Long-term follow-up after R-High CHOP/CHASER/LEED with Auto-PBSCT in untreated mantle cell lymphoma-Final analysis of JCOG0406.

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.

Long-term outcomes and central nervous system relapse in extranodal natural killer/T-cell lymphoma.

To elucidate the long-term outcomes of non-anthracycline-containing therapies and central nervous system (CNS) events in patients with extranodal NK/T-cell lymphoma, nasal type (ENKTL), the clinical data of 313 patients with ENKTL diagnosed between 2000 and 2013 in a nationwide retrospective study in Japan were updated and analyzed. At a median follow-up of 8.4 years, the 5-year overall survival (OS) and progression-free survival (PFS) were 71% and 64%, respectively, in 140 localized ENKTL patients who received radiotherapy-dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) in clinical practice. Nine (6.4%) patients experienced second malignancies. In 155 localized ENKTL patients treated with RT-DeVIC, 10 (6.5%) experienced CNS relapse (median, 12.8 months after diagnosis). In five of them, the events were confined to the CNS. Nine of the 10 patients who experienced CNS relapse died within 1 year after CNS relapse. Multivariate analysis identified gingival (hazard ratio [HR], 54.35; 95% confidence interval [CI], 8.60-343.35) and paranasal involvement (HR, 7.42; 95% CI, 1.78-30.89) as independent risk factors for CNS relapse. In 80 advanced ENKTL patients, 18 received steroid (dexamethasone), methotrexate, ifosfamide, L-asparaginase, and etoposide (SMILE) chemotherapy as first-line treatment. Patients who received SMILE as their first-line treatment tended to have better OS than those who did not (p = 0.071). Six (7.5%) advanced ENKTL patients experienced isolated CNS relapse (median, 2.6 months after diagnosis) and died within 4 months of relapse. No second malignancies were documented in advanced ENKTL patients. In the entire cohort, the median OS after first relapse or progression was 4.6 months. 12 patients who survived 5 years after PFS events were disease-free at the last follow-up. Of those, 11 (92%) underwent hematopoietic stem cell transplantation. Our 8-year follow-up revealed the long-term efficacy and safety of RT-DeVIC and SMILE. The risk of CNS relapse is an important consideration in advanced ENKTL.

Randomised phase II study to optimise melphalan, prednisolone, and bortezomib in untreated multiple myeloma (JCOG1105).

We conducted a randomised phase II study to determine the optimal dose and schedule of melphalan, prednisone, and bortezomib (MPB) (jRCTs031180097). Transplant-ineligible untreated multiple myeloma patients were randomised to Arm A (twice weekly bortezomib in one six-week cycle followed by eight five-week cycles of four times once weekly bortezomib with melphalan and prednisolone on days 1-4) or Arm B (nine four-week cycles of three times once weekly bortezomib with melphalan and prednisolone on days 1-4). The primary end-point was complete response (CR) rate. Of 91 patients randomised to two arms, 88 were eligible. The median cumulative bortezomib doses were 45·8 and 35·1 mg/m2 , CR rate was 18·6% [95% confidence interval (CI) 8·4-33·4] and 6·7% (95% CI 1·4-18·3), and the median progression-free survival (PFS) was 2·5 and 1·4 years in Arms A and B [hazard ratio (HR) 1·93 (95% CI 1·09-3·42)], respectively. Frequent grade ≥3 haematologic toxicities in Arms A and B were neutropenia (64·4% vs. 28·3%) and thrombocytopenia (35·6% vs. 10·9%). Grade 2/3 peripheral neuropathy was observed in 24·4/2·2% in Arm A and 8·7/0% in Arm B. In conclusion, Arm A was the more promising regimen, suggesting that the twice weekly schedule of bortezomib in the first cycle and higher cumulative dose of both bortezomib and melphalan influences the efficacy of modified MPB.

[Concurrent CALR and SF3B1 gene mutations in a patient with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis].

A 83-year-old female patient was admitted to our hospital due to hematological manifestation of juvenile granulocytes and macrocytic anemia. Bone marrow (BM) examination revealed erythroid dysplasia and cytoplasmic blasts, and hence the patient was diagnosed with myelodysplastic syndrome with ring sideroblasts and with single lineage dysplasia (MDS-RS-SLD). Erythrocyte transfusion was performed as a supportive therapy, and there was a gradual increase in the number of blood cells. Therefore, BM re-examination was performed and it was confirmed that the number of megakaryocytes increased, so the patient's condition was determined as myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and thrombocytosis (MDS/MPN with RS-T). Incidentally, gene mutation analysis showed CALR gene mutation. Thereafter, administration of hydroxycarbamide and anagrelide did not show adverse events and complications, and a good blood count control was obtained. Furthermore, it was also confirmed that an SF3B1 gene mutation is highly positive in MDS-RS. There was no report on CALR-mutant MDS/MPN in Japan, and it is a rare disease overseas.

