Anthony C Shelton

Pomalidomide and dexamethasone in the treatment of AL amyloidosis: results of a phase 1 and 2 trial

The objectives of a phase 1/2 trial of pomalidomide with dexamethasone for the treatment of light chain (AL) amyloidosis were to determine the safety, tolerability, maximum tolerated dose (MTD), recommended phase 2 dose, and hematologic and clinical response. A 3+3 dose-escalation phase (15 patients) was followed by an expansion cohort (12 patients) enrolled at the MTD. Pomalidomide was administered at 2 and 3 mg on days 1 to 28 (cohorts 1 and 2) and 4 mg on days 1 to 21 (cohort 3) every 28 days, with weekly dexamethasone at a dose of 20 mg. Twenty-seven patients with previously treated AL were enrolled, 15 during dose escalation (6 at 2 mg, 3 at 3 mg, and 6 at 4 mg) and 12 during dose expansion (all at 4 mg). One patient experienced dose-limiting toxicity at 4 mg; the MTD was determined as 4 mg. The most common grade ≥3 drug-related adverse events included myelosuppression and fatigue. Overall, hematologic response (HR) was 50% in 24 evaluable patients. The median time to best HR was 3 cycles, and median duration of HR was 15 months. Median overall survival has not yet been reached, with a median follow-up of 17.1 months and median event-free survival of 17.8 months. This trial was registered at www.clinicaltrials.gov as #NCT01570387.

Kidney dysfunction during lenalidomide treatment for AL amyloidosis

BACKGROUND Lenalidomide is an immunomodulatory agent used to treat plasma cell dyscrasias. We previously observed worsening of kidney function in a high proportion of patients with AL amyloidosis during lenalidomide treatment. The objective of this study is to characterize alterations in kidney function among patients with AL amyloidosis undergoing treatment with lenalidomide. METHODS This is a secondary analysis of an ongoing clinical trial at a single referral centre. Forty-one patients with AL amyloidosis received lenalidomide with or without dexamethasone in monthly cycles. Kidney dysfunction was defined as ≥ 50% increase in serum creatinine. Severe kidney dysfunction was defined as ≥ 100% increase in serum creatinine. Recovery of renal function was defined as a return of serum creatinine to within 25% of the pre-treatment value or discontinuation of dialysis. RESULTS Twenty-seven of 41 patients (66%) developed kidney dysfunction during lenalidomide treatment. The kidney dysfunction was severe in 13 of these patients (32%); four of whom required initiation of dialysis (10%). The median time to kidney dysfunction after starting lenalidomide was 44 days (interquartile range 15-108 days). Four of eight patients without underlying renal amyloidosis developed kidney dysfunction. Patients with severe kidney dysfunction were older and had a higher frequency of underlying renal amyloidosis, greater urinary protein excretion, and lower serum albumin. Recovery of renal function occurred in 12 patients (44%). CONCLUSIONS Among patients with AL amyloidosis, worsening of kidney function occurs frequently during lenalidomide treatment. While a causal role of the drug has not been established, our findings suggest that kidney function should be monitored closely during treatment with this drug.

Increases in B-type natriuretic peptide (BNP) during treatment with lenalidomide in AL amyloidosis

To the editor: The combination of lenalidomide and dexamethasone can produce hematologic responses in previously treated patients with AL amyloidosis.[1][1] Since this prospective study (ClinicalTrials.gov: [NCT00091260][2]) was initiated, NT-proBNP and BNP have been found to be useful biomarkers

Melphalan, lenalidomide and dexamethasone for the treatment of immunoglobulin light chain amyloidosis: results of a phase II trial

We report results of a phase II trial of combination of melphalan, lenalidomide, and dexamethasone for the treatment of immunoglobulin light chain (AL) amyloidosis. The primary objectives were tolerability and hematologic response rate; secondary objectives were organ responses and survival. Treatment protocol consisted of melphalan 5 mg/m2/day for four days, lenalidomide 10 mg/day for 21 days and dexamethasone 20–40 mg once a week every 28 days for a total of 12 cycles. Sixteen subjects were enrolled of whom 14 completed at least 3 cycles and were evaluable for response. Grade 3/4 toxicities were experienced by 88% (n=14), the most common being myelosuppression (n=7). Dose reductions occurred in 85% (n=12 of 14) of subjects. Hematologic partial and complete responses were achieved by 43% (n=6 of 14) and 7% (n=1 of 14), respectively. The median overall survival has not been reached and median progression-free survival is 24 months. In conclusion, this combination is associated with significant myelosuppression leading to dose modifications and producing minor hematologic responses in AL amyloidosis. http://clinicaltrials.gov/ct2/show/NCT00679367

Durable hematologic complete responses can be achieved with lenalidomide in AL amyloidosis

To the editor: In AL amyloidosis, amyloid fibril deposits, derived from immunoglobulin light chains produced by a clonal plasma cell dyscrasia, accumulate in extracellular tissues and damage vital organs.[1][1] Novel therapies used in multiple myeloma[2][2] can be effective in AL amyloidosis.

