Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone Research Articles

ML-3 A Case of Primary Central Nervous System Anaplastic Lymphoma Kinase Positive Anaplastic Large cell Lymphoma at Neurohypophysis and Pineal Gland

The majority of primary central nerve system (CNS) lymphomas (PCNSL) are diffuse large B-cell lymphomas. Anaplastic large cell lymphoma (ALCL) that is a type of T-cell tumor is very rare in the PCNSL. ALCLs are divided into two entities: anaplastic lymphoma kinase (ALK)-positive and ALK-negative. We report a case of a 26-year-old woman who presented with a one month historyof headache and nausea. Magnetic resonance imaging (MRI) of the brain revealed pituitary and pineal gland mass diagnosed as ALK-positive ALCL by endoscopic brain biopsy. She underwent chemotherapy following methotrexate (MTX) and cyclophosphamide + doxorubicin + vincristine + prednisolone (CHOP). The follow-up contrast-enhanced brain MRI showed no recurrent lesion after chemotherapy. In previous reports, most of the lesions were in cerebral hemisphere, dura mater and spinal cord. Many of these patients were given primary diagnoses of meningitis. To our knowledge, there is no case report of initial diagnosis of germinoma due to lesions in Neurohypophysis and pineal gland as in this case.

Chemotherapy for non-Hodgkin lymphoma in the hemodialysis patient: A comprehensive review.

Chemotherapy for non‐Hodgkin lymphoma (NHL) in the hemodialysis (HD) patient is a challenging situation. Because many drugs are predominantly eliminated by the kidneys, chemotherapy in the HD patient requires special considerations concerning dose adjustments to avoid overdose and toxicities. Conversely, some drugs are removed by HD and may expose the patient to undertreatment, therefore the timing of drug administration in relation to HD sessions must be carefully planned. Also, the metabolites of some drugs show different toxicities and dialysability as compared with the parent drug, therefore this must also be catered for. However, the pharmacokinetics of many chemotherapeutics and their metabolites in HD patients are unknown, and the fact that NHL patients are often treated with distinct multiagent chemotherapy regimens makes the situation more complicated. In a realm where uncertainty prevails, case reports and case series reporting on actual treatment and outcomes are extremely valuable and can aid physicians in decision making from drug selection to dosing. We carried out an exhaustive review of the literature and adopted 48 manuscripts consisting of 66 HD patients undergoing 71 chemotherapy regimens for NHL, summarized the data, and provide recommendations concerning dose adjustments and timing of administration for individual chemotherapeutics where possible. The chemotherapy regimens studied in this review include, but are not limited to, rituximab, cyclophosphamide + vincristine + prednisolone (CVP) and cyclophosphamide + doxorubicin + vincristine + prednisolone (CHOP)‐like regimens, chlorambucil, ibrutinib, bendamustine, methotrexate, platinum compounds, cytarabine, gemcitabine, etoposide, ifosfamide, melphalan, busulfan, fludarabine, mogamulizumab, brentuximab vedotin, and 90Y‐ibritumomab tiuxetan.

Survival Outcomes for Plasmablastic Lymphoma: An International, Multicentre Study By the Australasian Lymphoma Alliance

Survival Outcomes for Plasmablastic Lymphoma: An International, Multicentre Study By the Australasian Lymphoma Alliance

Patterns of Care and Clinical Outcomes in Peripheral T-Cell Lymphoma Patients Receiving First-Line Treatment in Routine Clinical Practice in France and the United Kingdom

