ABSTRACT
Several vaccine strategies have been tested for the treatment of follicular lymphoma; however, none have proven successful. In a phase I dose-escalation protocol, we developed a vaccine consisting of lethally irradiated whole lymphoma cells admixed with K562 cells that constitutively secreted granulocyte-macrophage colony-stimulating factor (GM-K562)(ClinicalTrials.gov identifier: NCT00487305). Patients with grade 1, 2, or 3 A follicular lymphoma were divided into 2 study tiers based on prior treatment and received a maximum of 6 vaccines. Vaccines contained dose levels of 5 × 106 or 1 × 107 GM-K562 cells admixed with autologous tumor cells at doses ranging from 1 × 105 to 5 × 107.Correlative studies did not demonstrate a significant immune response as assessed by delayed-type hypersensitivity reactions, B and T cell subsets, and natural killer cell subsets. Future vaccine studies should focus on identifying lymphoma-specific immunogenic proteins and modifying the vaccine immune adjuvant.
ABSTRACT
Bimolecular nucleophilic substitution (SN2) mechanisms occupy a central place in the historical development and teaching of the field of organic chemistry1. Despite the importance of SN2 pathways in synthesis, catalytic control of ionic SN2 pathways is rare and notably uncommon even in biocatalysis2,3, reflecting the fact that any electrostatic interaction between a catalyst and the reacting ion pair necessarily stabilizes its charge and, by extension, reduces polar reactivity. Nucleophilic halogenase enzymes navigate this tradeoff by desolvating and positioning the halide nucleophile precisely on the SN2 trajectory, using geometric preorganization to compensate for the attenuation of nucleophilicity4. Here we show that a small-molecule (646 Da) hydrogen-bond-donor (HBD) catalyst accelerates the SN2 step of an enantioselective Michaelis-Arbuzov reaction by recapitulating the geometric preorganization principle employed by enzymes. Mechanistic and computational investigations reveal that the HBD diminishes the reactivity of the chloride nucleophile yet accelerates the rate-determining dealkylation step by reorganizing both the phosphonium cation and the chloride anion into a geometry that is primed to enter the SN2 transition state. This new enantioselective Arbuzov reaction affords highly enantioselective access to an array of H-phosphinates, which are in turn versatile P-stereogenic building blocks amenable to myriad derivatizations. This work constitutes, to our knowledge, the first demonstration of catalytic enantiocontrol of the phosphonium dealkylation step, establishing a new platform for the synthesis of P-stereogenic compounds.
ABSTRACT
PI3K-δ inhibitors have shown impressive activity in lymphoid malignancies but have been hampered by autoimmune and infectious toxicities, leading to market withdrawals. We previously demonstrated activity of the PI3K-δγ inhibitor duvelisib in T cell lymphomas (TCLs) that was associated with inflammatory adverse events. As reported here, we conducted a phase 1b/2a study of duvelisib in combination with either romidepsin (n = 66) or bortezomib (n = 32) in patients with relapsed/refractory TCL and found that the addition of romidepsin, but not bortezomib, appeared to increase efficacy while attenuating PI3K inhibitor-driven toxicity. The primary endpoint of the study was to determine the safety and maximum tolerated dose of duvelisib, which was 75 mg twice daily when combined with romidepsin versus 25 mg twice daily when combined with bortezomib. The most common adverse events were neutropenia (42%, 25/59) and fatigue (37%, 22/59) in patients treated with duvelisib and romidepsin and diarrhea (48%, 11/23) and neutropenia (30%, 7/23) in patients treated with duvelisib and bortezomib. Duvelisib and romidepsin resulted in less grade 3/4 hepatotoxicity (14%, 8/59) compared to 40% (14/35) in our previous study with duvelisib monotherapy. This was associated with reductions in circulating inflammatory mediators and myeloid cell inflammatory gene expression. Secondary endpoints of overall and complete response rates were 55% (35/64) and 34% (22/64) for patients treated with duvelisib and romidepsin and 34% (11/32) and 13% (4/32) for patients treated with duvelisib and bortezomib. Among patients with peripheral T cell lymphomas (PTCLs), overall and complete response rates of duvelisib and romidepsin were 56% (27/48) and 44% (21/48), respectively, with exploratory analyses showing increased response rates in patients with a follicular helper T cell subtype. These findings support further development of combined PI3K and histone deacetylase (HDAC) inhibition in TCLs and suggest a unique strategy to enable PI3K inhibitor-based combinations for additional patient populations. ClinicalTrials.gov identifier: NCT02783625 .
