Study protocol for THINK : a multinational open-label phase I study to assess the safety and clinical activity of multiple administrations of NKR-2 in patients with different metastatic tumour types

Introduction: NKR-2 are autologous T cells genetically modified to express a chimeric antigen receptor (CAR) comprising a fusion of the natural killer group 2D (NKG2D) receptor with the CD3 zeta signalling domain, which associates with the adaptor molecule DNAX-activating protein of 10 kDa (DAP10) to provide co-stimulatory signal upon ligand binding. NKG2D binds eight different ligands expressed on the cell surface of many tumour cells and which are normally absent on non-neoplastic cells. In preclinical studies, NKR-2 demonstrated long-term antitumour activity towards a breadth of tumour indications, with maximum efficacy observed after multiple NKR-2 administrations. Importantly, NKR-2 targeted tumour cells and tumour neovasculature and the local tumour immunosuppressive microenvironment and this mechanism of action of NKR-2 was established in the absence of preconditioning. Methods and analysis: This open-label phase I study will assess the safety and clinical activity of NKR-2 treatment administered three times, with a 2-week interval between each administration in different tumour types. The study will contain two consecutive segments: a dose escalation phase followed by an expansion phase. The dose escalation study involves two arms, one in solid tumours (five specific indications) and one in haematological tumours (two specific indications) and will include three dose levels in each arm: 3x10(8), 1x10(9) and 3x10(9) NKR-2 per injection. On the identification of the recommended dose in the first segment, based on dose-limiting toxicity occurrences, the study will expand to seven different cohorts examining the seven different tumour types separately. Clinical responses will be determined according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria for solid tumours or international working group response criteria in haematological tumours. Ethics approval and dissemination: Ethical approval has been obtained at all sites. Written informed consent will be taken from all participants. The results of this study will be disseminated through presentation at international scientific conferences and reported in peer-reviewed scientific journals

Factors associated with self-perceived burden to the primary caregiver in older patients with hematologic malignancies: an exploratory study

Objective: Although cancer patients frequently experience self-perceived burden to others, this perception has not been enough studied. The aim of this study was to investigate the prevalence of selfperceived burden to the primary caregiver (SPB-PC) and associated factors in an older patient population with hematologic malignancies at the time of chemotherapy initiation. Methods: In total, 166 consecutive patients with hematologic malignancies aged ≥65 years were recruited at the time of chemotherapy initiation. Patients’ SPB-PC was assessed using a 100-mm visual analogue scale (VAS). Characteristics potentially associated with SPB-PC, including sociodemographic and medical characteristics, physical functioning status (Karnofsky performance score, activities of daily living (ADL)/instrumental ADL), symptoms (fatigue, pain, nausea, quality of life), psychological distress (Hospital Anxiety and Depression Scale (HADS)), perceived cognitive function (Functional Assessment of Cancer Therapy Cognitive (FACT-Cog) Scale), and patients’/primary caregivers’ personal relationship characteristics (family tie, support), were assessed. Results: Thirty-five percent of patients reported moderate to severe SPB-PC (VAS ≥ 50 mm). Patients’ SPB-PC was associated with lower Karnofsky performance (β = 0.135, p = 0.058) and ADL (β = 0.148, p = 0.037) scores, and higher HADS (β = 0.283, p<0.001) and FACT-Cog perceived cognitive impairments subscale (β = 0.211, p = 0.004) scores. The proportion of explained variance was 23.5%. Conclusions: Health care professionals should be aware that about one third of older cancer patients experience moderate to severe SPB-PC at the time of chemotherapy initiation. They should adapt their support of patients who report such a feeling

Response to rituximab induction is a predictive marker in B-cell post-transplant lymphoproliferative disorder and allows successful stratification into rituximab or r-chop consolidation in an international, prospective, multicenter Phase II trial