INTRODUCTION Peripheral T cell lymphomas (PTCL) are a rare and heterogenous group of aggressive non-Hodgkin lymphomas (NHL) that develop from mature T- and natural killer cells. They comprise approximately 10% of all newly diagnosed cases of NHL in Western populations. The current study characterizes real-world treatment patterns and outcomes among patients with PTCL in France and the United Kingdom (UK) in the first-line (1L) setting. METHODS A retrospective medical chart review study was undertaken at geographically disparate clinical sites in France and UK, where treating physicians were responsible for patient selection and data collection via structured case report forms. Adults (≥18 years) with newly diagnosed with PTCL between January 1, 2014 and December 31, 2016 were randomly selected for inclusion in the study. Eligible patients had received at least 1L treatment (1LT) for PTCL and had available clinical data for ≥1 year after PTCL diagnosis or until death. Patients enrolled in a clinical trial for 1L PTCL at any time between diagnosis and end of follow-up or who had any prior unresolved malignancy within 5 years of PTCL diagnosis were excluded. Demographic, clinical, and immunophenotypic/cytogenetic profiles of PTCL patients were assessed at diagnosis. Treatments received and best response as reported by the treating clinician (categorized as complete response [CR], partial response [PR], stable disease [SD], and progressive disease [PD]) at the end of 1LT are described. Data from both countries were pooled for the current analysis. RESULTS Overall, 32 haematologist/oncologists (France, 15; UK, 17) with a median of 12.5 years of clinical practice participated in the study. Most physicians in France practiced at a university hospital or a regional hospital centre (73.3%). In the UK, most physicians practiced at a specialist cancer/ tertiary referral treatment centre (47.1%). A total of 109 patients (France, 53; UK, 56) received at least 1L PTCL treatment during the study period. The median age at diagnosis was 63 years (range, 19 to 84 years), with a male predominance (57.8%). Eighty percent of patients had an ECOG performance status of 0-1 at diagnosis. B symptoms were present in 59.6% and extranodal disease was present in 35.8% patients at diagnosis. Most patients (72.5%) had stage III or IV disease and (64 of 102) 62.75% were classified as intermediate risk (score of 2-3) as per the International Prognostic Index. The most common histological subtypes were PTCL-not otherwise specified (NOS) (37.6%), angioimmunoblastic T-cell lymphoma (29.4%), and systemic anaplastic large cell lymphoma (20.2%). The median duration of follow-up was 34 months from the start of 1L PTCL treatment. Of those tested, 60.4% patients were positive for CD30 (information on threshold was not reported). Only 19.3% patients underwent testing for any cytogenetic marker. During follow-up, 28.4% of patients had died. In the 1L setting, 59.6% and 26.6% patients were treated with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) and with CHOEP/CHOEP‐like regimens (Table). Median duration of 1LT was 4.9 months. Stem cell transplant was undertaken in 29.4% patients as part of 1L treatment, of which 84.4% were autologous. PET-CT was used for response assessment in 56% of patients. Best response within 1 year of completing 1LT and before start of 2L treatment was assessed in 75/109 [68.8%] patients (Table); of whom 80% (60 patients) were reported to have a complete response (Table), and about 39% relapsed (within the first year) and went on to 2L treatment. The remaining 27 patients had best response assessed prior to completion of 1LT. Brentuximab vedotin (19%) and GemOx (19%) were the most common 2L treatments. CONCLUSIONS This retrospective observational study describes treatment patterns and key clinical outcomes among patients receiving 1L PTCL treatment in France and the UK. CHOP-based regimens were used to treat 59.6% of the study patients. Understanding distribution of PTCL subtypes and outcomes of treatment in routine clinical practice is complementary to data derived from clinical trials and crucial to facilitate improvement of survival outcomes through the introduction of novel therapies for this challenging group of rare malignancies. Disclosures Fox: Janssen: Consultancy; Adienne: Other: Travel Support; Takeda Pharmaceuticals: Consultancy; Atara Biotherapeutics: Consultancy; AbbVie: Consultancy; Gilead: Consultancy; Celgene: Consultancy; Sunesis: Consultancy. Ashaye:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd: Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Shah:Pfizer: Research Funding; Merck: Research Funding; Bayer: Research Funding. Dalal:Millennium Pharmaceuticals (Takeda): Other: I am a paid employee of Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Ltd. Truemper:Nordic Nanovector: Consultancy; Mundipharma: Research Funding; Janssen Oncology: Consultancy; Roche: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda: Consultancy, Research Funding.

Histiocytic Sarcoma: A Case Series of Extranodal and Nodal Presentations

Introduction: Histiocytic sarcoma is an aggressive malignancy of mature histocytes which often carries a poor prognosis. Histiocytic sarcoma is defined in the World Health Organisation (WHO) classification of histiocytic and dendritic cell neoplasms. Case Presentation: Case 1 depicts a 42 year old Malay gentleman with no premorbids presented to the haematology unit with a three month history of fever, night sweats, unintentional weight loss, left axillary and bilateral inguinal swellings which were progressively enlarging. Physical examination revealed a medium built gentleman with left axilla, bilateral inguinal lymphadenopathies and hepatosplenomegaly. Excision biopsies of the left axillary and inguinal lymph nodes were compatible with histiocytic sarcoma. He did not have any bone marrow infiltration. He was treated with 6 cycles of CHOP (Cyclophosphamide, doxorubicin, vincristine, prednisolone) polychemotherapy but he subsequently succumbed to severe hemophagocytic syndrome shortly after his 6th CHOP chemotherapy. Case 2 describes a 55-year-old previously healthy Malay gentleman who presented with perianal swelling and weight loss for two months. Physical examination revealed a large perianal swelling measuring 10 cm with bilateral inguinal lymphadenopathies. Anorectal tissue histology was compatible with the diagnosis of histiocytic sarcoma. He underwent a transverse colostomy which was subsequently reversed post-chemotherapy. He completed 6 cycles of CHOP chemotherapy followed by upfront consolidation autologous stem cell transplant. He is currently 9 months in complete remission. Conclusion: Histiocytic sarcoma remains a disease with poor treatment outcomes and high mortality. Understanding the pathogenesis and pathobiology of the disease will provide a future to the development of novel therapies.

