Analysis of data collected in the European Society for Blood and Marrow Transplantation (EBMT) Registry on a cohort of lymphoma patients receiving plerixafor

Plerixafor + granulocyte-colony stimulating factor (G-CSF) is administered to patients with lymphoma who are poor mobilizers of hematopoietic stem cells (HSCs) in Europe. This international, multicenter, non-interventional registry study (NCT01362972) evaluated long-term follow-up of patients with lymphoma who received plerixafor for HSC mobilization versus other mobilization methods. Propensity score matching was conducted to balance baseline characteristics between comparison groups. The following mobilization regimens were compared: G-CSF + plerixafor (G + P) versus G-CSF alone; G + P versus G-CSF + chemotherapy (G + C); and G-CSF + plerixafor + chemotherapy (G + P + C) versus G + C. The primary outcomes were progression-free survival (PFS), overall survival (OS), and cumulative incidence of relapse (CIR). Overall, 313/3749 (8.3%) eligible patients were mobilized with plerixafor-containing regimens. After propensity score matching, 70 versus 36 patients were matched in the G + P versus G-CSF alone cohort, 124 versus 124 in the G + P versus G + C cohort, and 130 versus 130 in the G + P + C versus G + C cohort. For both PFS and OS, the upper bound of confidence interval for the hazard ratio was >1.3 for all comparisons, implying that non-inferiority was not demonstrated. No major differences in PFS, OS, and CIR were observed between the plerixafor and comparison groups

Statins Impair Antitumor Effects of Rituximab by Inducing Conformational Changes of CD20

Jakub Golab and colleagues found that statins significantly decrease rituximab-mediated complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity against B cell lymphoma cells

Hematopoietic stem cell mobilization with the reversible CXCR4 receptor inhibitor plerixafor (AMD3100)—Polish compassionate use experience

Recent developments in the field of targeted therapy have led to the discovery of a new drug, plerixafor, that is a specific inhibitor of the CXCR4 receptor. Plerixafor acts in concert with granulocyte colony-stimulating factor (G-CSF) to increase the number of stem cells circulating in the peripheral blood (PB). Therefore, it has been applied in the field of hematopoietic stem cell mobilization. We analyzed retrospectively data regarding stem cell mobilization with plerixafor in a cohort of 61 patients suffering from multiple myeloma (N = 23), non-Hodgkin’s lymphoma (N = 20), or Hodgkin’s lymphoma (N = 18). At least one previous mobilization attempt had failed in 83.6% of these patients, whereas 16.4% were predicted to be poor mobilizers. The median number of CD34+ cells in the PB after the first administration of plerixafor was 22/μL (range of 0–121). In total, 85.2% of the patients proceeded to cell collection, and a median of two (range of 0–4) aphereses were performed. A minimum of 2.0 × 106 CD34+ cells per kilogram of the patient’s body weight (cells/kg b.w.) was collected from 65.6% of patients, and the median number of cells collected was 2.67 × 106 CD34+ cells/kg b.w. (0–8.0). Of the patients, 55.7% had already undergone autologous stem cell transplantation, and the median time to neutrophil and platelet reconstitution was 12 and 14 days, respectively. Cases of late graft failure were not observed. We identified the diagnosis of non-Hodgkin’s lymphoma and previous radiotherapy as independent factors that contributed to failure of mobilization. The current report demonstrates the satisfactory efficacy of plerixafor plus G-CSF for stem cell mobilization in heavily pre-treated poor or predicted poor mobilizers

SK053 An Inhibitor Of Enzymes Involved In Allosteric Disulfide Bonds Formation Induces Differentiation Of Human AML Cells

