Acute myeloid leukemia

Stopping Acute Myeloid Leukemia Stem Cells in Their Tracks.

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Researchers have identified growth regulators that trigger the proliferation of dormant leukemic stem cells in a specific type of acute myeloid leukemia, suggesting a possible approach to prevent relapse by using repurposed drugs. Credit: SciTechDaily.com

The discovery of two growth regulators involved in acute myeloid leukemia relapse offers hope for targeted therapies to prevent recurrence, emphasizing the need for further research to extend these findings to other leukemia subtypes.

The mystery of why myeloid leukemias start to grow again after chemotherapy has killed the bulk of malignant cells, and how growth may be blocked by repurposed drugs, has potentially been solved through new research.

The bone marrow of AML patients contains a rare population of leukemic stem cells (LSCs) that do not grow and therefore are not killed by chemotherapy. However, after treatment, these cells start to grow and produce AML cells, but it was unclear what kick-starts this process.

In a new study published in Nature Communications by researchers from the University of Birmingham, Newcastle University and the Princess Maxima Centre of Pediatric Oncology studied single cells from patients with t(8;21) Acute Myeloid Leukemia, a specific type of blood cancer, to investigate what made the rare LSCs grow.

Prof Constanze Bonifer from the Institute of Cancer and Genomic Sciences at the University of Birmingham who led the study said, “Leukemic stem cells normally seem asleep which is why they are not killed by chemotherapy, but we reasoned that something must trigger them to start growing in order for the leukemia to come back.

“These cells are very rare and difficult to study but by examining gene expression in single LSCs we found genes being expressed that encode for growth regulators normally not present in myeloid cells. Both cell types are found in the bone marrow alongside the AML cells, but healthy stem cells do not respond to their signals. By aberrantly upregulating these growth regulators, leukemic stem cells now can respond to growth factors that are present in the body and tell them to grow.”

Blocking Unwanted Stem Cell Growth

The growth regulators, identified in this study were KDR, the receptor for VEGF signaling which is normally only expressed in blood vessels and the IL-5 receptor which is normally only expressed on eosinophils. Moreover, VEGFA, the growth factor binding to KDR, was also expressed by the leukemia meaning it could trigger its own growth. Following identification of these receptors, the researchers confirmed that by activating them in the laboratory they were able to trigger stem cell growth. Importantly, they also showed that growth could be blocked in a dish and in mice by repurposing drugs against VEGF (Avastin, approved for various solid tumors including colorectal cancer) and IL-5 signaling (Fasenra, approved for eosinophilic asthma).

Prof Olaf Heidenreich from Newcastle University and the Princess Maxima Centre of Pediatric Oncology says, “An exciting result from these studies is the fact that the expression of these receptors is specific to this particular type of leukemia. They are expressed as a result of the presence of a specific disease-causing mutation giving rise to the onco-fusion protein RUNX1::ETO which reprograms the gene regulatory network that defines how a cell responds to outside growth signals. This work highlights the power of single cell analysis for digging deep into what regulates the growth of AML cells. It also highlights the fact that AML sub-types may have to be treated as separate entities.

New Hope for AML Patients

The first author of the study, Dr. Sophie Kellaway who is now continuing this research at the University of Nottingham says, “We were very excited to find not one but two new, and potentially druggable targets to prevent relapse in these patients. Being told your cancer has come back is devastating news and we want to prevent this happening. Unfortunately, as these receptors were so specific this would only work for t(8;21) acute myeloid leukemia and is not a magic bullet. However, inspection of other single cell data from different leukemia sub-types show that other growth regulatory pathways are upregulated in their stem cell population as well. We are now hoping to find those that can be hit in other types of AML.”

FDA Approves New Treatment for Patients With Acute Myeloid Leukemia

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The U.S. Food and Drug Administration today approved Daurismo (glasdegib) tablets to be used in combination with low-dose cytarabine (LDAC), a type of chemotherapy, for the treatment of newly-diagnosed acute myeloid leukemia (AML) in adults who are 75 years of age or older or who have other chronic health conditions or diseases (comorbidities) that may preclude the use of intensive chemotherapy.