HISTIOCYTIC SARCOMA: A CASE SERIES OF EXTRANODAL AND NODAL PRESENTATIONS

Introduction: Histiocytic sarcoma is an aggressive malignancy of mature histocytes which often carries a poor prognosis. Histiocytic sarcoma is defined in the World Health Organisation (WHO) classification of histiocytic and dendritic cell neoplasms. Case Presentation: Case 1 depicts a 42 year old Malay gentleman with no premorbids presented to the haematology unit with a three month history of fever, night sweats, unintentional weight loss, left axillary and bilateral inguinal swellings which were progressively enlarging. Physical examination revealed a medium built gentleman with left axilla, bilateral inguinal lymphadenopathies and hepatosplenomegaly. Excision biopsies of the left axillary and inguinal lymph nodes were compatible with histiocytic sarcoma. He did not have any bone marrow infiltration. He was treated with 6 cycles of CHOP (Cyclophosphamide, doxorubicin, vincristine, prednisolone) polychemotherapy but he subsequently succumbed to severe hemophagocytic syndrome shortly after his 6 th CHOP chemotherapy. Case 2 describes a 55 year old previously healthy Malay gentleman who presented with perianal swelling and weight loss for two months. Physical examination revealed a large perianal swelling measuring 10 cm with bilateral inguinal lymphadenopathies. Anorectal tissue histology was compatible with the diagnosis of histiocytic sarcoma. He underwent a transverse colostomy which was subsequently reversed post chemotherapy. He completed 6 cycles of CHOP chemotherapy followed by upfront consolidation autologous stem cell transplant. He is currently 9 months in complete remission. Conclusion: Histiocytic sarcoma remains a disease with poor treatment outcomes and high mortality. Understanding the pathogenesis and pathobiology of the disease will provide future to the development of novel therapies.

A Matched-Pair Analysis of EPOCH Versus CHOP As Frontline Therapy for Nodal Peripheral T-Cell Lymphoma, Excluding ALK-Positive Anaplastic T-Cell Lymphoma: A Multicenter Experience in Thailand

BACKGROUNDNodal peripheral T-cell lymphomas (PTCLs), except ALK-positive anaplastic large cell lymphoma (ALCL) have inferior outcomes compared with their B-cell counterparts. CHOP (Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone) is considered the standard therapy despite consistent results showing its ineffectiveness. The addition of etoposide (E) to chemotherapy showed encouraging results in selected subgroups of patients. We performed a matched-pair analysis comparing the efficacy of EPOCH to CHOP for untreated patients with nodal PTCLs, excluding ALK-positive ALCL.PATIENTS AND METHODSAccording to the Thai Lymphoma Study Group uniform treatment project, 58 patients with nodal PTCLs including angioimmunoblastic lymphoma, ALK-negative ALCL and PTCL, not otherwise specified received conventional EPOCH regimen as frontline therapy between January 2009 and December 2015. These patients were matched to 58 patients receiving CHOP (1:1) in multicenter registry of lymphoma in Thailand between 2007-2014 by center, International Prognostic Index (IPI) and age. Patients who underwent upfront autologous stem cell transplantation (ASCT) were censored at the time of transplantation.RESULTSThe baseline characteristics were well balanced between the two groups except a higher proportion of patients with ALK-negative ALCL in EPOCH group (24.1% vs 5.2%) (Table 1). The median cycle of chemotherapy was 6 (range, 1-8) in both groups. Four patients (6.9%) underwent upfront ASCT after EPOCH induction. The overall response rate for evaluable patients were 75.4% (complete response [CR] 57%) and 58% (CR 39%) in EPOCH and CHOP groups, respectively (P<0.0001). With a median follow up of 26 months, 4-year progression free survival (PFS) were 45.8% and 26.7% in EPOCH and CHOP group, respectively (P=0.022) (Figure 1). Projected overall survival (OS) at 4 years were 50.9% and 28.7% for EPOCH- and CHOP-treated patients, respectively (P=0.001) (Figure 2). By multivariate analysis, chemotherapy regimen was the only factor independently predicting PFS (Hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.04-3.19, P=0.034) and OS (HR 2.26, 95% CI 1.28-3.97, P=0.005).CONCLUSIONEPOCH provided superior outcomes than CHOP regimen as frontline therapy for patients with nodal PTCLS, excluding ALK-positive ALCL. The promising efficacy of EPOCH warrants further evaluation in prospective randomized controlled study. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Primary nodal peripheral T-cell lymphomas: diagnosis and therapeutic considerations.

