RESUMO
The production of cultured red blood cells (cRBC) for transfusion purposes requires large scale cultures and downstream processes to purify enucleated cRBC. The membrane composition, and cholesterol content in particular, are important during proliferation of (pro)erythroblasts and for cRBC quality. Therefore, we tested the requirement for cholesterol in the culture medium during expansion and differentiation of erythroid cultures with respect to proliferation, enucleation and purification by filtration. The low cholesterol level (22 µg/dl) in serum free medium was sufficient to expand (pro)erythroblast cultures. Addition of 2.0 or 5.0 mg/dL of free cholesterol at the start of differentiation induction inhibited enucleation compared to the default condition containing 3.3 mg/dl total cholesterol derived from the addition of Omniplasma to serum free medium. Addition of 5.0 mg/dl cholesterol at day 5 of differentiation did not affect the enucleation process but significantly increased recovery of enucleated cRBC following filtration over leukodepletion filters. The addition of cholesterol at day 5 increased the osmotic resistance of cRBC. In conclusion, cholesterol supplementation after the onset of enucleation improved the robustness of cRBC and increased the yield of enucleated cRBC in the purification process.
Assuntos
Colesterol , Meios de Cultura , Eritrócitos , Colesterol/metabolismo , Humanos , Eritrócitos/metabolismo , Meios de Cultura/química , Células Cultivadas , Diferenciação Celular/efeitos dos fármacos , Proliferação de Células/efeitos dos fármacos , Técnicas de Cultura de Células/métodos , Eritroblastos/metabolismo , Eritroblastos/citologia , Meios de Cultura Livres de SoroRESUMO
BACKGROUND: The introduction of rituximab significantly improved the prognosis of diffuse large B-cell lymphoma (DLBCL), emphasizing the importance of evaluating the long-term consequences of exposure to radiotherapy, alkylating agents and anthracycline-containing (immuno)chemotherapy among DLBCL survivors. METHODS: Long-term risk of subsequent malignant neoplasms (SMNs) was examined in a multicenter cohort comprising 2373 5-year DLBCL survivors treated at ages 15-61 years in 1989-2012. Observed SMN numbers were compared with expected cancer incidence to estimate standardized incidence ratios (SIRs) and absolute excess risks (AERs/10 000 person-years). Treatment-specific risks were assessed using multivariable Cox regression. RESULTS: After a median follow-up of 13.8 years, 321 survivors developed one or more SMNs (SIR 1.5, 95% CI 1.3-1.8, AER 51.8). SIRs remained increased for at least 20 years after first-line treatment (SIR ≥20-year follow-up 1.5, 95% CI 1.0-2.2, AER 81.8) and were highest among patients ≤40 years at first DLBCL treatment (SIR 2.7, 95% CI 2.0-3.5). Lung (SIR 2.0, 95% CI 1.5-2.7, AER 13.4) and gastrointestinal cancers (SIR 1.5, 95% CI 1.2-2.0, AER 11.8) accounted for the largest excess risks. Treatment with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin versus ≤2250 mg/m2/≤150 mg/m2, respectively, was associated with increased solid SMN risk (hazard ratio 1.5, 95% CI 1.0-2.2). Survivors who received rituximab had a lower risk of subdiaphragmatic solid SMNs (hazard ratio 0.5, 95% CI 0.3-1.0) compared with survivors who did not receive rituximab. CONCLUSION: Five-year DLBCL survivors have an increased risk of SMNs. Risks were higher for survivors ≤40 years at first treatment and survivors treated with >4500 mg/m2 cyclophosphamide/>300 mg/m2 doxorubicin, and may be lower for survivors treated in the rituximab era, emphasizing the need for studies with longer follow-up for rituximab-treated patients.
