Cryoglobulinemic vasculitis with interruption of ibrutinib therapy for chronic lymphocytic leukemia (CLL).

Chronic lymphocytic leukemia (CLL) can trigger autoimmune phenomena, with immune thrombocytopenia (ITP) the most common presentation. Upon cessation of CLL therapy, including ibrutinib, autoimmune flares can occur. In a 68-year-old man with CLL, ibrutinib was held for 2 weeks prior to elective shoulder surgery. Eleven days after stopping therapy, he presented with a purpuric rash on his right hip, buttock, and lower extremities. He experienced two episodes of seizure activity while hospitalized. MRI brain demonstrated patchy areas of altered signal involving deep white matter and sub-cortical white matter structures concerning for cerebral vasculitis. Although there was no evidence of hemolysis, serum cold agglutinin titer was elevated at > 1:512 and cryoglobulin levels were positive at 36%. He was diagnosed with type I cryoglobulinemia and treated with rituximab, plasmapheresis, methylprednisolone, and ibrutinib was restarted. This regimen resolved his symptoms. A rare complication of CLL is the production of cryoglobulins, which can present at initial diagnosis or in relapsed disease. Our case demonstrates that the cessation of ibrutinib therapy, even for a short time, can precipitate complications. To our knowledge, we report the first case of a patient with well-controlled CLL who rapidly developed cryoglobulinemic vasculitis after stopping ibrutinib therapy.

A retrospective comparison of venetoclax alone or in combination with an anti-CD20 monoclonal antibody in R/R CLL.

Venetoclax (VEN) is approved for relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL) as monotherapy (VENmono) or in combination with rituximab. Whether VEN plus anti-CD20 (VENcombo) is superior to VENmono is unknown. We conducted a multicenter, retrospective cohort analysis comparing 321 CLL patients treated with VENmono vs VENcombo across the United States and the United Kingdom. We examined demographics, baseline characteristics, dosing, adverse events, response rates, and outcomes. The primary endpoints were progression-free survival (PFS) and overall survival (OS), estimated by Kaplan-Meier method, in patients treated with VENmono vs VENcombo. Univariate and bivariate analyses were performed with COX regression. Three hundred twenty-one CLL patients were included (3 median prior treatments, 78% prior ibrutinib). The overall response rates (ORRs) were similar (VENmono, 81% ORR, 34% complete remission [CR] vs VENcombo, 84% ORR, 32% CR). With a median follow-up of 13.4 months, no differences in PFS and OS were observed between the groups. In unadjusted analyses, the hazard ratios (HRs) for PFS and OS for VENmono vs VENcombo were HR 1.0 (95% confidence interval [CI], 0.6-1.8; P = .7) and HR 1.2 (95% CI, 0.6-2.3; P = .5), respectively. When adjusting for differences between the cohorts, the addition of an anti-CD20 antibody in combination with VEN did not impact PFS (HR, 1.0; 95% CI, 0.5-2.0; P = .9) or OS (HR, 1.1; 95% CI, 0.4-2.6; P = .8). We demonstrate comparable efficacy between VENmono and VENcombo in a heavily pretreated, high-risk, retrospective cohort, in terms of both response data and survival outcomes. Prospective studies are needed to validate these findings.

Tumor Lysis, Adverse Events, and Dose Adjustments in 297 Venetoclax-Treated CLL Patients in Routine Clinical Practice.

PURPOSE: Clinical trials of venetoclax reported negligible rates of clinical tumor lysis syndrome (TLS) in patients with chronic lymphocytic leukemia (CLL) when using an extended dose escalation schedule. We aimed to understand TLS prophylaxis, rates of select adverse events (AE), and impact of dosing modifications in routine clinical practice. EXPERIMENTAL DESIGN: This retrospective cohort study included 297 CLL venetoclax-treated patients outside of clinical trials in academic and community centers. Demographics, baseline disease characteristics, venetoclax dosing, TLS risk and prophylaxis, and AEs were collected. RESULTS: The group was 69% male, 96% had relapsed/refractory CLL, 45% had deletion chromosome 17p, 84% had unmutated IGHV, 80% received venetoclax monotherapy, and median age was 67. TLS risk was categorized as low (40%), intermediate (32%), or high (28%), and 62% had imaging prior to venetoclax initiation. Clinical TLS occurred in 2.7% of patients and laboratory TLS occurred in 5.7%. Pre-venetoclax TLS risk group and creatinine clearance independently predict TLS development in multivariable analysis. Grade 3/4 AEs included neutropenia (39.6%), thrombocytopenia (29.2%), infection (25%), neutropenic fever (7.9%), and diarrhea (6.9%). Twenty-two patients (7.4%) discontinued venetoclax due to an AE. Progression-free survival was similar regardless of number of dose interruptions, length of dose interruption, and stable venetoclax dose. CONCLUSIONS: These data provide insights into current use of venetoclax in clinical practice, including TLS rates observed in clinical practice. We identified opportunities for improved adherence to TLS risk stratification and prophylaxis, which may improve safety.

