Lindsay Fischer

Patients with relapsed or refractory KMT2A rearranged acute leukemia obtained durable minimal residual disease (MRD)-negative remission rates as a result of treatment with revumenib, as demonstrated by recent study findings.

Results from the phase 2 AUGMENT-101 study were presented at the 

2023 American Society of Hematology Annual Meeting and Exposition

Of note, KMT2A rearranged acute leukemia involves genetic changes in the KMT2A gene, which plays a role in controlling cell growth. Rearrangement of this gene can result in uncontrolled cell division and the development of leukemia.

Additionally, a high proportion of patients on the trial were able to continue to transplant, which, according to Dr. Ibrahim Aldoss, is the goal of treatment in this setting.

“After achieving a response, 40% of responders were able to go on to allogeneic stem cell transplant, which is usually our ultimate goal for someone with relapsed/refractory leukemia,” Aldoss, who is a hematology oncologist at the City of Hope Comprehensive Cancer Center, explained in the presentation. “Half of the patients were able to continue revumenib as a maintenance therapy after the transplant.”

Further, investigators concluded that the safety profile is promising because the rate of side effect-related discontinuations and dose reductions were low. The rate of treatment-emergent side-effect-related discontinuation was 6%.

At a median follow-up of 6.1 months, the rate of overall response (patients who responded to treatment, including a partial or complete response) in the efficacy population (57 patients), was 63% (36 patients). This included a 23% complete remission (disappearance of all signs of cancer from treatment), complete remission with partial hematologic recovery (when certain levels of blood cells return to normal) rate and a 44% composite complete remission rate. The median duration of remission was six months.

Regarding best response, 10 patients achieved a complete remission (18%), three achieved a complete remission with partial hematologic recovery (5%), one achieved a complete remission with incomplete hematologic recovery (1.8%) and 11 achieved a complete remission with incomplete platelet recovery (19%). Ten patients reached a morphologic leukemia-free state (18%) and one patient achieved a partial response (1.8%).

Among those with negative MRD status, the complete remission and complete remission with partial hematologic recovery rate was 70% (seven out of 10 patients) and the composite complete remission rate was 68% (15 out of 22 patients).

The efficacy population included patients who had a confirmed KMT2A rearrangement and who remainedin follow-up for the prespecified amount of time.Of note, Aldoss also presented findings from a “safety population,” which included all patients who received at least one dose of revumenib, regardless of whether they had their KMT2A rearrangement confirmed and regardless of follow-up in the trial.

In the efficacy population, 86% of patients had acute myeloid leukemia (AML) and 12% had acute lymphoblastic leukemia (ALL), and 2% had mixed-phenotype acute leukemia or another subtype. The most common co-mutation was RAS (16%), followed by FLT3 (9%), and p53 (7%). A quarter (25%) of these patients had primary refractory disease, and the median number of prior treatment lines was two.

Most patients (72%) had previously received Venclexta (venetoclax), and nearly half (46%) had undergone prior hematopoietic stem cell transplantation (HSCT; a procedure that administers healthy stem cells to help produce new blood cells).

“These are heavily pretreated patients,” Aldoss underscored. “Close to half of these patients had at least three or more prior lines of therapy, and almost half of the patient had prior allogeneic stem cell transplant.”

The median age in the efficacy population was 34 years; 13 patients (22.8%) were under the age of 18 and 44 (77.2%) were 18 or older.

Any-severity nausea (44.7%), febrile neutropenia (38.3%), diarrhea (35.1%) and vomiting (30.9%), were the most common treatment-emergent side effects reported in the trial. Other treatment-emergent side effects, of any severity, that occurred in at least 25% of patients were differentiation syndrome (a large, rapid release of cytokines from leukemia cells that may be impacted by anticancer drugs; 27.7%), low potassium levels (27.7%), nosebleed (26.6%) and irregular heart rhythm (25.5%).

In terms of severe or worse treatment-emergent side effects, the most commonly reported ones were febrile neutropenia (fever and low neutrophil levels in blood; 37.2%), anemia (18.1%), decreased neutrophil count (a type of white blood cell; 16%), decreased white blood cell count (16%), and decreased platelet count (a piece of cell that helps with blood clotting; 14.9%).

Other severe or worse treatment-emergent side effects, occurring in at least 10% of patients, included differentiation syndrome (16%), irregular heart rhythm (13.8%), sepsis (an extreme immune response potentially leading to organ failure, tissue damage or death; 11.7%) and hypokalemia (10.6%).

