Safety and efficacy of Temsirolimus in combination with Bendamustine and Rituximab in relapsed mantle cell and follicular lymphoma

In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with r/r follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1-3 prior therapies received Bendamustine (90 mg/m(2), day 1+2) and Rituximab (375 mg/m(2), day 1) with Temsirolimus in doses from 25 to 75 mg added on day 1, 8, 15 of a 28-day cycle. Fifteen (11 MCL, 4 FL) patients were included in the phase I. Median age was 73 years and median pretreatment number was 2. No formal dose-limiting toxicity was observed. Dominant non-hematological side effects were fatigue in 11 (73%), nausea in 9 (60%), mucositis in 7 (47%) and vomiting in 6 patients (40%). Coug…

Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma:Â a Phase II Trial (GOAL)

Abstract Background: A substantial proportion of patients fail first line treatment of diffuse large B-cell lymphoma. Currently available salvage therapies are often ineffective and cannot be tolerated, especially for elderly patients. Thus, probably less than 25% of patients achieve a long lasting remission. Regimens like gemcitabine/oxaliplatin, or bendamustin, both in combination with rituximab are available for elderly or after failure of HDT, however induce only short lived responses. Obinutuzumab (GA101) is a type II anti-CD20 antibody, with preclinical evidence of superiority over rituximab in xenograft models of MCL and DLBCL. Recently a large phase III trial failed to show a benefi…

Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Results of the Part I Cohort of the STORM Trial

Abstract Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Patients and Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels for the m…

Temsirolimus in Combination with Bendamustine and Rituximab (BeRT) for the Treatment of Relapsed Mantle Cell and Follicular Lymphoma: Final Phase I/II Results

Abstract Background: mTOR inhibition has been shown to be effective in various subtypes of malignant lymphomas (Smith et al, JCO 2010). Furthermore, in relapsed MCL a phase III trial demonstrated superiority of Temsirolimus to chemotherapy. Although novel treatment options as Ibrutinib have changed the treatment landscape for MCL, no curative potential could be shown for this approach and novel concepts continue to be needed. Several trials provided promising results when Temsirolimus is combined with agents like Rituximab (Ansell et al, Lancet Oncology 2011) or chemoimmunotherapy, as shown in part I (phase I) of the reported trial (Hess, Leukemia, 2015). We now report the final analysis of…

The mTOR Inhibitor Temsirolimus Added to Rituximab Combined With Dexamethasone, Cytarabine, and Cisplatinum (R-DHAP) for the Treatment of Patients With Relapsed or Refractory DLBCL – Results From the Phase-II STORM Trial

There is a high need for novel treatment options in relapsed and refractory diffuse large B-cell lymphoma. Single agent mammalian target of rapamycin (mTOR) inhibitor treatment has shown promising efficacy in this entity. Here, we report on the results of the mTOR-inhibitor temsirolimus combined to standard rituximab-DHAP salvage regimen in a prospective, multicenter, phase II, open-label study. The STORM regimen consisted of rituximab 375 mg/m(2) (day 2) and DHAP (dexamethasone 40 mg day 3-6, cisplatinum 100 mg/m(2) day 3, cytarabine 2 × 2  g/m(2) day 4) with temsirolimus added on day 1 and 8 of a 21-day cycle, with 2 to 4 cycles planned. In part I, dose levels of 25, 50, 75, and 100 mg fo…

SAFETY AND CLINICAL ACTIVITY OF TEMSIROLIMUS IN COMBINATION WITH RITUXIMAB AND DHAP IN PATIENTS WITH RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA-REPORT OF THE PROSPECTIVE, MULTICENTER PHASE II STORM TRIAL

Safety and Clinical Activity of Temsirolimus in Combination with Rituximab and DHAP in Patients with Relapsed or Refractory Diffuse Large B-Cell Lymphoma - Report of the Prospective, Multicenter Phase II STORM Trial

