Foard, D

Fontana, M

Gillmore, JD

Hawkins, PN

Lachmann, HJ

Lane, T

Mahmood, S

Manwani, R

Quarta, C

Rezk, T

Sachchithanantham, S

Sharpley, F

Wechalekar, AD

Whelan, C

English

UCL Discovery

1  Treatment of IgM-associated immunoglobulin light chain amyloidosis with Rituximab-Bendamustine Richa Manwani1, Sajitha Sachchithanantham1, Shameem Mahmood1, Darren Foard1, Faye Sharpley1, Tamer Rezk1, Thirusha Lane1, Cristina Quarta1, Marianna Fontana1, Helen J Lachmann1, Julian D Gillmore1 Carol Whelan1, Philip N Hawkins1 and Ashutosh D Wechalekar1* 1 National Amyloidosis Centre, University College London (Royal Free Campus), Rowland Hill Street, London * Corresponding Author:  Dr Ashutosh Wechalekar, National Amyloidosis Centre, University College London (Royal Free Campus), Rowland Hill Street, London, UK, NW3 2PF Telephone number: +44 207 433 2733, Fax number: +44 207 433 2817 Email: a.wechalekar@ucl.ac.uk   Running head: IgM-associated immunoglobulin light chain amyloidosis Text word count: 1200 Number of figures: 1 Number of tables: 1 Number of references: 14      Blood First Edition Paper, prepublished online June 20, 2018; DOI 10.1182/blood-2018-04-846493 Copyright © 2018 American Society of HematologyFor personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom 2  Systemic AL amyloidosis (AL) is characterised by deposition of misfolded immunoglobulin light chains within organs.  AL with an IgM monoclonal protein (IgM-AL) accounts for 5-7% of AL and exhibits more prevalent lymph node, neuropathic and lung involvement, less prevalent cardiac involvement and lower amyloidogenic light chains.1  A reduction in intact monoclonal protein and free light chains is prognostic.1  A very good partial response (VGPR) is associated with better survival and organ responses but is challenging to achieve due to an unclear underlying diagnosis (usually lymphoplasmacytic lymphoma) and lack of treatment uniformity.  In a large retrospective study, we reported the use of twenty-two front-line regimens.1  Rituximab-based regimens are often used alongside bortezomib, alkylators or purine analogs; outcomes remain poor with few complete responses.1-3 Excellent haematological responses were reported in 12 IgM-AL patients treated with autologous stem cell transplantation4 – but given the older age of IgM-AL patients, this is often not an option.  Treatment of relapsed/refractory patients is particularly challenging and recent experience with ibrutinib was disappointing.5  Bendamustine, which has features of an alkylator and purine analog, is used alongside rituximab in newly diagnosed and relapsed/refractory non-Hodgkin lymphoma6 and in relapsed/refractory Waldenstrom’s Macroglobulinaemia (WM) with overall haematological response rate (ORR) of 83.3%.7  Bendamustine in relapsed/refractory AL (with a plasma cell dyscrasia) resulted in disappointing responses.8  There have been no studies focusing on the use of rituximab-bendamustine (BR) in IgM-AL.  We report efficacy of BR in untreated and relapsed/refractory IgM-AL.  Twenty-seven patients treated with BR between 2011-2017 were identified from the UK National Amyloidosis Centre database: twenty-two received BR first-line therapy and five as second-line.  For personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom 3  Twenty-five had a serum IgM M-protein.  Two had lymphoplasmacytic lymphoma on bone marrow examination but had a serum IgG M-protein (instead of IgM).   AL was confirmed on biopsy immunohistochemistry or proteomic analysis. All patients underwent serial biochemical tests for organ function, cardiac biomarkers, serum free light chains, serum and urine protein electrophoresis and immunofixation, echocardiography +/- cardiac MRI (unless contraindicated). Organ involvement was defined by international amyloidosis consensus criteria.9  Haematological responses were assessed according to AL amyloidosis response criteria.10  In patients with non-evaluable serum free light chains (dFLC<50mg/L), IgM M-protein was used for assessment.  Rituximab (375mg/m2) was administered intravenously on Day 1 as per local protocols. Bendamustine (90mg/m2) was administered intravenously over 30 minutes on Day 1 and 2. Four patients received additional corticosteroid therapy (three received weekly dexamethasone 20mg, one received once weekly dexamethasone 10mg).  BR was repeated every 28 days.   Outcome variables were haematological and organ response, overall survival (OS) progression-free survival (PFS, progression defined as progression to next treatment or death), and time-to-next-treatment (TNT).    