Costimulatory domains direct distinct fates of CAR-driven T-cell dysfunction.

T cells engineered to express chimeric antigen receptors (CARs) targeting CD19 have demonstrated impressive activity against relapsed or refractory B-cell cancers yet fail to induce durable remissions for nearly half of all patients treated. Enhancing the efficacy of this therapy requires detailed understanding of the molecular circuitry that restrains CAR-driven antitumor T-cell function. We developed and validated an in vitro model that drives T-cell dysfunction through chronic CAR activation and interrogated how CAR costimulatory domains, central components of CAR structure and function, contribute to T-cell failure. We found that chronic activation of CD28-based CARs results in activation of classical T-cell exhaustion programs and development of dysfunctional cells that bear the hallmarks of exhaustion. In contrast, 41BB-based CARs activate a divergent molecular program and direct differentiation of T cells into a novel cell state. Interrogation using CAR T cells from a patient with progressive lymphoma confirmed the activation of this novel program in a failing clinical product. Furthermore, we demonstrate that 41BB-dependent activation of the transcription factor FOXO3 is directly responsible for impairing CAR T-cell function. These findings identify that costimulatory domains are critical regulators of CAR-driven T-cell failure and that targeted interventions are required to overcome costimulation-dependent dysfunctional programs.

The role of allogeneic transplant for adult Ph+ ALL in CR1 with complete molecular remission: a retrospective analysis.

Historically, Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has been associated with poor outcomes, and allogeneic hematopoietic cell transplantation (allo-HCT) is recommended in first complete remission (CR1). However, in the tyrosine kinase inhibitor (TKI) era, rapid attainment of a complete molecular remission (CMR) is associated with excellent outcomes without allo-HCT, suggesting transplant may not be required for these patients. To test this hypothesis, we retrospectively identified adult patients with Ph+ ALL treated with induction therapy, including TKIs, and attained CMR within 90 days of diagnosis at 5 transplant centers in the United States. We compared outcomes of those who did and did not receive allo-HCT in first remission. We identified 230 patients (allo-HCT: 98; non-HCT: 132). The allo-HCT cohort was younger with better performance status. On multivariable analysis (MVA), allo-HCT was not associated with improved overall survival (adjusted hazard ratio [aHR]: 1.05; 95% CI, 0.63-1.73) or relapse-free survival (aHR: 0.86; 95% CI, 0.54-1.37) compared with non-HCT treatment. Allo-HCT was associated with a lower cumulative incidence of relapse (aHR: 0.32; 95% CI, 0.17-0.62) but higher non-relapse mortality (aHR: 2.59; 95% CI, 1.37-4.89). Propensity score matching analysis confirmed results of MVA. Comparison of reduced-intensity HCT to non-HCT showed no statistically significant difference in any of the above endpoints. In conclusion, adult patients with Ph+ ALL who achieved CMR within 90 days of starting treatment did not derive a survival benefit from allo-HCT in CR1 in this retrospective study.

A Single Reference Interval for Interpreting Serum Free Light Chains across Patients with Varying Renal Function.

BACKGROUND: Serum free light chain (sFLC) assays are interpreted using a sFLC-ratio-based reference interval (manufacturer's interval) that was defined using a cohort of healthy patients. However, renal impairment elevates the sFLC-ratio, leading to a high false positive rate when using the manufacturer's interval. Prior studies have developed renal-specific reference intervals; however, this approach has not been widely adopted due to practical limitations. Thus, there remains a critical need for a renally robust sFLC interpretation method. METHODS: Retrospective data mining was used to define patient cohorts that reflect the spectrum of renal function seen in clinical practice. Two new reference intervals, one based on the sFLC-ratio and one based on a novel principal component analysis (PCA)-based metric, were developed for the FREELITE assay (Binding Site) on the Roche Cobas c501 instrument (Roche). RESULTS: Compared to the manufacturer's reference interval, both new methods exhibited significantly lower false positive rates and greater robustness to renal function while maintaining equivalent sensitivity for monoclonal gammopathy (MG) diagnosis. While not significantly different, the point estimate for sensitivity was highest for the PCA-based approach. CONCLUSION: Renally robust sFLC interpretation using a single reference interval is possible given a reference cohort that reflects the variation in renal function observed in practice. Further studies are needed to achieve sufficient power and determine if the novel PCA-based metric offers superior sensitivity for MG diagnosis. These new methods offer the practical advantages of not requiring an estimated glomerular filtration rate result or multiple reference intervals, thereby lowering practical barriers to implementation.

The Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) Score for HLA Class I Graft-versus-Host Disparity Is Associated with Increased Acute Graft-versus-Host Disease in Haploidentical Transplantation with Post-Transplantation Cyclophosphamide.

The Predicted Indirectly Recognizable HLA Epitopes (PIRCHE) score quantifies the number of PIRCHEs in patient-donor pairs and represents an in silico measure of indirect alloreactivity. This biologic process is defined as T cell recognition of epitopes derived from mismatched, allogeneic HLA peptides that are subsequently presented by shared HLA molecules. Its association with clinical outcome has not been examined in haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplantation cyclophosphamide (PTCy). We hypothesized that the PIRCHE score (PS) would correlate with indirect alloreactivity and predict graft-versus-host disease (GVHD) risk and the incidence of relapse after haplo-HCT with PTCy. We retrospectively analyzed 148 patients who underwent peripheral blood stem cell T cell-replete haplo-HCT with PTCy at a single center between 2009 and 2016. For each patient-donor pair, the PS was calculated using the PIRCHE online matching tool. PSs were categorized by class and vector. The median class I graft-versus-host (GVH) PS was 11 (range, 0 to 56), and the median class I host-versus-graft (HVG) PS was 10 (range, 0 to 51). Class I GVH PS was associated with increased risk of grade II-IV acute GVHD (adjusted hazard ratio, 1.03 per PS unit increase; 95% confidence interval, 1.01 to 1.05; P= .008) but not of chronic GVHD or relapse. Our data show that use of the PS is a novel strategy for predicting clinical outcome in haplo-HCT; further studies using registry data and prospective cohorts are warranted to validate these findings.

The effect of donor type on outcomes in adults with acute myeloid leukemia after reduced-intensity hematopoietic peripheral blood cell transplant - a retrospective study.

We retrospectively analyzed outcomes in patients with acute myeloid leukemia (AML) receiving reduced-intensity conditioning (RIC) hematopoietic stem cell transplants (HCT) from a peripheral blood (PB) source. We identified 46 haploidentical HCT (haplo), 59 matched unrelated donor HCT (MUD), and 40 matched related donor HCT (SIB) patients at a single institution. Haplo had improved overall survival (OS) when compared to MUD, HR 2.03 (P = 0.01) but not SIB, HR 1.17 (P = 0.61). There were no differences in relapse rates or treatment-related mortality (TRM). Haplo had higher rates of acute graft-versus-host disease (GVHD) grade II-IV at day 180 than MUD (44% vs. 25%, P = 0.03) and SIB (44% vs. 13% P < 0.01). Rates of acute GVHD III-IV and chronic GVHD were similar among the groups. Haplo had slower engraftment rates compared to MUD with neutrophil engraftment at 87% vs. 93%, (P < 0.01) and platelet engraftment at 59% vs. 86%, (P < 0.01) at 28 days. Although patients receiving haplo had higher acute GVHD II-IV and slower engraftment, they did not have increased TRM. These data may suggest that patients receiving haplo have improved OS compared to MUD for AML patients receiving RIC transplants. This should be confirmed using a larger cohort.

Cutaneous graft-versus-host disease incidence is similar in haploidentical and matched unrelated hematopoietic transplant recipients: A retrospective cohort study.

