Immunotherapy in Acute Leukemias: Past Success Paves the Way for Future Progress.

Immunotherapy as a cancer treatment modality has undergone recent widespread proliferation across all cancer types, especially amongst patients with solid tumors. However, the longest tenured immunotherapy approach to cancer is allogeneic stem cell transplantation (allo-SCT) for two hematologic malignancies: acute myeloid and acute lymphoid leukemia (AML and ALL, respectively). While allo-SCT remains a standard of care for eligible patients, recent advances/applications of monoclonal antibodies, immune checkpoint inhibitors, bispecific T-cell engagers (BiTEs), and CAR T-cell therapy are changing the treatment landscape for these acute leukemias by either direct to tumor immune targeting or through decreased toxicities that expand patient eligibility. Pre-clinical data and clinical trials have shown promising results for novel immunotherapies in acute leukemia, and multiple ongoing trials are investigating these novel approaches. While there have been promising results with these approaches, particularly in the relapsed/refractory setting, there remain challenges in optimizing the use of these therapies, such as managing cytokine release syndrome and other immune-related toxicities. Immunotherapy is a rapidly evolving field in the treatment of acute leukemia and has the potential to significantly impact the management of both AML and ALL. This review highlights the history of immunotherapy in the treatment of acute leukemias, the evolution of immunotherapy into more targeted approaches, the potential benefits and limitations of different immune targeting approaches, and ongoing research and development in the field.

Choice of anticoagulation in patients with low risk antiphospholipid syndrome.

Antiphospholipid syndrome (APS) is an acquired hypercoagulable state necessitating long-term anticoagulation for secondary thrombosis prevention. Anticoagulation guidelines are predominantly based on data in high risk, triple positive patients, and favor Vitamin K antagonists over other forms of anticoagulation. The efficacy of alternative anticoagulants for secondary thrombosis prevention in low risk, single and double positive APS remains uncertain. This study aimed to assess the incidence of recurrent thrombosis and major bleeding for patient with low risk APS on long-term anticoagulation. We performed a retrospective cohort study of patients who met revised criteria for thrombotic APS between January, 2001 and April, 2021 and received care through the Lifespan Health System. Primary outcomes included recurrent thrombosis and WHO Grades 3 and 4 major bleeding. A total of 190 patients were followed over a median duration of 3.1 years. At time of APS diagnosis, 89 patients were treated with warfarin and 59 patients with a direct oral anticoagulant (DOAC). There were similar rates of recurrent thrombosis in low risk patients on warfarin versus DOACs (adjusted IRR 6.91; 95% CI 0.90-53.40, p = 0.064). Major bleeding events only occurred in low risk patients on warfarin (n = 8, log-rank p = 0.13). In conclusion, despite the choice of anticoagulation, patients with low risk APS had similar rates of recurrent thrombosis suggesting DOACs may be a potential treatment option for this cohort. There was a non-significant increase in major bleeding rates in low risk patients on warfarin versus DOACs. Study limitations include a retrospective study design and small event numbers.

Ixazomib, Oral Metronomic Cyclophosphamide, and Dexamethasone for First-Line Treatment of Multiple Myeloma: A Phase II Brown University Oncology Group Study.

BACKGROUND: Newly diagnosed multiple myeloma patients have many available treatment options. While lenalidomide, bortezomib, and dexamethasone (RVD) is the preferred initial treatment for many patients, several other agents may provide similar efficacy with less toxicity and improved ease of administration. METHODS: We evaluated the safety and efficacy of the all-oral regimen of ixazomib, cyclophosphamide, and dexamethasone with the use of metronomic cyclophosphamide dosing in the treatment of patients with newly diagnosed multiple myeloma. RESULTS: The study was stopped prior to planned enrollment due to slow recruitment, with 12 patients available for final analysis. The overall response rate was 58.3% with 2 patients achieving a very good partial response (16.7%) and 5 patients achieving a partial response (41.7%). Median progression-free survival was 16 months, and median overall survival was 43 months. There were no episodes of grade 3 or greater peripheral neuropathy. Grade 3 or greater dermatologic toxicity was experienced in 50% of patients. CONCLUSION: Although limited enrollment prevented full efficacy evaluation, our data do not support further study of metronomic cyclophosphamide in combination with ixazomib and dexamethasone in the treatment of newly diagnosed multiple myeloma. The activity of this regimen in the relapsed/refractory setting requires further study (ClinicalTrials.gov Identifier: NCT02412228).