ABSTRACT
We report asymmetric potassium-isothiourea-boronate-catalyzed Wittig olefinations of 4-substituted cyclohexanones with non-stabilized phosphorus ylides to afford highly enantioenriched axially chiral alkenes. The optimal catalyst features an unusual macrocyclic amide-potassium-boronate chelate. Kinetic and spectroscopic analyses are consistent with a Lewis acid mechanism for the catalytic olefination that results in the formation of the oxaphosphetane adduct under cryogenic conditions. Thermal fragmentation of the oxaphosphetane to the alkene product occurs after the reaction is complete. Computational studies indicate that cycloaddition proceeds via a stepwise mechanism involving enantiodetermining polar 1,2-addition to afford an intermediate potassium betaine complex.
ABSTRACT
STOP-CA was a multicenter, double-blind, randomized, placebo-controlled trial comparing atorvastatin to placebo in treatment-naïve lymphoma patients receiving anthracycline-based chemotherapy. We performed a preplanned subgroup to analyze the impact of atorvastatin on efficacy in patients with diffuse large B-cell lymphoma (DLBCL). Patients received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) at standard doses for six 21-day cycles and were randomly assigned to receive atorvastatin 40 mg daily (n = 55) or placebo (n = 47) for 12 months. The complete response (CR) rate was numerically higher in the atorvastatin arm (95% [52/55] vs. 85% [40/47], p = .18), but this was not statistically significant. Adverse event rates were similar between the atorvastatin and placebo arms. In summary, atorvastatin did not result in a statistically significant improvement in the CR rate or progression-free survival, but both were numerically improved in the atorvastatin arm. These data warrant further investigation into the potential therapeutic role of atorvastatin added to anthracycline-based chemotherapies.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols , Atorvastatin , Cyclophosphamide , Doxorubicin , Lymphoma, Large B-Cell, Diffuse , Prednisone , Rituximab , Vincristine , Humans , Atorvastatin/therapeutic use , Atorvastatin/administration & dosage , Atorvastatin/adverse effects , Lymphoma, Large B-Cell, Diffuse/drug therapy , Lymphoma, Large B-Cell, Diffuse/mortality , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Prednisone/therapeutic use , Prednisone/adverse effects , Prednisone/administration & dosage , Vincristine/therapeutic use , Vincristine/adverse effects , Rituximab/therapeutic use , Rituximab/adverse effects , Rituximab/administration & dosage , Doxorubicin/therapeutic use , Doxorubicin/adverse effects , Doxorubicin/administration & dosage , Cyclophosphamide/therapeutic use , Cyclophosphamide/adverse effects , Cyclophosphamide/administration & dosage , Male , Female , Middle Aged , Aged , Double-Blind Method , Treatment Outcome , AdultABSTRACT
PURPOSE: Develop a novel therapeutic strategy for patients with subtypes of mature T-cell and NK-cell neoplasms. EXPERIMENTAL DESIGN: Primary specimens, cell lines, patient-derived xenograft models, commercially available, and proprietary anti-KLRG1 antibodies were used for screening, target, and functional validation. RESULTS: Here we demonstrate that surface KLRG1 is highly expressed on tumor cells in subsets of patients with extranodal NK/T-cell lymphoma (ENKTCL), T-prolymphocytic leukemia (T-PLL), and gamma/delta T-cell lymphoma (G/D TCL). The