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CORD-19:185e78aee848db9cc3a4510619048a6e4acd22cc JSONTXT 9 Projects

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Id Subject Object Predicate Lexical cue
T1 0-116 Sentence denotes Febrile Hypotensive Reactions Following ABVD Chemotherapy in Patients With EBV-associated Classical Hodgkin Lymphoma
T2 118-126 Sentence denotes Abstract
T3 129-346 Sentence denotes Classical Hodgkin lymphoma (cHL) comprises approximately 10% of all cases of lymphoma worldwide and is curable with multi-agent chemotherapy in the majority of cases, including in patients with advanced stage disease.
T4 347-849 Sentence denotes The ABVD regimen (doxorubicin, bleomycin, vinblastine, and dacarbazine) is currently the most widely used front-line treatment for patients with early and advanced stage cHL, with no alternative regimen to date showing superior overall survival (OS). [1] [2] [3] Patients with human immunodeficiency virus (HIV) infection have an 11-fold increased risk for cHL, 4 and cHL is driven by the Epstein-Barr virus (EBV) in approximately 40% of cases, including nearly all cases associated with HIV infection.
T5 850-1073 Sentence denotes 5, 6 Multiple prognostic risk factors have been identified, and the International Prognostic Score (IPS) is widely used to provide riskstratification based upon clinical risk factors in patients with advanced stage disease.
T6 1074-1452 Sentence denotes 7 cHL is characterized by a relatively small proportion of pathologic Reed-Sternberg (RS) cells within a reactive inflammatory milieu and is associated with a state of increased Clinical Practice Points ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine) is a widely used front-line regimen for the treatment of early and advanced stage classical Hodgkin lymphoma (cHL).
T7 1453-1604 Sentence denotes A fulminant syndrome characterized by pyrexia and shock was observed in early trials of bleomycin, occurring more frequently in patients with lymphoma.
T8 1605-1838 Sentence denotes In the past 3 decades, only 1 case of a similar fulminant reaction following ABVD had been reported, and thus there is limited literature regarding the risk factors, clinical course, and management for this life-threatening syndrome.
T9 1839-2125 Sentence denotes We identified 3 patients experiencing febrile hypotensive reactions following ABVD chemotherapy at our institution with shared baseline clinical features, including stage IVB disease, high risk disease by International Prognostic Score, male gender, and Epstein-Barr virus-positive cHL.
T10 2126-2314 Sentence denotes All 3 patients experienced fever, rigors, tachycardia, shortness of breath or hypoxia, and an elevated venous lactate with onset less than 2 hours after completing the first ABVD infusion.
T11 2315-2527 Sentence denotes All patients received intravenous fluid resuscitations and corticosteroids, 2 patients required vasopressors owing to refractory hypotension, and 1 patient required mechanical ventilation for respiratory failure.
T12 2528-2575 Sentence denotes Symptoms resolved within 24 hours in all cases.
T13 2576-2773 Sentence denotes Two patients received bleomycin with subsequent cycles, and 1 patient was treated with AVD (doxorubicin, vinblastine, and dacarbazine); fulminant reactions were not observed with subsequent cycles.
T14 2774-2892 Sentence denotes Clinicians should be aware that fulminant febrile, hypotensive reactions can be seen following ABVD treatment for cHL.
T15 2893-3141 Sentence denotes Management with intravenous corticosteroids and intensive supportive care was associated with resolution within 24 hours of onset in the present series. cytokine production, including increased tumor necrosis factor-a, interleukin (IL)-6, and IL-8.
T16 3142-3221 Sentence denotes 8, 9 CD68þ macrophages are a prominent component of the tumor microenvironment.
T17 3222-3457 Sentence denotes A higher proportion of CD68þ cells in the tumor microenvironment are seen in EBV-positive cHL in comparison to EBV-negative cases, and a high proportion of tumor-associated CD68þ macrophages have been associated with inferior outcomes.
T18 3458-3605 Sentence denotes 10, 11 Bleomycin is an antibody complex derived from Streptomyces sp. with anti-neoplastic properties owing in part to inhibition of DNA synthesis.
