CME
Physicians: Maximum of 1.50 AMA PRA Category 1 Credits™
Released: August 25, 2023
Expiration: August 24, 2024
COMMANDS: Background
Eunice S. Wang, MD:
Key studies in leukemias from ASCO 2023 start with 2 potentially practice-changing trials in patients with MDS, which is commonly seen in the community setting.
The first trial is COMMANDS, which focused on the management of patients with lower risk, transfusion-dependent MDS.1 Two clinical trials previously showed a benefit with the use of luspatercept for patients with lower-risk MDS with a transfusion dependence. In the phase III MEDALIST study in patients with RBC transfusion‒dependent lower-risk MDS with RS, luspatercept demonstrated an improvement in RBC-transfusion independence (RBC-TI) compared with placebo.2 The phase II PACE study demonstrated a benefit with luspatercept in lower-risk patients with MDS and low transfusion burden.3 However, the question of whether luspatercept could be used in place of an ESA in patients with newly diagnosed, transfusion-dependent MDS regardless of RS status was still to be answered.
COMMANDS: Study Design
The global, open‑label, randomized phase III COMMANDS trial enrolled 356 adult patients with very low‒risk, low-risk, or intermediate‑risk MDS who had either RS or no RS who were transfusion dependent and ESA naive. Individuals were randomly assigned to receive luspatercept 1.0 mg/kg administered subcutaneously every 3 weeks, titrated up to 1.75 mg/kg maximum, or epoetin alfa 450 IU/kg subcutaneously each week, titrated up to 1050 IU/kg. The primary endpoint of the study was attaining RBC-TI for ≥12 weeks with a concurrent mean hemoglobin increase of ≥1.5 g/dL. Key secondary endpoints included hematologic improvement‒erythroid (HI-E) per the International Working Group (IWG) criteria for ≥8 weeks, RBC-TI for ≥24 weeks, RBC-TI for ≥12 weeks, time to first RBC transfusion, and safety.1
COMMANDS: Efficacy in ITT (Primary Endpoint)
The trial convincingly met its primary endpoint, with 58.5% of patients on the luspatercept arm attaining RBC-TI for ≥12 weeks with a concurrent hemoglobin increase of ≥1.5 g/dL compared with 31.2% of patients on the epoetin alfa arm (P <.0001), a highly significant difference.1
COMMANDS: Primary Endpoint by Patient Subgroups
Investigators also reported the primary endpoint of RBC-TI for ≥12 weeks with a concurrent hemoglobin increase of ≥1.5 g/dL by patient subgroups. Of note, based on prior data, we would expect luspatercept to have more activity in patients with disease characterized by RS than in those without RS. These results confirmed that, with the primary endpoint attained by 64.8% of patients who were RS positive receiving luspatercept and 25.9% of patients who were RS positive receiving epoetin alfa. By contrast, there was no notable difference between arms among patients who were RS negative, with the primary endpoint met in 41.0% of patients receiving luspatercept and 46.3% of patients receiving epoetin alfa.1
COMMANDS: Additional Efficacy Data and Treatment Discontinuation
The proportion of patients attaining RBC-TI for at least 8, 12, and 24 weeks also was significantly longer with luspatercept vs epoetin alfa.1 The median duration of RBC-TI with luspatercept of 126.6 weeks translates to >2 years, which is a highly statistically significant difference vs those receiving epoetin alfa, in the overall cohort comprising patients who were both RS positive and RS negative.
COMMANDS: Safety
Regarding safety, there was little difference in the safety profiles of these 2 treatments.1 The most frequent hematologic treatment-emergent adverse events (TEAEs) with luspatercept and epoetin alfa were anemia, reported in 9.6% and 9.7% of patients, respectively (7.3% and 6.8% grade 3/4), and thrombocytopenia, reported in 6.2% and 1.7% of patients, respectively (3.9% and 0.6% grade 3/4). TEAEs of interest with luspatercept and epoetin alfa included fatigue, reported in 14.6% and 6.8% of patients, respectively; diarrhea, reported in 14.6% and 11.4% of patients, respectively; peripheral edema, reported in 12.9% and 6.8% of patients, respectively; and asthenia, reported in 12.4% and 14.2% of patients, respectively. Rates of progression to high-risk MDS or acute myeloid leukemia (AML) were below 5% in both arms.