Proliferative potential and resistance to immune checkpoint blockade in lung cancer patients.

BACKGROUND: Resistance to immune checkpoint inhibitors (ICIs) has been linked to local immunosuppression independent of major ICI targets (e.g., PD-1). Clinical experience with response prediction based on PD-L1 expression suggests that other factors influence sensitivity to ICIs in non-small cell lung cancer (NSCLC) patients. METHODS: Tumor specimens from 120 NSCLC patients from 10 institutions were evaluated for PD-L1 expression by immunohistochemistry, and global proliferative profile by targeted RNA-seq. RESULTS: Cell proliferation, derived from the mean expression of 10 proliferation-associated genes (namely BUB1, CCNB2, CDK1, CDKN3, FOXM1, KIAA0101, MAD2L1, MELK, MKI67, and TOP2A), was identified as a marker of response to ICIs in NSCLC. Poorly, moderately, and highly proliferative tumors were somewhat equally represented in NSCLC, with tumors with the highest PD-L1 expression being more frequently moderately proliferative as compared to lesser levels of PD-L1 expression. Proliferation status had an impact on survival in patients with both PD-L1 positive and negative tumors. There was a significant survival advantage for moderately proliferative tumors compared to their combined highly/poorly counterparts (p = 0.021). Moderately proliferative PD-L1 positive tumors had a median survival of 14.6 months that was almost twice that of PD-L1 negative highly/poorly proliferative at 7.6 months (p = 0.028). Median survival in moderately proliferative PD-L1 negative tumors at 12.6 months was comparable to that of highly/poorly proliferative PD-L1 positive tumors at 11.5 months, but in both instances less than that of moderately proliferative PD-L1 positive tumors. Similar to survival, proliferation status has impact on disease control (DC) in patients with both PD-L1 positive and negative tumors. Patients with moderately versus those with poorly or highly proliferative tumors have a superior DC rate when combined with any classification schema used to score PD-L1 as a positive result (i.e., TPS ≥ 50% or ≥ 1%), and best displayed by a DC rate for moderately proliferative tumors of no less than 40% for any classification of PD-L1 as a negative result. While there is an over representation of moderately proliferative tumors as PD-L1 expression increases this does not account for the improved survival or higher disease control rates seen in PD-L1 negative tumors. CONCLUSIONS: Cell proliferation is potentially a new biomarker of response to ICIs in NSCLC and is applicable to PD-L1 negative tumors.

Next generation sequencing of PD-L1 for predicting response to immune checkpoint inhibitors.

