Single agent lenalidomide three times a week induceshematologic responses in AL amyloidosis patients on dialysis

Eben I. Lichtman, David C. Seldin, Anthony Shelton, and Vaishali Sanchorawala*

The combination of lenalidomide and dexamethasone can produce hematologic responses in previouslytreated patients with AL amyloidosis. Because lenalidomide is primarily excreted unchanged by the kidney,adjustments to the starting dose of lenalidomide are recommended to provide appropriate drug exposure inpatients with moderate or severe renal impairment and in patients on dialysis. Here, we report on a study ofpatients with AL amyloidosis on dialysis treated with lenalidomide at a dose of 10 mg orally three times aweek. Seven patients were enrolled. All patients had received prior treatment, with 57% receiving prior high-dose melphalan and stem cell transplantation. Two patients died before evaluation of response. The mostcommon adverse event was infection; no thromboembolic complications were seen. One patient requireddose-modification. Hematologic responses were obtained by four of the five evaluable patients. Medianoverall survival was 18 months. In conclusion, adjusted dose lenalidomide was reasonably tolerated andinduced sustained hematologic responses in previously treated patients with AL amyloidosis on dialysis.Am. J. Hematol. 89:706–708, 2014. VC 2014 Wiley Periodicals, Inc.

� IntroductionImmunoglobulin light chain (AL) amyloidosis, the most common form of systemic amyloidosis, is the result of immunoglobulin (Ig) light chain

production by clonal bone marrow plasma cells with subsequent widespread tissue deposition in the form of amyloid fibrils [1,2]. This oftenresults in multisystem organ dysfunction, with frequent manifestations including cardiac disease, peripheral and autonomic neuropathy, and renalfailure [3]. Clinically, evident kidney disease occurs in 50–80% of patients and up to one-third of these progresses requiring renal replacementtherapy [3,4].

The goal of treatment is to eliminate the clonal plasma cells producing amyloidogenic light chains [1]. Median survival without treatment is10–14 months [5]. Median survival in patients treated with oral melphalan and high-dose dexamethasone (MDex) is 5.1 years [6,7]. Median sur-vival in patients treated with high dose melphalan in combination with autologous peripheral blood stem cell transplant (HDM/SCT) is 6.3 years,but is extended to 13 years for those obtaining a complete hematologic response [8]. HDM/SCT can be used to treat selected patients on dialysis[9]. However, this aggressive treatment is only appropriate for a selected subset of patients given significant treatment-related mortality in the set-ting of multi-organ dysfunction. Novel immunomodulatory agents, including thalidomide, lenalidomide, and the proteasome inhibitors bortezomiband ixazomib, have been incorporated into single and multidrug regimens for AL, but there is little experience with these agents in patients ondialysis.

Lenalidomide has shown promising results when used in combination with dexamethasone in patients with AL amyloidosis. A prior study byour group reported a 67% overall hematologic response (HR), and a 29% complete response (CR) [10]. In a subsequent longer-term follow-up, wereported a median progression-free survival of 50 months among the 16% of patients who obtained a CR [11]. A similar study at the Mayo Clinicreported overall HR of 41% with a median progression-free survival of 19 months [12]. Fatigue and myelosuppression were the most commontreatment-related adverse events (35% each) and thromboembolic events were the most serious (9%) [10].

Lenalidomide has also shown promising results when combined with cyclophosphamide and dexamethasone, with reported HR rates up to 62%[13–15]. The combination of lenalidomide with melphalan and dexamethasone has been evaluated as well, but recent studies by our group andothers have shown high rates of toxicity [16,17].

Lenalidomide is primarily excreted by the kidneys, which represents �80% of total drug clearance in subjects with normal renal function [18].A pharmacokinetic study of lenalidomide in patients with renal impairment due to nonmalignant conditions showed that total drug exposureincreased substantially in patients with creatinine clearance (CrCl)< 50 mL/min, with exposure increased up to sixfold in patients with end-stagerenal disease (ESRD). Lenalidomide is dialyzable, with �31% of circulating drug being removed by a 4-hr dialysis session [18]. Adjustments to thestarting dose of lenalidomide are therefore recommended to provide appropriate drug exposure in patients with moderate to severe renal impair-ment and in those on dialysis [19]. Lenalidomide has never been studied in dialysis-dependent AL amyloidosis patients. We report here on a pro-spective clinical trial to evaluate the efficacy and toxicity of lenalidomide in this patient population.

Amyloidosis Center, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts

Conflicts of interest: The authors declare no financial conflicts.*Correspondence to: Vaishali Sanchorawala, MD, Section of Hematology/Oncology, FGH 1007, 820 Harrison Avenue, Boston, MA 02118. E-mail:vaishali.sanchorawala@bmc.orgContract grant sponsor: Celgene Corporation.Received for publication: 13 February 2014; Revised: 11 March 2014; Accepted: 23 March 2014Am. J. Hematol. 89:706–708, 2014.Published online: 26 March 2014 in Wiley Online Library (wileyonlinelibrary.com).DOI: 10.1002/ajh.23722

VC 2014 Wiley Periodicals, Inc.

