Cardiovascular Risks with Epidermal Growth Factor Receptor (EGFR) Tyrosine Kinase Inhibitors and Monoclonal Antibody Therapy.

PURPOSE OF REVIEW: Tyrosine kinase inhibitors (TKI) and monoclonal antibodies (mAbs) that target the epidermal growth factor receptor (EGFR) have changed the therapeutic landscape across a range of solid malignancies. However, there is little data regarding the cardiovascular (CV) impact of these agents. The purpose of this review is to discuss reported CV effects, pathophysiology, pre-treatment screening, diagnostic workup, and treatment recommendations in this patient population. RECENT FINDINGS: It is apparent that CV events are not class dependent, and while infrequently reported in clinical trials, unique CV toxicity may occur with EGFR inhibitors, including structural, electrical, and vascular events. There remains an unmet need to fully elucidate the spectrum of CV events associated with EGFR inhibitors. Early CV screening, close clinical monitoring, coupled with a multidisciplinary approach between medical and cardio-oncology is needed to minimize the potentially detrimental impact of cardiotoxicity in this patient population.

Acupuncture and Vitamin D for the Management of Aromatase Inhibitor-Induced Arthralgia.

PURPOSE OF REVIEW: Aromatase inhibitor-induced arthralgia (AIA) is a very common syndrome which significantly affects breast cancer survivors' quality of life, and it often leads to non-compliance with aromatase inhibitor (AI) therapy. However, the treatment of AIA remains a clinical challenge. Here, we will review the current data for acupuncture and vitamin D in the management of AIA. RECENT FINDINGS: Acupuncture has been shown to improve AIA symptoms, but it has not consistently been proven to offer significantly more clinical benefit than sham acupuncture. Similarly, while some vitamin D trials have shown benefit, the studies have not consistently shown improvement in AIA symptoms. Neither acupuncture nor vitamin D can be touted as standard treatments for AIA. However, many patients do experience subjective improvement of their symptoms with these therapies. When other treatments, such as exercise and duloxetine, are not feasible or not effective, it is reasonable to offer a trial of acupuncture or vitamin D to patients who are suffering from AIA, as the potential harms are very few, and they do offer possible relief from AIA symptoms.

Bilateral subdural hematomas, an unusual vaso-occlusive event and prolonged prothrombin time in a 58-year-old victim of an armed robbery.

Factor VII deficiency is one of the most common of rare bleeding disorders(1). This autosomal recessive disorder has a prevalence of 1:500,000 with geographic variations. Clinical manifestations vary from asymptomatic to severe mucocutaneous bleeding. According to the International Registry of Factor VII Deficiency (IRF7) epistaxis is the most common clinical manifestation. Gastrointestinal and central nervous system(CNS) bleeding are rare presentations.(2-4) We present here the case of a patient with life-threatening CNS bleeding who was found at the age of 58 years to have congenital factor VII deficiency.

Pulmonary Immune-Related Adverse Events of PD-1 Versus PD-L1 Checkpoint Inhibitors: A Retrospective Review of Pharmacovigilance.

