Published online 27 January 2009
Haematologica, Vol 94, Issue 3, 439-441 doi:10.3324/haematol.13364
Copyright © 2009 by Ferrata Storti Foundation
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Letters to the Editor

Donor lymphocyte infusions in amyloid light chain amyloidosis: induction of a "graft-versus-plasma cell-dyscrasia effect"

Stefan O. Schonland1, Nicolaus Kröger2, Christine Wolschke2, Peter Dreger1, Anthony D. Ho1, Ute Hegenbart1

1 Department of Internal Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Heidelberg
2 Department of Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany

Correspondence: Ute Hegenbart, MD, Amyloidosis Clinic Department of Internal Medicine V, Hematology, Oncology and Rheumatology, University of Heidelberg, Im Neuenheimer Feld 410 D-69120 Heidelberg, Germany. Phone: international +49.6221568001. Fax: international +49.6221564659. E-mail:ute.hegenbart{at}med.uni-heidelberg.de

Key words: AL amyloidosis, multiple myeloma and other Plasma Cell Dyscrasias, allogeneic transplantation, donor lymphocyte infusion, plasma cell chimerism.

Systemic amyloid light chain (AL) amyloidosis is a rare protein folding disorder with poor prognosis due to multiple organ impairment (mainly heart and kidney). Underlying disease is a monoclonal gammopathy in most patients, only a small portion has symptomatic multiple myeloma. Treatment results in AL amyloidosis have improved in recent years. Apart from high-dose chemotherapy with melphalan supported by autologous stem cells (HDM)1 and melphalan-dexamethasone combination therapy2 new drugs active in multiple myeloma (MM) have become available.3–5 The main goal of treatment is to improve or at least preserve the function of the affected organs by elimination or control of the monoclonal plasma cell disorder.1 Long-term survival (>10 years) in about 20% of patients with complete remission (CR) after HDM could be shown recently.6 However, more than 50% of the patients do not achieve CR or relapse after initial therapy. Treatment of these patients has not been well investigated. It was recently shown that allogeneic stem cell transplantation (allo-SCT) could be an option for eligible patients leading to sustained CR.7 However, allo-SCT is a clinical challenge in this fragile patient group. Donor lymphocyte infusion (DLI) might be an approach to further increase CR rate after allo-SCT using reduced-intensity conditioning (RIC) as shown in MM.8 However, there are no data about application of DLI in this rare and fatal disorder.

Two patients with systemic AL amyloidosis were treated with allo-SCT in both centers until 2007. We administered DLI in both patients because they did not reach CR after allo-SCT. Patient characteristics and treatment results are summarized in Table 1. They received HDM as upfront therapy. Dominant organs involved were kidney in Patient 1 and heart in Patient 2. Patient 2 had further involvement of gut (diarrhea) and macroglossia. Indication for allo-SCT was organ progression due to persistent amyloidogenic light chain production after HDM. RIC was performed with 2 Gy of total body irradiation and fludarabine. Donors were HLA-identical sibling in Patient 1 and HLA-matched (10/10 loci) unrelated donor in Patient 2. The indication for DLI in both patients was persistent amyloidogenic light chain production (without further organ progression) after allo-SCT. A dosage of 5x106 and 1x106 CD3 positive cells per kilogram body weight was applied respectively. Toxicity was graded according to the Common Toxicity Criteria (http://ctep.info.nih.gov/reporting/index.html). Standard criteria were used for grading of acute and chronic GvHD. Response to treatment was defined according to the amyloidosis Consensus Criteria.9 Organ response of soft tissues and gut (which is not included in the Consensus Criteria) was judged by clinical evidence. Hematologic response to DLI was investigated by free-light chain assay, immunofixation as well as by chimerism analysis of plasma cells as recently described.10 Written informed consent from the patients and approval from the ethics committee were obtained. Data were analyzed as of August 1st, 2008. The time from allograft to DLI was +207 days for Patient 1 and +275 days for Patient 2 after withdrawal of immunosuppression on day +141 and +190 respectively. No hematologic toxicity and no infections after DLI were observed. Patient 1 experienced limited chronic GvHD of the skin and mouth mucosa and was treated with topical steroids. Patient 2 experienced extensive chronic GvHD and received cyclosporine and prednisone for a short period of time. In Patient 1, CR of MM stage I was induced two months after occurrence of chronic GvHD (Figure 1A). At this timepoint the incomplete plasma cell chimerism converted into a full donor plasma cell chimerism. Organ response of the kidney occurred 15 months later (Figure 1B). Patient 2 achieved CR 5 months after occurrence of cGvHD and full donor plasma cell chimerism followed by reduction of the size of the tongue and frequency of diarrhea (Table 1). The criteria for cardiac response were not yet fulfilled (septum thickness unchanged, cardiac improvement only by one NYHA stage).


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  		Table 1. Patients’ characteristics.


