There is a pressing need for allogeneic chimeric antigen receptor (CAR)-immune cell therapies that are safe, effective and affordable. We conducted a phase 1/2 trial of cord blood-derived natural ...killer (NK) cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19
B cell malignancies. The primary objectives were safety and efficacy, defined as day 30 overall response (OR). Secondary objectives included day 100 response, progression-free survival, overall survival and CAR19/IL-15 NK cell persistence. No notable toxicities such as cytokine release syndrome, neurotoxicity or graft-versus-host disease were observed. The day 30 and day 100 OR rates were 48.6% for both. The 1-year overall survival and progression-free survival were 68% and 32%, respectively. Patients who achieved OR had higher levels and longer persistence of CAR-NK cells. Receiving CAR-NK cells from a cord blood unit (CBU) with nucleated red blood cells ≤ 8 × 10
and a collection-to-cryopreservation time ≤ 24 h was the most significant predictor for superior outcome. NK cells from these optimal CBUs were highly functional and enriched in effector-related genes. In contrast, NK cells from suboptimal CBUs had upregulation of inflammation, hypoxia and cellular stress programs. Finally, using multiple mouse models, we confirmed the superior antitumor activity of CAR/IL-15 NK cells from optimal CBUs in vivo. These findings uncover new features of CAR-NK cell biology and underscore the importance of donor selection for allogeneic cell therapies. ClinicalTrials.gov identifier: NCT03056339 .
Use of 2 units of cord blood, 1 of which had been cocultured with mesenchymal stem cells, produced more rapid hematopoietic engraftment than 2 units of unmanipulated cord blood.
Umbilical-cord blood ...is an attractive source of hematopoietic support for patients who lack a suitable HLA-matched donor. Despite the advantages offered by cord-blood transplantation, such as the use of a frozen, readily available allograft in patients who are members of minority groups, who often have limited access to adult donors, the clinical usefulness in adults has been restricted by the relatively low number of hematopoietic progenitors in a unit of cord blood.
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Delayed or failed engraftment of neutrophils and platelets with cord-blood transplantation can result in an increased risk of transplant-related complications or death and increased health care costs, . . .
Summary
Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is incurable with conventional therapies. Limited retrospective data have shown durable remissions after haematopoietic cell ...transplantation (HCT) allogeneic (allo) or autologous (auto). We conducted a multicentre retrospective study in BPDCN patients treated with allo‐HCT and auto‐HCT at 8 centres in the United States and Canada. Primary endpoint was overall survival (OS). The population consisted of 45 consecutive patients who received an allo‐HCT (n = 37) or an auto‐HCT (n = 8) regardless of age, pre‐transplant therapies, or remission status at transplantation. Allo‐HCT recipients were younger (50 (14–74) vs. 67 (45–72) years, P = 0·01) and had 1‐year and 3‐year OS of 68% 95% confidence interval (CI) = 49–81% and 58% (95% CI = 38–75%), respectively. Allo‐HCT in first complete remission (CR1) yielded superior 3‐year OS (versus not in CR1) 74% (95% CI = 48–89%) vs. 0, P < 0·0001. Allo‐HCT outcomes were not impacted by regimen intensity 3‐year OS for myeloablative conditioning = 61% (95% CI = 28–83%) vs. reduced‐intensity conditioning = 55% (95% CI = 28–76%). One‐year OS for auto‐HCT recipients was 11% (95% CI = 8–50%). These results demonstrate efficacy of allo‐HCT in BPDCN, especially in patients in CR1. Pertaining to auto‐HCT, our results suggest lack of efficacy against BPDCN, but this observation is limited by the small sample size. Larger prospective studies are needed to better define the role of HCT in BPDCN.
Autologous hematopoietic stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). However, many individuals are unable to collect optimal CD34
hematopoietic stem and progenitor ...cell (HSPC) numbers with granulocyte colony-stimulating factor (G-CSF) mobilization. Motixafortide is a novel cyclic-peptide CXCR4 inhibitor with extended in vivo activity. The GENESIS trial was a prospective, phase 3, double-blind, placebo-controlled, multicenter study with the objective of assessing the superiority of motixafortide + G-CSF over placebo + G-CSF to mobilize HSPCs for ASCT in MM. The primary endpoint was the proportion of patients collecting ≥6 × 10
CD34
cells kg
within two apheresis procedures; the secondary endpoint was to achieve this goal in one apheresis. A total of 122 adult patients with MM undergoing ASCT were enrolled at 18 sites across five countries and randomized (2:1) to motixafortide + G-CSF or placebo + G-CSF for HSPC mobilization. Motixafortide + G-CSF enabled 92.5% to successfully meet the primary endpoint versus 26.2% with placebo + G-CSF (odds ratio (OR) 53.3, 95% confidence interval (CI) 14.12-201.33, P < 0.0001). Motixafortide + G-CSF also enabled 88.8% to meet the secondary endpoint versus 9.5% with placebo + G-CSF (OR 118.0, 95% CI 25.36-549.35, P < 0.0001). Motixafortide + G-CSF was safe and well tolerated, with the most common treatment-emergent adverse events observed being transient, grade 1/2 injection site reactions (pain, 50%; erythema, 27.5%; pruritis, 21.3%). In conclusion, motixafortide + G-CSF mobilized significantly greater CD34
HSPC numbers within two apheresis procedures versus placebo + G-CSF while preferentially mobilizing increased numbers of immunophenotypically and transcriptionally primitive HSPCs. Trial Registration: ClinicalTrials.gov , NCT03246529.