Introduction: Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapeutics. However, immune-related adverse events (irAEs) increase morbidity and mortality and thereby limit therapeutic utility. The real-world incidence of the entire spectrum of pulmonary irAEs has not been systematically described. The objective of this study is to assess the risk of developing pulmonary irAEs (pneumonitis, pleural events [i.e., effusion and pleurisy], exacerbations of airway disease [i.e., bronchitis and bronchiectasis], and sarcoidosis) with exposure to five commonly used ICIs: nivolumab, pembrolizumab, durvalumab, avelumab, and atezolizumab. Methods: We conducted a retrospective review of the Food and Drug Administration Adverse Events Reporting System (FAERS) pharmacovigilance database. We collected data from 2012 to 2021 to assess the risk of pulmonary irAEs and performed a disproportionality analysis using Open-Vigil, a software package used for analysis of pharmacovigilance data, to calculate reporting odds ratios (RORs). We used 95% CIs to evaluate the precision of RORs. An ROR greater than 1 and the upper limit of the 95% CI indicated statistical significance. Results: A total of 17,273,403 events were reported in FAERS between 2012 and 2021. Of these, 88,099 (0.5%) were attributed to the PD-1 (programmed cell death protein 1) inhibitors and 21,905 (0.1%) to PD-L1 (programmed death ligand 1) inhibitors of interest. The most common indication for using the ICIs of interest was lung cancer: a total of 2832 (46.70%) for the PD-1 inhibitors and 1311 (70.9%) for the PD-L1 inhibitors. In the anti-PD-1 group, 2342 (38.6%) patients were hospitalized, and 1962 (32.4%) patients died from the lung adverse event. In the PD-L1 group, 744 (40.3%) patients were hospitalized, and 520 (28.1%) patients died from the event. Nivolumab resulted in the highest statistically significant risk (ROR, 10.5; 95% CI, 10.1-10.9) for pneumonitis. Avelumab had a lesser risk for pneumonitis (ROR, 0.2; 95% CI, 0.2-0.3). The risk for pleural events was highest with nivolumab (ROR, 3.6; 95% CI, 3.4-3.9), followed by pembrolizumab (ROR, 1.8; 95% CI; 1.6-2.0) (p < 0.001), with the lowest risks from durvalumab, atezolizumab, and avelumab. For ICI-related sarcoidosis, the risk was most significant with pembrolizumab (ROR, 3.6; 95% CI, 2.8-4.7), followed by nivolumab (ROR, 2.5; 95% CI, 1.9-3.5) (p < 0.001). The RORs for all five ICIs were less than 1 for exacerbations of airway diseases as compared with other drugs. Conclusion: Using a pharmacovigilance database, we found an increased risk of multiple pulmonary irAEs after ICI therapy, particularly with PD-1 inhibitors. Further work is needed to investigate the incidence of pulmonary irAEs other than pneumonitis.

Global Ophthalmology Practice Patterns during COVID-19 Pandemic and Lockdown.

AIM: To assess the impact of practice patterns amongst global ophthalmologists during severe acute respiratory syndrome Coronavirus 2 (SARS Cov2) causing Corona virus disease (COVID-19) and understand the various modifications made to address emergency surgeries and practice needs. METHODS: An online survey was sent to practicing ophthalmologists around the world through email, Whatsapp™ ListServ17.0™ (for pediatric ophthalmologists), WeChat™ (China) and ophthalmology associations (Indonesia, Philippines, Ireland). All queries were collected and categorized. Responses to the queries were given according to the recommendations by the Ophthalmology association. Practices ability to deal with the COVID were also classified according to country and type of access to PPE. Statistical analyses of the association between these data and queries, where appropriate were carried out. RESULTS: One thousand nine hundred sixteen ophthalmologists were invited to participate in a survey between April 10th and April 30th, 2020 of which 1207 responded, which is a response rate of approximately 63%. The majority of respondents were from India, Indonesia, China, Singapore and the USA. Our study indicates a precipitous drop in surgical procedures with 46% (n = 538) ophthalmologists ceased to operate on their patients and almost 40% (n = 486) were doing less than 25% of their original number of surgeries. The intent to resume elective surgeries was a consideration in 41% (n = 495) after an evaluation of the situation and in consultation with professional bodies. More than 2/3 of the respondents (n = 703) made it a priority to use and mandate their patients to practice physical distancing, wearing masks, and hand dis-infection for protection to limit the spread of infection. CONCLUSION: This global survey provides a real-world assessment of diverse practices that were in various forms of "shut down mode" and circumstances with varying capabilities to deal with COVID. It is unprecedented that the collective wisdom for a curtailment of practice has had an enormous immediate and far reaching implications on the livelihoods of ophthalmologists, their staff, and their families. Nevertheless, ophthalmologists and their staff remain resilient and have adapted to these changes pragmatically.

Primary diffuse large B-cell lymphoma of the uterus: A SEER database analysis.

ABSTRACT: Uterine diffuse large B-cell lymphoma (DLBCL) is a rare clinical condition. Most studies for uterine DLBCL are derived from case reports and series. Our main objective was to present a new case while also investigating the demographic, clinical characteristics, and survival of women with primary uterine DLBCL as compared to non-uterine DLBCL using the Surveillance, Epidemiology, and End Results incidence database. We queried the Surveillance, Epidemiology, and End Results database for women aged 18 years or older with a diagnosis of primary DLBCL from 1975 to 2017. The most common site of primary uterine DLBCL is the cervix uteri not otherwise specified, followed by endometrium, uterus not otherwise specified, corpus uteri, myometrium and isthmus uteri. Non-uterine DLBCL cases tend to be older than uterine DLBCL cases. Uterine DLBCL is most common among women aged 40 to 64 years. Patients with uterine DLBCL showed greater survival than non-uterine DLBCL patients, and patients treated in the rituximab era also exhibited a survival benefit. Both the elderly and African American cohorts experienced worse overall survival.

