ABSTRACT CD5‐positive diffuse large B‐cell lymphoma (CD5+ DLBCL) is characterized by a poor prognosis and frequent central nervous system (CNS) relapse. Sandwich therapy comprising dose‐adjusted (DA)‐EPOCH‐R (etoposide, prednisolone, vincristine, cyclophosphamide, doxorubicin, and rituximab) and high‐dose methotrexate (HD‐MTX) (DA‐EPOCH‐R/HD‐MTX) showed excellent efficacy and manageable safety in a phase II study of patients diagnosed with stage II–IV CD5+ DLBCL. To validate the results of that study and elucidate the current state of treatment for CD5+ DLBCL, we retrospectively analyzed the outcomes of patients with CD5+ DLBCL diagnosed between 2016 and 2021 who received anthracycline‐containing chemotherapy with rituximab. Among the 346 patients evaluated, 62 (18%) received DA‐EPOCH‐R/HD‐MTX. The median follow‐up time was 43 months. In 55 patients with stage II–IV disease treated with DA‐EPOCH‐R/HD‐MTX, the 2‐year overall survival (OS), progression‐free survival, and cumulative incidence of CNS relapse were 87% (95% CI, 73%–94%), 76% (95% CI, 61%–86%), and 7.3% (95% CI, 2.4%–16%), respectively. There were no treatment‐related deaths. Febrile neutropenia occurred in 18 (33%) patients. Multivariate analysis of the 346 patients identified elevated serum lactate dehydrogenase levels, multiple extranodal involvement, no intrathecal MTX (IT‐MTX), and no DA‐EPOCH‐R/HD‐MTX as independent risk factors for OS. Only one CNS relapse event was observed in 28 patients who received both HD‐MTX and IT‐MTX. Our study provides real‐world data on the treatments and outcomes of a large number of patients. The favorable survival and manageable toxicity of DA‐EPOCH‐R/HD‐MTX have been validated in clinical settings. The use of HD‐MTX and IT‐MTX might be effective for preventing CNS relapse in patients with CD5+ DLBCL.

