CME
Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™
Released: August 16, 2024
Expiration: February 15, 2025
ASC4FIRST: Background
There were 4 key trials in leukemias and MDS with interesting results that were presented at the ASCO 2024 meeting in Chicago, Illinois. The first of these is the ASC4FIRST trial for patients with newly diagnosed chronic myeloid leukemia (CML) who are in need of long-term upfront treatment options that optimize efficacy, safety, and tolerability.17,18
Many healthcare professionals who treat patients with newly diagnosed CML know that standard tyrosine kinase inhibitors (TKIs) targeting BCR-ABL are efficacious but often do not yield optimal responses because they are difficult to initiate, and of most importance, because it is challenging for patients with CML to remain on these agents for prolonged periods of time. Imatinib is a first-generation TKI which received FDA approval for patients with CML in 2001.19 It is the first approved targeted TKI therapy for patients with cancer. Thereafter, second-generation TKIs were developed. Although these second-generation TKIs result in faster and deeper molecular responses, they are also associated with toxicities that negatively affect patient adherence. Data have shown that up to one third of patients with CML are not compliant with their treatment schedules because of the associated AEs.20,21
Asciminib, a third-generation, first-in-class, BCR::ABL allosteric inhibitor, specifically targets the ABL myristoyl pocket.22 Its unique mechanism of action makes it distinct from all other TKIs in clinical use. Asciminib received FDA-accelerated approval for patients with Philadelphia chromosome-positive (Ph+) CML in chronic phase (CML-CP) who have previously received ≥2 TKIs, and those with Ph-positive CML-CP harboring the BCR-ABL T315I mutation.23 Although asciminib is in clinical use in the R/R setting, the ASC4FIRST trial investigated whether asciminib can be moved earlier in the treatment course for patients with newly diagnosed CML.17,18
ASC4FIRST: Study Design
ASC4FIRST is a multicenter, open-label, randomized phase III trial for patients aged 18 years or older with newly diagnosed Ph-positive CML-CP. Patients (N = 405) were randomized in a 1:1 ratio to receive either asciminib 80 mg/day (n = 201) or IS TKI (n = 204). Patients in the IS-TKI cohort received an available TKI, either imatinib or one of the second-generation TKIs (nilotinib, bosutinib, or dasatinib). The primary endpoint was MMR at Week 48 in the overall patient population and specifically among patients in the imatinib stratum.
As this is an international study, and because imatinib is the only TKI of choice for CML in many countries that participated in the trial, imatinib was specifically called out from the other TKIs in the IS-TKI cohort comparison. The key secondary endpoints of the study included MMR at Week 96, safety, tolerability, complete hematologic response, complete cytogenetic response, PFS, OS, event-free survival (EFS), and pharmacokinetics.
ASC4FIRST: Baseline Characteristics
The baseline patient characteristics were relatively well balanced between the treatment arms. The median age in the asciminib group was 52.0 years (range: 18-79) vs 50.5 years (range: 19-86) in the IS-TKI group. Most patients were aged 18 to younger than 65 years, and most had a low Framingham cardiovascular risk score and a low European Treatment and Outcome Study (EUTOS) long‐term survival (ELTS) score.
ASC4FIRST: Molecular Responses With Asciminib vs IS-TKIs
In the overall patient population, the primary endpoint of MMR at Week 48 was achieved by significantly more patients in the asciminib group vs the IS-TKI group (67.7% vs 49.0%, respectively). Among patients in the imatinib stratum, the MMR at Week 48 was 69.3% with asciminib vs 40.2% with IS-TKI. In the second-generation TKI stratum, the MMR at Week 48 was 66.0% with asciminib vs 57.8% with IS-TKI. These results were consistent with the rates of early molecular response at Week 12 and molecular responses (4 log and 4.5 log reductions) at Week 48 in the 2 groups. These results support asciminib as a potentially superior TKI based on the potency of molecular response vs all other TKIs at the time points studied in the trial.