Nodal peripheral T-cell lymphomas are a rare group of neoplasms derived from post-thymic and activated T lymphocytes. A review of scientific articles listed in PubMed, Lilacs, and the Cochrane Library databases was performed using the term “peripheral T-cell lymphomas”. According to the World Health Organization classification of hematopoietic tissue tumors, this group of neoplasms consists of peripheral T-cell lymphoma not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), anaplastic large cell lymphoma-anaplastic lymphoma kinase positive (ALCL-ALK+), and a provisional entity called anaplastic large cell lymphoma-anaplastic lymphoma kinase negative (ALCL-ALK−). Because the treatment and prognoses of these neoplasms involve different principles, it is essential to distinguish each one by its clinical, immunophenotypic, genetic, and molecular features. Except for anaplastic large cell lymphoma-anaplastic lymphoma kinase positive, which has no adverse international prognostic index, the prognosis of nodal peripheral T-cell lymphomas is worse than that of aggressive B-cell lymphomas. Chemotherapy based on anthracyclines provides poor outcomes because these neoplasms frequently have multidrug-resistant phenotypes. Based on this, the current tendency is to use intensified cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) regimens with the addition of new drugs, and autologous hematopoietic stem cell transplantation. This paper describes the clinical features and diagnostic methods, and proposes a therapeutic algorithm for nodal peripheral T-cell lymphoma patients.

Hepatosplenic T-cell lymphoma: Report of two cases

Hepatosplenic T-cell lymphoma (HSTCL) is a rare type of lymphoma. Presenting with hepatosplenomegaly, fever, cytopenia without significant lymphadenopathy, most patients are young men with poor outcomes. Here is the report of two cases of HSTCL from Maharaj Nakorn Chiang-Mai Hospital, Thailand. Both patients were middle-aged men presented with prolonged fever, hepatosplenomegaly and cytopenia. Abnormal lymphoid cells, not demonstrated by flow cytometry, were microscopically revealed in the patients’ bone marrow. The diagnosis of HSTCL was based on the histopathologic section obtained from splenectomy and liver biopsy. Both patients received cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) regimen initially while one of them was salvaged with etoposide, methylprednisolone, cytarabine, cisplatin (ESHAP) and methotrexate, high-dose cytarabine, methylprednisolone (cycle B of hyperCVAD) regimen. They responded poorly to chemotherapy and succumbed to severe sepsis. The presented cases confirmed that HSTCL is very difficult to diagnose and current treatment modalities appear to be ineffective

Antitumor effects of bevacizumab in a microenvironment‐dependent human adult T‐cell leukemia/lymphoma mouse model

The objective of this study was to evaluate the therapeutic potential of bevacizumab with or without systemic chemotherapy for adult T-cell leukemia/lymphoma (ATL) and clarify the significance of angiogenesis for ATL pathogenesis. NOD/Shi-scid, IL-2Rγ(null) (NOG) mice were used as recipients of tumor cells from a patient with ATL, which engraft and proliferate in a microenvironment-dependent manner. The ATL cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Injection of bevacizumab alone significantly increased necrosis and decreased vascularization in the tumor tissue. Levels of human soluble interleukin two receptor in the serum (reflecting the ATL tumor burden) of bevacizumab-treated mice were significantly lower than in untreated mice. Although bevacizumab monotherapy showed these clear anti-angiogenesis effects, it did not prolong survival. In contrast, injection of bevacizumab together with cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) led to a significant prolongation of survival of the ATL mice relative to CHOP alone. This is the first report to evaluate the efficacy of bevacizumab for ATL in a tumor microenvironment-dependent model. Bevacizumab therapy combined with chemotherapy could be a valuable treatment strategy for that subgroup of ATL probably depending to a large extent on angiogenesis via vascular endothelial growth factor.