T19 3606-3794 Sentence denotes 12 In early clinical investigation, bleomycin demonstrated single-agent activity in multiple solid organ malignancies, but the highest single-agent response rates were in Hodgkin lymphoma.
T20 3795-4011 Sentence denotes 13 Fever was reported in 20% to 50% of patients following singleagent bleomycin, typically occurring after the first dose, and was observed more frequently in patients with cHL compared with solid organ malignancies.
T21 4012-4277 Sentence denotes 14 Fever was typically self-limited, but in a review of the first 1174 patients treated with single-agent bleomycin, 4 cases of fulminant fever associated with hypotension and cardiorespiratory collapse leading to death were reported, all in patients with lymphoma.
T22 4278-4585 Sentence denotes In a preclinical study, bleomycin was shown to provoke fever in a dose-dependent manner in rabbits with onset 1 to 2 hours after administration, and supernatant from cultures of human and rabbit leukocytes with bleomycin induced a febrile response with shorter latency, suggesting a cytokinemediated effect.
T23 4586-4949 Sentence denotes 15 Subsequent cases of fatal or life-threatening febrile, hypotensive reactions in patients with lymphoma treated with bleomycin as part of multi-agent therapy have been reported, [16] [17] [18] [19] including a patient with a febrile, hypotensive reaction following treatment with ABVD associated with tumor lysis syndrome (TLS) and markedly elevated serum IL-6.
T24 4950-5200 Sentence denotes 19 Here we present 3 cases of patients with cHL experiencing fulminant febrile, hypotensive reactions shortly after their first dose of ABVD with similar baseline clinical features, including EBV-positive disease, and describe their clinical courses.
T25 5201-5279 Sentence denotes Cases were identified after surveying the lymphoma faculty at our institution.
T26 5280-5329 Sentence denotes Institutional review board approval was obtained.
T27 5330-5352 Sentence denotes Case Series Patient 1.
T28 5353-5518 Sentence denotes Patient 1 was 51 years old at initial presentation, with progressively worsening left inguinal lymph node enlargement, fever, malaise, night sweats, and weight loss.
T29 5519-5562 Sentence denotes He had no significant past medical history.
T30 5563-5739 Sentence denotes Physical examination was significant for temperature of 103.4 F, palpable spleen tip 2 cm below the mid-costal margin, and a large left inguinal lymph node measuring 10 Â 4 cm.
T31 5740-5876 Sentence denotes Computed tomography (CT) imaging revealed splenomegaly, and enlarged periaortic, celiac, retroperitoneal, and left inguinal lymph nodes.
T32 5877-6011 Sentence denotes Blood and urine cultures were collected and remained sterile; EBV polymerase chain reaction (PCR) was positive at 1,600,000 copies/mL.
T33 6012-6063 Sentence denotes Other laboratory values are summarized in Table 1 .
T34 6064-6321 Sentence denotes Core needle biopsy of the left inguinal lymph node showed cHL, with RS cells positive for Epstein-Barr encoding region (EBER) by in situ hybridization (ISH), and CD68 staining showed a predominance of macrophages comprising over 50% of the tumor background.
T35 6322-6378 Sentence denotes Bone marrow biopsy was negative for disease involvement.
T36 6379-6625 Sentence denotes Positron emission tomography (PET) scan showed diffuse hypermetabolic activity in lymph nodes above and below the diaphragm as well as focal sites of increased osseous uptake, consistent with Ann Arbor stage IVB disease, with IPS risk score of 6.
T37 6626-6724 Sentence denotes Intravenous ganciclovir was initiated for treatment of EBV viremia prior to starting chemotherapy.
T38 6725-6999 Sentence denotes The decision was made to begin treatment with ABVD while inpatient, with doxorubicin dose reduced by 50% (12.5 mg/m 2 ) given bilirubin elevation (3.5 on date of treatment) and risk for reduced clearance, and vinblastine, bleomycin, and dacarbazine given at standard dosing.