Background: CD5-positive diffuse large B-cell lymphoma (CD5+ DLBCL) is usually characterized by activated B-cell type, poor prognosis, and frequent central nervous system (CNS) relapse. A sandwich therapy of dose-adjusted (DA)-EPOCH-R combined with high-dose methotrexate (HD-MTX) (DA-EPOCH-R/HD-MTX) showed excellent efficacy in a phase II study for newly diagnosed stage II-IV CD5+ DLBCL, including 2-year (yr) overall survival (OS), progression-free survival (PFS), and CNS relapse rates of 89%, 79%, and 9%, respectively (Miyazaki K, et al. Haematologica, 2020). It has been introduced in practice in Japan; however, the current status of treatment and the prognosis in patients with CD5+ DLBCL are unclear. Methods: We retrospectively analyzed the prognosis and CNS relapse rate of consecutive patients with untreated CD5+ DLBCL who were diagnosed at 30 hospitals in Japan from January 2016 to December 2021. Patients who were diagnosed with double-/triple-hit lymphoma, those with CNS involvement at diagnosis, and those who had not received any anthracycline-containing chemotherapy with rituximab (R-chemo) were excluded. We identified risk factors for OS using Cox proportional hazards method. The outcomes in the stage II-IV patients who received DA-EPOCH-R/HD-MTX were compared with those of the phase II study. To evaluate the efficacy of CNS prophylaxis, we divided patients into four groups: HD-MTX alone, intrathecal administration of MTX alone (IT MTX), both HD-MTX and IT MTX (HD/IT MTX), and no CNS prophylaxis. Results: Among the413 enrolled patients, 20 were excluded due to ineligible diagnosis or insufficient clinical information, 18 had CNS involvement at diagnosis, and 27 did not receive R-chemo. As a result, 348 patients were eligible and showed the following features: median age, 71 yrs (range, 23-92); male sex, 54%; stage II-IV, 90%; stage III or IV, 73%; ECOG performance status (PS) > 1, 30%; > 1 extranodal site, 42%; elevated serum lactate dehydrogenase (sLDH) level, 71%; high-intermediate or high International Prognostic Index (IPI), 63%; high CNS-IPI, 41%; and B symptoms, 29%. According to Hans's criteria, the nongerminal center B-cell type accounted for 67% of the 276 cases examined. Among the 348 patients, 62 (18%) received DA-EPOCH-R/HD-MTX, and 286 (82%) were treated with other R-chemo, such as R-CHOP (n = 254). The median age was 63.5 yrs (range, 29-75) in the DA-EPOCH-R/HD-MTX group and 72 yrs (range, 23-92) in the other R-chemo group. The DA-EPOCH-R/HD-MTX group included significantly more patients aged ≤ 60 yrs ( P < 0.001), although it tended to have more patients with ECOG PS > 1 than the other R-chemo group ( P = 0.069). Patients who received IT MTX made up 16% of the DA-EPOCH-R/HD-MTX group and 31% in the other R-chemo group. HD-MTX was used in 100% of patients in the DA-EPOCH-R/HD-MTX group and 17% of patients in the other R-chemo group. Details of CNS prophylaxis were HD-MTX alone in 84 patients (24%), IT MTX alone in 70 (20%), both HD/IT MTX in 28 (8%), and no CNS prophylaxis in 166 (48%). At a median follow-up of 43 months, the 2-yr OS, PFS, and CNS relapse rates of patients with stage II-IV disease in the DA-EPOCH-R/HD-MTX group were 87% (95% CI, 73-94%), 78% (95% CI, 63-87%), and 7.3% (95% CI, 2.8-18.2%), respectively. There were no significant differences in OS or PFS between stage I and stage II-IV patients in the DA-EPOCH-R/HD-MTX group. In all 348 patients with stage I-IV, both the OS ( P = 0.044) and PFS ( P = 0.043) in the DA-EPOCH-R/HD-MTX group were longer than those in the other R-chemo group. The 2-yr OS in these groups were 89% and 78%, and their 2-yr PFS were 78% and 64%, respectively. Multivariate analysis identified elevated sLDH ( P = 0.005), > 1 extranodal involvement ( P < 0.001), no IT MTX ( P = 0.005), and no DA-EPOCH-R/HD-MTX ( P = 0.005) as independent risk factors for OS. The 2-yr CNS relapse rate was 6.5% in the DA-EPOCH-R/HD-MTX group (n = 4) and 10.0% in the other R-chemo group. There were no significant differences in the CNS relapse rate between the two groups ( P = 0.54). The 2-yr CNS relapse rates of HD-MTX, IT MTX alone, both HD/IT MTX, and no prophylaxis were 9.8%, 9.1%, 3.7% (n = 1), and 10.3%, respectively. Conclusions: Our results confirmed favorable survival in the phase II study of DA-EPOCH-R/HD-MTX in clinical settings. DA-EPOCH-R/HD-MTX and IT MTX were associated with longer OS of patients with CD5+ DLBCL in our study cohort, warranting further investigation.

Progression-free survival after R-High CHOP/CHASER/LEED with auto-PBSCT in untreated mantle cell lymphoma in JCOG0406 study. A continuous pattern of relapse was observed.