majority of the CD8+/CD57+ or CD3-/CD56+ leukemic cells derived from patients with T- and NK-large granular lymphocytic leukemia (T-LGLL and NK-LGLL), respectively, expressed surface KLRG1. The humanized afucosylated anti-KLRG1 monoclonal antibody (mAb208) optimized for mouse in vivo use depleted KLRG1+ TCL cells by mechanisms of ADCC, ADCP, and CDC rather than apoptosis. mAb208 induced ADCC and ADCP of T-LGLL patient-derived CD8+/CD57+ cells ex vivo. mAb208 effected ADCC of subsets of healthy donor-derived KLRG1+ NK, CD4+, CD8+ Tem, and TemRA cells while sparing KLRG1- naïve and CD8+ Tcm cells. Treatment of cell line and TCL patient-derived xenografts with mAb208 or anti-CD47 mAb alone and in combination with the PI3K-δ/γ inhibitor duvelisib extended survival. The depletion of macrophages in vivo antagonized mAb208 efficacy. CONCLUSIONS: Our findings suggest the potential benefit of a broader treatment strategy combining therapeutic antibodies with PI3Ki for the treatment of patients with mature T-cell and NK-cell neoplasms. See related commentary by Varma and Diefenbach, p. 2300.
Subject(s)
Lectins, C-Type , Receptors, Immunologic , Xenograft Model Antitumor Assays , Humans , Animals , Mice , Receptors, Immunologic/antagonists & inhibitors , Receptors, Immunologic/metabolism , Receptors, Immunologic/immunology , Lectins, C-Type/metabolism , Lectins, C-Type/immunology , Lectins, C-Type/antagonists & inhibitors , Cell Line, Tumor , Lymphoma, T-Cell/immunology , Lymphoma, T-Cell/pathology , Lymphoma, T-Cell/therapy , Lymphoma, T-Cell/drug therapy , Killer Cells, Natural/immunology , Killer Cells, Natural/metabolism , Antibodies, Monoclonal/therapeutic use , Antibodies, Monoclonal/pharmacologyABSTRACT
Antibodies targeting PD-1 or 4-1BB achieve objective responses in follicular lymphoma (FL), but only in a minority of patients. We hypothesized that targeting multiple immune receptors could overcome immune resistance and increase response rates in patients with relapsed/refractory FL. We therefore conducted a phase 1b trial testing time-limited therapy with different immunotherapy doublets targeting 4-1BB (utomilumab), OX-40 (ivuxolimab), and PD-L1 (avelumab) in combination with rituximab among patients with relapsed/refractory grade 1-3A FL. Patients were enrolled onto 2 of 3 planned cohorts (cohort 1 - rituximab/utomilumab/avelumab; cohort 2 - rituximab/ivuxolimab/utomilumab). 3+3 dose escalation was followed by dose expansion at the recommended phase 2 dose (RP2D). Twenty-four patients were enrolled (16 in cohort 1 and 9 in cohort 2, with one treated in both cohorts). No patients discontinued treatment due to adverse events and the RP2D was the highest dose level tested in both cohorts. In cohort 1, the objective and complete response rates were 44% and 19%, respectively (50% and 30%, respectively, at RP2D). In cohort 2, no responses were observed. The median progression-free survivals in cohorts 1 and 2 were 6.9 and 3.2 months, respectively. In cohort 1, higher density of PD-1+ tumor-infiltrating T-cells on baseline biopsies and lower density of 4-1BB+ and TIGIT+ T-cells in on-treatment biopsies were associated with response. Abundance of Akkermansia in stool samples was also associated with response. Our results support a possible role for 4-1BB agonist therapy in FL and suggest that features of the tumor microenvironment and stool microbiome may be associated with clinical outcomes (NCT03636503).
