Impact of Memory T Cells on SARS-COV-2 Vaccine Response in Hematopoietic Stem Cell Transplant.

During the COVID-19 pandemic, hematopoietic stem cell transplant (HSCT) recipients faced an elevated mortality rate from SARS-CoV-2 infection, ranging between 10-40%. The SARS-CoV-2 mRNA vaccines are important tools in preventing severe disease, yet their efficacy in the post-transplant setting remains unclear, especially in patients subjected to myeloablative chemotherapy and immunosuppression. We evaluated the humoral and adaptive immune responses to the SARS-CoV-2 mRNA vaccination series in 42 HSCT recipients and 5 healthy controls. Peripheral blood mononuclear nuclear cells and serum were prospectively collected before and after each dose of the SARS-CoV-2 vaccine. Post-vaccination responses were assessed by measuring anti-spike IgG and nucleocapsid titers, and antigen specific T cell activity, before and after vaccination. In order to examine mechanisms behind a lack of response, pre-and post-vaccine samples were selected based on humoral and cellular responses for single-cell RNA sequencing with TCR and BCR sequencing. Our observations revealed that while all participants eventually mounted a humoral response, transplant recipients had defects in memory T cell populations that were associated with an absence of T cell response, some of which could be detected pre-vaccination.

Cost-effectiveness of chimeric antigen receptor T-cell therapy in adults with relapsed or refractory follicular lymphoma.

Follicular lymphoma (FL) is traditionally considered treatable but incurable. In March 2021, the US Food and Drug Administration approved the use of chimeric antigen receptor (CAR) T-cell therapy in patients with relapsed or refractory (R/R) FL after ≥2 lines of therapy. Priced at $373 000, CAR T-cell therapy is potentially curative, and its cost-effectiveness compared with other modern R/R FL treatment strategies is unknown. We developed a Markov model to assess the cost-effectiveness of third-line CAR T-cell vs standard of care (SOC) therapies in adults with R/R FL. We estimated progression rates for patients receiving CAR T-cell and SOC therapies from the ZUMA-5 trial and the LEO CReWE study, respectively. We calculated costs, discounted life years, quality-adjusted life years (QALYs), and the incremental cost-effectiveness ratio (ICER) of CAR T-cell vs SOC therapies with a willingness-to-pay threshold of $150 000 per QALY. Our analysis was conducted from a US payer's perspective over a lifetime horizon. In our base-case model, the cost of the CAR T-cell strategy was $731 682 compared with $458 490 for SOC therapies. However, CAR T-cell therapy was associated with incremental clinical benefit of 1.50 QALYs, resulting in an ICER of $182 127 per QALY. Our model was most sensitive to the utilities associated with CAR T-cell therapy remission and third-line SOC therapies and to the total upfront CAR T-cell therapy cost. Under current pricing, CAR T-cell therapy is unlikely to be cost-effective in unselected patients with FL in the third-line setting. Both randomized clinical trials and longer term clinical follow-up can help clarify the benefits of CAR T-cell therapy and optimal sequencing in patients with FL.

Peripheral Blood Involvement at Staging in Patients With Aggressive Peripheral T-Cell Lymphoma.

INTRODUCTION: Peripheral T-Cell Lymphomas (PTCL) are a rare subgroup of lymphomas with a poor outcome.Traditional prognostic measures rely heavily on disease stage, and with the advent of targeted treatment, further stratificationcriteria are needed to guide treatment. To date, the impact of blood involvement at diagnosis on outcomes has not been assessed. MATERIALS AND METHODS: We retrospectively reviewed blood involvement by flow cytometry at diagnosis in 102 consecutivelytreated patients who had flow cytometry data available at diagnosis. Of these, 78 patients with nodal subtypes were identified andstudied in this analysis. RESULTS: Of 78 patients with nodal subtypes of PTCL who had flow data available at the time ofdiagnosis, circulating populations of malignant T cells matching those in the biopsied lymph nodes were found in 21 patients bymultiparameter flow cytometry. A positive flow cytometry was highly correlated with bone marrow involvement. The patientswith a negative flow cytometry had a trend toward a longer median PFS compared to those with a positive flow but there was noimpact on overall survival. CONCLUSIONS: Circulating malignant tumor cells can be found in the peripheral blood in a subset ofpatients with aggressive nodal T-cell lymphomas, including peripheral t-cell lymphoma not otherwise specified andangioimmunoblastic T-cell lymphomas, and blood involvement is correlated with bone marrow involvement.

