Experts Emphasize Importance of Preventing Progression in CML

Jorge E. Cortes, MD

Early diagnosis and early commencement of the most effective treatment available are essential in managing patients with chronic myeloid leukemia (CML), particularly since therapeutic options have expanded and testing technology has advanced.

Those were among the key take-home messages that CML experts conveyed during a recent OncLive Peer Exchange® roundtable entitled “Expert Perspectives on the Management of Chronic Myeloid Leukemia.”

The panel members were mindful of the advancements that have taken place in the CML field in the 15 years since the FDA approved imatinib (Gleevec) for the treatment of patients with Philadelphia chromosome-positive disease in 2001. Now, there are many nuanced treatment questions including the choice of frontline tyrosine kinase inhibitor (TKI) therapy, when to switch agents, and how best to monitor patients.

Choosing Upfront TKI Therapy

“The use of tyrosine kinase inhibitors targeting the BCRABL protein is the hallmark of therapy for patients with chronic myeloid leukemia and, as you know, it has transformed this disease from a life-threatening to a chronic one for most patients,” said moderator Jorge E. Cortes, MD. “We continue to refine our approaches to monitoring of CML and treatment of resistance to further improve outcomes for our patients.”The panelists agreed that getting patients started on therapy is vital to outcomes. “The sooner they start on definitive treatment, the sooner they’ll reach their treatment milestones, and this can have an impact on their overall survival,” said Kevin Kelly, MD, PhD.

To obtain baseline readings, Harry P. Erba, MD, PhD always orders three assays with new patients: chromosome analysis, FISH testing, and PCR testing, and then orders each test every 3 months. Do not rely on PCR alone, cautions Javier Pinilla-Ibarz, MD, PhD, since “some patients are diagnosed with false-positive low PCR levels.” As to next-generation sequencing, it is not quite ready for use in the clinic, said Pinilla-Ibarz. Performing a baseline bone marrow assessment at the time of diagnosis is “mandatory,” noted Cortes.

Kevin Kelly, MD, PhD

The most important goal of therapy “is the prevention of progression to accelerated phase and blast crisis,” stressed Erba. “It’s really important for the community oncologist to know that when we’re talking about progression, we’re not talking about losing a response and the white count goes up again.”

Rather, Erba said, “progression means that the biology of the disease has changed. The outcome of these patients is worse. Their survival is worse. They’re facing decisions about allogeneic transplant in that position, and when patients progress to accelerated phase or blast crisis, their median survival is about 10 months, So prevention of progression becomes the most important goal in my book, and treating patients with an agent that they can tolerate to do that is important.” Two large randomized controlled trials have shown that second-generation TKIs have fewer progressions to accelerated- or blast-phase disease compared with imatinib.

In the ENESTnd trial, nilotinib (Tasigna) demonstrated a significantly lower probability of progression than imatinib among patients newly diagnosed with CML in chronic phase after a 3-year follow-up.¹

In the DASISION trial, dasatinib (Sprycel) delivered faster and deeper responses than imatinib after a minimum follow-up of 3 years.² The median time to complete cytogenetic response was 3 months with dasatinib compared with 6 months for imatinib, and the proportion of patients with BCR-ABL transcript levels ≤10% was higher in the dasatinib arm.²

Harry P. Erba, MD, PhD

“All three drugs are very effective, but there is a slight benefit to the second-generation drugs,” said Kelly, noting that the newer drugs are “slightly better tolerated” compared with imatinib. He said his choice of TKI is also influenced by the patient’s comorbidities. He takes the time to sit with each patient and “have a discussion, very much a two-way street, and I assess the comorbidities.”

Once imatinib becomes available as a generic drug starting in February 2016,³ Kelly might, in a resource-poor setting, offer imatinib as a frontline treatment and then, if predefined endpoints are not being reached, switch to a second-generation TKI. But for patients at higher risk, those with higher Sokal scores, there is definite evidence that second-generation agents yield “a higher chance of getting into a major molecular response, into that safe haven phase at the 1-year time point, compared to the first-generation TKIs,” he said.

Both dasatinib and nilotinib bring approximately 50% of patients into a complete molecular remission, said Erba. Second-generation drugs “more quickly reduce the substrate of remaining residual leukemic cells that are at risk, potentially, to evolve mutations, which then can make it more complicated to treat the patient later,” explained David S. Snyder, MD.

Javier Pinilla-Ibarz, MD, PhD

The ENESTnd and DASISION trials demonstrated that patients more likely to reach the accelerated phase or blast crisis were those at high risk on Sokal or Hasford scoring systems. “So, certainly, for a patient at a high risk by Sokal diagnosis, there’s no question that I would be using a second-generation TKI,” said Snyder. “For a patient who is low risk, you might make more of an argument that imatinib could be appropriate, especially if you’re ready to make a change if you don’t reach the desired milestones.”