Abstract Purpose. To evaluate the safety, tolerability and efficacy of the combination of the mTOR inhibitor Temsirolimus and a standard salvage regimen (R-DHAP) in patients with relapsed or refractory diffuse large cell B-Cell lymphoma (DLBCL). Methods. This is a prospective, multicenter, phase II, open-label study. Patients with relapsed or refractory DLBCL with a maximum of two prior treatment lines were eligible. The STORM regimen consisted of Rituximab 375 mg/m² (day 2) and DHAP (Dexamethasone 40mg day 3-6, Cisplatine 100 mg/m² day 3, Cytarabine 2x2 g/m² day 4) with Temsirolimus added on day 1 and 8 of a 21 d cycle, with 2-4 cycles planned. In part I, dose levels of 25, 50, 75 and 100 …

Effects on Survival and Neurocognitive Functions of Whole-Brain Radiotherapy (WBRT) and Autologous Stem Cell Transplantation (ASCT) as Consolidation Options after High-Dose Methotrexate-Based Chemoimmunotherapy in Patients with Newly Diagnosed Primary CNS Lymphoma (PCNSL): Results of the Second Randomization of the IELSG32 Trial

Abstract Introduction: IELSG32 is an international randomized phase II trial with 2 key clinical questions in pts with PCNSL. The first question focused on optimal induction therapy, and results of the 1st randomization have demonstrated that MATRix combination (methotrexate (MTX), cytarabine (ARAC), thiotepa, rituximab (R)) is associated with significantly better outcome [Ferreri AJ, et al. Lancet Haematol 2016]. The second question addresses the efficacy and neurotolerability of ASCT, as an alternative to WBRT as consolidation. Herein, we report the results of the 2nd randomization (NCT01011920). Methods: HIV-neg pts 18-70 ys and ECOG PS ≤3 with new histology-proven PCNSL and measurable d…

Polatuzumab vedotin as a salvage and bridging treatment in relapsed or refractory large B-cell lymphomas

The antibody-drug conjugate polatuzumab vedotin (pola) has recently been approved in combination with bendamustine and rituximab (pola-BR) for patients with refractory or relapsed (r/r) large B-cell lymphoma (LBCL). To investigate the efficacy of pola-BR in a real-world setting, we retrospectively analyzed 105 patients with LBCL who were treated in 26 German centers under the national compassionate use program. Fifty-four patients received pola as a salvage treatment and 51 patients were treated with pola with the intention to bridge to chimeric antigen receptor (CAR) T-cell therapy (n = 41) or allogeneic hematopoietic cell transplantation (n = 10). Notably, patients in the salvage and brid…

REGGAE : a novel approach for the identification of key transcriptional regulators

Abstract Motivation Transcriptional regulators play a major role in most biological processes. Alterations in their activities are associated with a variety of diseases and in particular with tumor development and progression. Hence, it is important to assess the effects of deregulated regulators on pathological processes. Results Here, we present REGulator-Gene Association Enrichment (REGGAE), a novel method for the identification of key transcriptional regulators that have a significant effect on the expression of a given set of genes, e.g. genes that are differentially expressed between two sample groups. REGGAE uses a Kolmogorov–Smirnov-like test statistic that implicitly combines assoc…

High-dose methotrexate-based immuno-chemotherapy for elderly primary CNS lymphoma patients (PRIMAIN study)

Leukemia : normal and malignant hemopoiesis 31(4), 846-852 (2017). doi:10.1038/leu.2016.334

Final Results of a Phase I/II Trial of the Combination Bendamustine and Rituximab With Temsirolimus (BeRT) in Relapsed Mantle Cell Lymphoma and Follicular Lymphoma

Abstract. In this phase I/II study, we explored the combination of Temsirolimus with Bendamustine and Rituximab (BeRT) in patients with relapsed or refractory (r/r) follicular lymphoma (FL) or mantle cell lymphoma (MCL). Patients with 1 to 3 previous therapies received Bendamustine (90 mg/m2, day 1 + 2) and Rituximab (375 mg/m2, day 1) with Temsirolimus in doses from 25 to 75 mg in phase I and 50 mg Temsirolimus in phase II, added on day 1, 8, 15 of a 28 days cycle. The primary endpoint of the phase II was ORR at the end of treatment. Overall, 39 (29 MCL, 10 FL) patients were included. Median age was 71 years and median pretreatment number was 2. Grade 3/4 non-hematologic adverse events wer…

Synthetic lethal metabolic targeting of cellular senescence in cancer therapy.

