We describe a patient who underwent a successful heart and kidney transplant for light-chain amyloidosis. She had an excellent hematologic response to bortezomib/dexamethasone therapy. Follow-up therapy with lenalidomide was started, and the patient quickly had a fatal allograft rejection of the heart and kidney. We present evidence to support the theory that lenalidomide, a known immunomodulator, may have stimulated the immune system and precipitated the fatal rejection episode.
allogeneic haemotopoietic stem-cell transplantation
autologous stem-cell transplant
Novel agents, including lenalidomide and other potent thalidomide derivatives, are dramatically improving the prognosis of multiple myeloma and are increasingly being used for the closely related plasma-cell dyscrasia known as light-chain (AL) amyloidosis. Due to the efficacy of these new therapies and of autologous bone-marrow transplantation, solid organ transplantation is being judged an increasingly viable option for end-organ damage resulting from amyloidosis. Nevertheless, red flags of caution regarding this strategy should be raised by our experience with the following case.
A 68-year-old woman with restrictive cardiomyopathy and chronic renal dysfunction received a combined heart and kidney transplant for severe end-stage heart failure and renal dysfunction secondary to AL amyloidosis. The transplant was performed at a time when the patient was critically ill, requiring inotropic support and renal replacement therapy. The patient had no other clinically apparent amyloid-related organ dysfunction. She was not sensitized before transplantation; titers of antibodies against HLA class I and II antigens were undetected. Extensive amyloid deposition was found in the explanted heart and kidney. Confirmatory mass spectroscopy testing, performed on tissue specimens at the Mayo Clinic (Rochester, MN), confirmed that the amyloid proteins represented AL amyloidosis. A bone-marrow biopsy performed on posttransplant Day 24 revealed lambda-restricted plasma cells (12%) and vascular amyloid deposits. A skeletal X-ray survey was negative for lytic lesions, the serum calcium level was normal and serum protein electrophoresis revealed hypogammaglobulinemia but no paraprotein. Thus, diagnostic criteria were met for systemic AL amyloidosis as well as asymptomatic multiple myeloma. Serum free light chain levels were markedly abnormal (see below).
The patient's posttransplant course was largely uneventful except for aspiration pneumonia, and she was discharged from the hospital 42 days posttransplant with excellent renal and cardiac allograft function. A brief readmission was needed for placement of a nephrostomy tube for hydronephrosis on Day 76. The transplant immunosuppression regimen consisted of basiliximab induction (20 mg) on Days 1 and 5, as well as tacrolimus and prednisone. Chemotherapy for the plasma-cell dyscrasia was commenced on Day 33, initially with weekly bortezomib (1.3 g/m2 subcutaneously) and weekly dexamethasone (40 mg orally). There was evidence of a hematologic response after 6 weeks of therapy, with serum free lambda light chain levels falling from 16.6 to 10.4 mg/dL (normal 0.57–2.63 dL) and repeat bone marrow examination showing that plasma cells had been reduced to 1%. Serial echocardiograms done during this period revealed normal allograft function. Biopsies of the cardiac allograft, performed on posttransplant Days 12, 19, 36, 47, 50, and 75, were consistently negative for evidence of cellular or humoral rejection (all biopsies revealed negative C4d immunofluorescence staining). Right-sided cardiac catheter studies were done at the time of each biopsy and revealed excellent hemodynamic values. A renal biopsy performed on Day 26 was also negative for evidence of acute rejection.
Lenalidomide therapy, 15 mg daily, and aspirin therapy, 81 mg daily, were introduced on Day 101, and preparation began for an autologous stem-cell transplant (ASCT). On posttransplant Day 109, however, the patient presented to the emergency department with a high fever, a productive cough, evidence of a pulmonary infiltrate on her chest roentgenogram and pyuria. Lenalidomide therapy was discontinued on admission. Echocardiography, performed on admission, revealed no changes compared to the previously normal posttransplant results. Tacrolimus levels were therapeutic at the time of admission and during the hospitalization, ranging from 5.6 to 15.4 ng/mL. The patient was treated with broad-spectrum antibiotics and stress-dose steroids in the intensive care unit, where she was closely observed and received subcutaneous heparin for prophylaxis of deep venous thrombosis. She appeared to improve initially but had an unexpected and fatal cardiac arrest, with pulseless electrical activity, 6 days after admission. An autopsy revealed severe acute cellular rejection, necrosis, and arteritis in both the heart and kidney (Figures 1).
Patients with AL amyloidosis who present with severe heart failure due to cardiac amyloidosis rarely survive for longer than 6 months and have a 100% mortality rate at 2 years . In the 1990s, cardiac transplantation alone was proposed as a viable treatment option for patients with cardiac amyloidosis, but the intermediate and long-term results of transplantation were poor due to progression of systemic disease and amyloid infiltration of the allograft . Thus, until recently, systemic amyloidosis was generally considered a contraindication for cardiac transplantation. Conversely, as stem-cell transplantation was improving outcomes for many patients with AL amyloidosis, significant cardiac involvement emerged as the main contraindication for this therapy, leaving these relatively young patients without effective treatment options. New agents and treatment strategies have led to renewed interest in solid organ transplantation as a viable option. In 2004, Skinner et al.  demonstrated a complete hematologic response in 40% of patients who received high-dose melphalan followed by ASCT. Several recent series revealed that in selected patients with AL amyloidosis and heart failure, cardiac transplantation followed by ASCT offered survival of up to 60% at 7 years [4-6].
