Tandem cycles of high-dose melphalan and autologous stem cell transplantation increases the response rate in AL amyloidosis.

Clinical outcomes of patients with AL amyloidosis treated with high-dose melphalan and stem cell transplantation (HDM/SCT) are tightly linked to the achievement of a hematologic complete response (HCR). We conducted a prospective trial to determine whether a second cycle of HDM/SCT could induce HCR in patients in whom the plasma cell dyscrasia persisted following initial treatment with HDM/SCT. Sixty-two patients were enrolled. Nine patients (15%) were removed from the protocol. Of the 53 patients continuing in this study, four died within 100 days of treatment (8%), and 27 (55%) achieved an HCR at 6 months after the first cycle of HDM/SCT. Of the 22 patients who did not achieve an HCR after initial treatment, 17 received a second HDM/SCT, 1 died within 100 days of treatment (6%), while 5 (31%) achieved an HCR. Thus, the HCR rate was 67% (32/48) for surviving patients on study, 60% (32/53) for all patients who received initial cycle of HDM/SCT, and 56% (35/62) by intention-to-treat. The median survival for all patients enrolled on the trial has not yet been reached. Thus, tandem cycles of HDM/SCT can increase the proportion of patients who achieve an HCR.

Clinical and molecular characteristics of patients with non-amyloid light chain deposition disorders, and outcome following treatment with high-dose melphalan and autologous stem cell transplantation.

Light chain deposition disease (LCDD) is caused by a clonal plasma cell disorder in which fragments of monoclonal immunoglobulin light chains form non-fibrillary deposits in various tissues resulting in organ dysfunction. Crystal storing histiocytosis (CSH) is another light chain deposition disorder in which monoclonal light chains form intracytoplasmic crystals. Both are uncommon diseases for which there is limited treatment experience. Between 2003 and 2005, five patients with LCDD and one with CSH were treated at Boston University Medical Center with high-dose melphalan and autologous peripheral blood stem cell transplantation (HDM/SCT). Five of the six patients had predominantly renal involvement, and one patient with LCDD had biopsy-proven deposits in the myocardium. Molecular characterization revealed that the pathologic light chains were kappa in four of the six patients, and sequence analysis revealed unusual germline donor genes and high rates of amino-acid substitutions. One light chain sequence encoded a new potential N-linked glycosylation site, and another showed evidence of antigen selection. All patients are alive and five of the six patients are in complete hematologic remission at a median follow-up of 12 months (range 4-29 months) after HDM/SCT. In our experience, HDM/SCT is a feasible and effective treatment approach for these disorders.

High-dose intravenous melphalan and autologous stem cell transplantation as initial therapy or following two cycles of oral chemotherapy for the treatment of AL amyloidosis: results of a prospective randomized trial.

SUMMARY: A prospective randomized trial was conducted to study the timing of high-dose intravenous melphalan and autologous stem cell transplantation (HDM/SCT) in AL amyloidosis. In all, 100 newly diagnosed patients were randomized to receive HDM/SCT, either as initial therapy (Arm-1) or following two cycles of oral melphalan and prednisone (Arm-2). The objectives of the trial were to compare survival and hematologic and clinical responses. With a median follow-up of 45 months (range 24-70), the overall survival was not significantly different between the two treatment arms (P=0.39). The hematologic response and organ system improvements after treatment did not differ between the two groups. Fewer patients received HDM/SCT in Arm-2 because of disease progression during the oral chemotherapy phase of the study, rendering them ineligible for subsequent high-dose therapy. This affected patients with cardiac involvement particularly, and led to a trend for an early survival disadvantage in Arm-2. Hence, newly diagnosed patients with AL amyloidosis eligible for HDM/SCT did not benefit from initial treatment with oral melphalan and prednisone, and there was a survival disadvantage for patients with cardiac involvement if HDM/SCT was delayed by initial oral chemotherapy.

An overview of the use of high-dose melphalan with autologous stem cell transplantation for the treatment of AL amyloidosis.

