Geriatric screening tools predict survival outcomes in older patients with diffuse large B cell lymphoma.

The proportion of elderly patients with diffuse large B cell lymphoma (DLBCL) appears to be increasing, with outcomes varying widely because of the patients' heterogeneity. Geriatric assessment is used to predict prognosis in elderly patients with DLBCL, but the utility of two simple screening tools for patients with DLBCL, the Flemish version of the Triage Risk Screening Tool (fTRST) and G8, has remained to be elucidated. We retrospectively assessed patients using fTRST and G8, and evaluated the impacts of the scores on survival outcomes in older patients with newly diagnosed DLBCL. A total of 59 patients aged 65 years or older and who were diagnosed with DLBCL were included. The median age was 77 years (range, 65-91 years), and the initial treatments were R-CHOP (63%) and R-THPCOP (31%). The estimated 2-year overall survival (OS) rate was significantly lower in patients with abnormal fTRST scores (≥ 2; N = 17) than in those with normal fTRST scores (< 2; N = 42): (50.5% (95% CI, 22.7-73.0%) vs. 82.2% (95% CI, 63.8-91.8%), P = 0.007). The estimated 2-year OS rate was significantly lower also in patients with abnormal G8 scores (≤ 14; N = 38) than in those with normal G8 scores (> 14; N = 21): (66.1% (95% CI, 46.7-79.5%) vs. 86.8% (95% CI, 55.7-96.7%), P = 0.03, respectively). These associations were independently significant after adjusting for other significant factors by multivariate analysis. These results suggest that the easy-to-use geriatric screening tools, fTRST and G8, have strong prognostic value for OS in older patients with DLBCL.

Sinusitis caused by Exserohilum rostratum after cord blood transplantation for myelodysplastic syndrome: A case report and literature review.

Invasive fungal disease is a serious infectious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Exserohilum rostratum is a species causing phaeohyphomycosis, which rarely causes invasive disease in humans. We treated a case of sinusitis caused by E. rostratum after cord blood transplantation (CBT). A 60-year-old man with myelodysplastic syndrome, who had a medical history of an operation to correct deviation of the nasal septum, developed sinusitis caused by E. rostratum under prolonged profound neutropenia after a second CBT because of the graft rejection of the first transplantation. Liposomal amphotericin B improved the sinusitis. A literature review revealed nine reported cases of sinusitis caused by E. rostratum, including our case. Although five cases had severe neutropenia at onset (HSCT recipients, n = 2; aplastic anemia, n = 3), the remaining four had no preexisting immunosuppressive conditions. However, three of the four patients had preexisting nasal diseases with or without a history of surgery, as in our case. Excluding our case, the outcome was fatal in five neutropenic patients, whereas the four patients without neutropenia recovered. Although sinusitis caused by E. rostratum is rare, E. rostratum should be recognized as a possible pathogen causing sinusitis in highly immunosuppressed patients such as HSCT recipients. Preexisting nasal disease and/or nasal surgery could be risks for this infection.

Allogeneic hematopoietic stem cell transplantation following treatment with brentuximab vedotin for refractory Hodgkin lymphoma.

Brentuximab vedotin (BV) is a novel agent used for the treatment of relapsed or refractory Hodgkin lymphoma. We have described two patients with refractory Hodgkin lymphoma, who were successfully treated with BV followed by allogeneic hematopoietic stem cell transplantation (HSCT). Although both patients were resistant to conventional chemotherapies, they responded to four or five doses of BV given every 3 weeks. Then, the patients underwent bone marrow transplantation from unrelated donors after reduced-intensity conditioning consisting of fludarabine and melphalan. They remained progression-free for more than 3 years after the transplantation. These findings suggest that BV could be a promising bridging therapy to curative allogeneic HSCT for relapsed or refractory Hodgkin lymphoma. Further accumulation of such cases is warranted to evaluate the efficacy and safety of BV therapy prior to allogeneic HSCT.