Activated oncogenes and anticancer chemotherapy induce cellular senescence, a terminal growth arrest of viable cells characterized by S-phase entry-blocking histone 3 lysine 9 trimethylation (H3K9me3). Although therapy-induced senescence (TIS) improves long-term outcomes, potentially harmful properties of senescent tumour cells make their quantitative elimination a therapeutic priority. Here we use the Eµ-myc transgenic mouse lymphoma model in which TIS depends on the H3K9 histone methyltransferase Suv39h1 to show the mechanism and therapeutic exploitation of senescence-related metabolic reprogramming in vitro and in vivo. After senescence-inducing chemotherapy, TIS-competent lymphomas but …

90Yttrium-Ibritumomab Tiuxetan as First Line Treatment for Follicular Non-Hodgkin Lymphoma. 5 Year Results from an International Multicenter Phase II Clinical Trial

Abstract Purpose Updated 5 year results are presented from the multicenter phase II trial of 90Yttrium-Ibritumomab-Tiuxetan (90YIT) as first line stand-alone therapy for patients with follicular lymphoma (FL). Patients and Methods 59 patients with CD20-positive FL grade 1 to 3a in stages II with bulky disease (n=12), III (n= 26), or IV (n=21), and in need for therapy, were enrolled between 05/2007 and 06/2010. They received 90YIT according to standard procedure (rituximab 250 mg/m2 days -7 and 0, then 90YIT 15 MBq/kg (0.4mCi/kg) day 0; patients with platelet counts below 150.000/ul but above 100.000/ul received only 11 MBq/kg). Primary end point was the clinical and molecular remission rate…

Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial

Background The International Extranodal Lymphoma Study Group-32 (IELSG32) trial is an international randomised phase 2 study that addresses two key clinical questions in the treatment of patients with newly diagnosed primary CNS lymphoma. Results of the first randomisation have demonstrated that methotrexate, cytarabine, thiotepa, and rituximab (called the MATRix regimen) is the induction combination associated with significantly better outcome compared with the other induction combinations tested. Here, we report the results of the second randomisation that addresses the efficacy of myeloablative chemotherapy supported by autologous stem-cell transplantation (ASCT), as an alternative to wh…

Polatuzumab Vedotin in Relapsed and Refractory (r/r) Large B-Cell Lymphoma (LBCL): Real-World Data of the German National Compassionate Use Program (CUP)

Introduction The antibody-drug conjugate polatuzumab vedotin (Pola) has recently been approved in combination with bendamustine and rituximab (Pola-BR) for patients with r/r diffuse LBCL (DLBCL). Methods To characterize the efficacy of Pola-BR in a real-world setting, we retrospectively analyzed data from 97 patients with r/r LBCL who were treated with Pola in 24 German centers within the national CUP. Clinical baseline and follow-up (FU) data were collected by chart review and summarized descriptively. Progression-free survival (PFS) and overall survival (OS) were analyzed using Kaplan-Meier and Cox regression methods. Fisher's exact test was used to compare categorical factors between gro…

Chemoimmunotherapy with methotrexate, cytarabine, thiotepa, and rituximab (MATRix regimen) in patients with primary CNS lymphoma: results of the first randomisation of the International Extranodal Lymphoma Study Group-32 (IELSG32) phase 2 trial.

