Treatment strategies for relapsed and refractory aggressive non-Hodgkin's lymphoma

The aggressive non-Hodgkin's lymphomas (NHL) are a clinically heterogeneous group of lymphomas with disparate responses to standard chemotherapy regimens. Aggressive NHL includes diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL) and peripheral T-cell lymphomas (PTCL), among others. Significant advances have been made in the last decade in the initial treatment of DLBCL and MCL, but the treatment of relapsed or refractory disease remains difficult. The addition of rituximab to the treatment of DLBCL and MCL has improved clinical outcomes and is now a critical component of initial therapy and treatment of relapsed disease. The PTCLs, not having a similar agent to significantly change the treatment approach to these diseases, remain a difficult therapeutic problem. This review examines recent advances in the treatment of relapsed or refractory aggressive NHL and discusses novel approaches currently under investigation.     

Lenalidomide for the treatment of mantle cell lymphoma

Introduction: Although a variety of therapeutic schemes for Mantle Cell Lymphoma (MCL) have been attempted, the clinical outcome of patients continues to be unsatisfactory especially among patients with a very high-risk profile and in the relapsed/refractory setting. For this reason, recent clinical trials have explored novel approaches, either by the use of biological agents in chemotherapy-free schedules or by integrating them with chemoimmunotherapy regimens.

Areas covered: The efficacy of lenalidomide monotherapy and combination therapy established in clinical studies mainly involving relapsed/refractory MCL is reviewed. The mechanism of action of lenalidomide is also discussed. Furthermore, the current position of lenalidomide in the MCL treatment algorithm is debated.

Expert opinion: Lenalidomide demonstrated high efficacy and tolerability in several clinical trials as well as in retrospective real-world reports, even in patients who relapsed or were resistant to bortezomib and ibrutinib. In 2013, lenalidomide was approved by the Food and Drug Administration (FDA) for relapsed/refractory MCL after two prior therapies including at least one prior treatment with bortezomib. However, the potential synergistic anti-neoplastic effects of lenalidomide in combination with other biological agents, i.e. ibrutinib and venetoclax, especially in the management of p53-mutated cases, still remain an open issue.     

Lenalidomide in multiple myeloma: current role and future directions

Importance of the field: Lenalidomide and other new agents are improving survival of multiple myeloma patients. This review describes current data on lenalidomide in myeloma and how the unique properties of lenalidomide may lend its use in new settings, such as maintenance and preventive therapy.

Areas covered in this review: This review covers the activity of lenalidomide in multiple myeloma, efficacy in both newly diagnosed and relapsed/refractory patients, how to manage effectively common adverse events observed with lenalidomide, and its potential use in new settings based on clinical trials published up to 2009.

What the reader will gain: This review describes the mechanism of action of lenalidomide in myeloma which provides the basis for its clinical use in newly diagnosed, relapsed/refractory, and high-risk smoldering myeloma in combination with other agents. Strategies to reduce or effectively manage myelosuppression and thromboembolic events, the main adverse events associated with lenalidomide plus dexamethasone therapy, are also described.

Take home message: Lenalidomide is an oral immunomodulatory drug that is highly effective in treating multiple myeloma, has a favorable safety profile and is now being evaluated as maintenance therapy, preventive therapy and in combination with other new agents.     

Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignancies

Introduction: The B-cell receptor (BCR) is critical for the development and persistence of B-cell non-Hodgkin lymphoma (B-NHL). Protein kinase C-beta (PKC-β) has been identified as one of the key signaling hubs downstream of the BCR and constitutes a valuable target in B-NHL. As a potent PKC-β inhibitor, enzastaurin is currently being tested in Phase II/III trials.

Areas covered: This review summarizes the latest results and ongoing clinical trials with enzastaurin in light of basic scientific advances in the understanding of various lymphoid cancers, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) and Waldenström's macroglobulinemia (WM).

Expert opinion: While its continued clinical development is uncertain, enzastaurin should be regarded as a stepping stone for the development of future therapies; indeed, the recent research has provided valuable insight into the possible molecular mechanisms that explain its limited clinical activity especially in the treatment of DLBCL and MCL. It should be noted that there is still some interest in enzastaurin, in combination, for the treatment of WM.     

