The effects of allogeneic hematopoietic stem cell transplantation (allo‐HSCT) on systemic chronic active Epstein–Barr virus infection (sCAEBV) are yet to be analyzed in a large number of patients. ...Using the Japanese registry database, Transplant Registry Unification Management Program, we investigated the outcomes of 102 sCAEBV patients who underwent allo‐HSCT. The median age at HSCT was 21 years, and the three‐year overall survival (3‐year OS) rate was 72.5%. Of the 90 patients whose viral load after allo‐HSCT was evaluated, 56 (62.2%) achieved a virological complete response, defined by the complete resolution of disease activity with a significant decrease in EBV‐DNA in peripheral blood. The multivariate Cox proportional hazard model indicated that advanced age, in adolescents and young adults (AYA) (age, 15–39) and adults (age, ≥40 years) was a risk factor of poor OS. The hazard ratios (HRs) of the AYA and adult groups were 10.87 (95% confidence interval CI: 1.98–59.56, p = .006) and 15.93 (95% CI: 2.45–103.8, p = .004), respectively. Disease activity (HR 5.74), elevated soluble IL‐2 receptor (sIL‐2R) (≥ median, 691 U/mL) at HSCT (HR 6.93), and conditioning without radiotherapy (HR 3.53) were also independently associated with poor survival. Notably, 79% of radiotherapy doses were less than 6 Gy. Regardless of the presence of hemophagocytic lymphohistiocytosis, the group with a high sIL‐2R level (≥2000 U/mL) showed a poorer prognosis. Although allo‐HSCT is the only curative therapy for sCAEBV, treatment strategies need to be improved for high‐risk patients, especially those with high levels of sIL‐2R.
A 40-year-old woman developed therapy-related acute myeloid leukemia (t-AML) with inv(16)(p13.1q22) and a rare type D form of core-binding factor β-subunit gene-myosin heavy chain 11 gene ...(CBFB-MYH11) fusion transcript approximately 2.5 years after receiving chemoradiotherapy for uterine cervical cancer. t-AML with inv(16)(p13.1q22) and rare non-type A CBFB-MYH11 typically develops after exposure to a topoisomerase II inhibitor, with a short period of latency of one to five years. As the patient had no history of exposure to topoisomerase II inhibitors, among her previously used chemotherapeutics, the topoisomerase I inhibitor, irinotecan, was speculated to be the most plausible cause of t-AML in this case. The present case suggests that irinotecan may cause t-AML resembling that associated with topoisomerase II inhibitors.
Late-onset hemorrhagic cystitis (HC) is a well-known complication of bone marrow transplantation (BMT) that is mainly attributed to infection with BK virus (BKV) and adenovirus (AdV). From 1986 ...through 1998, 282 patients underwent BMT, and 45 of them developed HC. Urine samples tested positive for AdV in 26 patients, of which 22 showed virus type 11. Among patients who underwent allogeneic BMT, logistic regression analysis revealed acute graft-versus-host disease (grade, ⩾2) to be the most significant predictive factor for HC (P < .0001). In addition, a total of 193 urine samples regularly obtained from 26 consecutive patients who underwent allogeneic BMT were examined for BKV, JC virus (JCV), and AdV by means of polymerase chain reaction. Of patients without HC, approximately 30% of the specimens tested positive for BKV (58 samples) and JCV (55 samples), whereas 5 (3%) tested positive for AdV. Of the 3 samples obtained from patients with HC, the numbers of positive results for BKV, JCV, and AdV were 3, 1, and 1, respectively; the numbers of positive results increased to 14 of 17, 9 of 17, and 10 of 17, respectively, when we added another 14 samples obtained from 14 patients with HC (P < .0001, P = .026, and P < .0001, respectively). In conclusion, there was significant correlation between AdV and HC in the patients we studied.
Summary
Primary vitreoretinal lymphoma (PVRL) is a rare subtype of malignant lymphoma with a poor prognosis because of high frequency of central nervous system (CNS) progression. Identification of ...factors associated with CNS progression is essential to improve the prognosis of patients with PVRL. We conducted a retrospective study of 54 patients diagnosed with PVRL and treated at our hospital to identify factors associated with CNS progression and prognosis. All patients were treated with intravitreal methotrexate (MTX) injections in the affected eyes until lesion resolution. Twenty‐four patients were treated with systemic administration of high‐dose MTX (systemic HD‐MTX) every other week for a total of five cycles following intravitreal MTX injection. Of 24 patients, 20 completed five cycles of systemic HD‐MTX. The 5‐year cumulative incidence of CNS progression and overall survival (OS) rate were 78.0% and 69.0% respectively. By univariate and multivariate analyses, bilateral disease and the detection of B‐cell clonality confirmed by flow cytometric analysis were risk factors associated with CNS progression. Moreover, systemic HD‐MTX completion reduced the risk of CNS progression and was identified as a factor affecting OS. In this study, factors for CNS progression identified may potentially contribute to the optimized therapeutic stratification to improve the survival of patients with PVRL.