Table 1 shows baseline characteristics. Median age was 70 years (56-86 years). Cardiac, renal, liver, peripheral nerve, autonomic nerve and soft tissue involvement were found in 17 (63%), 17 (63%), 6 (22%), 6 (22%), 4 (15%), 2 (7%), respectively.  Lymphadenopathy was radiologically identified in 13 (48%); 7 (26%) had biopsy-proven lymph node amyloid deposition.  The Mayo 2004 cardiac stage was:  Stage I 30%, Stage II 48% and stage III 22%.  Median M-protein was 11.5g/l (1-30g/l); 19 For personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom 4  (70.4%) had evaluable free light chains. Of the remaining patients, all had an IgM M-protein (>5g/l) enabling response assessment.10   Twenty-one patients had available bone marrow data (trephine +/- flow cytometry): three normal, one plasma cell infiltration, fourteen lymphoplasmacytic lymphoma and three NHL not specifically classified. Five patients were treated with BR for refractory disease, previous therapies included bortezomib-cyclophosphamide-dexamethasone in two and in one case each: rituximab-bortezomib-dexamethasone, rituximab-cyclophosphamide-vincristine-prednisolone and rituximab-cyclophosphamide-dexamethasone.    The median number of BR cycles was 5 (range 1-8).  The median number of previous cycles in the second-line group was 6 (range 4-8).  Three patients received two-monthly rituximab maintenance (375mg/m2 intravenously) after first-line therapy with BR. All three remain on rituximab maintenance, with treatment duration thus far of 8, 10 and 11 months.   ORR on an intention-to-treat (ITT) and evaluable basis was 59% and 76%, respectively.  Haematological responses (ITT) were: complete response (CR) 11%, VGPR 37%, partial response (PR) 11% and no-response (NR) 41% (including 22% deaths).  In the first-line group, haematological responses were: CR 14%, VGPR 32%, PR 14% and NR 40% (including 18% deaths).  The evaluable responses were:  CR 17%, VGPR 39%, PR 17% and NR 27%.  Of three patients treated with two-monthly rituximab maintenance, one remains in VGPR, one in CR (having been in VGPR at time of completing BR) and one in PR (non-responder at time of completing BR). In five treated for refractory AL, three achieved a VGPR and two were non-responders (including one death). 3/17 For personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom 5  patients with cardiac involvement achieved NT-proBNP responses and 3/17 patients achieved renal responses by consensus criteria.10  Median follow-up was 18 months (3-55 months). Median OS was not reached (Figure 1A). Median OS was not reached in patients who achieved VGPR/better, compared to 9 months in patients who did not (Figure 1B).  Median PFS was 34 months. Five patients (18.5%) died within six months of diagnosis (three Mayo Stage II, two Stage III). On six month landmark analysis, median PFS was not reached. Of patients in the 6 month landmark analysis who achieved VGPR/better, median OS and PFS were not reached (compared to 34 and 11 months, respectively, in patients who did not).  Three patients progressed to next treatment (their response to BR was VGPR, PR and non-response). Median TNT was not reached, with 88% and 79% of evaluable patients (n=17) not progressing to next treatment at 1 and 3 years, respectively (Figure 1A).   Grade 3-4 toxicity included: diarrhoea 1 (3.7%), hypotension 2 (7.4%), non-neutropenic infection (11.1%), neutropenia 2 (7.4%), febrile neutropenia 2 (7.4%) (resulting in bendamustine dose reduction to 60mg/m2), rash 1 (3.7%), fluid overload 2 (7.4%) and GI bleeding 1 (3.7%). The most frequent Grade 1-2 toxicities were constipation (26%) and fatigue (30%).   The data from this small retrospective study demonstrates excellent haematological responses. Impressively, 48% achieved VGPR/better (ITT).  Sixty percent of patients treated with BR second-line achieved a VGPR.  Furthermore, rituximab maintenance upgraded responses in the few patients that received this therapy.   For personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom 6  Treatment in IgM-AL is not uniform, with poor responses to alkylators (responses 27-38%2,11,12) or purine-analogue/anthracycline-containing therapy 1,2.  Outcomes with bortezomib-based therapy are mixed:  VGPR/better 27% and 42% in two studies.1,13.  A rituximab-bortezomib combination improved responses, with ORR of 78%.3  The high prevalence of disease-related neuropathy in IgM-AL provokes reticence in using bortezomib.  