QuANTUM-First was a randomized, double-blind, placebo-controlled phase III trial examining whether addition of the second-generation FLT3 inhibitor quizartinib to intensive chemotherapy conveyed benefit for younger (aged 75 years and younger), fit patients with newly diagnosed FLT3-ITD‒mutant AML. In contrast to the RATIFY trial of midostaurin added to chemotherapy published in 2017, which included patients with either ITD or TKD mutations,¹ QuANTUM-First was restricted to those with ITD because of quizartinib selectively inhibiting ITD. The treatment regimen was a standard cytarabine and daunorubicin/idarubicin induction plus quizartinib or placebo, followed by high-dose cytarabine consolidation, again with quizartinib or placebo. Patients who achieved responses were allowed to proceed to allogeneic stem cell transplantation (alloSCT) followed by quizartinib or placebo maintenance for up to 3 months.

Previously published primary analysis at a median follow-up of 39.2 months showed that the median overall survival (OS) was significantly prolonged at 31.9 months with quizartinib vs 15.1 months with placebo (HR: 0.78; 95% CI: 0.62-0.98; P = .032).² This analysis examined the prognostic value of FLT3-ITD measurable residual disease (MRD) status on survival.³

MRD was assessed via bone marrow sampling at the time of screening and at sequential time points throughout the study until the end of treatment. Analyses attempted to determine whether obtaining MRD-negative or lower disease at certain time points correlated with clinical outcomes and whether the addition of quizartinib had any impact on the depth of response in terms of MRD at those time points. In addition, because FLT3-ITD mutations come in many forms, the investigators examined whether the presence of multiple ITDs or the length of the internal tandem duplication correlated with outcomes and whether quizartinib treatment had any impact on this correlation.³

QuANTUM-First differed from the prior RATIFY trial, which enrolled patients 59 years of age and younger,¹ by including older patients up to 75 years of age. However, the majority (>60%) of the patients on the QuANTUM-First trial still were younger than 60 years of age. The Eastern Cooperative Oncology Group (ECOG) performance status ranged from 0-2. The majority of patients had baseline FLT3 mutational assessments and MRD analyses based on bone marrow samples.³

The first analysis investigated whether MRD level correlates with OS regardless of treatment. As anticipated from a common sense point of view, patients who became MRD negative, meaning no measurable residual disease, clearly had improved OS at all time points (after induction, during treatment, and after the final consolidation).

On the right-hand side of the table, the number of patients with MRD-negative status is presented for the separate treatment arms. Quizartinib treatment led to more patients with MRD-negative status at all time points, ending with 55.8% of patients compared with 41.2% of patients with placebo after the last round of consolidation.³

Looking at OS at all time points in both treatment arms, patients who received quizartinib had prolonged survival compared with placebo regardless of MRD status at any time point. Of patients who achieved MRD-zero status, survival was extended with quizartinib vs placebo (HR: 0.753; 95% CI: 0.432-1.311), although the median was not reached for either treatment arm.³

Longer tandem duplications were associated with shortened survival across treatment arms (median: 17.0 months vs 40.7 months for those with greater or less than median ITD length, respectively). The benefit of quizartinib on survival was observed regardless of ITD insertion length.³

The next study investigated patients with AML who are unfit for intensive chemotherapy, for whom standard of care remains venetoclax plus azacitidine based on results of the phase III VIALE-A trial.^4,5 VIALE-A found that in patients aged 75 years and older or those otherwise considered unfit, venetoclax plus azacitidine led to a 67% ORR and a median OS of 14.7 months. This is a very effective regimen, but continued administration may lead to prolonged cytopenias, which are especially a concern given the older, frail nature of these patients. Long-term results of VIALE-A with a median 43 months of follow-up raised the question of whether continued venetoclax plus azacitidine treatment necessarily resulted in the best outcomes, or whether patients in response could have better quality of life with early treatment discontinuation. The ability to discontinue treatment also would have a positive impact on cost and convenience. This possibility would parallel current practice in CML, where many patients can stop BCR-ABL‒targeted tyrosine kinase inhibitor (TKI) treatment and continue to do well.  

The study designed to answer this question was STOP-VEN, a retrospective trial of 84 patients with newly diagnosed or R/R AML who were in remission. Enrolled patients were treated at French Innovative Leukemia Organization centers or the Moffitt Cancer Center in Tampa, Florida, between 2018 and 2023 and were retrospectively analyzed.⁶

Eligible patients had achieved a complete response (CR), CR with incomplete count recovery (CRi), or clearing of morphologic blasts) with venetoclax plus azacitidine and then discontinued venetoclax and/or azacitidine for ≥3 months. Primary endpoints were treatment-free remission and OS.

