The Journey of an Optimistic Oncologist

As a hematologist-oncologist, I can relate to former President Barack Obama’s sentiment in a 2016 editorial he wrote for Wired: Despite all we face, now is the greatest time to be alive. Some might find that perspective bold, but the belief in our readiness to confront challenges deeply resonates with me as a clinician who treats patients with blood cancers. There are no better days in oncology than today—except, of course, for tomorrow, which holds even more promise for our patients.

We are fortunate to practice medicine at a time when we’re discovering the cure for diseases that were once fatal. Today, we can offer our patients hope that what was completely unachievable only a few years ago is now achievable.

I want to redefine leukemias as curable or less curable—a reflection of my optimism in how this cancer is being managed—instead of how they are currently characterized: acute, chronic, early stage, or late stage.

Currently, hairy cell leukemia is one of two cancers with a very high cure rate (90%-95%). It can be cured with minimal intervention, essentially with chemotherapy, a drug called cladribine, and rituximab. The second is acute promyelocytic leukemia. Even with no chemotherapy, by giving all-trans-retinoic acid and arsenic trioxide, the cure rate in adult patients is 90% and above.

Chronic lymphocytic leukemia (CLL) also falls into the curable category. Today, patients with CLL can live a normal lifespan and receive a finite therapy, instead of being treated for life, by combining Bruton’s tyrosine kinase and B-cell lymphoma 2 inhibitors and eventually novel CD20 antibodies. The remission rate is quite good with one or two years of therapy, and patients can be expected to have a normal lifespan without continuing therapy.

Chronic myeloid leukemia (CML) is another form of leukemia that is curable. Until 2000, only a few patients were cured, and those were young patients who had a potential donor and transplantation. Today, with the availability of tyrosine kinase inhibitors (TKIs), a patient with CML who is responsive to treatment can expect to live a normal lifespan.

After we redefine leukemias, the next step is to ask, “In treating CML, even if we achieve a good response, can we stop therapy?” Today, with our treatment aimed at inducing deep and durable remissions, we’re looking not only to extend patients’ lifespans to normal, but also to free them from a lifetime of medication. We’re working toward inducing a deep remission that can be maintained for three to five years, offering a real chance at stopping therapy.

I want to highlight other curable leukemias that were incurable not too long ago.

The cure rate of Philadelphia-positive acute lymphoblastic leukemia (ALL) used to be 10%. Then we were able to offer transplant to these patients, improving the cure rate to 30% to 40%. Next, we added TKI to chemotherapy, which improved the survival rate to 50% to 60% but also resulted in a plateau of the cure rate. Today, with upfront immunotherapy and the combination of TKIs, we’re witnessing a survival rate of 90% in these patients, which is amazing.

ALL in younger patients was traditionally incurable, with cure rates that plateaued at 60%, regardless of the treatment regimen (pediatric or hyper-CVAD). Today, these patients are doing well with the integration of immunotherapy upfront, with cure rates of 80% to 85%.

For older patients with ALL, survival was very poor until 2010. Medicare data showed a survival rate of six to eight months, which was driven by poor biology, inducing resistance to chemotherapy and comorbidities and leading to poor tolerance to treatment intensity. The integration of immunotherapy upfront in these patients led to universal responses and a five-year survival rate of 50%.

Today, we are moving away from intensive chemotherapy and exploring chemotherapy-free approaches for more improved outcomes.

A notoriously challenging disease, acute myeloid leukemia (AML) used to have a survival rate of 10% to 20%. Today, younger patients with AML have improved outcomes, with a survival rate of approximately 60%, which can be attributed to better understanding of the disease biology, improved diagnoses, targeted therapies that are added to the treatment upfront, and better transplant techniques.

The management of older patients with AML remains challenging. Although we have a new standard of care—venetoclax and hypomethylating agents (HMAs)—improvement remains modest. We’re building on that regimen to further improve outcomes by treating patients with a triplet of cladribine, low-dose cytarabine, and venetoclax, alternating with an HMA and venetoclax. Overall, we have improved the cure rate to 50% to 60%. These patients are getting to transplant, and we have targeted therapies available to further improve outcomes.

Alongside our significant progress, several subtypes remain difficult to treat. Patients with MECOM AML have very poor outcomes, and we’re exploring new agents for this target. The AML subtype with KMT2Ar- or 11q23-rearranged disease is also challenging to treat. We are exploring a plethora of menin inhibitors in these patients, with very promising early results.

The evaluation of menin inhibitors in combination with intensive chemotherapy or targeted therapy with an HMA and venetoclax to further improve outcomes in frontline treatment is ongoing, and results will be reported soon.

Finally, in TP53-positive AML, none of the drugs explored thus far has succeeded, but additional agents are being investigated.

Other tough-to-treat leukemias include high-risk myelodysplastic syndromes (MDS), where we are eagerly awaiting the combination of an HMA and venetoclax. Once a patient fails frontline therapy, there are few treatment options available outside of clinical trials. However, I would again like to highlight my optimism. Several drugs are now approved in low-risk MDS, including luspatercept and oral decitabine. Imetelstat, a telomerase inhibitor, will hopefully receive approval soon.

We are making progress in developing effective therapies for myelofibrosis and myeloproliferative neoplasms. Treatment advances began with Janus kinase 2 (JAK2) inhibitors. Now, we are witnessing progress in several randomized trials exploring combinations of JAK2 inhibitors plus other agents, such as MDM2 inhibitors, BCLXL inhibitors, and other therapies, to further improve outcomes.

Today is the best day to practice medicine in leukemia. I’m optimistic that the cure of this disease will happen in our lifetime. We have everything we need. Trials are ongoing, and in the next few years, perhaps we will witness measured improvements in outcomes across all types of leukemia.

Elias Jabbour, MD, is a Professor in the Department of Leukemia at the MD Anderson Cancer Center.