Blinatumomab for Acute Lymphoblastic Leukemia Relapse after Allogeneic Hematopoietic Stem Cell Transplantation

Patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) following allogeneic hematopoietic stem cell transplantation (alloHSCT) have a poor prognosis, and alternative therapies are needed for this patient population. Blinatumomab, a bispecific T cell engager immunotherapy, was evaluated in an open-label, single-arm, phase II study of adults with R/R Philadelphia chromosome-negative B cell precursor ALL and resulted in a rate of complete remission (CR) or CR with partial hematologic recovery of peripheral blood counts (CRh) of 43% within 2 treatment cycles. We conducted an exploratory analysis to determine the efficacy and safety of blinatumomab in 64 patients who had relapsed following alloHSCT before enrollment in the phase II study. Forty-five percent of the patients (29 of 64) achieved a CR/CRh within the first 2 cycles of treatment, 22 of whom had a minimal residual disease (MRD) response (including 19 with a complete MRD response). After 1 year and 3 years of follow-up, the median relapse-free survival was 7.4 months for patients who achieved CR/CRh in the first 2 cycles, and the median overall survival was 8.5 months; overall survival rate (Kaplan-Meier estimate) was 36% at 1 year and 18% at 3 years. Grade 3 and 4 adverse events were reported in 20 patients (31%) and 28 patients (44%), respectively, with grade 3 and 4 neurologic events in 8 and 2 patients, respectively, and grade 3 cytokine release syndrome in 2 patients. Eight patients had fatal adverse events, including 5 due to infections. Seven patients had grade 64 3 graft-versus-host disease during the study, none of which resulted in the discontinuation of blinatumomab or hospitalization. Our data suggest that blinatumomab is an effective salvage therapy in this patient population

Comparative Analysis of Calcineurin Inhibitor-Based Methotrexate and Mycophenolate Mofetil-Containing Regimens for Prevention of Graft-versus-Host Disease after Reduced-Intensity Conditioning Allogeneic Transplantation

The combination of a calcineurin inhibitor (CNI) such as tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) has been commonly used for graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), but there are limited data comparing efficacy of the 2 regimens. We evaluated 1564 adult patients who underwent RIC alloHCT for acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) from 2000 to 2013 using HLA-identical sibling (matched related donor [MRD]) or unrelated donor (URD) peripheral blood graft and received CYSP or TAC with MTX or MMF for GVHD prophylaxis. Primary outcomes of the study were acute and chronic GVHD and overall survival (OS). The study divided the patient population into 4 cohorts based on regimen: MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP. In the URD group, MMF-CYSP was associated with increased risk of grade II to IV acute GVHD (relative risk [RR], 1.78; P <.001) and grade III to IV acute GVHD (RR, 1.93; P =.006) compared with MTX-TAC. In the URD group, use of MMF-TAC (versus MTX-TAC) lead to higher nonrelapse mortality. (hazard ratio, 1.48; P =.008). In either group, no there was no difference in chronic GVHD, disease-free survival, and OS among the GVHD prophylaxis regimens. For RIC alloHCT using MRD, there are no differences in outcomes based on GVHD prophylaxis. However, with URD RIC alloHCT, MMF-CYSP was inferior to MTX-based regimens for acute GVHD prevention, but all the regimens were equivalent in terms of chronic GVHD and OS. Prospective studies, targeting URD recipients are needed to confirm these results

Risk classification at diagnosis predicts post-HCT outcomes in intermediate-, adverse-risk, and KMT2A-rearranged AML

Little is known about whether risk classification at diagnosis predicts post-hematopoietic cell transplantation (HCT) outcomes in patients with acute myeloid leukemia (AML). We evaluated 8709 patients with AML from the CIBMTR database, and after selection and manual curation of the cytogenetics data, 3779 patients in first complete remission were included in the final analysis: 2384 with intermediate-risk, 969 with adverse-risk, and 426 with KMT2A-rearranged disease. An adjusted multivariable analysis detected an increased risk of relapse for patients with KMT2A-rearranged or adverse-risk AML as compared to those with intermediate-risk disease (hazards ratio [HR], 1.27; P 5.01; HR, 1.71; P,.001, respectively). Leukemia-free survival was similar for patients with KMT2A rearrangement or adverse risk (HR, 1.26; P 5.002, and HR, 1.47; P,.001), as was overall survival (HR, 1.32; P,.001, and HR, 1.45; P,.001). No differences in outcome were detected when patients were stratified by KMT2A fusion partner. This study is the largest conducted to date on post-HCT outcomes in AML, with manually curated cytogenetics used for risk stratification. Our work demonstrates that risk classification at diagnosis remains predictive of post-HCT outcomes in AML. It also highlights the critical need to develop novel treatment strategies for patients with KMT2A-rearranged and adverse-risk disease

