There are two very effective oral drugs currently approved in the USA for treating chronic lymphocytic leukemia (CLL), namely ibrutinib and idelalisib, which interfere with the B-cell receptor (BCR).
But at this point, we aren’t curing anyone with these meds, and although they are generally well-tolerated, some folks can’t stay on therapy due to side effects, so we need more treatment options.
One of the next generation of drugs closest to approval is duvelisib, formerly known as IPI-145. Let’s take a look at it.
Duvelisib is a PI3 kinase inhibitor and in that way is similar to idelalisib, but its activity has important differences.
Idelalisib and the experimental drug TGX 1202 both inhibit the δ (delta) isoform of PI3 kinase, whereas duvelisib inhibits both the δ and the γ (gamma) isoforms of the enzyme. So what does that mean?
Let’s look at some of the basic science first, then the data and finally the ongoing trials.
The PI3K (Phosphatidylinositol-4,5-bisphosphate 3-kinase) pathway includes four isoforms (varieties): alpha, beta, delta, and gamma (α, β, δ, and γ). PI3K-δ and PI3K-γ are primarily expressed in white blood cells. They perform different supportive roles in the life of the cells, including promoting cell proliferation and cell migration to form a network of nearby helpful cells. A treatment that is an inhibitor, like duvelisib would have the desired effect of blocking these activities in the cancerous (malignant) B-cells of CLL.
We know well that the BCR pathway activation is a powerful survival signal for malignant B cells, and we know that blocking it downstream through the PI3K pathway that BCR turns on has a potent anti-cancer effect. Blocking BCR is thought to be the primary way in which both PI3K inhibitors and BTK inhibitors such as ibrutinib, acalabrutinib, ONO/GS-4059 and BGB-3111 work in controlling CLL.
The γ isoform of PI3K adds another line of attack. It may have more to do with how the CLL cells link up with their support network or the tumor’s important microenvironment. Theoretically, if we can block both pathways, we cut off more survival and proliferative signals and prevent the malignant cells from escaping control.
One study published in BLOOD looked at a very tough group of relapsed and refractory patients. “Of the pts with baseline tests for mutations associated with poor CLL prognosis, 49% (23/47) had TP53mut and/or cytogenetic (del)17p and 89% (31/35) had an unmutated IGHV.” The overall response rate was 55%, irrespective of the risk factors including (del)17p.
Adverse events included low counts especially neutrophils and infections including pneumonia. It’s only an abstract of early data, so we need to be cautious in our interpretation of the data, but there was no mention of colitis or liver inflammation that has been a significant problem with idelalisib, especially in frontline use.
In one small trial of 12 patients that had progressed on ibrutinib, another tough bunch to treat, duvelisib worked for 6 but after 8 months only 2 patients were still on it.
A 2015 ASH abstract boasts an impressive 92% response rate in patients with relapsed CLL when used in combination with rituximab and bendamustine (BR) and the mean (average) overall survival time had not been met at the time of publication.
There are some trials to consider:
This would be mostly be for those patients who failed ibrutinib and as mentioned above, there is reason to be optimistic.
A Study of Duvelisib and Venetoclax in Subjects With Relapsed or Refractory Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, or Indolent or Aggressive Non-Hodgkin Lymphoma, Who Have Not Previously Received a Bcl-2 or PI3K Inhibitor
This is a sensible and powerful non-chemo drug combination, because we know that it is almost certainly going to take more than one drug to wipe out our CLL.
For treatment-naive young patients there is this next study that involves a chemotherapy backbone:
I expect a very high response rate with this potent combo. It would be especially worth considering if one needed treatment and was a low-risk patient, unmutated with no adverse prognostic markers. I would anticipate a very long remission based on the already strong FCR (Fludarabine, Cyclophosphamide, Rituximab) data for this population and with the added benefit of the kinase inhibitor. For a discussion of chemotherapy combinations from a patient’s perspective, take a look here.
Finally I will mention a closed trial because it is a Phase 3 trial that is likely providing the data that will result in the FDA approval of duvelisib.
We are lucky to have the therapies that are already approved, but I am excited to learn about new therapies coming along. We need them.
Brian Koffman, MD 5-16-16