Induction Therapy with Bortezomib Followed by Bortezomib-High Dose Melphalan and Stem Cell Transplantation for Light Chain Amyloidosis: Results of a Prospective Clinical Trial

The depth of hematologic response has been shown to correlate with survival and organ responses for patients with light chain (AL) amyloidosis. We conducted a prospective trial of 2 cycles of induction with bortezomib and dexamethasone on a twice a week schedule followed by conditioning with bortezomib and high-dose melphalan (HDM) and autologous stem cell transplantation (SCT). The objectives were hematologic responses, tolerability, and survival. Thirty-five patients were enrolled from 2010 to 2013. Of these, 30 proceeded with SCT, whereas 5 did not because of clinical deterioration during induction (n = 3) or complications after stem cell collection (n = 2). Two patients developed features of an autologous graft-versus-host disease-like syndrome post-SCT, which responded to steroids; no other unusual complications were seen. Treatment-related mortality occurred in 8.5% (3/35). Hematologic responses were achieved by 100% of the 27 assessable patients (63% complete response, 37% very good partial response [VGPR]) who completed the planned treatment. By intention-to-treat, hematologic responses occurred in 77% of patients (49% complete response, 29% VGPR). With a median follow-up of 36 months, the median overall survival and progression-free survival were not reached. In conclusion, incorporating bortezomib into induction and conditioning yielded a high rate of hematologic responses after HDM/SCT in patients with AL amyloidosis.

High-dose melphalan and autologous stem cell transplantation for AL amyloidosis: recent trends in treatment-related mortality and 1-year survival at a single institution

Treatment with high-dose melphalan chemotherapy supported by hematopoietic rescue with autologous stem cells produces high rates of hematologic responses and improvement in survival and organ function for patients with AL amyloidosis. Ongoing clinical trials explore pre-transplant induction regimens, post-transplant consolidation or maintenance approaches, and compare transplant to non-transplant regimens. To put these studies into context, we reviewed our recent experience with transplant for AL amyloidosis in the Amyloid Treatment and Research Program at Boston Medical Center and Boston University School of Medicine. Over the past 10 years, there was a steady reduction in rates of treatment-related mortality and improvement in 1-year survival, now approximately 5% and 90%, respectively, based upon an intention-to-treat analysis. Median overall survival of patients treated with this approach at our center exceeds 7.5 years. Introduction: Treatment of AL amyloidosis patients with high-dose intravenous melphalan chemotherapy and autologous hematopoietic stem cell support (HDM/SCT) produces a high rate of hematologic complete responses and improvement in organ function. Nephrotic syndrome can resolve [1], myocardial wall thickness can decline (MeierEwert et al., this volume), and quality of life improves [2]. Good outcomes are dependent upon the safe application of the therapy. Our first large patient series, published in 2004, reported a 100 day treatment-related mortality (TRM) of 14% [3]. Since then, we have refined patient selection and transplantation techniques and seen a concomitant decline in the rate of serious complications. Methods: Data on patients evaluated and treated in the Amyloid Treatment and Research Program at Boston University School of Medicine and Boston Medical Center were collected under protocols approved by the Boston University Medical Campus IRB after informed consent was signed. Data on patients enrolled into protocols using HDM/SCT from January 2000–December 2009 were reviewed retrospectively. Survival of all patients was determined through the end of December 2010, providing at least 1 year of follow-up on 100% of patients. Kaplan-Meier survival and confidence intervals for median overall and event-free survival were determined. Results and discussion: In the 10-year-period from January 2000 through December 2009, 323 patients began treatment on institutional or cooperative group protocols using HDM/SCT. The age range of enrolled patients was 28–80 years (median 57). The overall TRM was 8.4%, and the 1-year survival (1 YS) was 86.1% by intention-to-treat analysis. In the more recent 5-year-period from January 2005 through December 2009, 158 patients were treated; the age range was 28–77 years (median 57), the TRM was 5.1%, and the 1YS was 89.2%. Annual trends are plotted in Figure 1. The overall survival and progression free survival of all 323 patients are plotted in Figure 2. We attribute these improvements to two factors: firstly, rigorous selection of appropriate patients; and secondly, experienced multidisciplinary management during the peri-transplant period. Appropriate patient selection requires a comprehensive multidisciplinary clinical evaluation. The key evaluation components are summarized below. Chronological age is not a critical factor [4]. Patients who are potential candidates for HDM/SCT are assessed by sub-specialists highly familiar with the clinical manifestations of amyloidosis and with the complications of HDM/SCT. Cardiopulmonary function: Many studies have demonstrated that outcomes for patients with AL amyloidosis are driven by cardiac disease, defined by clinical parameters, echocardiographic parameters, and biomarkers for cardiac function. We use all of these to judge cardiac risk, including careful review of symptoms, physical examination for signs of heart Figure 1. Trends in TRM (lower line) and 1YS (upper line) each year in the 10-year-period from 2000 through the end of 2009, for a total of 323 patients. 127

