Clinical significance of total nucleated cell count in bone marrow of patients with acute lymphoblastic leukemia who underwent allogeneic hematopoietic stem cell transplantation.

The clinical implications of recipient bone marrow nucleated cell count (NCC) prior to allogeneic hematopoietic stem cell transplantation (allo-HSCT) remain unknown. We conducted a multicenter retrospective study to evaluate the clinical significance of bone marrow NCC prior to allo-HSCT in patients with acute lymphoblastic leukemia. Patients who were in remission and underwent the initial allo-HSCT were included and stratified into high- and low-NCC groups using an NCC of 10 × 104/µL as the cut-off. The 3-year overall survival (OS), non-relapse mortality (NRM), and relapse rates for the high- and low-NCC groups were 51.2 vs. 84.5% (p < 0.001), 27.5 vs. 6.5% (p < 0.001), and 31.1 vs. 24.4% (p = 0.322), respectively. The high-NCC group had significantly poorer OS and higher NRM when compared with the low-NCC group. In summary, high recipient bone marrow NCC is associated with higher NRM and lower OS following allo-HSCT.

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.

Impact of graft sources on immune reconstitution and survival outcomes following allogeneic stem cell transplantation.

We evaluated the kinetics of immune reconstitution (IR) after allogeneic hematopoietic cell transplantation (HSCT) and analyzed the clinical effect of IR on posttransplant outcomes. Absolute lymphocyte and its subset counts were measured using flow cytometry on days 28, 100, 180, 365, and 730 after transplantation in 358 adult patients who underwent HSCT between 2009 and 2017. On day 100 after HSCT, 310 surviving patients were analyzed. Bone marrow transplantation (BMT), peripheral blood stem cell transplantation (PBSCT), and cord blood transplantation (CBT) were performed in 119, 55, and 136 patients, respectively. Mature B-cell and differentiated natural killer (NK) cell subset counts significantly increased after CBT. The 2-year overall survival (OS), nonrelapse mortality (NRM), cumulative incidence of relapse, and chronic GVHD in BMT, PBSCT, and CBT were 62%, 67%, and 76% (P = .021); 17%, 17%, and 13% (P = .82); 33%, 40%, and 27% (P = .063); and 43%, 45%, and 28% (P = .025), respectively. Multivariate analysis showed that higher CD16+CD57- NK cell counts correlated with lower disease relapse, whereas higher CD20+ B-cell counts correlated with lower NRM. OS-favoring factors were higher CD16+CD57- NK cell count (hazard ratio, 0.36; 95% confidence interval, 0.22-0.60; P < .001) and CD20+ B-cell count (hazard ratio, 0.53; 95% confidence interval, 0.30-0.93; P < .001) and lower Disease Risk/HCT-Specific Comorbidity index score. Collective contribution of graft source-specific and event-related immune reconstitution might yield better posttransplant outcomes in CBT.

Predictive Values of Early Suppression of Tumorigenicity 2 for Acute GVHD and Transplant-related Complications after Allogeneic Stem Cell Transplantation: Prospective Observational Study

Objective: A soluble form of suppression of tumorigenicity 2 (sST2) has emerged as a biomarker for acute graft-versus-host disease (GVHD) and non-relapse mortality (NRM). We prospectively monitored sST2 levels during the early phase of hematopoietic stem cell transplantation (HSCT) and evaluated the clinical association with transplant-related complications including acute GVHD. Materials and Methods: Thirty-two adult Japanese patients who received a first allogeneic HSCT were enrolled in this study. Levels of sST2 were measured at fixed time points (pre-conditioning, day 0, day 14, day 21, and day 28). Results: The median age was 50.5 years (range=16-66). With a median follow-up of 21.5 months (range=0.9-35.4), 9 patients developed grade II-IV acute GVHD. Median sST2 levels on the day of HSCT were higher than baseline and reached the maximum value (92.7 ng/mL; range=0-419.7) on day 21 after HSCT. The optimal cut-off value of sST2 on day 14 for predicting grade II-IV acute GVHD was determined as 100 ng/mL by ROC analysis. The cumulative incidence of acute GVHD was 56.7% and 16.5% in the high- and low-sST2 groups, respectively (p<0.01). Multivariate analyses showed that high sST2 levels at day 14 were associated with a higher incidence of acute GVHD (hazard ratio=9.35, 95% confidence interval=2.92-30.0, p<0.01). The cumulative incidence of NRM was increased in the highs-ST2 group (33% vs 0%, p<0.01), but all the patients died of non-GVHD complications. Among 6 patients in the high-sST2 group without grade II-IV GVHD, 5 patients developed veno-occlusive disease (VOD) and one also had thrombotic microangiopathy (TMA). Conclusion: The early assessment of sST2 after HSCT yielded predictive values for the onset of acute GVHD and other transplant-related complications including VOD and TMA.