BACKGROUND: PD-L1 immunohistochemistry (IHC) has been traditionally used for predicting clinical responses to immune checkpoint inhibitors (ICIs). However, there are at least 4 different assays and antibodies used for PD-L1 IHC, each developed with a different ICI. We set to test if next generation RNA sequencing (RNA-seq) is a robust method to determine PD-L1 mRNA expression levels and furthermore, efficacy of predicting response to ICIs as compared to routinely used, standardized IHC procedures. METHODS: A total of 209 cancer patients treated on-label by FDA-approved ICIs, with evaluable responses were assessed for PD-L1 expression by RNA-seq and IHC, based on tumor proportion score (TPS) and immune cell staining (ICS). A subset of serially diluted cases was evaluated for RNA-seq assay performance across a broad range of PD-L1 expression levels. RESULTS: Assessment of PD-L1 mRNA levels by RNA-seq demonstrated robust linearity across high and low expression ranges. PD-L1 mRNA levels assessed by RNA-seq and IHC (TPS and ICS) were highly correlated (p < 2e-16). Sub-analyses showed sustained correlation when IHC results were classified as high or low by clinically accepted cut-offs (p < 0.01), and results did not differ by tumor type or anti-PD-L1 antibody used. Overall, a combined positive PD-L1 result (≥1% IHC TPS and high PD-L1 expression by RNA-Seq) was associated with a 2-to-5-fold higher overall response rate (ORR) compared to a double negative result. Standard assessments of sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) showed that a PD-L1 positive assessment for melanoma samples by RNA-seq had the lowest sensitivity (25%) but the highest PPV (72.7%). Among the three tumor types analyzed in this study, the only non-overlapping confidence interval for predicting response was for "RNA-seq low vs high" in melanoma. CONCLUSIONS: Measurement of PD-L1 mRNA expression by RNA-seq is comparable to PD-L1 expression by IHC both analytically and clinically in predicting ICI response. RNA-seq has the added advantages of being amenable to standardization and avoidance of interpretation bias. PD-L1 by RNA-seq needs to be validated in future prospective ICI clinical studies across multiple histologies.

Outcomes and Toxicities of Programmed Death-1 (PD-1) Inhibitors in Hodgkin Lymphoma Patients in the United States: A Real-World, Multicenter Retrospective Analysis.

BACKGROUND: Although classical Hodgkin lymphoma (cHL) is highly curable, 20%-30% of patients will not be cured with conventional treatments. The programmed death-1 (PD-1) inhibitors (PD-1i) nivolumab and pembrolizumab have been Food and Drug Administration-approved for relapsed/refractory (R/R) cHL. There is limited data on the real-world experience with PD-1i in cHL and it is unknown whether fewer selected patients treated with PD-1i derive benefits similar to those observed in published trials. MATERIALS AND METHODS: We performed a multicenter, retrospective analysis of R/R cHL patients treated with PD-1i in the nontrial setting. The primary objective was to describe progression-free survival (PFS) and overall survival (OS) in this population. Secondary objectives were to characterize response rates, toxicities, discontinuation patterns, and post-PD-1i therapies. RESULTS: The study included 53 patients from nine U.S. centers. Overall response rate (ORR), complete response (CR), and partial response (PR) to PD-1i were 68%, 45%, and 23%, respectively. Twelve-month OS and PFS were 89% and 75%, respectively; median PFS was 29 months. Ninety-six percent of patients with CR continue to respond at a median follow-up of 20 months. Toxicities were similar to those previously described. Seventy percent of patients treated with systemic therapy after PD-1i demonstrated objective responses. CONCLUSION: To our knowledge, this analysis is the first describing real-world experience with PD-1i in cHL patients in the U.S. Here, we demonstrate similar response rates compared to prior studies. The toxicity profile of PD-1i was similar to that seen in previous studies; we further describe toxicity patterns in those with prior autoimmune disease or allogeneic transplant. Post-PD-1i systemic therapies appear active. These results support the effectiveness and tolerability of PD-1i therapy in R/R cHL in a real-world setting. IMPLICATIONS FOR PRACTICE: Two PD-1 inhibitors have recently been approved for patients with relapsed/refractory classical Hodgkin lymphoma based on results from nonrandomized clinical trials. However, to date, there have been no studies evaluating the effectiveness and toxicity profile of these drugs in the real-world setting in the U.S. The present study demonstrates that patients treated in a real-world context experience similar rates of overall effectiveness compared with published clinical trials. Patients who discontinue PD-1 inhibitors may experience clinical responses to subsequent treatment with systemic chemotherapy or targeted therapy. This study provides clinicians with further insight into the effectiveness and tolerability of PD-1 inhibitors and suggests that when patients progress while on these drugs, conventional systemic chemotherapy may be an effective treatment option.

Metastatic Squamous Cell Carcinoma in the Gallbladder Fossa Complicated by a Duodenal Fistula.

Cancer of unknown primary is defined as a metastatic disease present in the absence of an identifiable primary site of origin. Squamous cell carcinoma (SCC) of unknown primary is a relatively uncommon subtype that usually involves metastases to the cervical or inguinal lymph nodes. We present a rare case of SCC of unknown primary metastasizing to the gallbladder fossa and creating a duodenal fistula. This case highlights the rarity of SCCs in the gallbladder region and the risks posed by chemotherapy in patients with gastrointestinal fistulas.