Purpose The Sequential Treatment of CD20-Positive Posttransplant Lymphoproliferative Disorder (PTLD-1) trial ( ClinicalTrials.gov identifier, NCT01458548) established sequential treatment with four cycles of rituximab followed by four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) chemotherapy as a standard in the management of post-transplant lymphoproliferative disorder (PTLD) and identified response to rituximab induction as a prognostic factor for overall survival. We hypothesized that rituximab consolidation might be sufficient treatment for patients with a complete response after rituximab induction. Patients and Methods In this prospective, international, multicenter phase II trial, 152 treatment-naive adult solid organ transplant recipients, with CD20+ PTLD unresponsive to immunosuppression reduction, were treated with four weekly doses of rituximab induction. After restaging, complete responders continued with four courses of rituximab consolidation every 21 days; all others received four courses of rituximab plus CHOP chemotherapy every 21 days. The primary end point was treatment efficacy measured as the response rate in patients who completed therapy and the response duration in those who completed therapy and responded. Secondary end points were frequency of infections, treatment-related mortality, and overall survival in the intention-to-treat population. Results One hundred eleven of 126 patients had a complete or partial response (88%; 95% CI, 81% to 93%), of whom 88 had a complete response (70%; 95% CI, 61% to 77%). Median response duration was not reached. The 3-year estimate was 82% (95% CI, 74% to 90%). Median overall survival was 6.6 years (95% CI, 5.5 to 7.6 years). The frequency of grade 3 or 4 infections and of treatment-related mortality was 34% (95% CI, 27% to 42%) and 8% (95% CI, 5% to 14%), respectively. Response to rituximab induction remained a prognostic factor for overall survival despite treatment stratification. Conclusion In B-cell PTLD, treatment stratification into rituximab or rituximab plus CHOP consolidation on the basis of response to rituximab induction is feasible, safe, and effective

Ibrutinib as initial therapy for patients with chronic lymphocytic leukemia

Background: chronic lymphocytic leukemia (CLL) primarily affects older persons who often have coexisting conditions in addition to disease-related immunosuppression and myelosuppression. We conducted an international, open-label, randomized phase 3 trial to compare two oral agents, ibrutinib and chlorambucil, in previously untreated older patients with CLL or small lymphocytic lymphoma. Methods: we randomly assigned 269 previously untreated patients who were 65 years of age or older and had CLL or small lymphocytic lymphoma to receive ibrutinib or chlorambucil. The primary end point was progression-free survival as assessed by an independent review committee. Results: the median age of the patients was 73 years. During a median follow-up period of 18.4 months, ibrutinib resulted in significantly longer progression-free survival than did chlorambucil (median, not reached vs. 18.9 months), with a risk of progression or death that was 84% lower with ibrutinib than that with chlorambucil (hazard ratio, 0.16; P<0.001). Ibrutinib significantly prolonged overall survival; the estimated survival rate at 24 months was 98% with ibrutinib versus 85% with chlorambucil, with a relative risk of death that was 84% lower in the ibrutinib group than in the chlorambucil group (hazard ratio, 0.16; P=0.001). The overall response rate was higher with ibrutinib than with chlorambucil (86% vs. 35%, P<0.001). The rates of sustained increases from baseline values in the hemoglobin and platelet levels were higher with ibrutinib. Adverse events of any grade that occurred in at least 20% of the patients receiving ibrutinib included diarrhea, fatigue, cough, and nausea; adverse events occurring in at least 20% of those receiving chlorambucil included nausea, fatigue, neutropenia, anemia, and vomiting. In the ibrutinib group, four patients had a grade 3 hemorrhage and one had a grade 4 hemorrhage. A total of 87% of the patients in the ibrutinib group are continuing to take ibrutinib. Conclusions: ibrutinib was superior to chlorambucil in previously untreated patients with CLL or small lymphocytic lymphoma, as assessed by progression-free survival, overall survival, response rate, and improvement in hematologic variables. (Funded by Pharmacyclics and others; RESONATE-2 ClinicalTrials.gov number, NCT01722487.)

Nucleoside analogs in chronic lymphoid malignancies : studies of the clinical effects and mechanisms of action of cladribine and fludarabine