A Prospective, Longitudinal Observation of the Incidence, Treatment, and Survival of Late Acute and Chronic Graft-versus-Host Disease by National Institutes of Health Criteria in a Japanese Cohort.

To prospectively validate the incidence, manifestations, and outcomes of graft-versus-host disease (GVHD) by National Institutes of Health criteria, we recruited 406 hematopoietic stem cell transplantation recipients at 16 transplant centers in Japan from May 2012 to June 2014. The 2-year cumulative incidence of late acute and chronic GVHD was 3.2% (n = 13) and 35.4% (n = 145), with a median onset of 3.6 and 4.7 months after transplant, respectively. The global severity at onset was mild in 30.3%, moderate in 43.5%, and severe in 26.2%. Eighty-two patients were followed up for 2 years, with 79.3% still manifesting GVHD symptoms, and 80.6% (n = 117) of the patients received systemic immunosuppressive treatment (IST), with a 2-year cumulative incidence of IST termination of 33.1%. Severe patients showed a significantly lower rate of IST termination than those with mild and moderate severities (mild, 38.5%; moderate, 40.9%; and severe, 17.2%). The 2-year incidence of nonrelapse mortality (NRM) and relapse was not significantly different according to the severity at onset (NRM: mild [16.6%] versus moderate [8.7%] versus severe [16.1%]; relapse: mild [14.9%] versus moderate [14.7%] versus severe [5.3%]). As a result, 2-year overall survival (OS) and GVHD-specific survival (GSS) were equivalent according to the severity at onset (mild: OS = 81.0%, GSS = 85.7%; moderate: OS = 84.2%, GSS = 92.5%; severe: OS = 83.9%, GSS = 89.2%). Our study helped identify the characteristics of late acute and chronic GVHD in Japanese patients. Further investigation is needed to identify an optimal endpoint for survival prediction.

Utility of a Reverse Phase Protein Array to Evaluate Multiple Biomarkers in Diffuse Large B-Cell Lymphoma.

PURPOSE: Diffuse large B-cell lymphoma (DLBCL), the most common non-Hodgkin lymphoma, is a heterogeneous lymphoma with different clinical manifestations and molecular alterations, and several markers are currently being measured routinely for its diagnosis, subtyping, or prognostication by immunohistochemistry (IHC). Here, the utility of a reverse-phase-protein-array (RPPA) as a novel supportive tool to measure multiple biomarkers for DLBCL diagnosis is validated. EXPERIMENTAL DESIGN: The expression of seven markers (CD5, CD10, BCL2, BCL6, MUM1, Ki-67, and C-MYC) is analyzed by RPPA and IHC using 37 DLBCL tissues, and the correlation between the two methods is determined. To normalize tumor content ratio in the tissues, the raw RPPA values of each marker are adjusted by that of CD20 or PAX-5. RESULTS: The CD20-adjusted data for CD5, MUM1, BCL2, Ki-67, and C-MYC has better correlation with IHC results than PAX-5-adjusted data. Receiver operating characteristic (ROC) analysis reveals that CD5, MUM1, BCL2, and C-MYC exhibit a better sensitivity and specificity >0.750. Furthermore, the CD20-adjusted C-MYC value strongly correlates with that of IHC, and has a particularly high specificity (0.882). CONCLUSIONS AND CLINICAL RELEVANCE: Although further investigation using a large number of DLBCL specimens needs to be conducted, these results suggest that RPPA could be applicable as a supportive tool for determining lymphoma prognosis.

