Characteristics of chronic lymphocytic leukemia in Japan: Comprehensive analysis of the CLLRSG-01 study.

Chronic lymphocytic leukemia (CLL) is rare in Japan. We conducted the nationwide, prospective observational study CLLRSG-01 to clarify the current state of CLL in Japan and to make accurate international comparisons by preparing naturally air-dried smears like those used in other countries. Of the 201 untreated patients enrolled and evaluated, 119 were diagnosed with CLL and 82 with non-CLL mature B-cell neoplasms, based on the WHO classification. Of the 119 CLL patients, 90 were classified as typical and 29 as atypical according to FAB classification morphology, with the proportion of atypical CLL consistent with reports from other countries. Immunophenotypic analyses by flow cytometry showed that 55% of Japanese CLL patients had a Matutes score of 4 or higher, which is lower than the rate of about 90% in Europeans. Mutated IGHV was identified in 80% of Japanese CLL patients, which is a higher rate than in Western patients. The most frequent IGHV gene was VH3-30 (15%), followed by VH3-23 (12%) and VH4-34 (10%). VH1-69, the most common gene in Western countries, was identified in only one patient. These results indicate that the pattern of immunophenotypes and IGHV gene usage in Japanese CLL patients differs from that in Western patients.

Anti-CD38 antibody isatuximab monotherapy for Japanese individuals with relapsed/refractory multiple myeloma: An update of the phase 1/2 ISLANDs study.

The primary analysis of the phase 1/2 ISLANDs study in Japanese individuals with relapsed/refractory multiple myeloma (RRMM) showed that isatuximab monotherapy was well tolerated and effective, even in participants with high-risk cytogenetic abnormalities. Here, we report a prespecified second analysis conducted 20 months after the first dosing of the last participant (ClinicalTrials.gov identifier: NCT02812706). The primary objectives were to evaluate the safety and tolerability of isatuximab in phase 1 and to evaluate the efficacy of isatuximab, including assessment of overall response rate (ORR) at the recommended dose (RD), in phase 2. In phase 1, three participants received isatuximab 10 mg/kg every week (QW) for 4 weeks/cycle followed by every 2 weeks (Q2W) and five participants received 20 mg/kg QW/Q2W. Since no dose-limiting toxicities occurred in phase 1, 20 mg/kg QW/Q2W was identified as the RD for the phase 2 study (n = 28). At the time of data cut-off, three participants (one in phase 1 and two in phase 2) continued to receive isatuximab; disease progression and treatment-related adverse events were the most common reasons for treatment discontinuation. The overall safety profile was consistent with the primary analysis. One death, not related to isatuximab treatment, was reported since the first analysis. The ORR and clinical benefit rate remained unchanged from the primary analysis at 36.4% (95% confidence interval [CI]: 20.4%-54.9%) and 54.5% (95% CI: 36.4%-71.9%), respectively. The median progression-free survival (PFS) was 5.6 months, longer than the median PFS reported in the primary analysis (4.7 months), whereas median overall survival was not reached. Overall, isatuximab 20 mg/kg QW/Q2W had an acceptable safety and tolerability profile and showed promising antitumor activity in Japanese individuals with RRMM.

Outcomes of methotrexate-associated lymphoproliferative disorders in rheumatoid arthritis patients treated with disease-modifying anti-rheumatic drugs.

Recently, the use of targeted synthetic or biological disease-modifying anti-rheumatic drugs (ts/bDMARDs) in addition to conventional synthetic (cs)DMARDs including methotrexate (MTX) for rheumatoid arthritis (RA) has increased. However, whether ts/bDMARDs are associated with the development and clinicopathological features of MTX-associated lymphoproliferative disorder (MTX-LPD) in patients with RA remains unknown. Therefore, we evaluated the clinical outcomes of 121 patients with MTX-LPD. Results showed that prior use of ts/bDMARDs was not associated with the different histopathological subtypes of MTX-LPD. Patients with polymorphic-type LPD had a better event-free survival than those with diffuse large B-cell lymphoma (DLBCL), classical Hodgkin lymphoma and peripheral T-cell lymphoma. The pathological subtype of lymphoma could predict the clinical outcome of MTX-LPD. In patients with DLBCL, the use of tumour necrosis factor-alpha (TNF-α) inhibitors prior to MTX-LPD onset was associated with a higher non-relapse mortality. Further, patients with RA previously treated with Janus kinase (JAK) inhibitors more commonly required chemotherapy than those treated with csDMARDs alone, indicating disease aggressiveness. Hence, special caution should be observed when managing patients with MTX-LPD previously treated with JAK or TNF-α inhibitors for RA.