COMMANDS: Key Takeaways
In this potentially practice-changing trial, patients with lower‑risk MDS with anemia who are candidates to receive transfusions or growth factors to reduce transfusion dependence benefitted from initiation of luspatercept vs ESAs.
In the past, these patients have typically been offered ESAs to reduce transfusion dependence. The current indication for luspatercept specifies that patients must have failed ESA therapy, potentially by demonstration of an elevated serum erythropoietin (EPO) level.4 This trial would move luspatercept from a second‑line refractory or resistant setting to the frontline setting. The duration of response (DoR), in particular, would be practice-changing for patients with RS. However, even for patients without RS, this is clearly a step forward based on the DoR.
It also is important to keep in mind that these patients are typically older individuals for whom quality of life and mitigation of symptoms are closely tied to transfusion dependency. This is particularly true for those with underlying pulmonary or cardiac comorbidities.
If luspatercept is approved for an expanded indication based on the COMMANDS patient population, I would suggest that it be used for frontline therapy of patients with low-risk MDS with anemia in place of current ESA therapy. In particular, I would make this recommendation for any patients with low-risk MDS with RS, as this agent is highly effective and clearly superior to ESAs for these patients. For patients with low-risk MDS without RS, the data suggest equivalent response rates with luspatercept or ESAs, but luspatercept potentially offers increased duration of transfusion independence. Less frequent clinic visits also may be a consideration, as luspatercept is administered every 3 weeks vs ESAs, which often are administered every 2 weeks.
IMerge: Study Design
The IMerge study focused on patients with low- or intermediate‑risk transfusion-dependent MDS in whom ESA therapy already has failed or who would be predicted to have low responses to ESA therapy based on a high serum EPO level. These patients are potentially one stage further down the treatment paradigm than the patient population in the COMMANDS study. We typically have considered whether these patients would be candidates for clinical trials or low‑dose hypomethylating agent (HMA) therapy. However, many of these individuals do not want to start lifelong HMA therapy, given that they have low-risk or intermediate-1‒risk disease. The IMerge trial was undertaken to assess whether the novel agent imetelstat could be another treatment modality to employ prior to initiation of HMA therapy.5
Imetelstat is an inhibitor of telomerase, an enzyme that is present at elevated levels in malignant and healthy stem cells to prevent a trigger for cell death.6 Typically, when cells proliferate, telomeres are cut down over time until they reach a critical length, at which point the cell is signaled to undergo cell death. In cancer cells, upregulation of telomerase prevents telomeres from reaching that critical point, contributing to cell immortalization.
Imetelstat targets telomerase and eliminates what we would consider to be MDS stem cells, thereby allowing for normal hematopoiesis to be restored in patients with MDS.
The IMerge trial enrolled patients with low-risk or intermediate-1‒risk MDS who were relapsed, refractory, or ineligible for ESAs; were RBC transfusion dependent; did not have del(5q); and had not received an HMA or lenalidomide. In total, 178 patients were randomly assigned to receive imetelstat 7.5 mg/kg IV every 4 weeks or placebo. The primary endpoint was 8-week RBC-TI. Key secondary endpoints included 24-week RBC-TI, transfusion independence duration, HI-E, and safety. Exploratory endpoints included changes in variant allele frequency (VAF) and patient-reported outcomes.5
IMerge: Rates of Durable RBC-TI Over Time
Imetelstat was associated with a significant improvement in rates of transfusion independence over time compared with placebo.5 The improvement with imetelstat vs placebo was observed at 8 weeks (39.8% vs 15.0%; P <.001), 16 weeks (31.4% vs 6.7%; P <.001), 24 weeks (28.0% vs 3.3%; P <.001), and 1 year (13.6% vs 1.7%; P = .012). A single continuous RBC-TI period was achieved by 83% of 8-week responders
IMerge: Duration of Transfusion Independence Among Patients Achieving 8-Week RBC-TI
The duration of transfusion independence was markedly improved with imetelstat vs placebo at 51.6 weeks and 13.3 weeks, respectively (HR: 0.23; 95% CI: 0.09-0.57; P <.001).5 This is a remarkable difference and is likely to translate into improved symptoms and quality of life for these individuals. One year without a transfusion is a significant clinical endpoint.
