Entinostat,a novel histone deacetylase inhibitor is active in B‐cell lymphoma and enhances the anti‐tumour activity of rituximab and chemotherapy agents

Histone deacetylases (HDACs) inhibitors are active in T‐cell lymphoma and are undergoing pre‐clinical and clinical testing in other neoplasms. Entinostat is an orally bioavailable class I HDAC inhibitor with a long half‐life, which is under evaluation in haematological and solid tumour malignancies. To define the activity and biological effects of entinostat in B‐cell lymphoma we studied its anti‐tumour activity in several rituximab‐sensitive or ‐resistant pre‐clinical models. We demonstrated that entinostat is active in rituximab‐sensitive cell lines (RSCL), rituximab‐resistant cell lines (RRCL) and primary tumour cells isolated from lymphoma patients (n = 36). Entinostat exposure decreased Bcl‐XL (BCL2L1) levels and induced apoptosis in cells. In RSCL and RRCL, entinostat induced p21 (CDKN1A) expression leading to G1 cell cycle arrest and exhibited additive effects when combined with bortezomib or cytarabine. Caspase inhibition diminished entinostat activity in some primary tumour cells suggesting that entinostat has dual mechanisms‐of‐action. In addition, entinostat increased the expression of CD20 and adhesion molecules. Perhaps related to these effects, we observed a synergistic activity between entinostat and rituximab in a lymphoma‐bearing severe combined immunodeficiency (SCID) mouse model. Our data suggests that entinostat is an active HDAC inhibitor that potentiates rituximab activity in vivo and supports its further clinical development in B‐cell lymphoma.     

Ofatumumab demonstrates activity against rituximab-sensitive and -resistant cell lines, lymphoma xenografts and primary tumour cells from patients with B-cell lymphoma

Ofatumumab is a new monoclonal antibody (mAb) targeting a novel membrane‐proximal epitope on CD20. To better define ofatumumab’s activity, we conducted pre‐clinical studies in rituximab‐sensitive cell lines (RSCL), rituximab‐resistant cell lines (RRCL), ofatumumab‐exposed cell lines (OECLs), primary lymphoma cells, and a lymphoma xenograft model. RRCL and OECL were generated by repeated exposure of sensitive cells to escalating doses of rituximab or ofatumumab ± human serum. Antibody‐dependent cellular cytotoxicity (ADCC) and complement‐mediated cytotoxicity (CMC) assays were performed to assess cellular sensitivity to rituximab or ofatumumab. Ofatumumab elicited a higher rate of CMC in RSCL, RRCL and primary tumour cells. The chronic exposure of lymphoma cells to ofatumumab resulted in rituximab resistance but less ofatumumab resistance. In an in vivo severe combined immunodeficiency mouse model of human lymphoma, ofatumumab prolonged median survival compared to rituximab. While rituximab CMC diminished with CD20 down‐regulation in RRCL passages, ofatumumab activity in vitro diminished to a lesser degree. Our data suggest that ofatumumab is more potent than rituximab in rituximab‐sensitive or rituximab‐resistant models and has the potential to decrease the development of biological resistance in patients with repeated exposure to anti‐CD20 mAbs.     

Distinct cellular and therapeutic effects of obatoclax in rituximab-sensitive and -resistant lymphomas

Bcl-2 proteins represent a rheostat that controls cellular viability. Obatoclax, a BH3-mimetic, has been designed to specifically target and counteract anti-apoptotic Bcl-2 proteins. We evaluated the biological effects of obatoclax on the anti-tumour activity of rituximab and chemotherapy agents. Obatoclax induced cell death of rituximab/chemotherapy-sensitive (RSCL), -resistant cell lines (RRCL) and primary tumour-cells derived from patients with B-cell lymphomas (N=39). Obatoclax also enhanced the activity of rituximab and had synergistic activity when combined with chemotherapy agents. The ability of Obatoclax to induce PARP cleavage varied between patient samples and was not observed in some RRCL. Inhibition of caspase activity did not affect obatoclax activity, suggesting the existence of caspase-independent death pathways. Autophagy was detected by LC3 conversion and/or electron microscopy in RRCL and in patient-derived tumour cells. Moreover, obatoclax activity was inhibited by Beclin-1 knockdown. In summary, obatoclax is an active Bcl-2 inhibitor that potentiates the activity of chemotherapy agents and, to a lesser degree, rituximab. Defining the molecular events triggered by obatoclax is necessary to further its clinical development and identify potential biomarkers that are predictive of response.     