NCCN Guidelines® Insights: Hodgkin Lymphoma, Version 2.2022.

Hodgkin lymphoma (HL) is an uncommon malignancy of B-cell origin. Classical HL (cHL) and nodular lymphocyte-predominant HL are the 2 main types of HL. The cure rates for HL have increased so markedly with the advent of modern treatment options that overriding treatment considerations often relate to long-term toxicity. These NCCN Guidelines Insights discuss the recent updates to the NCCN Guidelines for HL focusing on (1) radiation therapy dose constraints in the management of patients with HL, and (2) the management of advanced-stage and relapsed or refractory cHL.

Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease.

PURPOSE: Graft-versus-host disease (GVHD) causes morbidity and mortality following allogeneic hematopoietic cell transplantation. Naive T cells (TN) cause severe GVHD in murine models. We evaluated chronic GVHD (cGVHD) and other outcomes in three phase II clinical trials of TN-depletion of peripheral blood stem-cell (PBSC) grafts. METHODS: One hundred thirty-eight patients with acute leukemia received TN-depleted PBSC from HLA-matched related or unrelated donors following conditioning with high- or intermediate-dose total-body irradiation and chemotherapy. GVHD prophylaxis was with tacrolimus, with or without methotrexate or mycophenolate mofetil. Subjects received CD34-selected PBSC and a defined dose of memory T cells depleted of TN. Median follow-up was 4 years. The primary outcome of the analysis of cumulative data from the three trials was cGVHD. RESULTS: cGVHD was very infrequent and mild (3-year cumulative incidence total, 7% [95% CI, 2 to 11]; moderate, 1% [95% CI, 0 to 2]; severe, 0%). Grade III and IV acute GVHD (aGVHD) occurred in 4% (95% CI, 1 to 8) and 0%, respectively. The cumulative incidence of grade II aGVHD, which was mostly stage 1 upper gastrointestinal GVHD, was 71% (95% CI, 64 to 79). Recipients of matched related donor and matched unrelated donor grafts had similar rates of grade III aGVHD (5% [95% CI, 0 to 9] and 4% [95% CI, 0 to 9]) and cGVHD (7% [95% CI, 2 to 13] and 6% [95% CI, 0 to 12]). Overall survival, cGVHD-free, relapse-free survival, relapse, and nonrelapse mortality were, respectively, 77% (95% CI, 71 to 85), 68% (95% CI, 61 to 76), 23% (95% CI, 16 to 30), and 8% (95% CI, 3 to 13) at 3 years. CONCLUSION: Depletion of TN from PBSC allografts results in very low incidences of severe acute and any cGVHD, without apparent excess risks of relapse or nonrelapse mortality, distinguishing this novel graft engineering strategy from other hematopoietic cell transplantation approaches.

Venetoclax-based combinations in AML and high-risk MDS prior to and following allogeneic hematopoietic cell transplant.

The role of allogeneic hematopoietic cell transplant (allo-HCT) as consolidation after initial venetoclax therapy and the efficacy of venetoclax salvage therapy for relapse after allo-HCT in patients with acute myeloid leukemia (AML) are unclear. We conducted a retrospective study of patients with AML or myelodysplastic syndrome (MDS) who received venetoclax either before or after allo-HCT at Memorial Sloan Kettering Cancer Center and Yale University from 11 August 2016 to 16 November 2020. Among 39 heavily pretreated patients who received venetoclax before allo-HCT, median OS from allo-HCT was not reached after a median follow up of 12.5 months resulting in a 12-month OS estimate of 79.0%. In 37 patients who had received venetoclax-based combinations as salvage therapy after allo-HCT, the overall response rate was 32% with a median OS of 4.7 months (12-month OS estimate: 43.4%). Four patients underwent a second allo-HCT following venetoclax-based salvage therapy suggesting it as a potential salvage treatment option.

Tandem high-dose influenza vaccination is associated with more durable serologic immunity in patients with plasma cell dyscrasias.