Tumor Derived Extracellular Vesicles Modulate Gene Expression in T cells.

Extracellular vesicles (EVs) are excreted from all cells in the human body and are heterogeneous lipid bilayer particles containing proteins, RNA, DNA, and other cargo. T cells are primary players of the adaptive immune system and have a significant role in anti-cancer immunotherapies. Tumor derived EVs have diverse effects on host cells including modulating the immune response. In this study, we investigate the role acute myeloid leukemia (AML) derived EVs have on modulation of gene expression levels in three different T cell populations (CD8+, CD4+, and CD4 + CD39 + T cells). AML derived EVs modulate gene expression levels in all three cell populations with transcripts associated with major immunoregulatory pathways being significantly altered. Genes whose expression were significantly upregulated or downregulated were analyzed for gene ontogeny category expression and for the impact of the changes on specific immunoregulatory pathways. CD8 + T cells were modulated to a larger extent than other T cell populations and gene expression levels associated with proliferation and differentiation were influenced by AML-derived EVs.

Seroconversion and outcomes after initial and booster COVID-19 vaccination in adults with hematologic malignancies.

BACKGROUND: Patients with hematologic malignancies have impaired humoral immunity secondary to their malignancy and its treatment, placing them at risk of severe coronavirus disease-19 (COVID-19) infection and reduced response to vaccination. METHODS: The authors retrospectively analyzed serologic responses to initial and booster COVID-19 vaccination in 378 patients with hematologic malignancy and subsequently tracked COVID-19-related outcomes. RESULTS: Seroconversion occurred in 181 patients (48%) after initial vaccination; patients who had active malignancy or those who were recently treated with a B-cell-depleting monoclonal antibody had the lowest rates of seroconversion. For initial nonresponders to vaccination, seroconversion after a booster dose occurred in 48 of 85 patients (56%). The seroconversion rate after the booster was similar for patients on (53%) and off (58%) active therapy (p = .82). Thirty-three patients (8.8%) developed a COVID-19 infection, and there were three COVID-19-related deaths (0.8%). Although no significant association was observed between postvaccination seroconversion and the incidence of COVID-19 infection, no patient with seroconversion died from COVID-19, and no patient who received tixagevimab/cilgavimab (N = 25) was diagnosed with a COVID-19 infection. CONCLUSIONS: Booster vaccinations can promote seroconversion in a significant proportion of patients who are seronegative after the initial vaccination course regardless of the specific vaccine or on/off treatment status at the time of revaccination. Although postvaccination seroconversion may not be associated with a decrease in any (including asymptomatic) COVID-19 infection, the authors' experience suggested that effective vaccination (including a booster), supplemented by passive immunization using tixagevimab/cilgavimab in case of lack of seroconversion, effectively eliminated the risk of COVID-19 death in the otherwise high-risk population. LAY SUMMARY: Patients with hematologic malignancy, especially lymphoma, have an impaired response to coronavirus disease 2019 (COVID-19) vaccination. In this single-institution review, less than one half of the patients studied made detectable antibodies. For those who did not make detectable antibodies after initial vaccination, over one half (65%) were able to produce antibodies after booster vaccination. By the end of February 2022, 33 of the original 378 patients had a documented COVID-19 infection. The only deaths from COVID-19 were in those who had undetectable antibodies, and no patient who received prophylactic antibody therapy developed a COVID-19 infection.

Thrombosis in COVID 2022: An Updated Narrative Review of Current Literature and Inpatient Management.

Early in the pandemic, it was recognized that infection with COVID-19 was associated with an increased incidence in both venous and arterial thrombotic events leading to poor patient outcomes. Given the rapid rise of the pandemic, anticoagulation strategies were initially based upon retrospective and observational data with few high-quality randomized control trials to help direct strategies regarding the use of thromboprophylaxis during hospitalization, empiric therapeutic anticoagulation, and extended-duration thromboprophylaxis after discharge. Over the past year, several randomized control trials have now been published evaluating these strategies. In this article, we hope to review the current literature surrounding the use of intermediate-dose thromboprophylaxis, empiric therapeutic anticoagulation, and the use of extended-duration thromboprophylaxis for patients hospitalized with COVID-19.