ASC4FIRST: MMR at Week 48 by Subgroup: Asciminib vs IS-TKI (Full Set Analysis)
Analysis of MMR at Week 48 according to subgroup showed that asciminib benefited all patients regardless of ELTS risk score (low, intermediate, or high). When analyzed by age, asciminib was superior to all other TKIs regardless of age group category. Men benefited more from asciminib than women, but overall, sex played no role in the benefit of asciminib vs IS-TKI in CML. In general, the trend suggests that in all subgroups analyzed, asciminib resulted in deeper and more frequent molecular responses vs imatinib or all other TKIs in the treatment of newly diagnosed patients with Ph-positive CML-CP.
ASC4FIRST: Grade ≥3 Toxicity, Treatment Modification, and Hematologic Adverse Events
In addition, asciminib led to fewer treatment discontinuations than the second-generation TKIs (4.5% vs 9.8%, respectively). When looking at treatment-related AEs, it is particularly important to look at AEs that may require treatment adjustments. There were fewer dose adjustments or interruptions with asciminib compared with second-generation TKIs (30.0% vs 52.9%, respectively). There were fewer grade ≥3 AEs with asciminib (38.0%) vs imatinib (44.4%) or second-generation TKIs (54.9%). There were also fewer hematologic AEs overall with asciminib compared with second-generation TKIs. In particular, compared with patients who received second-generation TKIs, fewer patients treated with asciminib experienced thrombocytopenia (34.3% vs 28.0%, respectively), neutropenia (34.3% vs 25.0%, respectively), anemia (22.5% vs 11.5%, respectively) and lymphopenia (6.9% vs 6.0%, respectively).
ASC4FIRST: Nonhematologic AEs
In terms of the nonhematologic AEs, in particular, hepatic AEs and increased blood bilirubin, there were striking differences between asciminib and second-generation TKIs. With the second-generation TKIs, elevated alanine aminotransferase (18.6% vs 7.0%), elevated aspartate aminotransferase (14.7% vs 2.0%) and elevated blood bilirubin (10.8% vs 2.5%) were more frequently reported than with asciminib. Overall, the incidence of gastrointestinal AEs, fatigue, headache, rash, and muscle spasms was markedly higher with the second-generation TKIs compared with asciminib.
ASC4FIRST: Key Takeaways
In conclusion, the ASC4FIRST study demonstrated that first-line asciminib was superior to all standard-of-care TKIs including imatinib and all second-generation TKIs, inducing significantly higher rates of MMR at Week 48 among patients with newly diagnosed Ph-positive CML-CP. In summary, asciminib demonstrated a more favorable safety and tolerability profile compared with the second-generation TKIs, including a less frequent hematologic and nonhematologic AEs with asciminib. These results suggest that asciminib could potentially become a treatment of choice in the frontline setting.
MMR has previously been correlated with OS.24 However, for patients with CML, the question about whether the rapidity at which MMR is achieved is correlated with PFS and OS has remained an unanswered question. Although some data suggest that the second-generation TKIs can get patients with CML to achieve MMR faster, it does not necessarily mean that patients who achieve MMR at a slower pace do not achieve similar OS and PFS outcomes. Hence, a remaining question about the results of the ASC4FIRST study is whether achieving MMR in as little as 48 weeks with asciminib results in a difference in long-term PFS and OS outcomes for patients with CML. It is also important to note that achieving MMR rapidly and remaining in MMR for 2-3 years can also make patients with CML eligible for TKI discontinuation and time-limited TKI therapy earlier than the other TKIs, which could be an additional consideration, particularly for younger patients.
ASC4FIRST is a pivotal study because it is the first and only randomized study to compare different generations of BCR-ABL–targeted TKIs for patients with newly diagnosed CML. However, we will need longer-term follow-up to determine whether the molecular responses achieved by the patients will translate into long-term survival outcomes. A possible clinical implication of treating with a more potent TKI at diagnosis may be achieving MMR faster and potentially making patients eligible for TKI discontinuation at an earlier time point. For many of my patients with newly diagnosed Ph-positive CML-CP, the duration of treatment and when treatment will be discontinued is a common and highly relevant question at the initiation of CML therapy.
