[Successful child delivery in treatment-free remission of chronic myeloid leukemia after discontinuation of dasatinib].

A 21-year-old woman was diagnosed with chronic myeloid leukemia in March 2014. The patient and her family did not wish to freeze eggs before dasatinib initiation. After 66 months of oral dasatinib administration and 40 months of MR4.5 maintenance, the patient requested to discontinue dasatinib due to a desire to conceive. MR4.5 maintenance was continued, and she achieved spontaneous pregnancy 6 months after dasatinib discontinuation. The patient gave birth to a normal baby 13 months later and was on MR4.5 maintenance 21 months after dasatinib discontinuation.

Prophylactic antiviral therapy for hepatitis B virus surface antigen-positive patients with diffuse large B-cell lymphoma treated with rituximab-containing chemotherapy.

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.

Efficacy and safety of a 5-day regimen of azacitidine for patients with high-risk myelodysplastic syndromes.

Although a 7-day (d) regimen of azacitidine (AZA) is the standard treatment of high-risk myelodysplastic syndromes (MDS), AZA is difficult to administer during weekends in an outpatient setting. We retrospectively investigated the outcome of a 5-d regimen of AZA in patients with high-risk MDS. High-risk MDS was defined as MDS with intermediate-2- or high-risk MDS according to the International Prognostic Scoring System. Every months AZA was given at 75 mg/m(2) per day for 5-7 d in hospital for first cycle and 5 d in outpatient for second cycle and later. Between April 2011 and December 2013, AZA treatment was initiated in 25 patients (men, 22; women, 3; median age, 75 yr; age range, 59-86 yr). The median number of AZA cycles was 10 (range, 1-24). Twenty patients received more than three cycles of AZA and 13 (52%) achieved any hematological improvement (HI). The median time to first response was two cycles (1-3). The most common non-hematological adverse events were neutropenia in 21 patients and thrombocytopenia in 17 patients. Nineteen patients died. The main cause of death was disease progression (five patients) and infectious complications (11 patients). The median overall survival was 13.2 months. The 5-d AZA regimen showed a good continuation rate of more than three cycles and an equivalent HI with the 7-d regimen.

[Successful induction therapy for acute myeloid leukemia complicated with brain hemorrhage and hyperleukocytosis].

Adequate management of hyperleukocytosis in patients with acute myeloid leukemia (AML) is essential for the prevention of life-threatening complications related to leukostasis and tumor lysis syndrome, but the optimal therapeutic strategy remains unclear. We report a 15-year-old girl with newly diagnosed AML who had extreme hyperleukocytosis (leukocyte count at diagnosis, 733,000/µl) leading to a brain hemorrhage. She was initially treated with hydroxyurea, but presented with brain hemorrhage due to leukostasis and underwent leukapheresis emergently with intensive care and mechanical ventilation. Full-dose standard induction chemotherapy was initiated after achieving gradual cytoreduction (leukocyte count, 465,000/µl) within five days after the initiation of therapy with hydroxyurea and leukapheresis. These treatments were successful and she experienced no complications. The patient ultimately recovered fully and was discharged with complete remission of AML. Although the effects of hydroxyurea and leukapheresis in the setting of hyperleukocytosis are still controversial, these initial treatments may contribute to successful bridging therapy followed by subsequent induction chemotherapy, especially in AML cases with extreme hyperleukocytosis or life-threatening leukostasis.

Peripheral blood absolute lymphocyte/monocyte ratio as a useful prognostic factor in diffuse large B-cell lymphoma in the rituximab era.

