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Background The treatment strategy for diffuse large B-cell lymphoma (DLBCL) in elderly patients is problematic. Although several researchers have reported the effectiveness of comprehensive geriatric assessment (CGA) and the futility of curative treatment in ‘unfit’ patients with DLBCL, these propositions are not firmly established. Patients and methods We conducted a retrospective analysis using a database. Patients with DLBCL were eligible if ≧ 60 yr old. CGA stratification was performed using medical records. Results One hundred and 35 patients were identified. Anthracycline-based chemotherapy with curative intent was performed in 115 (85%) patients. According to CGA, 82 (61%) patients were classified as ‘fit’. Their 1-yr overall survival (OS) was significantly better than that of ‘unfit’ patients [91.3% vs. 53.8%, P

Lymphomatosis cerebri (LC) is a rare variant of primary central nervous system lymphoma, and it is characterized by diffuse cerebral infiltration of malignant lymphoma cells without evidence of a mass lesion. Herein, we report a patient with systemic peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) who had central nervous system involvement mimicking LC. A 72-year-old immunocompetent male presented with rapidly progressive dementia. Fluor-deoxy-glucose (FDG) -positron emission tomography revealed increased FDG uptake in the bone and skin. Histopathological examination of the skin lesion revealed PTCL-NOS infiltration. A FLAIR MRI scan of the brain revealed diffuse hyperintense lesions in the cerebral white matter of both hemispheres. These lesions were not enhanced with gadolinium, and there was no perceptible mass effect. We performed a brain biopsy, and the histology results were consistent with PTCL-NOS. The patient was treated with corticosteroid and chemotherapy; however the disease progressed, and he died 4 months after the diagnosis. This was a rare case of systemic lymphoma accompanied with central nervous system involvement mimicking LC.

Double-hit lymphomas are rare tumors that are defined by a chromosomal breakpoint affecting the MYC/8q24 locus in combination with another recurrent breakpoint, mainly a t(14; 18)(q32;q21)involving BCL2. We report a case of a 38-yearold woman with a 2-month history of abdominaldistention. 18F-FDG PET showed multiple positive systemic lymph nodes, positive peritoneum, and multiple positive intra-abdominal masses. Histopathology results of the cervical lymph node were compatible with double-hit follicular lymphoma(Grade 3A)because fluorescence in situ hybridization(FISH)demonstrated both MYC rearrangement and BCL2 gene fusion. She was initially started on R-CHOP(rituximab and doxorubicin, vincristine, cyclophosphamide, and prednisolone), but after one course the regimen was changed to dose-adjusted EPOCH-R(rituximab and doxorubicin, etoposide, vincristine, cyclophosphamide, and prednisolone). However, she showed no response to this chemotherapy regimen or haploidentical stem cell transplantation. The treatment strategy included salvage chemothera- py. An autologous and/or allogeneic hematopoietic transplantation is important for non-responders to DA-EPOCH-R.

Chronic impairment of cardiac function can be an important health risk and impair the quality of life, and may even be life-threatening for long-term survivors of allogeneic hematopoietic cell transplantation (HCT). However, risk factors for and/or the underlying mechanism of cardiac dysfunction in the chronic phase of HCT are still not fully understood. We retrospectively investigated factors affecting cardiac function and left-ventricular hypertrophy (LVH) in the chronic phase of HCT. Sixty-three recipients who survived for >1 year after receiving HCT were evaluated using echocardiography. Based on simple linear regression models, high-dose TBI-based conditioning was significantly associated with a decrease in left-ventricular ejection fraction and the early peak flow velocity/atrial peak flow velocity ratio, following HCT (coefficient=-5.550, P=0.02 and coefficient=-0.268, P=0.02, respectively). These associations remained significant with the use of multiple linear regression models. Additionally, the serum ferritin (s-ferritin) level before HCT was found to be a significant risk factor for LVH on multivariable logistic analysis (P=0.03). In conclusion, our study demonstrated that a myeloablative regimen, especially one that involved high-dose TBI, impaired cardiac function, and that a high s-ferritin level might be associated with the development of LVH in the chronic phase of HCT.

Immunomodulation induced by dasatinib is reportedly related to better prognosis in chronic myeloid leukemia (CML). However, the underlying mechanism has not yet been fully elucidated. The immunoprofiles of 63 patients in the chronic phase of CML were evaluated during treatment with a tyrosine kinase inhibitor (imatinib, n = 36; nilotinib, n = 9; dasatinib, n = 18). The numbers of CD56 + CD57 + and CD3 + CD57 + cells increased significantly in the dasatinib group. The numbers of regulatory T-cells were comparable among the three groups. Dasatinib markedly enhanced natural killer (NK)-cell reactivity. Only one patient treated with dasatinib showed a slight cytomegalovirus (CMV) reactivation. In contrast, nilotinib suppressed NK-cell reactivity. Plasma levels of interleukin-8 (IL-8), interferon-γ inducible protein-10 (IP-10) and monocyte chemoattractant protein-1 (MCP-1) were significantly elevated in all three groups, and plasma levels of granulocyte macrophage-colony stimulating factor (GM-CSF) were significantly elevated in the imatinib and dasatinib groups. Our results suggest the presence of a mechanism for dasatinib-associated immunomodulatory effects that is distinct from CMV reactivation and a decreased number of regulatory T-cells.

