Cardiac deposition of misfolded light chains is the leading cause of morbidity and mortality in patients with immunoglobulin (AL) amyloidosis. Cardiac defibrillators can be used in the management of ...patients with advanced cardiac amyloidosis, but data concerning the use of these devices in patients undergoing treatment with high-dose melphalan followed by autologous peripheral blood stem cell transplantation (HDM/SCT) is limited. Herein we describe a single-institution experience of HDM/SCT in 15 patients with cardiac defibrillators. During the peri-transplant period, five of these patients (33%) had detectable cardiac arrhythmias and two patients (13%) had implantable cardiac defibrillator (ICD) discharges. Thirteen of the 14 evaluable patients (93%) achieved at least a partial hematologic response. Transplant-related mortality was 6.7% and median overall survival was 40.8 months, with multiple patients achieving an overall survival of >10 years. These data highlight the feasibility of HDM/SCT in patients with an ICD due to advanced cardiac AL amyloidosis, but highlight the need for additional research to appropriately determine which patients will benefit from this aggressive therapy.
Late occurrence of antibody-mediated rejection (AMR), defined as occurring 6 months after transplantation, is associated with poor renal allograft survival, compared to early acute AMR and acute ...cellular rejection. The proteasome inhibitor bortezomib has multiple immunomodulatory effects on plasma cells, the source of donor-specific HLA antibodies which mediate AMR.
Consecutive patients who presented with biopsy-proven AMR and donor-specific anti-HLA antibodies (DSA) at a single institution between July 2011 and February 2015 were included. They received rituximab 375 mg/m
on day 1, bortezomib 1.3 mg/m
and methylprednisolone on days 1, 4, 8, 11, and plasmapheresis on days -1, 4, 8, 11, 14, 15, 17, with herpes zoster prophylaxis. The primary outcome was graft survival independent of dialysis. Patients were prospectively assessed with serial monitoring of renal function and proteinuria, and neuropathy symptoms. Toxicity determination was made by medical record review for hospitalizations within 3 months of therapy, or documentation of opportunistic infection.
Eleven patients were treated for late AMR (diagnosed at a median of 38 months post renal transplant) with this bortezomib-based protocol; 2 patients underwent the regimen twice. Of the 11 patients, 9 have functioning allografts (82% graft survival) with a median creatinine of 2.1 mg/dL (range 1.1 - 3.4 mg/dL), at a median follow-up of 50 months after AMR therapy (range 24 - 63 months). One patient was re-transplanted at 4 years post AMR treatment with no AMR recurrence to date at 2-years' follow-up, and a second patient re-initiated dialysis at 2 years post AMR treatment. Patient survival is 91% (10/11): 1 patient relocated out of state and was reported to have died from complications of hypertensive encephalopathy. The majority of patients (7/11) had several class I and class II DSA specificities; of these, 4 patients had negative class I DSA but persistent class II DSAs at 2 - 3 months post therapy. Only 1 patient who was positive for class II DSAs alone (DR53 and DQ2) converted to negative DSA, although DSA testing was delayed to 2 years' follow-up. Two patients were hospitalized within 1 month of the protocol, 1 for ileus and 1 for urinary tract infection and ruptured ovarian cyst. One other patient had herpes zoster.
Renal allograft survival was 82% at 4 years after bortezomib-based therapy for late onset AMR; toxicity profile of this regimen was acceptable. Eradication of DSAs may not be necessary for meaningful and durable renal response. .
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/m(2)/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.
The management of immunoglobulin light chain (AL) amyloidosis is complex. Emerging data have shown promising results for several novel agents. We review the management of AL amyloidosis, including ...factors that determine transplant eligibility, treatment options for transplant-ineligible patients, and treatment options for relapsed/refractory AL amyloidosis. For carefully selected patients, high-dose melphalan and stem cell transplantation is recommended. Transplant eligibility criteria generally include biopsy-proven amyloidosis, evidence of a plasma cell dyscrasia, involvement of at least one major organ, and adequate performance status. For transplant-ineligible patients, bortezomib-based regimens are recommended, including: 1) bortezomib, oral melphalan, and dexamethasone (BMDex); 2) bortezomib, cyclophosphamide, and dexamethasone (CyBorD or VCd); and 3) subcutaneous daratumumab (DARA SC) and VCd. The latter option is based on a landmark trial that led to the first US Food and Drug Administration-approved therapy for AL amyloidosis. For relapsed/refractory disease, novel therapeutics including proteosome inhibitors, immunomodulatory agents, and monoclonal antibodies have shown promising results. In this review, we summarize data for various therapeutics in different clinical scenarios of AL amyloidosis.