•Gemcitabine + busulfan + melphalan is used as a pre-transplant conditioning therapy.•Epigenetic modifiers enhance the efficacy of DNA alkylators + nucleoside analogs.•The cytotoxicity of venetoclax ...is due to inhibition of pro-survival BCL2.•Gemcitabine + busulfan + melphalan + panobinostat + venetoclax provides synergistic cytotoxicity to MM cells.•The five-drug combination inhibits the mTOR signaling pathway, and activates the unfolded protein response, and may be used as pre-transplant conditioning regimen.
Gemcitabine (Gem), busulfan (Bu), and melphalan (Mel) are used for hematopoietic stem cell transplantation. To further improve their efficacy, a preclinical study on their synergism with the histone deacetylase inhibitor panobinostat (Pano) and the BCL2 inhibitor venetoclax/ABT199 was performed. Multiple myeloma cell lines MM.1R and MC/CAR were exposed to ∼IC20 levels of the drugs. Synergistic cytotoxicity was observed in cells exposed to the five-drug combination as indicated by combination indexes <1, supported by ∼86% inhibition of proliferation and ∼84% annexin V positivity in MM.1R and ∼58% inhibition of proliferation and ∼46% annexin V positivity in MC/CAR cells. Activation of the DNA damage response and apoptosis were suggested by a modest increase in the phosphorylation of ATM and its substrates; significant cleavage of PARP1, caspase 3, and heat shock protein 90; DNA fragmentation; mitochondrial membrane depolarization; and reactive oxygen species production. The five-drug combination significantly decreased the levels of PI3K, AKT, mTOR, RAPTOR, P-P70S6K, and eIF2α, with concomitant increases in P-AMPK and its substrate Tuberin/TSC2, suggesting that the mTOR signaling pathway was compromised. Endoplasmic reticulum stress through activation of the unfolded protein response was also observed as suggested by increases in the levels of calnexin, BiP/GRP78, ERO1-Lα, and protein disulfide isomerase, which may relate to venetoclax-mediated inhibition of BCL2 in the endoplasmic reticulum. This is the first report on the effects of a venetoclax-containing regimen on the unfolded protein response. These results provide a rationale to propose a clinical trial on use of Gem + Bu + Mel + Pano + Venetoclax as part of a conditioning regimen for multiple myeloma patients undergoing autologous hematopoietic stem cell transplantation.
Background Patients with multiple myeloma (MM) remain at an increased risk of infection due to the disease process, as well as the ensuing treatments. Methods We performed a systematic review to ...evaluate the monthly risk of grade III/IV infection, pneumonia, and neutropenia in patients with myeloma enrolled in randomized clinical trials (RCTs). Results The risk of grade III or higher infection, pneumonia, and neutropenia persists among all phases of treatment. There was no statistical difference in grade III or higher infection, pneumonia, and neutropenia between frontline and relapsed/refractory setting. In the maintenance setting, the complications of infection, pneumonia, and neutropenia were low, but not negligible. Three-drug regimens were no more likely than two-drug regimens to have an increased risk of Grade III or higher infection. Conclusions This is the first study to quantify the monthly risk of grade III or higher infection, pneumonia, and neutropenia across different treatment regimens in the frontline, maintenance, and relapsed/refractory settings. The results of our systematic review demonstrate a significant risk for severe infection, pneumonia, and neutropenia in patients with MM. Further studies are needed to determine the value of antibiotic prophylaxis in a broader myeloma patient population, as well as other approaches that will further mitigate the morbidity and mortality related to infection in this vulnerable patient population. Keywords: Multiple myeloma, Proteasome inhibitors, Anti-CD38, Cytotoxic therapy, Infection
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Early autologous hematopoietic cell transplantation (AHCT) with post‐transplant maintenance therapy is standard of care in multiple myeloma (MM). While short‐term quality of life (QOL) deterioration ...after AHCT is known, the long‐term trajectories and symptom burden after transplantation are largely unknown. Toward this goal, a secondary analysis of QOL data of the BMT CTN 0702, a randomized controlled trial comparing outcomes of three treatment interventions after a single AHCT (N = 758), was conducted. FACT‐BMT scores up to 4 years post‐AHCT were analyzed. Symptom burden was studied using responses to 17 individual symptoms dichotomized as ‘none/mild’ for scores 0–2 and ‘moderate/severe’ for scores of 3 or 4. Patients with no moderate/severe symptom ratings were considered to have low symptom burden at 1‐year. Mean age at enrollment was 55.5 years with 17% African Americans. Median follow‐up was 6 years (range, 0.4–8.5 years). FACT‐BMT scores improved between enrollment and 1‐year and remained stable thereafter. Low symptom burden was reported by 27% of patients at baseline, 38% at 1‐year, and 32% at 4 years post‐AHCT. Predictors of low symptom burden at 1‐year included low symptom burden at baseline: OR 2.7 (1.8–4.1), p < 0.0001; older age: OR 2.1 (1.3–3.2), p = 0.0007; and was related to being employed: OR 2.1 (1.4–3.2), p = 0.0004). We conclude that MM survivors who achieve disease control after AHCT have excellent recovery of FACT‐BMT and subscale scores to population norms by 1‐year post‐transplant, though many patients continue to report moderate to severe severity in some symptoms at 1‐year and beyond.
Change in FACT‐BMT score between baseline and 1‐year post‐transplant after AHCT. Q4 represents the highest QOL score quartile and Q1 represents the lowest QOL score quartile.
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