Vadim Ivanov

Positron emission tomography response at the time of autologous stem cell transplantation predicts outcome of patients with relapsed and/or refractory Hodgkin’s lymphoma responding to prior salvage therapy

Background High-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin’s lymphoma although half of patients relapse after transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin’s lymphoma. Design and Methods We report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatment-refractory Hodgkin’s lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation. Results Five-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to 43% (P=0.034). Multivariate analysis showed that positron emission tomography status (hazard ratio: 5.26 [2.57–10.73]) and tandem transplantation (hazard ratio: 0.39 [0.19–0.78]) but not risk factors at relapse (hazard ratio: 1.77 [0.80–3.92]) significantly influenced progression-free survival, while only tomography status significantly influenced overall survival (hazard ratio: 4.03 [1.38–11.75]). Conclusions In patients with relapsed/refractory Hodgkin’s lymphoma responding to prior salvage therapy, positron emission tomography response at time of autologous stem cell transplantation favorably influences outcome and enables identification of patients requiring single or tandem transplantation.

Primary B-CLL resistance to NK cell cytotoxicity can be overcome in vitro and in vivo by priming NK cells and monoclonal antibody therapy.

Despite recent advances with monoclonal antibody therapy, chronic lymphocytic leukemia (CLL) remains incurable. Natural killer (NK) cells are potent antitumoral effectors, particularly against hematological malignancies. Defective recognition of B-CLL leukemic cells by NK cells has been previously described. Here, we deciphered the mechanisms that hamper NK cell-mediated clearance of B-CLL and evaluated the potential of NK cells as therapeutic tools for treatment of CLL. First of all, leukemic B cells resemble to normal B cells with a weak expression of ligands for NK receptors. Conversely, NK cells from B-CLL patients were functionally and phenotypically competent, despite a decrease of expression of the activating receptor NKp30. Consequently, resting allogeneic NK cells were unable to kill leukemic B cells in vitro. These data suggest that patients’ NK cells cannot initiate a proper immune reaction due to a lack of leukemic cell recognition. We next set up a xenotransplantation mouse model to study NK-CLL cell interactions. Together with our in vitro studies, in vivo data revealed that activation of NK cells is required in order to control B-CLL and that activated NK cells synergize to enhance rituximab effect on tumor load. This study points out the requirements for immune system manipulation for treatment of B-CLL in combination with monoclonal antibody therapy.

Efficacy and safety of lenalinomide combined with rituximab in patients with relapsed/refractory diffuse large B-cell lymphoma

Abstract Initial clinical trials demonstrated that lenalidomide monotherapy has a significant activity against some subtypes of lymphoma, but in diffuse large B-cell lymphoma (DLBCL) its activity is limited. The combination of lenalidomide with rituximab may be a promising therapeutic strategy. We retrospectively analyzed clinical outcomes in 17 patients with relapsed/refractory (R/R) DLBCL treated with lenalidomide, 25 mg/day for 21/28 days and rituximab, 375 mg/m2 on day 7 of every lenalidomide cycle, for a maximum of 12 months. The overall response rate (ORR) was 41.2% with 35.3% complete response (CR), while median response duration was 26.5 months at a median follow-up of 24.9 months. Two patients with CR relapsed after 4 and 27 months of CR, and another four are actually in CR at + 13, + 23, + 24 and + 29 months. The estimated 24-month overall survival (OS) was 45% and progression-free survival (PFS) was 38%. Adverse events were manageable and mostly included thrombocytopenia and neutropenia. Lenalidomide–rituximab is active in R/R DLBCL with an important percentage of continuous CR.

Rituximab-lenalidomide-dexamethasone induces complete and durable remission in relapsed refractory diffuse large B-cell non-Hodgkin lymphoma.

