Dr McCloskey highlights challenges in adverse event management and discusses unmet needs in the treatment of patients with leukemia.

Challenges in Managing Adverse Events and Unmet Needs in Leukemia

This is a synopsis of a Peer Exchange series featuring James K. McCloskey, MD, and Lori A. Leslie, MD, of John Theurer Cancer Center, Hackensack University Medical Center.

In concluding remarks on managing adverse events and addressing unmet needs in leukemia, James K. McCloskey, MD, Chief of the Leukemia Division at the John Theurer Cancer Center, notes challenges stemming from the underlying disease versus treatment-related effects. With patients often hospitalized and cytopenic at baseline, excellent communication and nursing care is imperative for adverse event monitoring and mitigation. Each leukemia subset also carries distinct unmet needs from relapse prevention to optimal sequencing of emerging targeted therapies.

Specifically in acute myeloid leukemia (AML), determining sequencing of molecularly-targeted agents is now a pressing question with multiple viable options for certain genotypes. As Dr. McCloskey explains, figuring out the ideal order for integrating FLT3, IDH1/2, and other inhibitors into frontline versus relapse settings remains an open need. Additionally, real-world data from community practices will grow increasingly important for translating clinical trial findings, like proper venetoclax dose reductions, into everyday care. While academic centers have optimized protocols, disseminating best practices into average clinics nationwide remains vital for patient benefit.

Overall, addressing adverse events and real-world evidence generation represent two cross-cutting needs as leukemia treatments rapidly advance. But with a proliferation of targets and therapeutic modalities on the horizon, the future is bright. Dr. McCloskey thanks attendees for joining this timely discussion around ASH 2022 data and the newly approved and emerging agents primed to transform patient outcomes across the leukemia landscape. By learning from prior challenges and leveraging real-world data, clinicians can collaboratively usher in a new era of practice-changing progress for blood cancer patients in need.

*Video synopsis is AI-generated and reviewed by OncLive editorial staff.

Videos

James K. McCloskey, MD, provides an overview of key takeaways from recent studies presented at the 2023 ASH Annual Meeting in leukemia.

Key Takeaways from Recent Updates in Leukemia

In closing remarks, James K. McCloskey, MD, Chief of the Leukemia Division at the John Theurer Cancer Center, reflects on the velocity of progress in myeloid diseases and leukemias. He notes several trials demonstrating clear benefits for patients with rare blood cancers lacking prior options. The pace of outcome improvements is accelerating, making this an exciting time in the field. However, challenges remain regarding disease rarity and treatment toxicities.

As Dr. McCloskey notes, overcoming these research barriers relies on strong community-academic partnerships. Tertiary centers depend on community physician referrals, especially for clinical trials accrual. All the myeloproliferative neoplasm and leukemia trials discussed, including TRANSFORM-1 in myelofibrosis and PhALLCON in Philadelphia chromosome-positive acute lymphoblastic leukemia, accrued New Jersey and New York patients through such collaborations. Thus, community trust and care coordination is crucial for translating cutting-edge leukemia research into patient benefits.

Additionally, balancing treatment safety in diseases already marked by low blood counts remains important. However, the toxicity profiles seem manageable, and the pace of therapeutic progress is startling. Treatments discussed like navitoclax and ponatinib combinations as well as newer agents on the horizon represent vast improvements over options merely 10 years prior. With multiple new approvals expected soon, marking increased commercial availability, the future is bright.

Overall, despite lingering challenges around rarity and side effects, myeloid malignancy and leukemia treatment is advancing faster than ever through fruitful community-academic partnerships. Continued coordinated efforts centered on patients are imperative to ensure research breakthroughs like those presented at the 2022 ASH Annual Meeting transform into real-world impact for blood cancer patients most in need.

An expert on leukemia provides comprehensive insights on the subgroup analysis of the phase 3 PhALLCON study of ponatinib in Ph+ acute lymphoblastic leukemia.

Subgroup Analysis of the Phase 3 PhALLCON Study of Ponatinib in Ph+ ALL

Shifting to Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL), James K. McCloskey, MD, Chief of the Leukemia Division at the John Theurer Cancer Center, discusses results from the phase 3 PhALLCON trial evaluating first-line ponatinib versus imatinib with chemotherapy. Unlike chronic phase chronic myeloid leukemia (CML), Ph+ ALL’s high relapse mortality necessitates maximally effective upfront therapy. Ponatinib’s potency against the emergent gatekeeper mutation T315I has made it an appealing option. However, randomized data was previously lacking.

PhALLCON fulfilled this need, combining ponatinib or imatinib with dose-adjusted chemotherapy backbones tailored to patients’ fitness. Updated results at the 2022 ASH Annual Meeting after a median 20 months of follow-up continue to demonstrate superior responses with ponatinib across all Ph+ ALL subsets. Specifically, major molecular response rates nearly quadrupled with ponatinib versus imatinib in patients over 60 years old, improving from 10% to 40%. This finding is clinically impactful since older patients have the greatest treatment challenges. Benefits were also seen for ponatinib in the P190 BCR-ABL variant and trended positive for the rarer P210 variant.