Unbiased Pharmacological Screening Identified New Therapeutic Strategies For Peripheral T-Cell Lymphomas (PTCLs)

T-cell non-Hodgkin lymphoma (T-NHL) responds poorly to standard chemotherapeutic regimens like CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone). In order to identify better therapeutic approaches we conducted a viability screening using a library of known anti-neoplastic agents. We performed a first screening in the PTCL-NOS cell line OCI-Ly12 using 101 approved oncology drugs obtained from the National Cancer Institute in 3 concentrations (10, 1, 0.1 μM). We measured cell viability after 48 h of exposure and calculated 50% growth inhibitory concentrations (GI50s). We found 30 drugs with GI50s&lt; 10 μM that were further tested at 0.1 μM in 3 additional cell lines: anaplastic lymphoma kinase (ALK)-positive anaplastic large cell lymphoma (ALCL): Karpas299, ALK-negative ALCL: OCI-Ly13.2, and cutaneous T-cell lymphoma (CTCL): HuT78. In this secondary screening, we found 3 drugs that killed &gt; 70% of cells in all 4 cell lines: bortezomib (proteasome inhibitor), romidepsin (histone deacetylase -HDAC- inhibitor) and dactinomycin (RNA polymerase -RNA-Pol- inhibitor). We then tested these 3 compounds with additional HDAC inhibitors (panobinostat, vorinostat, trichostatin A), at 6 concentrations, in an extended panel of 7 T-NHL cell lines (tertiary screening). We found that only romidepsin and dactinomycin had GI50s lower than their respective maximum plasma concentration (Cmax) in humans; we therefore focused further mechanistic studies in these two compounds. Romidepsin GI50 ranged from 10 nM (in Karpas299) to 200 nM (in Mac2A and SU-DHL1), which were lower than its Cmax (1850 nM). Administering the drug one or two times over the 48 h exposure yielded equivalent anti-lymphoma effect. To further characterize this effect and determine whether the biological change was transient or permanent, we treated cells with romidepsin once with their GI50 dose and measured cell proliferation, apoptosis and extent of histone 3 lysine 27 acetylation (H3K27Ac) by immunoblotting at 4, 8, 12 h, then daily for 7 days. We found that the main cellular effect of romidepsin was inhibition of cell proliferation rather than inducing cell death. This effect was associated with increasing H3K27Ac as early as 8 h, peaking at 24 h (∼30 fold to control), maintaining for 3 days with subsequently slow declining until day 7 (∼15 fold to control). Since romidepsin response rate in relapsed/refractory PTCL patients is ∼30%, we wished to determine whether it could be more active when combined with chemotherapy. We found that in all T-NHL cell lines, concomitant administration with doxorubicin or vincristine yielded synergistic killing effect by isobologram analysis. This data suggested that romidepsin could be a potent chemosensitizer in PTCLs. Dactinomycin is a weak reversible RNA-Pol elongation inhibitor that affects all 3 RNA-Pols, which confers broad anti-neoplastic activity, but also significant toxicity. To determine whether more selective RNA-Pol2 inhibitors are active in PTCL, we first analyzed the expression of cyclin-dependent kinase (CDK) complexes, CDK7/CCNH and CDK9/CCNT, responsible for RNA-Pol2 activation through phosphorylation, in T-NHL cell lines. We found overexpression of CDK7 by 3.06 fold (± 0.3) and CCNH by 2.1 fold (± 0.2) in all 7 PTCLs cell lines compared to tonsilar normal T cells. This prompted us to investigate the anti-proliferative effect of a recently described CDK7 inhibitor (CDK7i). CDK7i showed anti-proliferative effect in all 7 T-NHL cell lines tested with GI50 ranging from 0.2 μM (OCI-Ly13.2) to 2.3 μM (Mac2A), which were 5-10 times lower than the CDK7i chemical control. We found that this anti-proliferative effect correlated with a primary decrease in phospho-Ser5 RNA-Pol2 followed by a decrease in phospho-Ser2 RNA-Pol2 ultimately causing transcriptional inhibition of active loci. This effect led to a decrease in BCL2 and MYC mRNA levels in treated cells, which suggested that CDK7i could represents the first of a novel class of selective transcriptional inhibitors for PTCL treatment. In sum, we identified romidepsin as the most active drug for T-NHL and described a potential chemosensitizing effect. We also uncovered a potential novel target, CDK7, for the treatment of this disease. Disclosures: No relevant conflicts of interest to declare.

