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.

Increased MYC expression without MYC gene translocation in patients with the diffuse large B-cell-lymphoma subtype of iatrogenic immunodeficiency-associated lymphoproliferative disorders.

Post-transplant lymphoproliferative disorder (PTLD) and other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPD) are iatrogenic lymphoproliferative disorders (LPD) that develop in association with immunosuppressive treatment in the setting of organ transplantation and autoimmune disease, respectively. Each has a spectrum of pathologies ranging from lymphoid hyperplasia to lymphoma. To clarify the characteristics of the diffuse large B-cell lymphoma (DLBCL) subtype in a cohort of 25 patients with PTLD or OIIA-LPD from our institute, we selected 13 with a histological subtype of DLBCL, including 2 cases of PTLD and 11 of OIIA-LPD. The median patient age at diagnosis was 70 years, with a female predominance. Both PTLD cases developed after kidney transplant. Of the patients with OIIA-LPD, 10 had rheumatoid arthritis, 1 had mixed connective tissue disease, and 8 were treated using methotrexate. Both of the PTLD patients and 6 of the OIIA-LPD patients had extranodal manifestations. All patients except for one were classified as having the non-germinal center B-cell (non-GCB) subtype according to the Hans algorithm. Tissue samples from 8 patients were positive for CD30 and 8 were positive for Epstein-Barr virus (EBV)-encoded small RNA. Seven patients had MYC-positive tissue samples, but none had MYC translocation. Our study suggests that extranodal manifestations and the non-GCB subtype are common, that EBV is associated with the DLBCL subtype of PTLD and OIIA-LPD, and that anti-CD30 therapy is applicable. In addition, our patients with the DLBCL subtype of PTLD and OIIA-LPD exhibited MYC overexpression without MYC translocation, suggesting an alternative mechanism of MYC upregulation.

Increased serum C-reactive protein is an adverse prognostic factor in low-risk myelodysplastic syndromes.

Inflammatory cytokines play a role in hematopoiesis and development of myelodysplastic syndromes (MDS). Although increased serum levels of inflammatory cytokines are associated with poor survival in MDS patients, clinical management does not include assessment of inflammation. We investigated the significance of inflammation in MDS using serum C-reactive protein (CRP) levels, an indicator of the degree of systemic inflammation that can be used in routine practice. We hypothesized that serum CRP levels can be used to further classify low-risk MDS. We conducted a retrospective analysis of 90 patients with low-risk MDS, defined by the international prognostic scoring system (IPSS). We examined the prognostic relevance of CRP and known prognostic factors at diagnosis. Increased serum CRP (≥ 0.58 mg/dL) was associated with poor survival (hazard ratio [HR]: 17.63, 95% confidence interval [CI] 5.83-53.28, P < 0.001) both overall and among the 73 patients with low-risk MDS as defined by the revised IPSS (HR: 28.05, 95% CI 6.15-128.04, P < 0.001). Increased CRP might predict poor prognosis and serum CRP levels can indicate clonal hematopoiesis and non-hematological comorbidity in patients with low-risk MDS.

Elevated C-reactive protein level is associated with poor prognosis in follicular lymphoma patients undergoing rituximab-containing chemotherapy.

Although follicular lymphoma (FL) is a pathological entity characterized by relatively uniform histological and molecular findings, its clinical course is highly variable. Establishment of therapeutic strategies based on a simple and practical prognostic model is important. C-reactive protein (CRP) is an adverse prognostic marker for various tumors and aggressive lymphomas. However, the significance of serum CRP levels as a prognostic index in low-grade lymphomas, such as FL, has not been thoroughly investigated. We retrospectively analyzed the relationship between serum CRP levels at diagnosis and the prognosis in patients with FL (n = 61) undergoing rituximab-containing chemotherapy. Elevated CRP levels showed a significant association with elevated fibrinogen (P = 0.002) in univariate analysis. Patients with higher CRP levels (> 5 mg/L) had a significantly shorter progression-free survival in multivariate analysis (P = 0.044). We concluded that serum CRP levels are important in prognostic stratification of patients with FL.

Comparative Study of Tacrolimus and Short-Term Methotrexate: 2-Day versus 3-Day Methotrexate as Graft-versus-Host-Disease Prophylaxis after Umbilical Cord Blood Transplantation in Adults.