Bacteremia due to Capnocytophaga species during chemotherapy-induced neutropenia in patients with hematological malignancies.

The number of reported cases of infections due to Capnocytophaga species (spp.) is limited. We herein describe four cases developing bacteremia due to Capnocytophaga spp. during neutropenia after chemotherapy for hematological malignancies. At the onset of bacteremia, 3 of the 4 patients had oral mucositis, and 2 were co-infected with other bacteria. Two patients developed bacteremia while receiving fluoroquinolone as prophylaxis against bacterial infection. Bacteremia resolved with administration of antimicrobial agents in all patients and no recurrences were observed thereafter. The emergence of fluoroquinolone-resistant or beta-lactamase-producing Capnocytophaga spp. has recently been reported. Therefore, Capnocytophaga spp. could be causative pathogens in breakthrough and refractory infections under fluoroquinolone prophylaxis and empiric therapy, respectively, for febrile neutropenia. Capnocytophaga spp. should be recognized as one of the causative pathogens of febrile neutropenia. Furthermore, accumulation of cases and susceptibility data are required to establish an optimal treatment protocol.

Single-institutional retrospective analysis of Japanese patients with chronic lymphocytic leukemia.

Unlike in Western countries, chronic lymphocytic leukemia (CLL) is a rare lymphoid malignancy in Japan, and its clinical features remain to be elucidated in the Japanese population. Therefore, we retrospectively analyzed 29 Japanese CLL patients newly diagnosed at our institute. Seventeen (59%) were male, and their median age was 62 years. With a median follow-up period from diagnosis of 69 months (range, 3-170 months), 9 patients received some form of treatment for CLL. Three patients died of disease progression with or without infection (n=2) or skin cancer (n=1). Five-year overall and treatment-free survival rates were 83% (95%CI, 46-96%) and 67% (95%CI, 45-81%), respectively. Two patients received allogeneic hematopoietic stem cell transplantation for refractory disease, and both were alive without disease relapse at 53 and 110 months, respectively, after transplantation. These results suggest the clinical courses of Japanese patients with CLL to be comparable to those in Western countries. However, future studies of larger numbers of patients are needed to further elucidate the features and long-term clinical courses of CLL in the Japanese population.

[Cellulitis due to Achromobacter xylosoxidans during bortezomib therapy for multiple myeloma].

Achromobacter xylosoxidans (A. xylosoxidans) is a non-fermentative gram-negative rod. This organism is reportedly a causative pathogen of bacteremia mainly in patients with hematological disorders. However, only one case of cellulitis due to A. xylosoxidans associated with hematological malignancy has been reported. An 80-year-old man developed cellulitis and subsequent bacteremia due to A. xylosoxidans during bortezomib therapy for multiple myeloma. Although his condition was serious enough to require intensive care, he fully recovered with appropriate antimicrobial agents and supportive care. The isolate was broadly resistant to antimicrobial agents, including cefepime, amikacin, and ciprofloxacin. Therefore, the identification and selection of appropriate antimicrobial agents were considered to have contributed to the successful outcome in this case. Physicians should recognize A. xylosoxidans as a possible pathogen causing cellulitis and secondary bacteremia, as well as being aware of its broad resistance to antimicrobial agents.

[Bacteremia due to Rothia mucilaginosa after chemotherapy for myeloid malignancies].

The number of reported cases of bacteremia due to Rothia mucilaginosa (R. mucilaginosa), a component of the normal flora of human gastrointestinal tract mucosa, is limited. We encountered three cases of bacteremia due to R. mucilaginosa during neutropenia after chemotherapy for myeloid malignancies. Although all three patients were successfully treated with antimicrobial agents, one patient developed disseminated lesions in the lungs and soft tissue. The portal of R. mucilaginosa bacteremia is reportedly mucositis or dental disorders; however, no such complications were identified in our patients. Even in the absence of a preexisting portal, R. mucilaginosa should be recognized as a potential causative pathogen of bacteremia during neutropenic periods. Accumulations of cases and isolates are required to further elucidate the risk factors for developing R. mucilaginosa bacteremia, its clinical course, and the optimal antimicrobial treatment.