Anemia Associated with Worse Outcome in Diffuse Large B-Cell Lymphoma Patients: A Single-Center Retrospective Study

Objective: Useful prognostic biomarkers for diffuse large B-cell lymphoma (DLBCL) patients have been reported. To determine the prognostic value of hemoglobin (Hb) level in DLBCL patients, we performed a retrospective study. Materials and Methods: We evaluated disease outcome, progression-free survival (PFS), overall survival as the endpoint, and clinical and laboratory factors affecting the outcome of 185 DLBCL patients who had received rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone therapy during 2004-2014. Results: The study group included 121 men and 64 women with a median age of 66 years minimum-maximum: 21-83 years. In univariate analysis, factors independently associated with worse PFS were Eastern Cooperative Oncology Group performance status ≥2, Ann Arbor stage III or IV, anemia with Hb levels of <10 g/dL, and serum albumin of <3.5 g/dL. In multivariate analysis, anemia with Hb levels of <10 g/dL and Ann Arbor stage III or IV were found to be international index-independent prognostic factors (hazard ratio: 2.4; p=0.04). Conclusion: Anemia is an independent prognostic marker of poor outcome in DLBCL patients. Hb can be an easily available prognostic marker for risk stratification in these patients.

The standard international prognostic index for predicting the risk of CNS involvement in DLBCL without specific prophylaxis.

Central nervous system (CNS) involvement is a serious complication in patients with diffuse large B-cell lymphoma (DLBCL) and evaluating CNS risk is an important issue. Using the standard international prognostic index (IPI) and CNS-IPI, a recently proposed model including IPI risk factors and adrenal/kidney involvement, we assessed CNS risk in 1220 untreated DLBCL patients who received R-CHOP without prophylaxis. According to the standard IPI, the cumulative incidences of CNS involvement at 2 years were 1.3, 4.6, 8.8, and 12.7% in the low-, low-intermediate-, high-intermediate-, and high-risk groups, respectively (p <.001). This result is comparable with that of the CNS-IPI. Patients with breast involvement tended to have lower risk according to the standard IPI but showed frequent CNS involvement, similar to patients with testis involvement. The standard IPI is also a useful predictor of CNS involvement. Patients with breast/testis involvement would be candidates for prophylaxis regardless of the standard IPI risk.

Chronic lymphocytic leukemia/small lymphocytic lymphoma with t (2;18) (p12;q21) accompanied by a cutaneous nodule with histological features of diffuse large B-cell lymphoma.

A 73-year-old woman presented a 3-year history of indolent enlargement of cutaneous tumor nodules. Peripheral blood flow cytometry revealed thrombocytopenia (platelets; 85,000/µl) and the presence of an abnormal, small B lymphocyte population (CD5+, CD10-, CD20+, CD22+, CD23dim, FMC7+, SmIgλ+, and SmIgκ-; 4,000/µl). Skin biopsy indicated infiltration of CD5+, CD10-, CD20+, BCL2+, BCL6+, and cyclin D1- atypical large B-cells, suggesting diffuse large B-cell lymphoma. Cytogenetic analysis of the peripheral blood revealed a complex karyotype [t (2;18) (p12;q21) and +12]. Fluorescence in situ hybridization detected the presence of BCL2 split signal and the absence of IGH/CCND1 fusion signal. Cervical lymph node biopsy indicated a pseudofollicular pattern. The sequence of immunoglobulin heavy chain variable region from the peripheral blood and the skin tumor contained the same mutated pattern, and therefore, confirmed clonality. Because the patient's clinical course and skin tumor were indolent, the possibility of Richter syndrome was discarded, and the final diagnosis was chronic lymphocytic leukemia/small lymphocytic lymphoma, Rai stage IV and Binet stage C. The patient achieved complete remission after 4 cycles of a fludarabine plus rituximab regimen, without disease progression since >1 year of treatment.

Outcome and prognostic factors among patients who underwent a second transplantation for disease relapse post the first allogeneic cell transplantation.