Subject(s)
Antineoplastic Agents , Lymphoma, Follicular , Humans , Rituximab , Lymphoma, Follicular/drug therapy , Programmed Cell Death 1 Receptor , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Neoplasm Recurrence, Local/drug therapy , Antineoplastic Agents/therapeutic use , Antibodies, Monoclonal/adverse effects , Immunotherapy , Tumor MicroenvironmentABSTRACT
Importance: Anthracyclines treat a broad range of cancers. Basic and retrospective clinical data have suggested that use of atorvastatin may be associated with a reduction in cardiac dysfunction due to anthracycline use. Objective: To test whether atorvastatin is associated with a reduction in the proportion of patients with lymphoma receiving anthracyclines who develop cardiac dysfunction. Design, Setting, and Participants: Double-blind randomized clinical trial conducted at 9 academic medical centers in the US and Canada among 300 patients with lymphoma who were scheduled to receive anthracycline-based chemotherapy. Enrollment occurred between January 25, 2017, and September 10, 2021, with final follow-up on October 10, 2022. Interventions: Participants were randomized to receive atorvastatin, 40 mg/d (n = 150), or placebo (n = 150) for 12 months. Main Outcomes and Measures: The primary outcome was the proportion of participants with an absolute decline in left ventricular ejection fraction (LVEF) of ≥10% from prior to chemotherapy to a final value of <55% over 12 months. A secondary outcome was the proportion of participants with an absolute decline in LVEF of ≥5% from prior to chemotherapy to a final value of <55% over 12 months. Results: Of the 300 participants randomized (mean age, 50 [SD, 17] years; 142 women [47%]), 286 (95%) completed the trial. Among the entire cohort, the baseline mean LVEF was 63% (SD, 4.6%) and the follow-up LVEF was 58% (SD, 5.7%). Study drug adherence was noted in 91% of participants. At 12-month follow-up, 46 (15%) had a decline in LVEF of 10% or greater from prior to chemotherapy to a final value of less than 55%. The incidence of the primary end point was 9% (13/150) in the atorvastatin group and 22% (33/150) in the placebo group (P = .002). The odds of a 10% or greater decline in LVEF to a final value of less than 55% after anthracycline treatment was almost 3 times greater for participants randomized to placebo compared with those randomized to atorvastatin (odds ratio, 2.9; 95% CI, 1.4-6.4). Compared with placebo, atorvastatin also reduced the incidence of the secondary end point (13% vs 29%; P = .001). There were 13 adjudicated heart failure events (4%) over 24 months of follow-up. There was no difference in the rates of incident heart failure between study groups (3% with atorvastatin, 6% with placebo; P = .26). The number of serious related adverse events was low and similar between groups. Conclusions and Relevance: Among patients with lymphoma treated with anthracycline-based chemotherapy, atorvastatin reduced the incidence of cardiac dysfunction. This finding may support the use of atorvastatin in patients with lymphoma at high risk of cardiac dysfunction due to anthracycline use. Trial Registration: ClinicalTrials.gov Identifier: NCT02943590.
Subject(s)
Anthracyclines , Antibiotics, Antineoplastic , Atorvastatin , Cardiovascular Agents , Heart Diseases , Lymphoma , Female , Humans , Middle Aged , Anthracyclines/adverse effects , Anthracyclines/therapeutic use , Antibiotics, Antineoplastic/adverse effects , Antibiotics, Antineoplastic/therapeutic use , Atorvastatin/therapeutic use , Double-Blind Method , Heart Failure/etiology , Heart Failure/physiopathology , Heart Failure/prevention & control , Retrospective Studies , Stroke Volume , Ventricular Function, Left , Cardiovascular Agents/therapeutic use , Lymphoma/drug therapy , Heart Diseases/chemically induced , Heart Diseases/physiopathology , Heart Diseases/prevention & control , Follow-Up Studies , Male , Adult , AgedABSTRACT
A catalytic protio-semipinacol ring-expansion reaction has been developed for the highly enantioselective conversion of tertiary vinylic cyclopropyl alcohols into cyclobutanone products bearing α-quaternary stereogenic centers. The method relies on the cocatalytic effect of a chiral dual-hydrogen-bond donor (HBD) with hydrogen chloride. Experimental evidence is provided for a stepwise mechanism where protonation of the alkene generates a short-lived, high-energy carbocation, which is followed by C-C bond migration to deliver the enantioenriched product. This research applies strong acid/chiral HBD cocatalysis to weakly basic olefinic substrates and lays the foundation for further investigations of enantioselective reactions involving high-energy cationic intermediates.