Patients with plasma cell dyscrasias (PCDs) experience an increased burden of influenza, and current practice of single-dose annual influenza vaccination yields suboptimal protective immunity in these patients. Strategies to improve immunity to influenza in these patients are clearly needed. We performed a randomized, double-blind, placebo-controlled clinical trial comparing tandem Fluzone High-Dose influenza vaccination with standard-of-care influenza vaccination. Standard-of-care vaccination was single-dose age-based vaccination (standard dose, <65 years; high dose, ≥65 years), and patients in this arm received a saline placebo injection at 30 days. A total of 122 PCD patients were enrolled; 47 received single-dose standard-of-care vaccination, and 75 received 2 doses of Fluzone High-Dose vaccine. Rates of hemagglutinin inhibition (HAI) titer seroprotection against all 3 strains (H1N1, H3N2, and influenza B) were significantly higher for patients after tandem high-dose vaccination vs control (87.3% vs 63.2%; P = .003) and led to higher seroprotection at the end of flu season (60.0% vs 31.6%; P = .04). These data demonstrate that tandem high-dose influenza vaccination separated by 30 days leads to higher serologic HAI titer responses and more durable influenza-specific immunity in PCD patients. Similar vaccine strategies may also be essential to achieve protective immunity against other emerging pathogens such as novel coronavirus in these patients. This trial was registered at www.clinicaltrials.gov as #NCT02566265.

Mitigating the risk of COVID-19 exposure by transitioning from clinic-based to home-based immune globulin infusion.

PURPOSE: Intravenous immune globulin (IVIG) therapy is used in patients with hypogammaglobulinemia to lower the risk of infections. IVIG and subcutaneous IVIG (SCIG) therapy have been to shown to be safe and effective when administered as clinic-based infusions. Concern from both patients and providers for increased transmission of the coronavirus disease 2019 (COVID-19) virus to immunosuppressed patients with scheduled medical visits and procedures made it necessary for us to reassess our process of how we manage patient care in general and chronic clinic infusions in particular. Here we describe our experience of transitioning patients from clinic-based to home based IVIG and/or SCIG infusions to decrease the risk of COVID-19 exposure. METHODS: Criteria were developed to identify high-risk immunosuppressed patients who would be appropriate candidates for potential conversion to home based IVIG infusions. Data were collected via chart review, and cost analysis was performed using Medicare Part B reimbursement data. A patient outcome questionnaire was developed for administration through follow-up phone calls. RESULTS: From March to May 2020, 45 patients met criteria for home-based infusion, with 27 patients (60%) agreeing to home-based infusion. Posttransition patient outcomes assessment, conducted in 26 patients (96%), demonstrated good patient understanding of the home-based infusion process. No infusion-related complications were reported, and 24 patients (92%) had no concerns about receiving future IVIG and/or SCIG doses at home. No patient tested positive for COVID-19 during the study period. Clinic infusion visits decreased by 26.6 visits per month, resulting in a total of 106 hours of additional available infusion chair time per month and associated cost savings of $12,877. CONCLUSION: Transition of clinic based to home based IVIG/SCIG infusion can be successfully done to decrease potential exposure during a pandemic in a high-risk immunosuppressed population, with no impact on patient satisfaction, adherence, or efficacy. The home-based infusion initiative was associated with a reduction in costs to patients and an increase in available chair time in the infusion clinic.

Optimization of repeat plerixafor dosing for autologous peripheral blood stem-cell collection.

INTRODUCTION: Peripheral CD34+ cells may be mobilized using filgrastim alone or in combination with chemotherapy. The addition of plerixafor can be efficacious, though guidelines for repeat dosing are lacking. MATERIAL AND METHODS: This quality improvement project was initiated to generate guidelines for repeat plerixafor dosing after retrospective evaluation of data in adult patients undergoing autologous peripheral blood stem cell mobilization and collection. RESULTS: Analysis included 195 patients: 119 (61 %) with multiple myeloma and 76 (39 %) with lymphoma. Patients given at least one dose of plerixafor (n = 109) were further divided: Group 1) (A) goal of 3 × 10E6/kg and day 1 peripheral blood CD34+ count < 30 × 10E6/L, vs (B) ≥ 30 × 10 E6/L; Group 2) (A) goal of 6 × 10E6/kg and day 1 peripheral blood CD34+ count < 50 × 10E6/L or < 50 % of collection goal after day 1, vs (B) ≥ 50 % of collection goal after day 1. Ninety five percent of cases in Group 1B and 88 % of cases in Group 2B did not receive additional plerixafor doses and all of them achieved their collection goals. In contrast, those in Groups 1A and 2A required additional plerixafor dosing and some mobilizations/collections were futile. CONCLUSION: Based on these data, with consideration of collection goal, peripheral blood CD34+ count, and CD34+ cell bag count on collection day 1, we have generated institutional guidelines for collection initiation and repeat plerixafor dosing. Long term, we predict these guidelines will optimize pharmacy, apheresis, and stem cell processing resources while improving the patient experience.