Isatuximab monotherapy in relapsed/refractory multiple myeloma: A Japanese, multicenter, phase 1/2, safety and efficacy study.

Isatuximab, an anti-CD38 monoclonal antibody, targets cells that strongly express CD38 including malignant plasma cells. This open-label, single-arm, multicenter, phase 1/2 trial investigated the tolerability/safety and efficacy of isatuximab monotherapy in Japanese patients with heavily pretreated, relapsed/refractory multiple myeloma (RRMM). In Phase 1, patients were sequentially assigned to receive isatuximab once weekly (QW) in cycle 1 (4 weeks) and every 2 weeks (Q2W) in subsequent cycles. Cohort 1 (n = 3) received 10 mg/kg QW/Q2W; cohort 2 (n = 5) received 20 mg/kg QW/Q2W. No dose-limiting toxicities occurred; the recommended dose for the single-arm phase 2 study (n = 28) was 20 mg/kg QW/Q2W. The overall safety profile was consistent with the current knowledge of isatuximab. The most common adverse events were infusion reactions (42.9%; 12/28); all were grade 1/2 and generally occurred during the first infusion. The overall response rate with 20 mg/kg QW/Q2W isatuximab was 36.4% (12/33); patients with high-risk cytogenetic abnormalities had comparable results. In phase 2, the median progression-free survival was 4.7 (95% confidence interval, 3.75 to not reached) months. Median overall survival was not reached. Isatuximab monotherapy was well tolerated and effective in patients with heavily pretreated RRMM including high-risk cytogenetic patients. This trial is registered at ClinicalTrials.gov as NCT02812706.

Clinicopathological significance of CD79a expression in classic Hodgkin lymphoma.

Classic Hodgkin lymphoma (CHL) is a lymphoid neoplasia characterized by the presence of large tumor cells, referred to as Hodgkin and Reed-Sternberg (HRS) cells, originating from B-cells in an inflammatory background. As the clinical significance of B-cell markers has yet to be fully elucidated, this study aimed to clarify the clinicopathological significance of CD79a in 55 patients with CHL. They were immunohistochemically divided into two groups, comprising of 20 CD79a-positive and 35 CD79a-negative patients. There was no significant correlation between CD79a and CD20 expression (rs = 0.125, P = 0.362). CD79a-positive patients were significantly older at onset (P = 0.011). There was no significant correlation between CD79a-positivity and clinical stage (P = 0.203), mediastinal involvement (P = 0.399), extranodal involvement (P = 0.749), or laboratory findings, including serum levels of lactate dehydrogenase (P = 1) and soluble interleukin-2 receptor (P = 0.251). There were significant differences in overall survival (OS) (P = 0.005) and progression-free survival (PFS) (P = 0.007) between CD79a-positive and CD79a-negative patients (5-year OS: 64.6% and 90.5%; 5-year PFS: 44.0% and 76.6%, respectively). Five patients in whom the majority (> 80%) of HRS cells expressed CD79a consisted of 4 males and 1 female aged between 52 and 81 years; 4 of them were in a limited clinical stage. We concluded that CD79a-positive CHL may have unique clinicopathological features.

Pomalidomide and dexamethasone combination with additional cyclophosphamide in relapsed/refractory multiple myeloma (AMN001)-a trial by the Asian Myeloma Network.

Pomalidomide is a third generation immunomodulatory drug which in combination with dexamethasone, has been shown to be active in relapsed/refractory multiple myeloma. However, the data in Asian patients remain limited. We conducted a prospective phase two clinical trial in major cancer centers in Singapore, South Korea, Taiwan, Japan and Hong Kong to assess the efficacy and safety of pomalidomide and dexamethasone combination (PomDex) +/- cyclophosphamide in Asian patients with relapsed/refractory multiple myeloma who failed lenalidomide and bortezomib. Patients were treated with pomalidomide (4 mg daily for 21 days every 4 weeks) and dexamethasone (40 mg weekly). If there is less than a minimal response after three cycles of PomDex, cyclophosphamide 300 mg/m2 can be added (PomCyDex). A total of 136 patients were enrolled. The median PFS was 9 and 10.8 months for the PomDex and PomCyDex group, respectively. The median OS was 16.3 months. This regimen appears to be active across age groups and prior lines of treatment. This combination was overall well tolerated with grade 3 and 4 adverse events of mainly cytopenias. PomDex is highly active and well-tolerated in Asian patients. The addition of cyclophosphamide can improve the response and outcomes further in patients with suboptimal response to PomDex.