A 77-year-old-man was diagnosed with follicular lymphoma (FL), grade 3A. After six courses of R-THP-COP (rituximab, pirarubicin, cyclophosphamide, vincristine and prednisolone) therapy, he achieved complete remission (CR). He achieved a second CR after radiotherapy, a third CR after six courses of bendamustine /rituximab (BR) therapy, and a fourth CR after six courses of BR therapy. However 2 months after the last chemotherapy, his tumor progressed rapidly and he died. Autopsy results showed medium and large lymphoid cells with pleomorphic, irregular nuclei and prominent nucleoli infiltrated in multiple lymph nodes, the liver, the lung, and the spleen. The lymphoid cells were positive for CD3, CD8, granzymeB, TIA-1 and negative for CD4, CD20, CD79a, CD10, and CD56. Autopsy diagnosis was peripheral T-cell lymphoma, not otherwise specified. Occurrence of lymphoma in T-cell lineage should be considered, if the course of low-grade B-cell lymphomas, such as FL rapidly progresses.

Cutaneous extramedullary hematopoiesis has been reported in a small number of patients with myelofibrosis. A 79-year-old male with JAK2V617F-positive myelodysplastic/myeloproliferative neoplasm, unclassifiable (MDS-MPN-U), presented with multiple skin lesions. The skin lesions were papulonodular, reddish brown, and elastic hard on palpation. Based on a lesion biopsy, cutaneous extramedullary hematopoiesis associated with MDS/MPN-U was diagnosed. He died four months later due to exacerbation of MDS/MPN-U. Cutaneous invasion might be associated with progressive disease and a poor prognosis for MDS/MPN-U, as it is for myelofibrosis.

Patients with hyperleucocytic leukemia (WBC count10×10(4) mL) are at high risk of early mortality owing to pulmonary or cerebral leukostasis. Several researchers have reported the efficacy of immediate leukapheresis. Here, we report of a patient with chronic myelogenous leukemia in blast crisis and with pulmonary failure due to leukostasis who recovered after a combination therapy of leukapheresis and imatinib treatment.

A 19-year-old man with Philadelphia chromosome-positive acute lymphoblastic leukemia received an allogeneic hematopoietic cell transplant with unrelated bone marrow. On day 20, the patient developed impaired consciousness and disorientation. Examination of the cerebrospinal fluid showed 2×10(4) copies/mL of HHV6B. HHV6 encephalitis was diagnosed, as had HHV6 myelitis based on symptoms that included lancinating pain/pruritus in the lower limbs and dysuria/dyschezia. Concurrently, he showed sinus tachycardia. Even after clearance of the HHV6 genome from the plasma and CSF was achieved by treatment with foscarnet, sinus tachycardia persisted for another 100 days. We suspected prolonged sinus tachycardia due to dysautonomia caused by HHV6 encephalomyelitis.

Feasibility of umbilical cord blood transplantation with a myeloablative, reduced toxicity-conditioning regimen

A 20-year-old female presented with thirst, polyposia, and polyuria and was referred to our hospital because of leukocytosis and anemia. Bone marrow aspiration revealed 66.8% myeloperoxidase-positive blasts and trilineage myelodysplasia. The karyotype was 45, XX, inv(3)(q21q26.2), -7[19]. Therefore, a diagnosis of AML with inv(3)(q21q26.2) complicated by -7 was made. Moreover, hyposthenuria and a low anti-diuretic hormone (ADH) level were observed. Although cerebrospinal fluid analysis was normal, magnetic resonance imaging (MRI) revealed the absence of hyperintensity in the neurohypophysis in T1-weighted images. Therefore, she was also diagnosed with diabetes insipidus. After she was administered a desmopressin nasal spray, the volume of urine produced decreased. Following treatment with second induction therapy containing high-dose cytarabine for AML, she achieved complete remission in the bone marrow. Moreover, when the abnormality on MRI and the volume of urine were normalized, she discontinued desmopressin. Although diabetes insipidus is a rare complication of AML, the majority of AML patients who have diabetes insipidus have the abnormal karyotypes with inv(3)(q21q26.2)/t(3;3)(q21;q26.2) and monosomy 7. Further study is required to clarify the pathogenesis and develop a strategy for the treatment of this category of AML.

A small number of reports have described cases of heparin-induced thrombocytopenia complicating hematological disorders with impaired platelet production. We describe the case of a 66-year-old woman with acute myeloid leukemia who exhibited unexplained refractoriness to platelet transfusion, while receiving heparin flushes, and was found to have anti-platelet factor 4 (PF4)/heparin antibodies with high optical density (OD) values (>2 units) detected by an enzyme-linked immunosorbent assay. After cessation of heparin flushes, her refractoriness to platelet transfusion resolved. We retrospectively confirmed that the OD values for anti-PF4/heparin antibodies declined gradually; refractoriness to platelet transfusion resolved when the OD values fell below 1.0 units. Given the absence of any other evident explanation for this phenomenon, and the correlation between the OD values for anti-PF4/heparin antibodies and the efficacy of platelet transfusions, we conclude that the patient's refractoriness to platelet transfusion was most likely caused by anti-PF4/heparin antibodies that had platelet-activating properties.

