Ewa Paszkiewicz-Kozik

FcγRIIA and FcγRIIIA polymorphisms do not influence survival and response to rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone immunochemotherapy in patients with diffuse large B-cell lymphoma

Rituximab in combination with chemotherapy significantly improves outcome compared to chemotherapy alone, and therefore it has become a new standard for the treatment of non-Hodgkin lymphomas (NHLs). The precise mechanism of action of this anti-CD20 antibody is still unknown. In vitro studies suggest that rituximab may induce lysis of Blymphoma cells through the mechanisms of antibody-dependent cellular cytotoxicity (ADCC) [1,2], complement-dependent cytotoxicity [3], or direct signaling leading to apoptosis [4]. In ADCC, the antibody binds lymphoma cells and then is recognized by effector cells via their receptors (FcgRs) for immunoglobulin G (IgG), which leads to eradication of tumor cells. FcgRs have polymorphic alleles that can influence the binding of antibody and efficacy of the immunoresponse. Natural killer (NK) cells bearing homozygous FcgRIIIA-158V/V have higher affinity to IgG1 than cells with F/F or F/V alleles, and mediate ADCC more effectively [5,6]. Recently, it has been shown that the FcgRIIIA-158V allele is associated with rituximab-induced neutropenia [7]. Reports on the influence of FcgRIIA and FcgRIIIA single nucleotide polymorphisms (SNPs) on the survival of patients with diffuse large B-cell lymphoma (DLBCL) are inconsistent. The study by Mitrovic et al. [8] reported the absence of correlation of FcgRIIA and FcgRIIIA polymorphisms with response and survival of patients with DLBCL treated with rituximab (R) and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy. In contrast, Kim et al. [9] reported that this polymorphism is predictive in the response to R-CHOP in Korean patients with DLBCL, but does not influence survival. In terms of the FcgRIIA polymorphism, only one study demonstrated that the H/H genotype is correlated with response to rituximab in patients with non-Hodgkin lymphoma, but no difference in survival was found [10]. Encouraged by these findings, we examined the possible correlation between FcgRIIA-131H/R and FcgRIIIA-158V/F polymorphisms and the response rate and survival of patients with DLBCL. We studied 87 patients with DLBCL treated with R-CHOP between 2004 and 2007 at the Institute of Oncology. The median age of patients was 57 years (range 25–81) and the male/female ratio 41/46, and Ann Arbor stage was III–IV in 74%, lactate dehydrogenase (LDH) was4normal in 48%, extranodal sites were involved in 59%, and the International Prognostic Index (IPI) score was 0–2 in 76% of patients. Patients were treated with a median 6 cycles of R-CHOP (range 4–8). During a median observation time of 40 months, 21 patients had disease progression (median time to progression 9 months). There were 17 deaths. The study was approved by the Ethics Committee and all patients gave informed consent. Genotyping

Human regulatory T cells suppress proliferation of B lymphoma cells

Abstract Activated regulatory T cells (Tregs) suppress proliferation and differentiation of normal B cells. In our study, allogeneic polyclonal CD4 + CD25 + Tregs and CD4 + CD25 + CD127loTregs expanded in vitro in the presence of rapamycin and low dose IL-2 suppressed proliferation of 11 out of 12 established lymphoma B-cell lines. The effect of expanded CD4 + CD25 + Tregs on survival of freshly isolated lymphoma B cells maintained in culture with soluble multimeric CD40L and IL-4 was variable across lymphoma entities. The survival of freshly isolated follicular lymphoma cells usually decreased in cocultures with CD4 + CD25 + Tregs. Treg effect on chronic lymphocytic leukemia/small lymphocytic lymphoma cells ranged from suppression to help in individual patients. CD4 + CD25 + Tregs or CD4 + CD25 + CD127loTregs expanded ex vivo with rapamycin could be used to suppress regrowth of residual lymphoma after autologous hematopoietic cell transplantation (HCT), and to counteract both graft-versus-host disease and lymphoma re-growth after allogeneic HCT in select patients with lymphoma susceptible to the regulation by Tregs.

Unusual cyclin D1 positive marginal zone lymphoma of mediastinum.

We report a case of 43-yr-old Caucasian female with an unusual, cyclin D1 positive marginal zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT) type of the mediastinum. To date, only about 30 cases of this entity have been published. They occur mainly in Asian females with a history of coexisung autoimmune disease. To our knowledge, this is the first case of medistinal MZL with cyclin D1 expression. In the span of 6 yr this patients tumor recurred three times, was surgically treated, and initially diagnosed as paraganglioma. The diagnosis was based on histopathological examination only. Our final diagnosis of MZL was made by combined evaluation of histopathology (HP), immunohistochemistry (IH), flow cytometry (FCM), fluorescence in situ hybridization (FISH), and molecular biology studies. We found a positive cyclin D1 reaction by IH and cyclin D1 mRNA (CCND1) overexpression by reverse transcription polymerase chain reaction (RT-PCR). Very high cyclin D1 to β-actin mRNA ratio in this case was comparable with the ratio, characteristic for mantle cell lymphoma (MCL). However, there was no translocation t(11;14) found by FISH and an immunophenotype by IH and FCM was consistent with MZL ruling out MCL diagnosis. In addition, our case differs from other, previously reported thymic MZL lymphoma cases by no autoimmune disease association, Caucasian origin, and the absence of the plasmacytic differentiation on both HP/IH.