IMerge: 8-Week RBC-TI Rate in Key Patient Subgroups
There was a benefit with imetelstat across subgroups, including in patients who were RS positive and RS negative.5 This differs from the COMMANDS trial, in which luspatercept had a differential effect in patients who were RS positive and RS negative, likely because imetelstat is not particularly dependent on the biology that leads to RS. We also saw that the benefit of imetelstat was independent of serum EPO level and International Prognostic Scoring System risk category.
IMerge: Hemoglobin Responses
Among 8‑week transfusion independence responders, the median hemoglobin increase was 3.6 g/dL in the imetelstat arm and 0.8 g/dL in the placebo arm; the median hemoglobin peak was 11.3 g/dL and 8.9 g/dL, respectively.5 A graph of mean change in hemoglobin over time shows a clear difference with imetelstat vs placebo.
IMerge: HI-E Responses (IWG 2018)
HI-E response rates by the IWG 2018 criteria were significantly higher with imetelstat vs placebo in the entire cohort (42.4% vs 13.3%; P <.001).5 Among patients with low transfusion burden, there was no significant difference in HI-E response rate with imetelstat vs placebo (33.3% vs 22.2%; P = .562). However, among patients with a high transfusion burden, imetelstat was significantly more effective than placebo as assessed by major HI-E response rate (16-week RBC-TI; 30.9% vs 0%; P <.001) and minor HI-E response rate (50% RBC unit reduction in 16 weeks; 44.3% vs 9.5%; P <.001).
IMerge: Most Common AEs
Some increase in adverse events (AEs) was seen with imetelstat. When hematopoietic stem cells potentially switch over to producing RBCs or an erythroid response, there may be a temporary decrease in the ability of the stem cells to produce other cells, such as white blood cells (WBCs) and platelets. In the imetelstat arm, thrombocytopenia of any grade developed in 75% of patients (62% grade 3/4), neutropenia developed in 74% (68% grade 3/4), and anemia developed in 20% (19% grade 3/4).5 These typically were transient and most often occurred in cycles 1‑3. When neutropenia and thrombocytopenia were observed, the drug was commonly held, and most patients with dose modifications had mitigation of these effects.
Of note, the thrombocytopenia and neutropenia did not seem to be associated with clinical sequelae, so if they were discovered early, patients did not experience events such as bleeding episodes, increased infections, pneumonias, or neutropenic sepsis, and the cytopenias could be managed easily with dose modifications. Nonhematologic AEs were mostly low grade.
IMerge: Duration and Management of Cytopenias (Grade 3/4)
Rates of infection and bleeding were low and similar between arms.5 Patients were able to receive myeloid growth factors on both arms, and that also was mitigating for these effects. The median duration of grade 3/4 thrombocytopenia and neutropenia was <2 weeks; 86.4% of cases in the imetelstat arm resolved within 4 weeks. However, these cytopenias are something to watch out for when using this drug.
IMerge: Impact of Treatment on VAF of Genes Often Mutated in MDS
Evaluating the expression of gene mutations that commonly occur in MDS by measuring the VAF is one way to assess the amount of disease burden or the number of mutated stem cells. Changes in VAF suggest that a treatment is disease modifying via reduction in the quantity of mutated marrow cells. In this analysis, investigators assessed changes in the VAF of 4 commonly mutated genes (SF3B1, TET2, DNMT3A, and ASXL1) associated with the underlying MDS disease process.
The reductions in VAF were significantly greater with imetelstat vs placebo for SF3B1 (P <.001), TET2 (P = .032), and DNMT3A (P = .019), suggesting that the telomerase inhibitor was targeting the MDS cells and stem cells and was reducing the absolute number of these abnormal cells in patients.5
IMerge: Correlation of SF3B1 VAF Reduction With Clinical Outcomes With Imetelstat Treatment
In patients who received imetelstat, the maximum reduction in SF3B1 VAF was significantly associated with maximum increase in hemoglobin (P <.001) and longest RBC-TI duration (P <.001).5 If we hypothesize that the mechanism of action of imetelstat is to specifically target the MDS stem cells with elevated telomerase activity, the demonstration of decreased VAF and its correlation with clinical outcome does suggest that imetelstat could be a disease‑modifying agent that restores normal hematopoiesis.