Primary or AL amyloidosis results from a plasma cell dyscrasia in which fibrillar light chain protein deposition leads to organ failure and death. Standard treatment for AL amyloidosis has been oral melphalan and prednisone. However, this form of treatment modifies the natural history of this lethal disease only marginally, extending median survival from 13 months following diagnosis to 17 months. At Boston University Medical Center, we have developed treatment protocols using high-dose intravenous melphalan with autologous peripheral blood stem cell transplantation (HDM/SCT) to treat AL amyloidosis, and we have treated over 200 patients with HDM/SCT during the past six years. This extensive experience has shown that patients with AL amyloidosis, despite multisystem involvement and compromised organ function can tolerate this aggressive form of treatment. Furthermore, HDM/SCT results in durable hematologic responses in a substantial proportion of patients, and such responses are associated with clinical improvement, decreased amyloid-related organ dysfunction, and prolonged survival. However, toxicity from treatment is high (overall peri-transplant mortality, 14%), particularly for those patients with clinically significant cardiac involvement. For this reason, we believe a multidisciplinary management approach is essential when using HDM/SCT for treatment of AL amyloidosis. Based on our experience, we believe that HDM/SCT is the treatment of choice for patients with AL amyloidosis who have a good performance status and limited cardiac involvement at the time of diagnosis. HDM/SCT offers the best chance for hematologic remission, prolongation of survival, and reversal of amyloid-related disease. At the same time, we believe that HDM/SCT should continue to be examined in the context of clinical trials, directed at developing approaches to broaden the applicability of this therapy by minimizing toxicity and to increase the likelihood of complete hematologic responses.

MRI isolation of infected renal cyst in autosomal dominant polycystic kidney disease.

The use of gadolinium-enhanced magnetic resonance (MR) to isolate an infected renal cyst in the setting of autosomal dominant polycystic kidney disease (ADPKD) has not been previously described. A case in which T1- and T2-weighted and gadolinium-enhanced MR images were used to identify a single purulent cyst in a patient with ADPKD is herein presented. We suggest that gadolinium-enhanced MR be considered useful in the evaluation of ADPKD patients with suspected infected cyst.

Effect of dose-intensive intravenous melphalan and autologous blood stem-cell transplantation on al amyloidosis-associated renal disease.

BACKGROUND: Dose-intensive intravenous melphalan with autologous blood stem-cell transplantation induces remission of the plasma cell dyscrasia in a substantial proportion of patients with AL amyloidosis. The impact of this treatment on associated renal disease is not known. OBJECTIVE: To determine the effect of dose-intensive intravenous melphalan and autologous blood stem-cell transplantation on AL amyloidosis-associated renal disease. DESIGN: Prospective cohort study. SETTING: Academic medical center. PATIENTS: 65 patients with AL amyloidosis and urinary protein excretion greater than 1 g/24 h who received dose-intensive intravenous melphalan and autologous blood stem-cell transplantation between 1 July 1994 and 30 June 1998. MEASUREMENTS: 24-hour urinary protein excretion, serum cholesterol level, serum albumin level, creatinine clearance, urine and serum immunoelectrophoresis, and bone marrow biopsy. Renal response was defined as a greater than 50% reduction in urinary protein excretion in the absence of a 25% or greater reduction in creatinine clearance. Complete hematologic response was defined as absence of detectable monoclonal protein in serum and urine and a bone marrow specimen containing less than 5% plasma cells without clonal dominance of kappa or lambda isotype. RESULTS: Among the 50 patients who survived for at least 12 months, proteinuria, hypoalbuminemia, and hypercholesterolemia improved during follow-up; 36% met criteria for a renal response. Median 24-hour urinary protein excretion decreased from a baseline value of 9.6 g/24 h to 1.6 g/24 h at 12 months among patients with complete hematologic response, and 71% met criteria for a renal response. Twenty-hour urinary protein excretion did not decrease during follow-up among patients with persistent plasma cell disease, and only 11% had a renal response at 12 months (P < 0.001 for hematologic responders vs. nonresponders). CONCLUSION: Dose-intensive intravenous melphalan with autologous blood stem-cell transplantation improves the nephrotic syndrome in patients with AL amyloidosis-associated renal disease. The benefit is largely limited to patients achieving eradication of the underlying plasma cell dyscrasia.

Venous thromboembolism in end-stage renal disease.

Venous thromboembolic disease is considered an uncommon event in the end-stage renal disease (ESRD) population. We report five cases of venous thromboembolism (VTE) occurring in dialysis patients within a 1-year period at a single center. Analysis of these cases and review of the literature suggest that risk factors for VTE in the ESRD population are similar to those of the general population. Chronically ill, debilitated patients appear to be those most likely to develop VTE.

Intermediate-dose intravenous melphalan and blood stem cells mobilized with sequential GM+G-CSF or G-CSF alone to treat AL (amyloid light chain) amyloidosis.