The trial population was typical of patients who receive venetoclax plus azacitidine, with a median age of 75 years and a range of up to 89 years. Approximately one half had de novo disease, and cell counts were low at the time of discontinuation. Many patients had known mutations, including FLT3-ITD and TP53, which are associated with worse outcomes with this treatment regimen.⁶

Patients received a median of 4 cycles of venetoclax plus azacitidine, with the overwhelming majority achieving CR or CRi. Many patients were in MRD-negative CR, allowing investigators to examine the value of achieving a deep response in patients receiving a less-intensive treatment regimen. The primary reason for discontinuation was hematologic toxicities, followed by patient preference.⁶

The median treatment-free time period was 16 months for newly diagnosed patients and 10 months for patients with R/R disease. Median OS was very prolonged: 44 months in newly diagnosed patients and 19 months in patients with R/R disease.

For those who had achieved an MRD-negative response in the newly diagnosed setting, the majority were still alive, with a 2-year survival rate of 80%. That is impressive given that median OS in VIALE-A was 14 months. It also is promising to see that when relapsed patients were rechallenged with venetoclax plus azacitidine, 27% of newly diagnosed patients and 40% of patients with R/R disease were able to successfully obtain remission with that retreatment.⁶

The multivariate analysis shows that newly diagnosed patients had better outcomes than patients with R/R disease. Mutational analyses are shown, but these were in small patient numbers.⁶

The QuANTUM-First trial discussed earlier explored the addition of a FLT3 inhibitor to an intensive chemotherapy backbone for patients with FLT3-mutated disease. This next study applies a similar triplet approach to patients with FLT3-mutated disease who are unfit or who have relapsed following intensive chemotherapy by adding FLT3 inhibition to a nonintensive regimen.

This single-arm, multicohort phase I/II trial performed at the MD Anderson Cancer Center examined such a combination.⁷ The trial population included unfit patients with newly diagnosed FLT3-mutated AML, as well as patients with R/R FLT3-mutated disease. The triplet induction included decitabine for 10 days, venetoclax for 21 days, and quizartinib for 28 days initially, with an amendment later in the study reducing quizartinib to 14 days. Consolidation was more truncated, with 5 days of decitabine, 14 days of venetoclax, and quizartinib between 14 and 28 days, depending on tolerability.

Patients in the frontline cohort were older, with a median age of 70 years, and those in the R/R cohort were younger, with a median age of 59 years. Of note, only 14 patients were treated in the frontline cohort, so that should be considered when interpreting the results. Of the patients with R/R disease, the median number of previous therapies received was 3 (range 1-5). Most of these patients (56%) had previously received venetoclax plus a hypomethylating agent, and 83% of patients had previously received ≥1 prior FLT3 inhibitor. Therefore, in the R/R cohort, the study tested the triplet combination regimen in patients who had previously been exposed to a hypomethylating agent, venetoclax, and/or a FLT3 inhibitor.⁷

It was determined in the dose-finding phase that 40 mg of quizartinib led to significant toxicity, with grade 4 myelosuppression in the first 2 patients treated; 30 mg was selected as the quizartinib dose moving forward, and 100% response was seen in 6 patients treated with the triplet at this dose.⁷

Of the 43 patients in the R/R cohort, 65% achieved CRc, with most of these being morphologic leukemia-free state (34%) or CRi (19%). In addition, approximately one third of the patients achieved MRD negativity when determined by flow cytometry or polymerase chain reaction (PCR). In the subgroup analysis of patients with R/R FLT3-ITD mutation‒positive AML, 63% of those with prior exposure to gilteritinib achieved CRc, and 72% of those without any previous exposure to gilteritinib achieved CRc. The CRc rate was >50% regardless of prior exposure to a hypomethylating agent plus venetoclax or the RAS/MAPK, DNMT3A, and NPM1 mutation status.