Cardiotoxicity Associated with Anti-CD19 Chimeric Antigen Receptor T-Cell (CAR-T) Therapy: Recognition, Risk Factors, and Management.

Chimeric antigen receptor T-cells (CAR-T) are improving outcomes in pediatric and adult patients with relapsed or refractory B-cell acute lymphoblastic leukemias and subtypes of non-Hodgkin Lymphoma. As this treatment is being increasingly utilized, a better understanding of the unique toxicities associated with this therapy is warranted. While there is growing knowledge on the diagnosis and treatment of cytokine release syndrome (CRS), relatively little is known about the associated cardiac events that occur with CRS that may result in prolonged length of hospital stay, admission to the intensive care unit for pressor support, or cardiac death. This review focuses on the various manifestations of cardiotoxicity, potential risk factors, real world and clinical trial data on prevalence of reported cardiotoxicity events, and treatment recommendations.

A Phase II Study of the Efficacy and Safety of Chloroquine in Combination With Taxanes in the Treatment of Patients With Advanced or Metastatic Anthracycline-refractory Breast Cancer.

INTRODUCTION: Chemotherapy eliminates most of the cancer cells except those with potential for self-renewal and tumor initiation, called cancer stem cells (CSCs). Chloroquine, through bioinformatics, was found to be a potential agent to target CSCs. We designed a phase II trial to test the efficacy and safety of chloroquine in combination with taxane or taxane-like chemotherapy agents in patients with advanced or metastatic breast cancer who are refractory to anthracycline-based chemotherapy. PATIENTS AND METHODS: Female patients ≥ 18 years of age who had received prior anthracycline chemotherapy were enrolled in this study. Chloroquine 250 mg was given daily orally with either docetaxel or paclitaxel or nab-paclitaxel or ixabepilone every 3 weeks. The maximum number of 3-week cycles allowed was 6. The primary efficacy endpoint was the objective response rate (ORR). The secondary efficacy endpoints included progression-free survival (PFS) and safety analysis. RESULTS: Thirty-eight patients were enrolled in the study, and 31 patients were evaluated for response. The median age was 54.1 years (range, 31.7-78.1 years). The ORR was 45.16% (95% confidence interval [CI], 29.2%-62.2%), which was higher than the expected ORR of 30% (P = .03). Patients were followed for a median of 25.4 months and experienced a median PFS of 12.4 months (95% CI, 4.9-24.6 months) and a median OS of 25.4 months (95% CI, 13.7-83.5 months). The combination was well-tolerated, with only 13.15% of patients experiencing grade ≥ 3 adverse events. CONCLUSION: A combination of chloroquine with taxane or taxane-like chemotherapy was efficacious in patients with locally advanced or metastatic breast cancer with prior anthracycline-based chemotherapy.

Hepatitis B Virus Reactivation in Cancer Patients Treated With Immune Checkpoint Inhibitors.

There have been unique adverse events reported with targeted blockade of programmed death-1 (PD-1), programmed death-ligand-1 (PD-L1), and cytotoxic T-lymphocyte-associated protein-4 (CTLA4), including immune mediated toxicities. Recently, there have been reports of hepatitis B reactivation (HBVr) occurring with PD-1/PD-L1 inhibitors, which may result in treatment delays, interruptions, or discontinuation. This retrospective literature review and analysis of the Food and Drug Administration's (FDA) Adverse Events Reporting System (FAERS) queried reported cases of "Hepatitis B reactivation" reported with the PD-1/PD-L1 inhibitors "Pembrolizumab," "Atezolizumab," "Nivolumab," "Durvalumab," "Avelumab," and "Ipilimumab" from initial FDA approval to June 30, 2020. Disproportionality signal analysis was determined by calculating a reporting odds ratio (ROR) and 95% confidence intervals (CI). The ROR was considered significant when the lower and upper limits of the 95% CI were >1 and confirmed by the Fisher exact test (P<0.05). Pembrolizumab had a strong signal associated with HBVr, with a ROR of 2.32 (95% CI: 1.11-4.28) (P=0.013) and was the only statistically significant finding. There were no reports of HBVr with Ipilimumab or Avelumab. Additional prospective studies should be conducted to validate the findings of this retrospective pharmacovigilance analysis to determine the risk of HBVr in patients receiving immune checkpoint inhibitors.

