Int J Hematol (2011) 93:673–676 DOI 10.1007/s12185-011-0829-4
CASE REPORT
Durable hematological response and improvement of nephrotic syndrome on thalidomide therapy in a patient with refractory light chain deposition disease Haruyuki Fujita • Masakatsu Hishizawa • Soichiro Sakamoto • Tadakazu Kondo Norimistu Kadowaki • Takayuki Ishikawa • Junji Itoh • Atsushi Fukatsu • Takashi Uchiyama • Akifumi Takaori-Kondo
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Received: 15 September 2010 / Revised: 7 March 2011 / Accepted: 22 March 2011 / Published online: 9 April 2011 Ó The Japanese Society of Hematology 2011
Abstract Light chain deposition disease (LCDD) is a rare disease for which an optimal treatment is not yet available. Here, we report the clinical course of a 32-year-old woman with LCDD who was successfully treated with thalidomide. She presented with nephrotic syndrome. Based on the renal biopsy findings and the presence of monoclonal immunoglobulin light chains in her serum and urine, LCDD was diagnosed. Prednisolone and cytotoxic chemotherapy used for multiple myeloma proved ineffective. We initiated administration of thalidomide (100 mg daily) and dexamethasone (20 mg for 4 days per month). After 8 months of treatment, she achieved complete hematological remission, defined as the disappearance of monoclonal protein and a normalized free light chain ratio, which led to improvement of her renal insufficiency. She has shown sustained hematological and organ response for 31 months with thalidomide therapy. Thus, thalidomide therapy seems to be a promising approach to the treatment of LCDD. Keywords Thalidomide Light chain deposition disease (LCDD) Plasma cell dyscrasia
H. Fujita M. Hishizawa (&) S. Sakamoto T. Kondo N. Kadowaki T. Ishikawa T. Uchiyama A. Takaori-Kondo Department of Hematology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawaharacho Sakyo-ku, Kyoto 606-8507, Japan e-mail:
[email protected]
1 Introduction Light chain deposition disease (LCDD) is a rare systemic disorder characterized by monoclonal immunoglobulin light chain deposition in various tissues [1]. LCDD most preferentially affects the kidneys and usually manifests as nephrotic syndrome and/or renal failure; it can also involve other organs such as the heart, liver, and peripheral nerves [2, 3]. The mean patient age is 58 years (range 28–94 years), and the onset of LCDD at a young age is unusual [3]. Its histopathology is characterized by prominent tissue deposits of non-amyloid, non-fibrillary, and amorphous eosinophilic materials, which do not stain with Congo red [4]. LCDD is often associated with plasma cell dyscrasias, including multiple myeloma, or monoclonal gammopathy of undetermined significance (MGUS) [2]. If left untreated, most LCDD patients with renal involvement will progress to end-stage renal disease [5]. In many LCDD cases, patients have been treated with the chemotherapeutic regimens for multiple myeloma, but there was little evidence of any long-term benefit. Thalidomide, an immunomodulatory drug, has multiple mechanisms of action as an anti-myeloma agent. Numerous studies have shown the efficacy of thalidomide in the treatment of multiple myeloma [6, 7] and AL amyloidosis [8, 9]. In this study, we present a patient with LCDD accompanied by nephrotic syndrome, which was successfully treated with thalidomide.
J. Itoh Department of Laboratory Medicine, Nagoya City Midori General Hospital, Nagoya, Japan
2 Case report
A. Fukatsu Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
In November, 2007, a 32-year-old woman without significant past medical history was admitted to a nearby hospital
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Fig. 1 The histology of renal biopsy. a, b Nodular lesions with deposition of PAS-positive materials and sclerosis are shown (a PAS stain 9400, b PAM stain 9400). c Interstitium is preserved and thickening of the tubular basement membrane is noted (PAM stain 9400). d Electron micrograph of a glomerular basement membrane. Characteristic deposition of dense materials is found along endothelial side of the basement membrane (original magnification 93000)
because of weight gain and anasarca for several weeks. She presented with marked ascites, pitting edema of legs, and bilateral pleural effusions on a chest radiogram. Laboratory investigation revealed nephrotic syndrome. After a renal biopsy, she was referred to our hospital. Her blood pressure was 155/51 mmHg. The 24-h urine sample contained 5.7 g of protein, and her total serum protein and albumin were 5.3 and 3.2 g/dL, respectively. Her serum creatinine level was 1.3 mg/dL, and the estimated glomerular filtration rate was 39.8 mL/min. Her renal-biopsy specimen showed typical findings of LCDD (Fig. 1). Nodular lesions with periodic acid-Schiff (PAS)-positive materials and periodic acid-methenamine (PAM)-positive sclerotic lesions were found in the glomerulus. Congo red staining results were negative. The interstitium was preserved; however, an irregular thickening of the tubular basement membrane was observed. Electron microscopy showed deposition of dense materials along the endothelial side of the glomerular basement membrane. Although we could not directly demonstrate the deposition of light chains because of the lack of the sufficient frozen tissue, these histological
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findings were compatible with those of LCDD. The serum levels of IgG, IgA, and IgM were 518, 188, and 93 mg/dL, respectively. Immunofixation of serum revealed the presence of an IgG lambda monoclonal protein. Immunoelectrophoresis of the urine sample showed the presence of a moderate amount of lambda Bence-Jones protein with a large amount of albumin. Examination of the bone marrow aspirate showed that the marrow was normocellular with 2% atypical plasma cells. Congo red staining of the bone marrow and fat biopsy samples yielded negative results. LCDD was diagnosed on the basis of these findings. Initially, she was treated with 40 mg of prednisolone (0.8 mg/kg) daily, but her 24-h urinary protein excretion was still more than 5 g. After LCDD was diagnosed, she underwent chemotherapy regimens for multiple myeloma with minor modifications: VAD (4-day continuous infusion of daily dose of 0.4 mg vincristine and 9 mg/m2 doxorubicin, with 12 mg of dexamethasone for 4 days), and DCEP (4-day continuous infusion of daily doses of 400 mg/m2 cyclophosphamide and 40 mg/m2 etoposide, with 40 mg of dexamethasone for 4 days) [10, 11].
