Yasuhito Nannya

Prognostic value of the combination of serum l-kynurenine level and indoleamine 2,3-dioxygenase mRNA expression in acute myeloid leukemia

Takeshi Hara, Takuro Matsumoto, Yuhei Shibata, Nobuhiko Nakamura, Hiroshi Nakamura, Soranobu Ninomiya, Junichi Kitagawa, Yasuhito Nannya, Masahito Shimizu, Hiroyasu Ito, Kuniaki Saito and Hisashi Tsurumi First Department of Internal Medicine, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Informative Clinical Medicine, Gifu University Graduate School of Medicine, Gifu, Japan; Department of Human Health Sciences, Graduate School of Medicine and Faculty of Medicine, Kyoto University, Kyoto, Japan

Efficacy of rituximab maintenance therapy for aggressive B-cell lymphoma depends on use of rituximab in induction therapy: a meta-analysis of randomized controlled trials

Contrary to the established role of rituximab maintenance therapy for advanced follicular lymphoma with a high tumor burden,1 it remains controversial as to whether rituximab confers advantageous effects for aggressive lymphoma when used as maintenance therapy. Recently, a cardinal study from an Austrian group reported the results of the randomized NHL13 trial, which demonstrated no significant prolongation in event-free survival (EFS) by adding rituximab maintenance for patients with aggressive lymphoma who achieved CR/CRu with R-CHOP-like regimens.2 The interpretation of this study and previous trials featuring rituximab maintenance for aggressive lymphoma, suffers from the problem of inconsistent results, which are probably attributable to the different study designs among trials. Therefore, we conducted a meta-analysis to inquire into those features connected to the benefits associated with rituximab maintenance. We extracted studies by searching Medline (years dating from 1960 to May 2015), The Cochrane Library, and ongoing and unpublished trials.3,4 The terms “rituximab”, “maintenance”, and “lymphoma” were cross-searched. Out of the 739 candidate papers and clinical study registries, we extracted prospective randomized controlled trials where case cohorts were administered with single-agent rituximab as maintenance therapy for responding patients (PR or better) to induction treatments, with or without consolidative autologous stem-cell transplantation (ASCT), and were compared with control cohorts who were followed with observation alone. Studies focusing mainly on mantle cell lymphoma were excluded as the basic treatment scheme for mantle cell lymphoma differs to that for aggressive lymphoma. As a result, we extracted 4 relevant reports.2–5–7 The details of these studies are shown in Table 1. Three studies targeted untreated patients and the other targeted patients with relapsed/refractory status. Induction regimens included rituximab in two studies, and not in one. The remaining study had randomized patients into two arms of those receiving rituximab-containing and non-rituximab containing regimens before maintenance therapy, thus patients in this study were divided into rituximab-naive or not in the subgroup analysis.6 The pooled estimates of the effect were calculated using the random effects model using the DerSimonian-Laird method with inverse-variance weighting. Hazard ratio (HR) was selected to measure responses, and adverse effects were evaluated by using risk difference (RD). Three of the studies examined event-free survival (EFS) and one examined failure-free survival (FFS), and we used these parameters to estimate treatment effects, considering the similarity of endpoints. When HR was not available for a given study, data measurement was estimated using methods described by Tierney et al.8 We assessed the heterogeneity of the trial results using a chi-squared test of heterogeneity and the I2 measure of inconsistency. We analyzed the data for the 1546 patients with aggressive lymphoma from the 4 studies, which comprised 773 subjects in maintenance and 773 patients in observation arms. Overall, rituximab maintenance had significant impact on EFS (HR): 0.74, 95% confidential interval (CI): 0.62 – 0.89, P=0.0015). Heterogeneity among the trials was not statistically significant (P=0.58). To investigate the factors associated with the significant impact of rituximab maintenance, we performed subset analyses according to various parameters inherent to the study design of each report. The nonuse of rituximab as part of induction treatment prior to randomization was significantly associated with better EFS in the rituximab maintenance arm (HR: 0.52, 95% CI: 0.37 – 0.77, P<0.001). In contrast, rituximab maintenance had no impact on outcomes when patients had already received rituximab in induction therapy (HR: 0.84, 95%CI: 0.67 – 1.04, P=0.11). Furthermore, rituximab maintenance had positive effects when used for first-line therapy (HR: 0.70, 95% CI: 0.57 – 0.87, P=0.0012), but not in later lines of treatment (HR: 0.87, 95% CI: 0.61 – 1.23, P=0.42). When ASCT was not included in the treatments prior to randomization, rituximab maintenance significantly improved EFS (HR: 0.71, 95% CI: 0.56 – 0.91, P=0.006), whereas this effect was not significant when ASCT was included (HR: 0.79, 95% CI: 0.59 – 1.05, P=0.10). In order to examine the relative impact of these features, we conducted meta-analyses using mixed effects models treating these parameters (the conduct of ASCT prior to rituximab maintenance, the use of rituximab in induction treatment and first-line therapy for lymphoma) as categorical moderators. Rituximab administration prior to randomization remained the sole significant factor (rituximab during induction; (HR: 1.83, 95% CI: 1.08 – 3.09, P=0.025), ASCT before rituximab maintenance; (HR: 1.46, 95% CI: 0.75 – 2.83, P=0.26), rituximab as first-line therapy; (HR: 1.38, 95% CI: 0.62 – 3.07, P=0.42). This result suggests that rituximab maintenance does not have a positive effect on EFS when induction therapy contains rituximab. This result is important because rituximab is widely used as induction therapy for CD20-positive B-cell lymphoma in current practice. We also examined the side effects of rituximab maintenance therapy. Rituximab maintenance was associated with a higher incidence of neutropenia (RD: 0.06, 95% CI: 0.01 – 0.12, P=0.026) and a non-significant increase of infection (RD: 0.14, 95% CI: −0.08 – 0.36, P=0.21) in patients, compared with those in observation alone. Table 1. Summary of abstracted studies. Considering that, in the rituximab era, the role of consolidative autologous stem-cell transplantation proved to be ambiguous even for high-risk aggressive lymphoma,9 we should make an attempt to explore other modalities. Alternatively, identifying the beneficial features for patients from these consolidative treatments would be a realistic approach. Indeed, the NHL 13 study revealed an apparent difference of the effect of rituximab maintenance between male and female patients; only the males experienced a significant benefit, even following induction containing rituximab.2 This effect was likewise observed in the SMARTER-CHOP-14 study where rituximab administration was moved to a later phase, after induction.10 These results are attributed to higher rituximab clearance in males who are undertreated without rituximab maintenance.11 The risk of relapse at onset (age-adjusted International Prognostic Index) or disease status after induction (CR or PR) would also affect the applicability of rituximab maintenance and should be clarified. In conclusion, rituximab maintenance was not associated with better EFS in subjects generally. Rituximab has a positive effect on EFS only when it was not used in induction therapy, which is a rare situation nowadays, negating the practical usefulness of adding rituximab maintenance for aggressive lymphoma.