Lenalidomide in the treatment of chronic lymphocytic leukemia

Introduction: Lenalidomide is an immunomodulatory drug (IMiD) with a unique mode of action (MOA) that may vary across disease-type. It is currently approved in multiple myeloma (MM), myelodysplastic syndrome (MDS) and mantle cell lymphoma (MCL), yet is also clinically active in a host of lymphoproliferative diseases, including chronic lymphocytic leukemia (CLL). Due to its protean effects on the immune system, lenalidomide may be particularly appealing in CLL, which is distinct in its ability to evade immune recognition and cause immunosuppression.

Areas covered: This review recaps the biological mechanisms of lenalidomide specific for CLL, and summarizes the clinical data in previously untreated and relapsed/refractory (R/R) CLL patients, with emphasis on toxicity. Moreover, lenalidomide treatment is put into the context of the highly effective targeted agents that are drastically changing the therapeutic approach in CLL.

Expert opinion: Lenalidomide is a potent drug in CLL, both in first line and relapse. However, in comparison to other newly available agents, lenalidomide has slow onset of efficacy and notable toxicity profile that limits both its single agent use and combinations with chemotherapy. Future trials will hopefully direct our ability to harness lenalidomide MOA to best incorporate it in the rapidly evolving landscape of CLL treatment.     

Learning from the failures of drug discovery in B-cell non-Hodgkin lymphomas and perspectives for the future: chronic lymphocytic leukemia and diffuse large B-cell lymphoma as two ends of a spectrum in drug development

Introduction: Despite substantial recent advances, there is still an unmet need for better therapies in B-cell non Hodgkin lymphomas (B-NHL), especially in relapsed or refractory disease. Many novel targeted drugs have been developed based on a better molecular understanding of B-NHL.

Areas covered: This article focuses on chronic lymphocytic leukemia (CLL) as a representative for indolent lymphomas and paradigmatic for the tremendous progress in treating B-NHL on the one hand and diffuse large B-cell lymphoma (DLBCL) as a representative for aggressive lymphomas and paradigmatic for many unsolved problems in lymphoma treatment or the other hand. We highlight salient points in current therapies targeting genetic, epigenetic, immunological and microenvironmental alterations. Possible reasons for drug failure in clinical trials like tumor heterogeneity, clonal evolution and drug resistance mechanisms are discussed. Based thereon, some perspectives for further drug discovery are given.

Expert opinion: In view of the pathogenetic complexity of lymphomas, therapies targeting exclusively a single alteration may fail because resistance mechanisms are present either initially or evolve during treatment. Therefore, future therapies in B-NHL may have to target the greatest possible number of genetic, immunological or epigenetic alterations still allowing tolerability and to monitor these alterations during therapy.     

The preclinical discovery and development of bortezomib for the treatment of mantle cell lymphoma

Introduction: Mantle cell lymphoma (MCL) is an incurable, often aggressive B-cell malignancy. Bortezomib (BTZ), the 20S proteasome inhibitor was originally developed and approved for treatment of relapsed refractory multiple myeloma, and subsequently approved for treatment of MCL. BTZ’s single-agent activity induces clinical responses in approximately one-third of relapsed MCL patients. BTZ-containing combination therapies have further improved the quality and duration of clinical responses compared to standard chemotherapies in previously untreated MCL patients.

Areas covered: This review summarizes the discovery, mechanisms of -action and resistance, preclinical- clinical-developments, and FDA approval of BTZ for treatments of MCL.

Expert opinion: Preclinical MCL models demonstrated the apoptotic effect of BTZ through multiple mechanisms, as well as synergistic anti-MCL activity between BTZ and other chemotherapeutics. Single-agent and combinational clinical trials have validated the therapeutic potential of targeting the ubiquitin proteasome system (UPS) in MCL. However, inherent and acquired drug resistance remains a significant clinical problem and multiple potential mechanisms have been identified. Next-generation proteasome inhibitors with different pharmacodynamic properties from BTZ may partially address the issue of inherent resistance, with increased response rates noted in some diseases. In addition, upstream UPS components, e.g., E3 ligases or deubiquitinating enzymes, may also be targetable in MCL.     