T39 7000-7181 Sentence denotes Vital signs at initiation of treatment were significant for temperature (T) of 97.9 F, heart rate (HR) of 87, weight 112 kg, body max index (BMI) of 33.5 kg/m 2 , and body Table 1 .
T40 7182-7274 Sentence denotes Vasopressors were weaned off within 12 hours, and the patient was extubated within 24 hours.
T41 7275-7350 Sentence denotes Bleomycin was omitted from further cycles without subsequent complications.
T42 7351-7435 Sentence denotes After 6 cycles of treatment, PET imaging was consistent with complete response (CR).
T43 7436-7538 Sentence denotes The patient remains in follow-up with no evidence of relapse over 3 years after completion of therapy.
T44 7539-7549 Sentence denotes Patient 2.
T45 7550-7734 Sentence denotes Patient 2 was 28 years old at diagnosis with a history of HIV infection treated with anti-retroviral therapy; baseline CD4 count was 287 cells/mm 3 with an undetectable HIV viral load.
T46 7735-7797 Sentence denotes He presented with fever, shortness of breath, and a dry cough.
T47 7798-7941 Sentence denotes Physical examination was significant for dry mucous membranes, diminished breath sounds bilaterally, and an enlarged right axillary lymph node.
T48 7942-7996 Sentence denotes Baseline laboratory values are summarized in Table 1 .
T49 7997-8102 Sentence denotes CT scan of the chest revealed bilateral airspace consolidation and an enlarged right axillary lymph node.
T50 8103-8207 Sentence denotes Bone marrow biopsy was performed and was interpreted as nondiagnostic with necrotizing granulomas noted.
T51 8208-8340 Sentence denotes The patient was intubated on hospital day 3 for worsening respiratory status and diagnosed with acute respiratory distress syndrome.
T52 8341-8490 Sentence denotes Bronchiolar lavage was consistent with pneumocystis pneumonia, and treatment with methylprednisolone and trimethoprim/sulfamethoxazole was initiated.
T53 8491-8717 Sentence denotes On hospital day 14, the patient was extubated, and the following day, an excisional right axillary lymph node biopsy was performed that was consistent with cHL, and the patient was transferred to our hospital for further care.
T54 8718-9021 Sentence denotes The prior bone marrow biopsy was reviewed by hematopathology at our institution and read as consistent with cHL with extensive necrosis with scattered fibro-histiocytic infiltrates containing typical RS cells, positive for EBER by ISH, and numerous CD68þ macrophages present (percentage not enumerated).
T55 9022-9169 Sentence denotes PET scan showed mildly hypermetabolic left hilar and right peri-bronchial lymph nodes and hypermetabolic postoperative changes in the right axilla.
T56 9170-9288 Sentence denotes The patient was staged as Ann Arbor stage IVB given the presence of bone marrow involvement, with IPS risk score of 5.
T57 9289-9352 Sentence denotes Oral valgancyclovir was initiated for treatment of CMV viremia.
T58 9353-9410 Sentence denotes Therapy was initiated with ABVD given at standard dosing.
T59 9411-9477 Sentence denotes Vital signs prior to start of treatment were significant for T 99.
T60 9478-9489 Sentence denotes 8 Table 1 .
T61 9490-9581 Sentence denotes Blood cultures were collected and remained sterile, and cefepime was initiated empirically.
T62 9582-9680 Sentence denotes Intravenous saline and 50 mg hydrocortisone were administered as well as hydromorphone for rigors.
T63 9681-9777 Sentence denotes Symptoms rapidly improved, with normalization of lactate and resolution of fever within 6 hours.
T64 9778-9844 Sentence denotes Antibiotics were discontinued after 24 hours of negative cultures.
T65 9845-9969 Sentence denotes ABVD was continued with dexamethasone 20 mg premedication with subsequent infusions, and no further reactions were observed.
T66 9970-10060 Sentence denotes PET scan was performed after 3 cycles to evaluate response and showed progressive disease.
T67 10061-10183 Sentence denotes Platinum-based salvage therapy was initiated; the patient is currently alive receiving salvage therapy for refractory cHL.
T68 10184-10194 Sentence denotes Patient 3.