Methotrexate (MTX) in combination with a calcineurin inhibitor has been commonly used for prophylaxis of graft-versus-host disease (GVHD) following umbilical cord blood transplantation (UCBT) in Japan. However, the appropriate prophylactic MTX dosage in UCBT has not been established to date. To determine the preferential GVHD prophylaxis in UCBT, this study retrospectively investigated the administration of short-term MTX for 2 days versus 3 days. Of 103 adult patients submitted to UCBT enrolled in the study, 73 received tacrolimus (TAC) with 2 days of MTX given at 10 mg/m2 on day 1 and 7 mg/m2 on day 3 (very short-term [vs] MTX), whereas 30 patients received TAC with 3 days of MTX given at 10 mg/m2 on day 1, 7 mg/m2 on day 3, and 7 mg/m2 on day 6 (short-term [s] MTX). In univariate analysis, neutrophil engraftment was shown to be significantly better (P = .039) in the vsMTX/TAC group. Among high-risk patients, the vsMTX/TAC group also exhibited earlier neutrophil engraftment (P = .042); however, the incidence of acute GVHD was higher in the vsMTX/TAC group (P = .035) on univariate analysis. In multivariate analysis, compared with sMTX/TAC, vsMTX/TAC was associated with lower risk of relapse (hazard ratio, .27; 95% confidence interval, .11 to .64; P = .003) . These results suggest that vsMTX/TAC can be appropriate GVHD prophylaxis after UCBT, especially in higher-risk patients.

Refined Disease Risk Index for Hematological Malignancies, Including Rare Disorders, After Allogeneic Stem Cell Transplantation.

OBJECTIVE: The refined disease risk index (R-DRI) is a well-designed prognostic parameter that is based on only the disease type and status and is used for stratifying patients undergoing allogeneic hematopoietic stem cell transplantation (allo HSCT) into 4 risk groups. However, the application of the R-DRI for rare diseases has remained unclear. METHODS: We evaluated 135 patients who underwent allo HSCT for hematological malignancies including rare diseases, such as acute leukemia of ambiguous lineage, acute T-cell leukemia/lymphoma, extranodal natural killer T-cell lymphoma, and lymphoblastic lymphoma, at our institute. RESULTS: According to the R-DRI, overall survival (OS) and progression-free survival at 2 years for patients with the low, intermediate, high, and very high groups were 66.7% and 66.7%, 60.8% and 56.0%, 27.1% and 23.7%, and 5.9% and 5.1%, respectively (P < .0001 and P < .0001, respectively). OS showed no significant difference between B-cell non-Hodgkin lymphoma (B-NHL) and T-cell non-Hodgkin lymphoma (T-NHL) (P = .71). Moreover, OS at 1 year was 80%, 14.3%, 60%, and 0% for the intermediate risk group, the very high-risk group of B-NHL, the intermediate risk group, and the high-risk group of T-NHL, respectively (P = .035). CONCLUSION: We showed the applicability of the R-DRI for hematological malignancies, including rare disorders. However, we suggest that T-NHL patients may be better to be assigned between the nodal group and the extranodal group in the R-DRI.

[Development of cardiac tamponade and emergence of arrhythmia during chemotherapy for diffuse large B-cell lymphoma].

Cardiac involvement during lymphoma often causes complications, including arrhythmia. A 68-year-old male with cardiac tamponade was diagnosed with diffuse large B-cell lymphoma with cardiac involvement based on the presence of the tumor mass in the myocardium and lymphoma cells in the pericardial effusion. He developed atrial fibrillation, ventricular tachycardia, and atrial flutter after initiating chemotherapy. Following chemotherapy, sinus rhythm was restored without invasive treatment for arrhythmia, while the cardiac mass disappeared. No recurrent arrhythmias were observed. In lymphoma with cardiac involvement, unexpected arrhythmias can emerge after initiation of chemotherapy, which could potentially be related to accelerated cardiac remodeling owing to the rapid relief of cardiac damage. Follow-up using electrocardiogram is thus necessary during chemotherapy for cardiac lymphoma, despite the absence of arrhythmia at the time of diagnosis.

Impact of CD123 expression, analyzed by immunohistochemistry, on clinical outcomes in patients with acute myeloid leukemia.