Monitoring Responses

Noting that generic imatinib is on the way, Snyder “put a word out to the insurance companies who may feel motivated to require generic imatinib as first-line therapy for all patients and only go to second-generation TKIs when they fail … I think that strategy exposes patients to risk. We don’t know that we can salvage patients if they fail a first-line TKI to go to the second at that time.”Once patients start therapy, it is important to monitor them regularly, the panel members agreed. The National Comprehensive Cancer Network (NCCN) and European LeukemiaNet (ELN) offer guidelines.

“I tend to follow the NCCN guidelines,” said Kelly. “For safety considerations, I check CBC and chemistry every 2 weeks for the first 2 months and then I pay close attention to the 3-month BCRABL time point … Patients who achieve BCR-ABL less than 10% at 3 months have a better overall survival.” If they’re slightly above 10%, he waits for the 6-month findings, and then continues to check BCR-ABL every 3 months until the patient achieves a major molecular response.

“We’ve moved away from doing a lot of bone marrow biopsies and I think a lot of patients are very grateful for that,” noted Kelly. “But there still is a role for bone marrow biopsies, particularly when the BCR-ABL is hovering above the 1% mark, and we want to confirm that they’ve lost a complete cytogenetic response.”

David S. Snyder, MD

Although there has been discussion about whether selected patients might be permitted to discontinue pharmacotherapy, at present and outside of clinical trials the word on TKI discontinuation is “don’t try this at home,” said Pinilla-Ibarz. Of course, the situation might be different

Managing Toxicities

if a patient wants to become pregnant. In that situation, Kelly might discontinue but first “would like to see a complete molecular response that’s sustained preferably over a 2-year period.” Thereafter, he would monitor “very carefully” because “they can relapse—even late after discontinuation— with lymphoid blast crisis.”An important point to consider when managing patients taking TKI therapy is whether they are complying with their treatment plan, particularly if toxicities or financial considerations become issues. “Patients who don’t take their drugs don’t do as well,” commented Snyder, who noted that studies show “something like 85% of patients with CML are not consistently adherent.”

When to Switch Strategies

“Managing toxicities is key to keeping your patients on their therapy,” explained Erba. At the start of treatment with each new agent, he explains to patients that many toxicities are transient. He then continues to see patients every 3 months “even when they’ve been on therapy for 5 years and they’re doing great.” He continues to assess such things as side effects and financial barriers that might interfere with compliance. Of course, some of the complications associated with these drugs involve the cardiovascular and pulmonary systems, and it is not only oncologists who are capable of addressing them. Snyder advocates educating “our non-hematology colleagues in the community—the cardiologists, the pulmonologists who may be the first ones to see some of these patients with these complications.” “I would appeal to the community physicians and to all the physicians treating CML to really try to manage the toxicities as best as possible before making a switch to another agent,” said Kelly, who noted that some patients are being “switched very rapidly” among treatments “for minor toxicities or for any minor variations in the PCR.” As Snyder pointed out, switch to another drug and some additional toxicity might appear, “and maybe that one would be worse than what the patient has now.”For patients with a lack of response, Pinilla- Ibarz looks to either the NCCN or the ELN guidelines to guide decisions about switching to a different medicine. For the patient who started with imatinib, if a good response has not been achieved in 3 to 6 months, he may switch to a second-generation TKI. But if the patient started with a second-generation TKI, he might wait a little longer as “we may not have so many options.”

As to making changes based on intolerance, Snyder rarely does that. “It’s very common for patients to have low grade, grade 1, grade 2 toxicities with any of the TKIs,” he said. “For most of those toxicities, with time and support, those symptoms abate and patients can continue on. So I’m fairly slow to make changes based on intolerance and it’s pretty rare in my practice that I have to do that.” Erba finds that ABL mutational analysis provides useful information that helps him select the appropriate drug for the individual patient. He said nilotinib might be a better choice in patients with a codon 317 or a codon 299 mutation, while dasatinib may be a better choice for patients with P-loop mutations. The label indication of ponatinib (Iclusig) is for patients with a T315I mutation. For patients who do not achieve an adequate response, the approach depends in part on whether the patient is a candidate for allogeneic stem cell transplant. TKIs do not damage transplant outcomes, just as long as the patient is in the chronic phase of the disease. “So the trick is not letting them progress,” Erba said.

“Once a patient starts having particular resistance— intolerance is a different business -- but resistance to one TKI and definitely to two TKIs, it’s time to at least talk to the transplant doctor, at least see what options do we have for donors, etc,” said Cortes.

Although a decision to go forward with a transplant might not be made at that time, the patient has had the opportunity to learn what the procedure might mean and to investigate their donor options.

References

1. Larson RA, Hochhaus A, Hughes TP, et al. Nilotinib vs imatinib in patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase: ENESTnd 3-year follow-up. Leukemia. 2012;26(10):2197-2203.
2. Jabbour E, Kantarjian HM, Saglio G, et al. Early response with dasatinib or imatinib in chronic myeloid leukemia: 3-year follow-up from a randomized phase 3 trial (DASISION). Blood. 2014;123(4):494-500.
3. Sun Pharma announces US FDA approval for generic Gleevec [press release}. Sun Pharmaceutical Industries Ltd.; December 4, 2015. http://goo.gl/3QVsKW