La 2-Chloro-2’-désoxyadénosine (CdA, Cladribine) est un agent de chimiothérapie qui appartient à la famille des analogues des purines. La CdA est particulièrement active dans les néoplasies issues des tissues lymphoïdes, comme la leucémie lymphoïde chronique (LLC) de type B. La CdA est une pro-drogue qui n’est activée qu’après avoir été convertie en CdA triphosphate par des enzymes fortement exprimées dans les cellules lymphoïdes. Le CdA triphosphate, considéré comme le métabolite toxique de la CdA, inhibe la synthèse de l’ADN et de l’ARN, et active les voies de l’apoptose. Comme la réparation de l’ADN peut impliquer une néosynthèse d’ADN, il est concevable que celle-ci puisse également être inhibée par la CdA. Par conséquent, la CdA pourrait être capable d’accroître la toxicité des agents qui induisent des lésions de l’ADN susceptibles de réparation. Dans ce travail, nous avons d’abord démontré qu’il existait in vitro dans les lymphocytes LLC une forte cytotoxicité synergique entre la CdA et les agents alkylants ou les rayons UV, deux traitements qui induisent des lésions potentiellement réparables de l’ADN. Nous avons poursuivi nos efforts afin d’expliquer cette interaction. Nous avons observé que la CdA était capable d’inhiber la synthèse réparatrice de l’ADN, qu’elle survienne spontanément ou qu’elle soit provoquée par les agents alkylants ou les rayons UV. Nous avons émis l’hypothèse selon laquelle ce mécanisme est à la base de la synergie, et que l’impossibilité pour la cellule d’achever la réparation complète de l’ADN constitue un signal de mort cellulaire par apoptose. Les résultats obtenus in vitro nous ont encouragés à mettre sur pied une étude clinique de l’association de CdA avec le cyclophosphamide, un agent alkylant, pour des patients atteints de LLC ou de lymphomes indolents. Cette étude, construite comme une étude de Phase I, nous a permis de définir le dosage optimal des deux agents de chimiothérapie. Nous avons observé un taux de réponse encourageant, compte tenu du fait que la population étudiée était de mauvais pronostic. Certaines réponses se sont avérées durables, suggérant que la synergie observée in vitro s’était produite en clinique. En conclusion, nos études illustrent le bénéfice potentiel de l’association d’analogues des purines comme le CdA avec des agents de chimiothérapie qui ciblent l’ADN, comme le cyclophosphamide2-Chloro-2-deoxyadenosine (CdA, cladribine) is a chemotherapeutic agent belonging to the family of purine analogs. CdA is particularly active in malignancies arising from lymphoid tissues, such as B-cell chronic lymphocytic leukemia (CLL). CdA is a prodrug that must be converted into CdA triphosphate by the action of enzymes highly expressed in lymphoid cells, as an absolute requirement for cytotoxicity. CdA triphosphate inhibits various processes involved in DNA and RNA synthesis, and activates apoptotic pathways. Because enzymes involved in DNA synthesis are also involved in DNA repair, it is conceivable that CdA might interfere with forms of repair that require DNA synthesis. If this mechanistic interaction occurs, CdA should be able to enhance cell killing by agents that induce DNA lesions susceptible to removal by repair mechanisms. In the present work, we firstly demonstrated in CLL lymphocytes a strong synergistic interaction, in term of cell killing by apoptosis, between CdA and DNA alkylating agents or UV-C radiation, both conditions causing DNA damage susceptible to removal by repair processes. We then sought to explain the basis for this favorable interaction. We observed that CdA was able to inhibit DNA repair synthesis occurring in CLL cells, either spontaneously or after external DNA damage by UV-C light or mafosfamide. We hypothesized that the latter mechanism might be at the basis of synergism and that inability of leukemic cells to complete repair might signal toward apoptosis. Finally, the results obtained in vitro led us to study the combination of CdA with cyclophosphamide, an alkylating agent, in patients suffering CLL or indolent lymphomas. The study was conceived as a Phase I study, enabling us to determine the optimal dosage of both drugs. We observed an interesting response rate in very advanced patients with poor prognostic factors. Some of the responses were long-lasting, suggesting that in vitro synergism may have translated clinically. In conclusion, our studies illustrate the potential benefit of combining purine analogs, such as CdA, with other treatment modalities, here DNA-damaging conditions, in the hope of reinforcing their antitumoral activity.Thèse de doctorat en sciences biomédicales (SBIM 3)--UCL, 200

Place de la chimiothérapie dans la leucémie lymphoïde chronique

Place de la chimiothérapie dans la leucémie lymphoïde chroniqu

AICA-riboside (acadesine), an activator of AMP-activated protein kinase with potential for application in hematologic malignancies

IMPORTANCE OF THE FIELD: Despite considerable advances, B-cell chronic lymphocytic leukemia (CLL) is incurable with standard approaches. Thus, there remains a need for new therapies, particularly for patients who develop chemoresistance to DNA-targeting treatments. AICA-riboside (acadesine) is a nucleoside with a wide range of metabolic effects, including release of adenosine and activation of AMP-activated protein kinase (AMPK), which was initially developed as a cardioprotective agent. More recently, it has been shown that AICA-riboside induces apoptosis in various models of leukemia, including CLL. AREAS COVERED IN THIS REVIEW: The literature data show that apoptosis induced by AICA-riboside in CLL is not dependent on a functionally normal p53 pathway. Moreover, AICA-riboside is active towards resting and proliferative models of leukemia cells, including resistant phenotypes. Finally, studies in healthy subjects and during coronary artery bypass graft surgery show that AICA-riboside is devoid of serious toxicity. WHAT THE READER WILL GAIN: This paper reviews the mechanisms of action of AICA-riboside in normal and malignant cells and discusses how AICA-riboside could impact CLL treatment. TAKE HOME MESSAGE: We propose that AICA-riboside, which displays a relative selectivity and a favorable toxicity profile, may offer a new treatment option for CLL