Of note, there were no instances of treatment discontinuation related to differentiation syndrome, irregular heart rhythm or cytopenias (lower than normal number of blood cells).

Similar to the efficacy population, 83% of patients in the safety population had AML and 15% had ALL, while 2% had mixed-phenotype acute leukemia or another subtype. The most common co-mutation was RAS (13%), followed by FLT3 (7%), and p53 (5%).

A fifth (19%) of patients had primary refractory disease, and the median number of prior treatment lines was 2 (range, 1-11). Most patients (65%) had already received Venclexta and half (50%) had undergone prior HSCT.
The median age in this cohort was 37 years; 23 patients were pediatric (24.5%) and 71 were adults (75.5%).

There are currently no approved targeted therapies for patients with KMT2A rearrangements despite it being prevalent in up to 10% of acute leukemias.

Following chemotherapy and HSCT, most patients will relapse, and the rate of remission following relapse is low (complete remission, 5%), as is the median overall survival (2.4 months) in adults. The outcomes associated with infants and children after relapse also remain poor. 

“It's a disease with unmet therapeutic need,” Aldoss said. “These patients have (a) high risk of relapse after transplant and after chemotherapy and, in adults, remission rates after relapse — and median overall survival when the patients reach second salvage therapy or beyond — remain low.”

For more news on cancer updates, research and education, don’t forget to 

Articles

Children and adults with relapsed/refractory KMT2A rearranged acute leukemia may obtain promising response rates with revumenib, a novel targeted therapy.

MRD Negativity May Be Achievable With Revumenib in Some Leukemia Subset

The decision for patients to receive chemotherapy should depend on their response to endocrine therapy and gene expression testing, for patients with hormone receptor-positive, HER2-negative, non-invasive, early breast cancer, according to findings from the multicenter ADAPTcylcle trial, which were presented at the 

“Endocrine therapy response should be considered in addition to gene expression testing for routine decision-making regarding chemotherapy use in hormone receptor-positive, HER2-negative, (non-invasive), early breast cancer, to maximize the number of patients in whom chemotherapy can be spared,” Dr. Oleg Gluz, of the West German Study Group, said in a presentation in the findings.

Researchers screened 5,293 German women with intermediate- to high-risk hormone receptor-positive, HER2-negative, early breast cancer. Among this sample, there were 4,334 women with all the available characteristics to be evaluated for this study.

Ultimately, 1,684 patients were randomly assigned to receive either (neo)adjuvant endocrine therapy plus two years of Kisqali (ribociclib) or (neo)adjuvant chemotherapy with standard endocrine therapy as part of the ADAPTcycle trial. However, the findings presented at the 2023 Symposium are focused on the larger pool of 4,334 women who had been screened.

Of note, this sample included 1,423 patients endocrine therapy responders (63%), of which 659 (48.2%) were 50 years or younger, and 2,155 (72.7%) were older than 50 years.

An endocrine response was defined as Ki67 (a protein biomarker) below or equal to 10% after two to four weeks of preoperative endocrine treatment. Patients were assessed in subgroups according to endocrine therapy received, their age, and their recurrence score.

The median overall endocrine therapy response was 9.9 (min/max). In the younger population, the median response, specifically, was 9.2 (min/max) and in the older population, it was 10.3 (min/max).

The data showed that adding ovarian function suppression (OFS) to tamoxifen or aromatase inhibitors significantly increased the likelihood of response in premenopausal patients. The rates of responses were similar to those seen with postmenopausal patients previously treated with an aromatase inhibitor.

The findings suggested that when treated with optimal endocrine therapy, both pre- and postmenopausal patients have similar levels of endocrine therapy sensitivity, according to Gluz.

The researchers determined the likelihood of response to endocrine therapy in a group of 4,334 patients with hormone receptor-positive, HER2-negative, non-invasive, early breast cancer, by analyzing the screening cohort from the WSG ADAPTcycle trial.

“If you looked on the multivariable analysis for endocrine response as an endpoint, we have observed that treatment, age, recurrence score, and baseline Ki67 and estrogen receptor expression by immunohistochemistry…. all these factors were independently associated with endocrine responses in this cohort and provide further information,” Gluz said.