Targeting mTOR and DNA repair pathways in residual triple negative breast cancer post neoadjuvant chemotherapy.

Triple-negative breast cancer (TNBC) patients who do not achieve pathologic complete response post neoadjuvant chemotherapy have a poor prognosis. Alteration in PI3K/mTOR plus DNA repair pathways are some of the major mechanisms of chemotherapy resistance. We designed an open-label phase II clinical trial to evaluate if the combination of everolimus (mTOR inhibitor) plus cisplatin (interferes with DNA function) will improve the rate of pathologic response, as assessed by residual cancer burden (RCB). Twenty-four Stage II/III TNBC patients with residual cancer > 1 cm post neoadjuvant anthracycline and taxane-based chemotherapy were enrolled. Patients received everolimus daily orally at 10 mg for 12 weeks and cisplatin IV at 20 mg/m2 weekly for 4 cycles (21-day cycle), until definitive surgery. The primary endpoint was the rate of RCB-0-I at the surgery. The median age of the whole cohort was 50.1 years, with 66.7% non-Hispanic Caucasians. Of the 24 patients enrolled, 22 were included in the efficacy analysis. Twenty-one patients underwent definitive surgery while one patient developed distant metastasis. Five patients had RCB-I at surgery, a response rate of 23% (5/22). Patients with germline PALB2 mutation or somatic PI3KCA mutation had a pathologic response, achieving RCB-I at the surgery. Three patients had metaplastic histology achieving RCB-I at the surgery. Estimated OS at 1 year was 100% in the RCB-I group vs. 76.5% in others, which was not statistically significant due to the small sample size. Certain cohorts including PALB2 germline mutation carrier and somatic PI3KCA mutations warrant further investigation.Trial registration: Clinicaltrials.gov identifier: NCT01931163. https://clinicaltrials.gov/ct2/show/NCT01931163 .

A phase 1/2 clinical trial of the nitric oxide synthase inhibitor L-NMMA and taxane for treating chemoresistant triple-negative breast cancer.

The inducible nitric oxide signaling (iNOS) pathway is associated with poor prognosis in triple-negative breast cancer (TNBC). Prior studies using in vivo models showed that inhibition of the iNOS signaling pathway using the pan-NOS inhibitor NG-monomethyl-l-arginine (L-NMMA) reduced tumor growth and enhanced survival in patients with TNBC. Here, we report a first-in-class phase 1/2 trial of L-NMMA combined with taxane for treating patients with chemorefractory, locally advanced breast cancer (LABC) or metastatic TNBC. We also examined immune cell correlates of chemotherapy response. 35 patients with metastatic TNBC were recruited: 15 in the phase 1 trial and 24 in the phase 2 trial (including 4 recommended phase 2 dose patients from the phase 1 trial). The overall response rate was 45.8% (11 of 24): 81.8% (9 of 11) for patients with LABC and 15.4% (2 of 13) for patients with metastatic TNBC. Among the patients with LABC, three patients had a pathological complete response at surgery (27.3%). Grade ≥3 toxicity was noted in 21% of patients; however, no adverse events were attributed to L-NMMA. Immune cells analyzed by CyTOF indicated that chemotherapy nonresponders showed greater expression of markers associated with M2 macrophage polarization and increased concentrations of circulating IL-6 and IL-10 cytokines. In contrast, chemotherapy responders showed an increase in CD15+ neutrophils in blood, as well as a decrease in arginase (a marker of protumor N2 neutrophils) in tumor biopsies obtained at the end of treatment. L-NMMA combined with taxane warrants further investigation in larger clinical studies of patients with breast cancer.

Multiple myeloma with concurrent immune thrombocytopenic purpura.

Multiple myeloma (MM) is the second most common haematological malignancy in the USA. MM has been linked to various autoimmune disorders in many studies; one systemic review even suggested an increased risk of MM among patients with autoimmune disorders. MM is associated with many haematological, rheumatologic and neurological conditions. A few case reports suggest that MM can be associated with immune thrombocytopenic purpura (ITP), although this is rare. We present a case of MM with concurrent ITP which was refractory of steroids and intravenous immunoglobulin but had a response with anti-neoplastic therapy for MM. We also review all the cases of ITP with MM described in the literature. If conventional treatment for ITP associated with MM fails to improve platelet count, anti-neoplastic therapy for MM should be considered.

Mycobacterial Infections With Ruxolitinib: A Retrospective Pharmacovigilance Review.