Evaluation of safety and efficacy of transjugular liver biopsy in allogeneic hematopoietic stem cell transplant recipients.

We retrospectively evaluated the safety and utility of transjugular liver biopsy (TJLB) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Ten patients underwent HSCT between 1991 and 2013. Eight patients with thrombocytopenia received platelet transfusions before and/or during TJLB. No complications associated with TJLB were observed. Samples adequate for a pathological diagnosis were obtained in 9 of the 10 patients, and the diagnoses made by TJLB were graft-versus-host-disease in eight patients and non-specific hepatitis in one. These results suggest that TJLB is a safe and effective procedure for the evaluation of liver injury in HSCT recipients.

Maximum standard uptake value of 18F-fluorodeoxyglucose positron emission tomography is a prognostic factor for progression-free survival of newly diagnosed patients with diffuse large B cell lymphoma.

The treatment of patients with diffuse large B cell lymphoma (DLBCL) would be greatly facilitated with a rapid method for determining prognosis that can be performed more easily and earlier than cytological or specific pathological examinations. It has been suggested that newly diagnosed patients with DLBCL who have low maximum standard uptake value (SUV(max)) on (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) are more likely to be successfully treated and remain in remission compared with patients with high SUV(max), but this concept has been poorly studied. We retrospectively analyzed 50 patients with de novo DLBCL to evaluate the relationship between the SUV(max) and disease progression. For patients with low SUV(max) (n = 10) and high SUV(max) (n = 40) (P = 0.255), respectively, the 3-year overall survival rates were 90 and 72 %, and the progression-free survival (PFS) rates were 90 and 39 % (P = 0.012). By multivariate analysis, the revised International Prognostics Index (R-IPI) and SUV(max) at diagnosis were shown to predict longer PFS. The 3-year PFS for patients with low SUV(max) classified into the good prognosis group by R-IPI was 100 vs. 62 % for those with high SUV(max) (P = 0.161), and patients with low SUV(max) classified into the poor prognosis group by R-IPI was 80 vs. 18 % for those with high SUV(max) (P = 0.050). We conclude that the SUV(max) on FDG-PET for newly diagnosed patients with DLBCL is an important predictor of disease progression, especially for patients with poor prognosis by R-IPI.

[Sodium-losing nephropathy caused by tacrolimus after allogeneic hematopoietic stem cell transplantation].

A 39-year-old woman (Case 1) and a 57-year-old woman (Case 2) underwent allogeneic bone marrow transplantation for acute lymphoblastic leukemia and follicular lymphoma, respectively. Both patients had received tacrolimus orally for treatment of or prophylaxis against graft-versus-host disease. Seventeen months (Case 1) and 2 months (Case 2) post-transplantation, when the trough level of tacrolimus was maintained around 10 ng/ml, the serum sodium levels of Cases 1 and 2 decreased to 123.5 mEq/l and 125.6 mEq/l, respectively. Urinary sodium excretions increased to 186.8 mEq/day and 375.7 mEq/day, respectively. Sodium-losing nephropathy due to tacrolimus was diagnosed, and reducing the dose of tacrolimus with no other intervention resulted in resolution of the hyponatremia. Although sporadic kidney transplantation cases with sodium-losing nephropathy due to tacrolimus have been reported, no prior cases with this complication after hematopoietic stem cell transplantation (HSCT) have been reported. Sodium-losing nephropathy should be recognized as one of the renal toxicities of tacrolimus in HSCT as well as kidney recipients.

Long-term follow-up of reduced-intensity allogeneic hematopoietic stem cell transplantation for refractory or relapsed follicular lymphoma.

