Personalized medicine


Being able to tailor treatment to the specific characteristics of each patient is becoming more important. One way is to measure the diversity of the T cell receptor repertoire by next generation sequencing (NGS), which may help predict response to blinatumomab. A study with a single inhibitor that targets two pathways has demonstrated clinical activity in patients with different types of advanced NHL. And in CLL the development of targeted therapies based on increasing knowledge of the biology is rapidly changing the way patients are treated, as was discussed in the Plenary Session on Sunday.

TCR diversity associated with response to blinatumomab

The bispecific antibody blinatumomab directs cytotoxic T cells to CD19-expressing B cells, and has shown antitumor activity in patients with relapsed or refractory B cell precursor acute lymphoblastic leukemia (r/r BCP-ALL). However, approximately half of these patients do not achieve a deep response. At the EHA annual congress Dr Michaela Kotrova (University Hospital Schleswig-Holstein, Kiel, Germany) showed that a possible explanation might lie in the diversity of the patient’s T cell receptor Beta (TRB) repertoire.1

A high diversity of T cell receptors, present on the surface of T cells, is important for the recognition of a wide variety of pathogens. Kotrova and colleagues used amplicon NGS at an ultrahigh resolution to determine the DNA sequence of each TRB rearrangement in samples from 114 r/r BCP-ALL patients. Patients who had reached MRD negativity by day 29 of the first blinatumomab cycle were regarded as responders, whereas patients with quantifiable MRD at day 29 or MRD >1% at day 15 were regarded as persisters.

Before the start of treatment, responders had a significantly higher diversity of TRB repertoire than persisters (p=0.02). In each patient group, the TRB repertoire diversity increased during treatment. However, in responders this increase was sharp and highly significant (p<0.001), whereas in persisters the increase was not statistically significant (p=0.4). These results suggest that repertoire diversity may predict response to blinatumomab, however, larger studies are needed to confirm this, concluded Kotrova.

 

Dual targeting of SYK and JAK in advanced NHL

Targeting two different signaling pathways that lymphomas rely on for survival induced responses in patients with different types of advanced non-Hodgkin lymphomas (NHL). Dr Paul Hamlin (Memorial Sloan Kettering Cancer Center, New York, USA) presented interim results from a phase 2 study with cerdulatinib.2

The oral inhibitor cerdulatinib is unique in that it selectively targets two key pathways: B cell receptor signaling via SYK, and cytokine receptor signaling via JAK. Combined inhibition of these pathways induced apoptosis in cells from lymphoma patients who relapsed or were refractory to prior treatments due to defined mutations. An ongoing phase 2 study evaluates the safety and efficacy of cerdulatinib in patients with r/r NHL, including chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), indolent NHL, and peripheral T cell lymphoma (PTCL).

After three patients on 35 mg BID cerdulatinib experienced severe adverse events, the starting dose was adjusted to 30 mg BID. The most common adverse events were diarrhea, fatigue and nausea. Grade 3-4 adverse events included infection, abdominal pain, and hypertension.

Treatment with cerdulatinib effectively inhibited both the SYK and the JAK pathway. The overall response rate (ORR) was 50% (n=47), with mostly partial responses. The best responses were seen in CLL/SLL (67%; n=18) and FL (56%; n=9). One patient, the only PTCL patient evaluated thus far, achieved a complete response. Responses improved over time in most patients.

The study continues to enroll patients, and Hamlin expects updated results by the end of 2017.

 

Turning biology into targeted therapy in CLL

CLL has a complex molecular pathogenesis, and highly variable clinical course. In the Plenary Session on Sunday Dr Stephan Stilgenbauer (University of Ulm, Germany) discussed how knowledge of the biology of CLL has led to the development of several targeted therapies.

Risk stratification in CLL is mainly based on cytogenetic aberrations, such as del17p, which confers a poor prognosis. Addition of the CD20 monoclonal antibody rituximab to the chemotherapy combination of fludarabine and cyclophosphamide improved survival, as was shown in the CLL8 trail.3 Outcome with this combination was dependent on the presence or absence of TP53 and IGHV mutations. Many different driver mutations have been identified in CLL, some are relatively common, such as mutations in SF3B1, ATM and TP53, but most occur in only 1-2% of patients. However, many of these mutations are found in common pathways, suggesting a role for these pathways in the pathogenesis of CLL.

Several targeted therapies have been developed that target these cancer driver pathways, and have been successful in clinical studies. Stilgenbauer discussed studies with the immune-modulatory agent lenalidomide, the B cell receptor signaling inhibitors ibrutinib and idelalisib, and the BCL2 inhibitor venetoclax.4 He stressed the importance of an integrative approach in order to turn biologic data into novel therapies, combining molecular analyses, functional animal models, and clinical trials incorporating reference laboratories and biobanking.

 

Interested in the webcast of Dr Stilgenbauers presentation on targeted therapy in CLL?

 

References:

  1. Knecht H, et al. EHA 2017: abstract S803.
  2. Hamlin P, et al. EHA 2017: abstract S773.
  3. Hallek M, et al. Lancet 2010;376(9747):1164-74.
  4. Stilgenbauer S, et al. EHA2017: abstract S771