“Intensive chemotherapy is usually used to control AML, but many adults with AML are unable to have intensive chemotherapy because of its toxicities. Today’s approval gives health care providers another tool to use in the treatment of AML patients with various, unique needs. Clinical trials showed that overall survival was improved using Daurismo in combination with LDAC compared to LDAC alone for patients who would not tolerate intensive chemotherapy,” said Richard Pazdur, M.D., director of the FDA’s Oncology Center of Excellence and acting director of the Office of Hematology and Oncology Products in the FDA’s Center for Drug Evaluation and Research.

AML is a rapidly progressing cancer that forms in the bone marrow and results in an increased number of abnormal white blood cells in the bloodstream and bone marrow. The National Cancer Institute at the National Institutes of Health estimates that in 2018, approximately 19,520 people will be diagnosed with AML and approximately 10,670 patients with AML will die of the disease. Almost half of the adults diagnosed with AML are not treated with intensive chemotherapy because of comorbidities and chemotherapy related toxicities.

The efficacy of Daurismo was studied in a randomized clinical trial in which 111 adult patients with newly diagnosed AML were treated with either Daurismo in combination with LDAC or LDAC alone. The trial measured overall survival (OS) from the date of randomization to death from any cause. Results demonstrated a significant improvement in OS in patients treated with Daurismo. The median OS was 8.3 months for patients treated with Daurismo plus LDAC compared with 4.3 months for patients treated with LDAC only.

Common side effects reported by patients receiving Daurismo in clinical trials include low red blood cell count (anemia), tiredness (fatigue), bleeding (hemorrhage), fever with low white blood cell count (febrile neutropenia), muscle pain, nausea, swelling of the arms or legs (edema), low platelet counts (thrombocytopenia), shortness of breath (dyspnea), decreased appetite, distorted taste (dysgeusia), pain or sores in the mouth or throat (mucositis), constipation and rash.

The prescribing information for Daurismo includes a Boxed Warning to advise health care professionals and patients about the risk of embryo-fetal death or severe birth defects. Daurismo should not be used during pregnancy or while breastfeeding. Pregnancy testing should be conducted in females of reproductive age prior to initiation of Daurismo treatment and effective contraception should be used during treatment and for at least 30 days after the last dose. The Boxed Warning also advises male patients of the potential risk of drug exposure through semen and to use condoms with a pregnant partner or a female partner that could become pregnant both during treatment and for at least 30 days after the last dose. Daurismo must be dispensed with a patient Medication Guide that describes important information about the drug’s uses and risks. Patients should also be advised not to donate blood or blood products during treatment. Health care providers should also monitor patients for changes in the electrical activity of the heart, called QT prolongation.

The FDA granted this application Priority Review designation. Daurismo also received Orphan Drug designation, which provides incentives to assist and encourage the development of drugs for rare diseases.

The FDA granted the approval of Daurismo to Pfizer.

The FDA, an agency within the U.S. Department of Health and Human Services, protects the public health by assuring the safety, effectiveness, and security of human and veterinary drugs, vaccines and other biological products for human use, and medical devices. The agency also is responsible for the safety and security of our nation’s food supply, cosmetics, dietary supplements, products that give off electronic radiation, and for regulating tobacco products.

Antitibiotic-Chemo Combo Cuts Infection Risk in AML

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Children with acute myeloid leukemia (AML) had a significantly lower incidence of certain bacterial infections if they received fluoroquinolone prophylaxis after chemotherapy, a small retrospective study showed.

Children treated with levofloxacin had more than a 50% reduction in the incidence ofStreptococcus viridans infections compared with children who received chemotherapy without antibiotic prophylaxis, but did not eliminate infection by the organism. Gram-negative infections also occurred significantly less often with antibiotic prophylaxis.

Despite the benefits, the overall incidence of any clinical infection during chemotherapy was not significantly lower in the levofloxacin group, reported Asmaa Ferdjallah, MD, of Children’s Healthcare of Atlanta and Emory University, and colleagues here at the American Society of Pediatric Hematology/Oncology meeting.

“Prophylactic use of levofloxacin reduces the incidence of strep viridans infections,” Ferdjallah said. “However, strep viridans resistance is common in patients receiving levofloxacin prophylaxis. Levofloxacin prophylaxis reduces gram negative infections during period of neutropenia.”

Other potential contributors to the lower incidence of infection could not be ruled out, she added. During implementation of antibiotic prophylaxis for patients with AML, a strategy to improve central line care also was implemented. Additionally, chlorhexidine baths and oral hygiene protocols were initiated.