ABSTRACT
Autologous stem cell transplantation (ASCT) is often used as consolidation for several subtypes of peripheral T-cell lymphoma (PTCL) in first remission. However, many patients relapse after ASCT and have a very poor prognosis. There are no approved treatment options for posttransplantation maintenance or consolidation in PTCL. PD-1 blockade has demonstrated some efficacy for patients with PTCL. We, therefore, conducted a phase 2 multicenter study of the anti-PD-1 monoclonal antibody pembrolizumab after ASCT in patients with PTCL in first remission. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 8 cycles within 21 days from post-ASCT discharge (and within 60 days of stem cell infusion). The primary end point was progression-free survival (PFS) at 18 months after ASCT. Twenty-one patients were treated in this study and 67% (n = 14) completed 8 cycles of treatment. Among all patients who were evaluable, 13 of 21 were alive and achieved PFS at 18 months after ASCT, meeting the study's primary end point. The estimated 18-month PFS was 83.6% (95% confidence interval [CI], 68-100), and overall survival 94.4% (95% CI, 84-100). The toxicity profile was consistent with the known toxicity profile of pembrolizumab, with no grade 5 toxicities. In conclusion, PD-1 blockade after ASCT with pembrolizumab is feasible with a favorable safety profile and promising activity, supporting further confirmatory studies. This trial was registered at www.clinicaltrials.gov as #NCT02362997.
Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma, T-Cell, Peripheral , Humans , Disease-Free Survival , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Neoplasm Recurrence, Local/etiology , Transplantation, Autologous , Lymphoma, T-Cell, Peripheral/drug therapy , T-Lymphocytes/pathology , Stem Cell TransplantationABSTRACT
Asymmetric transition-metal catalysis represents a powerful strategy for accessing enantiomerically enriched molecules1-3. The classical strategy for inducing enantioselectivity with transition-metal catalysts relies on direct complexation of chiral ligands to produce a sterically constrained reactive metal site that allows formation of the major product enantiomer while effectively inhibiting the pathway to the minor enantiomer through steric repulsion4. The chiral-ligand strategy has proven applicable to a wide variety of highly enantioselective transition-metal-catalysed reactions, but important scenarios exist that impose limits to its successful adaptation. Here, we report a new approach for inducing enantioselectivity in transition-metal-catalysed reactions that relies on neutral hydrogen-bond donors (HBDs)5,6 that bind anions of cationic transition-metal complexes to achieve enantiocontrol and rate enhancement through ion pairing together with other non-covalent interactions7-9. A cooperative anion-binding effect of a chiral bis-thiourea HBD is demonstrated to lead to high enantioselectivity (up to 99% enantiomeric excess) in intramolecular ruthenium-catalysed propargylic substitution reactions10. Experimental and computational mechanistic studies show the attractive interactions between electron-deficient arene components of the HBD and the metal complex that underlie enantioinduction and the acceleration effect.