Primary vitreoretinal lymphoma (PVRL) is a rare subtype of malignant lymphoma with a poor prognosis because of high frequency of central nervous system (CNS) progression. We conducted a retrospective study of 54 patients diagnosed with PVRL and treated at our hospital, and bilateral disease and detection of B‐cell clonality confirmed by flow cytometric analysis were risk factors associated with CNS progression. Moreover, systemic high‐dose methotrexate completion reduced the risk of CNS progression and was identified as a factor affecting overall survival. In this study, factors for CNS progression identified may potentially contribute to the optimized therapeutic stratification to improve the survival of patients with PVRL.
Methotrexate (MTX)‐associated lymphoproliferative disorder (MTX‐LPD) is a troublesome problem in patients receiving MTX for rheumatoid arthritis (RA). However, its incidence, prognosis, and risk ...factors remain unclear. In this retrospective study, we evaluated the actual incidence, prognostic impact, and risk factors of MTX‐LPD. Of the 986 patients with RA treated with MTX, 90 patients experienced 95 new malignancies (NMs), with LPD as the most frequent in 26 patients. The cumulative LPD incidences were 1.3% and 4.7% at 5 and 10 years after MTX initiation, respectively. Among the 24 patients who discontinued MTX after developing LPD, 15 showed sustained regression, without difference in overall survival between patients with LPD and without NM. Inflammatory markers and absolute lymphocyte counts were not useful for early LPD development detection, but most of the patients with LPD had persistently elevated erythrocyte sedimentation ratios. Regarding concomitant drugs, tacrolimus increased the risk only if patients were not receiving biological disease‐modifying antirheumatic drugs (bDMARDs). bDMARDs did not increase the risk for any of the drugs or the number of classes used. The number of LPD cases was lower in patients with IL‐6A even after a long period after MTX, although with no statistically significant difference. Thus, approximately 1 in 20 patients with RA developed MTX‐LPD over the 10 years of MTX treatment, but it did not affect the survival of patients with RA. Tacrolimus increased the risk of developing LPD for certain patients and should be used with caution.
The cumulative lymphoproliferative disorder (LPD) incidences were 1.3% and 4.7% at 5 and 10 years after methotrexate (MTX) initiation, respectively. Among the 24 LPD patients who discontinued MTX after developing LPD, 15 showed sustained regression.
Systemic chronic active Epstein-Barr virus infection (sCAEBV) was defined as a T- or NK-cell neoplasm in the 2017 World Health Organization (WHO) classification. To clarify the clinical features of ...sCAEBV under this classification and review the effects of chemotherapy, we performed a nationwide survey in Japan from 2016 through 2018 of patients with sCAEBV newly diagnosed from January 2003 through March 2016. One hundred cases were evaluated. The patients were aged 1 to 78 years (median, 21) and included 53 males and 47 females. Spontaneous regression was not observed in patients with active disease. In the childhood-onset group (age, <9 years), 78% of the patients were male. In contrast, 85% of the patients in the elderly-onset group (age, >45 years) were female. The prognosis of the childhood-onset group was better than those of the adolescent/adult- and elderly-onset groups. The main chemotherapies used were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 cases and cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) in 45 cases. The rate of complete response (CR), defined as complete resolution of disease activity, was 17% for cooling therapy and 13% for CHOP. Virological CR was not observed. The 3-year overall survival rates in patients treated with chemotherapy only (n = 20), chemotherapy followed by allogeneic hematopoietic stem cell transplantation (allo-HSCT; n = 47), and allo-HSCT only (n = 12) were 0%, 65%, and 82%, respectively. Distinct characteristics were observed between childhood- and elderly-onset sCAEBV, and they appeared to be different disorders. Chemotherapy is currently insufficient to resolve disease activity and eradicate infected cells. The development of an effective treatment is urgently needed.
•Childhood- and elderly-onset sCAEBV, T- and NK-cell type, may be different disorders.•Chemotherapy is currently insufficient to resolve disease activity and eradicate infected cells of sCAEBV.
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Background and aims
Chronic active Epstein-Barr virus infection (CAEBV) is classified into T- or NK-cell neoplasms in the new WHO classification revised in 2017. Allogeneic stem cell transplantation ...(allo-HSCT) has recently been reported to be an effective treatment for this disorder. Conversely, effects of chemotherapies on CAEBV have not yet been examined in a large number of patients. To clarify clinical features and the current state of chemotherapies for CAEBV under the new definition of the disease, we performed a nationwide survey in Japan.