OBJECTIVES: The tumor microenvironment, including tumor-infiltrating lymphocytes and myeloid-derived cells, is an important factor in the pathogenesis and clinical behavior of malignant lymphoma. However, the prognostic significance of peripheral lymphocytes and monocytes in lymphoma remains unclear. METHODS: We evaluated the prognostic impact of the absolute lymphocyte count (ALC), absolute monocyte count (AMC), and lymphocyte/monocyte ratio (LMR) in 359 diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). RESULTS: The median follow-up time of the surviving patients was 58 months. Low ALC and an elevated AMC were both associated with poor survival rates. Receiver operating characteristic curve analysis showed that LMR was the best predictor of survival, with 4.0 as the cutoff point. Patients with LMR ≤4.0 were more likely to have an aggressive tumor, and this was associated with poor treatment responses. Patients with LMR ≤4.0 at diagnosis had significantly poorer overall survival (OS) and progression-free survival (PFS) than those with LMR >4.0. Multivariate analysis, which included prognostic factors of the International Prognostic Index, showed LMR ≤4.0 to be an independent predictor for the OS (hazard ratio [HR], 2.507; 95% confidence interval [CI], 1.255-5.007; P = 0.009) and PFS (HR, 2.063; 95% CI, 1.249-3.408; P = 0.005). CONCLUSIONS: The LMR at diagnosis, as a simple index which reflects host systemic immunity, predicts clinical outcomes in DLBCL patients treated with R-CHOP.

MIB-1 labeling index as a prognostic factor for patients with follicular lymphoma treated with rituximab plus CHOP therapy.

The MIB-1 labeling index, which is based on Ki67 immunostaining, is widely used to evaluate the proliferation of tumor cells in lymphoma. However, its clinical significance has not been fully assessed. We retrospectively evaluated the prognostic impact of the MIB-1 labeling index at the time of diagnosis, in 98 patients with follicular lymphoma (FL) grade 1-3b who were treated uniformly with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy. The 5-year progression-free survival (PFS) for an MIB-1 labeling index of ≥10% (n = 60) and <10% (n = 38) was 35% and 61%, respectively (P = 0.015). The 5-year overall survival (OS) for an MIB-1 labeling index of ≥10% and <10% was 77% and 92%, respectively (P = 0.025). Pathological grading was not correlated with PFS or OS. In multivariate analysis, an MIB-1 labeling index of ≥10% was independently associated with poor PFS and OS. In conclusion, an MIB-1 labeling index of 10% is a useful cut-off level for predicting the prognosis of patients with FL.

R-CHOP therapy alone in limited stage diffuse large B-cell lymphoma.

Long-term observation has identified a pattern of continuing relapse in limited stage diffuse large B-cell lymphoma (DLBCL) treated by three cycles of R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) plus involved-field irradiation. We retrospectively analysed 190 untreated patients with limited stage DLBCL treated by R-CHOP alone. All the patients were scheduled to undergo primary therapy with six cycles of full-dose R-CHOP. Cases with a dose reduction of more than 20% were excluded from the study. Additional local irradiation was allowed in patients with partial response (PR). Five patients received additional local irradiation after PR at the end of the R-CHOP therapy. The median observation period was 52 months. Median age at diagnosis was 63 years. The responses to therapy were 180 complete responses, eight PR, and two progression of disease (PD). The 5-year progression-free survival and 5-year overall survival rates were 84% and 90%, respectively, both in plateau. During the observation period, 29 patients experienced PD. The progression sites were the primary sites in 15 patients, outside the primary sites in 10, and undetermined in four patients. These results suggest that the 'standard' strategy of three cycles of R-CHOP followed by involved-field radiotherapy for limited stage DLBCL could be effectively replaced by six cycles of R-CHOP alone.

[Chronic myeloid leukemia maintained major molecular response with intermittent dosage of imatinib mesylate].

A 57-year-old woman was diagnosed as in the chronic myeloid leukemia-chronic phase. Imatinib mesylate(IM)was initiated at 400 mg daily. She achieved complete cytogenetic response at 3 months, and major molecular response at 10 months. IM was reduced to 300 mg daily at 12 months because of grade 1 nausea. IM was reduced to 300 mg for 5 days per week by her demand at 22 months. Major molecular response was maintained with 300 mg of IM for 3 days per week at 77 months. The intermittent IM therapy might be useful for CML patients who cannot tolerate the standard dose of IM.

Clinical impact of cigarette smoking on the outcomes of allogeneic hematopoietic stem cell transplantation: a multicenter retrospective study.