The prognosis for disease relapse after first hematopoietic cell transplantation (HCT1) is poor. Here, we present a retrospective multicenter study to evaluate the clinical outcome and the prognostic factors for second hematopoietic cell transplantation (HCT2). The cohort in this study comprised 60 patients diagnosed with acute leukemia, who underwent HCT2 due to hematological relapse after HCT1. The overall survival (OS) at two years, non-relapse mortality (NRM), and relapse mortality (RM) were 30.3%, 40.9%, and 28.8%, respectively. Multivariate analysis for OS identified the use of a donor other than matched-related (MR) donor (hazard ratios [HR] = 4.10, 95% confidence intervals [CI]: 1.72-9.74, p = .001) and high disease status (HR = 2.90, 95% CI: 1.28-6.56, p = .011) as the adverse risk factors for HCT2. On analyzing the combination of factors during HCT1 and HCT2, MR donor, reduced intensity conditioning regimen, and standard status were found to be significant as favorable prognostic factors for OS. Therefore, evaluating these prognostic factors would be helpful in taking decisions regarding post-relapse management.

Hyper-recovery of platelets after induction therapy is a predictor of relapse-free survival in acute myeloid leukemia.

We verified the association between standard clinical and laboratory variables and the risk of relapse in acute myeloid leukemia (AML), which led us to retrospectively examine the effect of regeneration of hematopoiesis in patients with newly diagnosed AML. We used data from 230 patients who obtained remission after cytarabine-based induction chemotherapy. Platelet counts ≥500 × 109/L and hemoglobin levels ≥9 g/dL on day 28 after treatment initiation were significantly associated with relapse-free survival (RFS) rate, conferring respective multivariate risk ratios of 0.38 (95% CI: 0.18-0.79) and 0.60 (95% CI: 0.40-0.89) for the occurrence of relapse or death. No disease relapse occurred in core binding factor leukemia patients whose platelet counts recovered ≥500 × 109/L at 28 days after therapy initiation. We conclude that regeneration of hematopoiesis, especially platelet hyper-recovery, after induction chemotherapy is a significant predictor of RFS in patients with AML.

Development of pulmonary arterial hypertension during oral dasatinib therapy for chronic myelogenous leukemia.

We present a 36-year-old woman who had been taking oral dasatinib for 3 years for the treatment of chronic myelogenous leukemia (CML). Although adverse events such as thrombocytopenia and pleural effusion developed, she showed a major molecular response (MMR) 22 months after the initiation of oral dasatinib administration, and the therapy was thus continued. Approximately 34 months after oral dasatinib initiation, she developed severe exertional dyspnea and had to be urgently hospitalized. There was no apparent pleural effusion increase, and neither imaging nor blood test results suggested pneumonia or other infections. Pulmonary arterial hypertension (PAH) was suspected on the basis of transthoracic echocardiography. PAH was then confirmed by right heart catheterization. Though dasatinib was discontinued on the day of hospitalization, pulmonary hypertension and heart failure progressed, and she did not respond to catecholamines or PDE5 (phosphodiesterase type 5) inhibitors. On the 4(th) hospital day, she experienced cardiopulmonary arrest and died 1 week later. Cases with PAH due to oral administration of dasatinib have been reported previously. However, cases showing the rapid progression documented in our patient are rare and we advocate that PAH be considered a potential adverse event associated with dasatinib therapy.

Allogeneic Hematopoietic Stem Cell Transplantation after Conditioning Regimens with Fludarabine/melphalan or Fludarabine/busulfan for Patients with Hematological Malignancies: A Single-center Analysis.

Objective Fludarabine plus melphalan (FM) and fludarabine plus busulfan (FB) are two major conditioning regimens for allogeneic hematopoietic stem cell transplantation (allo-HSCT). Methods We retrospectively analyzed patients who underwent allo-HSCT after a conditioning regimen consisting of FM or FB with/without total body irradiation for hematological malignancies between 2005 and 2014. Results There were 41 patients who met the criteria. The median follow-up time for the survivors was 3 years. Thirty-two patients received allo-HSCT after the FM regimen and nine patients received allo-HSCT after the FB regimen. Patients who received FB were older than those who received FM (p=0.041). There was no significant difference in the 3-year overall survival between patients who had received FB and those who had received FM (29.6% vs. 56.5%, p=0.267). The 3-year cumulative incidence of relapse was significantly higher in patients who had received FB than that in patients who had received FM (66.7% vs. 17.8%, p=0.004), and FB was an independent prognostic factor for relapse by a multivariate analysis (hazard ratio, 9.8; 95% confidential interval, 2.5-39.3; p=0.001). When we restricted the evaluation to patients with acute myeloid leukemia and myelodysplastic syndrome, the 3-year cumulative incidence of relapse was also significantly higher in patients who had received FB than that in patients who had received FM (75.0% vs. 16.1%, p=0.004). Conclusion The results suggest that FM may provide better disease control than FB.