Phase 1 study of oral azacitidine (CC-486) plus R-CHOP in previously untreated intermediate- to high-risk DLBCL.

Resistance to standard immunochemotherapy remains an unmet challenge in diffuse large B-cell lymphoma (DLBCL), and aberrant DNA methylation may contribute to chemoresistance. Promising early-phase results were reported with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) plus subcutaneous azacitidine, a hypomethylating agent. In this phase 1 study, we evaluated CC-486 (oral azacitidine) plus 6 cycles of R-CHOP in patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. CC-486 doses of 100, 150, 200, or 300 mg given 7 days before cycle 1 and on days 8-21 of cycles 1-5 were evaluated; additional patients were enrolled in the expansion phase to examine preliminary efficacy. The primary objectives were to determine the safety and the maximum tolerated dose (MTD) of CC-486 in combination with R-CHOP. The most common grade 3/4 toxicities were hematologic, including neutropenia (62.7%) and febrile neutropenia (25.4%); grade 3/4 nonhematologic toxicities were uncommon (<7%). The MTD was not established; 2 patients had dose-limiting toxicities (1 with grade 4 febrile neutropenia; 1 with grade 4 prolonged neutropenia). The recommended phase 2 dose was established as 300 mg. The overall response rate was 94.9%, with 52 patients (88.1%) achieving complete responses. With a median follow-up of 28.9 months, estimated 1- and 2-year progression-free survival rates were 84.1% and 78.6%, respectively. Overall, epigenetic priming with CC-486 before R-CHOP can be delivered with acceptable safety to patients with previously untreated intermediate- to high-risk DLBCL or grade 3B/transformed follicular lymphoma. ClinicalTrials.gov: NCT02343536.

Detection of clonotypic DNA in the cerebrospinal fluid as a marker of central nervous system invasion in lymphoma.

The diagnosis of parenchymal central nervous system (CNS) invasion and prediction of risk for future CNS recurrence are major challenges in the management of aggressive lymphomas, and accurate biomarkers are needed to supplement clinical risk predictors. For this purpose, we studied the results of a next-generation sequencing (NGS)-based assay that detects tumor-derived DNA for clonotypic immunoglobulin gene rearrangements in the cerebrospinal fluid (CSF) of patients with lymphomas. Used as a diagnostic tool, the NGS-minimal residual disease (NGS-MRD) assay detected clonotypic DNA in 100% of CSF samples from 13 patients with known CNS involvement. They included 7 patients with parenchymal brain disease only, whose CSF tested negative by standard cytology and flow cytometry, and 6 historical DNA aliquots collected from patients at a median of 39 months before accession, which had failed to show clonal rearrangements using standard polymerase chain reaction. For risk prognostication, we prospectively collected CSF from 22 patients with newly diagnosed B-cell lymphomas at high clinical risk of CNS recurrence, of whom 8 (36%) had detectable clonotypic DNA in the CSF. Despite intrathecal prophylaxis, a positive assay of CSF was associated with a 29% cumulative risk of CNS recurrence within 12 months of diagnosis, in contrast with a 0% risk among patients with negative CSF (P = .045). These observations suggest that detection of clonotypic DNA can aid in the diagnosis of suspected parenchymal brain recurrence in aggressive lymphoma. Furthermore, the NGS-MRD assay may enhance clinical risk assessment for CNS recurrence among patients with newly diagnosed lymphomas and help select those who may benefit most from novel approaches to CNS-directed prophylaxis.

3D tissue engineered plasma cultures support leukemic proliferation and induces drug resistance.

Chronic myeloid leukemia (CML), acute myeloid leukemia (AML), and chronic lymphocytic leukemia (CLL) are hematological malignancies that remain incurable despite novel treatments. In order to improve current treatments and clinical efficacy, there remains a need for more complex in vitro models that mimic the intricate human leukemic microenvironment. This study aimed to use 3D tissue engineered plasma cultures (3DTEPC) derived from CML, AML and CLL patients to promote proliferation of leukemic cells for use as a drug screening tool for treatment. 3DTEPC supported the growth of primary CML, AML and CLL cells and also induced significantly more drug resistance in CML, AML and CLL cell lines compared to 2D. The 3DTEPC created a more physiologically relevant environment for leukemia cell proliferation, provided a reliable model for growing leukemia patient samples, and serves as a relevant tool for drug screening and personalized medicine.

