Summary
The immunogenicity and safety of Pfizer‐BioNTech BNT162b2 mRNA vaccine in allogeneic haematopoietic stem cell transplantation (HSCT) recipients are unknown. We prospectively followed 152 HSCT ...recipients who were at least six months following transplantation and with no active acute graft‐versus‐host disease (GVHD). Blood samples were taken 2–4 weeks after the second vaccination and analyzed for receptor‐binding domain (RBD) antibodies and neutralizing antibodies (NA). 272 immunocompetent healthcare workers served as controls. At a median of 28 days after the second vaccination, 118 patients (77·6%) developed RBD immunoglobulin G (IgG) with a geometric mean titre (GMT) of 2·61 95% CI (confidence interval), 2·16–3·16. In the control group 269/272 (98·9%) developed RBD IgG, with a GMT of 5·98 (95% CI 5·70–6·28), P < 0·0001. The GMT of NA in HSCT recipients and controls was 116·0 (95% CI 76·5–175·9), and 427·9 (95% CI 354·3–516·7) respectively (P < 0001). Multivariate logistic regression analysis revealed that HSCT recipients with no chronic GVHD and no immunosuppressive therapy at the time of vaccination had significantly higher levels of NA following the second vaccination. Adverse events were minimal and were less common than in healthy controls. In conclusion; the BNT162b2 mRNA vaccination is safe and effective in HSCT recipients, especially those who are immunosuppression‐free. A significant fraction developed protecting NA.
Second allogeneic hematopoietic stem-cell transplantation (HSCT2) is a therapeutic option for patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) relapsing after a first ...transplant (HSCT1). However, patients allocated to HSCT2 may be a selected group with better prognosis and the added efficacy of HSCT2 is not well established. We retrospectively analyzed 407 consecutive patients with relapsed AML/MDS after HSCT1. Sixty-two patients had HSCT2 (15%) and 345 did not. The 2-year cumulative incidence rates of non-relapse mortality and relapse after HSCT2 were 26% (95% confidence interval 95% CI: 17-39%) and 50% (95% CI: 39-65%), respectively. The 5-year overall survival rates were 25% (95% CI: 14-36%) and 7% (95% CI: 4-10%) in the HSCT2 and no-HSCT2 groups, respectively. Multivariate analysis identified female gender (hazard ratio HR=0.31, P=0.001), short remission duration after HSCT1 (HR=2.31, P=0.05), acute graft-versus-host disease after HSCT1 (HR=2.27, P=0.035), HSCT2 from a haplo-identical donor (HR=13.4, P=0.001) or matched unrelated donor (HR=4.53, P=0.007) and relapse after HSCT1 in earlier years (HR=2.46, P=0.02) as factors predicting overall survival after HSCT2. Multivariate analysis of all patients including HSCT2 as a timedependent variable identified relapse within 6 months after HSCT1 (HR=2.32, P<0.001), acute graft-versus-host disease before relapse (HR=1.47, P=0.005), myeloablative conditioning in HSCT1 (HR=0.67, P=0.011), female gender (HR=0.71, P=0.007), relapse in earlier years (HR=1.33, P=0.031) and not having HSCT2 (HR=1.66, P=0.010) as predictive of overall survival after relapse. In conclusion, HSCT2 is associated with longer survival compared to non-transplant treatments and may be the preferred approach in a subset of patients with relapsed AML/MDS after HSCT1.
Autologous stem cell transplantation (ASCT) is a standard of care in newly-diagnosed multiple myeloma (MM) patients. Several studies before the introduction of novel therapies in MM, demonstrated a ...pegylated G-CSF to be successful in mobilizing peripheral blood stem cells (PBSCs). Lipegfilgrastim is a novel long-acting G-CSF that is produced by the conjugation of a single 20-kDa polyethelene glycol to the natural O-glycosylation site of G-CSF. Twenty-four MM patients were included for PBSCs mobilization with a single SC injection of 6 mg lipegfilgrastim. PBSC collection was started when the CD34
+
count was > 10 × 10
6
cells/L. The target progenitor cells were 6 × 10
6
cells/kg. The median day of apheresis was + 3 (range 2–5) following lipegfilgrastim. Median peripheral blood CD34
+
count pre-mobilization was of 22.65 (range 3.36–105) × 10
6
cells/L. The median number of leukaphaeresis procedures was 2 (range 1–4). The median mobilized CD34
+
cells/kg were 8.26 (range 0.77–12.42). One patient failed to mobilize and two patients mobilized < 6 × 10
6
cells/kg. Toxicity was mild and transient. Twenty-three patients underwent ASCT following high dose melphalan. All patients engrafted. As lipegfilgrastim is administered only once, it is conceivable that it improves both compliance and quality-of-life (NCT02488382).
