Following FDA Approvals, CML Pipeline Has Challenges

Michael J. Mauro, MD

The past year has seen the release of data regarding advances in the treatment of patients with chronic myeloid leukemia (CML), including some leading to recent regulatory approvals, but remaining challenges include conceptualizing treatment-free remission and optimal sequence of therapies.

In December 2017, the FDA approved bosutinib (Bosulif) for patients with Philadelphia chromosome-positive (Ph+) CML, based on findings from the BFORE trial. In the open-label phase III trial, the major molecular response at 12 months was 47.2% with bosutinib (95% CI, 40.9%-53.4%) compared with 36.9% (95% CI, 30.8%-43.0%) for imatinib (Gleevec; P = .02). The complete cytogenetic response rate by 12 months was 77.2% (95% CI, 72.0%-82.5%) with bosutinib versus 66.4% (95% CI, 60.4%- 72.4%) for imatinib (P = .0075).

More recently, in March 2018, the FDA approved nilotinib (Tasigna) for the first- and second-line treatment of pediatric patients aged 1 year and older with Ph+ CML in the chronic phase. In December 2017, the FDA updated the label for nilotinib with a provision stipulating that patients with Ph+ CML in the chronic phase who have received the drug for at least 3 years, and have achieved specific predetermined criteria, may be eligible to stop treatment.

OncLive: Please provide an overview of your presentation on advances in CML treatment.

At the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Michael J. Mauro, MD, discussed the recent updates in this landscape. In an interview during the meeting, Mauro, a hematologist and leader of the Myeloproliferative Neoplasms Program at Memorial Sloan Kettering Cancer Center in New York, described updates presented at the 2017 ASH Annual Meeting and the advances that are on the horizon for patients with CML.Mauro: I spoke about the 2017 ASH Annual Meeting, where several interesting and in-depth topics were covered. One of the most important topics was novel frontline treatments for patients with CML. Then, we saw the FDA approval of bosutinib. We are going to have 4 drugs approved in the frontline setting for chronic CML, which is exciting. It can be confusing, but it is our job to help navigate through the different options available.

Another important topic that was covered was how to conceptualize treatment-free remission, which is the end of treatment for patients with CML. It is exciting that tyrosine kinase inhibitor (TKI) therapy can put patients into a deep remission over time. This year, more details will be released about which subsets will benefit and when. Nearly half of patients can discontinue treatment safely and no longer need therapy.

[Also at the 2017 ASH Annual Meeting], we saw a presentation of a cardiology assessment on patients with CML. CML therapies may have different risks, but the excellent survival of these patients is something we need to pay attention to.

What trial led to the accelerated approval of bosutinib in the first-line setting for patients with CML?

Can you discuss treatment-free remission as a concept?

Can you comment on the pediatric approval of nilotinib in CML?

Can you elaborate on the potential of TKI therapy in this eld?

Please expand on these unmet needs.

We saw additional data on the option of treatment-free remission after second-line therapy, which is important as well. There have been some recent publications on fourth-generation drugs in CML. The compound ABL001 shows great promise by itself and in combination with other regimens. It may be an answer as it is a relatively low-risk agent and can salvage patients with resistance or tolerance.What led to the FDA approval of bosutinib was the BFORE trial, which was a randomized trial between imatinib and bosutinib. The main endpoint was molecular remission. Due to the design and approach, this study showed clear differences in outcomes at 12 months, which led to the FDA approval. In recent publications and at the 2017 ASH Annual Meeting, we saw 18-month updates, which saw improvements in the cytogenetic response and molecular response, and some hints toward protection against progression, as well.At the 2017 ASH Annual Meeting, we heard about the timing of treatment-free remission or treatment cessation. With a large data set, can we try to dissect what might be the ideal time to think about a patient in deep remission coming off the therapies? Is there a critical amount of time they should be in deep remission? We have seen many presentations and studies that all converge on many different facts, but that is still a bit of an unknown. We have some clarity that 5 to 6 years of treatment and at least 3 years of molecular remission seem to be the ideal time.Some additional late-breaking news is involving our pediatric patients with CML. This study of a TKI has been slower because of the safety concerns with a small number of patients but sequential trials have made some headway. At the 2017 ASCO Annual Meeting, we saw dasatinib (Sprycel) data that were convincing and helped us understand dosing and scheduling. Now, we have nilotinib approved for pediatric patients with CML. That extends the treatment options for children, who are a rare population but an important one.We have a great story with multiple treatment and multiple salvage therapy options for patients with CML. We have the ability to potentially think about treatment-free remission. We set the stage for other cancers with targeted drugs by being able to have a nonchemotherapy approach, treat patients well, and potentially cure a high-risk cancer such as CML. We need to be careful of the long-term follow-up of the safety profile and optimizing treatment-free remission and not be hasty or premature about it. We are still addressing the unmet needs for the work in pediatrics and how they resist disease. That is an area that we need to work on.Some of the most important unmet needs in CML would be what to do when a patient has been through multiple lines of therapy and either has a mixture of both intolerance or resistance. We have the sad situation of a patient who doesn’t have that low-risk oral therapy option that most patients do. The most promise comes from drugs such as ABL001, which is a novel TKI with a different mechanism of action than the other TKIs available. It is an oral agent that can be taken once or twice daily with excellent safety. Incorporating drugs into advance-phase disease in chemotherapy around bone marrow transplant is still a useful modality in CML, which is important for exploration. Now that we have so many treatment options, understanding how to sequence them properly, choosing the right drug according to safety profiles, and monitoring the patients properly will hopefully lead to a successful journey across the board.

Cortes JE, Gambacorti-Passerini C, Deininger MWN, et al. Bosutinib (BOS) versus imatinib (IM) for newly diagnosed chronic myeloid leukemia (CML): initial results from the BFORE tri- al. J Clin Oncol. 2017;35 (15 suppl; abstr 7002). doi: 10.1200/JCO.2017.35.15_suppl.7002.