Since the first and subsequent reports of its efficacy in myelodysplastic syndrome and multiple myeloma, there has been growing interest in lenalidomide as an anti-lymphoma therapy. Data emerging from initial clinical trials has demonstrated that lenalidomide has significant activity against different subtypes of aggressive B-cell lymphoma [1,2]. Two phase 2 studies of lenalidomide monotherapy in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (NHL; diffuse large B-cell [DLBCL], grade 3 follicular lymphoma, mantle-cell [MCL], and transformed NHL) were conducted in the USA (NHL-002) [3] and internationally (CC-5013-NHL003) [4]. The first study (49 patients) demonstrated a 35% overall response rate (ORR), which included 12% of patients with complete response, and a median duration of response (DR) of 10.4 months. The larger (217 patients) CC-5013-NHL-003 study confirmed these results in a similar patient population. Clinical responses were histologic subtypedependent and most prominent in MCL: ORR was 53%, with 20% CR and 33% PR. Median duration of response was 13.7 months and median progressionfree survival (PFS) was 5.6 months [5]. The results in patients with DLBCL (n1⁄4 108) were less encouraging, with ORR of 28%, short median PFS of 2.3 months, and median DR of 4.5 months. However, given the dismal prognosis of patients with relapsed DLBCL, this activity prompted us to utilize a lenalidomide-based combination in a single patient. Herein we report the case of a patient with DLBCL who was refractory to four previous lines of conventional immuno-chemotherapy, but achieved a remarkable sustained complete remission to treatment using the combination of lenalidomide with rituximab and dexamethasone. A 65-year-old male presented with 2 months’ history of abdominal pain and diarrhea. Colonoscopy revealed a left colon tumor, and biopsy showed histopathological features of DLBCL: proliferation of large immunoblastic and centroblastic cells expressing CD20 but also BCL2 and MUM1 without expression of CD10 and BCL6. The disease was classified by immunochemistry as ‘non-germinal center B-cell’ (non-GCB) according to the Hans decision tree [6]. The patient was staged as Ann Arbor IV, and received eight cycles of standard RCHOP-21 chemotherapy (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, 21day cycle). Complete response was confirmed by fluorodeoxyglucose positron emission tomographycomputed tomography (FDG PET-CT) and biopsy at the end of chemotherapy. The first relapse of DLBCL occurred 7 months later, and was confirmed by a new colon biopsy. The patient received two cycles of R-DHAC-21 (rituximab, carboplatin, cytarabine, and dexamethasone) as second-line treatment. After two cycles, the colonoscopy remained

A phase II trial of rituximab as adjuvant to intensive sequential chemotherapy in patients under 60 years with untreated poor-prognosis diffuse large B-cell lymphoma.

The potential benefit of rituximab as adjuvant to high-dose therapy (HDT) has been investigated in patients under 60 years with poor-risk (age-adjusted international prognostic index at 2–3) CD20+ diffuse large B-cell lymphoma (DLBCL). The treatment consisted of four cycles of high-dose CEOP (cyclophosphamide, epirubicin, vincristine, prednisone), plus etoposide and cisplatin during the two last cycles. Peripheral blood stem cells were collected after cycle 1, and reinfused after cycles 3 and 4. Four weekly rituximab infusions were subsequently delivered. Among the 36 patients included, 30 could complete chemotherapy schedule, and 24/36 received rituximab. A complete response occured in 26/36 patients (72%). With a median follow-up of 30 months, the estimated 5-year overall survival (OS) and event-free survival (EFS) rates (mean±s.d.) were 65±16 and 63±15%, respectively. For the 24 patients who received both chemotherapy and rituximab, the estimated 5-year OS and EFS rates were 86±14 and 82±15%. These data suggest that rituximab after HDT is feasible. Both complete remission rate and survival curves compare favorably with the poor outcome usually observed in high-risk DLBCL patients managed with HDT without rituximab.

Peripheral T-cell lymphomas: analysis of histology, staging and response to treatment of 208 cases at a single institution