Aberrant expression of the interleukin-3 receptor alpha chain (IL3RA or CD123) is frequently observed in patients with a subset of leukemic disorders, including acute myeloid leukemia (AML), particularly in leukemia stem cells. We analyzed the relationships between immunohistochemical (IHC) expression, including that of CD123, and clinical outcomes. This study involved a retrospective analysis of 48 patients diagnosed with de novo AML (M0-M5, n = 48) at our hospital between February 2008 and September 2015. Among patients with de novo AML, CD123 expression was associated with a failure to achieve complete response (CR) to initial induction chemotherapy (P = 0.044) and poor overall survival (OS) (P = 0.036). This is the first study using IHC to demonstrate that CD123 expression is associated with a poor CR rate and poor OS in de novo AML patients. These results support previous reports using flow cytometry (FCM). CD123 expression may thus be useful for assessing AML patients' prognoses. At the time of diagnosis, CD123 expression analysis using IHC may represent a clinically useful assessment for de novo AML patients.

Monitoring TIGIT/DNAM-1 and PVR/PVRL2 Immune Checkpoint Expression Levels in Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia.

After allogeneic stem cell transplantation (alloSCT), several immune checkpoints play an important role in the antileukemic immune response in the bone marrow (BM) microenvironment. However, immune checkpoint expression levels in the BM have not been reported after alloSCT in patients with acute myeloid leukemia (AML). We investigated the clinical impact of immune checkpoint expression in BM samples after alloSCT for AML. Higher expression of T cell immunoreceptor with Ig and ITIM domains (TIGIT) was associated with a decreased incidence of acute graft-versus-host disease (P = .048) and poor overall (P = .046) and progression-free survival (P = 0.024). In addition, higher expression of TIGIT at engraftment after alloSCT was correlated with a decreased number of natural killer cells in BM (P = .019). Monitoring TIGIT expression in the BM could be useful for predicting outcome after alloSCT for AML. Our findings raise the possibility that blockade of TIGIT would improve survival.

[Syndrome of inappropriate secretion of antidiuretic hormone in multiple myeloma patients treated with bortezomib, lenalidomide, and dexamethasone combination therapy].

Hyponatremia occurs while receiving bortezomib-containing combination therapy in multiple myeloma (MM) ; however, the mechanism of hyponatremia remains unclear. A 65-year-old female with MM was treated with bortezomib, lenalidomide, and dexamethasone. Fourteen days after chemotherapy initiation, she developed hyponatremia (serum sodium, 127 mEq/l, compared with 136 mEq/l before chemotherapy) with plasma hypo-osmolality and urine hyper-osmolality. She exhibited neither dehydration nor adrenal insufficiency. Her serum arginine vasopressin peptide (AVP) level was 1.5 pg/ml. She was diagnosed with syndrome of inappropriate secretion of antidiuretic hormone (SIADH), wherein causative roles of inflammatory cytokines were strongly suggested in the development because (1) SIADH was triggered by the cessation of the dexamethasone treatment and (2) hyponatremia was successfully treated with prednisolone, which was administered for the complication of drug eruption. Perhaps, bortezomib-induced immune reactions could be involved in a subset of hyponatremia during bortezomib-containing antimyeloma chemotherapy.

Status of Natural Killer Cell Recovery in Day 21 Bone Marrow after Allogeneic Hematopoietic Stem Cell Transplantation Predicts Clinical Outcome.

Rapid immune recovery following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is important for clinical outcome prediction. In most studies, immune recovery after allo-HSCT is monitored via peripheral blood. However, few reports regarding the status of absolute lymphocyte subsets in the bone marrow (BM) microenvironment have been undertaken. Therefore, we evaluated the clinical impact of immune recovery in the early period following allo-HSCT using BM samples. We showed that delayed natural killer cell recovery was independently associated with a poor prognosis for overall survival (hazard ratio [HR], 3.07; 95% confidence interval [CI], 1.37- 6.89; P = .007), progression-free survival (HR, 3.42; 95% CI, 1.47-7.94; P = .004), and nonrelapse mortality (HR, 6.68; 95% CI, 1.82-25.0; P = .004) by multivariate analysis. In addition, low NK cell counts were associated with the presence of 1 or more bacterial, viral, or fungal infections. Our results indicate that investigating absolute lymphocyte subsets in BM in the early phase following allo-HSCT can be useful for predicting and improving survival outcomes.

Association of red cell distribution width with clinical outcomes in myelodysplastic syndrome.