L‐asparaginase with methotrexate and dexamethasone is an effective treatment combination in blastic plasmacytoid dendritic cell neoplasm

L‐asparaginase with methotrexate and dexamethasone is an effective treatment combination in blastic plasmacytoid dendritic cell neoplasm

High Dose Etoposide Plus G-CSF As an Effective Mobilization Regimen in Patients with NHL Previously Treated with R-CHOP or CHOP Chemotherapy. Retrospective Multicenter Study

AbstractAbstract 1917 Background:High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a curative treatment in patients with non-Hodgkin's lymphoma (NHL). Various regimens have been used to mobilize the peripheral blood stem cell (PBSC). Recently, etoposide plus G-CSF is considered to be one of the effective mobilization regimen in NHL without increasing risk of tMDS/AML. But the efficacy and the toxicity of high dose etoposide plus G-CSF compared with other mobilization regimens are not well defined. So, we conducted a retrospective multicenter study to compare the efficacy and the toxicity of various mobilization regimens. Methods:A total of 115 patients with NHL who were treated only with Rituximab –CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or CHOP chemotherapy and sequentially underwent PBSC mobilization between 2006 and 2011 were analyzed. For PBSC mobilization, six kinds of chemo-mobilization regimens were used. Twenty nine patients received etoposide 1.5 g/m2 (HDVP16 group), 31 patients received high dose cyclophosphamide 4 g/m2 (HDCY group), 21 patients received DHAP (cisplatin, cytarabine, dexamethasone) regimen (DHAP group), 13 patients received ESHAP (etoposide, methylprednisolone, cytarabine, cisplatin) regimen (ESHAP group), 11 patients received R-CHOP (R-CHOP group) and 10 patients received ICE (ifosfamide, carboplatin, etoposide) regimen (ICE group). All patients administered G-CSF 10 ¥ìg/kg/day until apheresis completed. Efficacy of PBSC mobilization and chemotherapy related toxicities were compared between the groups. Results:Among the various mobilization regimens, high dose etoposide plus G-CSF was the most effective regimen for PBSC mobilization. A median total CD34+cells collected was highest in HDVP16 group (16.22 × 106 cells/kg) compared with other regimens (4.44 in the HDCY group, 12.00 in the DHAP group, 6.08 in the ESHAP group, 4.03 in the R-CHOP group, 2.37 in the ICE group, P<0.001). Successful mobilization (total CD34+ cell count > 5.0 × 106 cells/kg) rate at day 1 and successful mobilization rate at day 1 and 2 were 72.4 % and 75.9 % in the HDVP16 group, which was significantly higher than the HDCY group (12.9 % and 32.3 %), the DHAP group (19.0 % and 42.9 %), the R-CHOP group (36.4 % and 45.5 %) and the ICE group (10.0 % and 20.0 %) (P=0.017 and P=0.045). Only in the HDVP16 group, no patient failed to mobilize stem cell adequately (failure to mobilization: total CD34+ cell count < 2.0 × 106 cells/kg). In univariate analysis, successful stem cell mobilization at day 1 was independently influenced by mobilization regimen, especially high-dose etoposide regimen (Exp 23.625, P=0.005) and ESHAP regimen (Exp 10.500, P=0.049). Neutropenic fever, none of which were fatal, developed in 20 patients (68.2 %) in the HDVP16 group which was more frequent significantly than in the other regimens (14.3 % (P<0.001) in the DHAP group, 7.7 % (P=0.001) in the ESHAP group, 27.3 % (P=0.031) in the R-CHOP group, 10.0 % (P=0.003) in the ICE group). But incidence of neutropenic fever was similar between the HDVP16 group and the HDCY group (68.2 % vs 58.1 % (P=0.454)). Conclusions:High dose etoposide improves the effectiveness of mobilization with higher stem cell yield compared with other mobilization regimens. Especially when compared to high dose cyclophosphamide regimen, high dose etoposide regimen showed higher efficacy for mobilization and similar incidence of neutropenic fever. Although high dose etoposide regimen showed longer duration of neutropenia and higher incidence of neutropenic fever than other regimens, there is no mortalities and grade IV infections. High dose etoposide plus G-CSF, when compared with other mobilization regimens, is a highly effective mobilization regimen with acceptable toxicity in patients with NHL. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Navitoclax (ABT‐263) and bendamustine ± rituximab induce enhanced killing of non‐Hodgkin's lymphoma tumours in vivo

