Development and validation of an automated computational approach to grade immune effector cell-associated hematotoxicity.

Hematologic toxicity frequently complicates chimeric antigen receptor (CAR) T-cell therapy, resulting in significant morbidity and mortality. In an effort to standardize reporting, the European Hematology Association (EHA) and European Society of Blood and Marrow Transplantation (EBMT) devised the immune effector cell-associated hematotoxicity (ICAHT) grading system, distinguishing between early (day 0-30) and late (after day +30) events based on neutropenia depth and duration. However, manual implementation of ICAHT grading criteria is time-consuming and susceptible to subjectivity and error. To address these challenges, we introduce a novel computational approach, utilizing the R programming language, to automate early and late ICAHT grading. Given the complexities of early ICAHT grading, we benchmarked our approach both manually and computationally in two independent cohorts totaling 1251 patients. Our computational approach offers significant implications by streamlining grading processes, reducing manual time and effort, and promoting standardization across varied clinical settings. We provide this tool to the scientific community alongside a comprehensive implementation guide, fostering its widespread adoption and enhancing reporting consistency for ICAHT.

Human Herpesvirus-6 Reactivation and Disease Are Infrequent in Chimeric Antigen Receptor T-cell Therapy Recipients.

Human herpesvirus-6B (HHV-6B) reactivation and disease are increasingly reported after CAR-T-cell therapy (CARTx). HHV-6 reactivation in the CAR-T-cell product was recently reported, raising questions about product and patient management. Due to overlapping manifestations with immune effector cell-associated neurotoxicity syndrome, diagnosing HHV-6B encephalitis is challenging. We provide two lines of evidence assessing the incidence and outcomes of HHV-6B after CARTx. First, in a prospective study with weekly HHV-6B testing for up to 12 weeks post-infusion, HHV-6B reactivation occurred in eight of 89 participants; three had chromosomally integrated HHV-6 and were excluded, resulting in a cumulative incidence of HHV-6B reactivation of 6% (95% confidence interval (CI), 2.2-12.5%). HHV-6B detection was low level (median peak, 435 copies/mL; IQR, 164-979) and did not require therapy. Second, we retrospectively analyzed HHV-6B detection in blood and/or cerebrospinal fluid (CSF) within 12 weeks post-infusion in CARTx recipients. Of 626 patients, 24 had symptom-driven plasma testing with detection in one. Among 34 patients with CSF HHV-6 testing, one patient had possible HHV-6 encephalitis for a cumulative incidence of 0.17% (95% CI, 0.02-0.94%), although symptoms improved without treatment. Our data demonstrate that HHV-6B reactivation and disease are infrequent after CARTx. Routine HHV-6 monitoring is not warranted.

Chimeric antigen receptor and bispecific T-cell engager therapies in multiple myeloma patients with prior allogeneic transplantation.

Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR-T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo-HCT). Thirty-three MM patients with prior allo-HCT received CAR-T (n = 24) or BsAb (n = 9) therapy. CAR-T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR-T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR-T and 78% of BsAb recipients, while immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in three CAR-T patients. Infections of grade ≥3 were reported in 50% of CAR-T and 44% of BsAb recipients. No exacerbation of graft-versus-host disease occurred except in one BsAb recipient. CAR-T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo-HCT.

Factors associated with long-term outcomes of CD19 CAR T-cell therapy for relapsed/refractory CLL.

High response rates have been reported after CD19-targeted chimeric antigen receptor-modified (CD19 CAR) T-cell therapy for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL), yet the factors associated with duration of response in this setting are poorly characterized. We analyzed long-term outcomes in 47 patients with R/R CLL and/or Richter transformation treated on our phase 1/2 clinical trial of CD19 CAR T-cell therapy with an updated median follow-up of 79.6 months. Median progression-free survival (PFS) was 8.9 months, and the 6-year PFS was 17.8%. Maximum standardized uptake value (hazard ratio [HR], 1.15; 95% confidence interval [CI], 1.07-1.23; P < .001) and bulky disease (≥5 cm; HR, 2.12; 95% CI, 1.06-4.26; P = .034) before lymphodepletion were associated with shorter PFS. Day +28 complete response by positron emission tomography-computed tomography (HR, 0.13; 95% CI, 0.04-0.40; P < .001), day +28 measurable residual disease (MRD) negativity by multiparameter flow cytometry (HR, 0.08; 95% CI, 0.03-0.22; P < .001), day +28 MRD negativity by next-generation sequencing (HR, 0.21; 95% CI, 0.08-0.51; P < .001), higher peak CD8+ CAR T-cell expansion (HR, 0.49; 95% CI; 0.36-0.68; P < .001), higher peak CD4+ CAR T-cell expansion (HR, 0.47; 95% CI; 0.33-0.69; P < .001), and longer CAR T-cell persistence (HR, 0.56; 95% CI, 0.44-0.72; P < .001) were associated with longer PFS. The 6-year duration of response and overall survival were 26.4% and 31.2%, respectively. CD19 CAR T-cell therapy achieved durable responses with curative potential in a subset of patients with R/R CLL. This trial was registered at www.clinicaltrials.gov as #NCT01865617.