T69 10195-10433 Sentence denotes Patient 3 was 62 years old at initial presentation, with a prior history of chronic lymphocytic leukemia (CLL) treated with 6 cycles of obinutuzumab and otlertuzumab in an investigational protocol completed 3 months prior to presentation.
T70 10434-10595 Sentence denotes He was diagnosed with IGVH unmutated CLL after presenting with bulky lymphadenopathy; baseline cytogenetics were positive for trisomy 12 as the sole abnormality.
T71 10596-10720 Sentence denotes During treatment with obinutuzumab and otlertuzumab, he experienced clinical resolution of lymphadenopathy by physical exam.
T72 10721-10838 Sentence denotes At his end of therapy evaluation 3 months after his sixth cycle of treatment, he noted daily fevers as high as 103 F.
T73 10839-10891 Sentence denotes Physical exam showed no evidence of lymphadenopathy.
T74 10892-11035 Sentence denotes He was hospitalized for further evaluation with serum EBV PCR positive at 84,523 copies/mL; other laboratory values are summarized in Table 1 .
T75 11036-11139 Sentence denotes Blood and urine cultures were collected and remained sterile, and other infectious workup was negative.
T76 11140-11357 Sentence denotes Bone marrow biopsy revealed a hypercellular marrow with absent CLL cells by morphology or by flow cytometry, but classical RS cells were present, positive for EBER by ISH, with increased surrounding CD68þ macrophages.
T77 11358-11554 Sentence denotes PET scan showed hypermetabolic activity in cervical, mediastinal, abdominal, and pelvic lymph nodes as well as hypermetabolic liver lesions and diffuse increased uptake throughout the bone marrow.
T78 11555-11659 Sentence denotes The patient was staged as Ann Arbor stage IVB Richter transformation to cHL with an IPS risk score of 5.
T79 11660-11742 Sentence denotes Oral valacyclovir was initiated, and the patient was discharged from the hospital.
T80 11743-11851 Sentence denotes Upon outpatient evaluation, the decision was made to initiate treatment with ABVD, given at standard dosing.
T81 11852-11961 Sentence denotes Vital signs prior to treatment were significant for T 99.5 F, HR 130, weight 92.5 kg, BSA 2.17, and BMI 26.9.
T82 11962-12039 Sentence denotes At 16:20, bleomycin was administered, and dacarbazine was completed at 16:40.
T83 12040-12135 Sentence denotes At 17:17, rigors were noted with temperature of 103.5 F, and inpatient admission was requested.
T84 12136-12222 Sentence denotes By 18:15, confusion and lethargy were noted with T 106 F, HR 144, BP 92/53, and RR 27.
T85 12223-12335 Sentence denotes Hydrocortisone was administered intravenously (50 mg) as well as oral acetaminophen and normal saline hydration.
T86 12336-12504 Sentence denotes The patient developed progressive hypoxia with requirement of 13L oxygen by high-flow nasal canula; chest radiograph demonstrated a pulmonary edema pattern bilaterally.
T87 12505-12641 Sentence denotes Blood and urine cultures were collected and remained sterile, and an extended respiratory viral panel returned positive for coronavirus.
T88 12642-12693 Sentence denotes Other laboratory values are summarized in Table 1 .
T89 12694-12899 Sentence denotes Despite fluid resuscitation, the patient developed progressive hypotension; norepinephrine infusion was initiated to maintain a mean arterial BP of 65, and 20 mg intravenous dexamethasone was administered.
T90 12900-12991 Sentence denotes Hypotension quickly improved, and norepinephrine was titrated off within 12 hours of onset.
T91 12992-13174 Sentence denotes Intravenous antibiotics were discontinued after blood cultures remained sterile for 48 hours, oxygen was weaned off within 24 hours, and the patient was discharged on hospital day 3.
T92 13175-13313 Sentence denotes For the remaining cycles of ABVD, dexamethasone 6 mg was given for 2 days prior to treatment in addition to 12 mg on the day of treatment.
T93 13314-13438 Sentence denotes The patient experienced rigors at home after cycle 1 day 15 and took 6 mg of oral dexamethasone with resolution of symptoms.