Although allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative treatment for refractory or relapsed follicular lymphoma (FL), transplant-related mortality (TRM) greatly interferes with the success. A variety of reduced-intensity conditionings (RICs) have been used to reduce TRM, but an optimal conditioning for FL has not been fully established. We retrospectively evaluated the outcome of allogeneic HSCT for FL with RIC consisting of fludarabine and melphalan. Nineteen adult patients with relapsed or refractory FL were conditioned with fludarabine (125 mg/m2) and melphalan (140 mg/m2), and received grafts from an HLA-identical sibling (n = 6) or an unrelated donor (n = 13). For the prophylaxis of graft-versus-host disease (GVHD), cyclosporine A or tacrolimus with short-term methotrexate was given. There were no early deaths before engraftment, and all patients achieved engraftment. Three patients died of extensive-type chronic GVHD (n = 2) or bacterial infection (n = 1) without disease progression. With a median follow-up period of 75.2 months (range: 33.3­111.9 months), 16 patients were alive without disease progression. Both the 5-year overall and progression-free survival rates were 84.2% (95% CI: 67.7­100%). These results strongly suggest that allogeneic HSCT with RIC using fludarabine and melphalan could be a promising treatment choice for refractory or relapsed FL.

Variable magnitude of drug interaction between oral voriconazole and cyclosporine A in recipients of allogeneic hematopoietic stem cell transplantation.

Drug interaction between voriconazole and calcineurin inhibitors is often problematic after allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. We previously demonstrated an unpredictable inter-individual variability in the magnitude of this drug interaction; however, the route of drug administration was not taken into account. In this study, the drug interaction between voriconazole and calcineurin inhibitors was further analyzed under the condition that both agents were administered orally. Twenty adult recipients of HSCT who had already been on a steady dose of oral cyclosporine A (CsA) and were started on oral voriconazole (400 mg/d) were eligible. The changes in the concentration/dose (C/D) ratio of CsA were evaluated by comparing the trough concentrations of CsA measured before and 7-10 d after initiating voriconazole. The median C/D ratio of CsA increased significantly from 64.1 to 114.3 (ng/mL)/(mg/kg) after initiating voriconazole (p < 0.01), and the median increase was 83.0% (range, 0.3-224.7%). The plasma concentration of voriconazole did not correlate significantly with the increase of the C/D ratio (ρ = -0.18, p = 0.45). These results indicate that the magnitude of drug interaction between oral voriconazole and CsA is widely variable, and it could not be explained by the difference in the blood levels of voriconazole. Further studies are required to elucidate the mechanism for this variability.

[Follicular lymphoma showing long-term false positive results by FDG-PET after rituximab-containing chemotherapy].

We report a patient with follicular lymphoma who had false positive results on 18-fluorodeoxyglucose positron emission tomography (FDG-PET) tests for more than six months due to inflammatory reactions continuing over a long period of time after chemotherapy with rituximab. Although FDG-PET has advantages over other imaging methods when used for the evaluation of the response to chemotherapy and detection of recurrence, attention should be paid to the possibility of false positive results due to such inflammatory conditions, especially when rituximab is administered. Biopsy of the FDG-uptake lesions is strongly recommended if recurrence is suspected.

Cytomegalovirus retinitis after allogeneic hematopoietic stem cell transplantation under cytomegalovirus antigenemia-guided active screening.

Although cytomegalovirus (CMV) remains a leading cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation (HSCT), the incidence of CMV retinitis is considered to be lower than the incidence of CMV infection in other organs following allogeneic HSCT. In this study, the incidence and characteristics of CMV retinitis were retrospectively evaluated in recipients of allogeneic HSCT. Ophthalmological screening was performed at the development of ocular symptoms or positive CMV infection using peripheral blood evaluated by pp65 antigenemia or polymerase chain reaction. Of the 514 patients, 13 patients developed CMV retinitis. The median onset of CMV retinitis was day 34 (range, 21-118) post transplant, and the cumulative incidence was 2.5% (95% CI, 1.6-4.2) at 6 months after transplantation. Five patients presented ocular symptoms at the onset. In the remaining eight asymptomatic patients, the diagnosis of CMV retinitis was made by the screening guided by positive CMV infection. All evaluable patients responded to antiviral treatment but three showed incomplete improvement with ocular sequela. Our results suggest that the incidence of CMV retinitis after allogeneic HSCT is not negligible and active ophthalmological screening based not only on symptoms but also positive CMV infection monitoring contributes to the early diagnosis of CMV retinitis.