Late Reactivation of Hepatitis B Virus after Chemotherapies for Hematological Malignancies: A Case Report and Review of the Literature

Reactivation of hepatitis B virus (HBV) is a serious complication of immunosuppressive therapy and cytotoxic chemotherapy. The optimal duration of HBV-DNA monitoring for at-risk patients depends on the clinical features of reactivation, especially the range of potency from therapies to reactivation. We present a case of very late reactivation after chemotherapy for lymphoma and review previous reports of late reactivation cases. We also underscore the significance of developing an indicator for anti-HBV immunity which can be used to determine the optimal monitoring period.

R-THP-COP versus R-CHOP in patients younger than 70 years with untreated diffuse large B cell lymphoma: A randomized, open-label, noninferiority phase 3 trial

Pirarubicin (tetrahydropyranyl adriamycin [THP]) is an anthracyclin with less cardiotoxicity than doxorubicin (DOX). We previously reported the efficacy and safety of R‐THP‐COP consisting of rituximab (R), THP, cyclophosphamide (CPA), vincristine (VCR), and prednisolone (PSL) for diffuse large B cell lymphoma (DLBCL) in phase 2 studies. Here, we prospectively compared the efficacy and safety of the R‐THP‐COP and standard R‐CHOP regimen (consisting of R, CPA, DOX, VCR, and PSL) in a noninferiority phase 3 trial. This prospective, randomized phase 3 study included patients younger than 70 years of age with previously untreated DLBCL. The regimen consisted of R (day 1), DOX, or THP (day 3), CPA (day 3), VCR (day 3), and PSL for 5 days every 3 weeks for 6 to 8 cycles. Between July 5, 2006 and June 11, 2013, 81 patients were randomly assigned to the treatment groups (R‐CHOP group, 40 patients; R‐THP‐COP group, 41 patients). R‐THP‐COP was noninferior to R‐CHOP, as assessed by the primary endpoint of complete response rate (85% vs 85% respectively). With a median follow‐up of 75.2 months, the 5‐year overall survival was 87% in the R‐CHOP group and 82% in the R‐THP‐COP group (hazard ratio [HR]: 0.89, 95% confidence interval [CI]: 0.31‐2.49; P = .82). The 5‐year progression‐free survival was 74% in the R‐CHOP group and 79% in the R‐THP‐COP group (HR: 1.37, 95% CI: 0.56‐3.55; P = .49). No grade 3 cardiac side effects were observed in either group. No serious late adverse reactions were observed in either group, with the exception of therapy‐related acute myeloid leukemia in the R‐THP‐COP group. These data indicate that R‐THP‐COP is noninferior to R‐CHOP with regard to clinical response, and has an acceptable safety profile. Thus, this regimen may be an alternative therapy to R‐CHOP.