T94 13439-13517 Sentence denotes No subsequent episodes were noted, and the patient completed 6 cycles of ABVD.
T95 13518-13627 Sentence denotes End of therapy PET was consistent with CR, and end of therapy bone marrow biopsy was negative for cHL or CLL.
T96 13628-13951 Sentence denotes Within 6 months, relapse of CLL was diagnosed by bone marrow biopsy, and the patient opted to undergo allogeneic hematopoietic cell transplant (HCT) with reduced-intensity conditioning from a haplo-identical related donor for definitive treatment of CLL and to mitigate the risk of relapse of Richter transformation to cHL.
T97 13952-14056 Sentence denotes He remains alive in active follow-up with no evidence of relapse of CLL or cHL over 12 months after HCT.
T98 14057-14308 Sentence denotes Given the high probability of cure in cHL with front-line multiagent chemotherapy, short-and long-term toxicities from treatment are of particular importance, and awareness of potential therapyrelated toxicities and supportive management is essential.
T99 14309-14408 Sentence denotes In this case series, we highlight a rare, life-threatening early complication of therapy with ABVD.
T100 14409-14687 Sentence denotes All 3 cases occurred during cycle 1 day 1 of ABVD therapy, and the patients shared multiple baseline clinical characteristics including advanced stage disease, B symptoms, viremia, high risk IPS score, and EBER-positive disease (baseline characteristics summarized in Table 2 ).
T101 14688-15546 Sentence denotes The constellation of marked pyrexia, hypoperfusion, and respiratory failure in the absence of identified bacterial infection was reported as a rare complication in early clinical trials of single-agent bleomycin, 14 and at least 4 cases with a similar constellation of symptoms leading to fatal cardiorespiratory collapse in patients with lymphoma treated with bleomycin containing regimens were reported in the 1970s and 1980s. [16] [17] [18] 20 In a review performed in 2005 regarding the need to perform test dosing of bleomycin, the author postulated that the lack of reports of similar episodes in the 1990s or beyond may be owing to routine anti-emetic corticosteroid premedication with current bleomycin-containing regimens or that prior episodes were because of an unidentified contaminant that is no longer present in current bleomycin formulations.
T102 15547-15719 Sentence denotes 21 Since that time, there has been 1 subsequent case report of a febrile, hypotensive reaction with associated TLS within the first hour of the first ABVD infusion for cHL.
T103 15720-15875 Sentence denotes 19 This report and our series demonstrate that febrile hypotensive reactions can occur with modern bleomycin formulations and corticosteroid premedication.
T104 15876-15990 Sentence denotes TLS was not evident in the 3 cases from our institution and does not appear to be prerequisite for such reactions.
T105 15991-16171 Sentence denotes In our series, the time to onset was 60 to 90 minutes after completion of bleomycin infusion, which coincides with the onset of pyrexia in animal studies of single-agent bleomycin.
T106 16172-16384 Sentence denotes 15 The time course and the similarity to prior case reports following singleagent bleomycin treatment point to bleomycin as the causative agent, but it remains possible that other agents in ABVD are contributory.
T107 16385-16577 Sentence denotes Although fulminant febrile episodes were fatal in many early case reports, [16] [17] [18] 20 all 3 patients in the present series survived with resolution of symptoms within 24 hours of onset.
T108 16578-16727 Sentence denotes In addition to intensive supportive care, all patients received intravenous corticosteroid treatment after onset (management summarized in Table 3 ).
T109 16728-16870 Sentence denotes As this syndrome is clinically indistinguishable from bacterial sepsis, all patients received empiric antibiotics while cultures were pending.
T110 16871-17637 Sentence denotes The high fevers, cardiorespiratory collapse, and neurologic symptoms seen in this series and prior reports are similar to the cytokine release syndrome (CRS) seen following bispecific antibody and chimeric antigen receptor T cell therapy. [22] [23] [24] Multiple cytokines have been implicated in CRS, including interferon-g, IL-10, and IL-6, and monoclonal antibodies targeting the IL-6/IL-6 receptor axis such as tocilizumab are used for CRS treatment, 24, 25 Marked elevation of serum IL-6 was noted in the case report by Suzuki et al, 19 but to our knowledge, tocilizumab has not been used in the context of bleomycin-associated febrile, hypotensive reactions, and in all cases in the present series, symptoms resolved rapidly following corticosteroid treatment.