Reports on the efficacy of intravenous immunoglobulin (IVIG) prophylaxis against cytomegalovirus (CMV) infection after allogeneic hematopoietic cell transplantation (HCT) have often sparked controversy. In addition, we are not aware of any study that has examined whether prophylaxis with IVIG affects the incidence of CMV infection in high-risk patients--those who are elderly or have received human leukocyte antigen (HLA) mismatched HCT. In the present open-label, phase II study, we addressed this question. We enrolled 106 patients in the study. The cumulative incidences of CMV infection at 100 days after HCT were similar in the intervention and the control groups (68% and 64%, P=.89; 89% and 87%, P=.79, respectively, for patients 55 years or older and those who received HLA-mismatched HCT). In those who received HLA-mismatched HCT, 1-year overall survival after HCT was 46% in the intervention group and 40% in the control group (P=.31); for age≥55 years, the corresponding values were 46% and 40% (P=.27). Our data showed that prophylaxis with regular polyvalent IVIG did not affect the incidence of CMV infections or survival among older patients or those who receive HLA-mismatched HCT.

Background There has been insufficient examination of the factors affecting long-term survival of more than 5 years in patients with leukemia that is not in remission at transplantation. Method We retrospectively analyzed leukemia not in remission at allogeneic hematopoietic cell transplantation (allo-HCT) performed at our institution between January 1999 and July 2009. Forty-two patients with a median age of 39 years received intensified conditioning (n = 9), standard (n = 12) or reduced-intensity conditioning (n = 21) for allo-HCT. Fourteen patients received individual chemotherapy for cytoreduction during the three weeks prior to reduced-intensity conditioning. Diagnoses comprised acute leukemia (n = 29), chronic myeloid leukemia-accelerated phase (n = 2), myelodysplastic syndrome/acute myeloid leukemia (MDS/AML) (n = 10) and plasma cell leukemia (n = 1). In those with acute leukemia, cytogenetic abnormalities were intermediate (44%) or poor (56%). The median number of blast cells in bone marrow (BM) was 26.0% (range; 0.2-100) before the start of chemotherapy for allo-HCT. Six patients had leukemic involvement of the central nervous system. Stem cell sources were related BM (7%), related peripheral blood (31%), unrelated BM (48%) and unrelated cord blood (CB) (14%). Results Engraftment was achieved in 33 (79%) of 42 patients. Median time to engraftment was 17 days (range: 9-32). At five years, the cumulative probabilities of acute graft-versus-host disease (GVHD) and chronic GVHD were 63% and 37%, respectively. With a median follow-up of 85 months for surviving patients, the five-year Kaplan-Meier estimates of leukemia-free survival rate and overall survival (OS) were 17% and 19%, respectively. At five years, the cumulative probability of non-relapse mortality was 38%. In the univariable analyses of the influence of pre-transplant variables on OS, poor-risk cytogenetics, number of BM blasts (>26%), MDS overt AML and CB as stem cell source were significantly associated with worse prognosis (p = .03, p = .01, p = .02 and p < .001, respectively). In addition, based on a landmark analysis at 6 months post-transplant, the five-year Kaplan-Meier estimates of OS in patients with and without prior history of chronic GVHD were 64% and 17% (p = .022), respectively. Conclusion Graft-versus-leukemia effects possibly mediated by chronic GVHD may have played a crucial role in long-term survival in, or cure of active leukemia.

Thrombotic microangiopathy (TMA) impairs long-term survival after allogeneic hematopoietic stem cell transplantation (HSCT). As the allogeneic HSCT procedure has developed, addressing risk factors for TMA has become more complicated. The aim of this study was to investigate the impact of transplant-associated factors on TMA incidence in patients who have undergone HSCT in various settings. One hundred twenty-three consecutive allogeneic HSCT patients with hematologic diseases receiving myeloablative and reduced-intensity conditioning were evaluated retrospectively. Of 123 patients, 22 (17.9%) developed TMA after HSCT. Multivariate analysis showed the significance of GVHD grade II-IV, and the use of FK506 and the use of high-dose busulfan (Bu) (16 mg/kg) persisted. The hazard ratios of the use of FK506, the use of high-dose Bu (16 mg/kg), and GVHD grade II-IV for TMA were 8.7 (95% CI 2.0-37), 5.7 (95% CI 1.5-21), and 3.4 (95% CI 1.3-9.1), respectively. In the present study, reduced-intensity conditioning did not have an advantage over myeloablative conditioning in decreasing the incidence of TMA after HSCT. Our results also showed that high-dose Bu (16 mg/kg) for the conditioning and FK506 for the prophylaxis of GVHD might contribute more significantly to TMA onset after HSCT than other agents.