Visible absorption characteristics of the bis-(2,9-dimethyl-1,10-phenanthroline)- and bis-(4,4′,6,6′-tetramethyl-2,2′-bipyridine)-copper(I) ions

Spectrophotometric studies have indicated that the absorbing species in solution for the determination of copper using 2,9-dimethyl-1,1 0-phenanthroline (dmp) and 4,4’,6,6’-tetramethyl-2,2’-bipyridine (tmb) are the bis complex ions, [Cu(dmp)] and [Cu(tmb)], respectively. Solutions of the pure compounds, [Cu(ligand)] X where X = Cl, Br, I, NO, and ClO, have spectral characteristics in agreement with the earlier studies. In general, however, the solutions conform to Beer's law only when a large excess of the ligand is added. Deviations from Beer's law in the absence of excess ligand are attributed to dissociation of the [Cu-(ligand)]X complexes to the corresponding monochelate species. These ligands coordinate to many transition metals and their apparent specificity for copper in extraction procedures is probably due to complexes of other metals having wavelengths of maximum absorption well removed from the λ values for the copper complexes, or much lower molar absorptivities

Unimolecuclar fragmentation and isomerization of gaseous arsanyl cations Y-C6H4As+X (X = F, Cl, Br, I). The role of non-classical nido structures

Kirchhoff D, Grützmacher H-F. Unimolecuclar fragmentation and isomerization of gaseous arsanyl cations Y-C6H4As+X (X = F, Cl, Br, I). The role of non-classical nido structures. EUROPEAN JOURNAL OF MASS SPECTROMETRY. 2004;10(1):857-867.The halogeno-(4-halogenophenyl)arsanyl cations Y-C6H4As+X (X=F, Cl, Br, I) are abundant in the 70eV EI mass spectra of dihalogeno-(4-halogenophenyl)arsanes Y-C6H4AsX2. This has been used to study the unimolecular reactions of ions Y-C6H4As+X by techniques of tandem mass spectrometry with respect to a possible rearrangement to nido-isomers, eta(4)- (XYC6H4)As+, in which the As+ is capping a dihalogenobenzene moiety, YC(6)H(4)AX. The mass analyzed ion kinetic energy (MIKE) spectra of Y-C6H4As+X, 1a(+)-3a(+) and 5a(+) (X, Y=F, Cl, Br, see Scheme 2), display broad and even dish-topped peaks for the loss of HX and HY, respectively, indicating a large kinetic energy release (KER) during these reactions and the presence of a large reverse activation energy. The mean value of the KER, , is specific for the type of the halogen substituent but independent of its original position and is identical to found for the loss of HX or HY from metastable halogeno-phenylarsanyl cations, C6H5As-X or C6H4As+Y. These results give strong evidence for a positional change of X and Y in Y-C6H4As+X before fragmentation, plausibly via intermediate eta(4)-(XYC6H4)As+. However, the relative intensities of the signals for loss of HX and HY are different in the MIKE spectra of isomeric arsanyl cations and the spectra of the isomers obtained by collision-induced decomposition show that the metastable arsanyl cations represent a mixture of isomers with the original arsanyl cation prevailing. Clearly, interchange of halogen substituents in Y-C6H4XAs+ is slow compared with fragmentation and the intermediate nido-isomer, eta(4)-(XYC6H4)As+, is separated from the isomers of the classical structure of a halogeno-(halogenophenyl)arsanyl cation by substantial activation barriers. Therefore, in the case of 4a(+) and 6a(+) (X, Y = Cl, I), any rearrangement is obstructed by the facile loss of the weakly bonded I substituent. This reaction model was verified by theoretical calculations of relevant stationary points of the minimum energy reaction pathways (MERP) of fragmentation and rearrangement at the level UBHLYP/6-311+g(2d,p)//UBHLYP/6-31+g(d). In particular, the calculations show that the nido isomers, eta(4)-(XYC6H4)As+, are stable species but higher in energy than their "classical" isomers