Introduction Copy number alterations (CNAs) of chromosome 9p24.1 are frequently observed in patients (pts) with classic Hodgkin lymphoma (cHL), which result in increased expression of programmed death ligand-1 on Reed-Sternberg (RS) cells. The amplification of 9p24.1 was found in approximately 50% of pts with advanced-stage cHL, and was an independent prognostic factor for worse progression-free survival (PFS) (Roemer MG, et al. JCO. 2016). In addition, 9p24.1 CNAs is thought to be one of the potential predictive markers for response of immune checkpoint blockade for cHL (Gerhard-Hartmann E, et al. BJH. 2022). However, the incidence or prognostic impact of 9p24.1 CNAs in elderly pts with newly diagnosed advanced-stage cHL remains unclear. In this ancillary analysis of a multi-center retrospective study (HORIZON study, UMIN000033264), we evaluated clinical impact of 9p24.1 CNAs in elderly pts with newly diagnosed advanced-stage cHL who received a doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD). Methods The key eligibility criteria of the current analysis were as follows: 1) pts with histologically diagnosed cHL between 2007 and 2016 in each institution; 2) advanced-stage cHL (stage III, IV or IIB with bulky or extranodal lesion); 3) age at diagnosis > 60 years; 4) had received at least one cycle of ABVD as initial treatment including a modified ABVD regimen (dacarbazine dose reduced to 250 mg/m2); and 5) had available specimen for tissue fluorescence in situ hybridization (FISH) analysis. All specimens were centrally reviewed by 3 experienced hematopathologists and confirmed the diagnosis of cHL. In the tissue FISH analysis, CNAs of the 9q24.1 loci along with the expression of CD30 were simultaneously detected using a combination of immunofluorescence with Fluorescence Immunophenotyping and interphase Cytogenetics as a Tool for Investigation of Neoplasia (FICTION), as described previously (Martínez-Ramírez A, et al. Leukemia. 2004). A median number of 50 RS cells (range: 30 to 74 RS cells) per case were analyzed. According to the previous report (Roemer MG, et al. JCO. 2016), nuclei with a target:control probe ratio of ≥ 3:1 were defined as amplification, and those with a probe ratio of > 1:1 but , < 3:1 were classified as relative copy gain. Nuclei with a probe ratio of 1:1 but more than two copies of each probe were defined as polysomic for chromosome 9p. In each case, the percent and magnitude of 9p24.1 amplification, copy gain, polysomy, and normal copy numbers (disomy) were noted. Cases were classified by the highest observed level of 9p24.1 CNAs. As survival analysis, overall survival (OS), PFS, and event-free survival (EFS; defined as the time from a diagnosis of cHL to disease progression or relapse, subsequent systemic chemotherapy for cHL, or death due to any cause), were evaluated. Results Among 99 eligible pts, the median age was 71 years (interquartile range [IQR] 65-77). The numbers of pts with an ECOG performance status (PS) 2 or more and B symptoms were 17 (17%) and 50 (51%), respectively. Sixty pts (61%) had mixed cellularity cHL, and 28 pts (28%) had nodular sclerosis cHL. Forty-five pts (45%) were positive for EBV-encoded small RNA (EBER) in situ hybridization. Hypoalbuminemia [serum albumin <4 g/dL] and anemia [hemoglobin <10.5 g/dL], were observed in 84 (85%), and 37 pts (37%), respectively. All the 99 pts had 9p24.1 CNAs; 67 pts (68%) had amplification, and the remaining 32 pts (32%) had copy gain (Figure 1). Hypoalbuminemia and anemia were significantly more frequent among pts with 9p24.1 amplification. The incidence of 9p24.1 amplification in EBER-positive cases tend to be higher than that of EBER-negative cases (78% in pts with EBER- positive vs. 59% in pts with EBER-negative, P=0.056). With a median follow-up duration of 52 months, the estimated OS, PFS, and EFS at 5 years in pts with 9p24.1 amplification were 80.1%, 64.2%, 59.9%, respectively. The estimated 5-year OS, PFS, and EFS of pts with 9p24.1 copy gain were 71.2%, 58.4%, 55.7%, respectively. No statistical differences were observed regarding these survival parameters between those pts with amplification and copy gain. Conclusion This ancillary analysis showed that hypoalbuminemia and anemia were significantly more frequent among pts with 9p24.1 amplification. Nevertheless, 9p24.1 amplification was not a prognostic factor for OS, PFS, and EFS in elderly pts with advanced-stage cHL treated with ABVD in the present study. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