Evaluation of the Revised International Staging System (R-ISS) in Japanese patients with multiple myeloma.

In spite of recent development in the treatment armamentarium for multiple myeloma, overall survival (OS) still depends on risk status and sensitivity to treatment of each patient. We have evaluated the clinical relevance of the Revised International Staging System (R-ISS) by comparing it with the original ISS in 718 Japanese patients. The distribution of patients according to response was similar between the ISS and R-ISS stages. Treatment response was greatly influenced by initial treatment modalities and deeper response was observed more frequently in transplanted patients. The R-ISS discriminated the difference in OS between the stages more distinctly than the ISS (p = 9.0 × 10-15 and p = 4.0 × 10-10, respectively). Differences in OS were clarified by both R-ISS and ISS in non-transplanted patients (p = 2.4 × 10-12 and p = 1.4 × 10-8, respectively), but the ISS failed to distinguish the difference between the stages in transplanted patients (p = 0.13). In contrast, the R-ISS could at least discriminate the excellent prognosis of stage I patients whereas the distinction between stage II and III was not that clear (p = 0.033). The R-ISS stage II encompassed a large number of patients, and the prognosis was heterogeneous depending on the fulfillment of prognostic factors such as LDH and adverse cytogenetics. These results suggest that treatment factors and prognostic factors greatly affect the therapeutic response and outcome, and the R-ISS is superior to ISS in prognostication of both transplant-eligible and -ineligible patients in our current clinical practice.

Unsuppressed serum albumin levels may jeopardize the clinical relevance of the international staging system to patients with light chain myeloma.

The international staging system (ISS) is the most commonly used risk-stratification system for patients with multiple myeloma (MM) and is determined by serum albumin and ß2-microglobulin levels. In the two determinants, ß2-microglobulin levels are frequently observed to be elevated in patients with myeloma, particularly in those with renal impairment. In comparison with patients with intact immunoglobulin myeloma, patients with LC myeloma do not necessarily show decreased levels of serum albumin. The clinical impact of ISS in patients with LCMM, in particular the distinction between ISS I and II, may be complicated due to non-decreased levels of serum albumin in both stages. Accordingly, we have attempted to assess clinical relevance of the ISS in patients with LC myeloma. The clinical data of 1899 patients with MM diagnosed between January 2001 and December 2012 were collected from 38 affiliated hospitals of the Japanese Society of Myeloma. Significant difference was not found between stage I (n = 72) and stage II (n = 92) in LC myeloma patients (n = 307). The mean serum albumin concentration of patients with LC myeloma was within the reference range but higher than that of patients with IgG + IgA myeloma (n = 1501), which complicates the distinction between ISS stage I and II myeloma. Patients with LC myeloma had low frequencies of t(4; 14) and high frequency of elevated lactate dehydrogenase, and despite a relevant amount of missing data in our registry (R-ISS stage I; n = 11, stage II; n = 32, and stage III: n = 18), the information included in the R-ISS scoring system seems to be more accurate than ISS to obtain a reliable risk stratification approach in non-ISS stage III LC myeloma patients.

[Acute leukemia recurring as extramedullary tumors of the ovary following allogeneic hematopoietic stem cell transplantation].

The poor prognosis of extramedullary recurrence of acute leukemia following allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains a therapeutic challenge, and thus far no effective treatment method has been established. Here, we report two patients who presented with relapsed leukemia as extramedullary tumor in the ovary following allo-HSCT. Case 1: A 23-year-old female underwent unrelated allogeneic bone marrow transplantation during the second remission of acute myeloid leukemia. After 706 days post-transplant, bilateral ovarian tumors were detected during the pelvic ultrasound, and extramedullary recurrence in the bilateral ovaries was subsequently established on right salpingo-oophorectomy and biopsy of the left ovary. Following completed systemic chemotherapy and total body irradiation, the patient underwent unrelated cord blood transplantation (CBT) and remission was maintained without recurrence for 7 years after second transplantation. Case 2: A 49-year-old female underwent unrelated CBT during the second remission of acute lymphocytic leukemia. At 372 days post-transplant, a pelvic tumor was detected by FDG-PET/CT, and extramedullary recurrence in the right ovary was diagnosed on examination of the resected pelvic mass. Chemotherapy and radiation were performed, but the tumor recurred on day 1,027 and the patient died on day 1,603. Extramedullary recurrence of adult acute leukemia as a mass in the ovary following allo-HSCT has been rarely reported. Therefore, further accumulation of related case reports is desired.

Watch-and-wait policy versus rituximab-combined chemotherapy in Japanese patients with intestinal follicular lymphoma.