Early disease progression in patients with localized natural killer/T-cell lymphoma treated with concurrent chemoradiotherapy.

Prognosis of patients with localized nasal extranodal natural killer/T-cell lymphoma, nasal type (ENKL) has been improved by non-anthracycline-containing treatments such as concurrent chemoradiotherapy (CCRT). However, some patients experience early disease progression. To clarify the clinical features and outcomes of these patients, data from 165 patients with localized nasal ENKL who were diagnosed between 2000 and 2013 at 31 institutes in Japan and who received radiotherapy with dexamethasone, etoposide, ifosfamide, and carboplatin (RT-DeVIC) were retrospectively analyzed. Progression of disease within 2 years after diagnosis (POD24) was used as the definition of early progression. An independent dataset of 60 patients with localized nasal ENKL who received CCRT at Samsung Medical Center was used in the validation analysis. POD24 was documented in 23% of patients who received RT-DeVIC and in 25% of patients in the validation cohort. Overall survival (OS) from risk-defining events of the POD24 group was inferior to that of the reference group in both cohorts (P < .00001). In the RT-DeVIC cohort, pretreatment elevated levels of serum soluble interleukin-2 receptor (sIL-2R), lactate dehydrogenase, C-reactive protein, and detectable Epstein-Barr virus DNA in peripheral blood were associated with POD24. In the validation cohort, no pretreatment clinical factor associated with POD24 was identified. Our study indicates that POD24 is a strong indicator of survival in localized ENKL, despite the different CCRT regimens adopted. In the treatment of localized nasal ENKL, POD24 is useful for identifying patients who have unmet medical needs.

R-High-CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY.

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.

[Annuloaortic ectasia associated with antithrombin III deficiency; report of a case].

A 33-year-old male with hereditary deficiency of antithrombin III (AT III) was diagnosed with annuloaortic ectasia and scheduled for the aortic root replacement. As perioperative anticoagulation, AT III was administered to have its activity≥70% in addition to heparin. During the operation with cardiopulmonary bypass, 3,000 IU of AT III concentrate was infused, and there was no hemorrhagic complication. After the operation low-molecular-weight heparin was used instead of unfractionated heparin to avoid bleeding. However, renal infarction occurred on postoperative day 11. Heparin was continuously given in combination with 1,500 IU/day of AT III concentrate until oral warfarin reached within therapeutic range. The patient recovered without further sequelae. Cardiac surgery might be safely performed in patients with AT III deficiency by replenishing AT III concentrate to keep its activity higher than 80%.

[Fungemia caused by Scedosporium prolificans in myelodysplastic syndrome].

We report a case of fungemia caused by Scedosporium prolificans, an emerging pathogen. An 83-year-old man with myelodysplastic syndrome (MDS) and agranulocytosis was admitted for pneumonia in January 2009. He was treated with meropenem, minocycline, and gamma-globulin for pneumonia and G-CSF and platelet transfusion for MDS. Although he recovered from pneumonia as neutrophil count increased, intermittent fever continued. On hospital day 17, blood culture yielded fungal colonies indicating S. prolificans. Voriconazole was started immediately, but the man's general condition deteriorated with cerebral infarction and he died of cerebral hemorrhage on hospital day 65. Attention must therefore be paid to the increasing scedosporiosis incidence in Japan.

Whole brain radiation therapy for primary central nervous system marginal zone lymphoma: a case report.

A standard radiation therapy protocol for primary central nervous system marginal zone lymphoma (CNS-MZL) has not been established. The International Lymphoma Radiation Oncology Group suggested a radiation therapy dose of 30-36 Gy for lesions of well-defined CNS-MZL. We report a case of relatively low-dose whole brain radiation therapy (WBRT) for ill-defined CNS-MZL. A 56-year-old man who presented with sudden left-sided convulsions and impaired consciousness was diagnosed with CNS-MZL. The tumor had an ill-defined lesion, without cerebrospinal fluid involvement. WBRT, consisting of 25.2 Gy in 14 fractions, was administered owing to the difficulty in target delineation for focal radiation therapy. No chemotherapy was administered during the treatment course. After the 36-month follow-up period, the patient maintained complete remission without neurological disorders. This report describes the usefulness of relatively low-dose WBRT for ill-defined CNS-MZL.