Assuntos
Linfoma Difuso de Grandes Células B , Segunda Neoplasia Primária , Humanos , Rituximab/efeitos adversos , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologia , Sobreviventes , Ciclofosfamida , Doxorrubicina , Linfoma Difuso de Grandes Células B/epidemiologiaRESUMO
The consensus panel 2 (CP2) of the 11th International Workshop on Waldenström's macroglobulinemia (IWWM-11) has reviewed and incorporated current data to update the recommendations for treatment approaches in patients with relapsed or refractory WM (RRWM). The key recommendations from IWWM-11 CP2 include: (1) Chemoimmunotherapy (CIT) and/or a covalent Bruton tyrosine kinase (cBTKi) strategies are important options; their use should reflect the prior upfront strategy and are subject to their availability. (2) In selecting treatment, biological age, co-morbidities and fitness are important; nature of relapse, disease phenotype and WM-related complications, patient preferences and hematopoietic reserve are also critical factors while the composition of the BM disease and mutational status (MYD88, CXCR4, TP53) should also be noted. (3) The trigger for initiating treatment in RRWM should utilize knowledge of patients' prior disease characteristics to avoid unnecessary delays. (4) Risk factors for cBTKi related toxicities (cardiovascular dysfunction, bleeding risk and concurrent medication) should be addressed when choosing cBTKi. Mutational status (MYD88, CXCR4) may influence the cBTKi efficacy, and the role of TP53 disruptions requires further study) in the event of cBTKi failure dose intensity could be up titrated subject to toxicities. Options after BTKi failure include CIT with a non-cross-reactive regimen to one previously used CIT, addition of anti-CD20 antibody to BTKi, switching to a newer cBTKi or non-covalent BTKi, proteasome inhibitors, BCL-2 inhibitors, and new anti-CD20 combinations are additional options. Clinical trial participation should be encouraged for all patients with RRWM.
Assuntos
Antineoplásicos , Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Fator 88 de Diferenciação Mieloide/genética , Consenso , Recidiva Local de Neoplasia/induzido quimicamente , Recidiva Local de Neoplasia/tratamento farmacológico , Antineoplásicos/uso terapêuticoRESUMO
Recent advances in the understanding of Waldenström macroglobulinemia (WM) biology have impacted the development of effective novel agents and improved our knowledge of how the genomic background of WM may influence selection of therapy. Consensus Panel 7 (CP7) of the 11th International Workshop on WM was convened to examine the current generation of completed and ongoing clinical trials involving novel agents, consider updated data on WM genomics, and make recommendations on the design and prioritization of future clinical trials. CP7 considers limited duration and novel-novel agent combinations to be the priority for the next generation of clinical trials. Evaluation of MYD88, CXCR4 and TP53 at baseline in the context of clinical trials is crucial. The common chemoimmunotherapy backbones, bendamustine-rituximab (BR) and dexamethasone, rituximab and cyclophosphamide (DRC), may be considered standard-of-care for the frontline comparative studies. Key unanswered questions include the definition of frailty in WM; the importance of attaining a very good partial response or better (≥VGPR), within stipulated time frame, in determining survival outcomes; and the optimal treatment of WM populations with special needs.
Assuntos
Macroglobulinemia de Waldenstrom , Humanos , Macroglobulinemia de Waldenstrom/tratamento farmacológico , Macroglobulinemia de Waldenstrom/genética , Rituximab/uso terapêutico , Consenso , Ciclofosfamida/uso terapêutico , Cloridrato de Bendamustina/uso terapêuticoRESUMO
BACKGROUND: Several commercial and academic autologous chimeric antigen receptor T-cell (CAR-T) products targeting CD19 have been approved in Europe for relapsed/refractory B-cell acute lymphoblastic leukemia, high-grade B-cell lymphoma and mantle cell lymphoma. Products for other diseases such as multiple myeloma and follicular lymphoma are likely to be approved by the European Medicines Agency in the near future. DESIGN: The European Society for Blood and Marrow Transplantation (EBMT)-Joint Accreditation Committee of ISCT and EBMT (JACIE) and the European Haematology Association collaborated to draft best practice recommendations based on the current literature to support health care professionals in delivering consistent, high-quality care in this rapidly moving field. RESULTS: Thirty-six CAR-T experts (medical, nursing, pharmacy/laboratory) assembled to draft recommendations to cover all aspects of CAR-T patient care and supply chain management, from patient selection to long-term follow-up, post-authorisation safety surveillance and regulatory issues. CONCLUSIONS: We provide practical, clinically relevant recommendations on the use of these high-cost, logistically complex therapies for haematologists/oncologists, nurses and other stakeholders including pharmacists and health sector administrators involved in the delivery of CAR-T in the clinic.
