Induction Therapy with Bortezomib and Dexamethasone and Conditioning with High-Dose Melphalan and Bortezomib Followed by Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis: Long-Term Follow-Up Analysis.

In immunoglobulin light-chain (AL) amyloidosis, the depth of hematologic response to treatment is associated with improved survival and organ responses. We conducted a clinical trial using bortezomib in induction and in conditioning with melphalan before stem cell transplantation (SCT) for AL amyloidosis. The results of this clinical trial with a median follow-up of 36 months have been reported previously. Here we report the long-term results of this clinical trial with a median follow-up of 77 months. We describe survival, durability of hematologic and organ responses, and relapse rates. Thirty-five patients were enrolled between 2010 and 2013. Hematologic complete response and very good partial response (VGPR) were noted in 100% (27 of 27) of the evaluable patients at 6 months post-SCT. Four patients (15%) had hematologic relapse at a median of 42 months, and 1 patient (3.7%) had organ progression despite maintaining a VGPR at 37 months. The median overall survival and progression-free survival have not yet been reached at the time of this report. Renal and cardiac responses occurred in 65% and 88%, respectively, at 5 years post-SCT. The median time to renal and cardiac response was 12 months and 6 months, respectively. In conclusion, incorporating bortezomib into induction and conditioning yielded durable hematologic responses of AL amyloidosis, with corresponding organ responses and prolonged survival.

High-Dose Melphalan and Stem Cell Transplantation in Patients on Dialysis Due to Immunoglobulin Light-Chain Amyloidosis and Monoclonal Immunoglobulin Deposition Disease.

The kidney is the most common organ affected by immunoglobulin light-chain (AL) amyloidosis and monoclonal immunoglobulin deposition disease (MIDD), often leading to end-stage renal disease (ESRD). High-dose melphalan and stem cell transplantation (HDM/SCT) is effective for selected patients with AL amyloidosis, with high rates of complete hematologic response and potential for improved organ dysfunction. Data on tolerability and response to HDM/SCT in patients with ESRD due to AL amyloidosis and MIDD are limited. We analyzed data on toxicity, efficacy, and hematologic and renal response of HDM/SCT in 32 patients with AL amyloidosis and 4 patients with MIDD who were dialysis-dependent for ESRD treated at Boston Medical Center between 1994 and 2016. The most common grade 3/4 nonhematologic toxicities were infections (75%), metabolic abnormalities (56%), mucositis (42%), constitutional symptoms (39%), pulmonary complications (39%), and diarrhea (28%). Treatment related mortality (defined as death within 100 days of SCT) occurred in 8% (3 of 36). A complete hematologic response was achieved in 70% of evaluable patients (19 of 27) at 1 year after HDM/SCT. In the entire cohort, median overall survival (OS) after HDM/SCT was 5.8 years; median OS was 1 year for those who did not achieve a complete hematologic response and 8 years for those who did achieve a complete hematologic response. Twelve patients (33%) underwent kidney transplantation after successful treatment with HDM/SCT at a median of 2.4 years after SCT. HDM/SCT is safe and effective in inducing hematologic complete responses and prolonging survival in patients with ESRD from AL amyloidosis and MIDD. Achievement of a durable hematologic response can make these patients possible candidates for renal transplantation.

Modified High-Dose Melphalan and Autologous Stem Cell Transplantation for Immunoglobulin Light Chain Amyloidosis.

High-dose melphalan and autologous stem cell transplantation (HDM/SCT) have been used in patients with immunoglobulin light chain (AL) amyloidosis for over 2 decades now with durable responses, prolonged survival, and decreasing treatment-related mortality. Historically, patients with poorer baseline functional status, advanced age, renal compromise, and cardiac involvement have been treated with a risk-adapted modified conditioning dose of melphalan (mHDM) of 100 to 140 mg/m2 before SCT. In part because of these baseline characteristics, patients receiving mHDM/SCT have had poorer outcomes compared with patients receiving full-dose melphalan at 200 mg/m2. With the advent of novel therapeutic agents such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies for the treatment of AL amyloidosis, it is imperative to understand the long-term effects of mHDM/SCT. Here we report the long-term outcomes of 334 patients with AL amyloidosis treated with mHDM/SCT. Median overall survival was 6.1 years and median event-free survival 4.3 years, with median overall survival reaching 13.4 years for patients who had achieved a hematologic complete response (CR). Overall hematologic response rate was 69%, and treatment-related mortality was 3% after 2010. Thus, mHDM/SCT leads to prolonged survival and favorable outcomes, especially if a hematologic CR is achieved.

Durable renal response after combination of bortezomib, corticosteroids, rituximab, and plasmapheresis for late antibody-mediated renal transplant rejection
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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. MATERIALS AND METHODS: 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/m2 on day 1, bortezomib 1.3 mg/m2 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. RESULTS: 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. CONCLUSION: 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.
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Quality Management of massive transfusion protocol incorporating tranexamic acid adherence.