In the population of patients whose Ki67 scores were less than 10% at baseline, the rate of response in the 50 years or younger population was 34.7% (277 patients) with tamoxifen alone, 55.7% (142 patients) with tamoxifen and OFS, and 76.4% (240 patients) with an aromatase inhibitor plus OFS.

Among the 50 years or older cohort, the response rate was 43.8% (159 patients) with tamoxifen, 76.4% with aromatase inhibitors (1,892 patients) and 82.5% (104 patients) with endocrine therapy plus OFS.

In the ADAPT trial, the response rate with tamoxifen was 40.1% in the premenopausal population of endocrine responders, and the rate of responses with an aromatase inhibitor alone in the postmenopausal population was 81.5%. These findings from the larger population, therefore, confirmed the likelihood of these response rates.

Furthermore, as Gluz pointed out, adding the OFS increased the response rates in both populations.

“If ovarian suppression was added to (the) younger patient’s (treatment) in that short period of time before the surgery, the endocrine response rates brought was up to 77% in patients treated by aromatase inhibitors in this younger group,” he said, “(Response) levels which were (also) observed in older patients.”

Among patients who were 50 years or younger and whose recurrence scores were between 0 and 25, the response rates were 44.0% (201 patients) with tamoxifen alone, 68.1% (81 patients) with tamoxifen and OFS and 81.8% (126 patients) with an aromatase inhibitor plus OFS.

Among patients who were 50 years or younger and whose recurrence scores were between 26 and 100, the response rates were 15.8% (35 patients) with tamoxifen alone, 40.8% (29 patients) with tamoxifen and OFS and 66.7% (54 patients) with an aromatase inhibitor plus OFS.

Among patients who were older than 50 years and whose recurrence scores were 0 and 25, the response rates were 57.1% (141 patients) with tamoxifen alone and 87.9% (1,247 patients) with an aromatase inhibitor alone.

Among patients who were older than 50 years and whose recurrence scores were between 26 and 100, the response rates were 18.2% (14 patients) with tamoxifen alone and 55.6% (399 patients) with an aromatase inhibitor alone.

“As expected, patients with higher recurrence score levels had less endocrine response rates,” Gluz said. “But, if adequate endocrine treatment was (added), in the younger patients, we observed up to 67% endocrine responder (rates) in cases with higher recurrence scores and 55% of patients with (high) recurrent scores (achieved) endocrine response in our postmenopausal patients.”

Among patients who were 40 years or younger and whose recurrence scores were between 0 and 25, the response rates were 49.4% (41 patients) with tamoxifen alone, 70.6% (24 patients) with tamoxifen and OFS, and 93.5% (29 patients) with an aromatase inhibitor plus OFS.

Among patients who were younger than 40 years and whose recurrence scores were between 26 and 100, the response rates were 11.9% (seven patients) with tamoxifen alone, 39.3% (one patient) with tamoxifen and OFS, and 69.0% (20 patients) with an aromatase inhibitor plus OFS.

“In this population, we observed very substantial endocrine response rates — up to 94% in patients with recurrence scores up to 25 if OFS was done (in addition to aromatase inhibitors), and up to 70%, endocrine response rates in cases of recurrence scores over 25,” Gluz emphasized.

Previously, findings from the WSG ADAPT HR-positive/HER2-negative trial showcased “excellent” five-year patient outcomes. Specifically, the five-year distant disease-free survival (dDFS) rate associated with adjuvant endocrine therapy alone was 97% among a population of patients who were 50 years or younger, had N0-1 hormone receptor-positive/HER2-negative early breast cancer, had a recurrence score equal to or less than 25, and who had achieved a response to endocrine therapy after short preoperative endocrine therapy.

Since then, emerging data from other prospective trials have suggested that adjuvant chemotherapy plus endocrine therapy may be more effective in younger populations versus endocrine therapy alone, but not in postmenopausal patients. Investigators have theorized why this is — positing that distinct tumor biology in pre- vs postmenopausal patients, chemotherapy-induced amenorrhea, or the use of tamoxifen alone without ovarian suppression could be responsible. Yet the answer remains unknown.

These findings seek to better define the benefit of endocrine therapy and the likelihood of responses according to age and other stratification factors. Findings were based on the screening cohort of the WSG ADAPTcycle trial.

Follow-up from the ADAPTcycle will determine the impact of endocrine therapy response, with and without ovarian function suppression, on survival outcomes.

Results from the ADAPTcycle trial found that endocrine therapy plus ovarian suppression can generate high response rates in patients with HR-positive, early breast cancer, regardless of age.