Abstract Introduction of differentiation-inducing agents [all-trans retinoic acid (ATRA) and arsenic trioxide] to the treatment of acute promyelocytic leukemia (APL) was a remarkable therapeutic breakthrough resulting in cure rates exceeding 80%. However, there is no such significant progress in the treatment of other acute myeloid leukemia (AML) types. Thus search for new agents exerting anti-leukemic effects by targeting novel and unique cellular mechanisms is of utmost clinical importance. Numerous human proteins involved in tumor formation, such as C-terminal SRC kinase (CSK) or tissue factor, contain allosteric disulfide bonds that are cleaved by oxidoreductases or by thiol-disulfide exchange. Such disulfide modifications participate in post-translational protein control and affect protein function. Targeting of allosteric disulfide bonds is a novel promising strategy in cancer therapy (Hogg P, Nat Rev Cancer 2013). We have recently developed SK053, a small molecule inhibitor of thioredoxin/thioredoxin reductase system, that showed anti-tumor effects both in vitro and in murine tumor models (Klossowski S, Muchowicz A et al., J Med Chem 2012). Our ongoing studies revealed that SK053 is not a target-specific, but mechanism-selective inhibitor of enzymes involved in allosteric disulfide bonds formation such as protein disulfide isomerase (PDI). Its biotinylated form (SK231) precipitated PDI from human AML NB4 cells, and mass spectrometry analysis revealed that SK053 covalently binds to PDI. In a turbidimetric assay of insulin disulfide reduction SK053 inhibits the enzymatic activity of PDI with IC50 of 10 µM (Fig. 1B). Since PDI blocks translation of CCAAT enhancer binding protein alpha (CEBPA), one of the transcription factors crucial for normal neutrophils maturation (Haefliger S et al., Blood 2011), we set out to evaluate the activity of SK053 in human AML cells to see whether it can induce differentiation and cytostatic/cytotoxic effects against these cells. We observed that SK053 exerts significant cytostatic/cytotoxic activity in various types of human AML cells (HL60, NB4, KG-1 and MOLM14, Fig. 1A), and induces differentiation of AML blasts into more mature myeloid cells as evidenced morphologically in May-Grünwald-Giemsa staining, nitro blue tetrazolium (NBT) reduction assay as well as by increased expression of cell membrane differentiation markers (CD11b, CD14 and CD15), measured with flow cytometry. Moreover, incubation of AML cells with SK053 induces expression of CEBPA and hexokinase 3 (HK3) mRNA in quantitative RT-PCR (Fig. 1C) and increases amount of CEBPA protein in nuclear fraction measured with immunoblotting (Fig. 1D). Finally, SK053 induces differentiation of primary leukemic cells freshly isolated from AML patients. In summary, SK053 targets PDI and thioredoxin/thioredoxin reductase system, has significant anti-leukemic activity and induces differentiation of various types of human AML cells. Thus, targeting of enzymes involved in allosteric disulfide bonds formation with small molecule inhibitors presents a novel and promising therapeutic strategy in acute myeloid leukemia.Figure 1SK053 is a potent anti-leukemic agent that induces differentiation of human AML cells. (A) Cytostatic/cytotoxic activity of SK053 in human AML cell lines evaluated with trypan blue staining, mean percentage of dead cells ± SD, n=6; *P&lt;0.05 vs controls, one-way ANOVA with Dunett’s post test; (B) SK053 inhibits enzymatic activity of recombinant human PDI in a turbidimetric assay of insulin disulfide reduction; 130 µM bacitracin served as a positive control; (C) qPCR results presented as mean target-to-reference ratio ± SD (left) CEBPA expression in HL60 cells incubated for indicated time with 10 µM SK053; (right) HK3 expression in HL60 cells incubated for 48 hours with 10 µM SK053, or 1 µM ATRA (positive control); (D) SK053 increases amount of CEBPA protein in nuclear fraction of HL60 cells incubated for 2 or 5 days with 1 µM ATRA (positive control), 2 mM bacitracin (PDI inhibitor) or 10 µM SK053; the figure presents results of Western blot, HDAC2 served as a marker of nuclear fraction, ß-actin served as a loading control.Figure 1. SK053 is a potent anti-leukemic agent that induces differentiation of human AML cells. (A) Cytostatic/cytotoxic activity of SK053 in human AML cell lines evaluated with trypan blue staining, mean percentage of dead cells ± SD, n=6; *P&lt;0.05 vs controls, one-way ANOVA with Dunett’s post test; (B) SK053 inhibits enzymatic activity of recombinant human PDI in a turbidimetric assay of insulin disulfide reduction; 130 µM bacitracin served as a positive control; (C) qPCR results presented as mean target-to-reference ratio ± SD (left) CEBPA expression in HL60 cells incubated for indicated time with 10 µM SK053; (right) HK3 expression in HL60 cells incubated for 48 hours with 10 µM SK053, or 1 µM ATRA (positive control); (D) SK053 increases amount of CEBPA protein in nuclear fraction of HL60 cells incubated for 2 or 5 days with 1 µM ATRA (positive control), 2 mM bacitracin (PDI inhibitor) or 10 µM SK053; the figure presents results of Western blot, HDAC2 served as a marker of nuclear fraction, ß-actin served as a loading control. The research was supported by the Ministry of Science and Higher Education [IP2011038971 (DN)], National Science Centre Poland [NN405127640 (AM)] and a grant from the European Commission 7th Framework Programme: FP7-REGPOT-2012-CT2012-316254-BASTION. Disclosures: No relevant conflicts of interest to declare. </jats:sec

Clinicopathological characteristics and outcome of plasmablastic lymphoma patients: A single-center retrospective analysis.