BACKGROUND: Cutaneous graft-versus-host disease (GVHD) is common after hematopoietic cell transplants. Haploidentical transplants (Haplo) have historically higher rates of GVHD with overall outcomes improved with the use of posttransplant cyclophosphamide. Specific cutaneous outcomes have not been explored in haploidentical versus matched unrelated donor (MUD) transplants. OBJECTIVE: We sought to examine the incidence of GVHD in MUD and Haplo transplants. METHODS: This is a retrospective cohort study of patients' records that received MUD or Haplo transplants between 2010 and 2015 with determination of GVHD severity and features by one investigator. RESULTS: The Haplo cohort included more minorities (22.7% vs 6.8%; P < .001). The incidence of acute cutaneous GVHD was similar (Haplo 47.7% [95% confidence interval {CI} 37.0-58.6%] vs MUD 42.6% [95% CI 37.9-47.3%]; P = .41). Chronic GVHD was also similar (Haplo 17.1% [95% CI 9.9-26.6%] vs MUD 12.8% [95% CI 9.9-16.3%]; P = .31). The Haplo group had lower rates of sclerosis (13.3% [95% CI 1.7-4.05%] vs 50.9% [95% CI 37.3-64.4%]; P = .0095). Other secondary outcomes showed no difference. LIMITATIONS: Severity of GVHD was determined retrospectively and not all patients were seen by a dermatologist. CONCLUSIONS: No difference was observed between rates or severity of acute or chronic GVHD. Sclerosis was less common in the Haplo group.

Propensity Score Analysis of Conditioning Intensity in Peripheral Blood Haploidentical Hematopoietic Cell Transplantation.

T cell replete HLA-haploidentical hematopoietic cell transplantation (haplo-HCT) with post-transplant cyclophosphamide was originally described using a reduced-intensity conditioning (RIC) regimen. Given that myeloablative conditioning (MAC) is more effective at preventing disease relapse, we compared outcomes of patients receiving MAC and RIC regimens. We evaluated overall survival (OS), disease-free survival (DFS), relapse, nonrelapse mortality (NRM), and graft-versus-host disease (GVHD) of 148 patients that underwent haplo-HCT with either MAC (n = 61) or RIC (n = 87). Propensity score adjustment (PSA) was used to balance baseline characteristics between groups and more effectively compare outcomes based on conditioning intensity. After the PSA analysis, relapse was significantly decreased with MAC (hazard ratio [HR], .47; 95% confidence interval [CI], .31 to .70), but was associated with higher NRM (HR, 1.74; 95% CI, 1.13 to 2.67). OS and DFS were not significantly different between groups (HRs for MAC versus RIC were .87 [95% CI, .64 to 1.18] and .90 [95% CI, .68 to 1.18] for OS and DFS, respectively). Rates of acute and chronic GVHD were not significantly different between groups. This analysis suggests that both MAC and RIC regimens are effective in haplo-HCT and that MAC regimens may result in less relapse in selected patients. These results need to be verified in a larger registry study.

Haploidentical Hematopoietic Cell Transplant with Post-Transplant Cyclophosphamide and Peripheral Blood Stem Cell Grafts in Older Adults with Acute Myeloid Leukemia or Myelodysplastic Syndrome.