Smoking is associated with a high risk for different diseases including respiratory tract infections in immunocompetent patients. However, data about the effects of cigarette smoking on the outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) are limited. Therefore, we retrospectively investigated 608 patients aged ≥20 years with hematological disorders who received their first allo-HSCT at our group of hospitals between 2000 and 2015, and evaluated the impact of cigarette smoking before allo-HSCT on clinical outcomes by dividing patients into two groups according to the Brinkman index (BI) (nonsmokers or light smokers [BI: 0-500] and heavy smokers [BI: ≥ 500]). Multivariate analyses showed that heavy smoking was associated with a high 5-year cumulative incidence of chronic graft-versus-host disease (cGVHD) (hazard ratio [HR]: 1.73, 95% confidence interval [CI]: 1.15-2.61, p < 0.01). The 5-year overall survival (HR: 1.16, 95% CI: 0.86-1.58, p = 0.33) and disease-free survival (HR: 1.12, 95% CI: 0.83-1.52, p = 0.45) were similar between the two groups. Hence, cigarette smoking is correlated with cGVHD, although prospective studies must be conducted to further verify this result.

Comparison of Clinical Features Between Primary and Secondary Breast Diffuse Large B Cell Lymphoma: A Yokohama Cooperative Study Group for Hematology Multicenter Retrospective Study.

We performed a retrospective analysis of DLBCL with breast involvement to compare the prognosis of primary breast lymphoma (PBL) to secondary breast lymphoma (SBL; especially in limited stage cases). We retrospectively reviewed records of 25 diffuse large B-cell lymphoma (DLBCL) patients with breast involvement who received chemotherapy between January 2000 and August 2012. We compared clinical features and prognosis among patients with PBL (n = 11), limited stage SBL (LSBL; n = 6), and advanced stage SBL (ASBL, n = 8). The PBL group had significantly lesser patients with breast tumours (BTs) > 5 cm than the SBL group (P = 0.02). After a median follow-up of 71.3 months, we observed significantly better 5-year overall survival (OS) in the PBL group (90.0%) than in the LSBL (33.3%, P = 0.01) group, but not for progression-free survival (PFS). Patients with BT > 5 cm had worse OS (P = 0.01) and PFS (P = 0.04) than those with BT ≤ 5 cm. PBL had a better prognosis than SBL among limited stage DLBCL.

Computed tomography-defined sarcopenia: prognostic predictor of nonrelapse mortality after allogeneic hematopoietic stem cell transplantation: a multicenter retrospective study.

We analyzed clinical cutoffs for defining computed tomography (CT) methods for sarcopenia and examined the prognostic value of CT for allogeneic hematopoietic stem cell transplantation (allo-HCST) outcomes of patients with myeloid malignancy. One hundred twenty-five adult patients with acute myeloid leukemia and myelodysplastic syndrome who underwent first allo-HSCT between 2000 and 2017 were included. Sarcopenia was assessed using CT-based skeletal muscle index (SMI) and mean muscle attenuation at L3. A statistical difference in SMI was confirmed between sarcopenia (n = 52) and nonsarcopenia (n = 73) patients. There were no significant correlations of muscularity with age, performance status, or other characteristics of HSCT. After 2 years, overall survival (OS) was 43.5% and 70.1%, disease-free survival was 52.9% and 68.6%, nonrelapse mortality (NRM) was 20.8% and 8.4%, incidence of acute GVHD (≥ grade 2) was 38.8% and 39.1%, that of chronic GVHD was 53.2% and 37.3%, and median duration of hospitalization was 88 days and 74 days (P = 0.026), respectively, in the sarcopenia and nonsarcopenia groups. Multivariate analysis showed that presence of sarcopenia is a novel adverse factor for high NRM and poor OS. Pretransplant CT-defined sarcopenia is correlated with decreased OS, increased NRM, and prolonged hospitalization.

Impact of treatment-related weight changes from diagnosis to hematopoietic stem-cell transplantation on clinical outcome of acute myeloid leukemia.