An update on emerging drugs for Hodgkin lymphoma

Introduction: Most patients with Hodgkin lymphoma (HL) are cured with modern combined modality first-line treatments. Even ～ 50% of patients with relapsed/refractory HL can be cured with high-dose chemotherapy (HDCT) and autologous stem cell transplantation. However, chemotherapy and radiotherapy cause significant acute and long-term side effects and patients relapsing after HDCT have a dismal prognosis. New drugs are therefore needed to reduce the toxicity of first-line treatments and to increase the efficacy of relapse treatments. Moreover, new drugs are needed for the treatment of older patients with HL because results with current treatments are disappointing.

Areas covered: This article discusses promising new drugs for the treatment of classical HL that have been evaluated in the last years. There is a focus on the antibody drug conjugate brentuximab vedotin and its potential for the future treatment of HL. Moreover, data on the histone deacetylase inhibitors panobinostat and mocetinostat, the mammalian target of rapamycin inhibitor everolimus, the Janus kinase 2 inhibitor SB1518 and the immunomodulatory agent lenalidomide are summarized.

Expert opinion: Besides improving the prognosis of relapsed patients, new drugs should be used to replace the most toxic compounds in first-line therapy to reduce acute and long-term toxicities of the treatment.     

An evaluation of pixantrone for the treatment of non-Hodgkin’s lymphoma

ABSTRACT

Introduction: The overall prognosis for patients with relapsed or refractory aggressive non-Hodgkin’s lymphomas is poor. Only a minority of patients are able to receive autologous stem cell transplantation. Patients not transplant-eligible or patients relapsing after transplantation have an urgent need for effective treatment options. Pixantrone is the only compound approved in Europe for this situation.

Areas covered: This review describes the clinical development of pixantrone, starting with phase I trials up to phase III trials in order to define the role of pixantrone in treatment algorithms. The effectiveness of pixantrone is considered in relation to alternative therapeutic options. Furthermore, the similarities and differences between pixantrone and anthracyclines is highlighted, with a special focus on the mode of action and on cardiotoxicity.

Expert opinion: Pixantrone is a valuable treatment option in relapsed and refractory aggressive lymphomas, with documented disease responses, manageable toxicities and clear distinctions to anthracyclines. Additional studies are needed to evaluate the role of pixantrone in combination with other compounds, especially with upcoming targeted therapies, and to confirm the effectiveness of pixantrone in other lymphoma subtypes, e.g. follicular lymphomas.     

Clinical management of mantle cell lymphoma in the elderly

ABSTRACT

Introduction: Mantle cell lymphoma (MCL) is a disease with an indolent histology, but mostly aggressive clinical course. While treatment can yield more promising results in younger patients, the disease is most diagnosed at a median age of approximately 70 years, and treatment in this group still presents a major challenge for oncohematologists. Unfortunately, due to comorbidities and poorer general status, the implementation of intensive treatment approaches with the cytarabine-based regimens and autologous stem cell transplantation is generally not possible, and the disease remains incurable, especially in elderly patients.

Areas covered: In this paper, the authors discuss the therapeutic options available for older patients with MCL in the first line and relapsed/refractory settings, indicating new therapeutic options, which may achieve longer remissions and overall survival.

Expert opinion: Although great progress has been made in the treatment of MCL in recent years, there remains a need for new treatment lines which can allow improved patient outcomes. Novel agents targeting altered the signal transduction pathways in MCL cells may offer more promise than traditional chemotherapy or immunochemotherapy and are currently being tested in clinical trials.     

B细胞淋巴瘤IgH基因重排的检测及临床应用

目的建立克隆性免疫球蛋白重链(IgH)基因重排检测技术,探讨B淋巴细胞IgH基因重排在恶性淋巴瘤诊断的临床价值。方法选取62例B细胞性非霍奇金淋巴瘤(B-NHL),其中,弥漫大B淋巴瘤(DL-BCL)42例、滤泡性B细胞淋巴瘤(FL)15例、套细胞淋巴瘤(MCL)5例;15例未定性的淋巴组织增生性病变;20例良性淋巴组织反应性增生病例。从组织蜡块切片提取基因组DNA,经PCR扩增,聚丙烯酰胺凝胶电泳后银染显示基因重排结果。结果62例B-NHL中53例IgH基因重排(85.5%),其中DLBCL37例、FL13例、MC14例,阳性率分别为88.1%、86.7%、80.0%,各组间阳性率差异无统计学意义(P>0.05);15例未确诊的疑难病例中10例IgH基因重排,其中7例经随访或会诊确认为B-NHL;20例良性淋巴组织反应性增生病例IgH基因重排均为阴性,IgH基因重排检出率在淋巴瘤组与良性组之间差异有统计学意义(P<0.001)。结论PCR法检测B淋巴细胞IgH基因重排可作为淋巴细胞来源的良、恶性病变的一种辅助诊断手段,适用于石蜡标本,进行回顾性研究。     