Alkylating agents combined with corticosteroids have been a mainstay in the treatment of AL amyloidosis, just as they were for decades in the treatment of multiple myeloma. Oral melphalan plus prednisone or dexamethasone remains an effective treatment option for patients who are not candidates for ASCT (due to age or comorbidities), and high-dose alkylating agents are generally used as a preparatory regimen for those receiving ASCT [7, 8]. Lenalidomide, a potent derivative of thalidomide, has substantial efficacy in multiple myeloma, improving survival and becoming a first-line treatment option. In phase II clinical trials, lenalidomide has been efficacious in the treatment of AL amyloidosis, both as first-line therapy and as a salvage treatment for relapsed and refractory disease [8, 9]. The drug seems to act by inducing cell cycle arrest and down-regulating interleukin (IL)-6 and vascular endothelial growth factor in the tumor microenvironment . Lenalidomide is classed as an “IMiD,” which denotes a group of small molecule analogs of thalidomide with immumodulatory properties and anti-tumor activities . On a molar basis, lenalidomide is 200 000 times more potent than thalidomide at inhibiting tumor necrosis factor-alpha production . The precise molecular mechanisms have not been fully elucidated, but some of the effects appear related to up-regulation of activation receptors on natural killer (NK) cells and early activation and proliferation of T cells by costimulation of CD28, in turn leading to increased T cell-derived IL-2 and interferon (IFN)-gamma levels . These are precisely the mechanisms that are triggered in the cellular rejection cascade of solid organ transplants.
In our case, we hypothesize that the acute severe rejection of both organs was triggered by the initiation of lenalidomide therapy. This theory is supported by a recent report about the use of relatively low-dose lenalidomide (10 mg/day), started 1–6 months postallogeneic stem-cell transplantation as maintenance therapy in patients with multiple myeloma. In the phase-II HOVON 76 trial, 47% of the patients developed acute graft-versus-host disease (GVHD) a median of 18 days into lenalidomide therapy . Assays revealed significant increases in the levels of HLA-DR+, CD-4+ and CD-8+ cells, leading the researchers to conclude that lenalidomide maintenance therapy was not feasible. Induction of GVHD was also seen in a similar trial of lenalidomide (5 mg daily) given 100–180 days after allogeneic haematopoietic stem-cell transplantation (allo-SCT). In that study, GVHD occurred in 38% of the patients at a median interval of 22 days . Both studies provided immune monitoring, and the early time course of immune-stimulatory events may be relevant. In the second trial, peripheral blood assays indicated an increase in NK cell cytotoxicity and activation within the first month of lenalidomide treatment. T cell monitoring showed that CD3+/CD8+ levels increased significantly after the first 2 weeks of lenalidomide treatment; there was a strong increase in peripheral CD4+ IFN-gamma-secreting cells after 1 week and in CD8+ IFN-gamma-secreting cells after 3 weeks of treatment . The mechanisms of GVHD are known to be similar to those observed in solid organ transplant rejection, including the release of cytokines and antigen-presenting cells, as well as T cell interactions. These mechanisms induce proliferation and differentiation of T cell subsets, thus increasing IL-2 production, with the end result of inflammation and tissue destruction . Additionally, lenalidomide and pomalidomide have been shown to strongly inhibit the proliferation of FOXP3+ CTLA-4+CD4+CD25high T-regulatory cells (Tregs) in vitro . A reduction in Tregs could also have contributed to the unheralded and aggressive rejection observed in our case, as a depletion of Tregs using anti CD-25 antibody in naïve hosts before transplantation appears to hasten graft rejection [17, 18]. There is mounting evidence that Tregs have a key role in the prevention of rejection and the induction of tolerance in transplantation .
In our case, it is possible that the severe, acute, dual-organ rejection was unrelated to the initiation of lenalidomide therapy. However, the treating physicians were unable to identify any other precipitating factors (i.e. a change in baseline immune-suppression, another drug interaction or noncompliance) that would have explained this sudden, severe, and unheralded rejection in a patient who had previously shown excellent immune tolerance of her transplanted organs.
This case—along with the evidence of early immune activation seen in the two clinical trials of patients with multiple myeloma treated with allo-SCT, which quickly precipitated acute GVHD—should mandate extreme caution with, or even avoidance of, lenalidomide and potent related drugs in solid organ transplant recipients (as well as allo-SCT patients). It is critical to establish the safety of this class of immune modulator agents in allogeneic-transplant patients, as the use of these agents appears to cause a deleterious up-regulation of T cells and IL-2, resulting in an “immune-stimulatory effect” that may outweigh any potential antitumor benefit.
The authors thank Virginia C. Fairchild, of the Department of Scientific Publications at the Texas Heart Institute, for editorial assistance in preparing this manuscript.
The authors of this manuscript have conflicts of interest to disclose as described by the American Journal of Transplantation. In the last 2 years, Dr. Rice has been a consultant for Novartis Corporation (for the iron chelating drug deferasirox) and a member of the speakers' bureau for GlaxoSmithKline and Amgen (both for thrombopoietin-receptor agonist drugs); he did not receive honoraria of more than $13 000 for any of these consultancies, and none of them are relevant to the subject of this paper.