BACKGROUND: Ruxolitinib is a selective Janus kinase inhibitor (JAKI) 1/2 approved for the treatment of myelofibrosis (MF) and polycythemia vera (PV). These patients may be at risk for developing opportunistic infections. We assessed the number of patients that developed typical (Mycobacterium tuberculosis [MTB]) and atypical mycobacterial infections (AMI) while on treatment with ruxolitinib by utilizing the United States Food and Drug Administration (FDA) adverse events reporting system (FAERS). MATERIALS AND METHODS: This is a retrospective study utilizing FAERS, a pharmacovigilance database. We queried FAERS for cases of MTB and AMI secondary to ruxolitinib between January 1, 2011 and December 31, 2018. Disproportionality signal analysis was done by calculating the reporting odds ratio (ROR). ROR was considered significant when the lower limit of 95% confidence interval (CI) was > 1. RESULTS: There were 91 reported cases of MTB associated with ruxolitinib compared with 4575 cases from all other drugs. The ROR was significant at 9.2 (95% CI, 7.5-11.4). There were 23 reports of AMI with ruxolitinib compared with 1287 reported with all other drugs. The ROR was significant at 8.3 (95% CI, 5.5-12.6). Twelve (13.2%) patients with MTB and 8 (34.8%) with AMI died. CONCLUSION: Patients on ruxolitinib are at increased risk of developing MTB and AMI. Clinicians should be aware of this risk and consider screening patients for latent MTB prior to initiating ruxolitinib.

Radiation therapy in primary mediastinal large B-cell lymphoma treated with DA-R-EPOCH.

DA-R-EPOCH is used in PMBCL due to its good outcomes without radiation. We present three cases that required consolidation with radiation despite using this regimen. More studies are needed before considering DA-R-EPOCH standard of care.

Mycobacterial infections due to PD-1 and PD-L1 checkpoint inhibitors.

BACKGROUND: Immune checkpoint inhibitors that block programmed cell death-1 (PD-1) and programmed cell death ligand-1 (PD-L1) have improved outcomes for many cancer subtypes but do exhibit toxicity, in the form of immune-related adverse events. OBJECTIVE: The aim of this study was to investigate the emerging toxicities of PD-1 and PD-L1 inhibitors including acute or reactivation of tuberculosis (TB) and atypical mycobacterial infection (AMI). METHODS: This study was completed as a retrospective review using the US Food and Drug Administration Adverse Events Reporting System (FAERS) for incidence of TB and AMI due to PD-1 and PD-L1 inhibitors compared with other FDA (Food and Drug Administration) approved drugs. The statistical methods included disproportionality signal analysis using the reporting OR (ROR) to compare cases. The 95% Wald CI was reported to assess the precision of the ROR. RESULTS: Out of the 10 146 481 adverse events (AEs) reported to FAERS for all drugs between 1 January 2015 and 31 March 2020, 73 886 AEs were due to the five FDA approved PD-1/PD-L1 inhibitors. Seventy-two cases of TB were due to PD-1/PD-L1 inhibitors. Specifically, 45 cases (62.5%) due to nivolumab, 18 (25%) due to pembrolizumab, 5 (7%) due to atezolizumab and 4 (5.5%) due to durvalumab. There were 13 cases of AMI: 9 (69.3%) due to nivolumab, 2 (15.3%) due to pembrolizumab and 1 (7.7%) each due to durvalumab and atezolizumab. Avelumab was not attributed to any AE of TB or AMI. From analysis of the FAERS database, the calculated ROR for TB due to PD-1/PD-L1 inhibitors was 1.79 (95% CI, 1.42 to 2.26) (p<0.0001) and for AMI was 5.49 (95% CI, 3.15 to 9.55) (p<0.0001). CONCLUSION: PD-1/PD-L1 inhibitors used in the treatment of cancer subtypes is associated with increased TB and AMI risk. Although this complication is rare, clinicians using PD-1/PD-L1 inhibitors should be aware of the risks.

Clinical Utility of Reflex Ordered Testing for Molecular Biomarkers in Lung Adenocarcinoma.