Cytomegalovirus Pneumonia after Anti-CC-chemokine Receptor 4 Monoclonal Antibody (Mogamulizumab) Therapy in an Angioimmunoblastic T-cell Lymphoma Patient.

Angioimmunoblastic T-cell lymphoma (AITL) is an aggressive T-cell lymphoma. A 63-year-old man was diagnosed with AITL. He received 6 cycles of CHOP therapy, but showed progressive disease. Subsequently, he received ESHAP chemotherapy; however, it was not effective. He received mogamulizumab (an anti-CCR4 monoclonal antibody). After 4 cycles, his respiratory condition worsened and he was diagnosed with cytomegalovirus (CMV) pneumonia. Despite antiviral and antibiotic therapy, he died. We speculate that the combination of progressive lymphoma with mogamulizumab and chemotherapy likely caused CMV pneumonia. Because mogamulizumab therapy causes immunosuppression, if CMV pneumonia is suspected, then rapid treatment should be initiated.

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.

Impact of Human Herpesvirus-6 Reactivation on Outcomes of Allogeneic Hematopoietic Stem Cell Transplantation.

Human herpesvirus-6 (HHV-6) is known to reactivate after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and may be associated with development of acute graft-versus-host disease (GVHD) and nonrelapse mortality (NRM). However, the clinical significance of HHV-6 reactivation after allo-HSCT remains unclear. Therefore, we conducted a retrospective analysis to elucidate the impact of HHV-6 reactivation on transplantation outcomes. Of 236 patients who underwent allo-HSCT, 138 (58.5%) developed HHV-6 reactivation and 98 (41.5%) did not. Univariate analysis indicated that at 3 years, patients with HHV-6 reactivation had significantly higher NRM (27.7% versus 13.7%, P = .003) and worse overall survival (42.1% versus 59.0%, P = .008) than those without reactivation. In multivariate analysis, HHV-6 reactivation was associated with higher incidence of acute GVHD (hazard ratio [HR], 1.87; P = .01), cytomegalovirus reactivation (HR, 2.24; P < .001), and NRM (HR, 2.73; P = .007). Subgroup analysis stratified according to conditioning intensity indicated that a significant impact of HHV-6 reactivation on acute GVHD was observed only in patients who received myeloablative conditioning (MAC). These results indicate that HHV-6 reactivation was associated with development of acute GVHD, cytomegalovirus reactivation, and NRM. Furthermore, adverse impact of HHV-6 reactivation on transplantation outcomes was prominent in the setting of MAC.

[Analysis of prognostic factors in transplant-eligeble newly diagnosed myeloma patients treated with bortezomib plus dexamethasone as induction therapy].

We retrospectively analyzed, and herein discuss, the outcomes of and prognostic factors for 35 untreated multiple myeloma patients less than 65 years of age who received induction therapies with bortezomib (Bor) and dexamethasone (BD) for the purpose of up-front autologous peripheral blood stem cell transplantation (SCT). The overall response rate was 77% (27 cases, including 4 [11%] complete response and 13 [37%] very good partial response cases). The rate of SCT accomplishment was 51% (18 cases). The 3 year-progression free survival (PFS) rate for the SCT group was significantly higher than that of the non-SCT group (41% vs 0%, P=0.0037). This result reflects the significantly more severe adverse effects of induction therapy for the non-SCT than the SCT group. Among reasons for SCT drop-out, 29% of cases suffered severe peripheral neuropathy with features such as irreversible numbness and pain. The analysis of PFS revealed a cytogenetic factor, favorable chromosomal type at diagnosis, to predict a better outcome (P values on univariate and multivariate analyses were 0.0004 and 0.0405, respectively). Our observations suggest establishment of induction therapy, aimed at reducing adverse effects and overcoming unfavorable cytogenetic abnormalities, to be necessary for improving the outcomes of patients with multiple myeloma.

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.