A randomized phase 2/3 study of R-CHOP vs CHOP combined with dose-dense rituximab for DLBCL: the JCOG0601 trial.

Rituximab plus cyclophosphamide-doxorubicin-vincristine-prednisone (R-CHOP) is the standard of care for untreated diffuse large B-cell lymphoma (DLBCL). However, the schedule for rituximab administration has not been optimized. To compare standard R-CHOP with CHOP plus dose-dense weekly rituximab (RW-CHOP) in patients with untreated DLBCL, we conducted a phase 2/3 study (JCOG0601, jRCTs031180139). Patients were randomly assigned to R-CHOP (CHOP-21 with 8 doses of rituximab once every 3 weeks [375 mg/m2]) or RW-CHOP (CHOP-21 with 8 doses of weekly rituximab [375 mg/m2]) groups. The primary end point of the phase 2 component was percent complete response (%CR) of the RW-CHOP arm, whereas that of the phase 3 component was progression-free survival (PFS). Between December 2007 and December 2014, 421 untreated patients were randomly assigned to R-CHOP (213 patients) or RW-CHOP (208 patients). The %CR in the RW-CHOP arm was 85.3% and therefore met the prespecified decision criteria for the phase 2 component. With a median follow-up of 63.4 months, the 3-year PFS and overall survival were 79.2% and 88.7% in the R-CHOP arm and 80.3% and 90.4% in the RW-CHOP arm, respectively. There was no significant difference in PFS (hazard ratio, 0.95; 90.6% confidence interval, 0.68-1.31). Although the safety profile and efficacy of RW-CHOP was comparable with R-CHOP and its tolerability was acceptable, weekly rituximab in combination with CHOP during the early treatment period did not improve PFS in untreated patients with DLBCL. This trial was registered at jrct.niph.go.jp as #jRCTs031180139.

Splenic Marginal Zone B-Cell Lymphoma With Splenic Infarction in a Patient With Cold Agglutinin Disease.

We report a case of splenic marginal zone B-cell lymphoma discovered in a 73-year-old man with cold agglutinin disease. PET/CT revealed splenomegaly with focally intense uptake of F-FDG and diffusely increased bone marrow uptake, which was considered to be secondary to hemolytic anemia. Splenectomy was performed. The histopathology of the spleen showed splenic marginal zone B-cell lymphoma with partial splenic infarction, which correlated with the area of focal intense FDG uptake. Depending on the time since onset, splenic infarctions can present as focal FDG accumulation.

Final 3-year Results of the Dasatinib Discontinuation Trial in Patients With Chronic Myeloid Leukemia Who Received Dasatinib as a Second-line Treatment.

INTRODUCTION: We previously reported an interim analysis of the DADI (dasatinib discontinuation) trial. The results showed that 48% of patients with chronic myeloid leukemia in the chronic phase who maintained a deep molecular response (DMR) for ≥ 1 year could discontinue second- or subsequent-line dasatinib treatment safely at a median follow-up of 20 months. However, the results from longer follow-up periods would be much more useful from a clinical perspective. PATIENTS AND METHODS: The DADI trial was a prospective, multicenter trial conducted in Japan. After confirming a stable DMR for ≥ 1 year, dasatinib treatment subsequent to imatinib or nilotinib was discontinued. After discontinuation, the loss of DMR (even of 1 point) was defined as stringent molecular relapse, thereby triggering therapy resumption. The predictive factors of treatment-free remission (TFR) were analyzed. RESULTS: The median follow-up period was 44.0 months (interquartile range, 40.5-48.0 months). The estimated overall TFR rate at 36 months was 44.4% (95% confidence interval, 32.0%-56.2%). Only 2 patients developed a molecular relapse after the 1-year cutoff point. The presence of imatinib resistance was a significant risk factor for molecular relapse. Moreover, high natural killer cell and low γδ+ T-cell and CD4+ regulatory T-cell (CD25+CD127low) counts before discontinuation correlated significantly with successful therapy discontinuation. CONCLUSION: These findings suggest that discontinuation of second- or subsequent-line dasatinib after a sustained DMR of ≥ 1 year is feasible, especially for patients with no history of imatinib resistance. In addition, the natural killer cell count was associated with the TFR.

Discontinuation of dasatinib in patients with chronic myeloid leukaemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial.