INTRODUCTION: In order to standardize and expedite molecular biomarker testing, we implemented reflex ordered testing of targeted gene alterations in newly diagnosed lung adenocarcinomas within our hospital system. PATIENTS AND METHODS: Reflex ordered testing of specific molecular biomarkers at the time of pathologic diagnosis of lung adenocarcinoma was approved and adopted system-wide in our hospital during 2017. Through institutional review board approval, we retrospectively looked at cohort of patients whose specimens received a diagnosis of lung adenocarcinoma, with molecular biomarker testing performed at Houston Methodist Hospital between 2016 and 2018. We compared average turnaround time (TAT) from 2016 (prior to reflex ordered testing) to 2017 and 2018 (post reflex ordered testing). RESULTS: Standard molecular testing performed on 39 patients in 2016 had an average TAT of 52.6 days, whereas reflex ordered molecular testing in 2017 yielded an average TAT of 26.5 days (n = 127) and 15.6 days in 2018 (n = 54). The average TAT for reporting of molecular results significantly decreased by 37 days (P = .0002) within our hospital system post adoption of reflex ordered testing for lung adenocarcinoma. Reflex ordered testing also resulted in a higher variant detection rate than standard molecular biomarker ordering practices (48.8% vs. 25.6%; P < .05). Overall, the frequencies and types of variants identified among our cohort were similar to previous reports. CONCLUSIONS: Reflex ordered testing of molecular biomarkers in lung adenocarcinoma led to significantly decreased TAT within our hospital system and higher detection rates of targeted gene alterations.

T-cell lymphoma secondary to checkpoint inhibitor therapy.

BACKGROUND: Murine model suggests programmed cell death-1 (PD-1), an immune checkpoint not only plays role in tumor escape but is also a tumor suppressor for T-cells. But until, no reports of secondary T-cell lymphoma postuse of immune checkpoint inhibitors (ICIs) has been reported. Herein, we present a hitherto unreported phenomenon of secondary T-cell lymphoma when PD-1 inhibitor was used in a patient diagnosed with a tumor of epithelial origin. CASE REPORT: A man in mid-70s presented with biopsy-proven metastatic tumor of epithelial origin. Patient received carboplatin in combination with paclitaxel for four cycles leading to partial remission. The patient was subsequently switched to pembrolizumab due to persistent disease in the mediastinum. After four cycles of PD-1 inhibitor, patient presented with progression of disease and was diagnosed with biopsy-proven peripheral T-cell lymphoma-not otherwise specified. Based on the reported tumor suppressor function of PD-1 in murine models, we hypothesized that the use of PD-1 inhibitor caused clonal proliferation of abnormal T-cell clone leading to T-cell lymphoma. T-cell receptor (TCR) sequencing was performed by TCRß sequencing and T-cell clones from pre-ICI treatment specimen were compared with post-ICI treatment specimens. We show that one of the T-cell clones present in pre-ICI treatment specimen at a low frequency of had massive expansion to become most dominant clone in post-ICI treatment specimens leading to lymphoma. Moreover, targeted exome sequencing revealed a new TET2 mutation in the clone representing the lymphoma.Next, we retrospectively reviewed the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS), the pharmacovigilance database from 2012 to 2018 to find the reported incidence of this phenomenon and calculated the reporting OR (ROR) for disproportionality analysis for risk of T-cell lymphoma due to checkpoint inhibitors compared with other drugs. In FAERS, the incidence of T-cell lymphoma post-ICIs (pembrolizumab, nivolumab and ipilimumab) was found to be 0.02% with 17% mortality. The ROR probability of risk of T-cell lymphoma compared with other drugs in pharmacovigilance database was increased at 1.91. CONCLUSIONS: T-cell lymphoma is a rare sequela of ICIs with high mortality. Larger studies with long-term follow-up of patients receiving ICIs is needed.

The development of T-cell malignancies in patients with pre-existing myeloproliferative neoplasms: a report of three cases.

Secondary acute myeloid leukaemia complicating the natural disease course of pre-existing Philadelphia chromosome-negative myeloproliferative neoplasms (PN-MPN) is well documented and associated with treatment challenges and significant morbidity. The incidence of a T-cell malignancy developing in patients with pre-existing PN-MPN is uncommon, with one case documented in the literature. We present two cases of angioimmunoblastic T-cell lymphoma (AITL) and one case of T-cell acute lymphoblastic leukaemia (T-ALL) that developed in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), respectively. All malignancies were advanced at diagnosis and exhibited disease progression, regardless of the mutational status of the underlying ET/PMF, presence of cytogenetic abnormalities, type of T-cell neoplasm or systemic chemotherapy utilised. The median time to diagnosis of AITL or T-ALL from the onset of MPN was 4.5 years (range: 6 months-10 years). This single institutional case series demonstrates the possibility of an association between T-cell neoplasms and PN-MPNs.