ABSTRACT
While most patients with follicular lymphoma (FL) have excellent outcomes with frontline chemoimmunotherapy (CIT), a subset of patients will experience early progression, which is associated with poor subsequent outcomes. Novel biomarkers are needed to identify high-risk patients earlier. We hypothesized that interim positron emission tomography (PET) would predict progression-free survival (PFS) in this population. We retrospectively identified 128 patients with grade 1-3A FL who had an interim PET after 2-4 cycles of frontline CIT at 2 academic centers. PET scans were analyzed using Deauville score (DS) and change in maximum standardized uptake value (ΔSUVmax). Interim PET DS was a significant predictor of PFS (P < 0.003). Patients with a DS of 3 had outcomes similar to those of patients with a DS of 4, so were categorized as PET-positive for additional analyses. Interim PET remained a strong predictor of PFS (DS 3-5, hazard ratio [HR] 2.4, P = 0.006) in a multivariable analysis and was also an early predictor of both a positive end-of-treatment PET (P < 0.001) and progression of disease within 24 months (POD24) (P = 0.006). An optimal ΔSUVmax cutoff of 75% was selected using the bootstrap method. ΔSUVmax <75% was also a significant predictor of PFS on univariable and multivariable analyses (HR 2.8, P < 0.003). In a separate cohort of 50 patients with high-grade FL, interim PET interpreted using either DS (P < 0.001) or ΔSUVmax75% (P = 0.034) was also a significant predictor of inferior PFS. In conclusion, interim PET is an independent predictor of PFS and may be useful as a tool for response-adapted treatment strategies in FL.
ABSTRACT
This study investigated ibrutinib plus obinutuzumab in relapsed/refractory CLL, evaluating tolerability of 3 sequencing regimens as well as overall safety and efficacy. Fifty-two patients were initially randomized 1:1:1 to receive either obinutuzumab 1 month before ibrutinib initiation, ibrutinib 1 month prior to obinutuzumab initiation, or to start both drugs concomitantly. Higher rates of infusion-related reactions were observed with the first sequence, and only the latter 2 cohorts were expanded. Grade 4 hematologic toxicity was uncommon, and notable all-grade non-hematologic toxicities included bruising (58%), hypertension (46%), arthralgia (38%), diarrhea (37%), transaminitis (35%), atrial fibrillation (21%), and serious infection (17%). Best overall response rate was 96% (including 40% CR and 56% PR). Best rates of undetectable minimal residual disease in peripheral blood and bone marrow were 27% and 19%, respectively. With a median follow-up of 41.5 months, four-year progression-free and overall survival rates are 74% and 93%, respectively. Correlative studies demonstrated that serum CCL4 and CXCL13 levels were associated with clinical response, and BH3 profiling revealed increased BCL-2 and BCL-xL dependence in CLL cells from patients on treatment. Overall, ibrutinib plus obinutuzumab was highly active, with a manageable safety profile, supporting further investigation of this type of approach in relapsed/refractory CLL.
Subject(s)
Leukemia, Lymphocytic, Chronic, B-Cell , Humans , Antibodies, Monoclonal, Humanized/adverse effects , Piperidines/therapeutic use , Recurrence , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
Hemophagocytic lymphohistiocytosis (HLH) is a syndrome marked by a severe hyperinflammatory state characterized by aberrant T- and natural killer-cell activity leading to prolonged hypercytokinemia and can be rapidly fatal if not diagnosed and treated early. While upfront therapy is aimed at reducing hyperinflammation and controlling possible triggers, allogeneic hematopoietic stem cell transplantation (HSCT) is indicated for primary and relapsed/refractory cases to attain sustained remission. While this has been explored extensively in the pediatric population, there are limited data on adults undergoing HSCT for HLH. We analyzed transplant outcomes in an adult HLH population in the modern era who were transplanted at Dana-Farber Cancer Institute from 2010 onwards. Patients were uniformly transplanted on a reduced intensity platform incorporating early administration of alemtuzumab with standard infectious and graft-versus-host disease (GVHD) prophylaxis. Engraftment was documented for all patients. At 3 years after transplantation, overall survival (OS) was 75% (95% confidence interval [CI], 51-89) while 3-year progression-free survival (PFS) was 71% (95% CI, 46-86). The 3-year cumulative incidence of relapse was 15% (95% CI, 3.4-33). There were no isolated HLH relapses without relapse of malignancy. The cumulative incidence of nonrelapse mortality at 3 years was 15% (95% CI, 3.5-34). Infectious complications and GVHD outcomes were comparable to standard reduced-intensity conditioning (RIC) transplantation at our institute. Mixed chimerism was common but did not correlate with transplant outcomes. Our data suggest that the immune defect in HLH can be abrogated with allogeneic transplantation using a reduced intensity regimen with early administration of alemtuzumab as preconditioning, providing a potentially curative option for this difficult disease.