Immunogenomic Landscape Contributes to Hyperprogressive Disease after Anti-PD-1 Immunotherapy for Cancer.

Although PD-1-blocking immunotherapies demonstrate significant therapeutic promise, a subset of the patients could develop hyperprogressive disease (HPD) with accelerated tumor growth after anti-PD1 immunotherapy. To elucidate the underlying mechanisms, we compared the mutational and transcriptional landscapes between the pre- and post-therapy tumors of two patients developing HPD after anti-PD-1 immunotherapy. In post-therapy HPD tumors, somatic mutations were found in known cancer genes, including tumor suppressor genes such as TSC2 and VHL, along with transcriptional upregulation of oncogenic pathways, including IGF-1, ERK/MAPK, PI3K/AKT, and TGF-ß. We found that post-therapy HPD tumors were less immunogenic than pre-therapy tumors, concurrent with an increased presence of ILC3 cells, a subset of innate lymphoid cells. We also developed a gene expression signature predictive of HPD. In summary, we identified the genomics and immune features associated with HPD, which may help identify patients at risk of adverse clinical outcome after anti-PD-1 immunotherapy.

Real-world outcomes and management strategies for venetoclax-treated chronic lymphocytic leukemia patients in the United States.

Venetoclax is a BCL2 inhibitor approved for 17p-deleted relapsed/refractory chronic lymphocytic leukemia with activity following kinase inhibitors. We conducted a multicenter retrospective cohort analysis of patients with chronic lymphocytic leukemia treated with venetoclax to describe outcomes, toxicities, and treatment selection following venetoclax discontinuation. A total of 141 chronic lymphocytic leukemia patients were included (98% relapsed/refractory). Median age at venetoclax initiation was 67 years (range 37-91), median prior therapies was 3 (0-11), 81% unmutated IGHV, 45% del(17p), and 26.8% complex karyotype (≥ 3 abnormalities). Prior to venetoclax initiation, 89% received a B-cell receptor antagonist. For tumor lysis syndrome prophylaxis, 93% received allopurinol, 92% normal saline, and 45% rasburicase. Dose escalation to the maximum recommended dose of 400 mg daily was achieved in 85% of patients. Adverse events of interest included neutropenia in 47.4%, thrombocytopenia in 36%, tumor lysis syndrome in 13.4%, neutropenic fever in 11.6%, and diarrhea in 7.3%. The overall response rate to venetoclax was 72% (19.4% complete remission). With a median follow up of 7 months, median progression free survival and overall survival for the entire cohort have not been reached. To date, 41 venetoclax treated patients have discontinued therapy and 24 have received a subsequent therapy, most commonly ibrutinib. In the largest clinical experience of venetoclax-treated chronic lymphocytic leukemia patients, the majority successfully completed and maintained a maximum recommended dose. Response rates and duration of response appear comparable to clinical trial data. Venetoclax was active in patients with mutations known to confer ibrutinib resistance. Optimal sequencing of newer chronic lymphocytic leukemia therapies requires further study.

Predictive factors of daily opioid use and quality of life in adults with sickle cell disease.

OBJECTIVES: In adults with sickle cell disease (SCD), pain often necessitates opioid use. Few studies have examined the relationship between opioid use and health-related quality of life (HRQOL) in adults with SCD. We tested the hypothesis that higher doses of opioids are associated with worse HRQOL. METHODS: A cross-sectional cohort study was performed in adults with SCD who completed standardized and validated HRQOL questionnaires: Patient Health Questionnaire-15 (PHQ-15), Patient Health Questionnaire-9 (PHQ-9), Medical Outcome Study 36 Item Short Form (SF-36), and Generalized Anxiety Disorder questionnaire (GAD-7). Daily outpatient opioid dose was converted into morphine milligram equivalents (MME) and categorized as < 90 mg/day or ≥ 90 mg/day. Subject's questionnaire scores were compared by opioid dose. RESULTS: Ninety-nine adults completed questionnaires. The majority had HbSS and median age was 30 years. The median MME was 80 mg/day. When the association between HRQOL and opioid dose was compared, those prescribed ≥ 90 MME had significantly lower SF-36 subscale scores in 7 of 8 domains, and significantly higher severity scores in the PHQ-15, GAD-7, and the PHQ-9 in comparison those prescribed < 90 MME. Using a multivariable regression tree analysis, in addition to the presence of chronic pain, mental health, physical health, and somatic burden were key predictors of ≥ 90 MME opioid use. CONCLUSION: Higher daily opioid dose is associated with chronic pain. Among those with chronic pain, opioid dose ≥ 90 MME is associated with worse HRQOL.