Clinical characteristics and outcomes of COVID-19 in haematopoietic stem-cell transplantation recipients: an observational cohort study.

BACKGROUND: Haematopoietic stem-cell transplantation (HSCT) recipients are considered at high risk of poor outcomes after COVID-19 on the basis of their immunosuppressed status, but data from large studies in HSCT recipients are lacking. This study describes the characteristics and outcomes of HSCT recipients after developing COVID-19. METHODS: In response to the pandemic, the Center for International Blood and Marrow Transplant Research (CIBMTR) implemented a special form for COVID-19-related data capture on March 27, 2020. All patients-irrespective of age, diagnosis, donor type, graft source, or conditioning regimens-were included in the analysis with data cutoff of Aug 12, 2020. The main outcome was overall survival 30 days after a COVID-19 diagnosis. Overall survival probabilities were calculated using Kaplan-Meier estimator. Factors associated with mortality after COVID-19 diagnosis were examined using Cox proportional hazard models. FINDINGS: 318 HSCT recipients diagnosed with COVID-19 were reported to the CIBMTR. The median time from HSCT to COVID-19 diagnosis was 17 months (IQR 8-46) for allogeneic HSCT recipients and 23 months (8-51) for autologous HSCT recipients. The median follow-up of survivors was 21 days (IQR 8-41) for allogeneic HSCT recipients and 25 days (12-35) for autologous HSCT recipients. 34 (18%) of 184 allogeneic HSCT recipients were receiving immunosuppression within 6 months of COVID-19 diagnosis. Disease severity was mild in 155 (49%) of 318 patients, while severe disease requiring mechanical ventilation occurred in 45 (14%) of 318 patients-ie, 28 (15%) of 184 allogeneic HSCT recipients and 17 (13%) of 134 autologous HSCT recipients. At 30 days after the diagnosis of COVID-19, overall survival was 68% (95% CI 58-77) for recipients of allogeneic HSCT and 67% (55-78) for recipients of autologous HSCT. Age 50 years or older (hazard ratio 2·53, 95% CI 1·16-5·52; p=0·020); male sex (3·53; 1·44-8·67; p=0·006), and development of COVID-19 within 12 months of transplantation (2·67, 1·33-5·36; p=0·005) were associated with a higher risk of mortality among allogeneic HSCT recipients, and a disease indication of lymphoma was associated with a higher risk of mortality compared with plasma cell disorder or myeloma (2·41, [1·08-5·38]; p=0·033) in autologous HSCT recipients. INTERPRETATION: Recipients of autologous and allogeneic HSCT who develop COVID-19 have poor overall survival. These data emphasise the need for stringent surveillance and aggressive treatment measures in HSCT recipients who develop COVID-19. FUNDING: American Society of Hematology; Leukemia and Lymphoma Society; National Cancer Institute; National Heart, Lung and Blood Institute; National Institute of Allergy and Infectious Diseases; National Institutes of Health; National Cancer Institute; Health Resources and Services Administration; Office of Naval Research.

Myeloid sarcoma, chloroma, or extramedullary acute myeloid leukemia tumor: A tale of misnomers, controversy and the unresolved.