Revisiting the Utility of Granulocyte Colony-Stimulating Factor Post-Autologous Hematopoietic Stem Cell Transplantation for Outpatient-Based Transplantations.

The use of granulocyte colony-stimulating factor (G-CSF) after autologous stem cell transplantation (ASCT) has been shown to reduce the time to neutrophil engraftment, as well as the duration of hospitalization post-transplantation. However, prior studies have focused on inpatient-based ASCT, where patients are routinely admitted for conditioning and frequently remain hospitalized until signs of neutrophil recovery. Given improvements in post-transplantation care, an increasing number of patients, particularly those receiving ASCT for multiple myeloma, are now undergoing transplantation in an outpatient setting. We hypothesized that the routine use of G-CSF for outpatient-based ASCT might not result in the same benefit with respect to a reduced duration of hospitalization and thus should be reconsidered in this setting. We performed a retrospective cohort study of 633 consecutive patients with multiple myeloma (MM; n = 484) or non-Hodgkin lymphoma (NHL; n = 149) who underwent ASCT between September 2018 and February 2023. Outpatient ASCT comprised 258 (53%) of combined MM and NHL cases. Starting in September 2021, post-transplantation G-CSF was incorporated into the supportive care regimen for all ASCTs. A total of 410 patients (309 with MM, 101 with NHL) underwent ASCT during the pre-G-CSF policy period and 223 (175 with MM, 48 with NHL) did so in the post-G-CSF policy period. The primary outcome focused on the duration of hospitalization within the first 30 days following graft infusion. As expected, after implementation of the G-CSF policy, the time to neutrophil engraftment was reduced in the patients with MM (mean, -2.8 days; P < .0001) and patients with NHL (mean, -2.9 days; P < .0001). However, among the patients with MM, roughly one-half of whom underwent outpatient-based ASCT, the inpatient duration during the first 30 days was not reduced after G-CSF implementation (P = .40). Comparatively, the inpatient duration (mean, -1.8 days; P = .030) was reduced among patients with NHL, all of whom were electively admitted for ASCT. For patients with MM at an outpatient-based transplant center, incorporation of G-CSF post-ASCT resulted in reduced time to neutrophil engraftment but did not significantly reduce the time spent in the inpatient setting through day +30.

CD19 CAR-T therapy in solid organ transplant recipients: case report and systematic review.

Post-transplant lymphoproliferative disorder (PTLD) is a leading cause of cancer death in solid organ transplant recipients (SOTRs). Relapsed or refractory (R/R) PTLD portends a high risk of death and effective management is not well established. CD19-targeted CAR-T cell therapy has been utilized, but the risks and benefits are unknown. We report the first case of diffuse large B-cell lymphoma (DLBCL) PTLD treated with lisocabtagene maraleucel and present a systematic literature review of SOTRs with PTLD treated with CD19 CAR-T therapy. Our patient achieved a complete response (CR) with limited toxicity but experienced a CD19+ relapse 8 months after infusion despite CAR-T persistence. Literature review revealed 14 DLBCL and 2 Burkitt lymphoma PTLD cases treated with CD19 CAR-T cells. Kidney (n = 12), liver (n = 2), heart (n = 2), and pancreas after kidney (n = 1) transplant recipients were analyzed. The objective response rate (ORR) was 82.4% (14/17), with 58.5% (10/17) CRs and a 6.5-month median duration of response. Among kidney transplant recipients, the ORR was 91.7% (11/12). Allograft rejection occurred in 23.5% (4/17). No graft failure occurred. Our analysis suggests that CD19 CAR-T therapy offers short-term effectiveness and manageable toxicity in SOTRs with R/R PTLD. Further investigation through larger datasets and prospective study is needed.