Methods
Questionnaires were sent to all educational hospitals certified by the Japanese Society of Hematology and the Japanese Pediatric Society. Subjects were patients newly diagnosed with CAEBV between January 2003 and March 2016. CAEBV was diagnosed according to criteria suggested by the Research group of Measures against Intractable Diseases by Ministry of Health, Labour and Welfare of Japan in 2016: (1) elevated EBV DNA load in peripheral blood (PB) (>102.5 copies/μg DNA); (2) detection of EBV infection in T or NK cells from the affected tissues or PB; (3) systemic inflammatory symptoms (such as fever, lymphadenopathy, liver dysfunction, progressive skin lesions, vasculitis, and uveitis) persisting for >3 months; and (4) exclusion of other possible diagnoses, such as primary EBV infection, autoimmune disease, immunodeficiencies, and lymphomas. Patients who fulfilled (1)-(4) were diagnosed with CAEBV. These criteria were established based on those proposed by Okano et al.(Am J Hematol. 2005;80,p64) and Kimura et al.(Blood. 2012;119,p673) and were compatible with the definition of CAEBV described by WHO in 2017. The disease activity was defined according to the previous reports (Blood. 2012;119,p673 and BMT. 2016;51,p879) as follows: positive for fever, ALT level elevation, vasculitis, progressive skin lesions, or uveitis. Effects of treatments were evaluated as follows: partial response (PR), partial resolution of disease activity; complete response (CR), complete resolution of disease activity with EBV load in PB remaining high (>102.5 copies/μg DNA, which is the upper limit for healthy people); virological CR (vCR), CR with a significant decrease in the EBV DNA load in PB (<102.5 copies/μg DNA).
Results
Completed questionnaires were returned by 29 institutes and 100 patients were evaluated. They were 53 males and 47 females aged 1-78 (median, 21) years. Types of EBV-infected cells were as follows: CD4 (n = 25), CD8 (n = 13), and CD56 (n = 28). The 3-year overall survival (OS) from diagnosis was 58%.
Because different outcomes have been reported between children and adults with CAEBV, we divided patients into three groups according to their onset ages: childhood onset (CO) with patients aged <9 years, adolescent- and adult-onset (AAO), and advanced age-onset (AO) with patients aged >45 years. Seventy-eight percent patients in the CO group were males. Conversely, 85% patients in the AO group were females. The 3-year OS from diagnosis in the CO, AAO, and AO groups were 83%, 57%, and 31%, respectively. The prognosis of CO of CAEBV was significantly better than that of AAO (p = 0.0151) and AO (p = 0.0034) of CAEBV. Spontaneous regression was not observed in patients with active disease. Main chemotherapies employed were a combination of cyclosporine A, steroids, and etoposide (cooling therapy) in 52 patients and CHOP in 45 patients. The rate of CR + PR was as follows: cooling therapy, 57% and CHOP, 39%. Viral CR was not observed. Three-year OS from the start of treatment was 0% in patients treated with only chemotherapy (n = 20) and 69% in those who received allo-HSCT (n = 59).
Conclusions
Based on the difference in OS and increased prevalence of males in the CO group, it can be concluded that CO of CAEBV may be independent from AO and AAO of CAEBV. Chemotherapy alone is currently insufficient for eradicating infected cells and resolving CAEBV. The development of an effective treatment reagent is an urgent issue.
No relevant conflicts of interest to declare.
A 43-year-old man presenting with oral bleeding was diagnosed with acute promyelocytic leukemia (APL). Induction chemotherapy consisting of all-trans retinoic acid and idarubicin was initiated, and ...disseminated intravascular coagulation (DIC) was treated with fresh frozen plasma and recombinant thrombomodulin infusions. The patient was free from neurological symptoms throughout the clinical course. However, cerebral hemorrhagic lesions were detected incidentally on magnetic resonance imaging performed to screen for leukemic central nervous system invasion at 2 weeks after treatment initiation. Imaging findings suggested subacute or later-phase cerebral hemorrhage. Platelet transfusions and other supportive care was provided. Serial imaging evaluations confirmed reduction of the hemorrhagic lesions. Hematological remission was achieved after induction chemotherapy, and no symptoms due to cerebral hemorrhage developed during the subsequent consolidation therapy. As patients with APL characteristically experience hemorrhagic events due to bleeding tendency caused by DIC, physicians should be aware of the possibility of asymptomatic cerebral hemorrhage in these patients.
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