Massive transfusion protocols (MTP) vary at different institutions. We implemented an algorithm in the transfusion service to support our Level I trauma center in 2007 and periodically monitor MTP utilization as part of ongoing quality management. At the last review in 2013, median plasma: RBC ratio was 1:1.8. We undertook a retrospective 3-year review of MTP activations stratifying by trauma versus non-trauma indications, and blood component utilization of the massive transfusion (MT) cases, adding a review of tranexamic acid (TXA) administration to the audit. The median transfused plasma: RBC ratio was 1:1.9 in trauma MT, and 1:1.6 in the non-trauma MT cases. Non-trauma MT patients at our institution were significantly older and more coagulopathic at MTP initiation compared to trauma MT patients, received fewer RBC units (15.5 versus 20.2), and had higher mortality. TXA adherence increased over the 3-year period to 60% of all trauma MTP activations in 2017.

Evaluation of a new continuous mononuclear cell collection procedure in a single transplant center cohort enriched for AL amyloidosis patients.

BACKGROUND: The Spectra Optia continuous mononuclear cell (CMNC) program is newly available, and herein validated in a single-center cohort enriched with AL amyloidosis patients to collect a target CD34+ yield of 2.5 × 106 cells/kg within 2 days. METHODS: Consecutive autologous transplant patients in 2016 are included. Patients undergo leukapheresis with Optia CMNC and Spectra v4.7 over a 2-day cycle. Data collection includes collection efficiency, adverse events and engraftment kinetics. RESULTS: 36 leukapheresis procedures on 18 patients are included. The diagnoses are AL amyloidosis (9), myeloma (7), lymphoma (2), and scleroderma (1). Median age is 60; 12 are men. Plerixafor was employed pre-emptively in 6 cycles. Median blood CD34+ on Day 1 of leukapheresis was 46 cells/uL. Median number of blood volumes processed on Day 1 was 3.1. All collection cycles were completed within 2 days; only one in a heavily pretreated lymphoma patient did not reach the target requiring a second mobilization attempt. Mean collection efficiencies were comparable between the two devices. There were 2 adverse events: tubing rupture on the Optia; and one case of hypotension. All 18 patients underwent high-dose chemotherapy: median cell dose infused was 7.7 × 106 CD34+ cells/kg. Median days to neutrophil and platelet engraftment were 10 and 13 respectively. CONCLUSION: The Optia CMNC collection protocol is safe and effective in a small single-center autologous stem cell transplant cohort enriched for high-risk patients with AL amyloidosis and cardiac involvement. Caution is needed for tubing setup because there is less cumulative experience with Optia.

Thrombotic Microangiopathy: A Multidisciplinary Team Approach.

Thrombotic microangiopathy (TMA) is characterized by the presence of microangiopathic hemolytic anemia and thrombocytopenia along with organ dysfunction, and pathologically, by the presence of microthrombi in multiple microvascular beds. Delays in diagnosis and initiation of therapy are common due to the low incidence, variable presentation, and poor awareness of these diseases, underscoring the need for interdisciplinary approaches to clinical care for TMA. We describe a new approach to improve clinical management via a TMA team that originally stemmed from an Affinity Research Collaborative team focused on thrombosis and hemostasis. The TMA team consists of clinical faculty from different disciplines who together are charged with the responsibility to quickly analyze clinical presentations, guide laboratory testing, and streamline prompt institution of treatment. The TMA team also includes faculty members from a broad range of disciplines collaborating to elucidate the pathogenesis of TMA. To this end, a clinical database and biorepository have been constructed. TMA leaders educate front-line providers from other departments through presentations in various forums across multiple specialties. Facilitated by an Affinity Research Collaborative mechanism, we describe an interdisciplinary team dedicated to improving both clinical care and translational research in TMA.

Hemovigilance in Massachusetts and the adoption of statewide hospital blood bank reporting using the National Healthcare Safety Network.

A collaboration that grew over time between local hemovigilance stakeholders and the Massachusetts Department of Public Health (MDPH) resulted in the change from a paper-based method of reporting adverse reactions and monthly transfusion activity for regulatory compliance purposes to statewide adoption of electronic reporting via the National Healthcare Safety Network (NHSN). The NHSN is a web-based surveillance system that offers the capacity to capture transfusion-related adverse events, incidents, and monthly transfusion statistics from participating facilities. Massachusetts' hospital blood banks share the data they enter into NHSN with the MDPH to satisfy reporting requirements. Users of the NHSN Hemovigilance Module adhere to specified data entry guidelines, resulting in data that are comparable and standardized. Keys to successful statewide adoption of this reporting method include the fostering of strong partnerships with local hemovigilance champions and experts, engagement of regulatory and epidemiology divisions at the state health department, the leveraging of existing relationships with hospital NHSN administrators, and the existence of a regulatory deadline for implementation. Although limitations exist, successful implementation of statewide use of the NHSN Hemovigilance Module for hospital blood bank reporting is possible. The result is standardized, actionable data at both the hospital and state level that can facilitate interfacility comparisons, benchmarking, and opportunities for practice improvement.