BACKGROUND AND AIM: Few reports have demonstrated the effectiveness of treatments for intestinal follicular lymphoma (FL) because of the limited number of patients who undergo comprehensive small intestinal examinations. This study compared the efficacy of rituximab-combined chemotherapy in patients with asymptomatic and low tumor burden (LTB) intestinal FL, according to the criteria of the Groupe d'Etude des Lymphomes Folliculaires, with that of a "watch and wait" (W&W) approach. METHODS: The endoscopic examination for entire gastrointestinal tracts was performed in 29 Japanese patients with intestinal FL. These patients had CD21-positive follicular dendritic cells arranged in a duodenal pattern. In a prospective, two-center, open-label trial, this study evaluated the efficacy of rituximab-combined chemotherapy ([cyclophosphamide, doxorubicin, vincristine, and prednisone] or [cyclophosphamide, vincristine, and prednisone]) and prolonged treatment with rituximab (R-Chemo+prolongedR) in 14 patients and compared their outcomes with those of 15 patients managed with a W&W approach. RESULTS: Four patients managed with the W&W plan showed worsening macroscopic findings, lesion area enlargement, or clinical stage progression but stayed on this plan because they had LTB and experienced no changes in bowel function. In the R-Chemo+prolongedR group, all patients achieved complete remission; recurrence occurred in one patient, who was subsequently managed with the W&W plan because of LTB. There were no significant differences in progression-free survival between the two groups (P = 0.1045). Overall survival was 100% in both groups. CONCLUSIONS: The prognoses of patients with asymptomatic intestinal FL and LTB who were managed with a W&W strategy were comparable with those of patients receiving R-Chemo+prolongedR.

[Philadelphia chromosome-positive acute lymphoblastic leukemia complicated by concomitant Achromobacter xylosoxidans and Corynebacterium striatum bacteremia following allogeneic hematopoietic stem cell transplantation].

A 54-year-old woman with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) underwent hematopoietic stem cell transplantation from an HLA-matched sibling. Subsequently, she suffered from chronic graft versus host disease (GvHD) and received medical treatment. Fever developed on day 697 and resulted in a shock state at 10 h after the visit. Achromobacter xylosoxidans was detected in the initial blood culture on day 699. General conditions exacerbated even after the start of meropenem hydrate (MEPM, Meropen®) administration, with Corynebacterium striatum detected as an additional species in the initial blood culture on day 701. Although vancomycin hydrochloride (VCM, Vancomycin®) was administered, the conditions did not improve. She died on day 702. Between January 2012 and December 2016, A. xylosoxidans was detected only in nine cases in our hospital, which included five with hematological malignancies and only one (present) with sepsis. At the same time, Corynebacterium species were detected in blood cultures from 39 cases in our hospital, which included 31 with hematological malignancies. Some reports on drug-resistant A. xylosoxidans and C. striatum have been published. Infections with these species may become fatal when complicated by sepsis in immunocompromised patients with hematological malignancies. More cases should be accumulated for detailed investigation.

Successful haploidentical stem cell transplantation with prophylactic administration of liposomal amphotericin B after invasive pulmonary zygomycosis.

A 54-year-old woman with acute myeloid leukemia (AML) achieved complete remission by induction chemotherapy, but developed zygomycosis after consolidation therapy. As zygomycosis could not be cured by liposomal amphotericin B and micafungin, left lower lobectomy was performed. As AML relapsed 7 months after onset, she received haploidentical stem cell transplantation under administration of liposomal amphotericin B. Despite experiencing severe acute graft-versus-host disease, she remains alive with no relapse of either zygomycosis or AML.

Post-allogeneic stem cell transplant extramedullary relapse of acute megakaryoblastic leukemia initially detected by elevated WT1 mRNA levels in peripheral blood.

An 18-year-old male was admitted to our hospital for fever, and was diagnosed with acute megakaryoblastic leukemia (AML M7) based on the presence of CD42a and CD61 positive myeloblasts in peripheral blood (PB). Induction chemotherapy at our hospital resulted in complete remission (CR). Subsequently, he underwent unrelated HLA-DR one locus-mismatched allogeneic bone marrow (BM) transplantation. Although CR was maintained without development of graft-versus-host disease (GvHD), the WT1 mRNA level in PB was elevated on post-transplant day 134. As BM aspiration performed 1 week later confirmed maintenance of CR, and because the WT1 mRNA level in BM was not high in comparison with PB, we suspected extramedullary relapse. PET-CT demonstrated a thymic tumor and a gastric tumor with abnormal accumulation of FDG, and biopsy confirmed both to be extramedullary relapse of AML M7. Induction chemotherapy following local radiation therapy achieved a second CR, following which he received HLA haploidentical peripheral blood stem cell transplantation on day 256 after the first transplant. The patient is currently surviving free from both relapse and GvHD. High WT1 mRNA levels in PB as compared with BM should raise suspicion of extramedullary relapse, and PET-CT is very useful for whole body evaluation in such cases.