Melatonin inhibits cell proliferation and induces caspase activation and apoptosis in human malignant lymphoid cell lines

Abstract: Melatonin exerts strong anti‐tumour activity via several mechanisms, including anti‐proliferative and pro‐apoptotic effects in addition to its potent antioxidant activity. Several studies have investigated the effects of melatonin on haematological malignancies. However, the previous studies investigating lymphoid malignancies have been largely restricted to a single type of malignancy, Burkitt’s lymphoma (BL). Thus, we examined the actions of melatonin on the growth and apoptosis in a small panel of cell lines representing different human lymphoid malignancies including Ramos (Epstein–Barr virus–negative BL), SU‐DHL‐4 (diffuse large B cell lymphoma), DoHH2 (follicular B non‐Hodgkin lymphoma) and JURKAT (acute T cell leukaemia). We showed that melatonin promotes cell cycle arrest and apoptosis in all these cells, although there was marked variations in responses among different cell lines (sensitivity; Ramos/DoHH2 > SU‐DHL‐4 > JURKAT). Melatonin‐induced apoptosis was relatively rapid, with increased caspase 3 and PARP cleavage detected within 0.5–1 h following melatonin addition. Moreover, there was evidence for rapid processing of both caspase 9, as well as a breakdown of the mitochondrial inner transmembrane potential. On the contrary, caspase activation was detected only in SU‐DHL‐4 and Ramos cells following melatonin treatment suggesting that the extrinsic pathway does not make a consistent contribution to melatonin‐induced apoptosis in malignant lymphocytes. Although all cell lines expressed the high‐affinity melatonin receptors, MT1 and MT2, melatonin‐induced caspase activation appeared to be independent these receptors. Our findings confirm that melatonin could be a potential chemotherapeutic/preventive agent for malignant lymphocytes. However, it is necessary to take into account that different lymphoid malignancies may differ in their response to melatonin.     

Synergistic anti‐myeloma activity of the proteasome inhibitor marizomib and the IMiD® immunomodulatory drug pomalidomide

The proteasome inhibitor bortezomib is an effective therapy for the treatment of relapsed and refractory multiple myeloma (RRMM); however, prolonged treatment can be associated with toxicity, peripheral neuropathy and drug resistance. Our earlier studies showed that the novel proteasome inhibitor marizomib is distinct from bortezomib in its chemical structure, mechanisms of action and effects on proteasomal activities, and that it can overcome bortezomib resistance. Pomalidomide, like lenalidomide, has potent immunomodulatory activity and has been approved by the US Food and Drug Administration for the treatment of RRMM. Here, we demonstrate that combining low concentrations of marizomib with pomalidomide induces synergistic anti‐MM activity. Marizomib plus pomalidomide‐induced apoptosis is associated with: (i) activation of caspase‐8, caspase‐9, caspase‐3 and PARP cleavage, (ii) downregulation of cereblon (CRBN), IRF4, MYC and MCL1, and (iii) suppression of chymotrypsin‐like, caspase‐like, and trypsin‐like proteasome activities. CRBN‐siRNA attenuates marizomib plus pomalidomide‐induced MM cells death. Furthermore, marizomib plus pomalidomide inhibits the migration of MM cells and tumour‐associated angiogenesis, as well as overcomes cytoprotective effects of bone marrow microenvironment. In human MM xenograft model studies, the combination of marizomib and pomalidomide is well tolerated, inhibits tumour growth and prolongs survival. These preclinical studies provide the rationale for on‐going clinical trials of combined marizomib and pomalidomide to improve outcome in patients with RRMM.     

Ricolinostat (ACY‐1215) induced inhibition of aggresome formation accelerates carfilzomib‐induced multiple myeloma cell death

Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome‐proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti‐MM effects, even in bortezomib‐resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addition of ACY‐1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ‐induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.     