Assessment of Correlation Between Early and Late Efficacy Endpoints to Identify Potential Surrogacy Relationships in Non-Hodgkin Lymphoma: a Literature-Based Meta-analysis of 108 Phase II and Phase III Studies

Correlations between early and late efficacy endpoints were assessed to identify potential surrogate endpoints for overall survival (OS) or progression-free survival (PFS) with clinical trial-level data in three non-Hodgkin lymphoma (NHL) subtypes: diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL). One hundred and eight phase II–III trials (129 trial arms) in DLBCL, FL, and MCL were identified and included in the database. Correlations between efficacy endpoints were analyzed using weighted linear regression and Pearson’s coefficient of determination (R ²). In newly diagnosed DLBCL, 6-month PFS was strongly correlated with 2-year OS (R ²?=?0.81, 95% confidence interval [CI] 0.51–0.96). Six-month PFS was strongly correlated with 3-year PFS (R ²?=?0.89, 95% CI 0.62–0.96) in FL and was moderately correlated with 2-year OS (R ²?=?0.69, 95% CI 0.40–0.91) in MCL trials. Linear regression determined that a 10% increase in 6-month PFS would yield a 13%?±?1.2% increase in 2-year OS in DLBCL, a 23%?±?1.1% increase in 3-year PFS in FL, or a 6.7%?±?1.0% increase in 2-year OS in MCL. Both 6-month PFS and complete response (CR) rate were moderately correlated with median PFS in FL trials with R ²?=?0.66 (95% CI 0.52–0.98) and R ²?=?0.69 (95% CI 0.22–0.89), respectively. Six-month PFS is a potential surrogate endpoint for 2-year OS in newly diagnosed DLBCL and MCL and for 3-year PFS in FL. Both 6-month PFS and CR rate are potential surrogate endpoints for median PFS in FL patients. Confirmation and validation of these correlations may facilitate early interpretation of NHL trials.     

Richter’s syndrome of T-cell lineage (T rex lymphoma)

Abstract

By definition, Richter’s syndrome represents the transformation of low-grade B-cell lymphoma into high-grade B-cell lymphoma, usually refractory to treatment. Exceptional cases of transformation into very aggressive mature T-cell lymphomas have been described as an unusual manifestation of the syndrome in patients died after few months from the diagnosis, despite chemotherapy. The time is ripe to regroup these T lymphomas under a new pathological subset, through the unequivocal alternate naming of ‘T rex lymphoma’, by analogy with the aggressive behavior of the famous dinosaur (T. rex). In practice, it represents the transformation of low-grade B-cell lymphoma into high-grade T-cell lymphoma, burdened by a very poor prognosis, because of the underlying B-cell lymphoma, which negatively interferes with the immune response of the patient. Against this distinct lymphomatous T clone, the major therapeutic efforts should be addressed.     