Bacterial sepsis is a leading cause of morbidity and mortality in patients with AML. Contemporary studies have found microbiologically confirmed infections in one-third tothree-fourths of patients, associated with mortality of 6% to 11%.

Studies involving adults with cancer have suggested that fluoroquinolone prophylaxis can reduce infection-associated mortality. One study involving children with acute lymphoblastic leukemia showed an association between antibiotic prophylaxis and lower rates of hospitalization, intensive care admissions, and bacteremia.

The National Comprehensive Cancer Network suggests “consideration of fluoroquinolone prophylaxis” in patients with AML treated with chemotherapy, Ferdjallah said, and theInfectious Diseases Society of America specifically mentions consideration of levofloxacin prophylaxis, including consideration of use in high-risk pediatric patients.

In 2012, Children’s Healthcare of Atlanta implemented a policy of levofloxacin prophylaxis for all patients with newly diagnosed AML. Ferdjallah and colleagues examined the impact of the policy on bacterial infections during induction therapy and episodes of chemotherapy-induced neutropenia. Secondarily, they evaluated the incidence of fungal infections in patients receiving levofloxacin prophylaxis.

Investigators conducted a retrospective chart review of patients with newly diagnosed AML treated from September 2010 to September 2014, covering the 2 years before and after institution of the levofloxacin prophylaxis policy. The protocol stipulates initiation of levofloxacin on the first day of chemotherapy and continuation until cell count recovery.

They defined a bacterial infection as a positive blood, wound, or tissue culture and a fungal infection as a positive culture or CT findings in association with signs and symptoms consistent with infection.

The study population consisted of 39 patients who had a median age of 11 and age range of 15 months to 20 years. The patients received a cumulative total of 132 courses of cytarabine-containing chemotherapy: 80 courses with levofloxacin prophylaxis and 52 courses without levofloxacin.

Overall, gram-positive infections occurred during 23 (28.75%) courses of chemotherapy with levofloxacin prophylaxis and 20 (38.46%) courses of chemotherapy without prophylaxis, a difference that did not achieve statistical significance (P=0.213).

When Ferdjallah and colleagues analyzed infectious by S. viridans status, they found a significant reduction in S. viridans infections, from 28.85% during the period without levofloxacin prophylaxis to 12.5% with prophylaxis (P=0.024). Prophylaxis did not significantly affect the incidence of non-S. viridans infections (16.25% versus 9.6%,P=0.312).

Gram-positive organisms accounted for most of the chemotherapy-associated infections. Nonetheless, no patients who received levofloxacin prophylaxis developed a gram-negative infection as compared with five infections (9.62% of chemotherapy courses) in the no-prophylaxis group (P=0.024).

Levofloxacin prophylaxis was not associated with an increased risk of fungal infections, Ferdjallah said. Fungal infections occurred during two (2.5%) courses of chemotherapy in the prophylaxis group versus five (9.62%) courses in the no-prophylaxis group (P=0.112).

The total infection rate was substantially reduced with levofloxacin prophylaxis, but the difference did not achieve statistical significance (33.75% versus 50.0%, P=0.067).

Three patients died during induction or intensification of chemotherapy, including one infection-related death in a patient who did not receive levofloxacin prophylaxis.

During the discussion that followed her presentation, Ferdjallah acknowledged that a prospective randomized trial would be the optimal way to determine the value of fluoroquinolone prophylaxis during chemotherapy for AML. However, she questioned whether such a study would be feasible, given consistent evidence from observational studies in favor of prophylaxis.

Genomic Studies Allow Better Classification of Leukemias, Endometrial Tumors.

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Two studies, one of leukemia and the other of endometrial tumors, show the usefulness of genomics studies in finding unsuspected classifications, possibly useful for treating these cancers.

One study, published in the New England Journal of Medicine, examined 200 cases of acute myeloid leukemia. Genomic studies allowed the researchers to discern nine distinct categories, revealing “many potentially important biologic relationships.” For instance, certain mutations were associated with distinct patterns of RNA activity. The authors point out that the significance of such findings “is not yet clear.”

Another study, in Nature, of some 375 endometrial cancers found four distinct classes of the disease, as opposed to the two commonly used to stage treatment. In Journal Watch Oncology and Hematology, Virginia Kaklamani observes that breast cancer was the first to use molecular subtypes to guide treatment. The Nature study, she writes, is “a huge step toward applying this technique in other malignancies.”

Source:NEJM