Combination of SAHA and bortezomib up‐regulates CDKN2A and CDKN1A and induces apoptosis of Epstein‐Barr virus‐positive Wp‐restricted Burkitt lymphoma and lymphoblastoid cell lines

Epstein‐Barr virus (EBV) latent proteins exert anti‐apoptotic effects on EBV‐transformed lymphoid cells by down‐regulating BCL2L11 (BIM), CDKN2A (p16^INK4A) and CDKN1A (p21^WAF1). However, the potential therapeutic effects of targeting these anti‐apoptotic mechanisms remain unexplored. Here, we tested both in vitro and in vivo effects of the combination of histone deacetylase (HDAC) and proteasome inhibitors on the apoptosis of six endemic Burkitt lymphoma (BL) lines of different latency patterns (types I and III and Wp‐restricted) and three lymphoblastoid cell lines (LCLs). We found that the combination of HDAC and proteasome inhibitors (e.g. SAHA/bortezomib) synergistically induced the killing of Wp‐restricted and latency III BL and LCLs but not latency I BL cells. The synergistic killing was due to apoptosis, as evidenced by the high percentage of annexin V positivity and strong cleavage of PARP1 (PARP) and CASP3 (caspase‐3). Concomitantly, SAHA/bortezomib up‐regulated the expression of CDKN2A and CDKN1A but did not affect the level of BCL2L11 or BHRF1 (viral homologue of BCL2). The apoptotic effects were dependent on reactive oxygen species generation. Furthermore, SAHA/bortezomib suppressed the growth of Wp‐restricted BL xenografts in nude mice. This study provides the rationale to test the novel application of SAHA/bortezomib on the treatment of EBV‐associated Wp‐restricted BL and post‐transplant lymphoproliferative disorder.     

The novel atypical retinoid ST5589 down‐regulates Aurora Kinase A and has anti‐tumour activity in lymphoma pre‐clinical models

Despite the marked improvements in the treatment of lymphomas, there is still a need for new therapeutic agents. Synthetic retinoids represent a class of compounds with anti‐cancer activity. Here, we report the preclinical activity of a new member of this class, the ST1926‐derivative ST5589, in lymphomas. ST5589 presented a dose‐dependent anti‐proliferative activity in almost all of the 25 lymphoma cell lines analysed, with a median 50% inhibitory concentration of 433 nM. Apoptosis was observed in 8/11 cell lines. ST5589 induced changes in the gene expression profiles of the cell lines, including the down‐regulation of Aurora Kinase A (AURKA). Specific gene expression signatures were associated with a higher sensitivity to the compound and combination of ST5589 with carfilzomib revealed the importance of proteasome activity in mediating the anti‐tumour activity of ST5589. In conclusion, we have identified a new mechanism of action of atypical retinoids as anti‐cancer compounds, and the encouraging results obtained with the new ST1926‐derivative ST5589 provide the basis for further developments of the compound.     

Blockade of the MEK/ERK signalling cascade by AS703026, a novel selective MEK1/2 inhibitor,induces pleiotropic anti‐myeloma activity in vitro and in vivo

This study investigated the cytotoxicity and mechanism of action of AS703026, a novel, selective, orally bioavailable MEK1/2 inhibitor, in human multiple myeloma (MM). AS703026 inhibited growth and survival of MM cells and cytokine‐induced osteoclast differentiation more potently (9‐ to 10‐fold) than AZD6244. Inhibition of proliferation induced by AS703026 was mediated by G₀‐G₁ cell cycle arrest and was accompanied by reduction of MAF oncogene expression. AS703026 further induced apoptosis via caspase 3 and Poly ADP ribose polymerase (PARP) cleavage in MM cells, both in the presence or absence of bone marrow stromal cells (BMSCs). Importantly, AS703026 sensitized MM cells to a broad spectrum of conventional (dexamethasone, melphalan), novel or emerging (lenalidomide, perifosine, bortezomib, rapamycin) anti‐MM therapies. Significant tumour growth reduction in AS703026‐ vs. vehicle‐treated mice bearing H929 MM xenograft tumours correlated with downregulated pERK1/2, induced PARP cleavage, and decreased microvessels in vivo. Moreover, AS703026 (<200 nmol/l) was cytotoxic against the majority of tumour cells tested from patients with relapsed and refractory MM (84%), regardless of mutational status of RAS and BRAF genes. Importantly, BMSC‐induced viability of MM patient cells was similarly blocked within the same dose range. Our results therefore support clinical evaluation of AS703026, alone or in combination with other anti‐MM agents, to improve patient outcome.     