We conducted a nationwide retrospective analysis of 116 hepatitis B virus (HBV) surface antigen (HBsAg)‐positive patients with diffuse large B‐cell lymphoma (DLBCL) and 278 HBsAg‐negative patients with DLBCL, as a control cohort, who received rituximab‐containing regimens as an induction chemotherapy at 30 Japanese medical centers between January 2004 and December 2014. Hepatitis was defined as an absolute serum alanine aminotransferase (ALT) level of ≥100 U/L. HBV reactivation‐related hepatitis was defined as hepatitis with an absolute serum HBV DNA level of ≥3.3 log IU/mL or an absolute increase of ≥2 log compared with the baseline value. HBsAg‐positive patients were divided into three groups based on anti–HBV prophylactic therapy: no nucleos(t)ide analogue (non–NA, n = 9), lamivudine (LAM, n = 20), and entecavir (ETV, n = 87). The 4‐year cumulative incidence (CI) of hepatitis in HBsAg‐positive and HBsAg‐negative patients was 21.1% and 14.6% ( P = .081), respectively. The 4‐year CI of HBV reactivation‐related hepatitis was higher in HBsAg‐positive patients than in HBsAg‐negative patients (8.0% vs 0.4%; P < .001). Among HBsAg‐positive patients, the 4‐year CI of HBV reactivation‐related hepatitis was the highest in the non–NA group (33.3%), followed by the LAM (15.0%) and ETV (3.8%) groups ( P < .001). Of note, 3 non–NA patients (33%) and 1 LAM patient (5%) (but no ETV patients) died due to HBV hepatitis. Based on Cox multivariate analysis, HBsAg positivity was not associated with poor overall survival. Prophylactic use of ETV would reduce the occurrence of HBV reactivation‐related hepatitis and mortality in HBsAg‐positive DLBCL patients receiving rituximab‐containing chemotherapy.

Multiple myeloma (MM) is still extremely difficult to cure, and new therapeutic drugs are needed. We recently found that integrin β7 is constitutively activated in MM cells, and chimeric antigen receptor (CAR) T cells targeting activated integrin β7 have a significant anti-MM effect. In this study, we performed flow cytometry analysis of the expression of activated integrin β7 in bone marrow cells from 137 symptomatic MM patients. In 60/137 (44%) MM patients, activated integrin β7 was detected in most MM cells (> 80% of MM cells were in the positive gate). Activated integrin β7 was highly expressed in MM cells even in heavily treated patients. It also showed high expression in many CD38lo/−CD138−CD19+B cells, which reportedly include clonotypic B cells, in the bone marrow of MM patients. Taken together, these results suggest that CAR T-cell therapy targeting activated integrin β7 has the potential to benefit many patients with relapsed or refractory MM.

Background: CLL-like MBL is divided into low and high count, with significant clinical and biological differences. No studies have been conducted so far in CBL-MZ. Aims: In accordance to the proposed grouping of CLL-like MBL, we aimed to investigate the clinical significance of such distinction in MZL-like MBL. Methods: 95 consecutive CBL-MZ cases were analyzed, with any number of circulating CD5- CBL, no B-symptoms, organomegaly, lymphadenopathy, cytopenias or any other features indicating a known lymphoproliferative disorder. Patients were grouped in 3 categories: A. low count (CBL≤500/μL), B. high count (CBL > 500/μL and ≤5000/μL) and C. frank lymphocytosis (CBL>5000/μL). Using this subdivision a comparison of several laboratory and disease evolution parameters was performed. Results: 3/95 patients belonged to group A, 59 to group B and 33 to group C. The characteristics and outcome of the three groups are shown in table. Apart from WBC, ALC and CBL that differed significantly by definition, the only parameters that were statistically different between the three groups, were absolute neutrophil counts, CD11c expression, BM infiltration, and the frequency of evolution to SMZL. More specifically, the frequency of CD11c expression was highest in group C (68%) compared to group B (33%) and A (0%). Surprisingly, ANC were significantly higher with rising ALC. The percentage of BM infiltration differed significantly between the three groups and was highest in the lymphocytosis group (C); however, this difference was mainly due to the difference between group B and C. Notably, the three patients with low-count MBL had BM infiltration between 30–40%, which was similar to the group C. There was a trend for a higher frequency for SMZL evolution in group C. Four out of 5 patients who evolved to SMZL belonged to the group C, whereas the remaining one patient had a low-count MBL. At a median follow-up time of 42 months, need of therapy, time to progression (TTP), time to treatment (TTT) and overall survival (OS) did not differ significantly between the three groups. Not CBL counts, but elevated LDH and BM infiltration≥50% were the only significant factors for TTT by multivariate analysis. Treatment due to cytopenias was more frequent in group B.Summary/Conclusion: CBL-MZ patients have an excellent prognosis. The cut-off of 5x109//L CBL does not seem to be the optimal threshold to distinguish prognostically different subgroups, with the exception of SMZL development. BM infiltration≥50% and elevated LDH are associated with shorter TTT.