Bendamustine with or without rituximab provides an effective and more tolerable alternative to the polytherapy cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP) in the treatment of haematological tumours and is currently approved for the treatment of many haematological malignancies. Navitoclax (ABT-263) is a potent inhibitor of Bcl-2, Bcl-x(L) and Bcl-w, which has demonstrated efficacy in haematological tumours alone and in combination with other agents. This paper describes the in vivo efficacy of combining either bendamustine or bendamustine plus rituximab (BR) with navitoclax in xenograft models of non-Hodgkin's lymphoma Activity was tested in xenograft models of diffuse large B-cell lymphoma (DoHH-2, SuDHL-4), mantle cell lymphoma (Granta 519) and Burkitt's lymphoma (RAMOS). Activity was also monitored in a systemic model of Granta 519. Navitoclax potentiated bendamustine activity in all cell lines tested. Bendamustine activated p53 in Granta 519 tumours, concurrent with activation of caspase 3. Navitoclax also improved responses to bendamustine-rituximab (BR) in a subset of tumours. Navitoclax in combination with bendamustine and BR is a viable combination strategy for use in the clinic and demonstrated superior efficacy compared with previously reported data for navitoclax plus CHOP and rituximab-CHOP.

Phase II study of cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) therapy for newly diagnosed patients with low- and low–intermediate risk, aggressive non-Hodgkin’s lymphoma: final results of the Japan Clinical Oncology Group Study, JCOG9508

The regimen of cyclophosphamide, doxorubicin, vincristine, and prednisolone, known as CHOP therapy, has been established as the standard treatment for aggressive non-Hodgkin's lymphoma (NHL). Although patients categorized as low (L) and low-intermediate (L-I) risk using the International Prognostic Index have favorable prognoses in Western countries, the efficacy and safety of CHOP therapy has not been prospectively evaluated in Japan. We conducted a phase II study of CHOP in L and L-I risk Japanese patients, evaluating overall survival (OS) as the primary endpoint. A total of 213 patients were enrolled and treated with eight courses of CHOP. Efficacy was evaluated in 168 eligible patients (L risk, 87; L-I risk, 81). Five-year OS rates in all eligible, L, and L-I risk patients were 68% [95% confidence interval (CI): 61-76%], 73% (95% CI: 63-82%), and 64% (95% CI: 53-74%), respectively. The major toxicity observed was grade 4 neutropenia (64%). Grade 4 non-hematological toxicities were observed as follows: one case each of paralytic ileus, convulsions, hypoxemia due to interstitial pneumonia, and reactivated fulminant hepatitis B. These results show reasonable efficacy and safety of the CHOP regimen in Japanese patients with lower risk aggressive NHL (UMIN-CTR Number C000000053).

Potent antitumor effects of bevacizumab in a microenvironment-dependent human lymphoma mouse model

We established a mouse model of microenvironment-dependent human lymphoma, and assessed the therapeutic potential of bevacizumab, an antitumor agent acting on the microenvironment. NOD/Shi-scid, IL-2Rγnull (NOG) mice were used as recipients of primary tumor cells from a patient with diffuse large B-cell lymphoma (DLBCL), which engraft and proliferate in a microenvironment-dependent manner. The lymphoma cells could be serially transplanted in NOG mice, but could not be maintained in in vitro cultures. Injection of bevacizumab together with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) significantly increased necrosis and decreased vascularization in the tumor, compared with CHOP alone. Levels of human soluble interleukin-2 receptor (sIL2R) in the serum of bevacizumab+CHOP-treated mice (reflecting the DLBCL tumor burden) were significantly lower than in CHOP recipients. Mice receiving bevacizumab monotherapy also showed significant benefit in terms of tumor necrosis and vascularization, as well as decreased serum sIL2R concentrations. The present DLBCL model reflects the human DLBCL in vivo environment more appropriately than current mouse models using established tumor cell lines. This is the first report to evaluate the efficacy of bevacizumab in such a tumor microenvironment-dependent model. Bevacizumab may be a potential treatment strategy for DLBCL patients.

Cyclosporine in Relapsed Subcutaneous Panniculitis-like T-Cell Lymphoma after Autologous Hematopoietic Stem Cell Transplantation

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare T-cell lymphoma characterized by involvement of the subcutaneous tissue of neoplastic T lymphocytes. SPTCL with hemophagocytic syndrome (HPS) is associated with an aggressive clinical course and treatment of SPTCL with HPS is not well established. Cyclophosphamide, doxorubicin, vincristine, prednisolone (CHOP) therapy is not successful in most patients suffering from SPTCL with HPS. The role of high dose chemotherapy followed by hematopoietic stem cell transplantation (HSCT) remains controversial. We report a case of relapsed SPTCL after CHOP chemotherapy and salvage chemotherapy followed by autologous HSCT, which had rapid improvement within weeks after cyclosporine and prednisolone. Immunosuppressive therapy may be an important and successful treatment option in SPTCL patients, even though they may have clinically aggressive disease.