Interplay of Immunosuppression and Immunotherapy Among Patients With Cancer and COVID-19.

Importance: Cytokine storm due to COVID-19 can cause high morbidity and mortality and may be more common in patients with cancer treated with immunotherapy (IO) due to immune system activation. Objective: To determine the association of baseline immunosuppression and/or IO-based therapies with COVID-19 severity and cytokine storm in patients with cancer. Design, Setting, and Participants: This registry-based retrospective cohort study included 12 046 patients reported to the COVID-19 and Cancer Consortium (CCC19) registry from March 2020 to May 2022. The CCC19 registry is a centralized international multi-institutional registry of patients with COVID-19 with a current or past diagnosis of cancer. Records analyzed included patients with active or previous cancer who had a laboratory-confirmed infection with SARS-CoV-2 by polymerase chain reaction and/or serologic findings. Exposures: Immunosuppression due to therapy; systemic anticancer therapy (IO or non-IO). Main Outcomes and Measures: The primary outcome was a 5-level ordinal scale of COVID-19 severity: no complications; hospitalized without requiring oxygen; hospitalized and required oxygen; intensive care unit admission and/or mechanical ventilation; death. The secondary outcome was the occurrence of cytokine storm. Results: The median age of the entire cohort was 65 years (interquartile range [IQR], 54-74) years and 6359 patients were female (52.8%) and 6598 (54.8%) were non-Hispanic White. A total of 599 (5.0%) patients received IO, whereas 4327 (35.9%) received non-IO systemic anticancer therapies, and 7120 (59.1%) did not receive any antineoplastic regimen within 3 months prior to COVID-19 diagnosis. Although no difference in COVID-19 severity and cytokine storm was found in the IO group compared with the untreated group in the total cohort (adjusted odds ratio [aOR], 0.80; 95% CI, 0.56-1.13, and aOR, 0.89; 95% CI, 0.41-1.93, respectively), patients with baseline immunosuppression treated with IO (vs untreated) had worse COVID-19 severity and cytokine storm (aOR, 3.33; 95% CI, 1.38-8.01, and aOR, 4.41; 95% CI, 1.71-11.38, respectively). Patients with immunosuppression receiving non-IO therapies (vs untreated) also had worse COVID-19 severity (aOR, 1.79; 95% CI, 1.36-2.35) and cytokine storm (aOR, 2.32; 95% CI, 1.42-3.79). Conclusions and Relevance: This cohort study found that in patients with cancer and COVID-19, administration of systemic anticancer therapies, especially IO, in the context of baseline immunosuppression was associated with severe clinical outcomes and the development of cytokine storm. Trial Registration: ClinicalTrials.gov Identifier: NCT04354701.

Immune Checkpoint Inhibitor Use in Solid Organ Transplant Recipients: A Systematic Review.

Chronic immunosuppression in solid organ transplant recipients (SOTRs) leads to an increased risk of a wide variety of cancers. Immune checkpoint inhibitor (ICI) therapy is indicated for many of these; however, the risks and benefits of ICI use in the SOTR population have not been well characterized. We performed a systematic literature review identifying 119 reported cases of ICI use among SOTRs. Treatments used included PD-1 inhibition (75.6%), CTLA-4 inhibition (12.6%), PD-L1 inhibition (1.7%), and combination and/or sequential ICI therapy (10.1%). The most common cancers included cutaneous melanoma (35.3%), hepatocellular carcinoma (22.7%), and cutaneous squamous cell carcinoma (18.5%). The overall objective response rate (ORR) was 34.5%, with a median duration of response of 8.0 months. Ongoing response was seen in 21.0%. Cutaneous squamous cell carcinoma had significantly better ORR compared with other cancer types (68.2% vs 26.8%; odds ratio [OR], 5.85; P =.0006). Factors associated with improved ORR included increasing time from transplant to ICI (OR, 1.09; P =.008) and preemptive reduction in intensity of the graft maintenance immunosuppressive regimen (50.0% vs 18.5%; OR, 4.40; P =.0088). Rejection occurred in 41.2%, graft failure in 23.5%, and immune-related adverse events in 18.5%. Factors significantly associated with allograft rejection included allograft PD-L1 positivity (100% vs 0%; P<.0001) and absence of tacrolimus in the immunosuppressive regimen (48.7% vs 25.6%; OR, 0.36; P =.019). The most common cause of death was progressive malignancy (64.0%), followed by graft failure (24.0%). Our analysis provides current benchmark data to help inform management of SOTRs with advanced cancers that are reflected by our patient cohort. Biomarker development, more robust datasets, and prospective study of concomitant immunosuppression management may help refine decision-making in this complex scenario in the future. Close coordination of care between the medical oncologist and transplant specialist is encouraged to help optimize treatment outcomes.