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Fig. 2 Clinical course of the patient. Cre creatinine, Alb albumin, j/k ratio serum free light chain kappa and lambda ratio, VAD vincristine– doxorubicin–dexamethasone, DCEP dexamethasone– cyclophosphamide–etoposide– cisplatin (excluding cisplatin)
However, no improvement was noted in proteinuria, hypoalbuminemia, and renal impairment (Fig. 2). Then, we administered a combination of thalidomide (100 mg daily) and dexamethasone (20 mg for 4 days per month) after obtaining her written informed consent. Three months after initiating this treatment, both her serum creatinine and urine protein levels showed gradual decrease. Before treatment, her serum had elevated free lambda chain level (740 mg/L) and the free kappa–lambda ratio was 0.04 (normal range 0.248–1.804) (Fig. 2). In accordance with the improvement of these laboratory data, the kappa–lambda ratio normalized. During the first 8 months of the therapy, she often suffered from infections, such as bacterial pneumonia and repetitive upper respiratory tract infection. She did not receive any prophylaxis for infection because of renal insufficiency, and most of the affected infections were unpreventable. Thereafter, dexamethasone was discontinued; however, her hematological response was sustained, and the monoclonal protein became undetectable in her serum by immunofixation. Thalidomide therapy has allowed complete hematological remission and improvement of nephrotic syndrome for 31 months as of December 2010. After discontinuation of dexamethasone, she has been free from any life-threatening infections or toxicity of grade 2 or greater.
3 Discussion Major therapeutic efforts for treating LCDD have been directed toward reducing the synthesis of monoclonal proteins. In a few small series studies, high-dose melphalan combined with autologous stem cell transplantation (ASCT) has been reported useful for patients with LCDD [12–16]. A substantial population of patients who had renal impairment before ASCT achieved complete remission and
organ response. This suggests that high-dose melphalan may be a promising therapeutic option that can lead to a significant control of monoclonal free light chain production as well as improvement of renal function. However, this procedure often can be accompanied by severe toxicity, particularly if the patient suffers from severe renal insufficiency [12, 15]. Considering the potential adverse effects, we did not use high-dose melphalan followed by ASCT as the first-line therapy. Thalidomide has been shown to have significant therapeutic effects for the treatment of patients with myeloma or AL amyloidosis [6–9]. Promising treatment outcomes observed with thalidomide in myeloma and AL amyloidosis provide a rationale for evaluating this approach for LCDD treatment. However, a combination with thalidomide and dexamethasone for the treatment of AL amyloidosis was reported to have poor tolerance, especially when higher thalidomide doses were used; 50–65% of the patients experienced grade 3 and 4 toxicities [8, 9]. In the present case, the dose of thalidomide was 100 mg daily. After discontinuation of dexamethasone, the patient did not experience any severe toxicity. Low dose of single-agent thalidomide may have contributed to tolerance in this patient. Further, patients with AL amyloidosis often show cardiac or multiorgan involvement. Pharmacokinetic studies have demonstrated that the kidney is apparently not involved in thalidomide metabolism [17]. Given the fact that symptomatic extrarenal deposition of light chains is uncommon, thalidomide may be safely used for a substantial proportion of LCDD patients. After thalidomide induction, ASCT might be an alternative option as a consolidation treatment. However, other novel agents currently being used for multiple myeloma other than thalidomide may be effective for LCDD treatment. Bortezomib has been reported to be useful for
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patients with LCDD, resulting in hematological and organ responses [18]. Although it has not been reported to date, lenalidomide may also present as a promising alternative. Regarding the treatment of young myeloma patients, the favorable results obtained with novel agents are challenging the role of upfront ASCT. It remains controversial whether the use ASCT upfront or after relapse is more beneficial [19]. It is necessary to draw more definitive conclusions on the role of ASCT and/or novel agents in the therapeutic algorithm for LCDD from future prospective studies. In conclusion, thalidomide therapy was tolerable, and resulted in hematological response as well as in improvement of renal function in a patient with refractory LCDD. To date, there is no report that provides a detailed description of the efficacy of thalidomide for LCDD treatment. Our encouraging result warrants further trials of thalidomide therapy for patients with LCDD. Acknowledgments We thank Dr. Toyokazu Yoshioka (Nishikyoto Hospital, Kyoto) for performing the renal biopsy and providing critical data of the patient, and Dr. Kazuyuki Shimizu (Nagoya City Midori General Hospital, Nagoya) for critical reading of the manuscript.
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