IMerge: Key Takeaways
The IMerge trial demonstrated that in patients with lower‑risk MDS who are heavily dependent on RBCs, have failed ESAs, and otherwise would be considered for HMA therapy, the novel telomerase inhibitor imetelstat intriguingly appears to reduce mutant allele frequency and reduce transfusion dependence. This theoretically occurs by allowing normal hematopoietic stem cells to repopulate and regrow in the marrow.5 The DoR with this agent was remarkably prolonged compared with placebo.
These trial results were submitted recently to the FDA as part of a New Drug Application for imetelstat for the treatment of anemia in this population of patients with MDS who have R/R disease or who are ineligible for ESAs. If approved, imetelstat could represent a bridge in therapy to treat patients with low-risk or intermediate-risk MDS who are failing or not eligible for growth factors prior to initiation of HMAs (eg, azaciditine or decitabine). HMAs must be continued indefinitely and are associated with cytopenias, which can worsen transfusion dependence in the short term. Use of imetelstat every 3 weeks potentially could provide a DoR of 1 year, delaying the need for HMAs and providing prolonged quality of life for these patients.
Alliance A041703: Background
The next trial, Alliance A041703, focused on acute lymphocytic leukemia (ALL), which often is considered to primarily occur in a younger patient population. However, as we move into treating older individuals and as patients with cancer are aging, a second spike in the incidence of ALL is occurring in individuals 60-70 years of age.7 These patients traditionally have fared poorly with current chemotherapy regimens for ALL, which were developed in the pediatric setting and therefore involve administration of complicated regimens with high doses of cytotoxic therapies and which realistically are not tolerated in older adults.8
However, immunotherapy recently has been introduced for the treatment of patients with R/R ALL. These newer options include CAR T‑cell therapy, the antibody‒drug conjugate (ADC) inotuzumab ozogamicin, and the bispecific antibody blinatumomab, the latter of which has moved into the upfront setting for patients with measurable residual disease (MRD)‒positive and MRD‑negative disease in combination with pediatric‑inspired regimens.9-11
At ASCO and the European Hematology Association Annual Meeting, Wieduwult and colleagues presented the results of a small trial performed through the Alliance for Clinical Trials in Oncology cooperative group that evaluated the possibility of moving away from pediatric-inspired intensive chemotherapy regimens for ALL in these older patients and replacing them with immunotherapies that are more targeted toward the ALL cells. Of more importance, these new drugs may be more tolerable in this older and/or unfit patient population.12
Alliance A041703: Study Design
In the nonrandomized phase II Alliance A041703 trial, 33 patients aged 60 years and older with newly diagnosed, Ph‑negative, CD22‑positive B-cell ALL (B-ALL) who were not candidates for intensive chemotherapy or transplantation received a novel regimen that was largely chemotherapy free. Patients received an induction course of inotuzumab ozogamicin; those with adequate cytoreduction then received additional inotuzumab ozogamicin followed by consolidation with blinatumomab. Patients without adequate cytoreduction after inotuzumab proceeded directly to consolidation blinatumomab. The primary endpoint of this study was 1‑year event‑free survival (EFS). Secondary endpoints included overall survival (OS), relapse-free survival, MRD negativity, complete response (CR) rate, and safety.12
Alliance A041703: EFS (Primary Endpoint)
The trial met its primary endpoint, with this largely chemotherapy-free regimen demonstrating an impressive 1‑year EFS rate of 75% in this older population.12 Also remarkably, there was no difference in EFS by age. Outcomes were similar in patients younger than 70 years and in patients 70 years and older, an age category that often would be considered too old to be receiving intensive chemotherapy, specifically most pediatric‑inspired regimens. This combination of immunotherapies was not a curative regimen; relapses occurred in 27% of patients, and most of this population would be expected to relapse over time.
Alliance A041703: Hematologic Response
Overall, this chemotherapy‑free regimen of inotuzumab ozogamicin and blinatumomab did result in extremely high hematologic response rates, with 96% of patients attaining a CR, a CR with partial hematologic recovery (CRh), or a CR with incomplete blood count recovery (CRi).12 The CR, CRh, and CRi rates were 60%, 33%, and 3%, respectively.
Alliance A041703: OS and Deaths
The 1‑year OS rate was 84%, and median OS was not reached.12 Of the 9 deaths, 6 were due to relapsed ALL, 1 was due to an AE in refractory ALL, and 2 were due to an AE in remission.