Among the 14 patients with newly diagnosed disease, the CRc rate was 100%, including a CR rate of 79% and a CRi rate of 21%. The MRD negativity rate in this small cohort of 14 patients was impressive at 75% when determined by flow cytometry and 86% when assessed by PCR.⁷

Looking more closely at subgroup results in the R/R setting, OS is unsurprisingly greater in patients who showed a response: a median of 19 months for those with CR and 8.1 months for those with any type of response. Of note, meaningful survival outcomes were seen in patients who had previously been treated with venetoclax and hypomethylating agents or with gilteritinib.⁷

Of 14 patients treated in the frontline cohort, there were 4 deaths and 2 relapses; 8 of the 10 patients still alive at the time of analysis did not go on to stem cell transplant, meaning they had been able to continue on some level of consolidation or maintenance therapy.⁷

The major adverse event (AE), as touched on previously in the dose-finding phase, was myelosuppression. In patients treated with 28 days of quizartinib, cytopenias were seen that lasted 42-43 days, on average. For those treated with quizartinib reduced to 14 days, myelosuppression was improved to median durations of 35 or 36 days. This shorter duration of quizartinib did not appear to decrease efficacy.⁷

This next study returns to the importance of MRD assessment in determining the best setting to treat AML. Many healthcare professionals do not want to wait until overt relapse, because many times at that point, the disease is so clinically aggressive and treatment refractory that it is very challenging to get the leukemia back into remission. If MRD positivity is detected early, then treatment can potentially be pursued at that point to achieve MRD negativity instead of waiting until overt relapse. The other setting in which the MRD status is important is when planning to perform alloSCT, which can be curative for many patients. There are concerns about patients who clinically appear cured after transplant but are still MRD positive, suggesting the risk of imminent relapse and the need to act early to eliminate residual disease to prevent overt recurrence after transplant.

Sabatolimab is an antibody targeting TIM-3, which is expressed on leukemic stem cells and blasts and on immune cells in the marrow microenvironment.⁸ It is hypothesized that inhibiting TIM-3 could alter the adaptive and innate microenvironment to enhance mechanisms of disease control after transplant in myeloid diseases. The hypothesis is that sabatolimab monotherapy may be effective in the MRD setting, just as blinatumomab is used for MRD-positive patients with acute lymphoblastic leukemia to enhance donor immune cells to exert graft vs leukemia effects and eradicate residual AML cells.⁹

In STIMULUS-AML2, patients with AML who had achieved hematologic CR after alloSCT but still had evidence of MRD were treated with sabatolimab at several doses post transplant to discover whether this could eradicate MRD or prevent overt relapse.⁸ The data recently presented are from the safety run-in in which patients received 400 mg or 800 mg of the anti‒TIM-3 antibody sabatolimab. Primary endpoints were relapse-free survival (RFS) and safety.

Data from 21 patients were presented, divided almost equally between dose levels. These patients were mostly younger, as would be anticipated as candidates for alloSCT, and patients had an array of genetic risk levels. Of importance, a majority were MRD positive at the time of transplant, with the concern that they would be MRD positive post transplant with a high risk for disease relapse.⁸

Patients were required to demonstrate MRD by local assessment at least 60 days post transplant. Most of these were performed with PCR; fewer used flow cytometry, and 2 patients had chimerism analysis.⁸

The single dose of sabatolimab was very well-tolerated. Approximately 30% of patients experienced any treatment-related AEs. No acute or chronic graft vs host disease (GVHD) was seen; 1 patient had a myocarditis event that was considered a DLT at the 800-mg dose, and 5 patients died from overt relapse of AML.⁸

Treatment-related AEs in these 21 patients included grade 3 neutropenia and thrombocytopenia in 1 patient, the 1 incidence of myocarditis mentioned above, and 1 low-grade instance each of folliculitis and peripheral neuropathy.⁸

Preliminary efficacy data are intriguing, showing that one third of patients remain on treatment and in hematologic CR at the time of data collection. Response does not seem to be dose dependent, as the number of relapse-free patients was similar for each dose level. Many of the patients who remained disease free continued to receive additional cycles of sabatolimab in the following year.⁸

There has been growing excitement regarding menin inhibitors, which are novel targeted therapies for AML with KMT2A rearrangements (formerly known as mixed-lineage leukemia or MLL rearrangements). These agents act by blocking the activation of the pathogenic epigenetic complex resulting from this mutation. The leading menin inhibitor in clinical development is revumenib, formerly known as SNDX-5613. Data reported here are from patients treated with the recommended revumenib dose of 163 mg twice daily in the phase II expansion of AUGMENT-101.¹⁰ At ASH 2023, results from a cohort of 94 patients with R/R acute leukemias harboring KMT2Ar mutations were reported.