Successful treatment of breakthrough disseminated Trichosporon asahii fungemia in a patient with acute myeloid leukemia receiving itraconazole prophylaxis.

We encountered a case of a 73-year-old man with acute myeloid leukemia who developed Trichosporon asahii systemic infection while on itraconazole prophylaxis during severe neutropenia. Cryptococcal antigen was useful for diagnosis. Although itraconazole was ineffective in protecting against trichosporonosis, treatment was successful with voriconazole following liposomal amphotericin B.

Hyponatremia associated with human herpesvirus-6 (HHV-6) encephalitis after allogeneic hematopoietic stem cell transplantation: A presentation different from HHV-6 myelitis.

Human herpesvirus-6 (HHV-6) encephalitis and myelitis following allogeneic hematopoietic stem cell transplantation (HSCT) is frequently life-threatening. We retrospectively evaluated the clinical significance of hyponatremia in cases of HHV-6 encephalitis/myelitis. Using an institutional database and medical records, we identified and retrospectively analyzed 16 cases of HHV-6 encephalitis and/or myelitis after allogeneic HSCT. HHV-6 encephalitis and myelitis were defined as the symptoms/signs with HHV-6-DNA in the cerebrospinal fluid. Seizure and memory disorder were defined as symptoms/signs of encephalitis, and dysesthesia and vesicorectal disorder as those of myelitis. Five patients developed encephalitis with or without myelitis, and 11 patients developed myelitis alone. Hyponatremia (median 129.1 mEq/L; range 125.9-130.1) was observed in all five patients with HHV-6 encephalitis at diagnosis, and values were significantly lower than those in patients with HHV-6 myelitis alone (median 137.6; range 134.0-142.2; P < 0.01). In three of the five patients with encephalitis, the decrease in sodium level preceded the clinical onset of encephalitis by one or two days. These results suggest that hyponatremia may be an important manifestation of HHV-6 encephalitis, but not of myelitis, and could be a useful tool for the early prediction or diagnosis of HHV-6 encephalitis.

Effects of calcineurin inhibitors on sodium excretion in recipients of allogeneic hematopoietic stem cell transplantation.

Calcineurin inhibitors (CIs) such as cyclosporine A (CSA) and tacrolimus often cause renal dysfunction, resulting in increased serum creatinine, hyperkalemia, and hyperuricemia. However, the effects of CIs on sodium excretion have not been fully elucidated. We retrospectively evaluated the effects of CI administration on sodium excretion in recipients of allogeneic hematopoietic stem cell transplantation (HSCT). Fifty consecutive recipients each of allogeneic HSCT receiving either CSA or tacrolimus (100 patients in total) with available data for weekly fractional excretion of sodium (FENa) for a 4-week period after transplantation were enrolled in this retrospective analysis. No significant differences in patient characteristics were observed between CSA and tacrolimus groups except for the type of donor. FENa was significantly higher at the 3rd (1.25 ± 0.80) and 4th weeks (1.53 ± 1.06) after transplantation as compared with that at the 1st week (0.93 ± 0.51; P < 0.01, P < 0.001, respectively) in the tacrolimus group, but not at any time point in the CSA group. In addition, FENa was significantly higher in the tacrolimus group than the CSA group at the 4th week (1.53 ± 1.06 vs. 1.13 ± 0.80; P < 0.05). These results suggest that tacrolimus increases sodium excretion after allogeneic HSCT, and that this effect is minimal with CSA.