MANIFEST-2 Update: Background
Next is the MANIFEST-2 trial that is focused on patients with myelofibrosis (MF), a debilitating myeloproliferative disease.25 Patients with MF have the worst outcomes among all of the myeloproliferative neoplasms. This disease is associated with progressive cytopenias, bone marrow fibrosis, and splenomegaly. Laboratory studies have shown that dysregulation of the JAK/STAT signaling pathway and alterations in BET-mediated gene regulation play a role in the underlying pathogenesis of MF.26 Currently, the standard of care for patients with intermediate-risk and high-risk MF is the initiation of a JAK inhibitor alone.25
For many years, the standard-of-care JAK inhibitor was ruxolitinib, and the focus has been on the development of other JAK inhibitors. Over the years, a persistent question has been how to improve the efficacy of ruxolitinib or any JAK inhibitor in patients with newly diagnosed MF, especially those with intermediate-risk or high-risk disease. Unlike in other cancer types, the initial studies that demonstrated the benefit of ruxolitinib in MF did not focus on OS as the primary endpoints. Instead, the primary endpoint was the proportion of patients with a spleen volume reduction (SVR) of ≥35% from baseline to Week 24.27,28 In the landmark analysis of OS in the phase III PERSIST-2 trial of the JAK inhibitor pacritinib vs best available therapy for patients with MF and thrombocytopenia, achieving SVR was associated with a longer OS.29
Pelabresib is an oral small-molecule BET inhibitor that can potentially modify the pathobiology of MF.30 It acts by epigenetically modifying MF cells. At ASCO 2024, the updated results from the MANIFEST-2 trial of pelabresib in combination with ruxolitinib patients with newly diagnosed MF were presented.31
MANIFEST-2: Study Design
MANIFEST-2 is a double-blind, placebo-controlled phase III trial that randomly assigned 430 newly diagnosed patients with JAK inhibitor–naive, intermediate-risk or high-risk MF to receive the standard-of-care ruxolitinib plus placebo (n = 216) vs ruxolitinib plus pelabresib (n = 214). As in other previous studies, the primary endpoint was SVR by ≥35% at Week 24. The key secondary endpoints included safety, change in absolute total symptom score (TSS) from baseline to Week 24, and ≥50% reduction in TSS (TSS50) at Week 24.
MANIFEST-2 Update: Baseline Characteristics
The baseline characteristics of the patients enrolled on the trial reflect the typical characteristics of patients with MF. MF is primarily a disease of men aged in their 60s and 70s. The baseline characteristics were well balanced between the 2 treatment arms. All patients on the trial had intermediate-1–risk, intermediate-2–risk, or high-risk MF.
MANIFEST-2 Update: SVR35 at Week 24
The waterfall plot shows the SVR at Week 24 in patients who received placebo plus ruxolitinib vs pelabresib plus ruxolitinib. A greater number of patients who received treatment with pelabresib plus ruxolitinib achieved SVR ≥35% at Week 24 compared with those who received placebo plus ruxolitinib (65.9% vs 35.2%; 95% CI: 21.6-39.3; P <.001). At Week 24, SVR ≥35% was consistently greater with the addition of pelabresib to ruxolitinib across all key prespecified subgroups including baseline spleen volume and risk category using the dynamic international prognostic scoring system.
MANIFEST-2 Update: Absolute Change in TSS and TSS50 Response at Week 24
Pertaining to the absolute change in TSS from baseline and TSS50 response at Week 24, there was a trend toward more benefit with the addition of pelabresib to ruxolitinib, although the difference in response between the treatment arms was not statistically significant.
MANIFEST-2 Update: Additional Outcomes
Fewer patients experienced a loss of response to pelabresib plus ruxolitinib compared with those who received placebo plus ruxolitinib (13.4% vs 27.8%, respectively). In addition, only 9.3% of patients experienced both loss of response and >25% increase in spleen volume from nadir compared with 14.8% who received placebo and ruxolitinib. When SVR ≥35% and TSS50 were combined, the trend showed that more patients benefitted overall from the addition of pelabresib to ruxolitinib (40.2% vs 18.5%).