Current challenges in the management of essential thrombocythemia.

Essential thrombocythemia (ET), an uncommon blood cancer, is one of the classic myeloproliferative neoplasms, a category that also includes polycythemia vera and primary myelofibrosis. All 3 diseases are clonal hematopoietic stem cell disorders. Since 2005, when scientists discovered a molecular aberration driving clonal hematopoiesis in polycythemia vera, our understanding of the genomic underpinnings of these conditions has increased rapidly. Over the last decades, primary prevention of thrombotic and hemorrhagic complications has improved the lives of patients with ET, and the ability to characterize the disease by the presence or absence of molecular mutations has lent precision to our prognostic models. This review outlines a modern approach to the diagnosis and treatment of ET. It highlights the 2016 World Health Organization standards for differentiating the disease from primary myelofibrosis, which is key for an accurate prognosis. It also describes the current risk stratification models and discusses the vascular and hemorrhagic risks that affect patients with this chronic condition, including younger individuals and pregnant women. Finally, it outlines a simple-to-follow treatment algorithm that is based on an understanding of the vascular risks and provides a foundation for discussing treatment choices with patients.

Outcomes of Patients With Double-Hit Lymphoma Who Achieve First Complete Remission.

Purpose Patients with double-hit lymphoma (DHL) rarely achieve long-term survival following disease relapse. Some patients with DHL undergo consolidative autologous stem-cell transplantation (autoSCT) to reduce the risk of relapse, although the benefit of this treatment strategy is unclear. Methods Patients with DHL who achieved first complete remission following completion of front-line therapy with either rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or intensive front-line therapy, and deemed fit for autoSCT, were included. A landmark analysis was performed, with time zero defined as 3 months after completion of front-line therapy. Patients who experienced relapse before or who were not followed until that time were excluded. Results Relapse-free survival (RFS) and overall survival (OS) rates at 3 years were 80% and 87%, respectively, for all patients (n = 159). Three-year RFS and OS rates did not differ significantly for autoSCT (n = 62) versus non-autoSCT patients (n = 97), but 3-year RFS was inferior in patients who received R-CHOP compared with intensive therapy (56% v 88%; P = .002). Three-year RFS and OS did not differ significantly for patients in the R-CHOP or intensive therapy cohorts when analyzed by receipt of autoSCT. The median OS following relapse was 8.6 months. Conclusion In the largest reported series, to our knowledge, of patients with DHL to achieve first complete remission, consolidative autoSCT was not associated with improved 3-year RFS or OS. In addition, patients treated with R-CHOP experienced inferior 3-year RFS compared with those who received intensive front-line therapy. When considered in conjunction with reports of patients with newly diagnosed DHL, which demonstrate lower rates of disease response to R-CHOP compared with intensive front-line therapy, our findings further support the use of intensive front-line therapy for this patient population.

A Fatal Case of Immune Hyperhemolysis with Bone Marrow Necrosis in a Patient with Sickle Cell Disease.

In patients with sickle cell disease, hyperhemolysis is a rare but life-threatening complication of transfusion. In this case report, we describe a 61 year-old woman with hemoglobin sickle cell (SC) disease and history of alloimmunization who developed hyperhemolysis associated with a transfusion. She was found to have a warm and a clinically-significant cold autoantibody. Severe anemia (Hb 2.7 g/dL) with reticulocytopenia and thrombocytopenia prompted a bone marrow biopsy, which demonstrated extensive bone marrow necrosis. Despite treatment, the bone marrow failure did not improve and the patient died on hospital day 38. This case illustrates the potential risks of transfusion in a patient with sickle cell disease, especially one with previous hemolytic reactions. While uncommon, hyperhemolysis can cause death, in this case by extensive bone marrow necrosis. In patients with sickle cell disease, judicious use of red cell transfusions with phenotypically-matched units can diminish, but never completely abrogate, the risks associated with transfusion.