Many hematologic malignancies are diseases of aging, and the use of hematopoietic cell transplant (HCT) is growing rapidly among older adults. Modern post-transplant cyclophosphamide (PTCy) protocols with haploidentical (haplo) donors have dramatically expanded the donor pool for patients requiring HCT. Initial studies were performed with bone marrow grafts, which require the donor to undergo anesthesia during harvest. However, the use of mobilized peripheral blood stem cells (PBSCs) may be desirable, especially with older donors. However, data on PBSC haplo-HCT in older adults are lacking. To characterize the impact of age on outcomes in haplo-HCT, we identified all adult patients undergoing haplo-HCT with PTCy for acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) at our institution from January 2009 to June 2016. Patients were grouped into 3 cohorts: Age 1 (≤55), Age 2 (55 to 65), and Age 3 (≥65). To characterize the impact of donor type on outcomes in older patients, we identified age- and disease risk index (DRI)-matched patient age ≥ 65 undergoing HLA-matched unrelated donor (MUD) HCT for AML or MDS during the same time frame. Patients were scored for disease risk and underlying comorbidities using the DRI and HCT-specific comorbidity index. Overall survival (OS) was analyzed using 3 different Cox proportional hazards models. We identified 112 haplo-HCT patients, 95 with AML and 17 with MDS. There were 61 patients in Age 1, 29 patients in Age 2, and 22 in Age 3. Median OS was 448, 397, and 147 days in Age 1, Age 2, and Age 3 patients (log-rank, P = .04). After adjusting for other risk factors, age ≥ 65 was associated with significantly worse OS after haplo-HCT (aHR, 2.16; 95% CI, 1.15 to 4.07). There was a trend toward increased relapse among older patients at 2 years (56%; 95% CI, 32% to 79%) versus Age 1 (41%; 95% CI, 28% to 54%) and Age 2 (31%; 95% CI, 12% to 50%) (P = .08). Among patients age ≥ 65, donor type (MUD versus haplo) did not impact OS (aHR, 1.03; 95% CI, .56 to 1.88) after adjusting for other risk factors. Prior allo-HCT (aHR, 4.95; 95% CI, 1.82 to 13.49) and myeloablative conditioning (aHR, 1.97; 95% CI, 1.04 to 3.73) were associated with inferior survival. Although age ≥ 65 was associated with inferior OS in our haplo-HCT cohort, no difference was seen in survival between MUD and haplo-HCT. Therefore, the use of haploidentical donors in older patients is a reasonable treatment option, especially if there is concern for clinical deterioration. A careful pretransplant evaluation and analysis of risks and benefits is warranted when offering this transplant modality to older adults, especially in patients with previous transplant or poor performance status. Strategies to reduce the risk of relapse and decrease nonrelapse mortality in older adults are areas of ongoing research, and prospective studies are needed.

T Cell-Replete Peripheral Blood Haploidentical Hematopoietic Cell Transplantation with Post-Transplantation Cyclophosphamide Results in Outcomes Similar to Transplantation from Traditionally Matched Donors in Active Disease Acute Myeloid Leukemia.

Outcomes for patients with acute myeloid leukemia (AML) who fail to achieve complete remission remain poor. Hematopoietic cell transplantation (HCT) has been shown to induce long-term survival in AML patients with active disease. HCT is largely performed with HLA-matched unrelated or HLA-matched related donors. Recently, HCT with HLA-haploidentical related donors has been identified as a feasible option when HLA-matched donors are not immediately available. However, there are little data comparing outcomes for AML patients with active disease who receive haploidentical versus traditionally matched HCT. We retrospectively analyzed data from 99 AML patients with active disease undergoing allogeneic HCT at a single institution. Forty-three patients received unrelated donor HCT, 32 patients received matched related donor HCT, and 24 patients received peripheral blood haploidentical HCT with post-transplantation cyclophosphamide. We found no significant differences between treatment groups in terms of overall survival (OS), event-free survival, transplantation-related mortality, cumulative incidence of relapse, and cumulative incidence of acute and chronic graft-versus-host disease (GVHD). We performed univariate regression analysis of variables that modified OS in all patients and found only younger age at transplantation and development of chronic GVHD significantly improved outcome. Although limited by our relatively small sample size, these results indicate that haploidentical HCT in active AML patients have comparable outcomes to HCT with traditionally matched donors. Haploidentical HCT can be considered in this population of high-risk patients when matched donors are unavailable or when wait times for transplantation are unacceptably long.

Haploidentical Transplantation with Post-Transplantation Cyclophosphamide for High-Risk Acute Lymphoblastic Leukemia.