Unusual IgD+/CD38-follicular lymphoma with leukemic presentation

Follicular lymphoma (FL) is a low-grade lymphoma, with rare presentation of leukemic phase in peripheral blood at the diagnosis. We describe a 49-yr-old woman who developed leukemic phase of FL in a 3 mo period after histological diagnosis of peripheral lymph node. To confirm the final diagnosis, flow cytometry (FCM) of peripheral blood, nested PCR with bcl-2 rearrangement, and cytogenetic analysis of peripheral blood and bone marrow cells were done. Lymphoma cells were negative for CD38 and expressed monoclonal surface immunoglobulins with relatively strong and “bright” IgD and “dim” kappa-chain by FCM analysis. Although the patient presented with generalized lymphadenopathy, massive peripheral blood and bone marrow involvement, she achieved complete clinical response after first-line chemotherapy COP and rituximab. She is still in a good condition with follow up over 2 yr.

Polish Lymphoma Research Group Experience With Bexarotene in the Treatment of Cutaneous T-Cell Lymphoma

Bexarotene, a synthetic retinoid licensed for the treatment of refractory cutaneous T-cell lymphoma (CTCL), has been used clinically in Poland since 2007 in 21 patients. The objective of our retrospective, multicenter study was to evaluate our experience with bexarotene therapy, including efficacy, safety, and survival outcomes. We retrospectively identified 21 adult patients who were treated with bexarotene between the years 2007 and 2012. Starting dose of bexarotene was 300 mg/m2 per day. The analysis included 3 patients with early-stage mycosis fungoides (MF), 16 patients with advanced-stage MF, and 2 patients with Sézary syndrome (SS). The mean duration of therapy with bexarotene was 14.5 months. Use of bexarotene resulted in an overall response rate of 81.0%, although the overall mortality rate was 52.8%. In our study, early-stage CTCL responded better than advanced-stage CTCL (100.0% vs. 77.8%, respectively). The mean time to observable response was 1.8 months, and the mean duration of the response was 16.4 months. Most significant side effects were hyperlipidemia, hypothyroidism, and a bleeding gastric ulcer. Based on the results of our analysis, bexarotene is a valuable tool in the treatment of refractory early-stage CTCL. Although a majority of patients initially responded to therapy, the high mortality rate in the advanced-stage group suggests that bexarotene does not completely resolve the therapeutic problems in all stages of CTCL. Patient stratification for bexarotene treatment may need a thorough reassessment, in that bexarotene may not be an effective drug in the very advanced stages of CTCL.

Lenalidomide potentiates CD4 + CD25 + Treg-related suppression of lymphoma B-cell proliferation

We have previously found that ex vivo expanded human CD4+CD25+Treg cells suppress proliferation of lymphoma B-cell lines. Here we demonstrate that the immunomodulatory drug lenalidomide potentiates suppression of lymphoma B-cell proliferation by freshly isolated CD4+CD25+Tregs, as well as suppression by Tregs expanded polyclonally in the presence of rapamycin from CD4+CD25+T cells or CD4+CD25+CD127loT cells. The regulation of lymphoma cell proliferation by Tregs pre-expanded with “third-party” allogeneic MoDCs in the presence of rapamycin was also potentiated by lenalidomide. Lenalidomide contributed to the suppression exerted by Tregs despite concomitant downregulation of Treg proliferation. Lenalidomide did not reduce the suppression of conventional T cells by expanded Tregs. The exposure of polyclonally expanded Tregs to lenalidomide did not significantly alter their phenotype. There was no uniform pattern of lenalidomide effect on Treg-mediated regulation of lymphoma B cells freshly isolated from patients. Freshly isolated lymphoma cells activated with multimeric CD40L and IL-4 to support their survival in vitro varied in their sensitivity to lenalidomide, and the regulatory effect of Tregs on such lymphoma cells ranged from suppression to help in individual patients. Lenalidomide potentiated or attenuated Treg effects on the survival of freshly isolated lymphoma cells. A combination of lenalidomide treatment with adoptive transfer of CD4+CD25+Tregs or CD4+CD25+CD127loTregs expanded ex vivo could be used to suppress proliferation of residual lymphoma in select patients with lymphoma responsive to the regulation by Tregs and sensitive to lenalidomide.

