Hagop KantarjianLeukemia research and cancer drug policy

Advancing treatments in leukemia are transforming patient outcomes

4 Dec 2020 · 4 min

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In this expert panel discussion, the speakers review recent breakthroughs that are reshaping the therapeutic landscape of the major leukemias. For chronic myeloid leukemia (CML), they note that five BCR‑ABL tyrosine‑kinase inhibitors have turned the disease into a chronic condition with near‑normal life expectancy, and current trials aim for durable deep molecular responses that could allow treatment discontinuation. In chronic lymphocytic leukemia (CLL), the combination of ibrutinib (a BTK inhibitor) and venetoclax (a BCL‑2 inhibitor) achieves complete molecular response rates of ~90% and 5‑year survival of 90‑95%, with many patients remaining disease‑free after a limited 1‑2‑year course, suggesting a functional cure. For acute myeloid leukemia (AML), adding venetoclax to both low‑intensity and intensive chemotherapy regimens produces remarkable response rates, extending the benefit of targeted therapy to this aggressive disease. Finally, in acute lymphoblastic leukemia (ALL), integrating novel antibodies—belinatumab (a CD19‑targeting bispecific) and inotuzumab (a CD22‑directed antibody‑drug conjugate)—with chemotherapy markedly improves frontline and salvage outcomes, potentially achieving cure rates comparable to pediatric protocols but within a shorter 1‑1.5‑year treatment window. Across all subtypes, the panel emphasizes a historic shift from historically incurable diseases to potentially curable, time‑limited therapies.

Chapters

So as I stated in chronic myeloid leukemia, the 5 BCR-ABL kinase inhibitors have normalized the lives of patients. And now we are testing approaches that increase the incidence of durable elimination of the disease, what we call durable deep molecular response. So in CML, I think it's just a matter of fine-tuning the approach to these patients. But the large majority of patients with newly diagnosed CML could expect to live their normal life receiving one of those tyrosine kinase inhibitors.
In chronic lymphocytic leukemia, that's the second large in chronic leukemias. In chronic lymphocytic leukemia, we and other investigators from other institutions have have already reported that the combination of ibrutinib venetoclax is producing fantastic results with complete molecular response rates, which are in the range of 90%, and estimated survivals at 5 years, which are over 90 to 95%. So if you look at the 2 chronic leukemias, CML and CLL, when I started my career in 1991, we did not have any good approaches. In CML, we use busulfan or Hydria.
In CLL, we use chlorambucil.
And neither of these diseases were curable in those days.
Today, both CML and CLL are potentially functionally or molecularly curable. So if you look at CLL, the textbooks still say that CLL is incurable except with transplant.
I think since 2015, there are multiple pieces of evidence and publications that suggest that the combination of ibrutinib venetoclax produces complete molecular responses in most of these patients. And those complete molecular responses are durable, even after discontinuing the ibrutinib venetoclax, which is usually given for 1 to 2 years. So unlike CML, where many of the patients continue to need the BCR-ABL kinase inhibitor for their lifetime, in CLL, this disease has become functionally and molecularly curable with the couplets of ibrutinib, which is a Bruton tyrosine kinase inhibitor, and venetoclax, which is a BCL-2 inhibitor. I already discussed acute myeloid leukemia, and I pointed to the 2 sets of information, the low intensity therapy with venetoclax, and the intensive chemotherapy with venetoclax, which are producing fantastic results. The last leukemia that is important is acute lymphocytic leukemia. And here we and others have now shown that combining chemotherapy with the new antibodies such as belinatumumab, which is a bispecific, antibody construct that targets CD19, and inotuzumab, which is a monoclonal conjugated antibody that targets CD22. When we add those antibodies to chemotherapy in the salvage or the frontline setting, we are getting results that we've never had before. In particular, in the frontline setting, I think this kind of a combined modality therapy of chemotherapy with those 2 antibody cocktails, is going to allow us to increase the cure rate, perhaps to levels which are seen in pediatric leukemia.
But in contrast to the pediatric leukemia, we may be able to deliver these regimens over a period of 1 to 1.5 years, rather than the 3-year regimens which are used in pediatric leukemias.