BACKGROUND: Standard treatment for patients with primary CNS lymphoma remains to be defined. Active therapies are often associated with increased risk of haematological or neurological toxicity. In this trial, we addressed the tolerability and efficacy of adding rituximab with or without thiotepa to methotrexate-cytarabine combination therapy (the MATRix regimen), followed by a second randomisation comparing consolidation with whole-brain radiotherapy or autologous stem cell transplantation in patients with primary CNS lymphoma. We report the results of the first randomisation in this Article.METHODS: For the international randomised phase 2 International Extranodal Lymphoma Study Group-32 …

Obinutuzumab-Based Immunochemotherapy Prolongs Progression-Free Survival and Time to Next Anti-Lymphoma Treatment in Patients with Previously Untreated Follicular Lymphoma: Four-Year Results from the Phase III GALLIUM Study

Abstract Introduction: Immunochemotherapy is standard of care treatment for previously untreated patients (pts) with advanced stage follicular lymphoma (FL). However, the majority of pts relapse, with around 20% relapsing within 2 years. Obinutuzumab (GA101; G) is a glycoengineered type II anti-CD20 monoclonal antibody (mAb) with increased antibody-dependent cell-mediated phagocytosis and cytotoxicity, and direct B-cell killing, compared with the type I mAb rituximab (R). The randomized Phase III GALLIUM study (NCT01332968) compared the efficacy and safety of G-chemotherapy (G-chemo) vs R-chemotherapy (R-chemo) in previously untreated pts with advanced stage FL. In the primary analysis (PA)…

Obinutuzumab (GA101) in Combination with Pixantrone for the Treatment of Patients with Relapsed Aggressive B-Cell Lymphoma: Report on an Ongoing Phase II Trial (GOAL)

Abstract Background: Prognosis of diffuse large B-cell lymphoma (DLBCL) and other aggressive lymphoma entities has improved with the advent of Rituximab, and R-CHOP-21 and variants is SOC. Nevertheless, a substantial proportion of patients fail first line treatment. Salvage therapies are often effective. However, no more than 25-50% achieve a long term remission even when consolidative high dose chemotherapy (HDT) followed by hematopoietic stem cell transplantation (SCT) is applied. In case of failure or intolerance to HDT, regimen like Gemcitabine/Oxaliplatin are applied but show limited efficacy, indicating the need for new treatments. Obinutuzumab (GA101) is a type II anti-CD20 antibody.…

Regulation of hematopoietic growth factor production by genetically modified human bone marrow stromal cells expressing interleukin-1beta antisense RNA.

Interleukin-1 (IL-1) plays a major role in the regulation of bone marrow stromal cell function and hematopoiesis. It is known to induce secretion of the hematopoietic growth factors granulocyte colony-stimulating factor (G-CSF), granulocyte-macrophage CSF (GM-CSF), IL-6, and IL-8 as well as IL-1 itself in stromal cells. We investigated the role of IL-1beta-mediated growth factor production in the human stromal cell line L88/5. Using liposome-mediated DNA transfer, two stromal cell transfectants that constitutively express IL-1beta antisense (AS) RNA were generated. Expression of IL-1beta AS RNA and IL-1beta RNA was determined by RT-PCR. The stromal cell transfectants were strongly impaired …

(90)Yttrium-ibritumomab-tiuxetan as first-line treatment for follicular lymphoma: 30 months of follow-up data from an international multicenter phase II clinical trial.

Purpose We report on a multicenter phase II trial of 90yttrium-ibritumomab-tiuxetan (90YIT) as first-line stand-alone therapy for patients with follicular lymphoma (FL). Patients and Methods Fifty-nine patients with CD20+ FL grade 1 to 3a in stages II, III, or IV, age 50 years old or older requiring therapy were enrolled. They received 90YIT according to standard procedure. If complete response (CR) or unconfirmed complete response (CRu) without evidence for minimal residual disease (MRD) 6 months after application of 90YIT was achieved, patients were observed without further intervention. The same applied to patients with partial response (PR) or with stable disease (SD). Patients with CR …