We present three patients with aggressive non-Hodgkin's B-cell lymphoma (NHL) who received anti-CD19 chimeric antigen receptor T (CAR T) cells therapy after failure of several lines of chemotherapy ...that developed pseudo-progression. One-week clinical and radiological findings were consistent with tumor progression. Positron emission tomography-computed tomography (PET-CT) at 1 month post CAR T cells administration was consistent with treatment response. The rapid tumor growth and subsequent resolution are suggestive of tumor pseudo-progression mediated secondary to infiltration and immune activation of CAR T cells. Overall, 56 adult patients with NHL were enrolled in a phase 1b/2 in house clinical study with CD19 CAR T cells. Out of them 22/56 patients progressed as per PET-CT the 1 month post CAR T cells. In 14 patients, signs of progression started 7-10 days after CAR T cells infusion. In 11/14 patients, it was true progression, while in 3 it was pseudo-progression. Additional studies are warranted to describe the extent of this phenomenon and evaluate correlation with the CAR T activity and long-term disease control.
RATIONALE
Treosulfan is a substance that is being studied as part of the conditioning regimen given prior to allogeneic stem cell transplantation in patients with hematological malignancies. It is ...known to decompose into 1,2:3,4‐diepoxybutane (DEB) under physiologic conditions. In this study, we investigate whether N‐terminal valine adducts can be utilized to monitor differences in DEB formation of patients receiving treosulfan as part of the conditioning regimen for transplantation.
METHODS
Blood samples were collected from a group of 14 transplant recipients and analyzed for N,N‐(2,3‐dihydroxy‐1,4‐butadiyl)valine (pyr‐Val) and 2,3,4‐trihydroxybutylvaline (THB‐Val) adducts as biomarkers for drug uptake and metabolism before treosulfan treatment and 6 days after treatment.
RESULTS
A new direct injection liquid chromatography/tandem mass spectrometry (LC/MS/MS) method was developed and validated prior to clinical analysis. The assay precision was determined by 3 replicate analyses on 3 individual days using control globin spiked with known amounts of pyr‐Val and THB‐Val. The intra‐ and inter‐day precision coefficients of variance (CVs) and accuracy were < 10% and 15%, respectively. In clinical specimens, the means ± SD of pyr‐Val and THB‐Val background were 0.29 ± 0.10 pmol/g HB and 5.17 ± 1.7 pmol/g HB, respectively.
CONCLUSIONS
These values are similar to those found previously. Treosulfan treatment leads to a significant increase in pyr‐Val and THB‐Val adducts in each patient (Student's t‐test p <0.0001). The mean ± SD amounts of adduct formed were 245.3 ± 89.6 and 210 ± 78.5 pmol/g globin for pyr‐Val and THB‐Val, respectively. Importantly, these results show that this direct injection method can quantitate both background and treosulfan‐induced pyr‐Val and THB‐Val N‐terminal valine globin adducts in humans.
Acute graft-versus-host disease (aGVHD) is the major treatment-related complication after stem-cell transplantation (SCT) from unrelated donors. The proteasome-inhibitor bortezomib was added to GVHD ...prevention regimens with initial promise. However, two randomized studies failed to show efficacy. We explored the addition of carfilzomib, s second-generation proteasome inhibitor (20 mg/m
, intravenously on days +1 and +2) to cyclosporine/methotrexate backbone in 26 patients after SCT from unrelated donors. We compared outcomes to historical group of 100 patients given cyclosporine/methotrexate alone. Median follow-up was 34 months. There was no difference between the groups in engraftment or toxicities. The cumulative incidence of aGVHD grade II-IV, 6 months post transplant was 11% (95% CI, 4-32) and 39% (95% CI, 30-50), respectively (P = 0.01). The cumulative incidence of chronic GVHD, 2 years post transplant, was 49% (95% CI, 32-75) and 41% (95% CI, 33-52), respectively (P = 0.98). Three-year non-relapse mortality was 11% (95% CI, 4-33) and 18% (95% CI, 12-27, P = 0.45) while 3-year relapse rates were 8% (95% CI, 2-29) and 26% (95% CI, 18-36), respectively (P = 0.06). Three-year survival was 81% (95%CI, 66-96) and 56% (95% CI, 46-66), respectively (P = 0.05). In conclusion, carfilzomib with cyclosporine/methotrexate is safe, may reduce aGVHD, and possibly improve survival after unrelated donor SCT. These initial observations merit further study in larger comparative studies. ClinicalTrial.gov NCT01991301.