Consider Endocrine Therapy Responses When Planning Chemo in Breast Cancer Subset

A cancer diagnosis affects not only the patient with the disease, but the person caring for them, too. 

Allison Breininger’s life was changed forever when her husband, Sean, was diagnosed with Fanconi anemia — a rare genetic disease involving bone marrow failure and a significantly higher risk for developing cancer.

In the 12 years since Sean’s diagnosis, he has had tongue, bladder, prostate and skin cancer. He has undergone bone marrow transplant, as well as tongue and bladder resection, and most recently, esophageal surgery. Throughout all of this, Allison has been by his side.

Yet, when she was thrust into this role, she had no experience or medical training. She felt wholly unprepared to be pulled in so many directions. Suddenly, she was helping her husband recover from surgeries and relearn how to speak, while caring for their newly adopted young daughter and working. And although there were resources available for her husband, she, herself, felt forgotten in the cancer care landscape.

“I have gone through a traumatic experience as well,” she said, in an interview with CURE®’s sister publication,

 ahead of her husband’s most recent surgery. “For instance, I am about to go sit in a hospital all day, and we are not sure what the outcomes going to be. Afterwards, he will get medicine and rest, and I will be parenting, and working, and taking care of the household.”

“Caregivers are going through this really hard thing, while also doing so many other things,” she added. “Then, to add insult to injury, we are often unseen. People do not really even recognize that this hard thing is happening to us too.”

Prior to his diagnosis, Sean had been working in the nonprofit space and Allison was an educator. Together, they combined their background to create 

, whose mission is to change the way caregivers are seen and supported.

Their mission is accomplished in two ways. First, Allison offers direct support through one-on-one coaching with caregivers and hosting virtual support groups. Second, she works across community setting to teach individuals how to better support caregivers. She speaks to medical students and health care professionals to paint the picture of the caregiver experience for them, so they can learn to support not only the patient but the caregiver as well.

The Negative Space also recently received a grant to partner with the Hope Lodge, which is part of the American Cancer Society.

“As we know, when a patient checks into the Hope Lodge, they get this big ‘swag bag,’” Allison said. “The caregiver gets a folder. A folder filled with paperwork.”

The grant that she received allowed her to make caregiver gift boxes to greet those checking in.


“The next 142 caregivers that check into the Hope Lodge will get one of my caregiver gift boxes,” she said. “The theme is, ’I am part of the story.’” The boxes are filled with affirmations that the caregivers are indeed part of the story, comforting items like tea and essential oils, and connections to resources that they may need.

Of note, the term “negative space,” is an artistic concept. It lives alongside the positive space, or the subject of the composition; negative space is the space around and between the subject of an image. However, it is just as important as the subject itself, as it helps to define the boundaries of the positive space and brings balance to a work of art.

In Allison’s experience, the caregiver often represents this “negative space.” They are vital to the big picture, providing balance by constantly providing for the patients. Yet, the patients, themselves, represent the positive space, by being the focus of doctors, appointments, families, friends, and family schedules.

Through Allison’s work, including her speaking engagements and gift boxes, she is hoping to reframe how the world sees caregivers, highlighting their role in the overall composition of care.

“Think of everything that is in the background of a picture, the things that you don't really pay attention to or see or focus on,” she said. “If they were gone, the whole picture would change.”

“That is the case with caregivers as well.”

The Negative Space is not the only organization seeking to change the conversation around caregivers.

Hazel Moran, who leads the global patient insights and advocacy team at EMD Serrano, is also working to help create a web of caregiver advocacy. Her team serves the main liaison with patient organizations to find opportunities to support patients and caregivers.

Embracing Carers came about through collaboration between her company and the caregiving community, according to Moran. The initiative serves as a platform that hosts resources developed by patient organizations. As of October 2023, the website offers 5 United Nations-approved online training modules free of cost to caregivers. These modules are available in both English and Spanish and delve into intense clinical duties that many individuals be feel unprepared to tackle on their own, such as nursing nasogastric and gastronomy tubes.

“We are excited to be able to bring forward free training for caregivers on things like how to set up a home environment appropriately, to address caregiver-patient need, to optimize nutrition, and deal with feeding tubes,” she told 

. “These are basic modules that support caregivers and the roles that they have to have to do.”