Characterization of ibrutinib‐sensitive and ‐resistant mantle lymphoma cells

Ibrutinib inhibits Bruton tyrosine kinase (BTK), a key component of early B‐cell receptor (BCR) signalling pathways. A multicentre phase 2 trial of ibrutinib in patients with relapsed/refractory mantle cell lymphoma (MCL) demonstrated a remarkable response rate. However, approximately one‐third of patients have primary resistance to the drug while other patients appear to lose response and develop secondary resistance. Understanding the molecular mechanisms underlying ibrutinib sensitivity is of paramount importance. In this study, we investigated cell lines and primary MCL cells that display differential sensitivity to ibrutinib. We found that the primary cells display a higher BTK activity than normal B cells and MCL cells show differential sensitivity to BTK inhibition. Genetic knockdown of BTK inhibits the growth, survival and proliferation of ibrutinib‐sensitive but not resistant MCL cell lines, suggesting that ibrutinib acts through BTK to produce its anti‐tumour activities. Interestingly, inhibition of ERK1/2 and AKT, but not BTK phosphorylation per se, correlates well with cellular response to BTK inhibition in cell lines as well as in primary tumours. Our study suggests that, to prevent primary resistance or to overcome secondary resistance to BTK inhibition, a combinatory strategy that targets multiple components or multiple pathways may represent the most effective approach.     

Targeting of B‐cell receptor signalling in B‐cell malignancies

Pharmacological agents that inhibit enzymes of the B‐cell receptor (BCR) pathway are of increasing importance in the treatment of B‐cell malignancies. These include inhibitors of Bruton tyrosine kinase (BTK), phosphatidylinositol 3‐kinase (PI3K), splenic tyrosine kinase and protein kinase Cβ. Two agents are already approved in the USA and Europe: ibrutinib, a BTK inhibitor, for the treatment of chronic lymphatic leukaemia (CLL), mantle cell lymphoma (MCL) and Waldenström's macroglobulinemia; and idelalisib, a PI3Kδ inhibitor, for the treatment of CLL and follicular lymphoma. In addition, the role of these drugs in diffuse large B‐cell lymphoma and marginal zone lymphoma is under investigation, as single agents and in combination with chemotherapy. In CLL, both ibrutinib and idelalisib have an established role as first‐line therapy in patients with del(17p), and in MCL, ibrutinib is a standard option for patients relapsing after chemoimmunotherapy. Unexpected toxicities have been encountered when combining these potent new agents with other drugs, including chemotherapy and lenalidomide, and based on this experience the risks and benefits of novel combinations must be evaluated carefully. In this review, we summarize the efficacy and safety results with these inhibitors and discuss novel combinations that are under study and the future role of BCR inhibitors in these disorders.     

Immune checkpoint blockade immunotherapy to activate anti‐tumour T‐cell immunity

The tumour microenvironment plays a dual role in cancer: it can promote tumour progression by establishing pro‐tumour survival conditions but can also suppress tumour progression by killing cancer cells or inhibiting their outgrowth. These dynamically interconnected processes are under intense investigation to better understand cancer pathophysiology and allow identification of new therapeutic approaches. The ability of cancer cells to evade anti‐tumour T‐cell activity in the microenvironment has recently been accepted as a hallmark of cancer progression. This review will highlight the most promising therapeutic approach aimed at activating anti‐tumour T‐cell immunity in the cancer microenvironment: blocking inhibitory immune regulatory proteins (immune checkpoint ligands and receptors). There is emerging evidence that haematological tumours co‐opt immune checkpoints as a major immune resistance mechanism. Pre‐clinical findings indicate that targeted therapies and blockade of immune checkpoints could be combined to promote therapeutic synergy and long‐term anti‐tumour immunity to improve clinical outcomes for cancer patients.     

Anti‐leukaemic activity of the TYK2 selective inhibitor NDI‐031301 in T‐cell acute lymphoblastic leukaemia

Activation of tyrosine kinase 2 (TYK2) contributes to the aberrant survival of T‐cell acute lymphoblastic leukaemia (T‐ALL) cells. Here we demonstrate the anti‐leukaemic activity of a novel TYK2 inhibitor, NDI‐031301. NDI‐031301 is a potent and selective inhibitor of TYK2 that induced robust growth inhibition of human T‐ALL cell lines. NDI‐031301 treatment of human T‐ALL cell lines resulted in induction of apoptosis that was not observed with the JAK inhibitors tofacitinib and baricitinib. Further investigation revealed that NDI‐031301 treatment uniquely leads to activation of three mitogen‐activated protein kinases (MAPKs), resulting in phosphorylation of ERK, SAPK/JNK and p38 MAPK coincident with PARP cleavage. Activation of p38 MAPK occurred within 1 h of NDI‐031301 treatment and was responsible for NDI‐031301‐induced T‐ALL cell death, as pharmacological inhibition of p38 MAPK partially rescued apoptosis induced by TYK2 inhibitor. Finally, daily oral administration of NDI‐031301 at 100 mg/kg bid to immunodeficient mice engrafted with KOPT‐K1 T‐ALL cells was well tolerated, and led to decreased tumour burden and a significant survival benefit. These results support selective inhibition of TYK2 as a promising potential therapeutic strategy for T‐ALL.     