BACKGROUND: First-line imatinib treatment can be successfully discontinued in patients with chronic myeloid leukaemia after deep molecular response has been sustained for at least 2 years. We investigated the safety and efficacy of discontinuing second-line or subsequent dasatinib after at least 1 year of deep molecular response. METHODS: The Dasatinib Discontinuation trial was a prospective multicentre trial done in Japan. Eligible patients taking dasatinib and with confirmed stable deep molecular response were enrolled between April 1, 2011, and March 31, 2012. All patients received dasatinib consolidation therapy for at least 1 year. In those with sustained deep molecular response, dasatinib was discontinued. Patients were followed up every month in year 1 (clinical cutoff), every 3 months in year 2, and every 6 months in year 3 for deep molecular response and immunological profiles. The primary endpoint was the proportion of patients with treatment-free remission at 6 months after discontinuation. Molecular relapse was defined as loss of deep molecular response at any assessment. This study is registered, number UMIN000005130. FINDINGS: 88 patients were enrolled in the consolidation phase, 24 were excluded from the discontinuation phase due to fluctuations in BCR-ABL1 transcript levels. One patient was excluded because of positive expression of major and minor BCR-ABL1 transcripts in chronic myeloid leukaemia cells and the detection of minor BCR-ABL1 transcripts during consolidation. Thus, 63 patients discontinued dasatinib treatment. The 25 patients who were excluded from discontinuation continued to receive dasatinib and none showed disease progression. Median follow-up was 20.0 months (IQR 16.5-24.0). Of the 63 patients who discontinued and were not excluded, 30 patients maintained deep molecular response while 33 patients had molecular relapses, all within the first 7 months after discontinuation. The estimated overall treatment-free remission was 49% (95% CI 36-61) at 6 months. No severe treatment-related toxic effects were seen. Treatment was restarted in the 33 patients with relapse; rapid molecular responses were seen in all 33 patients, of whom 29 (88%) regained deep molecular response within 3 months, as did the remaining four by 6 months. INTERPRETATION: Dasatinib discontinuation after sustained deep molecular response for more than 1 year is feasible. FUNDING: Epidemiological and Clinical Research Information Network (ECRIN).

[An autopsy case of Ph1--positive acute lymphoblastic leukemia with disseminated infection of Fusarium solani].

A 56-year-old woman with Ph1--Positive acute Lymphoblastic Leukemia was admitted to our hospital for induction chemotherapy in June 1999. The patient was presented with a central scotoma of left eye during treatment course and was given diagnosis of endophthalmitis. Thereafter she also developed skin induration and suffered from serious pneumonia. Amphotericin B administration was started because of high titer of beta-D-glucan, but soon discontinued due to its adverse effect. Blood cultures yielded colonies of fungus and it was identified Fusarium solani. Her general condition deteriorated with progression of pneumonia, and she died of respiratory insufficiency. Autopsy was performed, and its specimen revealed the disseminated infection of Fusarium solani (lung, eye, heart, kidney and skin). We should pay special attention to the fusariosis in Japan also.

JAK2 V617F-dependent upregulation of PU.1 expression in the peripheral blood of myeloproliferative neoplasm patients.

Myeloproliferative neoplasms (MPN) are multiple disease entities characterized by clonal expansion of one or more of the myeloid lineages (i.e. granulocytic, erythroid, megakaryocytic and mast cell). JAK2 mutations, such as the common V617F substitution and the less common exon 12 mutations, are frequently detected in such tumor cells and have been incorporated into the diagnostic criteria published by the World Health Organization since 2008. However, the mechanism by which these mutations contribute to MPN development is poorly understood. We examined gene expression profiles of MPN patients focusing on genes in the JAK-STAT signaling pathway using low-density real-time PCR arrays. We identified the following 2 upregulated genes in MPN patients: a known target of the JAK-STAT axis, SOCS3, and a potentially novel target, SPI1, encoding PU.1. Induction of PU.1 expression by JAK2 V617F in JAK2-wildtype K562 cells and its downregulation by JAK2 siRNA transfection in JAK2 V617F-positive HEL cells supported this possibility. We also found that the ABL1 kinase inhibitor imatinib was very effective in suppressing PU.1 expression in BCR-ABL1-positive K562 cells but not in HEL cells. This suggests that PU.1 expression is regulated by both JAK2 and ABL1. The contribution of the two kinases in driving PU.1 expression was dominant for JAK2 and ABL1 in HEL and K562 cells, respectively. Therefore, PU.1 may be a common transcription factor upregulated in MPN. PU.1 is a transcription factor required for myeloid differentiation and is implicated in erythroid leukemia. Therefore, expression of PU.1 downstream of activated JAK2 may explain why JAK2 mutations are frequently observed in MPN patients.