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.

Outcome of AL amyloidosis after high-dose melphalan and autologous stem cell transplantation: long-term results in a series of 421 patients.

Previous studies have suggested that, in patients with AL amyloidosis treated with high-dose melphalan and autologous stem-cell transplantation (HDM/SCT), the greatest benefit is seen in those patients achieving a hematologic complete response (CR). We analyzed a series of 421 consecutive patients treated with HDM/SCT at a single referral center and compared outcomes for patients with and without CR. Treatment-related mortality was 11.4% overall (5.6% in the last 5 years). By intention-to-treat analysis, the CR rate was 34% and the median event-free survival (EFS) and overall survival (OS) were 2.6 and 6.3 years, respectively. Eighty-one patients died within the first year after HDM/SCT and were not evaluable for hematologic and organ response. Of 340 evaluable patients, 43% achieved CR and 78% of them experienced an organ response. For CR patients, median EFS and OS were 8.3 and 13.2 years, respectively. Among the 195 patients who did not obtain CR, 52% achieved an organ response, and their median EFS and OS were 2 and 5.9 years, respectively. Thus, treatment of selected AL patients with HDM/SCT resulted in a high organ response rate and long OS, even for those patients who did not achieve CR.

Safety and Efficacy of Propylene Glycol-Free Melphalan in Patients with AL Amyloidosis Undergoing Autologous Stem Cell Transplantation: Results of a Phase II Study.

Patients with systemic light chain (AL) amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) may develop renal and cardiac toxicities potentially exacerbated by the co-solvent propylene glycol in conventional melphalan formulations. We investigated the safety and efficacy of propylene glycol-free melphalan (PGF-Mel) during HDM/SCT in patients with AL amyloidosis (ClinicalTrials.gov identifier NCT02994784). The primary objective of this phase II, open-label study was evaluation for renal dysfunction, new cardiac arrhythmias, and postural hypotension related to autonomic dysfunction. Secondary objectives included time to neutrophil and platelet engraftment, treatment-related mortality (TRM), overall hematologic response, organ response, and number of peritransplantation hospitalizations. Twenty-eight patients with AL amyloidosis enrolled, of whom 27 underwent HDM/SCT. PGF-Mel at 140 to 200 mg/m2 was administered i.v. in 2 equally divided doses. Patients were monitored for up to 30 days after the last administration of PGF-Mel to assess for treatment-related toxicity. Patients were followed for 12 months from the time of treatment with HDM/SCT for evaluation of hematologic and organ responses. Kaplan-Meier analysis was used to estimate progression-free survival. Two patients (7%) developed renal dysfunction, 5 (19%) experienced new cardiac arrhythmias, and 3 (11%) developed orthostatic hypotension. All patients achieved neutrophil and platelet engraftment, at a median of 10 days and 17 days post-HDM/SCT, respectively. TRM on day +100 was 0%. Peritransplantation hospitalization was required for 23 patients (85%). The most common nonhematologic adverse events were diarrhea (93%), fatigue (82%), and nausea (74%). At 6 months post-HDM/SCT, hematologic complete response or very good partial response occurred in 66% of the patients. At 12 months post-HDM/SCT, renal response occurred in 12 of 23 (52%) patients with renal involvement, and cardiac response occurred in 3 of 11 (27%) patients with evaluable cardiac involvement. Our data indicate that PGF-Mel is safe and efficacious as a high-dose conditioning regimen for autologous SCT in patients with AL amyloidosis.

Amyloid deposits in the bone marrow of patients with immunoglobulin light chain amyloidosis do not impact stem cell mobilization or engraftment.

Amyloid deposits are often found in the bone marrow in patients with Immunoglobulin light chain (AL) amyloidosis. We sought to determine whether this affects stem cell collection or engraftment after high-dose melphalan and autologous stem cell transplantation (HDM-SCT). We reviewed data on 361 patients with AL amyloidosis who had Congo red staining of pretreatment bone marrow biopsy specimens and underwent HDM-SCT between July 1994 and December 2011. We analyzed data on stem cell yield, days of stem cell collection, and days to neutrophil and platelet engraftment posttransplantation. Bone marrow amyloid deposits were found in 65% of patients (n = 233). There were no significant differences in median number of stem cells collected and days to neutrophil or platelet engraftment between patients with bone marrow amyloid deposits and those without these deposits. Thus, our data indicate that although amyloid involvement of the bone marrow is common, it does not negatively affect stem cell mobilization or neutrophil and platelet engraftment after HDM-SCT.

Successful long-term management of aneurysm-associated chronic disseminated intravascular coagulation with low molecular weight heparin.

Disseminated intravascular coagulation (DIC) is a well-described complication of aortic aneurysm. In cases where surgical repair of the aneurysm is contraindicated, palliative therapy via medical management of the coagulopathy may be warranted. We present a case of aneurysm-associated DIC successfully managed with low molecular weight heparin.