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Phase I Study of Bendamustine and Melphalan Conditioning Followed By Autologous Hematopoietic Cell Transplantation for Treatment of Multiple Myeloma and B-Cell Lymphoma in Elderly Patients
High-dose chemo and autologous hematopoietic cell transplantation (AHCT) is an effective consolidation therapy in non-Hodgkin lymphoma (NHL) and multiple myeloma (MM); however, its use in elderly patients is limited by toxicity.
We conducted a phase 1 clinical trial to evaluate safety of novel conditioning for elderly NHL/MM patients with bendamustine 160 mg/m2 on days -3 and -2 and melphalan 140 mg/m2 on day -1 with AHCT day 0. Toxicity was assessed from conditioning to day +30 with CTCAE v5.0, excluding those responsive to supportive care. MD Anderson Symptom Inventory (MDASI) was collected day 0-14. C-reactive protein (CRP) on 0, 7 and 14. Comprehensive geriatric assessments (CGA) were done at baseline and day +30. Melphalan area-under-the-curve (AUC) calculated as previously described (Shah, et al. Clin Pharmacokinet 2021).
20 patients with R/R NHL and 7 with MM received this regimen. Ten NHL patients received Rituximab with conditioning, but this was discontinued after CIBMTR data demonstrated no benefit. In baseline CGA, 7% had impaired baseline ADL, 29% had impaired iADL, and 89% polypharmacy (> 5 drugs).
Mean age in NHL group was 74 years (69-81), all in remission at AHCT (Table). 14 patients had Karnofsky Performance Score (KPS) of 70 or 80; only 6 patents had KPS 90. Median melphalan AUC was 15.2 mg*hr/L (11.1–25.8). All engrafted, median time to engraftment (MTE) of neutrophils and platelets was at 10 and 23 days. PFS was 88% and 81% at 12 and 24 months. OS was not reached in 36 months. Non-relapse mortality (NRM) was 1 patient at 12 and 36 months, died from another cancer.
In MM cohort, mean age was 73 years (68-76) with KPS 70-90. Four patients had upfront transplant3 received multiple lines of therapy prior to AHCT. Melphalan AUC was 14.1 mg*hr/L (9.0-24.7). All engrafted, MTE for neutrophils and platelets at 9 and 17 days, respectively. PFS was 71% and 48% at 12 and 24-month follow up. OS was 86% and 71% at 12 and 24 months, respectively. TTR at 12 months was 29%.
Toxicity was low overall. The relatively high melphalan AUC was not unexpected due to age/renal function of the population. Despite this, toxicity was minimal with only one patient with G3 mucositis. Only 2 patients had G3 hyperglycemia and one grade 4 hyperglycemia, though all three had diabetes mellitus at baseline. One patient had G3 syncope. No deaths from toxicity occurred. MDASI shows fatigue, lack of appetite and dry mouth were present through day+ 14 (Fig. 1). CRP rose to mean 2.7 m/dL (0.1-17.7) around day 14 and fell to mean 0.5 mg/dL (0.1-6.3) at day 30 (Fig. 2).
. Bendamustine/melphalan conditioning for AHCT in the elderly with NHL/MM is safe with limited toxicity, and tolerable per patient reported outcomes with comparable survival to standard of care. Extending AHCT to this population is especially relevant in places where CAR-T cell (chimeric antigen receptor T-cell) therapy is not readily available
Common variation at 2p13.3, 3q29, 7p13 and 17q25.1 associated with susceptibility to pancreatic cancer
Pancreatic cancer is the fourth leading cause of cancer death in the developed world. Both inherited high-penetrance mutations in BRCA2 (ref. 2), ATM, PALB2 (ref. 4), BRCA1 (ref. 5), STK11 (ref. 6), CDKN2A and mismatch-repair genes and low-penetrance loci are associated with increased risk. To identify new risk loci, we performed a genome-wide association study on 9,925 pancreatic cancer cases and 11,569 controls, including 4,164 newly genotyped cases and 3,792 controls in 9 studies from North America, Central Europe and Australia. We identified three newly associated regions: 17q25.1 (LINC00673, rs11655237, odds ratio (OR) = 1.26, 95% confidence interval (CI) = 1.19-1.34, P = 1.42 × 10-14), 7p13 (SUGCT, rs17688601, OR = 0.88, 95% CI = 0.84-0.92, P = 1.41 × 10-8) and 3q29 (TP63, rs9854771, OR = 0.89, 95% CI = 0.85-0.93, P = 2.35 × 10-8). We detected significant association at 2p13.3 (ETAA1, rs1486134, OR = 1.14, 95% CI = 1.09-1.19, P = 3.36 × 10-9), a region with previous suggestive evidence in Han Chinese. We replicated previously reported associations at 9q34.2 (ABO), 13q22.1 (KLF5), 5p15.33 (TERT and CLPTM1), 13q12.2 (PDX1), 1q32.1 (NR5A2), 7q32.3 (LINC-PINT), 16q23.1 (BCAR1) and 22q12.1 (ZNRF3). Our study identifies new loci associated with pancreatic cancer risk