Listen to Amir T. Fathi, MD, discuss key findings from select studies in leukemias presented at the ASH 2025 Annual Meeting, including perspectives on the clinical implications of the data for patients with AML or CML.
In this podcast episode, Amir T. Fathi, MD, reviews data from select presentations in leukemias at the ASH 2025 Annual Meeting, and provides perspectives on the clinical implications of these data for patients with acute myeloid leukemia (AML) or chronic myeloid leukemia (CML), including:
Presenter:
Amir T. Fathi, MD
Director, Leukemia Program
Massachusetts General Hospital
Associate Professor of Medicine
Harvard Medical School
Boston, Massachusetts
Content based on an online CME program supported by educational grants from AstraZeneca, BeOne Medicines, Genentech, Geron Corporation, Incyte, Johnson & Johnson, Lilly, and Novartis Pharmaceuticals Corporation.
Link to full program:
https://bit.ly/48Ye45N
Introduction
Dr. Amir Fathi (Massachusetts General Hospital): This is Amir Fathi. I am the director of the leukemia program at Massachusetts General Hospital in Boston, Massachusetts. I am also an associate professor of medicine at Harvard Medical School. I am going to review some of the abstracts presented at this year's American Society of Hematology Meeting in Orlando, Florida.
PARADIGM – a phase 2 randomized multicenter study comparing azacitidine and venetoclax to conventional induction chemotherapy for newly diagnosed fit adults with AML
Induction chemotherapy: decades of “tradition”
The first abstract that I am going to go through is PARADIGM. This phase 2 randomized study comparing azacitidine and venetoclax versus traditional induction chemotherapy in fit patients with AML was presented at the scientific plenary session. This study specifically sought to assess the promise of azacitidine and venetoclax currently approved for older non-induction eligible patients in the induction-eligible population.
Toils of induction chemotherapy
As many know, intensive induction chemotherapy has been the conventional standard treatment for younger patients for many, many years, more than five decades, and it is associated with substantial morbidity and substantial burden for patients. They stay in the hospital for many days. They have infectious and bleeding complications. There are additional risks, psychosocial implications, mucositis, malnutrition, and it is quite hard on the health care system as well, given the prolonged hospitalizations impact on quality of life.
Azacitidine and venetoclax
Finding a more gentle regimen seemed suitable and azacitidine and venetoclax being approved in older patients based on the prior phase 3 study with a high response rate in that older patient population, as well as an improved overall survival, seemed a good candidate to compare against this very intensive therapy. We enrolled 172 patients on this randomized study, 86 on each arm.
Baseline characteristics
It is important to note the eligibility criteria. These were fit, induction-eligible patients, but they did not include certain mutational subtypes. FLT3 mutated patients were excluded. Younger NPM1-mutated patients were excluded. Core binding factor-altered patients were excluded. These patients were not part of the study, and any results that emerge from this study should not apply to those patients.
Safety and tolerability
We found that the combination of azacitidine and venetoclax was, as expected, quite well tolerated. There were significantly less patients impacted by grade 3 or higher infectious or bleeding complications on the azacitidine venetoclax arm versus the induction arm. There was less mortality at 30 days and 60 days on the azacitidine/venetoclax arm.
Clinical activity
There was a higher rate of overall response, a higher composite remission rate, a higher rate of CR plus CRh.
Event-free survival and overall survival
The primary end point, event-free survival, was improved in patients who received azacitidine venetoclax versus induction chemotherapy. Overall survival was not significantly different, but there was also a significant amount of crossover between arms after lack of response on either arm, making overall survival a challenging endpoint to interpret.
Transplant
Also important, among patients that received azacitidine/venetoclax, a higher proportion of them went to transplant after study treatment than those who received intensive therapy.
Conclusions
All in all, this trial was important because for the first time in a prospective fashion, it demonstrated the promise of a more gentle treatment in traditionally young, fit patients and found it to be superior to traditional induction chemotherapy.
Clinical implications
We feel, therefore, that this supports the use of azacitidine venetoclax in younger, fit, potentially transplant-eligible patients who are intermediate or adverse risk by ELN criteria and do not have FLT3 mutations. So, basically, the patient population that was studied.
SAVE: Phase I/II Study of Oral Revumenib Plus Decitabine/Cedazuridine and Venetoclax in Cohort of Patients with Newly Diagnosed AML
Now I am going to move on to the SAVE clinical trial. This was the phase 1/2 study of oral revumenib plus decitabine cedazuridine, which is an oral decitabine formulation, as well as venetoclax in patients with newly diagnosed AML.
SAVE (Newly Diagnosed AML Cohort): Background
As I mentioned earlier, hypomethylating agents and venetoclax are the current standard of care for older patients with newly diagnosed leukemia. The SAVE study, centered at MD Anderson, has looked at the menin inhibitor revumenib in combination with oral decitabine plus venetoclax to see, particularly in NPM1 and KMT2A altered patients, in whom menin inhibitors are thought to be quite effective because they release the block in differentiation and allow for response as monotherapy, so combining them with a standard of care such as HMA and venetoclax – in this case, decitabine, cedazuridine and venetoclax – seem to make sense.