AL amyloidosis patients ineligible for dose-intensive melphalan (200 mg/m2) were enrolled on a phase 11 trial to be treated with two cycles of intermediate-dose melphalan (IDM 100 mg/m2) and mobilized blood stem cells (BSC). For mobilization patients were randomized to either GM-CSF 250 microg/m2 for 3 d followed by G-CSF 10 microg/ kg for 3 d (GM+G), or G-CSF 10 microg/kg for 6 d (G-alone), with leukaphereses on days 5, 6 and 7. To minimize morbidity, we planned to support each cycle with 3 5 x 106 CD34+ cells/kg and had a collection target of 7 x 10(6) CD34+ cells/kg. Those who did not achieve the target were treated with one cycle of IDM. 30 patients, a median of 62 years old and 7 months from diagnosis, were enrolled. Both mobilization regimens were generally well tolerated, and similar in terms of CD34+ cells and CFU-GM collected, but only 6/28 patients achieved the collection target (GM+G four, G-alone two). Despite a 19% incidence of grade 4 toxicities, IDM therapy was well tolerated. At a median follow-up of 24 months (19-36) 57% of patients had survived, 17% with durable complete haematological responses and 40% with improved or stable amyloid organ involvement, including 3/9 patients with predominant cardiac amyloid who are alive 2-3 years after treatment. The 100 d mortality was 20%. In conclusion, no definitive differences were identified between the mobilization regimens and IDM was an active regimen in AL for selected patients.

Dose-intensive melphalan with blood stem-cell support for the treatment of AL (amyloid light-chain) amyloidosis: survival and responses in 25 patients.

AL (amyloid light-chain) amyloidosis is an uncommon plasma cell disorder in which depositions of amyloid light-chain protein cause progressive organ failure and death in a median of 13 months. Autologous stem-cell transplantation is effective therapy for multiple myeloma and therefore, we evaluated its efficacy for AL amyloidosis. Patients with adequate cardiac, pulmonary, and renal function had stem cells mobilized with granulocyte-colony stimulating factor and were treated with dose-intensive intravenous melphalan (200 mg/m2). Response to therapy was determined by survival and improvement of performance status, complete response or persistence of the clonal plasma cell disorder, and change in the function of organs involved with amyloid at baseline. We enrolled 25 patients with a median age of 48 years (range, 29-60), all of whom had biopsy-proven amyloidosis with clonal plasma cell disorders. Twenty-two (88%) were Southwest Oncology Group performance status 1 or 2 within a year of diagnosis, and 16 (64%) had received no prior therapy. Predominant amyloid-related organ involvement was cardiac (n = 8), renal (n = 7), hepatic (n = 6), neuropathic (n = 3), and lymphatic (n = 1). Fifteen patients had one or two organ systems involved, whereas 10 had three or more involved. With a median follow-up of 24 months (12-38), 17 of 25 patients (68%) are alive, and the median survival has not been reached. Thirteen of 21 patients (62%) evaluated 3 months posttransplant had complete responses of their clonal plasma cell disorders. Currently, two thirds of the surviving patients (11 of 17) have experienced improvements of amyloid-related organ involvement in all systems, whereas 4 of 17 have stable disease. The improvement in the median performance status of the 17 survivors at follow-up (0 [range, 0-3]) is statistically significant versus baseline (2 [range, 1-3]; P < . 01). Significant negative prognostic factors with respect to overall survival include amyloid involvement of more than two major organ systems and predominant cardiac involvement. Three patients have experienced relapses of the clonal plasma cell disorder at 12 and 24 months. Dose-intensive therapy should currently be considered as the preferred therapy for patients with AL amyloidosis who meet functional criteria for autologous transplantation.

Individual RNA recognition motifs of TIA-1 and TIAR have different RNA binding specificities.

TIA-1 and TIAR are two closely related RNA recognition motif (RRM) proteins which possess three RRM-type RNA binding domains (RRMs 1, 2, and 3). Although both proteins have been implicated as effectors of apoptotic cell death, the specific functions of TIA-1 and TIAR are not known. We have performed in vitro selection/amplification from pools of random RNA sequences to identify RNAs to which TIA-1 and TIAR bind with high affinity. Both proteins selected RNAs containing one or several short stretches of uridylate residues suggesting that the two proteins have similar RNA binding specificities. Replacement of the uridylate stretch with an equal number of cytidine residues eliminates the protein-RNA interaction. Mutational analysis indicates that, for both TIA-1 and TIAR, it is the second RNA binding domain (RRM 2) which mediates the specific binding to uridylate-rich RNAs. Although RRM 2 is both necessary and sufficient for this interaction, the affinity for the selected RNA (as determined by filter binding assays) does increase when the second domain of TIAR is expressed together with the first and third domains (Kd = 2 x 10(-8) M) rather than alone (Kd = 5 x 10(-8) M). Although RRM 3 (of either TIA-1 or TIAR) does not interact with the uridylate-rich sequences selected by the full-length proteins, it is a bona fide RNA binding domain capable of affinity-precipitating a population of cellular RNAs ranging in size from 0.5 to 5 kilobases. In contrast, RRM 1 does not affinity-precipitate cellular RNA. The inability of RRM 1 to interact with RNA may be due to the presence of negatively charged amino acids within the RNP 1 octamer.