T111 17638-17729 Sentence denotes Given the rarity of this syndrome, the safety of bleomycin rechallenge is not well-defined.
T112 17730-17888 Sentence denotes Bleomycin was omitted from subsequent cycles for Patient 1, but Patient 2 and 3 tolerated bleomycin in subsequent cycles with increased steroid premedication.
T113 17889-18139 Sentence denotes Although bleomycin does contribute to the activity of ABVD, it is the least active agent in the combination regimen 26 and can be safely omitted from cycles 3 to 6 of therapy for patients with advanced stage disease with negative interim PET imaging.
T114 18140-18475 Sentence denotes 27 The substitution of brentuximab vedotin for bleomycin (A-AVD) was compared with ABVD in patients with stage III/IV cHL in the phase III ECHE-LON-1 study, and resulted in a statistically significant improvement in the primary endpoint of modified progression-free survival at 2 years with no difference in OS at the time of analysis.
T115 18476-18762 Sentence denotes 2 A-AVD is approved by the United States Food and Drug Administration for front-line treatment of advanced stage cHL and would be an alternative consideration to bleomycin rechallenge or AVD therapy for advanced stage patients experiencing fulminant hyperpyrexia during cycle 1 of ABVD.
T116 18763-18889 Sentence denotes The shared clinical characteristics of the patients in our series may shed light on the pathophysiology of this rare syndrome.
T117 18890-19031 Sentence denotes As in prior reports, all patients in the present series were febrile prior to the start of therapy and presented with advanced stage disease.
T118 19032-19328 Sentence denotes As bleomycin can induce fever presumably through cytokine-mediated stimulation, 15 one possible explanation is that febrile patients have increased baseline levels of key cytokines, and the additive effect of cytokine stimulation by bleomycin crosses a threshold, triggering a fulminant reaction.
T119 19329-19548 Sentence denotes 17 Other common features of all 3 patients in this series include EBVþ disease and increased CD68þ tumor associated macrophages, and to our knowledge, this represents a novel observation not noted in prior case reports.
T120 19549-19753 Sentence denotes The majority of prior reports occurred before the development of standard of care ISH testing for EBER 28 or routine CD68 staining, and thus it is unknown whether prior cases shared these common features.
T121 19754-20109 Sentence denotes In comparison to EBV-negative cHL, EBV-positive disease has been associated with a gene expression signature of macrophage response including upregulation of CXCL10, CCL5, CD14, CD68, 29,30 regulatory T cell type 1 recruitment including upregulation of CCL20 31 and LAG3, 32 and altered cytokine signaling with upregulation of IL10, TGFB-1, IFNG, and TNF.
T122 20110-20352 Sentence denotes 32 The febrile, hypotensive syndrome following bleomycin treatment is clinically similar to CRS, a syndrome in which macrophage activating cytokines IL-10 and IL-6 are elevated, and macrophage activation appears to be central to pathogenesis.
T123 20353-20519 Sentence denotes 33 The mechanism of fulminant febrile hypotensive reactions following bleomycin requires further elucidation, including determining the role of macrophage activation.
T124 20520-20650 Sentence denotes Fulminant febrile, hypotensive reactions following ABVD therapy for cHL are a rare but life-threatening complication of treatment.
T125 20651-20705 Sentence denotes Associated TLS is not prerequisite for such reactions.
T126 20706-20880 Sentence denotes With intensive supportive care and corticosteroid treatment, all patients in the present series survived these reactions with resolution of symptoms within 24 hours of onset.
T127 20881-20962 Sentence denotes Clinician awareness of this rare syndrome is essential for successful management.
T128 20963-21027 Sentence denotes The authors have stated that they have no conflicts of interest.