7 research outputs found
Recommended from our members
Increased Bone Marrow Plasma Cells at Diagnosis Predicts Overall Mortality in AL Amyloidosis Patients Undergoing Risk-Adapted Stem Cell Transplant
Abstract
Background: High dose melphalan with autologous stem cell transplant (SCT) is an effective therapy for patients with light chain (AL) amyloidosis. With appropriate patient selection, risk-adapted melphalan dosing (RA-SCT), and post transplant consolidation in patients with <CR, treatment-related mortality is low and overall median survival (OS) in a large series is beyond 6 years and more than a decade for patients who achieve a complete hematologic remission (CR).1,2 However, some patients who achieve CR relapse within 2 years and have inferior OS. A recent study suggested that bone marrow plasmacytosis (BMPC) exceeding 10% at diagnosis is associated with an inferior survival, similar to patients considered to have AL with concurrent symptomatic multiple myeloma (MM) based on the presence of hypercalcemia, renal dysfunction, anemia and bone lesions (CRAB criteria).3 We aimed to confirm the prognostic significance of BMPC at diagnosis in AL patients who underwent RA-SCT +/- consolidation on OS and evaluate the impact on event-free survival (EFS).
Methods: We assessed the outcomes of all AL patients who underwent RA-SCT at Memorial Sloan Kettering Cancer Center. Patients with >2 major organs involved, NYHA class III/IV CHF, critical arrhythmias, cardiac syncope or concurrent symptomatic MM based on CRAB criteria were ineligible. Response was assessed at 3 and 12 months after RA-SCT; patients with < CR at 3 months were offered consolidation. EFS and OS were calculated from transplant to next treatment, death or last follow-up and were estimated by Kaplan-Meier methods. A one-year landmark was used to compare survival by treatment response (CR vs <CR). OS and EFS were compared across covariates of interest using the log-rank test. The patients were divided based upon percentage of BMPCs on initial diagnostic bone marrow using the highest estimate from the aspirate or biopsy. Cox proportional hazards model was used to examine the effect of BMPC on OS after adjusting for response at 1 year and cardiac stage.
Results: Between 2/2000 and 6/2011, 148 patients with AL amyloidosis underwent RA-SCT and were followed. Five patients without diagnostic bone marrow results available were excluded. Of those included, 63% (N=90) of patients had ≤ to 10% BMPC at diagnosis and 37% (N=53) had more than 10%. With a median follow up among survivors of 7.73 years, the median EFS is 4.82 years, 95% CI (3.84 – 6.23), and the median OS has not been reached. By univariate analysis, melphalan dose (200, 140, or 100mg/m2) (EFS P = 0.002, OS P = 0.002), organ involvement (≤ 1 vs >1) (EFS P = 10% BMPCs) (Figure 2). Achieving a CR at 1 year following RA-SCT was associated with superior EFS (P = 0.027) and OS (P = 0.043) (Figure 1) but was independent of whether or not CR was achieved with or without consolidation (EFS P = 0.14; OS P = 0.24). In multivariate analysis, higher burden of plasma cell disease at baseline remained an independent risk factor for OS [HR: 4.7 (95%CI: 1.7-12.9, p<0.01)], after adjusting for treatment response at 1 year and cardiac stage.
Conclusion: AL amyloidosis patients who are eligible for RA-SCT have excellent outcomes with OS at 10 years of 58% (95%CI: 47%-66%). Patients who achieve a CR with RA-SCT alone or with RA-SCT plus consolidation do equally well overall. Patients with greater burden of organ disease as indicated by number of organs involved, the requirement for dose reduction, or Mayo cardiac stage have inferior outcomes. This is unlikely to change without earlier diagnosis. The finding that greater plasma cell burden at diagnosis also impacts OS in patients who received RA-SCT independent of cardiac disease, treatment response and/or consolidation suggests that a more proliferative clone may require more MM-like therapy, and that these patients may benefit from more prolonged maintenance therapy. A clinical trial addressing this question in patients with AL amyloidosis is planned.
Figure 1 Figure 1.
Figure 2 Figure 2.
1. Gertz et al. BMT 2013; 48: 557.
2. Cibieira MT, et al. Blood 2011; 118: 4346.
3. Kourelis TV et al. JCO 2013; 31: 4319.
Disclosures
No relevant conflicts of interest to declare
Capivasertib in Hormone Receptor-Positive Advanced Breast Cancer.
Background: AKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of the AKT inhibitor capivasertib, as an addition to fulvestrant therapy, in patients with hormone receptor-positive advanced breast cancer are limited.
Methods: In a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy. Patients were randomly assigned in a 1:1 ratio to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed progression-free survival assessed both in the overall population and among patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumors. Safety was assessed.
Results: Overall, 708 patients underwent randomization; 289 patients (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4/6 inhibitor previously for advanced breast cancer. In the overall population, the median progression-free survival was 7.2 months in the capivasertib-fulvestrant group, as compared with 3.6 months in the placebo-fulvestrant group (hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.51 to 0.71; P<0.001). In the AKT pathway-altered population, the median progression-free survival was 7.3 months in the capivasertib-fulvestrant group, as compared with 3.1 months in the placebo-fulvestrant group (hazard ratio, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The most frequent adverse events of grade 3 or higher in patients receiving capivasertib-fulvestrant were rash (in 12.1% of patients, vs. in 0.3% of those receiving placebo-fulvestrant) and diarrhea (in 9.3% vs. 0.3%). Adverse events leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo.
Conclusions: Capivasertib-fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor. (Funded by AstraZeneca and the National Cancer Institute; CAPItello-291 ClinicalTrials.gov number, NCT04305496.)