Recently, clinical studies of cord blood transplantation (CBT) in adults after myeloablative or nonmyeloablative conditioning regimens showed cord blood (CB) could effectively restore hematopoiesis and was associated with acceptable levels of graft versus host disease (GVHD).This study reports the results of cord blood transplantation in 7 adults with hematological malignancies.Median age was 56 years (range, 43-69 years). HLA match was 4 of 6 in 4 cases and 5 of 6 in 3 cases. Median nucleated cell dose was 2.74 x 10(7) cells/kg (range, 2.13-3.80) and CD34+ cell dose was 1.15 x 10(5) cells/kg (range, 0.44-2.79). Three patients had primary graft failure. There was one early death at day 24 after CBT due to pneumonia. Three patients with engraftment are alive and free of disease at day 390, day 348 and day 164 after CBT. Acute GVHD grade II occurred in 2 cases with engraftment, and chronic GVHD occurred in 1 of 3 evaluable patients. Six patients with and without engraftment received more than 2.0 x 10(7) cells/kg nucleated cells. Three patients without engraftment received CD34+ cell dose less than that of 3 patients with engraftment.It is considered that graft CD34+ cell dose besides nucleated cell dose is important for engraftment. We believe that adult patients without suitable related or unrelated bone marrow donors should be considered as candidates for CBT by the choice of CB including both sufficient nucleated cell dose and CD34+ cell dose.

There have been many reports of patients with ampulla cardiomyopathy described as takotsubo-shaped cardiomyopathy in the cardiovascular field. This unique cardiomyopathy is characterized by transient apical ballooning and hypokinesis of the left ventricle. We describe 2 cases of ampulla cardiomyopathy associated with hemophagocytic lymphohistiocytosis (HLH). In both of the patients, ventricular dysfunction suddenly occurred during the active phase of HLH. In each case, the findings on ECG, echocardiogram and left ventriculogram were compatible with ampulla cardiomyopathy. To our knowledge, this communication is the first to report cases of ampulla cardiomyopathy associated with HLH. Our cases suggest that HLH hypercytokinemia may have a role in causing ampulla cardiomyopathy.

A 57-year-old man underwent an autologous hematopoietic stem cell transplant for mantle cell lymphoma in August 1999. Anemia and thrombocytopenia appeared in November 2001. He was diagnosed with further hematological examination as having acute myeloid leukemia with multilineage dysplasia following secondary myelodysplastic syndrome. He received the allogeneic hematopoietic stem cell transplant from his HLA DRB1 locus mismatched brother in May 2002. The nonmyeloablative preparative regimen consisted of fludarabine 30mg/m2 for 6 days and busulfan 4mg/kg for 2 days. Eosinophilia, decrease of lacrimal fluid and liver dysfunction appeared on Day 104. We diagnosed this as chronic GVHD and treated the patient with prednisolone 10 mg/day. Thereafter, his chronic GVHD gradually improved. He had fever and myalgia in the extremities and lumbar region with elevated serum CPK and aldolase in January 2003. Histological examination led to a diagnosis of polymyositis simultaneously with chronic GVHD. Prednisolone 50 mg/day as an initial dose was started for the polymyositis following which the prednisolone dose was gradually tapered off. The polymyositis improved promptly after the administration of prednisolone and remains in remission with a current maintenance program of prednisolone 5 mg/day.

We evaluated the performance of a fully-automated hematology analyser CELL-DYN 4000 (CD4000; Abbott Laboratories, CA, USA) for T-lymphocyte subset analysis using the samples from 58 patients with hematological disorders. A flow cytometer (CytoronAbsolute; Ortho Diagnostics, NJ, USA) was used for comparison. Good correlations were shown between CD4000 and CytoronAbsolute for the of CD3(+), CD4(+), and CD8(+) T-lymphocyte counts (for each of correlations, r = 0.992, 0.992, and 0.969, respectively). This good correlation was sustained even in 24 cases in which the CD4(+) T-lymphocyte counts were less than 200/microl. In this group the correlation coefficients (r-values) for the comparisons between CD3(+), CD4(+), and CD8(+) T-lymphocytes measured by CD4000 and CytoronAbsolute were 0.991, 0.976, and 0.990, respectively. The CD4000 T-lymphocyte assay is a completely automated method, and does not require opening of the sample tube, which reduces exposure to any biohazards such as HIV. Furthermore, the method is rapid and requires only 7 min for completion of the analysis.