Patients Recently Treated for B-lymphoid Malignancies Show Increased Risk of Severe COVID-19.

Patients with B-lymphoid malignancies have been consistently identified as a population at high risk of severe COVID-19. Whether this is exclusively due to cancer-related deficits in humoral and cellular immunity, or whether risk of severe COVID-19 is increased by anticancer therapy, is uncertain. Using data derived from the COVID-19 and Cancer Consortium (CCC19), we show that patients treated for B-lymphoid malignancies have an increased risk of severe COVID-19 compared with control populations of patients with non-B-lymphoid malignancies. Among patients with B-lymphoid malignancies, those who received anticancer therapy within 12 months of COVID-19 diagnosis experienced increased COVID-19 severity compared with patients with non-recently treated B-lymphoid malignancies, after adjustment for cancer status and several other prognostic factors. Our findings suggest that patients recently treated for a B-lymphoid malignancy are at uniquely high risk for severe COVID-19. SIGNIFICANCE: Our study suggests that recent therapy for a B-lymphoid malignancy is an independent risk factor for COVID-19 severity. These findings provide rationale to develop mitigation strategies targeted at the uniquely high-risk population of patients with recently treated B-lymphoid malignancies. This article is highlighted in the In This Issue feature, p. 171.

Transplant Onconephrology: An Update.

Transplant onconephrology is a growing specialty focused on the health care of kidney transplant recipients with cancer. Given the complexities associated with the care of transplant patients, along with the advent of novel cancer therapies such as immune checkpoint inhibitors and chimeric antigen-receptor T cells, there is a dire need for the subspecialty of transplant onconephrology. The management of cancer in the setting of kidney transplantation is best accomplished by a multidisciplinary team, including transplant nephrologists, oncologists, and patients. This review addresses the current state and future opportunities for transplant onconephrology, including the roles of the multidisciplinary team, and related scientific and clinical knowledge.

Chimeric Antigen Receptor T Cells for Multiple Myeloma: The Journey So Far-And the Road Ahead.

ABSTRACT: Despite improvements in effective therapy, multiple myeloma remains incurable, and virtually all patients will face relapsed disease at some point after diagnosis. The prognosis for relapsed myeloma after developing resistance to anti-CD38 monoclonal antibodies, proteasome inhibitors, immunomodulatory agents, and autologous stem cell transplantation has been poor; however, the development of immune effector cell therapy with chimeric antigen receptor (CAR) T cells may dramatically improve the outlook for patients, although none of these therapies are approved for MM to date. Herein, we review the development and history of CAR T-cell therapy for multiple myeloma, mechanisms of resistance, and strategies to improve outcomes with CAR T therapy.

A Case Report: Point-of-care Ultrasound in the Diagnosis of Post-Myocardial Infarction Ventricular Septal Rupture.

INTRODUCTION: Ventricular septal rupture (VSR) is a rare complication of ST-elevation myocardial infarction (STEMI), typically discovered post-revascularization. CASE REPORT: We present the first case of VSR detected on point-of-care ultrasound (POCUS) in the emergency department immediately prior to emergent angiography, with management positively affected by this discovery. The VSR was quickly confirmed via right heart catheterization. Subsequently, hemodynamic stability was achieved using an intra-aortic balloon pump. A delayed surgical VSR repair, with concomitant coronary artery bypass grafting, was implemented for definitive management. CONCLUSION: This case highlights the utility of POCUS in a STEMI patient with a suspected mechanical complication.

Microbial colonization influences early B-lineage development in the gut lamina propria.

