Glucocorticoids, particularly dexamethasone, are often used in combination with novel agents in multiple myeloma. This study compared the safety, rate, and extent of absorption of a single dose of an ...orally administered 20-mg dexamethasone tablet to five 4-mg tablets (total, 20 mg).
This was a single-center, open-label, randomized, 3-way crossover comparative study. Thirty-six volunteers received at least 1 dose of either a single 20-mg dexamethasone tablet, under fasting or fed conditions, or five 4-mg dexamethasone tablets (total, 20 mg). Blood samples were collected before study drug administration and at 21 time points for up to 36 hours after drug administration.
Mean area under the concentration-time curve from time zero to the time of last non-zero concentration (AUC0–t), mean area under the concentration-time curve from time zero to infinity (extrapolated) (AUC0–∞), and maximum observed concentration (Cmax) were 1314.38 ng × h/mL, 1329.24 ng × h/mL, and 257.22 ng/mL, respectively for fasting test formulation (single dexamethasone 20-mg tablet), 1339.74 ng × h/mL, 1358.07 ng × h/mL, and 194.56 ng/mL, respectively, for the fed test formulation (single dexamethasone 20-mg tablet), and 1325.12 ng × h/mL, 1342.12 ng × h/mL, and 244.12 ng/mL, respectively, for the reference formulation (5 dexamethasone 4-mg tablets). The median time of observed Cmax was 0.997 hours for the fasting and 2.502 hours for the fed test formulation, compared with 1.495 hours for the reference. Mean plasma elimination half-lives (t1/2) were 4.0 hours (test fasting), 4.03 hours (test fed), and 3.96 hours (reference). The point estimates and 90% confidence intervals (CIs) for AUC0-t, AUC0-∞, and Cmax were 99.37% (90% CI, 95.65%-103.24%), 99.24% (90% CI, 95.47%-103.16%), and 106.28% (90% CI, 97.69%-115.62%), respectively, satisfying the bioequivalence criteria of the United States Food and Drug Administration guidelines.
The 2 formulations were well-tolerated, and one 20-mg tablet or five 4-mg tablets of dexamethasone are bioequivalent under fasting conditions and thus may be prescribed interchangeably.
Patients with multiple myeloma often receive dexamethasone in combination with novel agent treatment. The current study compared the rate and extent of absorption of a single 20-mg dexamethasone tablet to five 4-mg tablets (total, 20 mg). Both formulations were well-tolerated and bioequivalent under fasting conditions, and dexamethasone 20-mg tablet under fed conditions demonstrated comparable total exposure to fasted conditions.
In this phase I/II clinical trial, we investigated the safety and efficacy of high doses of mb-IL21 ex vivo expanded donor-derived NK cells to decrease relapse in 25 patients with myeloid ...malignancies receiving haploidentical stem-cell transplantation (HSCT). Three doses of donor NK cells (1 × 10
-1 × 10
cells/kg/dose) were administered on days -2, +7, and +28. Results were compared with an independent contemporaneously treated case-matched cohort of 160 patients from the CIBMTR database.After a median follow-up of 24 months, the 2-year relapse rate was 4% vs. 38% (p = 0.014), and disease-free survival (DFS) was 66% vs. 44% (p = 0.1) in the cases and controls, respectively. Only one relapse occurred in the study group, in a patient with the high level of donor-specific anti-HLA antibodies (DSA) presented before transplantation. The 2-year relapse and DFS in patients without DSA was 0% vs. 40% and 72% vs. 44%, respectively with HR for DFS in controls of 2.64 (p = 0.029). NK cells in recipient blood were increased at day +30 in a dose-dependent manner compared with historical controls, and had a proliferating, mature, highly cytotoxic, NKG2C+/KIR+ phenotype.Administration of donor-derived expanded NK cells after haploidentical transplantation was safe, associated with NK cell-dominant immune reconstitution early post-transplant, preserved T-cell reconstitution, and improved relapse and DFS. TRIAL REGISTRATION: NCT01904136 ( https://clinicaltrials.gov/ct2/show/NCT01904136 ).
Summary
For diffuse large B‐cell lymphoma (DLBCL) patients progressing after autologous haematopoietic cell transplantation (autoHCT), allogeneic HCT (alloHCT) is often considered, although limited ...information is available to guide patient selection. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we identified 503 patients who underwent alloHCT after disease progression/relapse following a prior autoHCT. The 3‐year probabilities of non‐relapse mortality, progression/relapse, progression‐free survival (PFS) and overall survival (OS) were 30, 38, 31 and 37% respectively. Factors associated with inferior PFS on multivariate analysis included Karnofsky performance status (KPS) <80, chemoresistance, autoHCT to alloHCT interval <1‐year and myeloablative conditioning. Factors associated with worse OS on multivariate analysis included KPS<80, chemoresistance and myeloablative conditioning. Three adverse prognostic factors were used to construct a prognostic model for PFS, including KPS<80 (4 points), autoHCT to alloHCT interval <1‐year (2 points) and chemoresistant disease at alloHCT (5 points). This CIBMTR prognostic model classified patients into four groups: low‐risk (0 points), intermediate‐risk (2‐5 points), high‐risk (6‐9 points) or very high‐risk (11 points), predicting 3‐year PFS of 40, 32, 11 and 6%, respectively, with 3‐year OS probabilities of 43, 39, 19 and 11% respectively. In conclusion, the CIBMTR prognostic model identifies a subgroup of DLBCL patients experiencing long‐term survival with alloHCT after a failed prior autoHCT.
Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN) is an aggressive hematological malignancy; however, some patients achieve durable remission with allogeneic hematopoietic cell transplantation ...(allo-HCT). We report on all 17 patients with BPDCN who underwent allo-HCT at our center between 2000 and 2020. The median age was 39 (18-67) years. All (n = 16, 94%), except one patient, had systemic disease involving bone marrow and/or other organs. Ten patients (59%) were in first complete remission (CR1) at allo-HCT. The donor source was matched related or unrelated in ten (59%) and alternate donor in seven (41%) patients. Five (31%) patients developed acute graft-versus-host disease (GVHD), all grade I-II. The cumulative incidence (CI) of chronic GVHD at five-year was 34%. The CI of non-relapse mortality at one-year was 29%. Progression-free survival (PFS) rates at two-year and five-year were 49% (95% CI = 22-71%) and 39% (95% CI = 14-64%), respectively. The two-year and five-year overall survival (OS) rates were 65% (95% CI = 38-82%) and 40% (95% CI = 12-68%), respectively. The five-year rate for both PFS and OS was 80% in CR1 patients versus 0% in patients not in CR1. In conclusion, allo-HCT provides long-lasting remissions in BPDCN patients, particularly when performed in CR1.
Delayed engraftment is a major limitation of cord blood transplantation (CBT), due in part to a defect in the cord blood (CB) cells’ ability to home to the bone marrow. Because this defect appears ...related to low levels of fucosylation of cell surface molecules that are responsible for binding to P- and E-selectins constitutively expressed by the marrow microvasculature, and thus for marrow homing, we conducted a first-in-humans clinical trial to correct this deficiency. Patients with high-risk hematologic malignancies received myeloablative therapy followed by transplantation with 2 CB units, one of which was treated ex vivo for 30 minutes with the enzyme fucosyltransferase-VI and guanosine diphosphate fucose to enhance the interaction of CD34+ stem and early progenitor cells with microvessels. The results of enforced fucosylation for 22 patients enrolled in the trial were then compared with those for 31 historical controls who had undergone double unmanipulated CBT. The median time to neutrophil engraftment was 17 days (range, 12-34 days) compared with 26 days (range, 11-48 days) for controls (P = .0023). Platelet engraftment was also improved: median was 35 days (range, 18-100 days) compared with 45 days (range, 27-120 days) for controls (P = .0520). These findings support ex vivo fucosylation of multipotent CD34+ CB cells as a clinically feasible means to improve engraftment efficiency in the double CBT setting. The trial is registered to www.clinicaltrials.gov as #NCT01471067.
•Ex vivo fucosylation of cord blood cells improves their homing capacities, leading to faster neutrophil and platelet engraftments.•This method is quick, safe, and does not require a GMP laboratory; therefore, it can be used widely.
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.
Summary
Post‐transplantation cyclophosphamide (PTCy) is an effective strategy to prevent graft‐versus‐host disease (GVHD) after haploidentical haematopoietic cell transplantation (HCT). We determined ...the efficacy of PTCy‐based GVHD prophylaxis in human leucocyte antigen (HLA)‐mismatched unrelated donor (MMUD) HCT. We analysed 113 adult patients with high‐risk haematological malignancies who underwent one‐antigen MMUD transplantation between 2009 and 2013. Of these, 41 patients received PTCy, tacrolimus and mycophenolate mofetil (MMF) for GVHD prophylaxis; 72 patients received conventional prophylaxis with anti‐thymocyte globulin, tacrolimus and methotrexate. Graft source was primarily bone marrow (83% PTCy vs. 63% conventional group). Incidence of grade II–IV (37% vs. 36%, P = 0·8) and grade III–IV (17% vs. 12%, P = 0·5) acute GVHD was similar at day 100. However, the incidence of grade II‐IV acute GVHD by day 30 was significantly lower in the PTCy group (0% vs. 15%, P = 0·01). Median time to neutrophil (18 days vs. 12 days, P < 0·001) and platelet (25·5 days vs. 18 days, P = 0·05) engraftment was prolonged in PTCy group. Rates of graft failure, chronic GVHD, 2‐year non‐relapse mortality, relapse, progression‐free survival or overall survival were similar. Our results demonstrate that PTCy, tacrolimus and MMF for GVHD prophylaxis is safe and produced similar results as conventional prophylaxis in patients with one antigen HLA‐MMUD HCT.
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