To evaluate the results of high-dose chemotherapy (HDT) and autologous hematopoietic stem cell transplantation (ASCT) in patients with diffuse B-cell aggressive non-Hodgkin's lymphoma(NHL). Between 1991 and 2004, 25 patients who did not achieve complete remission and 26 in complete remission from conventional chemotherapy received HDC-ASCT. Of 25 patients with refractory NHL,14 were chemotherapy-sensitive before HDT-ASCT and 11 were chemotherapy-resistant. CR was achieved after HDC-ASCT in 50% of 14 chemotherapy sensitive patients and in none of 11 chemotherapy-resistant patients. The 5-year probability of event-free survival for chemotherapy-sensitive and chemotherapy-resistant patients was 51.3% and 20.8%, respectively (p0.05, log-rank test). Moreover, the 5-year probability of event-free survival for patients in the low-risk group with International Prognostic Index (IPI) and in the high-risk group with IPI was 75.0% and 16.3%, respectively (p0.05, log-rank test). HDT-ASCT should be considered for patients with refractory aggressive NHL who are chemotherapy-sensitive rather than chemotherapy-resistant. Twenty-six patients in complete remission received consolidation therapy with HDT-ASCT. The 5-year probability of disease-free survival for patients in the low-risk group and in the high-risk group was 68.8% and 60.0%,respectively (p = 0.9 6). HDT-ASCT should be considered for patients at high risk who achieve complete remission after induction treatment. In future, HDT-ASCT combined with rituximab as induction therapy or as consolidation therapy is needed for patients with aggressive NHL in the high-risk group.

A 48-year-old man was referred to Sakai Municipal Hospital with nasal discharge and right facial swelling. The pathological findings of a nasal cavity tumor revealed stage IIB NK/T-cell lymphoma. He was admitted to our hospital and received CHOP therapy, resulting in progressive disease. Irradiation therapy combined with DeVIC chemotherapy also could not shrink his lymphoma. Then, two courses of L-asparaginase(L-Asp) were administered, resulting in partial improvement of the nasal and pharynx lesions, resolution of the fever and improvement of his performance status. On the day before a third course of L-Asp, he again developed a lowgrade fever. Although L-Asp was administered for several days, marked elevation of serum LDH, AST, ALT level, and thrombocytopenia persisted, and he died. Post-mortem examinations revealed hemophagocytosis in the bone marrow and liver, and infiltration of lymphoma cells into multiple organs including left lower lung, liver, spleen and kidneys. Although L-Asp was effective against nasal NK/T-cell lymphoma resistant to combination chemotherapy and irradiation therapy, the effectiveness of the single agent with L-Asp was only transient. L-Asp based regimen should be used as first-line therapy if asparagine synthetase protein expression is low using an immunohistochemical method.

In human immunodeficiency virus (HIV) infection, CD4 cell counts are useful in defining the disease state, monitoring antiviral treatment, and identifying patients at risk for opportunistic infections. Counting CD4 cells typically relies on traditional immuno-flow cytometric analyzers that require opening the tube for manipulation of the blood sample. In addition to automated blood cell counting, the CELL-DYN 4000 hematology analyzer performs a completely enclosed and automated analysis of the T lymphocyte subsets. We studied the performance characteristics of this method in blood samples containing low levels of CD4+ T cells. In one set of experiments, we emulated low level CD4 counts by use of a CD4 Positive Isolation Kit to deplete the CD4+ cells from blood samples. We used the FACScan analyzer for reference counts. Measurements were made exactly 12 hr after venepuncture in samples that were stored at room temperature. In normal samples and those with low CD4+ cell counts, there was excellent correlation between the results of the CELL-DYN and FACScan methods. Using the CELL-DYN 4000 analyzer, the precision of CD4+ and CD8+ T-cell counts was high (CV = 2 to 8%). The CD4+ T-cell count was linear over a wide range (35 to 1640 cells/microl). This study shows that CD4 and CD8 T cell counts using the CELL-DYN 4000 analyzer is suitable for normal samples and also for those with low CD4+ T cell counts. The method is rapid and automated, and blood specimens remain enclosed, minimizing the biohazard of exposure to blood of HIV patients.

This article describes the first case of acute myeloid leukemia (AML) in a healthy donor at 14 months after granulocyte colony-stimulating factor (G-CSF)-primed peripheral blood stem cell (PBSC) harvest. In September 2001, a healthy 61-year-old female was given G-CSF prior to PBSC harvest for her brother with multiple myeloma. In spite of successful engraftment, the recipient died from a disease relapse. In November 2002, the donor, admitted with high fever and leukocytosis with 98.5% blastoid cells, was diagnosed as having AML (M1). Her leukemia cells were positive for CD13, CD33, and G-CSF receptor without chromosomal abnormality and responded to G-CSF in vitro. During chemotherapy, she died of progressive pneumonia. If our case is truly the first, the incidence of leukemia in donors may not be higher than that of naturally occurring leukemia. However, efforts towards an international long-term study, or at least to report every case similar to ours, would be required to be conclusive.