Thrombosis in COVID-19: A Narrative Review of Current Literature and Inpatient Management.

COVID-19 infection has been associated with an increased incidence of thrombotic events leading to poor patient outcomes. Given the rapid rise of the COVID-19 pandemic, the ability to conduct prospective trials has been limited and data regarding the use of standard-dose versus intermediate-dose thromboprophylaxis, use of empiric therapeutic anticoagulation, and use of extended-duration thromboprophylaxis after discharge has been largely based upon observational data without any high-quality prospective data guiding their use. In this article, we will review the incidence and frequency of arterial and venous thrombotic events along with the current literature surrounding the use of intermediate-dose thromboprophylaxis, empiric therapeutic anticoagulation, and use of extended-duration thromboprophylaxis for patients hospitalized with COVID-19.

Tumor lysis syndrome risk in outpatient versus inpatient administration of venetoclax and hypomethlators for acute myeloid leukemia.

INTRODUCTION: Venetoclax along with hypomethylating agents (HMAs) is the new standard therapy for older patients with acute myeloid leukemia (AML) not fit for intensive frontline induction chemotherapy. Venetoclax is associated with fatal episodes of tumor lysis syndrome (TLS) in chronic lymphocytic leukemia (CLL), and recommendations are for its initiation for CLL and AML in the inpatient setting with close monitoring. Herein, we evaluated the safety of outpatient venetoclax ramp up when given in addition to HMAs for the treatment of AML. METHODS: We conducted a retrospective review of patients diagnosed with AML at our institution from 12/1/2016 until 7/1/2020. We identified patients who received HMAs and venetoclax for AML, either as frontline or relapsed/refractory therapy. Records were reviewed for evidence of laboratory or clinical tumor lysis episodes in all patients. RESULTS: Between 12/1/2016 and 7/1/2020 43, patients at our institution received venetoclax/HMA for the treatment of AML. Thirty-nine patients (91%) had venetoclax initiation and ramp up in the outpatient setting. One episode of laboratory TLS (2.5%) was identified. This patient required admission to the hospital for rasburicase and IV fluids with resolution of the laboratory effects without resultant clinical TLS. There were no episodes of clinical TLS in either group. Thirty-day mortality from venetoclax initiation was 0% in both groups. CONCLUSION: Our experience with HMAs and venetoclax showed that outpatient ramp up of venetoclax is safe with a very low risk of laboratory TLS (2.5%) and no evidence of clinical TLS within our cohort.

Antibiotic use during cytarabine consolidation in acute myeloid leukemia.

Acute myeloid leukemia (AML) patients undergoing consolidation chemotherapy with intermediate or high-dose cytarabine (IDAC/HiDAC) are often placed on prophylactic antibacterials. This practice is largely based on the benefits of prophylaxis (PPX) during induction chemotherapy. However, recent concerns regarding antibacterial prophylaxis have emerged including risk of Clostridioides difficile colitis, medication toxicities, and the potential for fostering multidrug-resistant pathogens. We therefore retrospectively explored whether antibacterial PPX is beneficial during cytarabine consolidation. Adult AML patients who received IDAC/HiDAC at our institution from January 2007 to March 2018 were evaluated for receipt of antibacterial PPX. The primary endpoint was rate of febrile neutropenia (FN); secondary endpoints were rates of unplanned hospitalization, bacteremia, infection from resistant organisms, C. difficile colitis, and death from infection. One hundred twenty patients with data from 229 IDAC/HiDAC cycles were included. Patients who received antibacterial PPX were more often hospitalized during cytarabine cycle 1 (C1) than those who received no PPX. Patients who received PPX had significantly more episodes of bacteremia, in addition to infections from resistant, predominantly Gram-positive organisms during cycle 1 of consolidation than those without PPX. Antibacterial PPX during IDAC/HiDAC consolidation treatment at our institution did not decrease the rates of FN, hospitalization, or bacteremia and was associated with higher risk of infection from drug-resistant bacteria in C1. Prospective studies examining antibacterial prophylaxis during cytarabine consolidation for AML patients are necessary, with strong consideration made for institution-specific protocols.

Antifungal prophylaxis during 7 + 3 induction chemotherapy for acute myeloid leukemia is associated with improved survival, in a setting with low incidence of invasive mold infections.