706 American Journal of Hematology, Vol. 89, No. 7, July 2014 doi:10.1002/ajh.23722

RESEARCH ARTICLE AJHAJH

� MethodsThe study (ClinicalTrials.gov: NCT00091260) was approved by the Institutional

Review Board of the Boston University School of Medicine in accordance with fed-eral regulations. All patients provided written informed consent as per the Declara-tion of Helsinki. Patients were treated with lenalidomide alone or withdexamethasone at Boston Medical Center. All patients received lenalidomide at 10mg orally three times a week from days 1–21 of a 28 day cycle. For those patientson hemo or peritoneal dialysis, the lenalidomide dose was given after dialysis ses-sions. There was provision to add dexamethasone at 20 mg/week at the treatingclinician’s discretion if no hematologic response was achieved after three cycles.Treatment was discontinued for patients not demonstrating any hematologicresponse after six cycles. Patients received aspirin 325mg daily (unless already onanticoagulation therapy) and proton-pump inhibitor prophylaxis. Toxicity andresponses were evaluated after 1, 3, 6, 9, and 12 months of treatment. The NationalCancer Institute Common Terminology Criteria for Adverse Events (CTCAE), ver-sion 3, was used to grade adverse events. Organ responses were scored according topublished criteria developed by the ISA Consensus Panel at the 10th InternationalSymposium on Amyloidosis [20]. Hematologic responses were based upon quanti-tative measures of clonal plasma cell dyscrasia and were assessed starting at 3months after initiation of treatment. A CR was defined as the absence of monoclo-nal protein in serum and urine by immunofixation electrophoresis (IFE), normalserum free light chain (FLC) ratio, and polytypic plasma cells in the bone marrow.A near-complete response (nCR) was defined as the presence of monoclonal pro-tein in serum and urine by IFE with a normal serum FLC ratio and polytypicplasma cells in bone marrow. A partial response (PR) was defined as at least a 50%reduction in the serum free light chain, daily urinary light-chain excretion, or Mpeak on serum/urine protein electrophoresis. A minor response (MR) was definedas a reduction in one or more of the above parameters by at least 25% but lessthan 50%. Patients with less than a 25% reduction in all of the PR parameters werecategorized as persistent disease (PD).

� ResultsPatient characteristics

Seven patients with AL amyloidosis and dialysis dependence wereenrolled in the study between June 2007 and May 2010. The medianage was 61 years (range 45–72) and 71% were male. Three patients(43%) had lambda clonal plasma cell dyscrasia. Six patients (86%)had cardiac involvement. All patients were dialysis-dependent due toAL amyloidosis. Five patients were on hemodialysis and two were onperitoneal dialysis. The median duration of dialysis-dependence priorto enrollment was 7.1 months (range 2.3–56). All patients hadreceived prior treatment with a median number of treatment regi-mens of one. Four patients (57%) had received prior HDM-SCT(Table I).

Treatment characteristics and toxicity

The median number of cycles completed was 6 (range 0–27). Fiveof seven patients (71%) completed at least six cycles. One patientrequired dose modification to 5 mg lenalidomide after three cyclesdue to sinus bradycardia and syncope. No patient was treated withdexamethasone. Two patients died after enrollment due to disease-related complications, one due to heart failure after a single dose oflenalidomide (baseline Brain Natriuretic Peptide, (BNP) 11944 pg/mL, no follow-up BNP available after one dose of lenalidomide) andone due to dialysis line-related sepsis after two cycles of treatment.Six of the seven patients were evaluable for toxicities after at least onecycle of lenalidomide. Non-hematologic grade� 3 toxicities observedincluded fever/infection (n5 4), pulmonary or upper-respiratoryinfection (n5 3), fatigue (n5 2), sinus bradycardia (n5 1), syncope(n5 1), and rash (n5 1). Hematologic grade �3 toxicities includedneutropenia (n5 2). None of the patients developed thromboemboliccomplications (Table II).

Hematologic and organ responses, and survival

Five of the seven patients completed at least six cycles and wereevaluable for assessment of HR. One patient achieved a CR. Two offive achieved a nCR. One of five achieved a hematologic PR. The

overall HR rate (CR1 nCR1PR) was 80%. The median time to ini-tial HR (at least MR) was 6 months (range 3–9) and the median timeto best HR was 9 months (range 3–12). No patient developed dialysisindependence, or met other criteria for organ response. Four of sevenpatients had an increase in the serum BNP of >25% without develop-ment of other features of congestive heart failure. Three of those fourpatients also had an increase in Troponin I of >25% from the firstavailable measurement. Four of the seven patients were alive with amedian overall survival of 18 months (Fig. 1). Follow-up time rangedfrom 0.6 to 72 months from enrollment. No patient progressed toreceive further treatment after completion of the trial.

