Stage 3 Cancer: Definition, Diagnosis, Treatment, Prognosis
A Targeted Therapy Shows It Can Offer A 'last, Great Chance' For Some Acute Leukemia Patients
SAN DIEGO — One of the toughest subtypes of acute leukemia involves a genetic alteration in the KMT2A gene. Many cancers with this genetic alteration end up relapsing or don't respond to treatment, but new data presented at the annual American Society of Hematology meeting offer hope of a new targeted therapy for these patients.
The study, called the Phase 2 Augment-101 trial, tested Syndax's revumenib in patients with relapsed or refractory leukemia with these KMT2A genetic rearrangements. Overall, about 63% of the patients responded to the treatment, with many able to receive a potentially curative stem cell transplant later on, which is often the ultimate goal for patients with relapsed or refractory patients, said Ibrahim Aldoss, a hematologist-oncologist at City of Hope and the study's presenter, in an interview.
"KMT2A-rearranged diseases represent 10% of all leukemia. They can be exceptionally hard to treat," Aldoss said. "The median overall survival remains low with current available treatment. Right now there's no targeted therapy for KMT2A-rearranged disease. We're really excited about revumenib as it targets the mutation, and we're seeing encouraging outcomes."
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SubscribeHow To Improve Survival For Pediatric Leukemia Patients
It is well known that tobacco smoke adversely affects the prognosis of adult cancers, including myeloid leukemia. But less is known about the effects in children. Now, researchers at UC San Francisco and UC Berkeley are investigating the impact of pre- and post-natal exposures to tobacco smoke on the survival rate of children with acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML).
Leukemia is the most common childhood cancer comprised mainly of ALL followed by AML. Despite improvements in cancer survival, leukemia incidence has increased in recent decades in the United States, especially in the Latinx population and significant disparities persist by socioeconomic status (SES), race and ethnicity. Exposures to tobacco smoke from fathers before conception and from secondhand smoke after birth have been associated with increased risks of developing childhood ALL and AML. Yet minimal attention has been given to the possible impact of tobacco smoke on survival following leukemia diagnosis.
In a study published recently in Cancer Epidemiology, Biomarkers & Prevention, the UCSF research team showed that paternal preconception smoking decreased 5-year survival in children with AML.
The researchers evaluated whether pre- and post-natal exposures to tobacco smoke decreased 5-year survival of 1,235 childhood ALL and 188 childhood AML cases derived from a population-based case-control study in California. The patients were diagnosed between 1995 and 2015 (with a median follow-up time of 13.2 years). They analyzed data for tobacco smoking before conception, during pregnancy and after birth. The researchers also looked at parental education and income, clinical features and vital status through 2020, and also adjusted for sociodemographic characteristics and risk group (for ALL only).
About 23% of mothers and 39% of fathers reported smoking and 130 children with ALL and 52 with AML died within 5 years. For AML, increased risks of death were observed among children whose fathers smoked before conception compared to non-smoking fathers. It was observed that paternal preconception smoking may also reduce 5-year survival among ALL cases with particular molecular subtypes.
"As oncologists, knowing your patients' history of tobacco smoke exposure is important so that it can be integrated into prognostic discussions regarding childhood leukemias," said Lena Winestone, MD, senior author and UCSF assistant professor, specializing in pediatric malignancies. "At a minimum, primary care doctors can counsel families about the risks related to smoking in the pre-natal period for the health of future children."
In another study, published Nov. 3, 2023 in Pediatric Blood and Cancer, Winestone and her team explored racial and ethnic disparities in acuity among children with acute leukemia. Across acute leukemia types, first-line chemotherapy treatment carries the highest mortality and complications are substantially more common in patients with AML than ALL.
The researchers previously found that children with AML who required intensive care for multiorgan system failure at diagnosis had a 14 times higher risk of dying during the initial treatment phase compared with those not requiring such intervention. Black patients were more likely to require intensive care unit (ICU)-level resources at initial presentation compared with white patients.
However, after accounting for intensive care treatment within the first 72 hours of initial admission, the researchers found no racial differences in continued use of ICU-level resources during first line treatment or in subsequent chemotherapy. This finding suggested that clinical status in the peri-diagnostic period drives disparities in early mortality and overall survival in AML. In contrast, despite persistence of racial and ethnic disparities in ALL survival, induction mortality disparities have not been observed in recent clinical trials.
The researchers studied the cases of 899 patients with acute leukemia diagnosed at two large children's hospitals, and evaluated disparities in disease burden, organ dysfunction, vital signs and timing of therapy in children newly presenting with acute leukemia. They examined (EHR) data regarding racial, ethnic and socioeconomic status (SES) differences in presenting clinical severity and management to assess potential contributions to survival disparities. They hypothesized that Black patients were more likely to both present with abnormal vital signs and have abnormal labs within the first 72 hours following admission.
Black patients with AML had increased prevalence of elevated white blood cell count and uric acid; Black patients with ALL demonstrated increased prevalence of coagulopathy (prolonged or excessive bleeding). Black patients' presentation more frequently included multiple lab abnormalities consistent with advanced physiologic dysfunction. No differences were found in days to therapy initiation or vital signs at presentation.