We hypothesized that treatment-related weight loss is associated with worse outcomes following HSCT. Overall, 184 patients with AML who underwent induction therapy were classified according to d-BMI (BMI at transplant minus BMI at diagnosis) (kg/m2) as < -2, - 2 to + 2, and > + 2. At 1 year, OS was 67.9% (95% CI, 60.7-74.2), DFS was 64.1% (95% CI, 56.7-70.6), and GRFS was 40.2% (95% CI, 33.1-47.2). For d-BMI groups < - 2, - 2 to + 2, and > + 2, GRFS at 1 year was 16.1% (95% CI, 5.1-31.4), 45.4% (95% CI, 36.4-53.7), and 41.7% (95% CI, 22.2-60.1), respectively (P = 0.0067). Multivariate analysis showed that both worse OS (HR, 1.78; 95% CI, 1.02-3.14; P = 0.007) and GRFS (HR, 2.34; 95% CI, 1.26-4.35; P = 0.007) were associated with reduced BMI (d-BMI < - 2). Treatment-related weight reduction in AML was associated with poor outcome after HSCT.

The SIL index is a simple and objective prognostic indicator in diffuse large B-cell lymphoma.

We previously developed a prognostic index, SIL, which includes advanced stage (S), soluble interleukin-2 receptor level (I), and elevated lactate dehydrogenase level (L) in diffuse large B-cell lymphoma (DLBCL) patients treated with rituximab, cyclophosphamide, hydroxydaunomycin, oncovin, and prednisone (R-CHOP). This time we evaluated the index in a larger cohort and its utility in the risk stratification. The above three factors were independent risk of progression-free survival (PFS). Five-year PFS rates in the standard-risk (SIL index: 0 or 1, n = 367) and high-risk groups (SIL index: 2 or 3, n = 205) were 79% and 53%, respectively (p < 0.0001). When the patients were divided by age (≤60 years and >60 years), the SIL index was a good prognostic indicator for PFS in both groups as well as divided by the number of extranodal involvement site (0-1 and >1). The SIL index is a simple and objective prognostic indicator in DLBCL.

Beta-2 microglobulin is a strong prognostic factor in patients with DLBCL receiving R-CHOP therapy.

Useful prognostic markers for patients with diffuse large B cell lymphoma (DLBCL) have been reported. To identify which biomarker best predicts the prognosis of patients with DLBCL, we performed a retrospective study that included 319 DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) therapy between 2003 and 2012. We assessed the prognostic significance of six biomarkers [lactate dehydrogenase, soluble interleukin-2 receptor, thymidine kinase activity, beta-2 microglobulin (B2M), C-reactive protein, and ferritin] and representative clinical characteristics using progression-free survival (PFS) as the endpoint. The study group included 181 men and 138 women with a median age of 63 years (range, 22-89 years). In a multivariate analysis, the serum B2M level most strongly correlated with PFS (hazard ratio, 2.11; P=0.04). In a univariate analysis, patients with serum B2M levels >1.75µg/mL (n=210) had a worse 3-year PFS rate (71.2%) than those with B2M levels <1.75µg/mL (n=109; 90.0%). Therefore, serum B2M level at the time of diagnosis is a useful prognostic indicator in DLBCL patients receiving R-CHOP.

R-CHOP therapy alone for limited-stage follicular lymphoma.

Irradiation therapy alone is a standard strategy for limited-stage FL, leading to a 10-year progression-free survival (PFS) rate of 30-50%. However, we have been administering R-CHOP therapy alone to patients with limited-stage FL. A total of 35 patients with newly diagnosed FL received R-CHOP therapy with curative intent between 2002 and 2009. The median age of the 35 patients was 61 years; 7 patients had in CS 1 FL, and 28 patients, CS 2 FL. The median number of R-CHOP cycles was 6. On completion of the R-CHOP therapy, 33 patients achieved complete response and 1 showed partial response (PR). The patient showing PR after the completion of R-CHOP was administered additional irradiation. The remaining 1 patient was not evaluated because of discontinuation of hospital visit. In all the 35 patients, the 5-year PFS rate was 70%, and the 5-year overall survival rate was 92%. In the 15 patients with a PFS>5 years, only 1 patient showed disease progression. The outcome of R-CHOP therapy alone in patients with limited-stage FL was at least equivalent to the reported outcome of irradiation therapy alone. R-CHOP therapy could be an alternative to irradiation therapy in limited-stage FL patients.

Analysis of outcomes in patients with supra-diaphragmatic vs infra-diaphragmatic diffuse large B cell lymphoma treated with R-CHOP therapy.