Assuntos
Hematologia , Receptores de Antígenos Quiméricos , Acreditação , Adulto , Medula Óssea , Humanos , Imunoterapia Adotiva , Receptores de Antígenos de Linfócitos TRESUMO
OBJECTIVES: To evaluate the effects of exercise interventions on sleep disturbances and sleep quality in patients with mixed cancer diagnoses, and identify demographic, clinical, and intervention-related moderators of these effects. METHODS: Individual patient data (IPD) and aggregated meta-analyses of randomized controlled trials (RCTs). Using data from the Predicting OptimaL cAncer RehabIlitation and Supportive care project, IPD of 2173 adults (mean ageâ¯=â¯54.8) with cancer from 17 RCTs were analyzed. A complementary systematic search was conducted (until November 2018) to study the overall effects and test the representativeness of analyzed IPD. Effect sizes of exercise effects on self-reported sleep outcomes were calculated for all included RCTs. Linear mixed-effect models were used to evaluate the effects of exercise on post-intervention outcome values, adjusting for baseline values. Moderator effects were studied by testing interactions for demographic, clinical and intervention-related characteristics. RESULTS: For all 27 eligible RCTs from the updated search, exercise interventions significantly decreased sleep disturbances in adults with cancer (gâ¯=â¯-0.09, 95% CI [-0.16; -0.02]). No significant effect was obtained for sleep quality. RCTs included in IPD analyses constituted a representative sample of the published literature. The intervention effects on sleep disturbances were not significantly moderated by any demographic, clinical, or intervention-related factor, nor by sleep disturbances. CONCLUSIONS: This meta-analysis provides some evidence that, compared to control conditions, exercise interventions may improve sleep disturbances, but not sleep quality, in cancer patients, although this effect is of a small magnitude. Among the investigated variables, none was found to significantly moderate the effect of exercise interventions on sleep disturbances.
Assuntos
Exercício Físico , Neoplasias/fisiopatologia , Sono/fisiologia , Adulto , Humanos , Qualidade de Vida , Transtornos do Sono-VigíliaRESUMO
PURPOSE: This qualitative study aimed to identify hematopoietic stem cell transplantation (HSCT) survivors' (1) work perceptions; (2) barriers to and facilitators of return to work (RTW); and (3) possible solutions to improve RTW. METHOD: Fifteen patients treated with HSCT 1-5 years ago participated in face-to-face semi-structured interviews. Interviews were analyzed following the steps of thematic content analyses. RESULTS: RTW was often characterized as a complex and prolonged trajectory, and it was frequently incomplete in working hours, tasks, and/or responsibilities. Work perceptions varied between patients; most valued work as positive, but some also reported a decline in work capacity and/or in importance. Perceived barriers included the duration and side effects of cancer treatment, the presence of comorbidity and poor health before diagnosis, having difficulties commuting and doing household tasks. Perceived facilitators were financial incentives, keeping in touch with the workplace, support of other patients and family, and looking after one's health. Proposed solutions to improve RTW included discussing RTW at the hospital, enhanced employer support, improved accessibility of rehabilitation programs, and more information about the consequences of being sick-listed. CONCLUSIONS: Many HSCT survivors value work as important and they are motivated to RTW. Insight in work perceptions, RTW barriers, and solutions might help researchers, healthcare professionals, and employers to develop and/or tailor individualized multidisciplinary care to facilitate RTW.