"Our study demonstrated that high disease burden at presentation of newly diagnosed AML is more prevalent in Black children than non-Hispanic white children," said study first author Winestone. "Black patients also have a greater than 2-fold risk of presenting with substantial dysfunction in multiple systems across acute leukemia types. Together these findings start to identify the factors that drive racial disparities in early death and highlight the need for interventions to address access to care for children with leukemia."
For the tobacco exposure study:
Funding: The research was supported by the California Tobacco-Related Disease Research Program (TRDRP) grant #T31IP1502. Collection and/or maintenance of the original CCLS data were partly supported by the National Institute of Environmental Health Sciences (NIEHS) grants #P42ES004705, R01ES009137, and R24ES028524, and the UK Children with Cancer grant #2006/052.
Additional authors: Please see the study.
For the Racial and ethnic disparities study:
Funding: Alex's Lemonade Stand Foundation for Childhood Cancer, an American Society of Hematology Scholar Award, and an American Cancer Society (CSDG-21-093-01-HOPS)
Additional authors: Please see the study.
About UCSF Health: UCSF Health is recognized worldwide for its innovative patient care, reflecting the latest medical knowledge, advanced technologies and pioneering research. It includes the flagship UCSF Medical Center, which is a top-ranked specialty hospital, as well as UCSF Benioff Children's Hospitals, with campuses in San Francisco and Oakland, Langley Porter Psychiatric Hospital and Clinics, UCSF Benioff Children's Physicians and the UCSF Faculty Practice. These hospitals serve as the academic medical center of the University of California, San Francisco, which is world-renowned for its graduate-level health sciences education and biomedical research. UCSF Health has affiliations with hospitals and health organizations throughout the Bay Area. Visit www.Ucsfhealth.Org. Follow UCSF Health on Facebook or on Twitter.
Moleculin Presents Positive Interim Data From Phase 1B/2 Clinical Trial In AML At Meeting With KOL's In Conjunction With ASH Annual Meeting
- CR rate of 36% in Intent to Treat or ITT (n=11) subjects with durability
- CR rate of 44% in subjects treated with Annamycin (n=9)
- Durability of CR's up to 8 months & climbing (no relapses to date)
- Recruitment in MB-106 Phase 1B/2 clinical trial reaches 59%
- Announces Publication for 65th ASH Annual Meeting and Exposition
- Annamycin continues to be 100% non-cardiotoxic
HOUSTON, Dec. 11, 2023 /PRNewswire/ -- Moleculin Biotech, Inc., (Nasdaq: MBRX) ("Moleculin" or the "Company"), a clinical stage pharmaceutical company with a growing pipeline, including Phase 2 clinical programs, for hard-to-treat tumors and viruses, today announced the presentation of preliminary efficacy findings from the Company's ongoing European Phase 1B/2 clinical trial evaluating Annamycin for the treatment of acute myeloid leukemia or AML (MB-106) to key opinion leaders and current investigators at a meeting held in conjunction with the 65th American Society of Hematology Meeting and Exposition (ASH) in San Diego on December 10, 2023. Additionally, the Company will have a paper published on its MB-106 clinical trial as part of ASH. A link will be provided on the Company's website once this publication is available online.
Moleculin Biotech, Inc. Is a clinical stage pharmaceutical company focused on the development of a broad portfolio of oncology drug candidates for the treatment of highly resistant tumors. (PRNewsfoto/Moleculin Biotech, Inc.)
The KOL presentation included an update to the positive preliminary efficacy findings previously reported on MB-106. To date, among patients who had an evaluable post treatment bone marrow biopsy, or who dropped out due to an adverse event (AE), there have been 4 complete responses (CR's) or 36% of the intent to treat (ITT) subjects (n=11) and 44% of the subjects treated (dosed with Annamycin) (n=9). Two subjects experienced adverse events and were not dosed with one being an allergic reaction to Annamycin, the first the Company has seen in over 70 subjects dosed in the Company's multiple Annamycin clinical trials; the second dropout was due to an allergic reaction to cytarabine. There continues to be no evidence of cardiotoxicity as measured by ejection fraction, strain analyses, ECGs, and cardiac biomarkers including Troponin-I and T in MB-106.
Story continues
"We believe that our growing body of preliminary clinical data demonstrated by Annamycin in the treatment of patients with AML continues to be highly encouraging and bolsters our confidence in its potential to be a meaningful option for patients," commented Walter Klemp, Chairman and Chief Executive Officer of Moleculin. "While still preliminary, the complete response rate we are seeing continues to reflect what we believe is an efficacy level greater than we need for eventual approval of Annamycin. Our recruitment rate continues to exceed expectations and we are optimistic that we will be fully recruited within the next few months."