Lenalidomide in myelodysplastic syndrome and multiple myeloma

The use of thalidomide is limited by adverse effects of sedation, constipation, neuropathy and thromboembolism. In order to discover more potent and less toxic immunomodulators than thalidomide, its chemical structure was modified and lenalidomide was formed. Lenalidomide is approved by the US FDA for the treatment of patients with low-risk myelodysplastic syndrome (MDS) with deletion 5q cytogenetic abnormality. Two studies and a case report have evaluated lenalidomide in these MDS patients and showed significantly higher cytogenetic responses and durable red blood cell transfusion independence. Lenalidomide should be the drug of choice for patients with low and intermediate-1 risk MDS (based on the International Prognostic Scoring System) with chromosome 5q31 deletion with or without other karyotype abnormalities. Lenalidomide, in combination with dexamethasone, has been compared with dexamethasone alone in patients with relapsed or refractory multiple myeloma (MM) in two studies (MM-009 in North America and MM-010 in Europe, Israel and Australia). In these two phase III trials, lenalidomide demonstrated impressive (58-59%) response rates with dexamethasone. Lenalidomide has also been shown to overcome thalidomide resistance in MM patients. Therefore, the lenalidomide plus dexamethasone regimen provides another treatment option, in addition to first line MM treatment regimens of bortezomib, thalidomide or high-dose dexamethasone, for the treatment of relapsed or refractory MM.Lenalidomide does not produce significant sedation, constipation or neuropathy, but does lead to significant myelosuppression, unlike thalidomide. The prescribing information has a black box warning for risk of myelosuppression, deep vein thrombosis/pulmonary embolism and teratogenicity. Administration of lenalidomide is recommended at a starting dose of 10 mg/day orally for deletion 5q in MDS patients. Significant risk of myelosuppression may lead to dose reduction in the majority of these patients. Clinical trials of relapsed and refractory MM have shown that lenalidomide is clinically efficacious at a dosage of 25 mg/day when administered in combination with dexamethasone. Lenalidomide should be continued until disease progression in both MDS and MM patients.     

Treatment options for mantle cell lymphoma

Introduction: In this article, we provide an accurate overview of both standard treatment option and novel promising therapeutics. Major impact is on novel agents now being tested in randomized clinical trials. While the initial data are promising, they may rapidly expand treatment options, change existing paradigms and further improve outcomes for mantle cell lymphoma (MCL) patients.

Areas covered: MCL is a disease with indolent histology, but aggressive clinical course. However, for now, MCL remains incurable and the search for the most effective and tumor-specific treatment still represents a great challenge for oncohematologists. However, the implementation of chemotherapy together with the anti-CD20 antibody rituximab, as well as the growing use of autologous stem cell transplantation in first remission, have improved effects of treatment in MCL, including even some improvement in overall survival. Recently, treatment modalities for MCL have been expanded by strategies based on several biologically targeted agents, including m-TOR kinase or proteasome inhibitors and immunomodulatory agents, such as lenalidomide. B-cell receptor pathway inhibitors, such as ibrutinib and idelalisib, and histone deacetylase or cyclin-dependent kinase inhibitors have also shown promising activity in resistant or relapsed disease.

Expert opinion: Although enormous progress was made in the treatment of MCL over the last year, the disease remains incurable. One chance for the significant life prolongation is intensive treatment with consolidative auto SCT. However, real progress may be afforded by developing the novel agents described in this article. In this way, MCL may soon become another potentially curable oncological malignancy.     

The discovery and development of romidepsin for the treatment of T-cell lymphoma

Introduction: Romidepsin is a potent and selective inhibitor of histone deacetylases (HDCAi). It is also the only bicyclic inhibitor to undergo clinical assessment and is considered a promising drug for the treatment of T-cell lymphomas. The cellular action of romidepsin results in enhanced histone acetylation, as well as the acetylation of other nuclear or cytoplasmic proteins, influencing cell cycle, apoptosis, and angiogenesis. In phase II studies involving patients with relapsed or refractory of cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL), romidepsin produced overall response rates (ORR) of 34–35% and 25–38%, with complete response (CR) rates of 6% and 15–18%, respectively.

Areas covered: This review summarizes the development of romidepsin, the mechanisms behind its antineoplastic action and its pharmacology. It also covers its pharmacokinetic and pharmacodynamic properties, as well as the preclinical and clinical data on its activity in T-cell lymphoma.

Expert opinion: Since there are only few effective therapies available for T-cell lymphomas, romidepsin is a valuable option for relapsed/refractory patients with both CTCL and PTCL. It’s also generally well tolerated, and gives potentially durable responses for patients with advanced and symptomatic disease. Combinations of romidepsin with other antineoplastic agents may also further improve drug response and outcomes in T-cell lymphoma.     

New treatment options for chronic lymphocytic leukemia

Introduction: Chemoimmunotherapy is the gold standard of therapy for patients with advanced chronic lymphocytic leukemia (CLL), resulting in high and durable complete response rates. However, all patients eventually relapse and CLL remains incurable. Newer and more rationally developed compounds are needed to improve CLL therapy, particularly in cases of refractory disease.

