CLL/SLL,   DLBCL,  FL,  MCL,  WM

The success of ibrutinib in treating B cell malignancies: CLL, MCL, WM, FL and DLBCL

Ibrutinib is an oral, potent small molecule agent that binds to BTK (Burton’s Tyrosine Kinase) inhibitor in B cell malignancies. In this article published in Hematology and Oncology in July 16, by G. Varma, T. P. Johnson and R. Advani, key clinical studies in different phases regarding treatment of B cell malignancies have been described.

The key findings of the clinical studies are as follows:

  • CLL (HELIOS, RESONATE 1, RESONATE 2): Ibrutinib has been shown to decrease tumor cell survival and proliferation. Various monotherapies and combination therapies have demonstrated an improvement in overall response rates (ORR), i.e. efficacy ranging between 79%-100% and has proven to be highly efficacious across CLL subtypes
  • MCL (SHINE): Ibrutinib in monotherapy and combination therapy (bendamustine + rituximab, BR) in relapsed/refractory MCL patients has shown an improvement in ORR (67%-88%). Several trials evaluating the combination of ibrutinib with other agents which could be used as frontline therapy are ongoing
  • WM (iNNOVATE): Phase I trials have shown an improvement in not only in the quality of response during prolonged therapy with an ORR of 90.5%, but also in overall survival of 95.52% and minimal toxicity
  • FL (SELENE): Interim data from phase II trial of ibrutinib as a single-agent in patients with relapsed/refractory FL shows only moderate response, i.e., ORR of 38%. Data on ibrutinib in FL is not as robust as those seen in other histology types
  • DLBLC (PHOENIX): Other promising trials in the different subtypes of DLBLC show an ORR upto 100%. However, patients respond differently to standard treatment approaches with the least outcome in activated B-cell (ABC) DLBLC subtype. New trials are ongoing evaluating the use of ibrutinib with other chemo-immunotherapies mainly in ABC DLBLC

Adverse events (AEs) and its management: Ibrutinib is well tolerated across histological types, with the majority of the adverse events being grade 1 and 2, i.e. non-haemotologic toxicities such as nausea and diarrhoea. Haemorrhagic events are the most common adverse events in Grade 3 and 4 toxicities although these are infrequent. Corticosteroids are occasionally required for management of AEs

Conclusions
  • Although Ibrutinib has shown to offer unique therapeutic promise to patients with high risk or relapsed disease after conventional therapies, the questions regarding optimal duration of therapy for patients achieving complete response remain unanswered.
  • Evaluating the cost of continuous treatment with ibrutinib and treatment options for patients resistant to ibrutinib also need to be established.
  • Clinical studies using pro-apoptotic agents such as venetoclax and other BTK inhibitors are currently underway.

The full article can be found here.

 Bruton’s Tyrosine Kinase Inhibitors in Chronic Lymphocytic Leukemia and Lymphoma

Abstract

The development of Bruton’s tyrosine kinase (BTK) inhibitors and their introduction into clinical practice represent a major advance in the treatment of chronic lymphocytic leukemia (CLL) and other B-cell lymphomas. Although ibrutinib is the only BTK inhibitor that has been approved by the US Food and Drug Administration, several others are under investigation. Ibrutinib is currently approved for use in relapsed/refractory CLL, CLL with 17p deletion (del[17p]), relapsed or refractory mantle cell lymphoma, and Waldenström macroglobulinemia. Although it is clear that ibrutinib has altered treatment paradigms and outcomes in these diseases, several questions remain regarding (1) its role in frontline vs salvage therapy; (2) its use as a single agent vs in combination with biologic agents, other small molecules, or traditional chemoimmunotherapy; (3) the optimal duration of treatment; and (4) the treatment of patients who cannot tolerate or have disease resistant to ibrutinib. Because sparse clinical data are available on other BTK inhibitors, it is unclear at present whether their clinical efficacy and toxicity will differ from those of ibrutinib.

 Reference:
  1. Varma G et al., Bruton's tyrosine kinase inhibitors in chronic lymphocytic leukemia and lymphoma. Clin Adv Hematol Oncol.2016 Jul;14(7):543-54.