SAVE: Study Design
Dr. Issa and colleagues have previously reported data on relapsed refractory patients having very good responses with this triplet regimen. At this year's ASH meeting, they actually presented some data on newly diagnosed patients with NPM1 mutations, KMT2A rearrangements, and including also NUP98 alterations, with revumenib, decitabine/cedazuridine and venetoclax. They found that the triplet regimen was quite well tolerated. There was some signal for cytopenias, but overall there was not a significant challenge with dosing.
SAVE (Newly Diagnosed AML Cohort): Response
The overall response rate across all patients was 86%. The composite remission rate was 79% in the NPM1 mutated group, and 86% in the KMT2A rearranged group. Of note, this is data on just 21 patients, 14 with NPM1 mutations, seven with KMT2A rearranged, so not a lot of patients. Despite that, within this small group the response rate was quite impressive and the responses seem to be deep, at least based on the MRD data presented. It looks like a substantial proportion of patients had MRD negative remissions, so that is quite promising.
SAVE (Newly Diagnosed AML Cohort): Patient Outcomes
Overall, I think this is promising. We will need to have additional information to emerge. Of note, there were four deaths among this cohort. All of them seem to be related to infectious complications. This may be related to the cytopenias that sometimes arise from this particular triplet. I think we need to learn more about that. The presenters did speak on that particular issue, but I think, regardless, we do have some data here that suggests that the triplet combination using revumenib, oral decitabine, and venetoclax is highly promising. We will need additional data with additional patients to see whether this is promising in a larger patient population.
Ziftomenib in combination with venetoclax and azacitidine in newly diagnosed NPM1-m in AML. Phase 1b results from KOMET-007
Let us move on now to yet another menin inhibitor. We talked about revumenib. Now we can talk about ziftomenib, again in combination with venetoclax and azacitidine and other hypomethylating agents. Venetoclax and hypomethylating agents, whether azacitidine or decitabine, are the standard of care for older patients. We talked about revumenib in combination.
Background
Now we will be talking about ziftomenib in combination. This data is from the KOMET-007 study, which has looked at various combinations of ziftomenib with standard therapies in AML. Dr. Roboz presented this abstract specifically in newly diagnosed patients that were older or not eligible for intensive therapy.
Study design
The n for this presentation was higher at around 40 patients. Several of them, albeit a minority, had FLT3 mutations and IDH mutations. The treatment was quite well tolerated. There was not a substantial amount of toxicity. There was not a significant number of patients with QT prolongation. Only one reported case of emergent QT prolongation among the 40 patients that were treated.
Overall composite remission rate
The overall composite remission rate here, again highly impressive at 86%. The majority of the composite remissions were actual CRs, which is quite promising, also.
MRD negativity
Dr. Roboz also presented some data on MRD negativity. Most of the patients per central MRD testing, which is important because the sponsor actually used central MRD testing, achieved MRD negativity by a threshold of less than or equal to 0.1%, and 44% achieved MRD negativity with a threshold of 0.01%. A decent number of patients achieved MRD negativity on this study.
Phase 3 in plan
Additional data will emerge. It is also important that there are plans for phase 3 studies of this combination, as well as the combination with intensive chemotherapy for upfront AML patients that are going to be part of the KOMET-017 study of ziftomenib plus standard therapy. That trial has just been launched and we are moving forward with that.
Venetoclax and azacitidine with gilteritinib in patients with newly diagnosed FLT3mut+ AML ineligible for intensive induction chemotherapy: interim results from the phase 1/2 VICEROY study
Introduction
Let us now move forward and talk about data from the VICEROY study. Now we are moving from menin inhibitors. We are moving on to gilteritinib, a FLT3 inhibitor. Again, combined with the standard treatment for older patients, venetoclax and azacitidine in FLT3 mutated patients. This is the combination of venetoclax, azacitidine, gilteritinib in newly diagnosed FLT3 mutated patients.
Methods
In a single center study prior to this multicenter effort, the triplet combination of azacitidine, venetoclax, and gilteritinib led to a complete remission rate of 90% with a median overall survival which was not reached. The VICEROY study attempted to do a larger randomized phase 1/2 study, basically looking at the triplet combination in a larger, multicenter group to assess its true promise. The primary endpoints were dose limiting toxicities, safety, tolerability, and to get a better sense of the response rates.
Patient demographic and clinical characteristics
The median ages for this study were approximately 75 years old, so an older patient population. Included both ITD and TKD FLT3 mutations.
Safety summary
Of note, there were safety data presented. A decent proportion of patients experienced febrile neutropenia, pneumonia, sepsis, but it was a minority of patients. In terms of therapy emergent adverse events, most patients had therapy related emergent adverse events. Most of them were infectious in nature. However, these did not result in a substantial number of deaths. There were no deaths in the first 30 days and one death within the first 60 days, so early mortality was quite promising, suggestive of tolerability of this triplet regimen.