Currently, the median age of subjects in MB-106 is 69 years with a median number of prior therapies for AML of one. While two of the Company's complete responders are too recent to measure durability, the Company is seeing durability as high as 8 months and climbing, and the Company has yet to see any relapses of CR's experienced to date in the trial. The Company has recruited 16 subjects to date with 2 subjects withdrawing from the trial due to adverse events and 3 other subjects having received treatment and not having the bone marrow aspirate fully evaluated.
Additionally, one of the subjects treated but not evaluated experienced a grade 4 serious adverse event (SAE) with septic shock caused by Escherichia coli (E. Coli) and was reported on a Suspect Adverse Reaction Report to the appropriate regulatory bodies and ethics committees. The subject was treated for the infection, the SAE is still reported as "ongoing," and the subject is recovering. This subject will be evaluated until resolution of the SAE and will be assessed for efficacy per protocol.
The presentation to the KOL's mentioned above will be posted on the Company's website and filed on Form 8-K with the Securities and Exchange Commission.
Annamycin currently has Fast Track Status and Orphan Drug Designation from the U.S. Food and Drug Administration for the treatment of relapsed or refractory acute myeloid leukemia, in addition to Orphan Drug Designation for the treatment of soft tissue sarcoma. For more information about the MB-106 Phase 1B/2 trial, visit clinicaltrialsregister.Eu and reference EudraCT 2020-005493-10 or clinicaltrials.Gov and reference NCT05319587.
About Annamycin
Annamycin is the Company's next-generation anthracycline that has been shown in animal models to accumulate in the lungs at up to 30-fold the level of doxorubicin. Importantly, Annamycin has also demonstrated a lack of cardiotoxicity in multiple early-stage human clinical trials, including ongoing trials for the treatment of AML and STS lung metastases. For that reason, although additional data will be necessary, the Company believes Annamycin may not face the same usage limitations imposed on doxorubicin, one of the most common currently approved anthracyclines. Annamycin is currently in development for the treatment of AML and STS lung metastases and the Company believes the drug may have the potential to treat additional indications.
About "Complete Remission"
Per the American Cancer Society, the goal of treatment for acute myeloid leukemia is to put the leukemia into complete remission (the bone marrow and blood cell counts return to normal), preferably a complete molecular remission (no signs of leukemia in the bone marrow, even using sensitive lab tests), and to keep it that way. Source: https://www.Cancer.Org/cancer/types/acute-myeloid-leukemia/treating/response-rates.Html
About Moleculin Biotech, Inc.
Moleculin Biotech, Inc. Is a clinical stage pharmaceutical company with a growing pipeline, including Phase 2 clinical programs, for hard-to-treat tumors and viruses. The Company's lead program, Annamycin is a next-generation anthracycline designed to avoid multidrug resistance mechanisms with little to no cardiotoxicity. Annamycin is currently in development for the treatment of relapsed or refractory acute myeloid leukemia (AML) and soft tissue sarcoma (STS) lung metastases.
Additionally, the Company is developing WP1066, an Immune/Transcription Modulator capable of inhibiting p-STAT3 and other oncogenic transcription factors while also stimulating a natural immune response, targeting brain tumors, pancreatic and other cancers, and WP1220, an analog to WP1066, for the topical treatment of cutaneous T-cell lymphoma. Moleculin is also engaged in the development of a portfolio of antimetabolites, including WP1122 for the potential treatment of COVID-19 and other viruses, as well as cancer indications including brain tumors, pancreatic and other cancers.
For more information about the Company, please visit www.Moleculin.Com and connect on Twitter, LinkedIn and Facebook.
Forward-Looking Statements
Some of the statements in this release are forward-looking statements within the meaning of Section 27A of the Securities Act of 1933, Section 21E of the Securities Exchange Act of 1934 and the Private Securities Litigation Reform Act of 1995, which involve risks and uncertainties. Forward-looking statements in this press release include, without limitation, Moleculin's ability to continue the Phase 2 portion of the clinical trial on a timely basis. Although Moleculin believes that the expectations reflected in such forward-looking statements are reasonable as of the date made, expectations may prove to have been materially different from the results expressed or implied by such forward-looking statements. Moleculin has attempted to identify forward-looking statements by terminology including 'believes,' 'estimates,' 'anticipates,' 'expects,' 'plans,' 'projects,' 'intends,' 'potential,' 'may,' 'could,' 'might,' 'will,' 'should,' 'approximately' or other words that convey uncertainty of future events or outcomes to identify these forward-looking statements. These statements are only predictions and involve known and unknown risks, uncertainties, and other factors, including those discussed under Item 1A. "Risk Factors" in our most recently filed Form 10-K filed with the Securities and Exchange Commission ("SEC") and updated from time to time in our Form 10-Q filings and in our other public filings with the SEC. Any forward-looking statements contained in this release speak only as of its date. We undertake no obligation to update any forward-looking statements contained in this release to reflect events or circumstances occurring after its date or to reflect the occurrence of unanticipated events.
Investor Contact:
JTC Team, LLCJenene Thomas(833) 475-8247MBRX@jtcir.Com
Cision
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SOURCE Moleculin Biotech, Inc.
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