A 67-year-old male was referred to our hospital because of anemia, thrombocytopenia, and massive ascites. A diagnosis of systemic mastocytosis was made based on the observation of many mast cells in his bone marrow, elevated serum tryptase levels, and the presence of c-kit point mutation Asp816Val. Dasatinib and cladribine were ineffective, and a large volume of ascites was removed approximately every 3 days. Then, following an asthma attack, the patient was treated with pranlukast, a leukotriene receptor antagonist (LTRA). After LTRA treatment initiation, the frequency of ascites drainage decreased, and no puncture was necessary from the 10th day after the start of LTRA. Interferon α (IFN-α) was administered from the 15th day after the start of LTRA. Thereafter, his anemia and thrombocytopenia gradually improved, the ascites disappeared, the mast cells in his bone marrow were significantly reduced, and the Asp816Val mutation disappeared. Because persistent monocytosis was evident, he was suspected of chronic myelomonocytic leukemia but has not been diagnosed and is undergoing watchful waiting. This was considered to be a rare case of refractory ascites in which IFN-α was effective and LTRA might have been beneficial.

An 80-year-old man presented with the accumulation of pleural fluid in the right thoracic cavity. Serum electrophoresis revealed an M-component and immunofixation confirmed IgM/λ. The level of IgM was 1,526 mg/dL. Imaging studies showed an infiltrative condition of the ipsilateral lung parenchyma. The fluid contained abundant neoplastic cells with the morphological and immunophenotypic features of plasma cells, which expressed IgM/λ monoclonal immunoglobulins on the cell surface and in the cytoplasm. The karyotype was 48,XY,+3,add(9)(p13),+12,add(14)(q32),del(16)(q22),-18,+mar, and a series of fluorescence in situ hybridization studies demonstrated that the add(14) chromosome represented der(14)t(14;18)(q32;q21), at which the MALT1-immunoglobulin heavy-chain (IGH) fusion gene was localized. A long-distance polymerase chain reaction amplified the fragment encompassing the two genes, showing that the junction occurred at the J6 segment of IGH and 3.7-kb upstream of the MALT1 breakpoint cluster. We propose that this case represents an extreme form of the plasmacytic differentiation of extranodal marginal zone lymphoma that developed in the lung.

Although induction immunochemotherapy including high‐dose cytarabine and rituximab followed by high‐dose chemotherapy ( HDC ) with autologous stem cell transplantation ( ASCT ) is recommended for younger patients (≤65 years old) with untreated mantle cell lymphoma ( MCL ), no standard induction and HDC regimen has been established. We conducted a phase II study of induction immunochemotherapy of R‐High‐ CHOP / CHASER followed by HDC of LEED with ASCT in younger patients with untreated advanced MCL . Eligibility criteria included untreated MCL , stage II bulky to IV , and age 20‐65 years. Patients received 1 cycle of R‐High‐ CHOP followed by 3 cycles of CHASER every 3 weeks. Peripheral blood stem cells ( PBSC ) were harvested during CHASER . LEED with ASCT was delivered to patients who responded to R‐High‐ CHOP / CHASER . Primary endpoint was 2‐year progression‐free survival ( PFS ). From June 2008 to June 2012, 45 patients (median age 59 years; range 38‐65 years) were enrolled. PBSC were successfully harvested from 36 of 43 patients. Thirty‐five patients completed ASCT . Two‐year PFS was 77% (80% CI 68‐84), which met the primary endpoint. Five‐year PFS and overall survival were 52% (95% CI 34‐68%) and 71% (95% CI 51‐84%), respectively. Overall response and complete response rates after induction immunochemotherapy were 96% and 82%, respectively. The most common grade 4 toxicities were hematological. In younger patients with untreated MCL , R‐High‐ CHOP / CHASER / LEED with ASCT showed high efficacy and acceptable toxicity, and it can now be considered a standard treatment option.