Encouragingly, safety profiles were comparable between ponatinib and imatinib with no new toxicities, complementing data from the OPTIC trial in CML. As Dr. McCloskey notes, these results continue building the evidence base for ponatinib’s approval in frontline Ph+ ALL. Its combination with blinatumomab is also yielding exciting chemo-free remission durability data. Overall, PhALLCON’s efficacy and safety updates further support ponatinib’s paradigm-changing potential to raise the treatment bar in Ph+ ALL, especially for older patients most in need of improved outcomes.

Focusing on chronic myeloid leukemia, James K. McCloskey, MD, reviews the long-term results of the OPTIC trial presented at ASH 2023.

Long-Term Results of the OPTIC Trial in CML

Shifting focus to chronic myeloid leukemia (CML), James K. McCloskey, MD, Chief of the Leukemia Division at the John Theurer Cancer Center, notes that while the majority of CML patients respond well long-term to tyrosine kinase inhibitors (TKIs), some develop resistance or intolerance, requiring alternate options like ponatinib. Previously, the phase 2 PACE trial explored ponatinib across CML stages and Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Though effective, vascular toxicity concerns prompted ponatinib’s temporary removal from the market. However, many clinicians observed lower side effect rates with reduced ponatinib doses, necessitating additional evidence.

The phase 3 OPTIC trial fulfilled this need, randomizing chronic-phase CML patients with TKI resistance/intolerance to starting doses of ponatinib at 45 mg, 30 mg, or 15 mg daily. Once achieving molecular response, patients were dose-reduced to 15 mg with the goal of maintaining efficacy while lowering cumulative exposure and subsequent toxicity risks. Updated OPTIC data at the 2022 ASH Annual Meeting provided key 2-year safety information from all 283 treated patients. While the 45 mg cohort showed the fastest and most robust responses, confirming this as the ideal starting dose, critically, no increases occurred in cardiovascular adverse event rates. Rates remained consistent across prior analyses and the 45 mg versus 30 mg arms.

Specifically, at 4 years, 60% of 45 mg-initiated patients achieved deep molecular responses, with >70% progression-free survival across ponatinib arms at 2 years and ~90% overall survival. Thus, ponatinib’s risk-benefit profile supports its use as standard-of-care for T315I mutated CML, complementing next-generation TKIs like asciminib which lack efficacy in this mutation. Per Dr. McCloskey, OPTIC’s longer-term safety data reassures current real-world practices of initiating ponatinib at 45 mg and de-escalating upon response. With careful cardiac monitoring, dose-optimized ponatinib remains imperative for these difficult-to-treat patients.

Following ASH 2023, a hematologist-oncologist discusses recent updates on approved and emerging therapies for patients with leukemia, highlighting TRANSFORM-1.

Recent Data from ASH 2023 in Leukemia

In this discussion on recent updates in the treatment of myelofibrosis, James K. McCloskey, MD, Chief of the Leukemia Division at the John Theurer Cancer Center, notes that while JAK inhibitors like ruxolitinib have offered symptom control and spleen volume reduction for myelofibrosis patients, substantial unmet needs remain regarding disease modification and survival improvement. However, data presented at the 2022 ASH Annual Meeting highlighted synergistic JAK inhibitor combinations that may finally offer disease modification.

Specifically, Dr. McCloskey discusses results from the double-blinded, placebo-controlled, phase 3 TRANSFORM-1 trial evaluating ruxolitinib plus navitoclax (a BCL-2 protein inhibitor) versus ruxolitinib plus placebo in JAK inhibitor-naïve patients with primary or secondary myelofibrosis. With a median 14 month follow-up of the 252 enrolled patients, the primary endpoint of ≥35% spleen volume reduction (SVR35) at week 24 occurred in 63% of the navitoclax arm versus 31% of placebo arm. Importantly, 77% of navitoclax patients achieved SVR35 at any timepoint compared to only 42% for placebo. Thus, the combination exhibited the most robust spleen responses observed to date.

Comparable results were seen in trials adding BET inhibitors like pelabresib to ruxolitinib, with twice the SVR35 rates versus ruxolitinib alone. However, neither the navitoclax or pelabresib trials showed clear improvements in symptom score reduction, contrasting the FDA’s traditional emphasis on patient-reported outcomes. As Dr. McCloskey notes, while symptom improvements remain critical in myelofibrosis management, the implications of symptom scores may need to be reweighted for combinatorial agents versus single agents.

In summary, these randomized trials finally demonstrate profound spleen responses from JAK inhibitor combinations, constituting a potential breakthrough for disease modification in myelofibrosis. Further analyses of clinical implications are still needed, especially regarding if enhanced spleen control translates into survival benefits. Additionally, refinements in managing adverse effects like cytopenias remain important for successful adoption into real-world clinical practice. Overall though, these combination strategies represent the most exciting advance for myelofibrosis treatment in years.