MANIFEST-2 Update: Heme-Related Outcomes
Although there was a trend toward improved hemoglobin response among patients who received pelabresib plus ruxolitinib vs placebo plus ruxolitinib, the benefit was not significantly different. Only 30.3% of patients who received pelabresib plus ruxolitinib needed red blood cell transfusion within the first 24 weeks of treatment compared with 40.3% of those who received placebo plus ruxolitinib. Regarding change in reticulin fibrosis grade between the treatment arms, improvement by ≥1 grade was seen in 38.3% of patients who received pelabresib vs 25.3% of those who received ruxolitinib only. More severe marrow fibrosis (worsening by ≥1 grade) was identified in 17.0% of patients on the pelabresib plus ruxolitinib arm compared with 27.7% of those on the placebo plus ruxolitinib arm.
MANIFEST-2 Update: Safety
Treatment with pelabresib plus ruxolitinib was relatively well tolerated. Pelabresib was discontinued in 12.3%, dose reduced in 32.5%, and interrupted in 32.1% of patients whereas placebo was discontinued in 7.5%, dose reduced in 29.0%, and interrupted in 22.9%. On the pelabresib plus ruxolitinib arm, ruxolitinib was discontinued in 9.9%, dose reduced in 47.6%, and interrupted in 23.1% of patients compared with 6.1%, 41.6%, and 16.4% of patients, respectively, on the placebo plus ruxolitinib arm.
MANIFEST-2 Update: Treatment-Emergent AEs
More patients on the pelabresib plus ruxolitinib arm experienced thrombocytopenia (52.8% vs 37.4%), dysgeusia (18.4% vs 3.7%), and muscle spasms (11.3% vs 4.2%) compared with those who received placebo plus ruxolitinib. In general, however, it appears that the AEs on both arms were relatively similar. No new significant AEs were reported with the addition of pelabresib to ruxolitinib.
MANIFEST-2 Update: Key Takeaways
In newly diagnosed patients with intermediate-risk or high-risk MF, the addition of a BET inhibitor to ruxolitinib appeared to be beneficial. There was an improvement in SVR ≥35% which is hypothesized to translate into improved OS outcomes. Reticulin fibrosis grade and hemoglobin response were improved in more patients who received pelabresib vs those who did not. However, there was no statistically significant difference in TSS from baseline or TSS50 response at Week 24—2 key secondary endpoints of the trial. Therefore, it remains unclear if pelabresib in combination with ruxolitinib will become the new standard of care for newly diagnosed patients with MF or whether all key secondary endpoints need to be met before the combination is approved for this indication. Alternatively, this decision may be delayed to wait for the results of other phase III trials using alternative add-on therapy to ruxolitinib to determine if those other combinations will prove to be more effective for patients with MF in the upfront setting. As yet, it is not clear if the combination of pelabresib and ruxolitinib will be moving forward.
FELIX: Background
The next study is focused on patients with R/R B-cell acute lymphoblastic leukemia (ALL). The FELIX trial is evaluating a new-generation CAR T-cell therapy for adult patients with R/R B-cell ALL (NCT04404660). Obecabtagene autoleucel (obe-cel) is a novel, fast off-rate CD19-directed CAR T-cell therapy.32 It is under development for the treatment of patients with B-cell malignancies. It is hypothesized that because of its novel CAR T technology, it would elicit improved efficacy and potentially induce less immune-related AEs as compared with the other currently available CAR T-cell therapies. At ASCO 2024, results of the efficacy and persistence of obe-cel in adult patients with R/R B-cell ALL were reported.33
FELIX: Study Design
FELIX is an open-label, single-arm phase Ib/II study with a straightforward design. Patients with CD19-positive R/R B-cell ALL were eligible for participation including those with Ph-positive ALL who had failed previous therapy with a TKI or for whom TKI therapy was contraindicated. In total, 127 patients were eligible to participate in the study. As appropriate, patients received bridging therapy and underwent lymphodepletion before receiving obe-cel infusions on Days 1 and 10 at a dose that is based on prelymphodepletion leukemic burden. For the phase I portion of the study, the primary endpoint was safety. For the phase II portion, the key primary endpoint was ORR. Other outcome measures for the phase II portion included the proportion of patients achieving MRD-negative CR, CR rate, duration of response, PFS, OS, and CAR T-cell expansion and persistence.
