Matthew Davids , MD

Jennifer Woyach , MD

Disclaimer : The following positions were assigned to the participants and do not necessarily reflect ASH opinions , the participants ’ opinions , or what they do in daily practice .

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Chronic lymphocytic leukemia ( CLL ) has long been considered an incurable disease . The goal of traditional frontline treatments is to minimize disease burden and allow patients to achieve durable remissions . However , with the advent of new targeted agents and immunotherapeutic options , investigators are devising new drug combinations that some believe may finally cure the disease . The term “ cure ” also needs to be defined .

In this edition of Drawing First Blood , ASH Clinical News invited Matthew Davids , MD , MMSc , and Jennifer Woyach , MD , to debate whether newer agents will transform CLL into a curable disease . Dr . Davids , of Dana-Farber Cancer Institute , will argue on the “ pro ” side , and Dr . Woyach , of The Ohio State University Comprehensive Cancer Center , will argue on the “ con ” side .

Matthew Davids , MD : Historically , CLL has been considered an incurable disease but , with recent evidence from trials of chemoimmunotherapy combination regimens , we have seen that these approaches have curative potential in subsets of younger , fit patients with CLL and IGHVmutated disease .

For example , the combination of fludarabine , cyclophosphamide , and rituximab ( FCR ) led to long-term progression-free survival ( PFS ) after a median follow-up of nearly 13 years in this patient group . 1

I am optimistic that with several of the highly active novel agents – including PI3K inhibitors like idelalisib , BCL2 inhibitors like venetoclax , and anti-CD20 monoclonal antibodies like rituximab and obinutuzumab – entering the treatment landscape , we will be able to increase the curative potential of our available regimens . That is the rationale behind our ibrutinib plus FCR ( iFCR ) study – in which we saw a 37-percent complete response rate in previously untreated patients – as well as the ibrutinib plus FCG study at MD Anderson Cancer Center . 2 , 3

Jennifer Woyach , MD : I agree , especially about the great responses that have been seen with adding novel agents to chemoimmunotherapy in the attempt to cure CLL . However , we don ’ t yet have enough data about newer agents without chemotherapy to say that we can cure the disease . I also think it ’ s important for us , as a field , to decide for which patients curing disease should be our treatment goal , because that will not necessarily be the goal for every patient – especially if we can induce long-term remissions with continuous therapy .

Dr . Davids : We are fortunate in CLL to have a variety of effective chemoimmunotherapy regimens for frontline treatment ( including FCR , bendamustine plus rituximab , and chlorambucil plus obinutuzumab ), but each of these regimens carries substantial risks and toxicities , particularly for older , frailer patients who often have multiple medical comorbidities . That has been part of the inspiration to develop novel agents that are both better tolerated than existing regimens and highly effective for our patients .

Dr . Woyach : The first novel agent that was approved by the U . S . Food and Drug Administration ( FDA ) for the frontline treatment of CLL was ibrutinib , which is an irreversible inhibitor of Bruton tyrosine kinase ( BTK ). Ibrutinib is effective , with the limitation that it has to be given indefinitely . Ongoing research is focused on whether we can combine ibrutinib or other BTK inhibitors with additional newer agents or chemoimmunotherapy regimens to get patients to a point where they can safely discontinue therapy .

Also , if we ’ re discussing potentially curative therapies , we have to mention that chimeric antigen receptor ( CAR ) T-cell therapies are being investigated in CLL . Most target the CD19 antigen , although there are other targets in development . I believe this approach has the potential to induce minimal residual disease ( MRD )– negative complete responses and , hopefully , a long duration of remission and potential cure for some patients .

Dr . Davids : In the last couple of years , long-term data from trials of FCR or other chemoimmunotherapy regimens have started to emerge that will help us determine in whom a cure is possible . These are truly long-term data for FCR , in particular from the FCR300 trial at MD Anderson Cancer Center , which now has up to 15 years of follow-up data available . 1 The phase II trial enrolled younger patients – the median age of participants was 57 years , and 24 percent were aged 65 or older – with IGHVmutated disease . The investigators found that this patient subgroup has a good chance of achieving long-term disease-free survival after FCR . Half of patients achieved MRD-negative status , and , in this group , the PFS rate at 12.8 years was approximately 80 percent . Similar data , albeit with shorter follow-up , are now emerging from the CLL8 trial from the German CLL Study Group – validating the findings reported in the older MD Anderson trial . 4 After approximately six years of follow-up , the FCR combination improved PFS and overall survival in patients with previously untreated , IGHV-mutated CLL , compared with fludarabine plus cyclophosphamide .

We also recently saw a robust retrospective dataset from the Italian group

50 ASH Clinical News

September 2018