The World Health Organization classification and definition of "myeloid sarcoma" is imprecise and misleading. A more accurate term is "extramedullary acute myeloid leukemia tumor (eAML)." The pathogenesis of eAML has been associated with aberrancy of cellular adhesion molecules, chemokine receptors/ligands and RAS-MAPK/ERK signaling. eAML can present with or without synchronous or metachronous intramedullary acute myeloid leukemia (AML) so a bone marrow evaluation is always recommended. Accurate diagnosis of eAML requires tissue biopsy. eAML confined to one or a few sites is frequently treated with local therapy such as radiotherapy. About 75-90% of patients with isolated eAML will develop metachronous intramedullary AML with a median latency period ranging from 4 to 12 months; thus, patients with isolated eAML may also be treated with systemic anti-leukemia therapy. eAML does not appear to have an independent prognostic impact; selection of post-remission therapy including allogeneic hematopoietic cell transplant (alloHCT) is typically guided by intramedullary disease risk. Management of isolated eAML should be individualized based on patient characteristics as well as eAML location and cytogenetic/molecular features. The role of PET/CT in eAML is also currently being elucidated. Improving outcomes of patients with eAML requires further knowledge of its etiology and mechanism(s) as well as therapeutic approaches beyond conventional chemotherapy, ideally in the context of controlled trials.

Outcomes for allogeneic stem cell transplantation in refractory mycosis fungoides and primary cutaneous gamma Delta T cell lymphomas.

We report results on 23 patients with cutaneous T cell lymphoma (7 primary cutaneous γδ T cell lymphoma [PCGDT], 16 mycosis fungoides/Sézary syndrome [MF/SS]) who underwent allogeneic stem cell transplantation. All pts had skin involvement, 14 had total skin electron beam before conditioning. Donors were 10/10 HLA matched related (13), 5/10 haploidentical (4), and matched unrelated (5) or mismatched unrelated (1). Thirteen were in a clinical complete remission at the time of transplant. The 100-day transplant related mortality for the MF/SS and PCGDT patients was 12% and 29%, respectively. At a median follow up of 5.5 years, the overall survival and disease-free survival for MF/SS patients was 75% and 64%, respectively, and 6 of 10 MF/SS pts in long term complete response had a partial response at the time of transplant. Of seven PCGDT patients, four of seven are alive at a median follow up of 5 years and three are disease-free.

Attenuated Novel SARS Coronavirus 2 Infection in an Allogeneic Hematopoietic Stem Cell Transplant Patient on Ruxolitinib.

Severe acute respiratory syndrome coronavirus 2 (SARS CoV-2) has a high death rate in patients with comorbidities or in an immunocompromised state. We report a mild and attenuated SARS CoV-2 infection in a patient who is 17 months post stem cell transplantation and maintained on the JAK/STAT inhibitor ruxolitinib, a proposed novel therapy for SARS CoV-2 pneumonia.

Hodgkin Lymphoma, Version 2.2020, NCCN Clinical Practice Guidelines in Oncology.

The NCCN Clinical Practice Guidelines in Oncology for Hodgkin Lymphoma (HL) provide recommendations for the management of adult patients with HL. The NCCN panel meets at least annually to review comments from reviewers within their institutions, examine relevant data, and reevaluate and update their recommendations. Current management of classic HL involves initial treatment with chemotherapy alone or combined modality therapy followed by restaging with PET/CT to assess treatment response. Overall, the introduction of less toxic and more effective regimens has significantly advanced HL cure rates. This portion of the NCCN Guidelines focuses on the management of classic HL.

Tocilizumab Treatment for Cytokine Release Syndrome in Hospitalized Patients With Coronavirus Disease 2019: Survival and Clinical Outcomes.