FELIX: Baseline Characteristics
The median age of patients on the trial was 47 years (range: 20-81), and among the cohort of patients with ≥5% bone marrow blasts, the median age was 50 years (range: 20-81). Similar numbers of males and females were included in the study. In the overall patient population, 35.5% had received ≥3 previous lines of therapy, 44.1% had undergone allogeneic SCT, and 16.5% had previously received both blinatumomab and inotuzumab.
FELIX: Remissions and Survival
Remission rates, specifically CR and CR with incomplete hematologic recovery (CRi), were achieved by 99 patients (78%). Among the 99 patients who achieved CR/CRi, 40% had ongoing remission without the need for SCT or other subsequent treatment, and 18% underwent subsequent SCT and were in remission with negative MRD at a median follow-up of 21.5 months. However, 36% experienced relapse or died. The median EFS with SCT censoring was almost 12 months; without SCT censoring, the median EFS was 9 months. The 1-year EFS rate was 49.5% with SCT censoring vs 44.0% without SCT censoring. The median OS was longer at 23.8 months with SCT censoring compared with 15.6 months without SCT censoring. With or without subsequent SCT following CAR T-cell therapy, the 1-year OS rate for all patients was approximately 60%.
Overall, an important point of these results is the demonstration that a certain percentage of patients who received obe-cel and remained in remission after obe-cel therapy did not undergo subsequent allogeneic SCT. Currently, most healthcare professionals in the field have felt that SCT is required after all therapy (including chemotherapy and CAR T-cell therapy) for R/R B-cell ALL to achieve prolonged OS in this patient population.
FELIX: CAR T-Cell Persistence and Long-term EFS
Treatment with obe-cel demonstrated evidence of persistent and detectable transfected CAR T-cells in patients over time, and this has been associated with improved survival rates. The results suggest that CAR T-cell persistence is directly related to the improved EFS observed in these patients.
FELIX: Key Takeaways
The phase Ib/II FELIX study demonstrated that following treatment with obe-cel, almost one half (≥44%) of patients remained event free at 12 months. The 12-month OS rate was approximately 60% in all patients with R/R ALL after receiving obe-cel with similar outcomes with and without the need for subsequent therapy including SCT. These results offer the tantalizing possibility that obe-cel may be an ideal therapy for these patients and could become a preferred treatment of choice for patients in this setting because of the possibility that they may be able to achieve long-term response and disease control without the AEs, mortality, and morbidity associated with allogeneic SCT. Certainly, the results require additional follow-up, and pharmacokinetic and pharmacodynamic studies to elucidate which patients may benefit most from its use if it becomes standard of care.
Palliative Care in AML/MDS: Background
It is important to end this section with a study that looks beyond disease remission and disease control in the care of our patients with hematologic cancer to examine the overall quality of life and other aspects of patient care. Therefore, the focus of the next study is on the role of palliative care in adult patients with acute myeloid leukemia (AML)/MDS who often face poor prognosis, have heavy symptom burden, and receive intensive treatments that reduce quality of life especially toward the end of life.34-36 Many of these older patients in their 70s or 80s are not able to achieve cure with the currently available regimens for AML/MDS, as this would require allogeneic SCT. The integration of palliative care into therapy has been shown to be beneficial for patients with solid tumors, but in hematologic malignancies, only a few studies of supportive care options at the end of life have been performed, especially for patients with AML/MDS.37 This specific study investigates the integration of a collaborative palliative and oncology care model for patients with AML/MDS receiving nonintensive chemotherapy.38
Palliative Care in AML/MDS: Study Design
This multisite, randomized, open-label trial enrolled 115 patients with newly diagnosed or R/R AML or high-risk MDS who were within 30 days of starting nonintensive therapy. These patients were randomly assigned to receive either palliative care intervention or usual care that allows palliative care consultation at request. Patients on the palliative care intervention arm had monthly outpatient visits with a palliative care professional and ≥2 times per week during each hospital admission. The primary outcome was the time from documentation of end-of-life care preferences to death. The secondary outcomes included patient-reported end-of-life care discussions, hospitalization at end of life, hospice utilization, quality of life at 3 months, and psychological distress at 3 months.