Assuntos
Neoplasias Hematológicas/psicologia , Retorno ao Trabalho/psicologia , Transplante de Células-Tronco/métodos , Adulto , Sobreviventes de Câncer/psicologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Motivação , Pesquisa Qualitativa , Local de TrabalhoAssuntos
Oncologia/normas , Recidiva Local de Neoplasia/terapia , Medicina de Precisão/normas , Sociedades Médicas/normas , Macroglobulinemia de Waldenstrom/terapia , Assistência ao Convalescente/métodos , Assistência ao Convalescente/normas , Idade de Início , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Doenças Assintomáticas/terapia , Medula Óssea/patologia , Europa (Continente) , Humanos , Incidência , Oncologia/métodos , Fator 88 de Diferenciação Mieloide/genética , Recidiva Local de Neoplasia/diagnóstico , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Plasmaferese/métodos , Plasmaferese/normas , Medicina de Precisão/métodos , Receptores CXCR4/genética , Transplante de Células-Tronco/métodos , Transplante de Células-Tronco/normas , Sobrevivência , Transplante Autólogo/métodos , Transplante Autólogo/normas , Resultado do Tratamento , Macroglobulinemia de Waldenstrom/diagnóstico , Macroglobulinemia de Waldenstrom/epidemiologia , Macroglobulinemia de Waldenstrom/patologiaRESUMO
The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR)=0.76, 95% confidence interval (95% CI) of 0.65-0.89, P=0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR=0.89, 95% CI: 0.74-1.08, P=0.24). The incidence of SPM were similar between the two arms (7% each, P=0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size ⩾10%) and renal impairment at baseline (serum creatinine >2 mg dl-1) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR=1.02, P=0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.
Assuntos
Bortezomib/administração & dosagem , Mieloma Múltiplo/tratamento farmacológico , Adolescente , Adulto , Idoso , Aberrações Cromossômicas/efeitos dos fármacos , Feminino , Seguimentos , Transplante de Células-Tronco Hematopoéticas/métodos , Humanos , Masculino , Melfalan/uso terapêutico , Pessoa de Meia-Idade , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Prognóstico , Intervalo Livre de Progressão , Talidomida/uso terapêutico , Transplante Autólogo/métodos , Adulto JovemRESUMO
Burkitt lymphoma is an aggressive B cell malignancy accounting for 1-2% of all adult lymphomas. Treatment with dose-intensive, multi-agent chemotherapy is effective but associated with considerable toxicity. In this observational study, we compared real-world efficacy, toxicity, and costs of four frequently employed treatment strategies for Burkitt lymphoma: the Lymphome Malins B (LMB), the Berlin-Frankfurt-Münster (BFM), the HOVON, and the CODOX-M/IVAC regimens. We collected data from 147 adult patients treated in eight referral centers. Following central pathology assessment, 105 of these cases were accepted as Burkitt lymphoma, resulting in the following treatment groups: LMB 36 patients, BFM 19 patients, HOVON 29 patients, and CODOX-M/IVAC 21 patients (median age 39 years, range 14-74; mean duration of follow-up 47 months). There was no significant difference between age, sex ratio, disease stage, or percentage HIV-positive patients between the treatment groups. Five-year progression-free survival (69%, p = 0.966) and 5-year overall survival (69%, p = 0.981) were comparable for all treatment groups. Treatment-related toxicity was also comparable with only hepatotoxicity seen more frequently in the CODOX/M-IVAC group (p = 0.004). Costs were determined by the number of rituximab gifts and the number of inpatients days. Overall, CODOX-M/IVAC had the most beneficial profile with regards to costs, treatment duration, and percentage of patients completing planned treatment. We conclude that the four treatment protocols for Burkitt lymphoma yield nearly identical results with regards to efficacy and safety but differ in treatment duration and costs. These differences may help guide future choice of treatment.