Following ASH 2023, a hematologist-oncologist discusses recent updates on approved and emerging therapies for patients with leukemia, highlighting the TRANSFORM-1 trial looking at navitoclax plus ruxolitinib.

James K. McCloskey, MD, a specialist in leukemia, discusses how the treatment landscape has changed in recent years.

The Evolving Treatment Landscape of Leukemia

In this discussion, James K. McCloskey, MD, Chief of the Leukemia Division at the John Theurer Cancer Center, discusses recent data from ASH and potential impacts on leukemia management. Dr. McCloskey notes that leukemia encompasses a heterogeneous group of diseases including most myeloid malignancies, bone marrow failure syndromes, and acute lymphoblastic leukemia (ALL). Advances have differed between diseases like chronic myeloid leukemia (CML) and acute myeloid leukemia (AML), myelodysplastic syndromes (MDS), or myelofibrosis. However, a common theme is exploiting understanding of genetic drivers of these diseases to develop targeted molecular agents. Early clinical research showed efficacy of these agents in relapsed/refractory settings as single agents. Now, combination regimens and new molecular pathways are improving upfront outcomes, despite research challenges due to the rarity of molecular subtypes. Recent abstracts at ASH continue exploring applications of molecularly targeted agents to enable more precise, personalized leukemia treatment.

Specifically regarding CML, tyrosine kinase inhibitors (TKIs) like imatinib have greatly improved survival over the last 20 years. However, some patients develop resistance or intolerance leading to investigations of alternate TKIs like ponatinib. The OPTIC trial compared ponatinib to standard dose imatinib, demonstrating superior major molecular response (MMR) rates by 12 months for ponatinib, with manageable side effects. Alternatively, the PACE trial explored ascending doses of ponatinib for patients resistant or intolerant to prior TKIs. Lower ponatinib doses demonstrated clinical activity in these difficult-to-treat patients, enabling continuation of TKI therapy.

In ALL, introducing targeted agents like the CD3/CD19 bispecific antibody drug conjugate blinatumomab and CD3 BiTE immunotherapy tafasitamab to chemotherapy backbones have led to improved remission rates and survival, especially in high-risk and relapsed/refractory patients. The comprehensive PhALLCON study is further exploring combinations with these immunotherapies to boost responses. The selective BET protein inhibitor INCB057643 also showed promise in early phase studies for relapsed/refractory patients, warranting further investigation.

Overall, these varied therapeutic approaches represent the wider paradigm shift toward molecularly targeted and immunotherapy-based combinations to drive more durable remissions, longer survival, and eventual cures for leukemia patients.

Dr McCloskey on Flow Cytometry and Machine Learning in Hematologic Malignancy Diagnosis

James K. McCloskey, MD, interim chief, Division of Leukemia, John Theurer Cancer Center, Hackensack Meridian Health, discusses findings from a study on next-generation sequencing (NGS) of flow cytometry CD markers, as well as the potential for machine learning to replace flow cytometry analyses in patients with hematologic neoplasms.

Although flow cytometry is widely used to diagnose patients with hematologic malignancies, the analysis of the data generated by this approach is subjective, and several neoplasms are difficult to diagnose using flow cytometry alone. Machine learning algorithms may compensate for the loss of subclonal analysis that occurs during the joint sequencing of cells in NGS. McCloskey and colleagues conducted a study to explore the potential use of a machine learning algorithm alongside RNA levels of CD markers to differentiate diagnoses between patients with various types of hematologic malignancies.

This study included 369 RNA samples from normal people to serve as a control and approximately 400 samples from patients with a variety of hematologic neoplasms. The malignancies diagnosed included acute myeloid leukemia (AML; n = 172), myelodysplastic syndrome (MDS; n = 218), myeloproliferative neoplasms (n = 68), acute lymphoblastic leukemia (n = 93), chronic lymphocytic leukemia (n = 74), mantle cell lymphoma (n = 38), and multiple myeloma (n = 83).

This study demonstrated that RNA sequencing of CD markers with the assistance of a machine learning computer model could reliably diagnose patients with hematologic malignancies, McCloskey said. Furthermore, this diagnostic method could differentiate between patients with hematologic neoplasms and healthy people. It could also differentiate between historically challenging diagnoses including AML and MDS with a high degree of specificity and sensitivity, McCloskey explained. Although the methods for diagnosing patients with diseases such as AML and MDS are evolving, this analysis provides insights into the potential role of machine learning in this area, McCloskey noted. Importantly, some patients who are diagnosed with MDS per World Health Organization criteria might exhibit disease characteristics more similar to that of AML, McCloskey concluded.

James K. McCloskey, MD, discusses the potential for machine learning to replace flow cytometry analyses in patients with hematologic neoplasms.

James K. McCloskey, MD