Abstract
Effective systemic therapies suppress toxic light chain production leading to an increased proportion of patients with light chain (AL) amyloidosis who survive longer albeit with end-stage ...renal disease. There is a critical need to identify patients in this population who benefit from renal transplantation. This multicenter, observational study from five countries includes 237 patients with AL amyloidosis who underwent renal transplantation between 1987 and 2020. With a median follow-up of 8.5 years, the median overall survival from renal transplantation was 8.6 years and was significantly longer in patients with complete and very good partial hematologic responses (CR + VGPR) compared to less than VGPR (9 versus 6.8 years; HR: 1.5,
P
= 0.04 95% CI: 1–2.1) at renal transplantation. Median graft survival was 7.8 years and was better in the CR + VGPR group (8.3 vs 5.7 years, HR: 1.4,
P
= 0.05 95% CI: 1–2). The frequency and time to amyloid recurrence in the graft was also lower (16% vs 37%,
p
= 0.01) and longer (median time not achieved vs 10 years,
p
= 0.001) in the CR + VGPR group. Comparing CR vs. VGPR there was no difference in overall or graft survival. Although 69 patients (29%) experienced hematologic relapse, treatment effectively prevented graft loss in the majority (87%). Renal transplantation in selected AL amyloidosis patients is associated with extended overall and renal graft survival. Patients with hematologic CR or VGPR have the most favorable outcomes, and these patients should be considered for renal transplantation.
Immunoglobulin light-chain (AL) amyloidosis affects multiple systemic organs. However, determination of the precise extent of organ involvement remains challenging. Targeted amyloid imaging with ...18F-florbetapir PET/CT offers the potential to detect AL deposits in multiple organs. The primary aim of this study was to determine the distribution and frequency of AL deposits in the various organs of subjects with systemic AL amyloidosis using 18F-florbetapir PET/CT. Methods: This prospective study included 40 subjects with biopsy-proven AL amyloidosis including active AL amyloidosis (n = 30) or AL amyloidosis in hematologic remission for more than 1 y (n = 10). All subjects underwent 18F-florbetapir PET/CT, skull base to below the kidney scan field, from 60 to 90 min after injection of radiotracer. Volume-of-interest measurements of SUVmax were obtained using Hermes software for the parotid gland, tongue, thyroid, lung, gastric wall, pancreas, spleen, kidney, muscle, abdominal fat, lower thoracic spine, vertebral body, and humeral head. Uptake in each organ was visually compared with that in spine bone marrow. An SUVmax of at least 2.5 was considered abnormal in all organs other than the liver. Results: Compared with the international consensus definition of organ involvement, 18F-florbetapir PET/CT identified amyloid deposits in substantially higher percentages of subjects for several organ systems, including parotid gland (50% vs. 3%), tongue (53% vs. 10%), and lung (35% vs. 10%). In several organ systems, including kidney (13% vs. 28%) and abdominal wall fat (10% vs. 13%), PET identified involvement in fewer subjects than did international consensus. Quantitative analysis of 18F-florbetapir PET/CT revealed more frequent organ involvement than did visual analysis in the tongue, thyroid, lung, pancreas, kidney, muscle, and humeral head. Extensive organ amyloid deposits were observed in active AL as well as in AL remission cohorts, and in both cardiac and noncardiac AL cohorts. Conclusion: 18F-florbetapir PET/CT detected widespread organ amyloid deposition in subjects with both active AL and AL hematologic remission. In most instances, amyloid deposits in the various organs were not associated with clinical symptoms and, thus, were unrecognized. Early recognition of systemic organ involvement may help tailor treatment, and noninvasive monitoring of organ-level disease may guide management with novel fibril-resorbing therapies.
Nephrogenic diabetes insipidus is a condition characterized by polyuria with dilute urine due to the inability of the principal cells of the renal collecting ducts to respond to antidiuretic hormone ...and concentrate urine. Nephrogenic diabetes insipidus can be drug induced, and several chemotherapeutic agents have been reported to cause it. Bendamustine is a traditional chemotherapeutic agent being studied for treatment for relapsed systemic AL amyloidosis. We report a case of a 59-year-old man with AL amyloidosis who developed partial nephrogenic diabetes insipidus after receiving bendamustine for treatment of AL amyloidosis. The nephrogenic diabetes insipidus responded well to sodium restriction, hydrochlorothiazide, and desmopressin treatment, allowing the patient to receive subsequent bendamustine cycles without polyuria. Nephrogenic diabetes insipidus resolved shortly after completion of bendamustine therapy.
Patients with immunoglobulin light chain amyloidosis are at risk for both thrombotic and bleeding complications. While the hemostatic defects have been extensively studied, less is known about ...thrombotic complications in this disease. This retrospective study examined the frequency of venous thromboembolism in 929 patients with immunoglobulin light chain amyloidosis presenting to a single referral center, correlated risk of venous thromboembolism with clinical and laboratory factors, and examined complications of anticoagulation in this population. Sixty-five patients (7%) were documented as having at least one venous thromboembolic event. Eighty percent of these patients had events within one year prior to or following diagnosis. Lower serum albumin was associated with increased risk of VTE, with a hazard ratio of 4.30 (CI 1.60-11.55; P=0.0038) for serum albumin less than 3 g/dL compared to serum albumin greater than 4 g/dL. Severe bleeding complications were observed in 5 out of 57 patients with venous thromboembolism undergoing treatment with anticoagulation. Prospective investigation should be undertaken to better risk stratify these patients and to determine the optimal strategies for prophylaxis against and management of venous thromboembolism.
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