Studies showed red cell distribution width (RDW) can improve the detection of morphological changes in red blood cells and the understanding of their contribution to dyserythropoiesis in myelodysplastic syndrome (MDS). The purpose of the study was to evaluate dyserythropoiesis in MDS by RDW analysis and to explore the utility of RDW in clinical practice. We retrospectively analyzed laboratory and clinical data of 101 patients (59 patients was refractory anemia (RA) according to the French-American-British (FAB) classification). In patients with RA, RDW was showed weak inverse correlation with both hemoglobin concentration (Hb) (rs = -0.37, P = 0.0035) and mean corpuscular hemoglobin concentration (MCHC) (rs = -0.36, P = 0.0047). On the other hand, RDW was showed weak correlation with the number of ringed sideroblasts in bone marrow (rs = 0.31, P = 0.023). The increased RDW (≥15.0%) was associated with shorter overall survival (OS) (P = 0.0086). In patients with refractory anemia with excess blasts (RAEB) and RAEB in transformation (RAEB-t), effect of RDW on OS was less evident. These results suggested that increased RDW might reflect dyserythropoiesis, associated with deregulated hemoglobin synthesis and iron metabolism in MDS. Furthermore, increased RDW may have potential to be a prognostic significance in RA.

Association of Soluble Interleukin-2 Receptor and C-Reactive Protein with the Efficacy of Bendamustine Salvage Treatment for Indolent Lymphomas and Mantle Cell Lymphoma.

Bendamustine has demonstrated favourable efficacy in relapsed or refractory indolent lymphoma and mantle cell lymphoma. We retrospectively evaluated the pre-treatment clinical and laboratory factors and their correlation with the clinical outcome of these lymphomas. We analysed 53 patients who had been treated with bendamustine alone (n = 6) or rituximab plus bendamustine (n = 47). The overall response rate was 81.1%, with a complete response (CR) rate of 39.6%. The CR rate was significantly low in patients who had elevated levels of soluble interleukin-2 receptor (p = 0.024) and C-reactive protein (CRP; p = 0.004). The 1-year overall survival (OS) rate was 79.3%. An elevated CRP was associated with a short OS (p = 0.056). The present findings suggest that the lymphoma microenvironment and immune response were involved in the effects of bendamustine. These findings are also important in order to understand the pathophysiology of refractory lymphoma and to find effective strategies using bendamustine.

Efficacy of palonosetron to prevent delayed nausea and vomiting in non-Hodgkin's lymphoma patients undergoing repeated cycles of the CHOP regimen.

PURPOSE: Few studies have investigated the effect of palonosetron on delayed chemotherapy-induced nausea and vomiting in lymphoma patients receiving the CHOP regimen. We conducted a prospective clinical trial to assess the efficacy of palonosetron in patients receiving the CHOP regimen. METHODS: Complete control (CC: emesis-free and mild nausea) during delayed phase (24-120 h) was the primary endpoint. The secondary endpoint was complete response (CR: emesis-free) during acute (0-24 h), delayed, and overall phases (0-120 h), and CC during acute and overall phases. Palonosetron (0.75 mg) was administered before chemotherapy on day 1 of both the first and second CHOP cycles. RESULTS: The efficacy of palonosetron in preventing emesis was evaluated in 40 patients. Across two cycles, over 85% of patients achieved CR. As the primary endpoint, the proportion of patients achieving CC in the delayed phase increased from 70% (cycle 1) to 85% (cycle 2). CR rate in the delayed phase increased from 85% (cycle 1) to 95% (cycle 2). CONCLUSION: These results suggest that the antiemetic effects during the delayed phase were inferior to those in the acute phase during the first cycle. However, even at the same dose of palonosetron, CR and CC rates increased in the second cycle.

Umbilical cord blood transplantation for adults using tacrolimus with two-day very-short-term methotrexate for graft-versus-host disease prophylaxis.