Haploidentical transplantation performed with post-transplantation cyclophosphamide (PTCy)-based graft-versus-host disease (GVHD) prophylaxis has been associated with favorable outcomes for patients with acute myeloid leukemia and lymphomas. However, it remains unclear if such approach is effective for patients with acute lymphoblastic leukemia (ALL). We analyzed outcomes of 109 consecutively treated ALL patients 18 years of age and older at 5 institutions. The median age was 32 years and the median follow-up for survivors was 13 months. Thirty-two patients were in first complete remission (CR1), while the rest were beyond CR1. Neutrophil engraftment occurred in 95% of the patients. The cumulative incidences of grades II to IV and III and IV acute GVHD at day 100 after transplantation were 32% and 11%, respectively, whereas chronic GVHD, nonrelapse mortality, relapse rate, and disease-free survival (DFS) at 1 year after transplantation were 32%, 21%, 27%, and 51%, respectively. Patients in CR1 had 52% DFS at 3 years. These results suggest that haploidentical transplants performed with PTCy-based GVHD prophylaxis provide a very suitable alternative to HLA-matched transplantations for patients with ALL.

Cardiomyopathy in patients after posttransplant cyclophosphamide-based hematopoietic cell transplantation.

BACKGROUND: The use of posttransplant cyclophosphamide (PT-Cy) has contributed significantly to the success of haploidentical hematopoietic cell transplantation (HCT). Furthermore, several studies have shown promising results in the human leukocyte antigen-matched setting. However, the use of high-dose cyclophosphamide has been associated with the development of cardiomyopathy. There is a paucity of data concerning posttransplant cardiac complications in patients undergoing PT-Cy-based HCT. METHODS: A retrospective analysis of 176 patients undergoing HCT with PT-Cy was performed. The overall survival, left ventricular ejection fractions, brain natriuretic peptide levels, and cardiac comorbidities were reviewed. The associations between comorbidities and the onset of heart failure were assessed with a Cox proportional hazards model. RESULTS: Pretransplant cardiomyopathy was found in 16 patients (9.1%) but had no effect on their posttransplant overall survival. Thirty-five patients (21.9%) developed posttransplant cardiomyopathy, which correlated with increased mortality, but this was not statistically different from the frequency-matched non-PT-Cy cohort. The majority of these cardiomyopathies occurred in the setting of an infectious milieu. An age greater than 60 years and an HCT comorbidity index score equal to or greater than 4 were the only risk factors that correlated with posttransplant cardiomyopathy. CONCLUSIONS: The presence of pretransplant cardiomyopathy does not negatively affect overall survival for patients who undergo HCT with PT-Cy. Furthermore, cardiomyopathy in PT-Cy patients is not caused by PT-Cy but is mostly concurrent with infectious complications and is associated with reduced overall survival. Traditional cardiovascular risk factors do not fully predict the occurrence of posttransplant cardiomyopathy. Future research is required to unravel predictive factors for cardiomyopathy after PT-Cy-based HCT. Cancer 2017;123:1800-1809. © 2017 American Cancer Society.

Epidemiology of infections following haploidentical peripheral blood hematopoietic cell transplantation.

BACKGROUND: The use of T-cell replete haploidentical hematopoietic cell transplant (haplo-HCT) has increased substantially since the introduction of post-transplant cyclophosphamide (PTCy) regimens. Limited data exist concerning infectious complications of haplo-HCT utilizing mobilized peripheral blood (PB) hematopoietic cells. METHODS: This retrospective cohort study included all adult patients at our institution undergoing PB haplo-HCT with PTCy between June 2009 and June 2015. Infections were microbiologically confirmed. Invasive fungal infections (IFI) classified as "proven" or "probable" by standard definitions were included. RESULTS: In total, 104 patients were identified. Median follow-up was 218 days (range: 6-1576). A total of 322 episodes of infection were recorded. Eighty-nine percent of patients experienced at least one infection. Median time to first infection was 22 days. Patients experiencing at least one bacterial, viral, and IFI were 62%, 72%, and 6%, respectively. The majority (69%) of bacterial infections were caused by enteric organisms. Seven cases of Staphylococcus aureus infection were recorded, with one bacteremia case. Cytomegalovirus (CMV) viremia occurred in 54/71 (76%) at-risk patients at a median time of 24 days. Sixteen (15%) patients developed CMV disease. Nineteen percent (20/104) of patients developed BK polyomavirus-associated cystitis. Six (6%) patients experienced a total of seven IFI. Infection was the primary cause of death for 12% (6/51) of patients and was a secondary cause for 41%. CONCLUSION: In PB haplo-HCT patients, a high incidence of CMV viremia and disease was observed. Infections with enteric bacteria were common. Fungal and staphylococcal infections were uncommon. Further studies are needed to compare infectious complications in haplo-HCT with other transplant modalities.

