All the developments described so far had left the highest risk patients—those with del17p and p53 dysfunctions—almost untouched. These patients who had low response rates and short PFS even with intensive induction treatment options, such as FCR. The only patients in this group who were able to achieve longer survival were in the small group of CLL patients who qualify for allogeneic transplant [
22]. Some success in this group had been reported for alemtuzumab therapies (e. g., in combination with high-dose corticosteroids and at a high price regarding infections), but that was swept away by things to come.
In parallel to the increase in interest in treating CLL, there was a surge in understanding of the disease biology. Importantly, it became clear that CLL was not merely genetically programmed to proliferate and survive, but relied extensively on microenvironmental interactions for these outcomes [
23]. It thus became clear that there would be signaling pathways that provide essential signals for the development of CLL and that these signaling pathways may serve as important targets for the development of treatment. The kinase inhibitors ibrutinib and idelalisib, targeting components involved in the B cell receptor signaling cascade, both showed very interesting phenomenology of response [
24,
25]. In fact, both drugs were able to rapidly shrink lymph node masses even in massively pretreated patients (a feat that chemoimmunotherapy has very big problems with). However, apparently the inhibitors did not kill the CLL cells rapidly, but rather spilled them from the lymph nodes (and bone marrow) into the peripheral blood, where a sometimes dramatic increase in lymphocytosis could be observed. This lymphocytosis then decreases over time and the drugs produce a very high rate of partial, but durable remissions under continuing treatment. Also there is a clear tendency for improvement of response qualities over time. Complete remissions, or even MRD negativity, however, remain rare. Thus, the currently used treatment paradigm for these drugs is to treat until progression. The tolerability of the drugs is good compared with chemoimmunotherapy, but both substances have a distinct set of rare side effects that mandate specific management. Excitingly the control of clones with functional p53 deficiency by these drugs is much better than with standard treatment, giving this subgroup important avenues to improved survival [
26,
27]. However, with longer observation times the impression is that pretreated and/or p53 deficient CLL has a steady rate of relapse even from these treatments [
28]. Thus, alternatives are still needed. Most recently, direct targeting of the cell death machinery, via the Bcl-2 specific “BH3-mimetic” venetoclax has entered the field. Venetoclax produced relevant disease control in pretreated patients and in patients with del17p, adding another option to the armamentarium [
29]. Importantly, venetoclax was effective in patients previously treated with kinase inhibitors, giving those patients a salvage option (only presented in abstract form so far). In initial experience, venetoclax led to a high rate of relevant tumor lysis syndromes, but since a slow ramp up of the dose has been mandated this has not proven to be a big problem. Outside of the spectrum of currently licensed options, there are highly relevant developments in the area of immunomodulation (e. g., lenalidomide) [
30,
31] and immunotherapy (e. g., CAR T cells) [
32] that need to be mentioned but cannot be discussed in the brevity of the overview.
We have, thus, arrived at an exciting moment in CLL history, with lots of options to develop in the future and quite a bit of uncertainty about the optimal treatment pathways of today and tomorrow. As combination approaches with novel drugs are in development, we face the tangible possibility of cure or very long-term control for our patients. This has clearly been a very exciting decade for those interested in CLL, leaving the community both happy and hopeful.