Out of the 57 patients treated with revumenib in the efficacy population, 86% had AML, 12% had ALL, and 1 patient had mixed phenotype leukemia. The majority were older patients, but 13 patients (23%) were younger than 18 years of age. These patients had received a median of 2 prior lines of therapy, with 46% having received ≥3 prior lines of therapy; 75% had received prior venetoclax-based regimens, and almost one half had received prior alloSCT. Overall, this is a prognostically poor patient population.¹⁰

In these prognostically poor patients, ORR was 63%, which breaks down into a CR rate of 18%, CR/CRh/CR with incomplete platelet recovery/CRi rate of 44%, and morphologic leukemia-free state of 18%. The median time to response was <2 months. The median OS (without censoring for transplant) in the efficacy population was 8 months, with a range of approximately 4-11 months.¹⁰

The CR/CRh rate was identical regardless of prior stem cell transplantation at 23%. This rate was higher in patients who had received 1 prior line of therapy compared with those who had received ≥2 lines of therapy (47% vs 12%-14%), suggesting that this agent may be more efficacious in the upfront setting than in patients who are heavily pretreated.¹⁰

Response rates were analyzed by type of KMT2A rearrangement, but no clear pattern of association was seen. Patient numbers were quite small in each group.¹⁰

The median duration of CR/CRh was approximately 6 months. In these patients with R/R disease, the ability to proceed to alloSCT may be the best predictor of long-term response. Here, 14 of 36 patients were able to proceed to transplant; one half of those patients restarted revumenib treatment in the posttransplant setting.¹⁰

The phase I study of revumenib found some evidence of QTc prolongation, which was considered the DLT.¹¹ At the recommended phase II dose used here, this still occurred at any grade in 26% of patients and grade ≥3 in 14% of patients.¹⁰ Differentiation syndrome also emerged in this cohort, at any grade in 28% of patients and grade ≥3 in 16% of patients. The differentiation syndrome is likely due to the underlying mechanism of action of menin inhibitors, similar to that first seen with IDH inhibitors in APL. These 2 AEs are the ones to watch for carefully with this agent.

ASCEND-CML was a prospective, open-label phase II study using asciminib at 40 mg twice daily in 101 patients with newly diagnosed chronic-phase CML.

Responses were evaluated in 3-month intervals, primarily by P210 BCR::ABL1. Early molecular response was defined as BCR::ABL1 <10% by Month 3, and major molecular response was defined as BCR::ABL1 <0.1% by Month 12. For patients who achieved a major molecular response, the asciminib dose was changed to 80 mg once daily, whereas those with a suboptimal response received asciminib 80 mg twice daily. For those with treatment failure, asciminib was administered in combination with imatinib, dasatinib, or nilotinib.

Coprimary endpoints for ASCEND-CML were early molecular response and major molecular response.¹⁶

The participants enrolled on ASCEND-CML were mostly middle-aged male patients. The majority of these patients had low-risk (67%) or intermediate-risk (28%) disease at the time of their diagnosis. The median follow-up for this report was relatively short at 23 months, which is why we have the 3- and 12-month milestones.¹⁶

At 3 months, 93% of patients achieved an early molecular response, and 48% of patients achieved a major molecular response.¹⁶

At 12 months, the major molecular response rate had gone up to 78%. Almost one third of patients had a 4.5-log reduction in BCR::ABL1 at that 12-month time point (BCR::ABL1 ≤0.0032%). The cumulative instance of major molecular response at 12 months was approximately 78% and at 24 months was approximately 87%.¹⁶

Out of 101 patients, 6 discontinued treatment because of intolerance, and a small number of patients were noted to have therapeutic resistance. These individuals were taken off the study mostly because of the presence of mutations or lack of clinical response.¹⁶

This study enrolled 125 patients with standard- or high-risk newly diagnosed APL. During induction, patients with standard-risk APL were assigned to receive arsenic trioxide/all-trans retinoic acid/ascorbic acid (AAA) with daunorubicin, and those with high-risk APL received AAA only. Both groups subsequently received AAA for consolidation and maintenance.

Primary endpoints included OS, RFS, and safety. The secondary endpoint was molecular response via molecular monitoring of bone marrow and peripheral blood after each cycle, every 8 weeks during maintenance, and every 3 months for 2 years after maintenance completion (NCT03624270).²¹

The median age of patients enrolled on this trial was 49 years, and most patients had classical APL pathology. Nine patients had CNS involvement, and most (74%) participants had standard-risk APL.²¹

At a median follow-up of 31 months, all patients on this trial achieved CR; 3-year OS and RFS rates were 97% each.²¹

The most common AEs were grade 1 headache and grade 2 hepatotoxicity, including transaminitis. Grade 3 or 4 AEs were rare in this trial, and there were no reports of treatment-related discontinuations or death. Of interest, all patients who developed APL differentiation syndrome within 14 days of treatment initiation responded fully to dexamethasone.²¹