Severe Cytokine-Release Syndrome after T Cell-Replete Peripheral Blood Haploidentical Donor Transplantation Is Associated with Poor Survival and Anti-IL-6 Therapy Is Safe and Well Tolerated.

Use of high-dose post-transplantation cyclophosphamide for graft-versus-host disease prophylaxis has expanded the use of unmanipulated haploidentical hematopoietic cell transplantation. The immediate post-transplantation course in T cell-replete peripheral blood haploidentical hematopoietic cell transplantation (haplo-HCT) is often complicated by symptoms resembling cytokine-release syndrome (CRS), previously described in recipients of targeted cellular therapeutics. However, we know little about the incidence and impact of CRS on outcomes in these patients. To understand this syndrome in haplo-HCT patients, we reviewed data from 75 consecutive patients who received granulocyte colony-stimulating factor-mobilized T cell-replete peripheral blood haplo-HCT at a single center. Using CRS criteria described in recipients of chimeric antigen receptor T cell therapies, we found 65 of 75 (87%) met criteria for CRS, although most cases were only mild (grades 1 or 2). However, 9 patients (12%) experienced severe (grades 3 or 4) CRS. Median survival was 2.6 months (95% confidence interval [CI], .43 to 5.8) in patients with severe CRS, compared with 13.1 months (95% CI, 8.1 to not reached) in patients with mild CRS. Transplantation-related mortality was worse in the severe CRS cohort with a hazard ratio of 4.59 (95% CI, 1.43 to 14.67) compared with that in the mild CRS cohort. Severe CRS patients had a significant delay in median time for neutrophil engraftment. Serum IL-6 levels were measured in 10 haplo-HCT patients and were elevated in the early post-transplantation setting. Seven patients with CRS were treated with tocilizumab, resulting in a complete resolution of their CRS symptoms. Severe CRS represents a potential complication of peripheral blood haplo-HCT and is associated with worse outcomes. Anti-IL-6 receptor therapy is associated with rapid resolution of the CRS symptoms.

Remobilization of hematopoietic stem cells in healthy donors for allogeneic transplantation.

BACKGROUND: The need to repeat peripheral blood (PB) stem cell mobilization and collection in healthy donors arises infrequently but may be required due to insufficient initial collection, graft failure, or relapse of the recipient's disease. Little data exist on the efficacy of remobilization. Therefore, we retrospectively reviewed 18 years of remobilization records from healthy stem cell donors at our institution. STUDY DESIGN AND METHODS: We identified 62 healthy donors who underwent remobilization, a cohort of 30 mobilized and remobilized with cytokines and a cohort of 32 mobilized with a CXCR4 antagonist and remobilized with cytokines. For each cohort we compared the PB CD34+/L level, the number of CD34+ cells collected/kg (recipient weight), and the number of CD34+ cells/L collected on the first day of leukapheresis during initial mobilization and remobilization. RESULTS: Initial mobilization with cytokines was associated with reduced remobilization. The mean PB CD34/L level at initial mobilization was 69 × 10(6) compared to 37 × 10(6) at remobilization (p = 0.029). In contrast, initial mobilization with a CXCR4 antagonist was not associated with reduced remobilization. The mean PB CD34/L level at initial mobilization was 15 × 10(6) compared to 68 × 10(6) at remobilization (p < 0.001). In both cohorts, initial mobilization results were positively correlated with remobilization results but the interval between was not. CONCLUSIONS: This study suggests that poor remobilization yields may be due to decreased efficacy of cytokines after repeat exposure. The underlying mechanism of these findings remains unclear and further studies are needed.

