Subsets of younger, fit patients with CLL and IGHV-mutated disease treated with fludarabine, cyclophosphamide, and rituximab (FCR) have experienced long-term progression-free survival (PFS) after a median follow-up of nearly 13 years, and I think that the concept of potentially curative therapy is an important one. Many clinicians are uncomfortable using the term curative and prefer to speak in terms of very long remissions. However, I would be willing to use that term, given the right set of circumstances. 

If you look at the data with FCR, the plateau of the PFS curve does not emerge for several years. This plateau effect (ie, no new cases of disease progression despite increasingly lengthy follow-up) is most evident in patients with mutated IGHV. In contrast, there does not appear to be a difference in outcomes based on IGHV mutation status with the novel molecules, such as ibrutinib or venetoclax, although a difference may appear with longer-term follow-up. So far, with 5 to 6 years of follow-up for ibrutinib, the PFS curves of mutated vs unmutated patients have not separated. If the treatment had been FCR, and we were at the 5- to 6-year timepoint, the PFS curve would have separated into 2 curves by IGHV mutation status long ago. Thus far, for both ibrutinib and venetoclax, no difference in PFS has been seen between mutated and unmutated disease, which raises some interesting questions.  Does mutated disease inherently have a more favorable prognosis, or was that true only when the treatment had been chemoimmunotherapy? Although we do not yet have a definitive answer, if I had to guess, I would be inclined to think that IGHV-mutated disease has a better prognosis inherently, and that, if curative treatment were to emerge, it would emerge first in this group of patients. But, right now, with the limited follow-up that we have on the small molecules, IGHV mutation status is not even a prognostic factor. 

We also do not know whether a plateau of the PFS curve occurs with small molecules in the same way that it does with FCR, and we cannot assume that it does. We simply do not have long enough follow-up to know the answer. We do not really have a proxy or an intermediate end point that is predictive of cure either. Minimal residual disease (MRD) is possibly predictive of durability, but, in my opinion, you cannot say that it is predictive of cure because we know that there are MRD undetectable patients who do relapse. Ultimately, cured patients will not have detectable MRD, so I think that MRD negativity is necessary for cure, but it is not sufficient.