Subject(s)
Graft vs Host Disease , Lymphohistiocytosis, Hemophagocytic , Humans , Child , Adult , Lymphohistiocytosis, Hemophagocytic/etiology , Lymphohistiocytosis, Hemophagocytic/therapy , Alemtuzumab/therapeutic use , Transplantation Conditioning , Transplantation, Homologous , Graft vs Host Disease/prevention & control , RecurrenceABSTRACT
ABVD (Adriamycin, bleomycin, vinblastine, dacarbazine) with or without radiation has been the standard treatment for limited-stage Hodgkin lymphoma (HL) but carries risks of bleomycin lung injury and radiation toxicity. Brentuximab vedotin (BV) is approved with AVD for stage III-IV HL, but carries increased risks of peripheral neuropathy (PN) and neutropenic fever, likely due to overlapping toxicity between BV and vinblastine. We therefore evaluated BV in combination with AD for 4 or 6 cycles based on interim positron emission tomography response. Thirty-four patients with nonbulky stage I-II HL were enrolled. Risk was early favorable in 53% and unfavorable in 47%. The overall and complete response rates (CRRs) were 100% and 97%, respectively, with a 5-year progression-free survival (PFS) of 91%. No differences in outcome were observed based on stage (I vs II) or risk status (early favorable vs unfavorable). The most common adverse events were nausea (85%), peripheral sensory neuropathy (59%), and fatigue (56%). There were no cases of grade-4 neutropenia or neutropenic fever, and no patient received granulocyte-colony stimulating factor. Most cases of PN were grade 1, and no patient experienced grade ≥3 PN. BV-AD produced a high CRR and durable PFS with most patients requiring 4 cycles of therapy. Compared with BV-AVD, the toxicity profile appeared improved, with predominantly grade 1 reversible PN and no case of grade 4 neutropenia or neutropenic fever. This regimen warrants further study in HL and may serve as a backbone for the addition of novel agents. This trial is registered on clinicaltrials.gov (NCT02505269).
Subject(s)
Hodgkin Disease , Neutropenia , Humans , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Bleomycin/adverse effects , Brentuximab Vedotin/adverse effects , Dacarbazine/adverse effects , Doxorubicin/adverse effects , Hodgkin Disease/pathology , Neutropenia/chemically induced , Vinblastine/adverse effectsABSTRACT
Improved biomarkers are required to guide the optimal use of autologous stem cell transplantation (ASCT) in patients with relapsed/refractory (R/R) diffuse large B-cell lymphoma (DLBCL). We hypothesized that minimal residual disease (MRD) identified using immunoglobulin high-throughput sequencing in apheresis stem cell (ASC) samples, post-ASCT peripheral blood mononuclear cell (PBMC), and plasma samples could predict relapse. We studied 159 patients with R/R DLBCL who underwent ASCT, of whom 98 had an ASC sample and 60 had post-ASCT surveillance samples. After a median post-ASCT follow-up of 60 months, the 5-year progression-free survival (PFS) was 48%. MRD was detected in of 23/98 (23%) ASC samples and was associated with very poor PFS (5-year PFS 13% vs 53%, P < .001) and inferior overall survival (52% vs 68%, P = .05). The sensitivity and specificity of ASC MRD positivity for progression and death were 36% and 93%, respectively. Positive ASC MRD remained a significant predictor of PFS in multivariable analysis (hazard ratio [HR], 3.7; P < .001). Post-ASCT surveillance MRD testing of plasma, but not PBMC samples, reliably identified patients with an impending relapse. A positive plasma MRD result was associated with inferior PFS (HR, 3.0; P = .016) in a multivariable analysis. The median lead time from MRD detection to relapse was 62 days (range, 0-518 days). In conclusion, the detection of MRD in ASC samples is associated with a very high risk of relapse, justifying alternative treatment strategies or trials of novel consolidation options in these patients. Furthermore, post-ASCT MRD monitoring may facilitate the evaluation of the early initiation of treatment at molecular relapse. This trial has been registered at www.clinicaltrials.gov as #NCT02362997.
