational analysis of the CDR3 sequence Ying et al. J Clin Invest, 2012

31 Myeloma cast nephropathy : pathophysiology Effect of a cyclized competitor peptide with strong affinity for THP - In vitro inhibition of LC binding to THP - In vivo prevention of cast formation and renal LC accumulation in a rodent model of MCN Ying et al. J Clin Invest, 2012

32 Treatment of myeloma cast nephropathy : Symptomatic measures Urgent treatment required to reduce concentration and precipitation of urine FLCs Vigorous rehydration with saline and alkaline fluids Urine ph 7.0 Correction of hypercalcemia : rehydration (avoid loop diuretics), bisphosphonates Stop NSAIDs, RAS blockers Treatment of concomitant infections with non-nephrotoxic antibiotics

33 Treatment of myeloma cast nephropathy : Which chemotherapy? High-dose steroids (HD-Dex) + Drugs which do not require dose adaptation to reduced GFR : Adriamycin Cyclophosphamide Bendamustine Thalidomide Bortezomib ~ No randomized trial in myeloma patients with renal impairment

34 Treatment of MCN : Bortezomib Bortezomib and renal response N Regimen PR Renal response Dialysis withdrawal OS 2 yrs Toxicity Dimopoulos BD ± various 59% (CR 30%) 2/9 Similar to pts without RI Morabito 117 BD ± 73% 41% 3/14 51% Similar to pts 2010 various without RI Ludwig BD + doxo. 66% 62% (CR 31%) 58% Similar to pts without RI Predicting factors of renal response : LC myeloma, absence of previous chemo., egfr > 30 ml/min/1.73m 2 Dimopoulos et al. Clin Lymphoma Myeloma 2009; 9: 302 Baseline egfr and hematological response Ludwig et al. J Clin Oncol 2010; 28: 4635

35 Treatment of myeloma cast nephropathy : FLC removal Is there a role for plasmapheresis? Randomized prospective trial : 104 MM with AKI 5 to 7 PE sessions (50 ml/kg) + VAD or MP vs chemo. alone No significant difference in the two arms for the primary study end-point : death/need for dialysis/severe CKD with DFG < 30ml/min/1.73 m 2 Clark WF, et al. Ann Intern Med 2005; 143: 777

36 Median number of PE = 8 (3-14) Renal response = 12/14 (86%) CR = 6/14 (43%) Burnette, Leung & Rajkumar. N Engl J Med 2011; 364:

37 Treatment of MCN : FLC removal High cut-off dialysis using the HCO dialyzer Gambro Efficient FLC removal (35-70% reduction after 2 h) Albumin loss «HCO extended dialysis» and MCN Daily dialysis (8h x 5 days, then OD, then 6h x3/week) + chemiotherapy HD-Dex + Thali/ bortezomib Dialysis independence: ~ 60% (>75% if FLC response) Predicting factors of renal response : EULITE and MYRE trials Reduction in serum FLC levels 60% at D12 and D21 Time of HCO dialysis initiation: 3.5 vs 7 days Hutchison CA et al. JASN 2007, 2011 cjasn 2009 NDT 2012

38 Study objectives : 1. Epidemiology AKI and multiple myeloma : MYRE trial (NCT ) Frequency of MCN and other renal disorders in patients with monoclonal gammopathy and renal impairment 2. Treatment of MCN In patients with newly diagnosed MM and AKI secondary to MCN *Not requiring dialysis, comparison of : Bortezomib (Velcade ) + Dex (VD) Bortezomib (Velcade ) + Dex + Cyclophosphamide (VCD) *Requiring dialysis = Bortezomib + Dex, comparaison of : 2 intensive hemodialysis regimens - high cut-off dialyzer (Gambro Theralite 2.1 m 2 ) - conventional high-flux dialyzer

39 Acknowledgements Services de Néphrologie et Pathologie, CHU Poitiers Estelle Desport Corinne Lacombe, Beatrice Fernandez, Nathalie Quellard, Jean-Michel Goujon CNRS UMR7276, Limoges Christophe Sirac, Michel Cogné, Sébastien Bender, Claire Carrion Department and Laboratory of Nephrology, UCL Medical School, Brussels Olivier Devuyst, Sara Terryn, Claudia Raggi Centre de référence Amylose AL et autres maladies par dépôts d Ig monoclonales