Invasive fungal infections (IFIs) are a major cause of morbidity and mortality in patients undergoing induction chemotherapy for acute myeloid leukemia (AML). In this patient population, antifungal prophylaxis (AP) has been associated with decreased incidence of IFIs and better survival. However, some centers have not adopted AP during induction chemotherapy for AML, as it is unclear whether AP improves outcomes in settings where the incidence of invasive mold infections is low. We retrospectively assessed the differences in clinical outcomes and resource utilization in patients undergoing 7 + 3 induction chemotherapy for AML, after implementing a policy of AP as part of a dedicated inpatient malignant hematology service (HS) at Rhode Island Hospital. Between January 1, 2007 and April 1, 2019, 56 patients with AML received AP during 7 + 3 induction chemotherapy and 52 patients did not, without significant differences in their baseline characteristics. Use of AP was associated with less proven or probable IFI (0% vs. 6%, P = 0.1) and lower all-cause in-hospital mortality (7% vs. 21%, P < 0.05), without significant increases in resource utilization or toxicities. Empiric and targeted antifungal therapies were more frequently started in the non-AP group (69%) than changed in the AP group (41%, P < 0.005). Having a dedicated inpatient malignant hematology service was also associated with improved outcomes. However, use of AP was associated with better survival (30-day post-induction survival log-rank P < 0.05), prior to the implementation of this clinical service as well, which is suggestive of an independent benefit from AP.

Outcomes of lenalidomide- or bortezomib-based regimens in older patients with plasma cell myeloma.

The "triplet" regimen of lenalidomide, bortezomib, and dexamethasone (RVD) showed survival advantage over lenalidomide-dexamethasone (RD) in clinical trials, but older patients with myeloma often receive doublet regimens (RD or bortezomib-dexamethasone, VD), or VD plus cyclophosphamide (VCD). We compared these first-line regimens using real-world data from Medicare beneficiaries receiving therapy between 2007 and 2015. In each comparative analysis, we balanced confounding characteristics using a propensity score. Outcomes included overall (OS) and event-free survival (EFS, reporting hazard ratios [HR] with 95% confidence intervals [CI]), adverse events, and costs. We identified 6076 patients with median age 76 and median OS of 2.6 years. In the comparison of RVD vs RD/VD doublets, RVD showed significantly better OS (HR = 0.83; 95% CI, 0.72-0.95) and EFS (HR = 0.68; 95% CI, 0.61-0.76). So, RVD was associated with more frequent hospitalizations, anemia, and neuropathy, but no increase in thromboembolism or secondary cancers. Costs were higher with RVD. In the comparison of RD vs VD, RD demonstrated better EFS (HR = 0.74; 95% CI, 0.68-0.81) and marginally better OS (HR = 0.91; 95% CI, 0.83-0.99). And, RD resulted in significantly more thromboembolic events, less neuropathy, and no significant difference in hospitalizations, transfusions, or secondary cancers. In the comparison of VCD vs VD, we observed no significant difference in any outcome. Superior survival favors RVD over doublet regimens, but even in 2015 RVD was applied for only about 25% of Medicare beneficiaries with myeloma. For patients not eligible for RVD due to toxicity, VCD offers no survival benefit over VD. Lenalidomide-dexamethasone may be the preferred line doublet considering its advantage over VD.

Enforcing the "4T": An In-Line Calculator for HIT Antibody Ordering in the Electronic Medical Record.

Heparin-induced thrombocytopenia (HIT) remains a difficult clinical diagnosis, even with the under-utilized standardized scoring systems, like the '4T' score, to aid in clinical decision-making. Our quality improvement study sought to assess the use of '4T' score, improve the use of HIT antibody (HITA) testing and improvement management of possible HIT by implementing an in-line calculator with guidance within our electronic medical record (EMR) at our institution. We retrospectively reviewed patient charts between October 2017 and October 2018, assessing practices before and after implementation of the '4T' in-line calculator in April 2018. HITA were ordered inappropriately (for 4T <4) in 141 (67%) of 210 instances (75 before and 66 after). We found no statistically significant difference in positive predictive value (PPV) or 4T documentation in provider notes after its implementation. We were able to identify problematic areas in HIT management, such as the ordering of non-heparin anticoagulants, and implement additional changes addressing these problems.

Intensity of anticoagulation and survival in patients hospitalized with COVID-19 pneumonia.

