Haematological cancer

Lee, Singh et al. find that cancer-specific intronic polyadenylation events occur frequently in tumour suppressor genes in chronic lymphocytic leukaemia (CLL) and generate truncated proteins that could act as CLL drivers.

Yao et al. have established that acute lymphoblastic leukaemia cells bypass the need to metastasize via the circulation to the CNS and instead use a direct route migrating along the vascular channels that bridge the bone marrow to the meninges in an α6 integrin-dependent manner.

Two groups have used targeted sequencing to identify features of clonal haematopoiesis in healthy individuals including the number of somatic mutations, the presence of specific mutations and clonal size, which predict risk of developing acute myeloid leukaemia years before diagnosis.

Analyses of clinical trial patients with exceptional responses show that adoptive T cell therapy can be optimised to improve effectiveness in patients of chronic lymphocytic leukaemia and breast cancer.

Good et al. use deep phenotypic single-cell analyses and machine learning to identify developmentally dependent cell signalling states in B cell precursor acute lymphoblastic leukaemia that are predictive of relapse.

A paper inNature Medicinedescribes a novel, orally available splicing modulator that preferentially kills cancer cells with mutations in splicing factors in culture and in mouse models.

The approval of blinatumomab based on achievement of undetectable minimal residual disease (MRD) in patients with B cell acute lymphoblastic leukaemia in complete remission is the first of its kind and raises important considerations. This drug might improve outcomes in this setting, although considerable evidence is needed to validate the performance of MRD as a surrogate end point and confirm the hypothesis.

The prognostic significance of residual disease, measured by flow cytometry or PCR-based assays, has been established in patients with acute myeloid leukaemia (AML). The results of a recent study involving almost 500 patients in morphological remission demonstrate that detection of persistent mutations using next-generation sequencing provides information complementary to that obtained using the established methods and offer insights into AML evolution.

Recent genomic and transcriptomic analyses of diffuse large B cell lymphoma (DLBCL) have provided important new insights into the heterogeneous biology of this disease. The findings provide opportunities to improve treatment strategies, although considerable work is needed to establish and optimize the clinical applicability and utility of molecular classifications of DLBCL.

In 2017, three groundbreaking immunotherapies for relapsed and/or refractory B-cell acute lymphoblastic leukaemia (ALL) were approved based on impressive outcomes observed in clinical trials. Additional breakthroughs included seminal research into ALL genomics and the importance of adherence to chemotherapy, which will have direct implications for clinical care.

On 30^th August 2017, tisagenlecleucel became the first chimeric antigen receptor (CAR)-T-cell therapy to be approved by the FDA. This approval has important implications for health-care systems because the use of this promising treatment presents considerable logistical, toxicological, and financial challenges. Moreover, the high price tag of US$475,000 is questionable, considering the major role of US taxpayers in covering the development, delivery, and supportive-care costs of this treatment.

Response criteria for disease assessment have important therapeutic and prognostic implications in clinical trials and in routine clinical practice. The Lugano classification has been used widely for evaluation of the response of patients with lymphoma to treatment, although the alternative Response Evaluation Criteria In Lymphoma 2017 (RECIL 2017) classification was recently proposed; these criteria are compared herein.

The current standard-of-care therapy for patients with multiple myeloma is autologous stem-cell transplantation; however, whether this approach should be enhanced or displaced by triplet combination therapy is the subject of ongoing debate. We discuss the latest trial that has attempted to address this question and the impact of transplantation and triplet therapy assessment and surrogate end points in future trial design.

Chimeric antigen receptor (CAR) T cell therapies have impressive activity in the treatment of cancer but are associated with potentially fatal toxicities. In light of the approval of CAR T cell therapy for paediatric patients, a panel of experts from the Hematopoietic Stem Cell Transplantation (HSCT) Subgroup of the Pediatric Acute Lung Injury and Sepsis Investigators (PALISI) Network, the CAR T Cell Therapy-Associated Toxicity (CARTOX) Program at The University of Texas MD Anderson Cancer Center, and several other institutions have developed consensus guidelines for the use and management of these treatments in paediatric patients, which are presented herein.

In this Review, Greaves describes the evidence supporting the model that infections early in life reduce the risk of childhood common B cell precursor acute lymphoblastic leukaemia (BCP-ALL) development. Given this evidence, paediatric BCP-ALL may be a preventable cancer.