Introduction: The treatment strategy for diffuse large B-cell lymphoma (DLBCL) in elderly patients is problematic. Recently, the Comprehensive Geriatric Assessment (CGA) has been proposed as an objective tool to identify those who can safely tolerate curative treatment. Although several researchers have reported the effectiveness of CGA in patients with aggressive B-cell non-Hodgkin lymphoma and revealed that intensive treatment cannot improve the outcomes of patients identified by CGA as unfit, compared with palliative treatment, the effectiveness of CGA and the effects of treatment are not firmly established. In the present study of elderly patients, we evaluated clinical outcomes and the prognostic value of clinical and biological parameters, including CGA stratification and treatment. Methods: We conducted a retrospective analysis using a database at our hospital. Patients were eligible if aged 60 years or older and diagnosed with DLBCL between November 1, 2000 and August 31, 2013. CGA stratification was performed using medical records, including assessment of the following four parameters: 1) age >= 80 years; 2) ADL including bathing, dressing, toileting, transferring, feeding, and continence; 3) comorbidity score according to the Cumulative Illness Rating Score for Geriatrics (CIRS-G) and evaluated for all organs/systems as follows: no problem – 1, mild problem – 2, moderate disabilities or morbidities (requiring treatment) – 3, severe and significant chronic disabilities – 4, and extremely severe disabilities – 5 ; and 4) geriatric syndrome, defined as the occurrence of dementia, delirium, depression, incontinence, falls, osteoporosis, neglect and abuse, or failure to thrive. Patients were classified as "fit" if they were aged We classified treatment as CHOP+-R, THP-COP+-R (THP-COP: pirarubicin 30 mg/m2, cyclophosphamide 500 mg/m2 and vincristine 1 mg/m2 on day 1 and predonisolone 30 mg/day on days 1–5), surgery alone, and palliative therapy (radiation, low-dose chemotherapy, rituximab alone, and corticosteroids). We compared overall survival (OS), progression free survival (PFS), complete response rate (CRR) and overall response rate (ORR) with each CGA stratification and treatment. Results: 87 patients were identified, with a median age of 72 years (range 60–84), 59% >= 70 years, and 16% >= 80 years; 53% male; 67% Stage III/IV; 62% IPI high–int/high, 20% loss of ADL and 13% geriatric syndrome. 70% were CGA fit and 30% unfit. 39% were treated with CHOP+-R, 53% THP-COP+-R, 2% surgery alone, 6% palliative therapy and 84% received rituximab. Median observation time was 859 days (range 40–4955). Univariate analysis showed the parameters negatively affecting OS were: loss of ADL (p At five years, the outcomes of the patients treated with CHOP+-R and THP-COP+-R were similar in terms of OS (85.0% vs 77.2%; p=0.95), see figure 1, PFS (56.4% vs 66.9%; p=0.96), CRR and ORR. The patients treated aggressively (CHOP or THP-COP +- R) had significantly better OS, PFS, CRR and ORR compared with those receiving palliation. We also observed better outcomes in terms of OS (p Conclusions: In this study, we observed similar outcomes regarding OS and PFS between two aggressive treatments (CHOP or THP-COP +- R). The patients treated aggressively had significantly better outcomes compared to those receiving palliation, irrespective of CGA stratification. Intensive treatment should be considered even for unfit patients. Disclosures No relevant conflicts of interest to declare.