Cord blood transplantation (CBT) is an alternative approach to allogeneic stem cell transplantation. However, CBT is associated with issues including pre-engraftment immune reaction (PIR), engraftment syndrome (ES), and graft failure (GF). Tacrolimus (TAC) and short-term methotrexate (sMTX: days 1, 3, 6, and/or 11) are used for graft-versus-host disease (GVHD) prophylaxis during CBT; however, sMTX does not accelerate neutrophil engraftment. Therefore, we hypothesized that lower doses of sMTX [very-short-term MTX (vsMTX): 10 and 7mg/m(2) on days 1 and 3, respectively] with TAC reduce the risk of GF without increasing post-transplantation immune reactions during CBT. We retrospectively analyzed 40 patients who received TAC with vsMTX for GVHD prophylaxis. PIR and ES developed in 4 patients. The cumulative incidence of neutrophil engraft at day 60 was 92.5%. No cases of primary graft failure were noted. The cumulative incidence of grades II-III GVHD was 48.1% at day 100, and the cumulative 100-day incidence of nonrelapse mortality was 12.5%. This study suggests that TAC with vsMTX reduces the risk of PIR and ES during CBT and stimulates neutrophil engraftment, but may be associated with slightly higher aGVHD compared with calcineurin inhibitor and sMTX. Therefore, we recommend vsMTX plus TAC as an option for GVHD prophylaxis during CBT.

Age and Bone Marrow Cellularity are Associated with Response to Eltrombopag in Japanese Adult Immune Thrombocytopenia Patients: A Retrospective Single-Center Study.

In the present retrospective single-center study, we examined the efficacy and safety of eltrombopag, a thrombopoietin (TPO) -receptor agonist (TPO-RA), and found clinical factors associated with its efficacy in Japanese patients with chronic immune thrombocytopenia (ITP). According to the definition of a response, which is to attain a platelet count of more than 50,000/µL at least once during eltrombopag treatment, 42 enrolled patients were divided into two groups: responders (29 patients, 69%) and non-responders (13 patients, 31%). In analyses of the clinical and laboratory data of these two groups, we extracted two factors that are significantly associated with a better response to eltrombopag, which have not been recognized previously, namely, (1) an older age of patients at eltrombopag initiation (≥ 70 years old) and (2) normal or decreased cellularity of iliac bone marrow (BM) biopsy at diagnosis. The significance of patient age contradicts previous findings from studies in which the Caucasian population was the major focus. However, factors such as changes of pharmacokinetics might modulate the effects of eltrombopag in older patients in Japan because East Asians show higher bioavailability of eltrombopag by as-yet-unknown mechanisms. BM cellularity in ITP may represent an impairment and/or lower responsiveness of pluripotent hematopoietic stem cells, not limited to the megakaryocyte (MgK) -platelet axis, to endogenous TPO, because recent evidence shows that TPO-RA can successfully restore hematopoiesis in aplastic anemia. These results should be useful for the therapeutic use of TPO-RA for ITP and also related thrombocytopenia in Japan.

A case of Degos disease: demonstration of C5b-9-mediated vascular injury.

A 68-year-old Japanese male presented with atrophic erythematous white lesions with peripheral dark reddish rims on his back. Multiple ulcers were detected from his stomach to his large intestine using endoscopy. Although the patient was given high doses of a steroid, aspirin, dipyridamole, and intravenous immunoglobulin therapy, he died of gastrointestinal hemorrhage, perforation and septic shock. An autopsy examination revealed pauci-inflammatory thrombotic microangiopathy with endothelial cell injury, fibrous occlusive arteriopathy, and vascular C5b-9 deposition in the wall of the gastrointestinal tract from the esophagus to the large intestine as well as in the dermis of the skin.

Serum anticyclic citrullinated protein antibody titers are correlated with the response to biological agents in patients with rheumatoid arthritis.

Anticyclic citrullinated protein antibody (ACPA) is known as an important indicator for diagnosis of rheumatoid arthritis (RA). Our aim was to examine the relationship between the serum ACPA titer at baseline and responsiveness to biological agents (antagonists of either tumor necrosis factor or interleukin 6) in patients with RA. ACPA was measured using second-generation chemiluminescent enzyme immunoassay. Disease activity was assessed using disease activity scores 28. Fifty-seven RA patients with biological agents were enrolled, and the median ACPA titer at baseline was 110.0 U/mL. The median ACPA titer was 23.3 U/mL and 183.0 U/mL in the good and moderate response groups, respectively, which were significantly lower than in the no response group (404.0 U/mL). In addition, 69.2% and 26.9% of patients with low (<100 U/mL) and moderate (100-499 U/mL) basal ACPA titers showed a moderate to good response. Of the patients with higher (≥500 U/mL) basal ACPA titers, only 14.0% and 42.5% showed a good or moderate response, respectively. The remission rate was 77.8% in the ACPA-negative, which was significantly higher than the rate of 25% in the ACPA-positive patients. The results suggest that the ACPA titers are correlated with the efficacy of the biological agents used in patients with RA.