A Research Module for the Organic Chemistry Laboratory: Multistep Synthesis of a Fluorous Dye Molecule.

A multi-session research-like module has been developed for use in the undergraduate organic teaching laboratory curriculum. Students are tasked with planning and executing the synthesis of a novel fluorous dye molecule and using it to explore a fluorous affinity chromatography separation technique, which is the first implementation of this technique in a teaching laboratory. Key elements of the project include gradually introducing students to the use of the chemical literature to facilitate their searching, as well as deliberate constraints designed to force them to think critically about reaction design and optimization in organic chemistry. The project also introduces students to some advanced laboratory practices such as Schlenk techniques, degassing of reaction mixtures, affinity chromatography, and microwave-assisted chemistry. This provides students a teaching laboratory experience that closely mirrors authentic synthetic organic chemistry practice in laboratories throughout the world.

Pretransplant Desensitization of Donor-Specific Anti-HLA Antibodies with Plasmapheresis and Immunoglobulin Produces Equivalent Outcomes to Patients with No Donor Specific Antibodies in Haploidentical Hematopoietic Cell Transplant.

In patients requiring haploidentical hematopoietic cell transplant (haplo-HCT), the presence of donor specific anti-HLA antibodies (DSAs) is associated with high rates of primary graft failure and poor overall survival (OS). There is limited data regarding the effect of desensitization. Adult patients undergoing haplo-HCT at Washington University School of Medicine from 2009-2021 were identified. Patients were divided into three cohorts: no DSA, untreated DSA or treated DSA. DSA testing was performed. Desensitization therapy using plasmapheresis and IVIg (immunoglobulin) was performed. We retrospectively identified 304 patients for study inclusion. 14 of 30 patients with DSAs underwent desensitization. By day +2, 57% of patients cleared all DSAs. OS was expectedly worse in patients with untreated DSAs. There were similar results between treated DSA and patients without DSA (OS median: control: 352 days vs. treated: 1331 days vs. untreated: 137 days, p = 0.02). RFS was also significantly different between the groups however with similar RFS in treated DSA and control groups (RFS median: control: 248 vs. treated: 322 v. untreated: 119, p = 0.03). Desensitization before haplo-HCT produces similar outcomes to patients without DSAs. While the optimal desensitization protocol has not been established, all patients received a backbone of plasmapheresis and immunoglobulin.

A single-cell atlas characterizes dysregulation of the bone marrow immune microenvironment associated with outcomes in multiple myeloma.

Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies. We generated a transcriptome profile of 1,149,344 single cells from the bone marrow of 263 newly diagnosed patients enrolled in the CoMMpass study and characterized immune and hematopoietic cell populations. Associating cell abundances and gene expression with disease progression revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing patients. Furthermore, signaling analyses suggested active intercellular communication involving APRIL-BCMA, potentially promoting tumor growth and survival. Finally, we demonstrate that integrating immune cell levels with genetic information can significantly improve patient stratification.

Catalytic, enantioselective 1,3-dipolar cycloadditions of nitrile imines with methyleneindolinones.

Catalytic, enantioselective 1,3-dipolar cycloadditions of nitrile imines with methyleneindolinones are reported. The spiro[pyrazolin-3,3'-oxindole] products are formed in good yields (up to 98%) and high enantioselectivity (up to 99% ee).

Alternaric acid: formal synthesis and related studies.

A silyl glyoxylate three-component-coupling methodology has been exploited to achieve a formal synthesis, an analogue to an intermediate in a distinct formal synthetic route, and a third (unique) approach to the natural product alternaric acid. Highlighted in this study is the versatility of silyl glyoxylates to engage a variety of nucleophile and electrophile pairs to provide wide latitude in the approach to complex molecule synthesis.