Red cell storage age policy for patients with sickle cell disease: A survey of transfusion service directors in the United States.

In patients with sickle cell disease (SCD), the effects of the red cell storage lesion are not well defined. The objective of this study was to determine the prevalence of transfusion services that limit red cell units by storage age for patients with SCD. We developed a 22 question survey of transfusion service director opinions and their corresponding blood bank policies. Target subjects were systematically identified on the AABB website. Responses were recorded in SurveyMonkey and summarized using standard statistical techniques. Ninety transfusion service directors responded to the survey. Response rate was 22%. Only 23% of respondents had storage age policies in place for patients with SCD, even though 36% of respondents consider older units to be potentially harmful in this patient population. Of those with a policy, a less-than 15 day storage age requirement was most often used (75%), but practices varied, and most respondents (65%) agreed that evidence-based guidelines regarding storage age are needed for patients with SCD. Policies, practices and opinions about the risks of older units for patients with SCD vary. As patients with SCD may have unique susceptibilities to features of the red cell storage lesion, prospective studies in this population are needed to determine best practice.

De novo CD5+ diffuse large B-cell lymphoma: Adverse outcomes with and without stem cell transplantation in a large, multicenter, rituximab treated cohort.

De novo CD5+ diffuse large B-cell lymphomas (DLBCL) are a distinct subgroup of DLBCL with poor prognosis. However the role of rituximab-containing therapy and salvage stem cell transplantation in this patients' population remain to be defined. We retrospectively reviewed clinical features and outcomes of 102 patients with de novo CD5+ DLBCL treated with rituximab-containing therapy at nine different institutions. By Hans' criteria, 64 patients had activated B-cell (ABC) subtype, 24 germinal center B-cell (GCB) subtype, and 14 were not evaluated. No patients had a myc translocation. Eighty-three patients were treated with rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone (R-CHOP), 7 with rituximab, etoposide, cyclophosphamide, doxorubicin, vincristine, prednisone (R-EPOCH), and 6 with R-CHOP with methotrexate, 3 g/m(2) . The overall response rate to front-line therapy was 85%. The 3-year progression free survival (PFS) and overall survival (OS) for all patients were 40 and 65%, respectively. The 3-year PFS for ABC- and GCB-subtypes was 34 and 45%, respectively. The 3-year OS for ABC- and GCB-subtypes was 62 and 67%, respectively. The median time to second treatment failure was 3 months and 1 month for ABC- and GCB-subtypes, respectively. Twenty of 28 (71%) transplanted patients with autologous, allogeneic, or both, relapsed. This study confirms the poor prognosis of de novo CD5+ DLBCL in a large multi-center cohort despite initial rituximab-containing chemotherapy and suggests that stem cell transplantation fails to salvage the majority of these patients. Approaches to prevent recurrence and/or novel therapies for relapsed disease are needed for this subgroup of DLBCL patients.

Post-transplant lymphoproliferative disorders.

Post-transplant lymphoproliferative disorders (PTLD) are a serious complication after solid organ or allogeneic hematopoietic stem cell transplantation and include a range of diseases from benign proliferations to malignant lymphomas. Risk factors for developing PTLD include Epstein-Barr virus (EBV) infection, recipient age, transplanted organ, type of immunosuppression, and genetics. Uncontrolled proliferation of EBV-infected B cells is implicated in EBV-positive PTLD, whereas the pathogenesis of EBV-negative PTLD may be similar to non-Hodgkin's lymphoma in the general population. The World Health Organization (WHO) classifies PTLD into four categories: early lesions, polymorphic PTLD, monomorphic PTLD, and classical Hodgkin's lymphoma (cHL). Treatment is aimed at cure of PTLD, while maintaining transplanted organ function. However, there are no established guidelines for the treatment of PTLD. Immune suppression reduction (ISR) is the first line of treatment in most cases, with more recent data suggesting early use of rituximab. In more aggressive forms of PTLD, upfront chemotherapy may offer a better and more durable response. Sequential therapy using rituximab followed by chemotherapy has demonstrated promising results and may establish a standard of care. Novel therapies including anti-viral agents, adoptive immunotherapy, and monoclonal antibodies targeting cytokines require further study in the prevention and treatment of PTLD.