BACKGROUND: SARS-CoV-2 infection has noted derangements in coagulation markers along with significant thrombotic complications. Post-mortem examinations show severe endothelial injury and widespread thrombotic microangiopathy in the pulmonary vasculature. Early reports describing the use of prophylactic anticoagulation demonstrated improved survival, leading to the adoption of prophylactic and therapeutic anticoagulation guided by D-dimer levels. The clinical usefulness of D-dimer values, trends, and more intensive anticoagulation remains an area of clinical interest. OBJECTIVES: Assess the outcomes and laboratory trends in COVID-19 patients stratified by intensity of anticoagulation at time of admission. PATIENTS AND METHODS: Retrospectively review the differences in clinical outcomes and laboratory trends in patients hospitalized with COVID-19 in the Lifespan Health System. RESULTS: Between 27 February and 24 April 2020, 468 patients were hospitalized. Initial use of high-intensity thromboprophylaxis was associated with improved 30-day mortality (adjusted RR 0.26; 95% confidence interval [CI], 0.07-0.97; p = 0.045) without a significant increased rate of bleeding (p = 0.11). In severe COVID-19, D-dimer significantly increased during hospitalization with standard thromboprophylaxis (p < 0.001) but remained stable or decreased with high-intensity prophylaxis or therapeutic anticoagulation. CONCLUSION: Patients who received high-intensity prophylactic anticoagulation had a downtrend in D-dimer levels and improved 30-day mortality. This suggests a role in anticoagulation in mitigating adverse outcomes associated with COVID-19; however, further randomized, prospective studies are needed.

Preliminary findings regarding the use of direct oral anticoagulants in cerebral venous thrombosis.

BACKGROUND: Direct oral anticoagulants (DOACs) have entered the treatment paradigms of various conditions based upon large randomized controlled trials. However, use of DOACs for thrombosis at unusual sites, such as cerebral venous thrombosis (CVT), is less clear as the ability to conduct large randomized controlled trials is limited by its rarity. Furthermore, its use in the setting of malignancy or in the elderly remains an area of ongoing research. OBJECTIVE: Our aim was to assess the outcomes in CVT patients treated with DOACs compared to warfarin. We also sought to elucidate whether its use was safe in the setting of malignancy or in the elderly. METHODS: Retrospectively assess the differences in clinical outcomes in patients hospitalized with CVT in the Lifespan Health System. RESULTS: Between 1 July 2004 and 1 March 2020, 46 adult patients with CVT fulfilled inclusion criteria. No significant differences in outcomes were observed between the DOAC (N = 8) and vitamin K antagonist (VKA) (N = 38) cohorts. The use of DOACs did not result in an increased rate of acute complications, recurrent venous thromboembolism (VTE) and/or CVT, World Health Organization (WHO) grade 3 or 4 bleeding rates, or differences in clinical improvement per the modified Rankin scale. Furthermore, in patients with underlying metastatic cancer (N = 2) or in patients > 80 (N = 1) who received a DOAC, there was no increase in adverse events or significant differences in outcome when compared to warfarin. CONCLUSION: Patients who received a DOAC in the treatment of CVT demonstrated no differences in outcomes when compared to warfarin.

Adjuvant chemotherapy administration and survival outcomes of lymphoma survivors with common solid tumors: a population-based study†.

Using the Surveillance, Epidemiology, and End Results database (2004-2015), we compared adjuvant chemotherapy use and survival for three common solid tumors in patients with and without history of lymphoma (DLBCL: diffuse large B cell, HL: Hodgkin lymphoma). Among patients with breast (n = 531,243), colon (n = 108,196), and lung (n = 23,179) cancers, we identified 361, 134, and 37 DLBCL survivors, and 349, 73, and 25 HL survivors, respectively. We found no significant difference between lymphoma survivors and controls in the use of adjuvant chemotherapy, except HL survivors with colon cancer, who had a lower rate. Among chemotherapy recipients, OS was significantly worse among HL survivors with all three cancers, and DLBCL survivors with breast cancer (hazard ratio [HR] 1.57-2.28). HL survivors had significantly higher mortality from cardiovascular diseases in breast and lung cancers (sub-HR, 7.96-9.64), which suggests that worse survival in this population might be due to late or cumulative toxicities of cancer-directed treatment.