In recent years, a number of novel agents have been added to the therapeutic armamentarium for patients with chronic lymphocytic leukaemia (CLL). Herein, Jan A. Burger and Susan O’Brien outline the emerging paradigm of individualized therapy for patients with CLL aimed at exploiting the advantages of these novel agents but also integrating traditional therapies for selected patients.

The multiple myelomas (MMs) are heterogeneous malignancies that are nearly always associated with chromosomal abnormalities, which can be considered either primary or secondary abnormalities. The classification of MM according to the underlying primary cytogenetic abnormality might enable the development of better treatment strategies. The authors describe treatment approaches that consider the current standard of care for patients with MM along with recommendations for certain subgroups of patients.

This Review discusses the mutational landscape and evolution of follicular lymphoma. Deciphering the earliest initiating lesions and the molecular alterations leading to disease progression might help identify the most relevant targets for therapy of these tumours.

In this Review, Burger and Wiestner describe the latest insights into B cell receptor (BCR) signalling with respect to its contribution to B cell malignancies and discuss how inhibitors that target kinases downstream of the BCR are changing treatment outcomes for patients with B cell neoplasms.

Both multiple myeloma and acute myeloid leukaemia are often preceded by defined precursor stages of neoplasia, which can aid efforts to unravel the mechanisms of disease progression. Herein, the authors review studies of the important roles of microenvironmental factors in promoting the development and progression of haematological cancers in these precursor conditions. Potential therapeutic strategies targeting the abnormal bone-marrow microenvironment are discussed.

Chimeric antigen receptor (CAR)-T-cell therapies are showing great promise in the treatment of cancer, particularly B-cell malignancies, but are associated with characteristic, potentially fatal toxicities, principally cytokine-release syndrome, CAR-T-cell-related encephalopathy syndrome, and haemophagocytic lymphohistiocytosis/macrophage-activation syndrome. Herein, the CAR-T-cell-therapy-associated TOXicity (CARTOX) Working Group, comprising multidisciplinary investigators from various institutions with clinical experience in the use of a range of CAR-T-cell platforms, review these acute toxicities and provide monitoring, grading, and management recommendations.

Cell-based immunotherapies are showing great promise in the treatment of even the most treatment-refractory of haematological malignancies. Herein, Jennifer Brudno and James Kochenderfer review the results obtained to date with CAR-T-cell therapies for lymphoma. They also discuss what has been learned regarding the limitations of CAR-T-cell therapies and areas for improvement relating to toxicity management, the design of CAR-T-cell products, conditioning regimens, and combination therapies.

Therapy-related myeloid neoplasms occur as a late complication following chemotherapy and/or radiotherapy administered for a primary condition. In this Review, McNerneyet al. discuss recent studies that have improved our understanding of the aetiology of this disease.

This Review describes our current understanding of the relationship between genotype and phenotype in myelodysplastic syndromes/myeloproliferative neoplasms (MDS/MPN) and discusses how this knowledge could be used to inform strategies to develop more effective treatments and improve clinical success.

The treatment landscape for lymphoma has become crowded, requiring efficient prioritization for expedited drug development. New challenges include the optimal duration of therapy, as well as the need to balance cost, benefit, and late-onset toxicity. Herein, the authors overview of the most-promising agents in clinical development for the treatment of lymphoma, and provide expert opinion on new strategies to streamline drug development as well as approaches for patient selection and for incorporating new end points into clinical trials.

Immune-checkpoint inhibitors are revolutionizing the treatment of many types of solid cancer. Expression of the inhibitory immune-checkpoint proteins programmed cell-death 1 (PD-1) and its ligands (PD-L1 and PD-L2) are frequently detected in haematological malignancies, and agents targeting these proteins have activity in such diseases, notably Hodgkin lymphoma. Herein, the current evidence supporting the roles of PD-1–PD-L1 blockade in the treatment of various B-cell malignancies is reviewed.

Improved therapies have allowed many patients with cancer to achieve complete remission, but they retain minimal residual disease (MRD), which causes relapse. This Opinion article argues that iterative detection, profiling and targeting of MRD could improve outcomes, including cure rates.

Recent studies have suggested that autoimmunity checkpoints (AICs) are fully functional in B cell leukaemias and lymphomas, despite malignant transformation. This Opinion article proposes that targeted engagement of AICs might represent a therapeutic opportunity to overcome drug resistance in B cell malignancies.