Risk of second primary malignancy in patients with AL amyloidosis treated with lenalidomide

To The Editor: Second primary malignancy (SPM) is a growing issue for cancer survivors [1,2]. SPM has been associated with radiation therapy, anthracyclines, alkylating agents, and topoisomerase inhibitors [3]. Recently an increased incidence of invasive SPM has been observed with lenalidomide (7.6%) compared with controls (2.9%) in patients with newly diagnosed myeloma receiving lenalidomide in combination with melphalan [4] or as long-term maintenance therapy following high-dose melphalan with autologous stem cell transplantation [5,6]. In a retrospective pooled analysis of 11 clinical trials of lenalidomide-based therapy for relapsed/refractory myeloma, the overall incidence rate (IR, events per 100 patient-years) of invasive SPM was 2.08 [7]. Lenalidomide treatment can be effective in AL amyloidosis. In 2007, our group and the Mayo Clinic described promising results of phase 2 trials [8,9]. In view of emerging data on SPM in myeloma with lenalidomide treatment, we performed a post hoc analysis for the incidence of SPM in the patients with AL amyloidosis treated with lenalidomide at Boston Medical Center. Occurrence of SPM was reported by the patient and/or referring physician and confirmed by the site by reviewing the pathology. Between 2004 and 2011, 82 patients with AL amyloidosis were treated with lenalidomide and dexamethasone (ClinicalTrials.gov: NCT00091260) [9]. The median age was 62 years (range, 40–82) and 63% were male. Seventy-eight patients (95%) had received prior therapy (94% prior melphalan-based therapy). The median duration of lenalidomide treatment was nine cycles (range, 1–69). Sixteen (20%) patients received lenalidomide treatment for > 24 months. Hematologic response was evaluated in 68 patients after completion of three cycles of therapy; patients who withdrew from the study or who had not completed at least three cycles were not evaluable for response assessment. A complete hematologic response was seen in 11 patients (16%) and a partial hematologic response was seen in 30 patients (44%), for an overall response rate of 60%. The median time to best hematologic response was 6 months. Thirty patients (44%) had a measurable organ response. The median overall survival is not yet reached with a median follow-up for 32 months (range, 3–92). Six patients were noted to develop SPM. The total follow-up was 2.46 per 100 patient-years. One patient developed primary lung cancer with metastases after 24 months of lenalidomide therapy; he was a cigarette smoker and had prior treatment with oral melphalan. Additionally, five patients developed nonmelanoma skin cancer. There were no cases of hematologic malignancy or B-cell lymphoproliferative disorder. Therefore, the IR of invasive cancer (without nonmelanoma skin cancers) was only 0.44 per 100 patient-years (95% CI, 0.05–2.88) in this trial. This compares favorably to the annual incidence of invasive cancers in the United States for the general population. Age-specific IRs of invasive cancers across all sites identified through the SEER program are 1.26 among persons aged 60–64 years; 1.74 among persons aged 65–69 years; 2.09 among persons aged 70–74 years; 2.39 among persons aged 75–79 years; 2.46 among persons aged 80–84 years; and 2.18 among persons aged 85 years [10]. In summary, lenalidomide-based treatment in AL amyloidosis did not appear to increase the IR for invasive SPM compared to the IR for invasive cancers in general population. Longer follow-up and additional patient accrual may be needed to better define the risk of SPM in this patient population.

Hospital admissions following outpatient administration of high-dose melphalan and autologous SCT for AL amyloidosis

Hospital admissions following outpatient administration of high-dose melphalan and autologous SCT for AL amyloidosis

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

The combination of lenalidomide and dexamethasone can produce hematologic responses in previously treated 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 in patients with moderate or severe renal impairment and in patients on dialysis. Here, we report on a study of patients with AL amyloidosis on dialysis treated with lenalidomide at a dose of 10 mg orally three times a week. 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 most common adverse event was infection; no thromboembolic complications were seen. One patient required dose‐modification. Hematologic responses were obtained by four of the five evaluable patients. Median overall survival was 18 months. In conclusion, adjusted dose lenalidomide was reasonably tolerated and induced sustained hematologic responses in previously treated patients with AL amyloidosis on dialysis. Am. J. Hematol. 89:706–708, 2014.