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Linfoma de Burkitt/tratamento farmacológico , Análise Custo-Benefício , Infecções por HIV/tratamento farmacológico , Adolescente , Adulto , Idoso , Linfoma de Burkitt/complicações , Linfoma de Burkitt/economia , Linfoma de Burkitt/mortalidade , Carmustina/economia , Carmustina/uso terapêutico , Ciclofosfamida/economia , Ciclofosfamida/uso terapêutico , Citarabina/economia , Citarabina/uso terapêutico , Etoposídeo/economia , Etoposídeo/uso terapêutico , Feminino , Infecções por HIV/complicações , Infecções por HIV/economia , Infecções por HIV/mortalidade , Humanos , Ifosfamida/economia , Ifosfamida/uso terapêutico , Masculino , Melfalan/economia , Melfalan/uso terapêutico , Metotrexato/economia , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Retrospectivos , Rituximab/economia , Rituximab/uso terapêutico , Análise de SobrevidaRESUMO
This paper describes the process evaluation of an 18-week supervised exercise programme in 50 patients treated with high-dose chemotherapy followed by autologous stem cell transplantation. The intervention included 30 exercise sessions with six resistance exercises and interval training. We evaluated the context, dose delivered and received, and patients' and physiotherapists' satisfaction with the intervention. Ninety-two per cent of the patients trained within 15 km of their home address, with an average session attendance of 86%. Most patients trained at the prescribed intensity for four of the six resistance exercises, but the dose delivered and received of the two remaining resistance exercises and interval training could not be determined. Both patients and physiotherapists highly appreciated the programme (score of 8.3 and 7.9 out of 10 respectively). This process evaluation provided valuable lessons for future trials: (1) It is possible to deliver supervised exercise training to this patient group in local physiotherapy practices; (2) to determine dose received all intervention components should be standardised; and (3) to optimise data collection, all study materials should be tested more extensively prior to the start of the intervention.
Assuntos
Antineoplásicos/administração & dosagem , Terapia por Exercício/métodos , Linfoma não Hodgkin/reabilitação , Mieloma Múltiplo/reabilitação , Avaliação de Processos em Cuidados de Saúde , Transplante de Células-Tronco , Adulto , Idoso , Exercício Físico , Feminino , Treinamento Intervalado de Alta Intensidade/métodos , Humanos , Linfoma não Hodgkin/terapia , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/terapia , Avaliação de Resultados em Cuidados de Saúde , Satisfação do Paciente , Fisioterapeutas , Treinamento Resistido/métodos , Transplante Autólogo , Adulto JovemRESUMO
Allogeneic stem cell transplantation (allo-SCT) with or without donor lymphocyte infusions (DLI) is the only curative option for several hematological malignancies. Unfortunately, allo-SCT is often associated with GvHD, and patients often relapse. We therefore aim to improve the graft-versus-tumor effect, without increasing the risk of GvHD, by targeting hematopoietic lineage-restricted and tumor-associated minor histocompatibility antigens using peptide-loaded dendritic cell (DC) vaccinations. In the present multicenter study, we report the feasibility, safety and efficacy of this concept. We treated nine multiple myeloma patients with persistent or relapsed disease after allo-SCT and a previous DLI, with donor monocyte-derived mHag-peptide-loaded DC vaccinations combined with a second DLI. Vaccinations were well tolerated and no occurrence of GvHD was observed. In five out of nine patients, we were able to show the induction of mHag-specific CD8+ T cells in peripheral blood. Five out of nine patients, of which four developed mHag-specific T cells, showed stable disease (SD) for 3.5-10 months. This study shows that mHag-based donor monocyte-derived DC vaccination combined with DLI is safe, feasible and capable of inducing objective mHag-specific T-cell responses. Future research should focus on further improvement of the vaccination strategy, toward translating the observed T-cell responses into robust clinical responses.