Triplet exposure and time to hematologic recovery
Triplet exposure and time to hematologic recovery was also presented at the meeting. In general, the median time to ANC recovery of 500 and a platelet recovery of 50 were 43 by cycle two and 36 by cycle four. This is perhaps slightly longer than what would be expected, but not substantially so with azacitidine and venetoclax alone. In that range of approximately 38 to 42 is what the authors presented with various venetoclax doses.
CR and CRc rates
The composite remission rates were also presented. Quite promising around 90%, with the majority of them being CR. It looks like the single center experience may be replicating now in the multicenter experience.
OS
The median follow up for overall survival was 19 months, and the 12-month overall survival was 60%. The median overall survival was 23 months.
Improved long-term tolerability and efficacy of asciminib-based combination therapies in newly diagnosed CML patients – the fascination trial
Let us now move on to the next study. This one is on the topic of CML, chronic myeloid leukemia. I am going to be discussing two abstracts on CML. One is to specifically look at the long term tolerability and activity of asciminib combinations in newly diagnosed CML patients. Currently, asciminib is approved for use in the United States in the front line, and we have increasingly started to use it because it is well-tolerated and quite effective and active against the more challenging ABL kinase mutational subtype of T315I alterations.
[00:15:08]
Background and study objectives
This study specifically sought to assess the promise of asciminib in combination with other TKIs, and assess the ability to potentially combine asciminib with nilotinib, dasatinib, and imatinib. Based on a PCR assessment at 24 months to make a determination of whether to continue with the combination with asciminib or to then go on to asciminib monotherapy, and then following month 36 to have a treatment-free attempt, so a potential for patients to go off of treatment altogether if they have had a deep enough sustained response.
Study design
This study was accrued throughout Germany. They looked at various combinations of TKIs with asciminib.
Adverse events
In general, it appears that the combinations were fairly well tolerated, although there were some degree of toxicities throughout.
Response rates
The response rates seem to be quite promising, and more so than would be expected with asciminib alone.
Summary and conclusions
Overall, the authors felt that this study called the FASCINATION study, the combination of asciminib with various TKIs, is associated with impressive and high rates of deep molecular response. The tolerability may be a little bit more enhanced or impacted than asciminib monotherapy. The three-year follow up shows perhaps a higher activity, but continued need for monitoring of this tolerability.
Asciminib in CML in chronic phase: positive primary results of the phase 2 ASC2ESCALATE trial in the cohort of patients with 1 prior TKI
The next abstract that I am going to present is the ASC2ESCALATE trial, led by Dr. Jorge Cortes and presented by him at this year's ASH meeting. This time looking at asciminib not as frontline therapy, but as second line therapy.
Study design
This specifically wanted to assess at week 48 whether escalating the dose of asciminib led to improved activity while maintaining safety and tolerability. Patients on a second line cohort received asciminib at a dose of 80mg a day, and at six months and 12 month that dose was increased first to 200mg and daily and then to 200mg twice daily.
Demographics and baseline characteristics
Of note, the patients that enrolled on this study, in their frontline treatment, had received a variety of different TKIs, and the reason that they came off of that frontline therapy was a combination of a lack of efficacy, as well as a lack of tolerability. For 57 of the 101 patients - was due to a lack of efficacy. 44 patients were because of a lack of tolerability. That is relevant because, generally speaking, a lack of efficacy portends for a poorer result over time with subsequent treatments.
Prior TKI therapy and baseline response level
In general, it appears that patients that had an increase in dose over time continue to respond and do well with treatment, with deepening of molecular response over time. It is important to note that most patients that had dose escalation on this study had discontinued their prior TKI due to lack of efficacy rather than tolerability. Most of them had actually received prior dasatinib.
AEs of special interest
Most of the toxicities that were of special interest were, as would be expected, GI toxicity, lipase elevation, some degree of cytopenias, but there was no impressive change in the signal for toxicity or tolerability. Overall, this treatment was well tolerated.
Conclusions
The study met its primary objective. 59.4% of patients achieved a major molecular response at week 48. Deep molecular responses were achieved by more people over time, including about 30% at week 48. It is important to note that a minority of patients on study actually needed dose escalations. Not everybody got a dose escalation, and remained at a dose of 80 mg a day. The increase in dose did not seem to impact the safety profile.
Clinical implications
How does this impact what we do in the clinical setting? I would say as of now, it provides us some reassurance that if we need to increase the dose, we can do so safely. It is also reassuring that most patients do not need an increase in dose, and that 80 mg a day could very well be sufficient in controlling the disease of most patients with chronic phase CML based on this study in the second line setting. [00:20:51]
General overview of the six studies reviewed
Today I reviewed six abstracts from the American Society of Hematology meeting, four on AML, two on CML. The AML studies were a range of different studies, some looking at novel triplet combinations, including menin inhibitors and FLT3 inhibitors, and the paradigm study presented at the plenary that compared non-intensive HMA venetoclax to traditional intensive chemotherapy and showed superiority. All of these will hopefully help advance the field and the care of our patients, as well as their tolerability.
As far as CML, asciminib seems to be ascendant and being increasingly used because of its tolerability profile and its activity. These studies that I discussed assess whether increasing the dose or combining it with other TKIs may enhance activity while maintaining safety.