Transplantation-associated thrombotic microangiopathy (TA-TMA) is a devastating complication of hematopoietic stem cell transplantation. TA-TMA likely represents the final stage of vascular endothelial injury; however, its pathophysiology is largely unknown, making clinical management difficult. Recently, the association of neutrophil extracellular traps (NETs) with the development of thrombotic thrombocytopenic purpura and hemolytic uremic syndrome has been reported. Thus, we explored whether NETs are also relevant to the occurrence of TA-TMA. We retrospectively analyzed post-transplant trends of serum NET levels in 90 patients, 11 of whom developed TA-TMA. Relative to baseline (before the conditioning regimen), elevated serum NET levels either at 4 weeks after transplantation or as early as the day of transplantation were associated with significantly increased risk of TA-TMA. In contrast, thrombomodulin, a potential marker for TA-TMA, was not helpful to predict the occurrence of TA-TMA in our study. In addition, we directly detected glomerular deposition of NETs in 2 TA-TMA patients. Increased NET levels are a significant risk factor for TA-TMA, suggesting that NET level is a useful biomarker for TA-TMA.
We report the case of a 45-year-old male patient who developed human herpesvirus 6 (HHV6)-associated pleurisy after an unrelated cord blood transplantation (CBT) for acute lymphoblastic leukemia. A large amount of pleural effusion accompanied by interstitial pneumonitis was noted on the right side on day 37 posttransplantation. A real-time quantitative PCR (RQ-PCR) assay revealed that the HHV6 viral load was substantially higher in the pleural effusion than in the peripheral blood plasma at the onset of pleurisy, with 2.2 × 102 and 7.9 × 103 copies of HHV6 DNA/mL in the peripheral blood plasma and the supernatant of the pleural effusion, respectively. Moreover, HHV6 DNA was still detected in the pleural effusion after antiviral therapy. Therefore, the pleural cavity may have been the primary site of HHV6 replication in the present case. To our knowledge, the present study is the first detailed report of adult HHV6-associated pleurisy after CBT. HHV6-associated pleurisy should be considered a potential complication when pleural effusion of unknown cause is encountered after CBT, even in the absence of HHV6 DNA in the peripheral blood.
A 61-year-old man was admitted to our hospital with fever and massive leukocytosis. A bone marrow smear revealed an increased density of myeloid cells in various stages of maturation as well as dysplasia in the neutrophils. There was no proliferation of blasts, eosinophils, or basophils. Genomic analysis of the bone marrow cells revealed no detectable abnormalities associated with myeloproliferative neoplasms, including BCR-ABL1. Therefore, the patient was diagnosed with atypical chronic myeloid leukemia (aCML). Chromosomal analysis revealed the presence of 1-17 double minute chromosomes (dmin) in 20 of 20 tumor cells examined. Multiple MYC signals were detected via interphase fluorescence in situ hybridization, indicating MYC gene amplification in the dmins. Three months after the oral administration of hydroxyurea, leukocytosis reoccurred. Therefore, induction therapy followed with umbilical cord blood transplantation was performed. However, MYC signals remained detectable in the bone marrow sample obtained immediately after neutrophil engraftment, indicating the presence of residual tumor cells. To the best of our knowledge, this is the first case report of aCML with dmin gene amplification, suggesting that the dmin MYC amplification exacerbated the patient's disease.
In this multicenter, single-arm, phase II study, the efficacy and safety of ibrutinib were examined in Japanese patients with relapsed or refractory mantle cell lymphoma (MCL). Patients (age ≥20 years) with relapsed or refractory MCL who had progressed after receiving at least one prior treatment regimen, were enrolled. Patients were treated with oral ibrutinib (560 mg once daily; 28-day cycle) until disease progression (or relapse), unacceptable toxicity, or study end. The primary end-point was overall response rate. Secondary end-points included duration of response (DOR), time to response, progression-free survival (PFS), overall survival, and safety. Of the 16 patients who received treatment, 5 patients discontinued the study (progressive disease, 4; sepsis, 1). Median duration of ibrutinib exposure was 6.5 months (range, 2.8-8.3 months). The overall response rate was 87.5% (90% confidence interval, 65.6-97.7; complete response = 2 [12.5%]; partial response = 12 [75.0%]). Median time to response for all responders (n = 14) was 1.8 months (range, 0.7-5.3 months). The median DOR and PFS were not estimable due to censoring (range: DOR, 1.1-6.4+ months; PFS, 2.8-8.0+ months). Overall survival data were immature due to the limited observation period. A total of 8/16 patients (50%) had at least one grade 3 adverse event (AE), and 5 (31.3%) patients reported serious AEs. The most commonly reported AEs were diarrhea and stomatitis (37.5% each), platelet count decrease (31.3%), and anemia (25%). Overall, orally administered single agent ibrutinib was efficacious with an acceptable safety profile in Japanese patients with relapsed or refractory MCL. Clinical trial registration NCT02169180 (ClinicalTrials.gov).
We report here a patient with extremely indolent mantle cell lymphoma (MCL) who had progressed and required immunochemotherapy 20 years after diagnostic splenectomy. Non-nodal, indolent MCL patients may progress after such an extraordinary long indolent phase, and we recommend lifelong follow up for such cases.