Figure 10940439
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  		Figure 1. Description of hematologic and organ response in Patient 1 (AL {kappa}+). (A) FLC {kappa} during treatment course. *2 cycles of bortezomib were administered for re-induction before allo-SCT and DLI. (B) Illustration of kidney response. Bars denote proteinuria and the line the creatinine-clearance. A 50% reduction of proteinuria was achieved since May 2008. cGvHD: chronic graft-versus-host-disease; CR: complete remission with conversion to 100% donor plasma cell chimerism; DLI: donor lymphocyte infusion; FLC: free-light chain.

Allo-SCT might be a curative approach for AL amyloidosis patients who failed melphalan based chemotherapy,7 but is restricted to patients having a suitable donor and good performance status. In recent years, the introduction of RIC has allowed also patients with impaired organ functions to receive allo-SCT. It is known that the risk of TRM after RIC is reduced compared to conventional conditioning.11

This is the first report of donor lymphocyte infusions in AL amyloidosis. The procedure was safe and successful. Our patients achieved a sustained CR for the first time in their disease course (followed by organ response in Patient 1 and clinical improvement in Patient 2). The conversion to a full donor plasma cell chimerism might be a surrogate marker for a molecular complete response.10 The efficacy of DLI to induce CR in HDM refractory patients with AL amyloidosis provides strong evidence that potent immunological effects can also be induced in clonal plasma cell disorders other than MM. It might be even more effective in these because the clonal plasma cell burden is not as high and the plasma cells are considered to be more indolent in AL amyloidosis.12 However, as shown in MM this potent graft-versus-plasma-cell-dyscrasia-effect is also associated with the occurrence of chronic GvHD.

In summary, our report provides the rationale to further investigate allo-SCT and post-transplant immunotherapeutic strategies in systemic AL amyloidosis.

References

  1. Skinner M, Sanchorawala V, Seldin DC, Dember LM, Falk RH, Berk JL, et al. High-dose melphalan and autologous stem-cell transplantation in patients with AL amyloidosis: an 8-year study. Ann Intern Med 2004;140:85-93.[Abstract/Free Full Text]
  2. Palladini G, Perfetti V, Obici L, Caccialanza R, Semino A, Adami F, et al. Association of melphalan and high-dose dexamethasone is effective and well tolerated in patients with AL (primary) amyloidosis who are ineligible for stem cell transplantation. Blood 2004;103:2936-8.[Abstract/Free Full Text]
  3. Sanchorawala V, Wright DG, Rosenzweig M, Finn KT, Fennessey S, Zeldis JB, et al. Lenalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 2 trial. Blood 2007;109:492-6.[Abstract/Free Full Text]
  4. Dispenzieri A, Lacy MQ, Zeldenrust SR, Hayman SR, Kumar SK, Geyer SM, et al. The activity of lenalidomide with or without dexamethasone in patients with primary systemic amyloidosis. Blood 2007;109:465-70.[Abstract/Free Full Text]
  5. Kastritis E, Anagnostopoulos A, Roussou M, Toumanidis S, Pamboukas C, Migkou M, et al. Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone. Haematologica 2007;92:1351-8.[Abstract/Free Full Text]
  6. Sanchorawala V, Skinner M, Quillen K, Finn KT, Doros G, Seldin DC. Long-term outcome of patients with AL amyloidosis treated with high-dose melphalan and stem-cell transplantation. Blood 2007;110:3561-3.[Abstract/Free Full Text]
  7. Schonland SO, Lokhorst H, Buzyn A, Leblond V, Hegenbart U, Bandini G, et al. Allogeneic and syngeneic hematopoietic cell transplantation in patients with amyloid light-chain amyloidosis: a report from the European Group for Blood and Marrow Transplantation. Blood 2006;107:2578-84.[Abstract/Free Full Text]
  8. Kroger N, Kruger W, Renges H, Zabelina T, Stute N, Jung R, et al. Donor lymphocyte infusion enhances remission status in patients with persistent disease after allografting for multiple myeloma. Br J Haematol 2001;112:421-3.[CrossRef][Web of Science][Medline]
  9. Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, 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;79:319-28.[CrossRef][Web of Science][Medline]
  10. Kroger N, Zagrivnaja M, Schwartz S, Badbaran A, Zabelina T, Lioznov M, et al. Kinetics of plasma-cell chimerism after allogeneic stem cell transplantation by highly sensitive real-time PCR based on sequence polymorphism and its value to quantify minimal residual disease in patients with multiple myeloma. Exp Hematol 2006;34:688-94.[CrossRef][Web of Science][Medline]
  11. Crawley C, Iacobelli S, Bjorkstrand B, Apperley JF, Niederwieser D, Gahrton G. Reduced-intensity conditioning for myeloma: lower nonrelapse mortality but higher relapse rates compared with myeloablative conditioning. Blood 2007;109:3588-94.[Abstract/Free Full Text]
  12. Bochtler T, Hegenbart U, Cremer FW, Heiss C, Benner A, Hose D, et al. Evaluation of the cytogenetic aberration pattern in amyloid light chain amyloidosis as compared to monoclonal gammopathy of undetermined significance reveals common pathways of karyotypic instability. Blood 2008;111:4700-5.[Abstract/Free Full Text]




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