The RAG1/RAG2 endonuclease (RAG) initiates the V(D)J recombination reaction that assembles immunoglobulin heavy (IgH) and light (IgL) chain variable region exons from germline gene segments to generate primary antibody repertoires. IgH V(D)J assembly occurs in progenitor (pro-) B cells followed by that of IgL in precursor (pre-) B cells. Expression of IgH µ and IgL (Igκ or Igλ) chains generates IgM, which is expressed on immature B cells as the B-cell antigen-binding receptor (BCR). Rag expression can continue in immature B cells, allowing continued Igκ V(D)J recombination that replaces the initial VκJκ exon with one that generates a new specificity. This 'receptor editing' process, which can also lead to Igλ V(D)J recombination and expression, provides a mechanism whereby antigen encounter at the Rag-expressing immature B-cell stage helps shape pre-immune BCR repertoires. As the major site of postnatal B-cell development, the bone marrow is the principal location of primary immunoglobulin repertoire diversification in mice. Here we report that early B-cell development also occurs within the mouse intestinal lamina propria (LP), where the associated V(D)J recombination/receptor editing processes modulate primary LP immunoglobulin repertoires. At weanling age in normally housed mice, the LP contains a population of Rag-expressing B-lineage cells that harbour intermediates indicative of ongoing V(D)J recombination and which contain cells with pro-B, pre-B and editing phenotypes. Consistent with LP-specific receptor editing, Rag-expressing LP B-lineage cells have similar VH repertoires, but significantly different Vκ repertoires, compared to those of Rag2-expressing bone marrow counterparts. Moreover, colonization of germ-free mice leads to an increased ratio of Igλ-expressing versus Igκ-expressing B cells specifically in the LP. We conclude that B-cell development occurs in the intestinal mucosa, where it is regulated by extracellular signals from commensal microbes that influence gut immunoglobulin repertoires.

Reprogramming IgH isotype-switched B cells to functional-grade induced pluripotent stem cells.

Induced pluripotent stem cells (iPSCs) can be formed from somatic cells by a defined set of genetic factors; however, aberrant epigenetic silencing of the imprinted Dlk1-Dio3 gene cluster often hinders their developmental potency and ability to contribute to high-grade chimerism in mice. Here, we describe an approach that allows splenic B cells activated to undergo Ig heavy-chain (IgH) class-switch recombination (CSR) to be reprogrammed into iPSCs that contribute to high-grade chimerism in mice. Treatment of naïve splenic B cells in culture with anti-CD40 plus IL-4 induces IgH CSR from IgM to IgG1 and IgE. CSR leads to irreversible IgH locus deletions wherein the IgM-producing Cµ exons are permanently excised from the B-cell genome. We find that anti-CD40 plus IL-4-activated B cells produce iPSCs that are uniformly hypermethylated in the imprinted Dlk1-Dio3 gene cluster and fail to produce chimerism in mice. However, treatment of activated B cells with the methyltransferase inhibitor 5-aza-2'-deoxycytidine before and at early stages of reprogramming attenuates hypermethylation of the Dlk1-Dio3 locus in resultant iPSCs and enables them to form high-grade chimerism in mice. These conditions allowed us to produce chimeric mice in which all mature B cells were derived entirely from IgG1-expressing B-cell-derived iPSCs. We conclude that culture conditions of activated B cells before and at early stages of reprogramming influence the developmental potency of resultant iPSCs.

Immature B cells preferentially switch to IgE with increased direct Sµ to Sε recombination.

Immunoglobulin heavy chain (IgH) class-switch recombination (CSR) replaces initially expressed Cµ (IgM) constant regions (C(H)) exons with downstream C(H) exons. Stimulation of B cells with anti-CD40 plus interleukin-4 induces CSR from Cµ to Cγ1 (IgG1) and Cε (IgE), the latter of which contributes to the pathogenesis of atopic diseases. Although Cε CSR can occur directly from Cµ, most mature peripheral B cells undergo CSR to Cε indirectly, namely from Cµ to Cγ1, and subsequently to Cε. Physiological mechanisms that influence CSR to Cγ1 versus Cε are incompletely understood. In this study, we report a role for B cell developmental maturity in IgE CSR. Based in part on a novel flow cytometric IgE CSR assay, we show that immature B cells preferentially switch to IgE versus IgG1 through a mechanism involving increased direct CSR from Cµ to Cε. Our findings suggest that IgE dysregulation in certain immunodeficiencies may be related to impaired B cell maturation.