A phase 1/2 trial of ublituximab,a novel anti‐CD20 monoclonal antibody,in patients with B‐cell non‐Hodgkin lymphoma or chronic lymphocytic leukaemia previously exposed to rituximab

This phase 1/2 study evaluated the safety, pharmacokinetic behavior and anti‐tumour activity of ublituximab, a unique type I, chimeric, glycoengineered anti‐CD 20 monoclonal antibody, in rituximab‐relapsed or ‐refractory patients with B‐cell non‐Hodgkin lymphoma (B‐NHL ) or chronic lymphocytic leukaemia (CLL ). Induction therapy (doses of 450–1200 mg) consisted of 4 weekly infusions in cycle 1 for NHL and 3 weekly infusions in cycles 1 and 2 for CLL . Patients received ublituximab maintenance monthly during cycles 3–5, then once every 3 months for up to 2 years. Enrolled patients with B‐NHL (n  = 27) and CLL (n  = 8) had a median of 3 prior therapies. No dose‐limiting toxicities or unexpected adverse events (AE s) occurred. The most common AE s were infusion‐related reactions (40%; grade 3/4, 0%); fatigue (37%; grade 3/4, 3%); pyrexia (29%; grade 3/4, 0%); and diarrhoea (26%; grade 3/4, 0%). Common haematological AE s were neutropenia (14%; grade 3/4, 14%) and anaemia (11%; grade 3/4, 6%). The overall response rate for evaluable patients (n  = 31) was 45% (13% complete responses, 32% partial responses). Median duration of response and progression‐free survival were 9·2 months and 7·7 months, respectively. Ublituximab was well‐tolerated and efficacious in a heterogeneous and highly rituximab‐pre‐treated patient population.     

Immunotherapy with the trifunctional anti‐CD20 x anti‐CD3 antibody FBTA05 (Lymphomun) in paediatric high‐risk patients with recurrent CD20‐positive B cell malignancies

Children with B cell malignancies refractory to standard therapy are known to have a poor prognosis and very limited treatment options. Here, we report on the treatment and follow‐up of ten patients diagnosed with relapsed or refractory mature B‐cell Non Hodgkin Lymphoma (B‐NHL), Burkitt leukaemia (B‐AL) or pre B‐acute lymphoblastic leukaemia (pre B‐ALL). All children were treated with FBTA05 (now designated Lymphomun), an anti‐CD3 x anti‐CD20 trifunctional bispecific antibody (trAb) in compassionate use. Within individual treatment schedules, Lymphomun was applied (a) after allogeneic stem cell transplantation (allo‐SCT, n = 6) to induce sustained long‐term remission, or (b) stand alone prior to subsequent chemotherapy to eradicate residual disease before allo‐SCT (n = 4). Nine of ten children displayed a clinical response: three stable diseases (SD), one partial remission (PR) and five induced or sustained complete remissions (CR). Five of these nine responders died during follow‐up. The other patients still maintain CR with a current overall survival of 874–1424 days (median: 1150 days). In conclusion, despite the dismal clinical prognosis of children refractory to standard therapy, immunotherapy with Lymphomun resulted in a favourable clinical outcome in this cohort of refractory paediatric patients.     

Recent advances in antibody‐based therapies for Hodgkin Lymphoma

Although a poster child for the development and refinement of multi‐modal multi‐agent therapeutic strategies, Hodgkin Lymphoma has, until recently, lagged behind other lymphomas in terms of the use of therapeutic monoclonal antibodies. This situation has now changed dramatically, with the rapid emergence both of a toxin‐conjugated tumour‐selective anti‐CD30 antibody, and of antibodies targeting immunological checkpoints, most notably PD‐1 (also termed PDCD1). The former provides an efficient targeting vehicle for delivery of a potent synthetic anti‐mitotic drug, with ultimate efficacy independent of immunological activity. The latter are members of a class of drugs representing a new paradigm in immune‐oncological therapies that are designed to enhance pre‐existent anti‐tumour T cell activities. The role of both in the overall treatment pathway will continue to evolve over coming years. Hodgkin Lymphoma has once again become emblematic of the major trend shifts in cancer therapy.     