� Conclusions and DiscussionSingle agent lenalidomide was used as second line therapy for

patients with AL amyloidosis on dialysis as an investigational strategyto prevent progression of disease in other organs. At a dose of 10 mgthree times a week, it was reasonably tolerated and induced sustainedhematologic responses in a small group of previously-treated patientswith AL amyloidosis on dialysis. Lenalidomide in patients with nor-mal renal function is known to produce increased toxicity among

TABLE I. Patient Characteristics

Characteristic Value

Median age, y (range) 61 (45–72)No. male/female 5/2No. with j/k isotype 4/3% BM plasma cells, % (range) 5 (<5–20)No. PD/HD 2/5Median time of dialysis dependence, mo. (range) 7 (2–56)Median time from diagnosis to enrollment, mo. (range) 12 (5.1–75)Elevated BNP levels (>100 pg/mL), no. (%) 6 (86)Median BNP concentration, pg/mL (range) 472 (38–11944)Median baseline Troponin I, ng/mL (range)a 0.195 (0.032–0.28)Median baseline total CK, U/L (range) 87 (48–474)Median 24 h urine protein, g (range)b 5.84 (0.73–11.72)Median alkaline phosphatase, U/L (range) 112 (80–419)Median albumin, g/dL (range) 3.8 (2.3–4.2)Median number of organs involved, no. (range) 2 (1–3)Organ involvement other than ESRD, no. (%) 6 (86)Cardiac 6 (86)Hepatic 2 (29)Autonomic neuropathy 1 (29)Soft tissue, Macroglossia 1 (29)GI 1 (29)

Prior treatment, no. (%) 7 (100)With HDM/SCT 4 (57)With bortezomib 2 (29)With MDex 2 (29)With MPred 1 (14)

a Baseline Troponin I only available for 3 of the 7 patients.b Baseline 24 h urine protein available for 5 of 7 patients (2 patientsanuric).

TABLE II. Treatment Characteristics

Characteristic Value

Median number of cycles, no. (range) 6 (0–27)Dose modifications, no (%) 1 (14)Grade �3 hematologic toxicity, no (%) 3 (43)Neutropenia 2 (29)Febrile neutropenia 0

Grade �3 non-hematologic toxicity, no (%) 6 (86)Fatigue 2 (29)Cardiac 1 (14)Pulmonary 2 (29)

RESEARCH ARTICLE Lenalidomide in ESRD and AL amyloidosis

doi:10.1002/ajh.23722 American Journal of Hematology, Vol. 89, No. 7, July 2014 707

patients with AL amyloidosis as compared with multiple myelomapatients, most likely due to impaired organ function. Previous studiesfound that the standard dose of 25 mg/day used in multiple myelomaresulted in excessive toxicities, and subsequent studies have used areduced dose of 15 mg/day in this population [10,11]. There are,however, no prior studies of lenalidomide in patients with AL amyloi-dosis with dialysis-dependent ESRD and the tolerability of lenalido-mide in this population was previously unknown. A recent study oflenalidomide treatment in multiple myeloma patients with renalinsufficiency reported a good side-effect profile but only includedthree patients on hemodialysis [21]. The patients in our study experi-enced higher rates of adverse events, especially pulmonary and other

infections, than those with normal renal function. This is most likelyexplained by the immune dysregulation associated with ESRD. Ofnote, no thromboembolic complications were seen in this study, com-pared with rates of up to 9% in prior studies of patients [10,12].

It is also important to note that median BNP, which has been vali-dated as a prognostic marker in patients with AL amyloidosis andESRD [22], paradoxically increased following treatment with lenalido-mide despite other indications of HR. Paradoxical increases in BNPhave previously been observed in patients following treatment withlenalidomide and, although the mechanism is not clear, this is notfelt to represent disease progression [23,24]. It has been suggestedthat the increase in BNP seen with immunomodulatory agents maybe due to fluid retention, and that troponin levels may better corre-late with disease activity in this population [24]. However, the utilityof such criteria is not yet clear, especially in patients with ESRD.

The relatively slow hematologic response times observed in thisstudy (median of 6 months to initial HR) could represent an impor-tant limitation to using single-agent lenalidomide in this population.This is concerning given the high-percentage of patients with cardiacinvolvement, where rapid responses are desirable.

In summary, dose-adjusted lenalidomide was tolerable and effectivein AL amyloidosis patients on dialysis. Future studies in this patientpopulation might investigate, following the dosing regimen describedhere, the use of lenalidomide in combination regimens, in earlierstages of disease, or as maintenance therapy.

� Author ContributionsEIL analyzed data and wrote the manuscript. DCS designed and

performed research and edited manuscript. ACS collected data. VSdesigned research, performed research, analyzed data, wrote themanuscript.

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Figure 1. Kaplan–Meier survival plot of AL amyloidosis patients withdialysis-dependent ESRD who were treated with lenalidomide.

Lichtman et al. RESEARCH ARTICLE

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