Standard CHOP immuno-chemotherapy of primary mediastinal lymphomas

Primary mediastinal lymphoma (PMBCL) is an aggressive diffuse large B-cell lymphoma entity. It is a rare disease with specific clinical symptoms. The tumor is predominantly localized in the mediastinum but grows rapidly and infiltrates the surrounding tissues and organs. Two thirds of the patients are young females. Previous studies showed that third generation treatments are more effective than former standard cyclophosphamide-doxorubicin-vincristine-prednisolone (CHOP) regimens. Authors' goal was to assess whether adding the anti-CD20 monoclonal antibody, rituximab to the standard CHOP regimen improves the efficacy of the treatment compared to their previous results with CHOP and third generation chemotherapy regimens. Between October, 2002 and December, 2004 they have started the rituximab-CHOP (R-CHOP) treatment of 20 newly diagnosed, previously untreated PMBCL patients. Results were compared to the data of 24 patients receiving CHOP (n = 9) or procarbazin-prednisolone-doxorubicin-cyclophosphamide-etoposide-cytosin-arabinoside-bleomycin-vincristin-methotrexate (ProMACE-CytaBOM) (n = 15) treatment in the past. During an average follow-up of 64.6 months, the 5-year overall survival (OS) rate was significantly higher in the R-CHOP group compared to the CHOP treatment (79.4% vs. 33.3%; p = 0.026). However, due to the low number of cases, significant statistical difference could not be demonstrated in the 5-year event-free survival (EFS: 70.0% vs. 33.3%; p>0.05), disease-free survival (DFS: 70.0% vs. 33.3%; p>0.05) and relapse-free survival rate (RFS: 93.0% vs. 100%; p> 0.05), despite of the remarkable numeric difference. When comparing the 5-year survival rates of R-CHOP and ProMACE-CytaBOM treatments, the results were very similar without any significant statistical difference between the two types of treatment (OS: 79.4% vs. 80%; EFS: 70.0% vs. 60.0%; DFS: 70.0% vs. 60.0%; RFS: 93.0% vs. 82.0%; p> 0.05 in all cases). With adding rituximab to CHOP treatment, which was previously considered an insufficient treatment on its own, authors have obtained as good results in treating PMBCL as with third generation regimens. Patients have received the R-CHOP treatments without major side effects and mainly as out-patients. Standard R-CHOP treatment could therefore replace the more toxic third generation regimens in PMBCL as well. The data are comparable with those reported in the international literature.

In‐vivo purging of the circulating clonal T‐cells with Alemtuzumab prior to autologous peripheral blood hematopoietic cell mobilization and transplantation

<i>In‐vivo</i> purging of the circulating clonal T‐cells with Alemtuzumab prior to autologous peripheral blood hematopoietic cell mobilization and transplantation

Anemia and erythropoiesis-stimulating agent administration in patients with non-Hodgkin lymphoma treated with cyclophosphamide, doxorubicin, vincristine, and prednisolone ± rituximab chemotherapy: results from an observational study

CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) ± rituximab [(±R)CHOP] is the current standard of care for aggressive non-Hodgkin lymphoma (NHL). Anemia resulting from chemotherapy can be treated with erythropoiesis-stimulating agents (ESAs). As part of the observational IMPACT NHL study, data were collected on ESA use and anemia-related outcomes in 1829 adults receiving (±R)CHOP-14 or (±R)CHOP-21. Overall, 33% of patients were anemic during chemotherapy. Older age, lower baseline hemoglobin (Hb), worse performance status, more advanced disease stage, and use of CHOP-14 were significant predictors of transfusion and anemia in logistic regression models. ESAs were received by 404 patients, usually in response to low or declining Hb levels. Most patients (65%) had Hb 9–11 g/dL at ESA initiation, and 89% (Kaplan–Meier percentage) achieved Hb 10–12 g/dL. In conclusion, two-thirds of anemic patients with NHL receiving (±R)CHOP initiated ESA treatment at Hb 9–11 g/dL, and most achieved target Hb levels (10–12 g/dL).