The objective of this prospective clinical trial (JALSG-STIM213, UMIN000011971) was to evaluate treatment-free remission (TFR) rates after discontinuation of imatinib in chronic myeloid leukemia (CML). CML patients who received imatinib treatment for at least 3 years and sustained deep molecular response for at least 2 years were eligible. Molecular recurrence was defined as loss of major molecular response (MMR). Of the 68 eligible patients, 38.2% were women, the median age was 55.0 years, and the median duration of imatinib treatment was 97.5 months. The 12-month TFR rate was 67.6%. Patients who lost MMR were immediately treated with imatinib again; all re-achieved MMR. Three-year treatment-free survival (TFS) was estimated as 64.6% using the Kaplan–Meier method. Undetectable molecular residual disease (UMRD) was defined as no BCR-ABL1 in > 100,000 ABL1 control genes using international scale polymerase chain reaction. UMRD at the study baseline was found to be predictive of continuation of TFR. Our findings suggest that CML patients who meet all the eligibility criteria that have commonly been used in the TFR trials are able to discontinue imatinib use safely. TFR may thus be valuable as a new goal for CML treatment in Japan.

Aim: Multicenter phase II study has been conducted to investigate whether myeloablative regimen consisting of intravenous busulfan (ivBu), fludarabine (Flu) + /− total body irradiation (TBI) intensified by filgrastim-priming and cytarabine can be feasible and effective for elderly recipients (UMIN-CTR UMIN000010697, and UMIN000010698). Method: This study started in August 2013, and 65 centers participated. Patients aged from 55 to 70 with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) who were planned for allo-SCT (bone marrow (BM), peripheral blood (PB), and cord blood (CB)) were enrolled. Pretransplant conditioining consisting of filgrastim (200 µg/m2from day −8 to −2), cytarabine (100 mg/m2 from day −7 to −4 as continuous infusion followed by 2g/m2 twice daily for 3 hours each from day −3 to −2), Flu (30 mg/m2 from day −7 to −2), ivBu (3.2 mg/kg divided by 4 daily from day −7 to −4) with or without TBI (2-4 Gy) depending on types of donor cells. Calcineurine inhibitors + methotrexate for BM or PB recipients, and tacrolimus + mycophenolate mofetil were used for CB recipients. Result: Sixty-eight patients were enrolled, 7 were excluded due to withdrawal of consent or disqualification after enrollment and thus 61 were subjected to the analysis. Median age was 63 (55-70), 40 males and 21 females, 40 AML and 21 MDS were included. Forty (65.6%) were in non-remission status before transplantation. Donors were 4 related BM, 5 related PB, 23 unrelated BM, and 29 CB. Fifty-five achieved neutrophil recovery. Six who failed engraftment were due to death before engraftment from non-relapse mortality (NRM) (5 CB, and 1 unrelated BM recipients). Cumulative incidences of engraftment were 100% in related, 95.7% in unrelated BM, and 82.8% in CB recipients. Median days of engraftment were 16 in related, 18 in unrelated BM, and 25 in CB recipients. There were 6 VOD/SOS observed. Up to 24 months post-transplant, there were 28 NRM and 16 relapse. Cumulative incidences of NRM and relapse at 2 years post-transplant were 45.9% and 26.4%, respectively. Overall (OS) and event-free survivals (EFS) were estimated to be 29.3% and 27.7% at 2 years post-transplant. There were no statistically significant differences among donor types with respect to NRM, relapse, OS, and EFS. There was no statistically significant difference between those in remission and not in remission with respect to relapse rate (24.0% vs. 27.8%, P = .78), that were comparable to those included in JSCT-FB09&10 study (19% in remission and 30.2% not in remission), in which only Flu + ivBu+/−TBI was used. Conclusions: Intensified conditioning using filgrastim-priming and cytarabine in addition to Flu + ivBu+/−TBI myeloablative conditioning is feasible to those older than 54 years. However, no significant reduction of relapse incidence was observed and the positive impact of adding filgrastim-priming and cytarabine was not shown.