Assuntos
Antígenos de Neoplasias/imunologia , Doadores de Sangue , Células Dendríticas , Antígenos HLA/imunologia , Imunidade Celular , Transfusão de Linfócitos , Mieloma Múltiplo , Transplante de Células-Tronco , Vacinação , Adulto , Idoso , Aloenxertos , Células Dendríticas/imunologia , Células Dendríticas/transplante , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Mieloma Múltiplo/mortalidade , Mieloma Múltiplo/patologia , Mieloma Múltiplo/terapia , Peptídeos/imunologiaRESUMO
Deletion or mutation of the gene encoding the deubiquitinating enzyme CYLD is a common genomic aberration in multiple myeloma (MM). However, the functional consequence of CYLD loss and the mechanism underlying its putative role as a tumor suppressor gene in the pathogenesis of MM has not been established. Here, we show that CYLD expression is highly variable in myeloma cell lines and primary MMs and that low CYLD expression is associated with disease progression from monoclonal gammopathy of undetermined significance to MM, and with poor overall and progression free-survival of MM patients. Functional assays revealed that CYLD represses MM cell proliferation and survival. Furthermore, CYLD acts as a negative regulator of NF-κB and Wnt/ß-catenin signaling and loss of CYLD sensitizes MM cells to NF-κB-stimuli and Wnt ligands. Interestingly, in primary MMs, low CYLD expression strongly correlated with a proliferative and Wnt signaling-gene expression signature, but not with an NFκB target gene signature. Altogether, our findings identify CYLD as a negative regulator of NF-κB and Wnt/ß-catenin signaling in MM and indicate that loss of CYLD enhances MM aggressiveness through Wnt pathway activation. Thus, targeting the Wnt pathway could be a promising therapeutic strategy in MM with loss of CYLD activity.
Assuntos
Mieloma Múltiplo/metabolismo , Mieloma Múltiplo/patologia , Proteínas Supressoras de Tumor/deficiência , Via de Sinalização Wnt , Estudos de Casos e Controles , Enzima Desubiquitinante CYLD , Humanos , Mieloma Múltiplo/genética , NF-kappa B/metabolismo , Transfecção , Proteínas Supressoras de Tumor/genética , Proteínas Supressoras de Tumor/metabolismoRESUMO
CAR T-cells are autologous T-cells transduced with a chimeric antigen receptor (CAR). The CAR contains an antigen recognition part (originating from an antibody), a T-cell receptor transmembrane and cytoplasmic signalling part, and one or more co-stimulatory domains. While CAR T-cells can be directed against any tumour target, most experience thus far has been obtained with targeting of the B-cell antigen CD19 that is expressed by B-cell acute lymphocytic leukaemia, chronic lymphocytic leukaemia and other B-cell lymphomas. The first clinical results are promising, although there are profound differences in response between patients with different haematological malignancies. Treatment-related side effects have been observed that require specific management. This review will explain the mechanism of action, summarise the experience to date and point out future directions for this hopeful new addition to the therapeutic armamentarium in the treatment of lymphoproliferative B-cell malignancies.
Assuntos
Transtornos Linfoproliferativos/terapia , Receptores de Antígenos de Linfócitos T/uso terapêutico , Linfócitos B , Ensaios Clínicos como Assunto , Humanos , Receptores de Antígenos de Linfócitos T/administração & dosagem , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos TRESUMO
The phosphoinositide 3-kinases (PI3Ks) are critical components of the B-cell receptor (BCR) pathway and have an important role in the pathobiology of chronic lymphocytic leukemia (CLL). Inhibitors of PI3Kδ block BCR-mediated cross-talk between CLL cells and the lymph node microenvironment and provide significant clinical benefit to CLL patients. However, the PI3Kδ inhibitors applied thus far have limited direct impact on leukemia cell survival and thus are unlikely to eradicate the disease. The use of inhibitors of multiple isoforms of PI3K might lead to deeper remissions. Here we demonstrate that the pan-PI3K/mammalian target of rapamycin inhibitor SAR245409 (voxtalisib/XL765) was more pro-apoptotic to CLL cells--irrespective of their ATM/p53 status--than PI3Kα or PI3Kδ isoform selective inhibitors. Furthermore, SAR245409 blocked CLL survival, adhesion and proliferation. Moreover, SAR245409 was a more potent inhibitor of T-cell-mediated production of cytokines, which support CLL survival. Taken together, our in vitro data provide a rationale for the evaluation of a pan-PI3K inhibitor in CLL patients.