Other modules address stool collection and disposing of human waste, proper use of catheters and managing incontinence, and understanding digestive problems that may arise. For those who are interested, there is also the option to receive UN certification as a professional caregiver after completing the training courses.

“This is just the beginning,” Moran said. “We're already thinking about what do we need to do next.”

Cancer caregivers go through trauma that is often unseen and unrecognized, though some organizations are trying to change that. 

Cancer Caregivers Are ‘Often Unseen’ 

There may be opportunities to improve cost discussions and documentations, including better price transparency, an expert said. 

Most patients with cancer do not have a documented discussion about the financial costs of treatment, according to a recent study presented at the 2023 ASCO Quality Care Symposium.

Specifically, the study demonstrated that in a population of 1,767 patients with non–small cell lung cancer (NSCLC) and 689 patients with melanoma, 20.3% vs 24.0%, respectively, had a documented cost discussion in their medical record.

“Three-fourths of patients with stage 3/4 non-small cell lung cancer or melanoma did not have a documented cost discussion in their medical records,” Robin Yabroff, said in a presentation of the findings.

The study also showed that cost-of-care discussions were less likely among those with private insurance, in hospitals without a residency program and among those who were not receiving systemic therapy.

The Financial Toxicity of Cancer Treatment

Moving forward, Yabroff noted that there may be opportunities to improve cost discussions and documentations, including better price transparency.

“Frequently, the cost of a specific care to a specific patient is not always available,” Yabroff, who is scientific vice president of health services research with the American Cancer Society, said.

“However, we do know that if patients have health insurance coverage, we know what their out-of-pocket maximum will be for that year. That information may be very useful for patients.”

As Yabroff explained, new approvals in oncology have offered patients new systemic treatments — however, they often come with high price tags and high out-of-pocket costs.

Medical financial burden is also common, and patients with financial hardship during treatment are more likely to experience symptom burden, worse health-related quality-of-life outcomes, and face an increased mortality risk.

Since the early 2000s, the median monthly price of new cancer drugs has been higher than the median monthly household income. In 2017, the median annual price of a new anti-cancer drug was $172,199. By 2021, this number had increased to $250,775.

Despite these high price tags, discussions around cost remain rare. Investigators therefore designed this study to examine the rate of cost discussions in individuals who just received a diagnosis of either advanced NSCLC and melanoma, as these cancers have the high-cost treatment options.

To do so, investigators looked at the 2017 and 2018 NCI patterns of care studies, this included 12 population-based Surveillance, Epidemiology, and End Results Program (SEER) registries. Data was collected about patient demographics, their cancer type, and the characteristics of the hospital where they were receiving treatment.

Of note, certain limitations may have impacted the study results, according to Yabroff. Specifically, it is possible that cost-of-care discussions happened that were not recorded. Also, this study looked at patients diagnosed between 2017 and 2018, yet more recent expensive treatments have since been approved. The records used for data collection did not offer any information about treating clinicians or contact with patients.

As Dr. Veena Shankaran, pointed out, the phrase “cost-of-care conversation” is vague

“What is a cost of care conversation?” she said in a postpresentation discussion of the findings. 

“The content of these conversations really can't be captured in an electronic medical record and undoubtedly, there will be quite a bit of heterogeneity.”

Shankaran, who is a professor in the cancer prevention program with the Fred Hutchinson Cancer Center, as well as co-director of the Hutchinson Institute for Cancer Outcomes Research, went on to argue that there is certainly value in providing this intervention, and that it could be pushed further.

“We have the opportunity to start thinking about who benefits most and why,” she said. “Out-of-pocket cost estimates, for example, may not help a Medicaid patient who simultaneously has very little to no cost sharing for treatment, yet also may face significant challenges for many other reasons.”

She also proposed that moving forward, research should be centered less on reactive models than proactive ones. According to Shankaran, financial hardship is often identified late into treatment, when screening should be conducted both upfront and longitudinally.

“Many questions in the field around financial screening, including who to screen and how often, (remain),” she said. “(But) I think the consensus is that we need to screen everybody, and we need to screen them longitudinally.”

Most patients with cancer may not be discussing the cost of care with their clinicians, according to recent research. 

Lindsay Fischer

MRD Negativity May Be Achievable With Revumenib in Some Leukemia Subset

Consider Endocrine Therapy Responses When Planning Chemo in Breast Cancer Subset

Cancer Caregivers Are ‘Often Unseen’

Cancer Costs Conversations Are Important, But Underutilized

Latest News