Preclinical evaluation of the BET bromodomain inhibitor BAY 1238097 for the treatment of lymphoma

The epigenome is often deregulated in cancer and treatment with inhibitors of bromodomain and extra‐terminal proteins, the readers of epigenetic acetylation marks, represents a novel therapeutic approach. Here, we have characterized the anti‐tumour activity of the novel bromodomain and extra‐terminal (BET) inhibitor BAY 1238097 in preclinical lymphoma models. BAY 1238097 showed anti‐proliferative activity in a large panel of lymphoma‐derived cell lines, with a median 50% inhibitory concentration between 70 and 208 nmol/l. The compound showed strong anti‐tumour efficacy in vivo as a single agent in two diffuse large B cell lymphoma models. Gene expression profiling showed BAY 1238097 targeted the NFKB/TLR/JAK/STAT signalling pathways, MYC and E2F1‐regulated genes, cell cycle regulation and chromatin structure. The gene expression profiling signatures also highly overlapped with the signatures obtained with other BET Bromodomain inhibitors and partially overlapped with HDAC‐inhibitors, mTOR inhibitors and demethylating agents. Notably, BAY 1238097 presented in vitro synergism with EZH2, mTOR and BTK inhibitors. In conclusion, the BET inhibitor BAY 1238097 presented promising anti‐lymphoma preclinical activity in vitro and in vivo, mediated by the interference with biological processes driving the lymphoma cells. Our data also indicate the use of combination schemes targeting EZH2, mTOR and BTK alongside BET bromodomains.     

Targeting anti‐apoptotic BCL2 family proteins in haematological malignancies – from pathogenesis to treatment

The B‐cell lymphoma 2 (BCL 2) family of proteins comprise key regulators of apoptosis and are implicated in the pathogenesis of many malignancies, including lymphomas and leukaemias. Targeting of BCL 2 proteins can be directly toxic to tumour cells or render them more sensitive to chemotherapy. Inhibition of the anti‐apoptotic functions of BCL 2 proteins using structure‐based design to produce specific inhibitors of protein–protein interactions has been achieved for BCL 2, MCL 1 and BCL ‐X_L (also termed BCL 2L1), providing an armamentarium of new targeted therapies called BH 3‐mimetics. The first BCL 2‐specific inhibitor, venetoclax, has shown extraordinary single agent activity in chronic lymphocytic leukaemia (CLL ), with surprisingly little toxicity given the expression of BCL 2 in normal tissues. Despite success in CLL , where sensitivity to BCL 2 inhibition is seen in nearly all cases, key questions have not yet been addressed. For example, responses to venetoclax in other B‐cell and myeloid malignancies are heterogeneous, highlighting the need to identify biomarkers that correlate with response and, secondly, to identify/develop other specific compounds that synergise with BCL 2 inhibition. In this review, we summarise the biology of BCL 2 proteins, the mechanism of action of BH 3‐mimetics and the status of their clinical development in haematological malignancies.     

A multicentre phase II study of vorinostat in patients with relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Although initial rituximab‐containing chemotherapies achieve high response rates, indolent B‐cell non‐Hodgkin lymphoma (B‐NHL), such as follicular lymphoma (FL), is still incurable. Therefore, new effective agents with novel mechanisms are anticipated. In this multicentre phase II study, patients with relapsed/refractory indolent B‐NHL and mantle cell lymphoma (MCL) received vorinostat 200 mg twice daily for 14 consecutive days in a 21‐d cycle until disease progression or unacceptable toxicity occurred. The primary endpoint was overall response rate (ORR) in FL patients and safety and tolerability in all patients. Secondary endpoints included progression‐free survival (PFS). Fifty‐six eligible patients were enrolled; 50 patients (39 with FL, seven with other B‐NHL, and four with MCL) were evaluable for ORR, and 40 patients had received rituximab‐containing prior chemotherapeutic regimens. For the 39 patients with FL, the ORR was 49% [95% confidence interval (CI): 32·4, 65·2] and the median PFS was 20 months (95% CI: 11·2, 29·7). Major toxicities were manageable grade 3/4 thrombocytopenia and neutropenia. Vorinostat offers sustained antitumour activity in patients with relapsed or refractory FL with an acceptable safety profile. Further investigation of vorinostat for clinical efficacy is warranted.