Serum concentrations of l‐kynurenine predict clinical outcomes of patients with peripheral T‐cell lymphoma, not otherwise specified

Indoleamine 2,3‐dioxygenase exerts intense immunomodulatory effects due to enzymatic activities that catalyze the breakdown of the essential amino acid l‐tryptophan. The activity of indoleamine 2,3‐dioxygenase can be estimated by measuring serum l‐kynurenine concentrations. Here, we aimed to determine the role of l‐kynurenine as a prognostic factor for peripheral T‐cell lymphoma, not otherwise specified (PTCL‐NOS) in a retrospective analysis of data derived from 31 consecutive patients between June 2000 and March 2013 who were histologically diagnosed with PTCL‐NOS according to the World Health Organization classification and treated with 6−8 cycles of cyclophosphamide, doxorubicin or pirarubicin, vincristine, and prednisolone. l‐kynurenine concentrations in serum samples collected at admission were measured using high‐performance liquid chromatography. The median serum concentration of l‐kynurenine was 3.28 (range 0.92–8.16) μM. The l‐kynurenine cutoff was set at 3.07 μM using receiver operating characteristics curves. The complete remission rates of patients with l‐kynurenine <3.07 and ≥3.07 μM were 69% and 51%, respectively. The 5‐year overall survival (OS) rates for patients with l‐kynurenine <3.07 and ≥3.07 μM were 80.2% and 23.4%, respectively (p < 0.001). More advanced age, poor performance status, elevated lactate dehydrogenase, an unfavorable International Prognostic Index, and a poor prognostic index for T‐cell lymphoma were significantly worse factors for OS. Multivariate analyses revealed only l‐kynurenine as an independent prognostic factor for OS. In conclusion, serum concentrations of l‐kynurenine might comprise a novel prognostic factor with which to determine the outcomes of treatment for PTCL‐NOS. Copyright

Multiple myeloma with Russell bodies and needle-shaped crystalline inclusions.

karyotyping was 45, XY, −7, −18, +r1 in 8 of 20 cells, and monosomy 7 was confirmed by FISH analysis (41 %). Given these findings, she was diagnosed with MM accompanied by myelodysplastic syndrome (MDS); refractory cytopenia with multilineage dysplasia (RCMD). We performed one course of high dose dexamethasone followed by four courses of lenalidomide plus dexamethasone. Marked decrease of myeloma cells (plasma; 1.0 %, Russell body-positive cells: 0.8 %, and needle-shaped crystalline inclusions body-positive cells; 2.8 %) and monosomy 7 signal (41 to 1 % by FISH analysis) in the bone marrow were achieved. Five months later, MDS progressed to RAEB-2 with increase of myeloblasts to 19.2 % in bone marrow and monosomy 7 cells to 60 % in FISH analysis, whilst plasma cells did not increase. Russell bodies, which are usually observed in multiple myeloma, are intracytoplasmic inclusions formed with abnormal accumulation of immunoglobulins [1]. Needle-shaped crystalline inclusions are rarely seen in B cell lymphoproliferative disorders including reactive proliferations [2–6]. The first case with crystal-like inclusion was described in 1976 [7], and chemical and ultrastructural characterization of the inclusions revealed as derived from immunoglobulin light chains [2]. Morphological characteristics may include rod, needle, rectangular and rhomboid [5]. They are often seen with other inclusion bodies, such as Russell bodies and Dutcher bodies. This suggests that these inclusions are formed by the same mechanisms, and are attributable to abnormalities in immunoglobulin production. Needle-shaped crystalline inclusions showed same structures with Russell bodies by electron microscopic examination and assumed to be overproduced immunoglobulin. In the present case, needle-shaped crystalline inclusions were stained with anti-IgA antibody (Fig. 1e). Myeloma cells with crystalline inclusions is reported to A 69-year-old male was referred to the hematology department for examination of pancytopenia, which worsened during follow-up of HCV-associated hepatocellular carcinoma treated with transarterial chemoembolization. Complete blood count showed moderately decreased WBC (11.0 × 10/L) with normal differentiation and severe anemia (Hb 45 g/L) and thrombocytopenia (platelet 3.0 × 10/L). Blood chemistry showed marked increase of IgA (1798 mg/dL) and normal IgG (1381 mg/dL) and IgM (78 mg/dL). Immunoelectrophoresis indicated monoclonal IgA-kappa immunoglobulin. Bone marrow aspiration revealed a nearly normal amount of plasma cells (1.8 %), but featured an increase of abnormal cells containing Russell bodies (17.4 %) and needle-shaped crystalline inclusions (5.6 %) (Fig. 1a–c). These cells were positive for CD138, IgA, and kappa light chain but not for lambda (Fig. 1d–g). The patient was diagnosed with multiple myeloma (MM), IgA kappa type, Durie-Salmon stage IIIA. In bone marrow, dysplasia in myeloid and erythroid series and increase of myeloblasts (4.8 %) were observed. G-banding