Immune reconstitution affects clinical outcomes after allogeneic hematopoietic stem cell transplantation (HSCT), and it has been suggested that lymphocyte recovery affects survival after HSCT. However, few studies have examined lymphocyte recovery in Asian patients who received mycophenolate mofetil (MMF) prophylaxis for graft-versus-host disease. We retrospectively evaluated early lymphocyte recovery after HSCT among Japanese adults who received MMF prophylaxis. Patients were divided into two groups according to their median absolute lymphocyte count (ALC) on day 28 after HSCT as follows: the "low ALC group" (≤ 0.22 × 109 cells/L) and the "high ALC group" (> 0.22 × 109 cells/L). With a median follow-up of 317 days, the high ALC group showed significantly better overall survival than the low ALC group (at 1 year: 62 vs. 46%, P = 0.02). The high ALC group also tended to have better non-relapse mortality than the low ALC group (at 1 year: 13 vs. 23%, P = 0.08). There was no significant difference in relapse rate between the high and low ALC groups (at 1 year: 29 vs. 35%, P = 0.2). We conclude that among Japanese patients who received MMF prophylaxis, ALC on day 28 after HSCT was effective in predicting overall survival and non-relapse mortality.

The standard CHOP therapy for peripheral T-cell lymphoma has resulted in unsatisfactory outcomes and it is still not clear what is the optimal front-line therapy. We conducted a multicenter phase II study of dose-adjusted etoposide, doxorubicin, and cyclophosphamide with vincristine and prednisone (EPOCH) for untreated peripheral T-cell lymphoma patients. In this prospective study, 41 patients were treated with dose-adjusted-EPOCH as initial therapy: peripheral T-cell lymphoma-not otherwise specified, n=21; angioimmunoblastic T-cell lymphoma, n=17; anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, n=2; and anaplastic lymphoma kinase-negative anaplastic large cell lymphoma, n=1. Median patient age was 64 years (range: 32–79 years). According to the International Prognostic Index criteria, 51.2% were at high-intermediate or high risk. The overall response and complete response rates were 78.0% [95% confidence interval (CI): 62.4–89.4%] and 61.0% (95%CI: 44.5–75.8%), respectively. At the median follow up of 24.0 months, the 2-year progression-free survival and overall survival were 53.3% (95%CI: 36.4–67.5%) and 73.2% (95%CI: 56.8–84.1%), respectively. The younger patients (≤ 60 years old) had a high response rate (overall response 94.1% and complete response 70.6%) and survival rate (progression-free survival 62.5% and overall survival 82.4%). The most common grade ≥ 3 adverse events were neutropenia (74.5%), anemia (40.8%), thrombocytopenia (22.0%), and febrile neutropenia (9.0%). Dose-adjusted-EPOCH had a high response rate with a tolerable toxicity profile. Our results indicate that dose-adjusted-EPOCH is a reasonable first-line approach for peripheral T-cell lymphoma patients and may improve outcomes.

Introduction: Peripheral T-cell lymphomas (PTCLs) are rare and heterogeneous diseases that represent around 10-15% of non-Hodgkin's lymphoma (NHL) in adults. The most common subtypes are the nodal T cell lymphomas, not otherwise specified (PTCL-NOS), angioimmunoblastic T cell lymphoma (AITL), anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL) and ALK-negative ALCL. There is no standard therapy for PTCLs, however, cyclophosphamide, prednisone, vincristine, hydroxyl doxorubicin (CHOP) is the most commonly used, resulting poor overall survival. The addition of etoposide to CHOP-based regimens improved CR in PTCL patients in some studies. Dose-adjusted EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin) plus rituximab regimen were reported excellent outcome in primary mediastinal B-cell lymphoma, as well as germinal center B-cell diffuse large B-cell lymphoma and Burkitt lymphoma. In this study, we undertook a multicenter phase II, prospective study to evaluate whether dose-adjusted EPOCH may improve outcomes in patients with the nodal PTCLs.

To identify strategies for reducing emesis induced by the CHOP regimen, which includes high-dose steroids, we prospectively evaluated the efficacy of palonosetron in Japanese patients. Palonosetron was administered at a dose of 0.75 mg via intravenous injection over 30 min before chemotherapy on day 1. Patients kept diaries of chemotherapy-induced nausea and vomiting (CINV) incidence from the start of chemotherapy until 168 h afterwards, in which they documented the occurrence and severity of nausea, vomiting, anorexia, and the use of rescue medication. The primary endpoint was the overall occurrence rate of nausea, vomiting, and anorexia; these rates were 56, 12, and 62 %, respectively, including all grades. The rates and severity of symptoms tended to worsen 120–168 h after completing oral prednisolone. We defined complete response (CR) as no vomiting and no use of rescue therapy. The CR rates of post palonosetron 0.75 mg treatment in the acute (0–24 h), delayed (24–168 h), and overall phases (0–168 h) were 86, 66, and 62 %, respectively. Antiemetic strategies of CHOP regimen for day 6 and, thereafter, should be investigated.