Abstract Peripheral T-cell lymphomas are characterized by a poor clinical outcome. We retrospectively analyzed 208 adults treated in our institution between 2000 and 2011. Median age at diagnosis was 55 years. Fifty-one percent had B symptoms and 51% serum elevated lactate dehydrogenase (LDH) levels. Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 0–1 in 63% and 2–4 in 37%. According to Ann Arbor classification, 16% were at stage I–II and 84% at stage III–IV. Histological subtypes were: 39% peripheral T-cell non-Hodgkin lymphoma (NHL) unspecified (PTCL-U), 19.5% anaplastic large cell lymphoma (ALCL), with 9.5% ALK+ and 10% ALK−, and 25% angioimmunoblastic lymphoma (AILT). Primary extranodal lymphoma represented 17%, and 8% were diagnosed with hemophagocytosis. Induction chemotherapy was CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in 87% of patients. The median number of chemotherapy cycles was 2 (1–7). A complete response was obtained in 57% of the patients. Among them, 32% had an autologous stem cell transplant (ASCT) and 10% allogeneic SCT, while 38% were primary refractory. Five-year overall survival (OS) was 28.5% (22.3–36.3), and 5-year event-free survival (EFS) was 18.4% (13.4–25.3). A multivariate analysis showed that ALCL-ALK+ (p = 0.004), AILT (p < 0.01), extranodal involvement (p = 0.001), PS > 1 (p = 0.04), LDH < normal (p = 0.003) and hemophagocytosis (p = 0.001) were independent adverse factors for OS. We conclude that conventional chemotherapy with intensive treatment is not sufficient to improve the response rate. Optimal management is required.

Large B-cell lymphomas in adolescents and young adults in comparison to adult patients: a matched-control analysis in 55 patients.

Abstract The aim of our study was to assess whether large B-cell lymphoma (LBCL) in adolescents and young adults (AYA) should be considered as a clinocopathological entity, and to evaluate the prognostic value of age. Fifty-five patients aged > 15–30 years were fully matched to 365 adult patients aged 31–65 years. We found a high incidence of primary mediastinal thymic LBCL subtype (33% vs. 5%), while histological transformation was rare (2% vs. 14%). LBCL in AYA presented with a bulky mediastinal mass (51% vs. 21%), and the lactate dehydrogenase (LDH) value was significantly higher (73% vs. 54%). The complete response rate to chemotherapy was similar in the two groups. Five-year overall survival (OS) and event-free survival (EFS) of AYA were 73% and 68%, respectively. The matched-control analysis showed no difference for either OS or EFS. LBCL in AYA presents with some critical features which differ from those of older adults. However, the outcome is equivalent to that observed in older patients.

Response to lenalidomide in relapsed/refractory T-cell lymphoma might be steroid-dependent.

e18556 Background: The prognosis of patients with relapsed/refractory (R/R) T-cell lymphoma (TCL) remains very poor. Novel therapeutic approaches are needed to further improve outcomes. Lenalidomide (LEN) is an immunomodulatory drug that has demonstrated efficacy in several lymphoid malignancies. Recent trial of Lenalidomide in R/R Tcell lymphoma showed some clinical activity with 30% ORR and median PFS of 96 d. Unfortunately no CR was obtained. This limited activity might be improved by combining of LEN with other active drugs. Recently it was confirmed that dexamethasone (DEX) enhances antiproliferative activity of LEN in myeloma and lymphoma cells. At the same time DEX antagonized the immunostimulatory effects of LEN, but in a dose-dependent manner. METHODS We report 2 patients with R/R TCL in whom the combination LEN+steroids permitted to obtain durable responses. RESULTS First patient was the 32 y.o. male with heavily pre-treated (5 lines) refractory ALK+anaplastic LCL. Patient received 18 cycles of LEN 25 mg/d for 21/28 d with DEX 10 mg/w (first 6 cycles), than with Prednisolone 20-30 mg/d for next 12 cycles with obtaining good clinical and partial radiological response. Because of psycotics episodes steroids were stopped for 2-3 weeks on several occasions. Cessation of steroids was accompanying by reappearance of B-sympthoms and peripheral lymphoadenopathy. Reintroduction of steroids was accompanied by rapid and complete disappearance of symptoms. Second patient was 63 y.o. man with R/R T angioimmunoblastic lymphoma progressing after 2 lines of chemotherapy (8 RCHOP+7 RDHAC in 16 months).Treatment with LEN 15 mg 21/28 days + weekly DEX 20 mg induced PET-negative CR after 4 cycles with remission duration of 9 months. In both patients clinical response was observed after the first month of treatment. CONCLUSIONS It is possible that in R/R TCL the combination LEN + low dose steroids leeds to synergy of cytotoxic and immunomodulatory effects. Considering the rapid onset of response do we have to integrate less toxic and probably more efficacious new strategies at an earlier stade?