Furthermore, bortezomib is not funded in the UK for lymphoproliferative disorders.  The few patients eligible for ASCT appear to have good outcomes (ORR 89% and 67% organ responses) but transplant-related mortality was 8%.4  In a large European study, only 1.8% of patients were treated with ASCT.1  Disappointingly, the efficacy of ibrutinib in WM (ORR of 91%) 14 was not replicated in AL.5    In conclusion, this study suggests that first-line BR leads to high response rates in IgM-AL.  Bendamustine is not neurotoxic, dosing is not affected by renal impairment and there is no known cardiac toxicity, rendering BR a widely applicable therapy in IgM-AL.  Response appears durable and maintenance rituximab may upgrade depth of response.  The limitation of this study is one shared with almost all literature in IgM-AL given its rarity: it is small and retrospective.  Larger collaborative studies are needed to confirm these results and combination with novel proteasome inhibitors should be explored to further improve outcomes.   Acknowledgements We wish to acknowledge our staff in echocardiography, histopathology and those involved in the clinical care of our patients.  Authorship contributions For personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom 7  RM and AW designed the manuscript, collected and analysed data, and wrote the paper. The remaining authors managed the patients and provided critical input prior to submission.   Disclosure of conflict of interest None of the authors have any relevant conflicts of interest to disclose.   Institutional review board approval  The Alchemy study is performed in accordance with the recommendations guiding physicians in biomedical research involving human subjects adopted by the 18th World Medical Assembly, Helsinki, Finland, 1964, amended at the 52nd World Medical Association General Assembly, Edinburgh, Scotland, 2000. Informed written consent is obtained from the patients prior to registration into the study. The right of a patient to refuse participation without giving reasons is respected.  Patients remain free to withdraw at any time from the study without giving reasons and without prejudicing his/her further treatment. Study granted approval by the appropriate NHS Research Ethics Committee.  References 1. Sachchithanantham S, Roussel M, Palladini G, et al. European Collaborative Study Defining Clinical Profile Outcomes and Novel Prognostic Criteria in Monoclonal Immunoglobulin M-Related Light Chain Amyloidosis. J Clin Oncol. 2016;34(17):2037-2045. 2. Terrier B, Jaccard A, Harousseau JL, et al. The clinical spectrum of IgM-related amyloidosis: a French nationwide retrospective study of 72 patients. Medicine (Baltimore). 2008;87(2):99-109. 3. Palladini G, Foli A, Russo P, et al. Treatment of IgM-associated AL amyloidosis with the combination of rituximab, bortezomib, and dexamethasone. Clin Lymphoma Myeloma Leuk. 2011;11(1):143-145. 4. Valente M, Roy V, Lacy MQ, Dispenzieri A, Gertz MA. Autologous stem cell transplantation and IgM amyloidosis. Leuk Lymphoma. 2006;47(6):1006-1012. For personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom 8  5. Pika T, Hegenbart U, Flodrova P, Maier B, Kimmich C, Schonland SO. First report of ibrutinib in IgM-related amyloidosis: few responses, poor tolerability, and short survival. Blood. 2018;131(3):368-371. 6. Rummel MJ, Niederle N, Maschmeyer G, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-1210. 7. Treon SP, Hanzis C, Tripsas C, et al. Bendamustine therapy in patients with relapsed or refractory Waldenstrom's macroglobulinemia. Clin Lymphoma Myeloma Leuk. 2011;11(1):133-135. 8. Milani P, Schonland S, Palladini G, et al. Response to bendamustine is associated with a survival advantage in a heavily pretreated patients with AL amyloidosis. Amyloid. 2017;24(sup1):56-57. 9. Gertz MA, Comenzo R, Falk RH, et al. Definition of organ involvement and treatment response in immunoglobulin light chain amyloidosis (AL): a consensus opinion from the 10th International Symposium on Amyloid and Amyloidosis, Tours, France, 18-22 April 2004. Am J Hematol. 2005;79(4):319-328. 10. Comenzo RL, Reece D, Palladini G, et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia. 2012;26(11):2317-2325. 11. Wechalekar AD, Lachmann HJ, Goodman HJ, Bradwell A, Hawkins PN, Gillmore JD. AL amyloidosis associated with IgM paraproteinemia: clinical profile and treatment outcome. Blood. 2008;112(10):4009-4016. 