Steroid-resistant (SR) acute graft-versus-host disease (aGvHD) is a life-threatening complication of allogeneic stem cell transplantation. Vedolizumab is a monoclonal antibody that impairs homing of ...T cells to the gastrointestinal (GI) endothelium by blocking the α4β7 integrin. We retrospectively analyzed outcomes following vedolizumab administration for treatment of SR GI GvHD. Overall, 29 patients from three transplantation centers were included. Histopathology was available in 24 (83%) patients. The overall response rate (ORR) was 23/29 (79%); 8 (28%) patients had a complete response and 15 (52%) a partial response. Vedolizumab was administered as a 2nd-line or ≥3rd-line treatment in 13 (45%) and 16 (55%) patients, respectively. ORR in the former groups was 13/13 (100%) versus 10/16 (63%) in the latter (p = 0.012); corresponding CR rates were 7/13 (54%) versus 1/16 (6%) (p = 0.005). Early administration of vedolizumab was also associated with a greater likelihood of patients being off immunosuppression ((9/13 (69%) versus 3/16 (19%), p = 0.007) and free from fatal infectious complications (5/13 versus 14/16, p = 0.006). Overall, our data suggest that vedolizumab, especially if administered early in the disease course, may ameliorate severe SR GI aGvHD. The timing, role, and safety of vedolizumab should be further explored in prospective clinical trials.
Risk stratification is important for balancing potential risks and benefits of allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. We retrospectively studied ...1119 patients undergoing allogenic-HSCT in a single center for five hematological indications assessing the prognostic role of LDH at admission for survival (OS), progression-free survival (PFS), relapse incidence (RI), and nonrelapse mortality (NRM). In non-Hodgkin lymphoma (NHL) and acute myeloid leukemia (AML), higher than median LDH had an adverse effect on survival. The prognostic significance was strongest in AML, with higher LDH levels having lower 1-and 3-year survival 69.2% vs. 50.8%, P < 0.001 and 51.9% vs. 39.2%, P < 0.001, respectively, reduced 1-and 3-year PFS 62.4% vs. 42.1%, P < 0.001 48% vs. 35.2%, P < 0.001, respectively, higher cumulative incidence of 1-and 3-year NRM 11% vs. 17.3%, p = 0.01 and 15.7% vs. 19.6%, P = 0.04, and higher 1-and 3-year relapse incidence (RI) 26.7% vs. 40.7%, p < .0001 36.2% vs. 40.7%, respectively, P < 0.0001). In multivariate analysis LDH maintained significant prognostic capacity in OS, PFS and RI. These findings in AML, validated in an independent cohort, suggest that LDH is a readily available tool that could be integrated into transplant risk assessments to aid decision-making and identify high-risk patients who may benefit from post-transplant pharmacological or cellular strategies.
Clinical decisions in allogeneic hematopoietic stem cell transplantation (allo-HSCT) are supported by the use of prognostic scores for outcome prediction. Scores vary in their features and in the ...composition of development cohorts. We sought to externally validate and compare the performance of 8 commonly applied scoring systems on a cohort of allo-HSCT recipients. Among 528 patients studied, acute myeloid leukemia was the leading transplant indication (44%) and 46% of patients had a matched sibling donor. Most models successfully grouped patients into higher and lower risk strata, supporting their use for risk classification. However, discrimination varied (2-year overall survival area under the receiver operating characteristic curve AUC: revised Pretransplantation Assessment of Mortality rPAM, 0.64; PAM, 0.63; revised Disease Risk Index rDRI, 0.62; Endothelial Activation and Stress Index EASIx, 0.60; combined European Society for Blood and Marrow Transplantation EBMT/Hematopoietic Cell Transplantation-specific Comorbidity Index HCT-CI, 0.58; EBMT, 0.58; Comorbidity-Age, 0.58; HCT-CI, 0.55); AUC ranges from 0.5 (random) to 1.0 (perfect prediction). rPAM and PAM, which had the greatest predictive capacity across all outcomes, are comprehensive models including patient, disease, and transplantation information. Interestingly, EASIx, a biomarker-driven model, had comparable performance for nonrelapse mortality (NRM; 2-year AUC, 0.65) but no predictive value for relapse (2-year AUC, 0.53). Overall, allo-HSCT prognostic systems may be useful for risk stratification, but individual prediction remains a challenge, as reflected by the scores' limited discriminative capacity.
•Prognostic capacity varied across 8 allogeneic transplantation scores, with rPAM showing modest benefit across several outcomes.•EASIx, a biomarker-based prediction model, is among the strongest predictive scores of NRM.
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