The prognostic implications of infra-diaphragmatic (InD) versus supra-diaphragmatic (SpD) primary lesions in limited-stage diffuse large B-cell lymphoma (DLBCL) remains unknown. This retrospective study aimed to assess the prognostic impact of spD and InD lesions as well as presence of gastrointestinal (GI) involvements in adults with limited-stage DLBCL. We analyzed data from 178 patients with limited-stage DLBCL who were treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone therapy at 7 institutions of the Yokohama City University Hematology Group between 2003 and 2009. The median age was 63 years (range, 18-80 years). The primary sites were SpD in 109 patients, and InD in 69. No statistical differences in progression-free survival (PFS) or overall survival (OS) were observed between patients with SpD lesions and those with InD lesions. However, when patients with SpD lesions, InD lesions with (n=35), and without (n=34) GI involvement were compared, the presence of GI lesions was associated with favorable PFS. The multivariate analysis revealed that SpD or InD localization had no independent effect on PFS or OS, whereas the presence of GI lesions was correlated with favorable PFS (P=0.024, HR 0.09).

Serum ferritin level is prognostic of patient outcome in extranodal NK/T cell lymphoma, nasal type.

The objective of the current study was to assess the prognostic factors in patients with extranodal natural killer (NK)/T cell lymphoma, nasal type (ENKL). We retrospectively analyzed 35 patients who were diagnosed with ENKL between 1998 and 2011. The median patient age was 63 years, and the male/female ratio was 22:13; twenty patients had localized ENKL, and 26 had a good Eastern Cooperative Oncology Group performance status (score 0 or 1). B symptoms were present in 17 patients. Twenty-five patients presented with nasal or paranasal lesions, or both. With a median follow-up duration among patients still alive at their last follow-up of 47 months (range 8-93 months), the 3-year overall survival (OS) rate was 44.5 %. Multivariate analysis revealed that advanced disease stage (P = 0.002), the presence of extranasal disease (P = 0.013), and serum ferritin levels greater than 300 ng/ml (P < 0.001) were significant and independent (negative) prognostic factors. High serum ferritin levels were associated with the presence of B symptoms, elevated lactate dehydrogenase levels, and high soluble interleukin-2 receptor levels, but not with clinical stage. Patients with high ferritin levels had a remarkably low remission rate (23 %) and a short OS time (median: 4 months). Serum ferritin level at the time of diagnosis of ENKL was a useful prognostic factor.

Absolute monocyte count in follicular lymphoma patients treated with rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone.

Elevated absolute monocyte counts (AMCs) have been reported to indicate poor prognosis for patients with lymphoproliferative disease, including those with follicular lymphoma (FL) receiving various treatments. We evaluated the prognostic impact of AMC in 150 consecutive FL patients who received rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) therapy. Progression-free survival (PFS) did not differ significantly according to the AMC level. Univariate and multivariate analyses did not indicate a prognostic significance of AMC for PFS. Thus, the AMC is not a prognostic factor for FL patients treated with R-CHOP. However, immunochemotherapy might influence the prognostic impact of AMC.

Standard R-CHOP therapy in follicular lymphoma and diffuse large B-cell lymphoma.

The introduction of rituximab (R) has measurably improved the outcome of patients with follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL). To evaluate the outcome of patients with FL and DLBCL under R plus CHOP therapy, we performed a retrospective analysis in Yokohama City University Hematology Group in Japan. Five hundred and twenty-six patients (158, FL ; 368, DLBCL) were scheduled to undergo primary therapy with 6 cycles of full-dose R-CHOP therapy with curative intent. The median observation periods in living patients with FL and DLBCL were 45 months and 43 months, respectively. The complete response, 5-year progression-free survival (PFS), and 5-year overall survival (OS) rates were 86%, 50%, and 92% in the FL group, and 89%, 72%, and 80% in the DLBCL group, respectively. Although PFS was significantly better in the DLBCL group than in the FL group, OS was significantly better in FL patients. We also found that the OS and PFS of grade 3 FL patients were not statistically different from those with grade 1-2. These findings indicate that all grades of FL should be categorized simply as "FL" with regard to R-CHOP therapy. Our results also demonstrate the incurability of FL (grade 1-3B), even with R-CHOP therapy.