Background : The clonal expansion of PIGA mutant hematopoietic stem cells (HSCs) can be induced by secondary driver mutations in genes such as HMGA2 and JAK2 in some patients with paroxysmal nocturnal hemoglobinuria (PNH). Theoretically, this type of PNH may be cured by molecular targeted therapy if the therapy is specific for the driver mutations and can eliminate PIGA mutant HSCs that acquired a proliferative advantage. However, this theory has not been proven because of the lack of an appropriate targeted therapy for known driver mutations responsible for clonal expansion of PIGA mutant HSCs. We recently treated a case of PNH complicated by chronic myeloid leukemia (CML) with nilotinib and observed a complete molecular response of CML followed by a complete disappearance of glycosylphosphatidylinositol-anchored protein-deficient (GPI-AP-, PNH-type) cells after 19 months of treatment. Case report : The patient, a 27-year-old Japanese woman, developed severe anemia with leukocytosis and thrombocytosis in 2013. The laboratory findings on admission were as follows: white blood cell count of 18.7x109/L with 1.7% stab neutrophils, 5.4% segmented neutrophils, 9.3% basophils, 1.3% promyelocytes, 5.0% myelocytes, 3.0% metamyelocytes, 18.0% lymphocytes and 0.7% blasts; hemoglobin (Hb)=6.0 g/dL, platelets=1,000x109/L, 20.0% reticulocytes, total/direct bilirubin=1.9/0.3 mg/dL, LDH=1963 IU/L and haptoglobin <10 mg/dL. A high-sensitivity flow cytometry analysis of the patient's peripheral blood at diagnosis revealed that 99.2% of granulocytes, 75.7% of erythrocytes and 99.3% of monocytes were GPI-AP-, while no T cells, B cells or NK cells had the PNH-phenotype (Figure 1A). This GPI-AP- cell distribution pattern was in sharp contrast to that of a patient with typical PNH who showed various percentages of GPI-AP- cells in all lineages of leukocytes and erythrocytes (Figure 1B). A fluorescent in situ hybridization analysis showed that 98.0% of the patient's granulocytes were BCR-ABL gene-fusion positive. Deep sequencing of leukocytes obtained at diagnosis showed a G279T (Q93H) mutation in exon 4 of the PIGA gene. The patient was diagnosed with PNH complicated by CML in the chronic phase, and was treated with nilotinib at 400 mg/day. The percentage of GPI-AP- cells rapidly decreased in response to nilotinib, with 0.02% GPI-AP- granulocytes after six months of nilotinib therapy when the patient's BCR-ABL mRNA decreased to 0.007%. BCR-ABL mRNA decreased to less than 0.0035% 15 months after therapy; however, small populations of GPI-AP- granulocytes (0.01%) and erythrocytes (0.005%) were still detected at this time (Figure 1A). GPI-AP- cells became undetectable after 19 months of nilotinib therapy, suggesting that the BCR/ABL fusion occurred in a subclone of a PIGA mutant hematopoietic progenitor cell (HPC). The patient was continuing nilotinib as of August 2015 without any signs of an increase in the BCR-ABL mRNA copy number. Conclusions : This case indicates the BCR-ABL fusion can be a driver mutation capable of inducing the clonal expansion of PIGA mutant clones. More importantly, the origin of PNH in our case proved to be a minor HPC clone with a PIGA mutation, suggesting that PNH can be derived from an HPC with a limited life span only if a potent second hit occurs in the PIGA mutant HPC. The identification of driver mutations in patients with PNH may therefore lead to the development of targeted therapy capable of curing PNH. ![Figure][1] Disclosures No relevant conflicts of interest to declare. [1]: pending:yes

Paroxysmal nocturnal hemoglobinuria induced by the occurrence of BCR-ABL in a PIGA mutant hematopoietic progenitor cell