Abstract 2000 The long-term survival rate after allogeneic hematopoietic cell transplantation (HCT) has been significantly improved over recent decades due to improvements in the HCT procedure. However, chronic complications such as cardiovascular disease have become increasingly evident and constitute a serious problem among long-term survivors after HCT. It is well-known that high-dose cyclophosphamide (CY) used for conditioning is one of the major causes of acute cardiotoxicity after HCT; however, it is still unclear which factors contribute to chronic cardiotoxicity. Although there is a possibility that chronic GVHD (cGVHD) causes cardiac tissue damage via cytokines such as IL-2, or TNF-alpha, it is unclear whether or not cGVHD influences cardiac function. In the present retrospective cohort study, we investigated which factors affected cardiac function and left ventricular hypertrophy (LVH) in the chronic phase after HCT. We examined left ventricular systolic and diastolic functions and LVH in patients who received HCT between April 2000 and March 2011 and survived for more than one year post-HCT. Only the patients who had undergone an echocardiographic examination before HCT were eligible for the study. We assessed left ventricular ejection fraction (LVEF) as a surrogate marker of LV systolic function and the early peak flow velocity/atrial peak flow velocity (E/A) as a surrogate marker of LV diastolic function using echocardiography. LVH after HCT was identified when the interventricular septal wall (IVS) and/or the posterior wall (PW) became more than 12 mm thick after HCT. We examined the factors that could have had some influence on cardiac function after HCT including age, sex, cumulative dose of anthracycline, use of high-dose CY in the conditioning, total body irradiation (TBI), intensity of conditioning regimen (myeloablative vs. reduced intensity conditioning), a history of hypertension, hemoglobin and serum ferritin levels. A total of 58 patients (25 males and 33 females) were eligible for participation in the study. The median age of enrolled patients was 46 years (range: 21–73). The median cumulative dose of anthracycline was 90 mg/m2 (0–431mg/m2). Forty-nine patients received myeloablative conditioning and 20 of these patients received myeloabative conditioning with TBI 12 Gy. Twenty-four patients were treated for cGVHD and 7 had a history of hypertension and 2 had an LVEF of less than 55% before HCT. Six had an LVEF of less than 55% at more than 1 year after HCT. In the multiple regression analysis that assessed the relationship between LVEF or E/A and the factors, myeloablative conditioning with TBI 12Gy was significantly associated with a decrease in LVEF after HCT (coefficient= −7.57, P=.001). However, in a comparison of Ara-C/CY/TBI and CY/TBI conditioning, the degree of change in the LVEF before and after HCT was similar between the two groups (repeated measures of ANOVA analysis. P=.0972). Patients who had received myeloablative conditioning had a significant decrease in E/A after HCT(coefficient= -.31, P=.02). Furthermore, a history of hypertension was also slightly associated with a decrease in E/A after HCT(coefficient= -.30, P=.05). In addition, only age was identified as a significant risk factor of left ventricular hypertrophy after HCT in the multivariate logistic analysis. However, in the present study, we could not identify a significant impact of cGVHD on cardiac function and LVH post HCT. We concluded, based on our results, that the presence of cGVHD did not significantly contribute to a decrease in cardiac function in the chronic phase after HCT. Our results also suggest that the intensity of conditioning for HCT had a significant effect on chronic cardiac function after HCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 3764 Recent reports showed that dasatinib induces significant immunostimulation with clonal expansion of large granular lymphocytes (LGL) which, in chronic myeloid leukemia (CML), is related to both better prognosis and to autoimmune-like side effects. It is speculated that lower levels of circulating T-regulatory cells play a partial role in LGL proliferation in patients receiving dasatinib. The immunoprofile was studied using flow cytometry to evaluate lymphocyte subsets and NK-cell reactivity in the peripheral blood of 61 patients in the chronic phase of CML during treatment with a tyrosine kinase inhibitor (TKI) (Median age: 58 years; imatinib 36, nilotinib 9, dasatinib 16). Furthermore, we measured plasma levels of 27 types of cytokines or chemokines in 58 patients in the chronic phase of CML so that a comprehensive comparison could be made of the differences in immunoprofile among the patients receiving these three TKIs. There were no significant differences between the three TKI-treated groups in terms of CD4/8 ratios or the number of T-cells (CD3+CD8+ or CD4+) and NK cells (CD3-CD56+). However, the number of NK-LGL (CD56+CD57+) and T-LGL (CD3+CD57+) increased significantly in the group that received dasatinib. Furthermore, dasatinib significantly enhanced NK-cell reactivity as compared to imatinib and nilotinib. In contrast nilotinib significantly suppressed NK-cell reactivity (E/T ratio =10:1: Median (interquartile range), 8.7% (5.0–16.2), 5.2% (4.8–11.4), 20.8% (13.4–33.3), for imatinib, nilotinib and dasatinib, respectively). In addition, the number of regulatory T-cells (CD4+CD25int-hiCD127low) was similar among the three groups (Median (interquartile range), 36/mm3 (27–53), 48/mm3 (34–60), 39/mm3 (26–53), for imatinib, nilotinib and dasatinib, respectively). Furthermore, in the analysis of cytokines and chemokines, plasma levels of IL-8, IP-10, and MCP-1 were significantly elevated while the level of PDGF-bb was significantly decreased in all three groups compared to those of healthy control. Plasma levels of IL-1 beta, IFN-gamma, and FGF-basic were significantly decreased in only the dasatinib group compared to those of control (P=.02, P=.04, P=.03, respectively). In addition, plasma levels of GM-CSF were significantly elevated in the imatinib and dasatinib groups (Median (interquartile range), 6.1 pg/ml (2.7–11.7) and 7.9 pg/ml (4.5–8.2), P=.02, and P=.03, respectively) but not in the nilotinib group (P=.34) when compared to those of control. In the multiple regression analysis that evaluated the relationship between NK-reactivity and cytokines or chemokines in the patients receiving dasatinib, only plasma levels of GM-CSF were significantly associated with NK-reactivity (P=.03). Notably, in our data, dasatinib and nilotinib exerted opposite effects on NK-cell reactivity, expansion of LGL, and showed different cytokine and chemokine profiles. Based on our results, the activation of NK-cell reactivity induced by dasatinib might be caused by a mechanism other than a decrease in the number of regulatory T-cells. Additionally, in an unphysiological immunological status mediated by dasatinib, GM-CSF might make some contribution to NK-cell reactivity. Disclosures: Nakamae: BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Hino:BMS: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau.