Alliance A041703: Safety
AEs were largely due to cytopenias and were manageable in these older patients. The most frequent grade ≥3 AEs were decreased neutrophil count (87.9%), decreased platelet count (72.7%), anemia (42.4%), and decreased WBC count (39.4%).12 The most frequent grade 4 AEs were decreased neutrophil count (69.7%), decreased platelet count (57.6%), and decreased WBC count (24.2%). Deaths on treatment included 1 patient each with encephalopathy and respiratory failure.
Alliance A041703: Key Takeaways
Although ALL typically is considered a pediatric cancer, it is being diagnosed increasingly in older adults who often are not candidates for pediatric-type intensive combination chemotherapy. This trial suggests that 2 antibody-based therapies, inotuzumab ozogamicin and blinatumomab, may provide a highly effective chemotherapy-free strategy for these patients. Preliminary findings in 33 patients indicate high response rates of 85% to 97% after 1-2 cycles of therapy, and 84% of patients were alive 1 year after diagnosis.12 This study parallels a similar strategy in Ph-positive B-ALL, in which the chemotherapy-free combination of blinatumomab with the BCR-ABL inhibitor ponatinib has resulted in high response rates and prolonged OS in newly diagnosed older patients, similar to the patients with Ph-negative B-ALL receiving treatment in Alliance A041703.13
CPX-351 vs 7+3 Cardiotoxicity: Study Design
This final study compared the cardiotoxicity of different intensive chemotherapy regimens for older patients with AML. The median age at presentation of AML is between 67 and 70 years.14 Many patients who have secondary AML arising out of prior MDS or prior therapy‑related MDS are eligible for treatment with the liposomal formulation of cytarabine and daunorubicin (CPX-351) as opposed to our standard 7+3.15 Because many older patients have underlying cardiac disease, there has been interest in understanding whether CPX-351, which we know has increased penetration of drug into the bone marrow space (probably accounting for its increased efficacy), is delivering more anthracycline to the heart, leading to additional toxicity.
To assess this, investigators conducted a retrospective analysis evaluating changes in cardiac function in the phase III trial comparing CPX-351 vs 7+3 in 309 older adults with newly diagnosed high-risk or secondary AML.16
CPX-351 vs 7+3 Cardiotoxicity: Median Change in LVEF and GLS Compared With Baseline
CPX-351 was associated with smaller changes from baseline in median left ventricular ejection fraction (LVEF) compared with 7+3.16 This was observed at follow-up 1 (-1.6 vs 3.4) and follow-up 2 (‑3.0 vs -5.0). Median changes from baseline in median global longitudinal strain (GLS) also were smaller with CPX-351 vs 7+3 at follow-up 1 (0.7 vs 1.4) but were similar between arms at follow-up 2 (2.0 vs 1.9). These findings suggest less cardiotoxicity with CPX-351 compared with standard 7+3.
CPX-351 vs 7+3 Cardiotoxicity: Clinically Significant Change in LVEF and GLS
Clinically significant changes in cardiac function again were—surprisingly—less common with CPX-351 than with standard 7+3 at both follow-ups, as assessed by both LVEF and GLS.16
CPX-351 vs 7+3 Cardiotoxicity: Any-Grade Cardiac AEs
We would expect some degree of cardiac mortality and morbidity in this population. However, rates of any-grade cardiac AEs were generally equivalent or potentially a bit lower with CPX-351 compared with 7+3.16 The most frequent cardiac AEs were tachycardia, occurring in 21.0% of patients receiving CPX-351 vs 8.9% of patients receiving 7+3; atrial fibrillation/flutter, occurring in 7.0% vs 11.0% of patients, respectively; and pericardial effusion, occurring in 5.3% vs 2.2% of patients, respectively.
CPX-351 vs 7+3 Cardiotoxicity: Grade 3/4 Cardiac AEs
Regarding severe cardiac AEs, we historically have seen things like atrial fibrillation and left ventricular dysfunction with anthracyclines.17 In this trial, rates of grade 3/4 cardiac AEs were very low with both regimens, and there was no significant increase with CPX-351.16
CPX-351 vs 7+3 Cardiotoxicity: Key Takeaways
Overall, CPX-351 was associated with less cardiotoxicity than standard 7+3 in this analysis.16 For a population of older patients who may already have compromised cardiac function or suspected underlying myocardial disease, the delivery of both of these intensive regimens seems to be tolerable and feasible.
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