12. Palladini G, Russo P, Bosoni T, et al. AL amyloidosis associated with IgM monoclonal protein: a distinct clinical entity. Clin Lymphoma Myeloma. 2009;9(1):80-83. 13. Sissoko M, Sanchorawala V, Seldin D, et al. Clinical presentation and treatment responses in IgM-related AL amyloidosis. Amyloid. 2015;22(4):229-235. 14. Treon SP, Tripsas CK, Meid K, et al. Ibrutinib in previously treated Waldenstrom's macroglobulinemia. N Engl J Med. 2015;372(15):1430-1440.    For personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom 9  Table 1. Baseline characteristics. n=27 Median (range) / n(%) Median age (years) 70 (range 56-86) Male:Female 16 (59%):11 (41%) NYHA class 1 2 3 4  12 (44%) 14 (52%) 1 (4%) 0 ECOG  0 1 2 3 4  7 (26%) 15 (56%) 5 (18%) 0 0 Cardiac involvement 17 (63%) Median NT-proBNP (ng/l) 978 (range 42-5708) Median cardiac troponin T (ng/l) 31.5 (range 3-122) Mayo Stage I II IIIA (NT-proBNP ≤8500ng/l) IIIB (NT-proBNP>8500ng/l)  8 (30%) 13 (48%) 6 (22%) 0 Median systolic blood pressure (mmHg) 119 (range 100-164) Median left ventricular wall thickness (mm) 11 (range 8.5-18) Median LV ejection fraction (%) 60 (range 36-72) Renal involvement 17 (63%) Median serum creatinine (umol/l) 98 (range 46-493) Median GFR (ml/min) 68 (range 10-100) Median proteinuria (g/24h) 0.8 (range 0.1-34.6) Liver involvement 6 (22%) Median serum bilirubin (umol/l) 6 (range 2-50) Median ALP (units/l) 105 (range 25-1879) Soft tissue involvement 2 (7%) Peripheral nerve involvement 6  (22%) Autonomic nerve involvement 4 (15%) Lymph node involvement 13 (48%) GI involvement 0 Median number of involved organs 1 (range 1-4) Involved light chains: Kappa Lambda No monoclonal light chain excess  7 (26%) 12 (44%) 8 (30%) Median dFLC (mg/l) 59.8 (range 2.2 – 856.4) IgM kappa M-protein IgM lambda M-protein 11 (44%) 14 (56%) Median serum monoclonal protein (g/l) 11.5 (range 1-30)  For personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom 10  Figure 1. Overall survival (OS) and time-to-next-treatment (TNT). A) This shows the overall survival (OS) on an ITT basis (n=27) and time-to-next-treatment (TNT) on an evaluable basis (n=17). Median OS and median TNT were not reached.  OS at 1 year and 3 years was  65% and 56%.  At 1 and 3 years,  88% and 79% of evaluable patients (n=17) had not progressed to further treatment.  B) Median OS was not reached in those patients who achieved a very good partial response (VGPR) or better with 92% alive at 2 years; median OS was 9 months in patients who did not achieve a VGPR.     For personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom For personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom doi:10.1182/blood-2018-04-846493Prepublished online June 20, 2018;   Carol Whelan, Philip N. Hawkins and Ashutosh D. WechalekarTamer Rezk, Thirusha Lane, Cristina Quarta, Marianna Fontana, Helen J. Lachmann, Julian D. Gillmore, Richa Manwani BMBS, Sajitha Sachchithanantham, Shameem Mahmood, Darren Foard, Faye Sharpley, Rituximab-BendamustineTreatment of IgM-associated immunoglobulin light chain amyloidosis with http://www.bloodjournal.org/site/misc/rights.xhtml#repub_requestsInformation about reproducing this article in parts or in its entirety may be found online at:http://www.bloodjournal.org/site/misc/rights.xhtml#reprintsInformation about ordering reprints may be found online at:http://www.bloodjournal.org/site/subscriptions/index.xhtmlInformation about subscriptions and ASH membership may be found online at:    digital object identifier (DOIs) and date of initial publication. indexed by PubMed from initial publication. Citations to Advance online articles must include final publication). Advance online articles are citable and establish publication priority; they areappeared in the paper journal (edited, typeset versions may be posted when available prior to Advance online articles have been peer reviewed and accepted for publication but have not yet  Copyright 2011 by The American Society of Hematology; all rights reserved.Hematology, 2021 L St, NW, Suite 900, Washington DC 20036.Blood (print ISSN 0006-4971, online ISSN 1528-0020), is published weekly by the American Society ofFor personal use only.on July 5, 2018. by guest  www.bloodjournal.orgFrom 

Treatment of IgM-associated immunoglobulin light chain amyloidosis with Rituximab-Bendamustine

https://discovery.ucl.ac.uk/10051886/1/blood-2018-04-846493.full.pdf

Treatment of IgM-associated immunoglobulin light chain amyloidosis with Rituximab-Bendamustine

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UCL Discovery