e20034 Background: Plasmablastic lymphoma (PBL) is a rare CD20-negative lymphoma with an aggressive clinical course and short median survival ranging from 9 to 32 months. It is often associated with HIV infection but it also affects immunocompetent patients. Due to the rare occurrence most data comes from small, retrospective series. Methods: This is a retrospective single-center analysis of PBL patients (pts) referred to MSCNRIO between 2003-2019. Diagnosis was established according to the WHO 2017 classification criteria. Kaplan–Meier method was used for calculating overall survival (OS) and progression-free-survival (PFS) and the log-rank test for comparisons. Univariate analysis of prognostic factors was carried out. Results: 24 pts with a diagnosis of PBL were included. The median age at diagnosis was 54 years (range 29-90). 15 pts (63%) were men. LDH was elevated in 10 pts (41%). Stage III or IV was reported in 21 (87.5%) pts, IPI score of 3-5 in 12 (50%) and ECOG performance status &gt; 1 in 7 pts (29%). 20 pts (83.3%) had extranodal involvement, including oropharynx (n = 12), gastrointestinal tract (n = 1), bone marrow (n = 7), skeletal bone (n = 9), central nervous system (n = 3), skin and subcutaneous tissue (n = 2). Only 3 pts (13%) were infected by HIV, 2 had history of immunosuppressive therapy. Pathologically, all cases were negative for CD20 and positive for CD38 or CD138 expression. Ki67 &gt; 90% was noted in 16 cases (66%). 11 pts received CHOP chemotherapy, 3 pts - thalidomide- and 4 pts - bortezomib-based regimens, 1 was treated with both agents. 4 pts received different protocols; 1 pt received no treatment. CR was observed in 8 pts (33%), PR in 6 (25%) and no response in 10 (42%). 2 pts received ASCT in the 1st remission. 17 pts (71%) experienced relapsed/progressive disease. 16 pts died: 11 from disease progression, 2 from other neoplasm. With a median follow-up of 20 months (range 2-122) median OS was 21 months and 2-year OS rate was 46% (95%C.I 27%, 65%). 2-year PFS rate was 37% (95% C.I. 17%, 57%), with median PFS 12 months (range 0.7-105). On univariate analysis there was a trend for correlation of high IPI with PFS; (95%C.I 0.99-1.03, P= 0.08). Achieving CR significantly correlated with better OS (HR 5; 95% C.I. 1.41-17; P= 0.01)) and PFS (HR 5.1, 95%C.I. 1.4, 18; P= 0.004). Conclusions: Our results confirm other reported data on PBL. Patients in our cohort shared typical clinical features but majority of them were immunocompetent. PBL prognosis remains poor despite incorporating novel agents into treatment and requires new therapeutic approaches. </jats:p

High efficacy of intensive immunochemotherapy for primary mediastinal B-cell lymphoma with prolonged follow up

AbstractPrimary mediastinal B-cell lymphoma (PMBL) is currently curable in 85–95% of patients. Treatment regimens frequently used include RCHOP ± radiotherapy, DAEPOCH-R, or occasionally more intensive protocols. Here we present results of treatment of 124 patients with PMBL over a period between 2004 and 2017 with the use of a protocol designed for aggressive B-cell lymphoma GMALL/B-ALL/NHL2002 including 6 cycles of alternating immunochemotherapy with intermediate-dose methotrexate in each cycle, and reduced total doxorubicin dose (100 mg/m2 for whole treatment). Majority of patients (77%) received consolidative radiotherapy. A median (range) age of patients was 30 (18–59) years, and 60% were female. With a median (range) follow up of 9 (1–17) years, 5-year overall survival (OS) and 5-year progression free survival (PFS) were 94% and 92%, respectively. Positron emission tomography—computed tomography (PET-CT) results at the end of chemotherapy were predictive for outcome: OS and PFS at 5 year were 96% and 94% in PET-CT negative patients, respectively, and 70% and 70% in PET-CT-positive patients (p = 0.004 for OS, p = 0.01 for PFS). Eight (6%) patients had recurrent/refractory disease, however, no central nervous system (CNS) relapse was observed. Acute toxicity included pancytopenia grade 3/4, neutropenic fever, and treatment related mortality rate of 0.8%. Second malignancies and late cardiotoxicity occurred in 2.4% and 2.4% of patients, respectively. Intensive alternating immunochemotherapy protocol GMALL/B-ALL/NHL2002 is curative for more than 90% of PMBL patients and late toxicity in young patients is moderated. The attenuated dose of doxorubicin and intermediate dose of methotrexate may contribute to low incidence of late cardiotoxicity and effective CNS prophylaxis.</jats:p