Background: Chronic graft-versus-host disease (cGVHD) remains the major cause of late morbidity and non relapse mortality after allogeneic hematopoietic stem cell transplantation (allo-HSCT). However, the pathogenesis of cGVHD is poorly understood. This study was designed to explore the immunological mechanism of cGVHD with comprehensive analysis of peripheral T cell subsets (CD4, CD8, Th1, Th2, γδ-T and NKT), dendritic cell (DC) subsets and serum 17 different cytokines. Methods: 20 patients (pts) with complete donor cell engraftment over 100 days after allo-HSCT were enrolled, including 6 pts without cGVHD (control) and 14 pts with cGVHD (5 limited/ 9 extensive). All of the pts with extensive cGVHD were under systemic immunosuppressive therapy, and the pts with limited cGVHD or without cGVHD were free from immunosuppressant. T cell subsets including CD4 (CD3+CD4+CD8−), CD8 (CD3+CD4−CD8+), Th1 (CD4+CXCR3+CCR4−), Th2 (CD4+CXCR3−CCR4+), γδ-T (CD3+TCRVδ2+), and NKT (CD3+CD161+) and DC subsets (CD11c+DC and CD123+DC) were determined with a flow cytometer. Serum cytokines, including IL–1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNF-α, IFN-γ, G-CSF, GM-CSF, MIP-1β, and MCP-1) were analyzed by Bio-Plex Cytokine Assay. Differences among extensive cGVHD, limited cGVHD and control were evaluated by one-way ANOVA followed by Bonferroni method as a post hoc test. Results: A significant difference was found only in γδ-T cells, but not in any of the other cells, including CD4, CD8, Th1, Th2, NKT, and DC subsets among extensive cGVHD, limited cGVHD and control. There was a significant decrease in the mean absolute number of γδ-T cells in extensive cGVHD (4.0 /μl, n=9, p Discussion: γδ-T cells have been reported to control the innate immune system and participate in anti-tumor or anti-infection immunity in a major histocompatibility complex-unrestricted manner. Our data suggest the possible involvement of the reduction of γδ-T cells in the pathogenesis of cGVHD, and the usefulness of monitoring γδ-T cells in predicting the development of cGVHD after allo-HSCT.

Thrombotic microangiopathy (TMA) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a serious complication with a high mortality. Acute GVHD (aGVHD) is one of risk factors for TMA and often overlaps it. In particular, gastrointestinal endothelium is a common target of aGVHD and TMA, which makes clinical diagnosis of TMA difficult, leading to delay early and appropriate treatment for it. In this study, to gain more insight into differences between TMA and aGVHD, comprehensive immunological analysis was performed. Methods: We determined kinetics of peripheral T cell subsets (CD4, CD8, Th1, Th2, γδ-T, NKT) and dendritic cell (DC) subsets (CD11c+DC and CD123+DC), serum 17 different cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, TNF-α, IFN-γ, G-CSF, GM-CSF, MIP-1β, MCP-1), and C-reactive protein (CRP) at the onsets of aGVHD or TMA in 25 patients undergoing allo-HSCT. T cell subsets including CD4 (CD3+CD4+CD8−), CD8 (CD3+CD4−CD8+), Th1 (CD4+CXCR3+CCR4−), Th2 (CD4+CXCR3−CCR4+), γδ-T (CD3+TCR-Vδ2+), and NKT (CD3+CD161+) and DC subsets were determined with a flow cytometer. TMA was diagnosed, following Iacopino’s criteria (Iacopino et al, Bone Marrow Tranplant. 24: 47, 1999). Data of aGVHD or TMA were compared with those of control without either aGVHD nor TMA between on 30 days and 60 days after allo-HSCT. Results: There was a significant decrease in the percentage of Th1 cells in CD4+T cells in TMA (9.1%, n=10), compared to in aGVHD (24.9%, n=9, p=0.003) or in control (21.6%, n=12, p=0.009). In contrast, the percentage of Th2 cells in CD4+T cells was higher in TMA (20.2%) than in aGVHD (9.3%, p Conclusion: Preferential Th2 and CD4 polarizations were observed at the onset of TMA. Thus, simultaneous monitoring of Th1, Th2, CD4 and CD8 was suggested to become a useful immunological parameter for differentiating TMA from aGVHD after allo-HSCT.

Peripheral blood stem cell harvest (PBSCH) has been widely performed for rescue following high-dose chemotherapy or as an alternative to BMT for allogeneic stem cell transplantation. However, severe complications, which caused sudden death, were reported in PBSCH from healthy donors. Recent cumulative evidence shows that decrease in cardiovascular signal variability of the R-R period (heart rate variability, HRV) is strongly associated with sudden death and/or cardiac event after a myocardial infarction. Furthermore, usefulness of HRV as a clinical tool has been explored in numerous conditions such as hypertrophic cardiomyopathy, obstructive sleep apnea, diabetic neuropathy, and various neurological alterations. Two types, time domain and frequency domain, are included in HRV analysis. In this study, we investigated HRV during and after apheresis for PBSCH in 23 cases [8 autologous transplant patients, 15 allogeneic transplant donors; 8 men, 15 women; median age 47 years (27–55)]. Date from 24-hour ambulatory ECG recordings were analyzed with R-R data analysis software (MemCalc/CHIRAM version 1, Suwatrust, Tokyo, Japan). Acknowledged simple markers in time domain analysis are the standard deviation of all normal beats (SDNN) and the square root of the mean of the sum of squared differences between adjacent normal-to-normal intervals (r-MSSD). On the other hand, markers in frequency domain analysis include LH, low frequency power (0.04–0.15Hz); HF, high frequency power (0.15–0.4 Hz); LH/HF ratio; VLF, very low frequency power (0.003–0.04 Hz); and ULF, ultra low frequency power (