This study enrolled 363 patients with ESA-naive, very low‒, low-, or intermediate-risk MDS who required regular transfusions. The standard of care for this patient population typically is an erythropoietic agent, and this trial randomized patients to receive either luspatercept or epoetin alfa. Treatment continued until progressive disease or lack of benefit according to the International Working Group 2006 criteria. The primary endpoint was RBC-TI for >12 weeks with a concurrent mean hemoglobin increase of ≥1.5 g/dL up to Week 24, and key secondary endpoints included safety and erythroid hematologic improvement (NCT03682536).²⁴

The arms of this trial were well-balanced. The median age of enrolled patients was 74 years, and most patients (approximately 63%) had a transfusion burden of <3 units/8 weeks. There was a preponderance of patients with SF3B1-mutated MDS enrolled on this trial. Approximately 63% of patients on the luspatercept arm and 56% of those on the epoetin alfa arm harbored SF3B1 mutations. In addition, approximately 72% to 73% of patients on both arms were positive for ringed sideroblasts in the marrow. Of note, these biological features are known to correlate with high response to luspatercept therapy.

When looking at the intention-to-treat population, luspatercept resulted in a significantly higher rate of RBC-TI for ≥12 weeks with a concurrent hemoglobin increase of ≥1.5 g/dL compared with epoetin alfa (60.4% vs 34.8%; P <.0001). The superiority of luspatercept vs epoetin alfa in achieving RBC-TI was clearly seen in patients with SF3B1-mutated MDS (70.2% vs 32.7%) and those with ring sideroblasts (65.4% vs 29.2%), and this trend was consistent irrespective of baseline serum erythropoietin level.²⁴

In addition, patients with low- and intermediate-risk MDS treated with luspatercept demonstrated superior response rates vs epoetin alfa in all key secondary trial endpoints, including RBC-TI at ≥12 weeks and ≥24 weeks of treatment. Luspatercept therapy also was associated with 74.2% of patients who achieved hematologic improvement in the erythroid lineage at ≥8 weeks vs 53% of patients who received epoetin alfa (P <.0001).²⁴

As expected, luspatercept was more effective in patients who had SF3B1 mutations or the presence of ring sideroblasts. The mean duration of RBC-TI was 126.6 weeks and 89.7 weeks in the luspatercept and ESA arms, respectively.²⁴

The median duration of treatment in the luspatercept and epoetin alfa arms was 51.3 and 37.0 weeks, respectively. There were more treatment-emergent AEs among patients receiving luspatercept, as well as more AEs in general. Over time, rates of fatigue and asthenia decreased, and events were mostly grade 1/2 in the luspatercept arm. Of interest, there were a similar number of deaths. Overall, luspatercept was considered to be a safe agent in this setting.²⁴

IMerge was an international, double-blind phase III trial that enrolled 178 patients with low- or intermediate-1‒risk MDS who were RBC transfusion dependent and refractory to or relapsed on an ESA or erythropoietin. Participants were randomly assigned to receive imetelstat or placebo. This particular analysis evaluated the rates of RBC-TI across risk categories using the IPSS, the IPSS-R, or the modified IPSS (IPSS-M) (NCT02598661).^26,27

This outlines the variety of the IPSS, IPSS-R, and IPSS-M risk scores of patients enrolled on this trial. The majority of patients were characterized as having low-risk MDS (67% by IPSS, 75% by IPSS-R, and 63% by IPSS-M).^26,27

As mentioned previously, durable RBC-TI was observed over time with imetelstat treatment. RBC-TI of ≥8 weeks was 40% with imetelstat vs 15% with placebo (P <.0008). Of note, 83% of patients who responded at 8 weeks of treatment achieved RBC-TI.^26,27

Imetelstat demonstrated a significant improvement in RBC-TI vs placebo, regardless of IPSS risk category. For patients with IPSS low risk, RBC-TI was 28.8% vs 5.1% at ≥24 weeks (P = .003). For patients with IPSS intermediate-1 risk, RBC-TI was 39.5% vs 4.8% at ≥8 weeks (P = .004) and 26.3% vs 0% at ≥24 weeks (P = .009).²⁶

Across IPSS-R subgroups, the transfusion-independence benefit with imetelstat still holds true compared with placebo. Furthermore, the rate of response among patients with intermediate-risk disease was similar to that of patients with low-risk disease. No responses were seen among patients with intermediate-risk disease who were receiving placebo. Patients with very low‒ or high-risk disease were not assessed because of low patient numbers.²⁶

When stratifying by cytogenic risk, imetelstat also increased the proportion of patients with RBC-TI, regardless of IPSS-R risk category.²⁶

RBC-TI continued to be improved across all IPSS-M risk categories, and one third of patients with higher-risk MDS experienced RBC-TI of ≥8 weeks.^26,27