The treatment landscape of B-cell lymphomas is evolving with the advent of novel agents including immune and cellular therapies. Bispecific antibodies (bsAbs) are molecules that recognise two different antigens and are used to engage effector cells, such as T-cells, to kill malignant B-cells. Several bispecific antibodies have entered early phase clinical development since the approval of the CD19/CD3 bispecific antibody, blinatumomab, for relapsed/refractory acute lymphoblastic leukaemia. Novel bsAbs include CD20/CD3 antibodies that are being investigated in both aggressive and indolent non-Hodgkin lymphoma with encouraging overall response rates including complete remissions. These results are seen even in heavily pre-treated patient populations such as those who have relapsed after chimeric antigen receptor T-cell therapy. Potential toxicities include cytokine release syndrome, neurotoxicity and tumour flare, with a number of strategies existing to mitigate these risks. Here, we review the development of bsAbs, their mechanism of action and the different types of bsAbs and how they differ in structure. We will present the currently available data from clinical trials regarding response rates, progression free survival and outcomes across a range of non-Hodgkin lymphoma subtypes. Finally, we will discuss the key toxicities of bsAbs, their rates and management of these adverse events.

Effective available treatment options for patients with chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) who relapse after becoming refractory to both a covalent Bruton Tyrosine Kinase inhibitor (cBTKi) and a B cell leukemia/lymphoma 2 inhibitor (BCL2i) remain limited, and prognosis is very poor. Emerging areas of drug development include cellular therapies such as chimeric antigen receptor T-cell therapy and bispecific antibodies. However, cost, accessibility, toxicity, and the need for either prolonged or repeated hospitalization prevent universal application of these therapies. Given this area of unmet clinical need, we present this review article on Bruton Tyrosine Kinase (BTK) degraders in patients with CLL/SLL. We focus on their development as a drug class, the up-to-date clinical data available, as well as future directions. BTK protein degraders are a novel drug class with an alternate mechanism of action (MOA), compared to cBTKis and non-covalent BTKis (ncBTKis), causing ubiquitination of BTK, thereby leading to its degradation through the proteasome. Encouraging pre-clinical data show that this MOA allows BTK protein degraders to overcome common BTK mutations. We focus on four agents which are under investigation in B-cell malignancies in early clinical trials: BGB-16673, NX-2127, NX-5948, and AC676. Preliminary data suggest a comparable safety and toxicity profile between agents across this drug class with many patients on phase 1 trials deriving durable clinical benefit. Optimal sequencing of BTK degraders in the therapeutic landscape of CLL/SLL treatment is yet to be established. Further trials investigating these agents in combination with other targeted CLL agents may help to further understand their applicability. An effective, tolerable oral class of drugs would be invaluable in the treatment of patients with multiply relapsed CLL/SLL.

The last decade has seen a significant leap in our understanding of the wide range of genetic lesions underpinning acute lymphoblastic leukaemia (ALL). Next generation sequencing has led to the identification of driver mutations with significant implications on prognosis and has defined entities such as BCR-ABL-like ALL, where targeted therapies such as tyrosine kinase inhibitors (TKIs) and JAK inhibitors may play a role in its treatment. In Philadelphia positive ALL, the introduction of TKIs into frontline treatment regimens has already transformed patient outcomes. In B-ALL, agents targeting surface receptors CD19, CD20 and CD22, including monoclonal antibodies, bispecific T cell engagers, antibody drug conjugates and chimeric antigen receptor (CAR) T cells, have shown significant activity but come with unique toxicities and have implications for how treatment is sequenced. Advances in T-ALL have lagged behind those seen in B-ALL. However, agents such as nelarabine, bortezomib and CAR T cell therapy targeting T cell antigens have been examined with promising results seen. As our understanding of disease biology in ALL grows, as does our ability to target pathways such as apoptosis, through BH3 mimetics, chemokines and epigenetic regulators. This review aims to highlight a range of available and emerging targeted therapeutics in ALL, to explore their mechanisms of action and to discuss the current evidence for their use.

Lay abstract In the last decade, the treatment of chronic lymphocytic leukemia (CLL) has shifted away from using chemotherapy agents toward newer drugs including some that may be taken orally. Here, we give an overview of two of these new drugs: obinutuzumab, a newer version of rituximab; and the orally administered venetoclax. Venetoclax, an oral agent that promotes cell death in CLL cells, has been shown to be superior to traditional chemotherapy agents when used in combination with obinutuzumab or rituximab in newly diagnosed or relapsed CLL patients. Obinutuzumab is an antibody, given as an infusion, which targets a protein on the surface of CLL cells called CD20 and has been combined effectively with venetoclax. In the last decade, the treatment of chronic lymphocytic leukemia (CLL) has shifted away from chemoimmunotherapy toward targeted novel agents such as small molecule inhibitors and antibodies. Here, we give an overview of the pharmacology of venetoclax and obinutuzumab and the evidence from early phase to Phase III trials that have shaped how they are used in the treatment of CLL. Venetoclax, an oral anti-apoptotic BCL-2 inhibitor, in combination with a CD20 antibody has shown superiority to chemoimmunotherapy in treatment-naive and relapsed/refractory CLL. Obinutuzumab is a novel anti-CD20 monoclonal antibody that has been safely combined with novel agents including venetoclax and Bruton tyrosine kinase inhibitors and has shown superiority over rituximab when combined with chlorambucil.

We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group (GLOW) retrospective database of 2243 patients with stage I-IV disease diagnosed from 1992-2021 at 38 international institutions. 779 patients were stage IA with median age of 35 years (range=3-89) and median follow-up of 6.1 years. The 6-year PFS and OS were 86.3% and 97.7%, respectively. Outcomes were analyzed for two groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n=99) had a 6-year PFS of 65.5% versus 90.5% for those who received RT (n=53). Patients with unresected disease (n=627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n=31), 89.6% for RT alone (n=325), 76.8% for ABVD alone (n=40), and 94.3% for ABVD+RT (n=130). 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests 1) RT improves the PFS in patients with completely resected disease; 2) Rituximab or ABVD alone do not appear to achieve a durable response; 3) Chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.