Palliative Care in AML/MDS: Baseline Characteristics
The study was performed in a largely older patient population with a median age of approximately 70 years on both treatment arms. Most patients were White but the study included patients of other races. Overall, the baseline characteristics were fairly well balanced between the 2 arms.
Palliative Care in AML/MDS: Documentation of EOL Care Preferences (Primary Outcome)
End-of-life care preferences were documented for more of the patients who received palliative care intervention (96.5%) vs those who received usual care (68.4%). End-of-life care preferences were documented much earlier among patients who received palliative care intervention compared with those who received usual care (41 days vs 1.5 days before death; P <.001).
Palliative Care in AML/MDS: EOL Secondary Outcomes
There were more patient-reported end of life care discussions in the palliative care arm compared with patients in the usual care arm (56.9% vs 14%; P <.001). The rate of hospitalization in the last 30 days of life was lower in the palliative care arm compared with the usual care arm (70.6% vs 91.9%; P = .031). There was a trend toward more hospice utilization in the palliative care intervention arm compared with the usual care arm (55.9% vs 48.6%; P = .637).
Palliative Care in AML/MDS: Patient-Reported and Longitudinal Secondary Outcomes
At 3 months and 6 months from baseline, patient-reported quality of life was significantly improved in the palliative care arm compared with the usual care arm. There was a trend toward improved depression and anxiety symptoms with palliative care intervention vs usual care.
Palliative Care in AML/MDS: Key Takeaways
Among patients with newly diagnosed or R/R AML or high-risk MDS receiving nonintensive therapy, integrated palliative care intervention resulted in earlier documentation of end-of-life care discussions. The rate of discussion and documentation of end-of-life care preferences was significantly improved with integrated palliative care compared with usual care. Of importance, for patients with these diseases, this is the first randomized study to assess whether the integration of palliative care intervention could be of use and whether it could be considered to be a new standard of care to optimize other aspects of patient care beyond just disease control.
Overall Conclusions
This overview of important studies in leukemias/MDS presented at the 2024 ASCO annual meeting covers a range of diseases and treatment options. ASC4FIRST and MANIFEST-2 focus on potential new standards of care for newly diagnosed patients with cancer. The ASC4FIRST trial highlights efficacy and safety of the new-generation BCR::ABL allosteric inhibitor asciminib, which has a novel mechanism of action. Asciminib outperformed all other TKIs studied, in that it rapidly induced MMR in adult patients with newly diagnosed CML-CP. The MANIFEST-2 trial demonstrated for the first time that the addition of an agent to ruxolitinib is potentially more beneficial than ruxolitinib alone for patients with intermediate-risk or high-risk MF. The addition of pelabresib to ruxolitinib demonstrated SVR ≥35% in more patients vs placebo plus ruxolitinib. However, there appeared to be no significant difference in disease-related symptoms with the addition of pelabresib to ruxolitinib, suggesting that an agent with a different mechanism of action and/or the use of different approaches may still be needed to address these different aspects of determining disease progression.
Obe-cel is an impressive addition to the current armamentarium of CAR T-cell therapies for adult patients with R/R B-cell ALL. Obe-cel is associated with a very low rate of immune-related AEs and in the FELIX trial, it demonstrated a very high CR/CRi rate of 78% in this setting. Of importance, the finding that approximately 60% of patients were still alive at 12 months, even without subsequent SCT, makes obe-cel a highly promising treatment approach. Finally, with the focus on other aspects of cancer care, it is important to remember that not all patients with hematologic cancers can receive curative therapy. For these individuals, it is clear that early palliative care interventions for older patients with AML/MDS receiving nonintensive therapy is beneficial compared with usual care.
In conclusion, the future of the leukemia/MDS field remains bright with advances occurring in the newly diagnosed, R/R and end-of-life disease settings.
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