BACKGROUND: Tocilizumab, an IL-6 receptor antagonist, can be used to treat cytokine release syndrome (CRS), with observed improvements in a coronavirus disease 2019 (COVID-19) case series. RESEARCH QUESTION: The goal of this study was to determine if tocilizumab benefits patients hospitalized with COVID-19. STUDY DESIGN AND METHODS: This observational study of consecutive COVID-19 patients hospitalized between March 10, 2020, and March 31, 2020, and followed up through April 21, 2020, was conducted by chart review. Patients were treated with tocilizumab using an algorithm that targeted CRS. Survival and mechanical ventilation (MV) outcomes were reported for 14 days and stratified according to disease severity designated at admission (severe, ≥ 3 L supplemental oxygen to maintain oxygen saturation > 93%). For tocilizumab-treated patients, pre/post analyses of clinical response, biomarkers, and safety outcomes were assessed. Post hoc survival analyses were conducted for race/ethnicity. RESULTS: Among the 239 patients, median age was 64 years; 36% and 19% were black and Hispanic, respectively. Hospital census increased exponentially, yet MV census did not. Severe disease was associated with lower survival (78% vs 93%; P < .001), greater proportion requiring MV (44% vs 5%; P < .001), and longer median MV days (5.5 vs 1.0; P = .003). Tocilizumab-treated patients (n = 153 [64%]) comprised 90% of those with severe disease; 44% of patients with nonsevere disease received tocilizumab for evolving CRS. Tocilizumab-treated patients with severe disease had higher admission levels of high-sensitivity C-reactive protein (120 vs 71 mg/L; P < .001) and received tocilizumab sooner (2 vs 3 days; P < .001), but their survival was similar to that of patients with nonsevere disease (83% vs 91%; P = .11). For tocilizumab-treated patients requiring MV, survival was 75% (95% CI, 64-89). Following tocilizumab treatment, few adverse events occurred, and oxygenation and inflammatory biomarkers (eg, high-sensitivity C-reactive protein, IL-6) improved; however, D-dimer and soluble IL-2 receptor (also termed CD25) levels increased significantly. Survival in black and Hispanic patients, after controlling for age, was significantly higher than in white patients (log-rank test, P = .002). INTERPRETATION: A treatment algorithm that included tocilizumab to target CRS may influence MV and survival outcomes. In tocilizumab-treated patients, oxygenation and inflammatory biomarkers improved, with higher than expected survival. Randomized trials must confirm these findings.

Clinical outcomes and characteristics of patients with TP53-mutated acute myeloid leukemia or myelodysplastic syndromes: a single center experience.

Mutations in the tumor suppressor gene TP53 are detected in 5-10% of patients with acute myeloid leukemia (AML) and myelodysplastic syndromes. TP53 mutations have been associated with complex karyotypes, therapy-related malignancies, lower response rates to cytotoxic chemotherapy, and an overall adverse prognosis. In this single-center retrospective study, we analyzed the clinicopathologic characteristics and outcomes of 83 patients with TP53-mutated myeloid malignancies treated at Yale Cancer Center between 9/2015 and 5/2019. Complex karyotypes (n = 75; 90%) and therapy-related malignancies (n = 32; 39%) were common. Median overall survival (OS) was 7.6 months. Intensive chemotherapy did not improve OS compared to lower-intensity treatment for AML patients. Patients who underwent allogeneic hematopoietic stem cell transplant (alloHSCT) had a significantly longer median OS, despite relatively limited follow-up. In conclusion, our data confirm the limited efficacy of intensive chemotherapy approaches for TP53-mutated patients with myeloid neoplasms and suggest that a minority of patients achieve long-term survival with alloHSCT.

Cardiotoxicity in Hematopoietic Stem Cell Transplant: Keeping the Beat.

INTRODUCTION: The number of hematopoietic stem cell transplants (HSCTs) performed in the United States and worldwide is increasing. Cardiac events have been well described in HSCT, and the incidence and type of cardiac events have not changed over recent decades. PATIENTS AND METHODS: This study adds to the body of evidence in describing the incidence and type of cardiac events experienced by an allogeneic and autologous HSCT population at a single institution from 2012 to 2017. RESULTS: Sixty-five (9.8%) patients experienced cardiac events, including atrial arrhythmia (N = 39), acute heart failure (N = 9), acute coronary syndrome (N = 7), and new onset hypertension (N = 9), with a few instances of bradycardia, ventricular arrhythmia, pericardial effusion, and pericarditis. Our multivariable regression analysis identified age (older), creatinine (higher), and history of coronary artery disease to significantly correlate with risk of cardiac event (P = .005, P = .039, and P = .038, respectively). A subgroup analysis of those patients experiencing a cardiac event found pre-transplant atrial dilation by trans-thoracic echocardiogram to correlate with increased risk of atrial arrhythmia (33.8% vs. 9.7%; P = .03). Patients developing a CE had an increased risk of death within 1 year (11% vs. 32%; P < .001). CONCLUSION: We review our results in context of other important HSCT cardiac studies to illuminate the most relevant factors of medical history, laboratory data, and cardiac measurements that will identify patients at higher risk, allowing for intervention to improve HSCT outcomes.