Subject(s)
Hematopoietic Stem Cell Transplantation , Lymphoma, Large B-Cell, Diffuse , Humans , Neoplasm, Residual/diagnosis , Leukocytes, Mononuclear , Neoplasm Recurrence, Local , Transplantation, Autologous , Stem Cell Transplantation , Lymphoma, Large B-Cell, Diffuse/diagnosis , Lymphoma, Large B-Cell, Diffuse/therapyABSTRACT
Although solutions of hydrogen chloride in ethereal solvents like diethyl ether or dioxane are commonly employed in the laboratory, the solution structure of these reagents has yet to be firmly established. Here, we analyze solutions of ethereal hydrogen chloride or deuterium chloride in toluene, in dichloromethane, or in the absence of a co-solvent by in situ infrared spectroscopy. The resulting spectra are inconsistent with free HCl or often-proposed 1:1 HCl-ether complexes but closely match the predicted spectra of oxonium ions generated via protonation of diethyl ether. Molecular dynamics simulation of the oxonium chloride complexes provides evidence for an outer-sphere contact ion pair. These results suggest new approaches for tuning the acidity of strong Brønsted acids in organic solvents and demonstrate the importance of conducting spectroscopic measurements under reaction-relevant conditions.
ABSTRACT
DISEASE OVERVIEW: Follicular lymphoma (FL) is generally an indolent B cell lymphoproliferative disorder of transformed follicular center B cells. FL is characterized by diffuse lymphadenopathy, bone marrow involvement, and splenomegaly. Extranodal involvement is less common. Cytopenias are relatively common but constitutional symptoms of fever, night sweats, and weight loss are uncommon in the absence of transformation to diffuse large B cell lymphoma. DIAGNOSIS: The diagnosis is based on histology from a biopsy of a lymph node or other affected tissue. Incisional biopsy is preferred over needle biopsies in order to give adequate tissue to assign grade and assess for transformation. Immunohistochemical staining is positive in virtually all cases for cell surface CD19, CD20, CD10, and monoclonal immunoglobulin, as well as cytoplasmic expression of bcl-2 protein. The overwhelming majority of cases have the characteristic t(14;18) translocation involving the IgH/bcl-2 genes. RISK STRATIFICATION: The Follicular Lymphoma International Prognostic Index (FLIPI) uses five independent predictors of inferior survival: age >60 years, hemoglobin <12 g/dL, serum LDH > normal, Ann Arbor stage III/IV, number of involved nodal areas >4. The presence of 0-1, 2, and ≥3 adverse factors defines low, intermediate, and high-risk disease. There are other clinical prognostic models but the FLIPI remains the most common. Other factors such as time to relapse of less than 2 years from chemoimmunotherapy and specific gene mutations may also be useful for prognosis. Regardless of the prognostic model used, modern therapies have demonstrably improved prognosis. RISK-ADAPTED THERAPY: Observation continues to be appropriate for asymptomatic patients with low bulk disease and no cytopenias. There is no overall survival (OS) advantage for early treatment with either chemotherapy or single-agent rituximab. For patients needing therapy, most patients are treated with chemoimmunotherapy, which has improved overall response rates (ORR), DOR, and OS. Randomized studies have shown additional benefits for maintenance of rituximab. Lenalidomide was non-inferior to chemoimmunotherapy in a randomized front-line study and, when combined with rituximab, was superior to rituximab alone in relapsed FL. Kinase inhibitors, stem cell transplantation (SCT), and chimeric antigen receptor T cells (CAR-T) are also considered for recurrent disease.