Areas covered: Following a literature search on PubMed using ‘chronic’, ‘lymphocytic’, ‘treatment’ and ‘therapy’ as keywords, results obtained with novel agents were critically analyzed. Abstracts presented during 2013 at ASH, EHA, ICML, IWCLL and ASCO meetings were also included in the search.

Expert opinion: New monoclonal antibodies, lenalidomide, B-cell receptor-signal transduction inhibitors and pro-apoptotic molecules have shown efficacy in patients with relapsed or refractory disease. Hopefully, the combined use of these molecules in risk-adapted treatment strategies will improve the outcome of patients with CLL and pave the way for their long-term control.     

CD19-targeted immunotherapies for treatment of patients with non-Hodgkin B-cell lymphomas

Introduction: Ubiquitous expression of CD19 on B cell non-Hodgkin lymphoma identified it as a potential target for immune-based therapies.

Areas covered: This article reviews the current literature on anti-CD19 therapies currently in clinical trials including monoclonal antibodies (mAb), antibody targeted cytotoxic drug conjugates (ADC), bispecific antibodies, and chimeric antigen receptor (CAR) modified T cells.

Expert opinion: Naked anti-CD19 mAbs have shown little clinical benefit in B cell lymphomas. Despite unusual toxicity profiles with many anti-CD19 ADCs slowing development, durable remissions in a substantial minority of patients with refractory aggressive lymphomas should encourage continued efforts in this area. Blinatumomab, an anti-CD19 bispecific T cell engager, has shown impressive responses in relapse/refractory diffuse large B cell lymphoma (DLBCL), but is plagued by neurotoxicity issues and the need for continuous infusion. CD19 targeting CAR-T cell therapies are the most promising, with the potential for curing a third of refractory DLBCL patients. There is still much work to be done to address potentially life-threatening cytokine release syndrome and neurotoxicity, an extended production time precluding patients with rapidly progressive disease, and treatment expense. However, if the promise of CAR-T cell technology is confirmed, this will likely change the approach and prognosis for relapse/refractory aggressive lymphoma.     

Protein kinase inhibitors against malignant lymphoma

Introduction: Tyrosine kinases (TKs) are intimately involved in multiple signal transduction pathways regulating survival, activation, proliferation and differentiation of lymphoid cells. Deregulation or overexpression of specific oncogenic TKs is implicated in maintaining the malignant phenotype in B-lineage lymphoid malignancies. Several novel targeted TK inhibitors (TKIs) have recently emerged as active in the treatment of relapsed or refractory B-cell lymphomas that inhibit critical signaling pathways, promote apoptotic mechanisms or modulate the tumor microenvironment.

Areas covered: In this review, the authors summarize the clinical outcomes of newer TKIs in various B-cell lymphomas from published and ongoing clinical studies and abstracts from major cancer and hematology conferences.

Expert opinion: Multiple clinical trials have demonstrated that robust antitumor activity can be obtained with TKIs directed toward specific oncogenic TKs that are genetically deregulated in various subtypes of B-cell lymphomas. Clinical success of targeting TKIs is dependent upon on identifying reliable molecular and clinical markers associated with select cohorts of patients. Further understanding of the signaling pathways should stimulate the identification of novel molecular targets and expand the development of new therapeutic options and individualized therapies.     

Enzastaurin hydrochloride for lymphoma: reassessing the results of clinical trials in light of recent advances in the biology of B-cell malignancies

Introduction: The B-cell receptor (BCR) is critical for the development and persistence of B-cell non-Hodgkin lymphoma (B-NHL). Protein kinase C-beta (PKC-?) has been identified as one of the key signaling hubs downstream of the BCR and constitutes a valuable target in B-NHL. As a potent PKC-? inhibitor, enzastaurin is currently being tested in Phase II/III trials. Areas covered: This review summarizes the latest results and ongoing clinical trials with enzastaurin in light of basic scientific advances in the understanding of various lymphoid cancers, including diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), follicular lymphoma (FL), chronic lymphocytic leukemia (CLL) and Waldenstr?m's macroglobulinemia (WM). Expert opinion: While its continued clinical development is uncertain, enzastaurin should be regarded as a stepping stone for the development of future therapies; indeed, the recent research has provided valuable insight into the possible molecular mechanisms that explain its limited clinical activity especially in the treatment of DLBCL and MCL. It should be noted that there is still some interest in enzastaurin, in combination, for the treatment of WM.