Resminostat in patients with relapsed or refractory Hodgkin lymphoma: results of the phase II SAPHIRE study

Abstract This open-label, single-arm phase II study examined efficacy, safety, pharmacokinetics, and biomarkers of histone deacetylase (HDAC) inhibitor resminostat in patients with relapsed or refractory Hodgkin lymphoma. Thirty-seven heavily pretreated patients received 600 (19 patients) or 800 mg (18 patients) oral resminostat daily for the initial 5 days of 14-day treatment cycles. Objective response rate (ORR) (primary) was 34% reaching disease control in 54% patients. Most patients (69%) showed reduced tumor size and reduced [18F]-FDG uptake in target lesions (71%). Median progression-free survival (PFS) was 2.3 months (95%CI [1.3; 3.3]) and median overall survival (OS) was 12.5 months (95%CI [9.6; 18.6]). Patients who responded or stabilized under resminostat had a 10-month longer OS than patients who progressed. Efficacy assessment, pharmacodynamics, and exploratory biomarker results followed plasma levels, showed target engagement and epigenetic modulations. Common drug-related adverse events (AEs) were nausea, vomiting, anemia, thrombocytopenia, and fatigue, mainly grade 1 or 2.

Prospective study of brentuximab vedotin in relapsed/refractory Hodgkin lymphoma patients who are not suitable for stem cell transplant or multi-agent chemotherapy

Some patients with relapsed/refractory Hodgkin lymphoma (HL) are not considered suitable for stem cell transplant (SCT) and have a poor prognosis. This phase IV study (NCT01990534) evaluated brentuximab vedotin (1·8 mg/kg intravenously once every 3 weeks) in 60 patients (aged ≥18 years) with CD30‐positive relapsed/refractory HL, a history of ≥1 prior systemic chemotherapy regimen, who were considered unsuitable for SCT/multi‐agent chemotherapy. Primary endpoint was overall response rate (ORR) per independent review facility (IRF). Secondary endpoints included duration of response (DOR), progression‐free survival (PFS) per IRF, overall survival (OS), proportion proceeding to SCT and safety. The ORR was 50%, with 12% CR; 47% proceeded to SCT. Median DOR was 4·6 months and median duration of CR was 6·1 months. After a median follow‐up of 6·9 and 16·6 months, median PFS and OS were 4·8 months (95% confidence interval, 3·0–5·3) and not reached, respectively; estimated OS rate was 86% at 12 months. Most common adverse events (≥10%) were peripheral neuropathy (35%), pyrexia (18%), diarrhoea and neutropenia (each 10%). Brentuximab vedotin showed notable activity with a safety profile consistent with known toxicities, and may act as a bridge to SCT, enabling high‐risk patients who achieve suboptimal response to frontline/salvage chemotherapy/radiotherapy to receive potentially curative SCT.

Wczesna niehematologiczna toksyczność po chemioterapii w wysokich dawkach i autologicznym przeszczepieniu komórek krwiotwórczych u chorych na nowotwory limfoidalne powyżej 60. roku życia

STRESZCZENIE Chemioterapia w wysokich dawkach (HDT) z autologicznym przeszczepieniem szpiku (AutoHCT) jest leczeniem z wyboru w przypadkach nowotworow hematologicznych, w ktorych standardowa terapia nie pozwala na uzyskanie dobrych wynikow leczenia. Pacjenci powyzej 60. roku zycia ze wspolistniejącymi chorobami są wylączani z HDT ze wzgledu na toksycznośc wielonarządową i śmiertelnośc okoloprzeszczepową. Celem badania byla analiza czestości i stopnia nasilenia powiklan narządowych we wczesnym okresie, do 30 dni po autotransplantacji, u chorych na chloniaki w wieku 60 lat i wiecej. W latach 2005–2011 zakwalifikowano do leczenia mieloablacyjnego 44 chorych. Mediana wieku wynosila 62 lata (zakres: 60–67). Chemioterapie BEAM (karmustyna, etopozyd, cytarabina, melfalan) podano 16 chorym, melfalan 200 otrzymalo 22 chorych, 6 chorym podano inne kondycjonowanie (cytarabina, melfalan lub cyklofosfamid). W 32% przypadkow stwierdzono choroby wspolistniejące, w tym w 71% choroby sercowo-naczyniowe. Wczesną wielonarządową toksycznośc stwierdzono w 84% przypadkow. Najczestszym powiklaniem byly zaburzenia zolądkowo-jelitowe (77% chorych). Biegunka III-IV stopnia wystąpila u 24 chorych (55%), przedluzone powyzej 7 dni wymioty u 17 chorych (40%). Zmiany śluzowkowe jamy ustnej III-IV stopnia obserwowano u 15 chorych (34%). Gorączka neutropeniczna (59%), z sepsą wystąpila u 1 chorego (2%). Powiklania kardiologiczne stwierdzono u 4 chorych (9%). Mediana czasu hospitalizacji wynosila 21 dni (16–44). Jeden chory zmarl z powodu toksyczności związanej z autotransplantacją (2%). We wczesnym okresie potransplantacyjnym, u chorych powyzej 60. roku HDT towarzyszy znaczna toksycznośc narządowa. Do najczestszych niehematologicznych objawow ubocznych leczenia mieloablacyjnego nalezą powiklania z przewodu pokarmowego, gorączka neutropeniczna, powiklania kardiologiczne. Przy niskiej śmiertelności okoloprzeszczepowej (2%) HDT jest procedurą bezpieczną dla osob starszych.