Prognostic Significance of New-Onset Atrial Fibrillation in Patients With Non-Hodgkin's Lymphoma Treated With Anthracyclines.

Cancer therapeutics-related cardiac dysfunction induced by anthracycline is highly problematic, and its early recognition is of importance. Atrial fibrillation (AF) is sometimes seen after anthracycline chemotherapy. We aimed to test whether new-onset AF predicts anthracycline-induced heart failure. We prospectively studied 249 lymphoma patients who received anthracyclines. The patients were followed up with a frequent electrocardiographic examination. Fifteen patients (6%) newly developed AF after the chemotherapy, and during a mean follow-up of 34 months, they had a higher incidence of acute heart failure (40% vs 3.8%; p <0.001) and greater all-cause mortality (60% vs 14.1%; p <0.001) than those without AF. The onset of AF preceded the development of heart failure by a mean of 2.4 months. New-onset AF was independently associated with both acute heart failure (hazard ratio 12.78; p <0.001) and all-cause mortality (hazard ratio 4.77; p <0.001). The cumulative anthracycline dose did not differ between the patients with and without heart failure, yet it was another independent predictor of the mortality. In conclusion, new-onset AF may predict unfavorable outcomes after anthracycline chemotherapy in patients with malignant lymphoma.

The role of "watch and wait" in intestinal follicular lymphoma in rituximab era.

OBJECTIVE: There is no consensus regarding the best treatment for intestinal follicular lymphoma (FL). We used "watch and wait" for patients with intestinal FL with low-tumor-burden (LTB) criteria and without mass formation causing bowel obstruction. We investigated the overall survival (OS) and time to treatment required (TTR). METHODS: Thirty-three intestinal FL patients [clinical stage (CS) I:16, II1:0, II2:7, IV:10; median observation period: 45.5 months, range: 13-110 months] were diagnosed via endoscopy. Detailed clinical and pathological examinations were performed, and neoplastic process behavior was monitored. RESULTS: All of the 33 patients were WHO grade 1. FL lesions in the digestive tract were found frequently in the second-fourth portion of the duodenum in 91% of the patients; 87% of those patients had lesions in a broader area including the small intestine. Two patients had an enlargement of the area of the lesions and a worsening of the macroscopic findings. Three patients had CS progression; however, these remained within the indication for "watch and wait." Two patients with transformation into diffuse large B-cell lymphoma received rituximab and chemotherapy, which led to complete remission. The OS was 100%. The time to treatment required (TTR) was 49 months in one patient and 37 months in one patient. CONCLUSION: Intestinal FL in CS I-IV with broad infiltration of the digestive tract meeting the criteria for LTB had a remarkably slow course. This study suggests that "watch and wait" is appropriate for the treatment of LTB intestinal FL even in the era of rituximab.

Survival of multiple myeloma patients aged 65-70 years in the era of novel agents and autologous stem cell transplantation. A multicenter retrospective collaborative study of the Japanese Society of Myeloma and the European Myeloma Network.

Novel agents such as thalidomide, lenalidomide and bortezomib have dramatically changed the treatment paradigm of multiple myeloma (MM). However, it is not clear whether these agents improve the prognosis of elderly patients who have undergone autologous stem cell transplantation (auto-SCT). We retrospectively analyzed the outcome of 318 newly diagnosed patients aged 65­70 years who were treated between January 1, 2004, and December 31, 2009. As initial therapy, 192 patients were treated with conventional chemotherapy,88 with novel agent-containing regimens, 21 with conventional chemotherapy plus auto-SCT and the remaining 17 with novel agents plus auto-SCT. The median progression-free survival was 19.1, 24.5, 26.8 and 35.2 months, respectively, and the 5-year overall survival (OS) was 40, 62, 63 and 87%, respectively. Initial therapy with novel agents (p < 0.001) or auto-SCT (p < 0.02) significantly improved OS compared with the group without these treatment modalities. Salvage therapy with novel agents also significantly improved survival after relapse compared with conventional chemotherapy alone (p < 0.04). In a multivariate analysis, the use of novel agents was an independent prognostic factor significantly associated with extended OS(p < 0.003). These results indicate that novel agents and auto-SCT had a major impact on OS in eligible patients in this subgroup of MM.