Frontline nilotinib supported for newly diagnosed CP-CML

Long-term results from the ENESTnd trial indicate a favourable risk-benefit profile for frontline use of nilotinib in patients within 6 months of chronic phase-chronic myeloid leukaemia (CP-CML) diagnosis.

"Throughout the study, nilotinib has demonstrated several benefits over imatinib in surrogate endpoints of therapeutic efficacy, such as higher rates of response and lower rates of disease progression, death due to advanced CML and treatment-emergent BCR-ABL mutations", the researchers report in Leukemia.

"The risk of AEs [adverse events] (regardless of AE type) appears to be similar with nilotinib and imatinib; however, each TKI [tyrosine kinase inhibitor] is associated with different types of AEs, including a higher risk of CVEs [cardiovascular events] with nilotinib vs imatinib."

By 5 years, 77.0% of the 282 patients randomly assigned to receive nilotinib 300 mg twice daily and 77.2% of the 281 using nilotinib 400 mg twice daily achieved a major molecular response (BCR-ABL ≤0.1% on the International Scale [BCR-ABLIS]) compared with 60.4% of the 283 patients given imatinib 400 mg once daily.

Deep molecular responses by 5 years were also more common with nilotinib 300 mg and 400 mg than with imatinib, with rates of MR4 (BCR-ABLIS ≤0.01%) of 65.6%, 63.0% and 41.7%, respectively. The corresponding rates for MR4.5 (BCR-ABLIS ≤0.0032%) were 53.5%, 52.3% and 31.4%.

And estimated 5-year progression-free survival was 92.2%, 95.8% and 91.0% for the nilotinib 300 mg and 400 mg groups and the imatinib group, respectively. Overall survival at 5 years was estimated to be 93.7%, 96.2% and 91.7%, respectively.

Long-term dasatinib findings support first-line use in CML

In continuation of my update on dasatinib

Final DASISION study findings confirm dasatinib to be an effective, long-term treatment for patients with a new diagnosis of chronic phase-chronic myeloid leukaemia (CP-CML).

 dasatinib

After 5 years, 61% of 259 patients randomly assigned to receive dasatinib 100 mg/day were still taking the tyrosine kinase inhibitor (TKI), while 63% of the 260 patients started on imatinib 400 mg/day continued with their treatment, the investigators report in the Journal of Clinical Oncology.

The primary endpoint of complete cytogenetic response (CCyR) at 5 years had been achieved by 28% of dasatinib-treated patients and 26% of their imatinib-treated counterparts, although the researchers note that these values may have been higher if bone marrow samples had been tested in the patients at the end of the study.

Cumulative 5-year rates of major molecular response (MMR) and molecular responses with a 4.5-log (MR4.5) reduction in BCR-ABL1 transcripts from baseline were also comparable in the dasatinib and imatinib treatment arms, at 76% versus 64%, and 42% versus 33%, respectively, say Jorge Cortes, from the University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors.

Five-year estimated overall survival was 91.0% for the dasatinib group and 90.0% for those given imatinib. And estimated progression-free survival was a corresponding 85.0% and 86.0% with 4.6% and 7.3% of patients transforming to accelerated or blast phase CML during a period of follow-up that continued beyond TKI discontinuation.

In all, 84% of dasatinib-treated patients and 64% of imatinib-treated patients achievedBCR-ABL1 of 10% or less within 3 months of treatment. Compared with patients who did not reach this target, these individuals were more likely to achieve CCyR, MMR and MR4.5over 5 years, had higher rates of overall and progression-free survival, and were less likely to have transformation.

Cortes et al note that no new adverse effects were reported for dasatinib or imatinib by the end of the 5-year study period and just 15% and 11% of adverse effects were grade 3 or 4 in the groups, respectively.

Patients given dasatinib had higher rates of grade 3 or 4 neutropenia (29 vs 24%), anaemia (13 vs 9%) and thrombocytopenia (22 vs 14%) but lower rates of other nonhaematological side effects, except for any grade of pleural effusion (28.0 vs 0.8%). Discontinuation for drug-related side effects occurred in 16% and 7% of dasatinib- and imatinib-treated patients, respectively.

Pulmonary hypertension was reported in 5.0% and 0.4% of the dasatinib and imatinib groups, respectively, with 12 of the 14 diagnoses deemed to be drug related. Arterial ischaemic events were "uncommon" in both groups, affecting 5.0% and 2.0%, respectively.

However, there was a "disproportionate number" of deaths from infection in the dasatinib versus imatinib groups (11 vs 1), with seven deaths reported between 69 days and 4.5 years after dasatinib discontinuation.

"It will be important to prospectively and intentionally look at a possible imbalance in the occurrence of infections and, if present, determine a possible mechanism(s) for dasatinib-related infectious complications", the investigators comment.

"These results suggest that first-line dasatinib should continue to be considered a standard first-line therapy for patients with newly diagnosed CML-CP", the researchers conclude.

While patients given dasatinib were more likely to achieve early treatment milestones, the authors explain that the high rates of CCyR and overall survival in both treatment arms mean a longer follow-up period and larger study population are likely needed to demonstrate any significant difference in survival between the TKIs.

Low doses of imatinib drug can push immune system to combat bacterial infections

In contiuation of my update on Imatinib

Low doses of the anti-cancer drug imatinib can spur the bone marrow to produce more innate immune cells to fight against bacterial infections, Emory researchers have found.

The results were published March 30, 2015 in the journal PLOS Pathogens.

The findings suggest imatinib, known commercially as Gleevec , or related drugs could help doctors treat a wide variety of infections, including those that are resistant to antibiotics, or in patients who have weakened immune systems. The research was performed in mice and on human bone marrow cells in vitro, but provides information on how to dose imatinib for new clinical applications.

"We think that low doses of imatinib are mimicking 'emergency hematopoiesis,' a normal early response to infection," says senior author Daniel Kalman, PhD, professor of pathology and laboratory medicine at Emory University School of Medicine.

Ref : http://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1004770

Low doses of imatinib drug can push immune system to combat bacterial infections

Nilotinib more efficiant over Imatinib for (Ph+ CML)....

Nilotinib (see structure) :

Nilotinib, in the form of the hydrochloride monohydrate salt, is a tyrosine kinase inhibitor, approved as Tasigna in USA and the EU for drug - resistant chronic myelogenous leukemia (June 2006), resistant to treatment with imatinib (Gleevec), another tyrosine kinase inhibitor currently used as a first-line treatment.

In a recently held large clinical trial, nilotinib demonstrated greater efficacy over the current gold standard treatment, imatinib, in adult patients with newly diagnosed Philadelphia chromosome-positive chronic myeloid leukaemia (Ph+ CML) in the chronic phase.

As per the claim by the researchers, in the first head-to-head study of these two oral treatments as initial therapy for this life-threatening leukaemia, nilotinib demonstrated statistically significant improvement over imatinib in key measures of effectiveness used in the trial. The trial showed that at 12 months, significantly fewer patients on nilotinib 300mg twice-daily progressed from the initial chronic phase of the disease to the later accelerated or blast crisis phases than those on imatinib 400mg once-daily. This demonstrates that nilotinib provided significantly better control of the disease compared to imatinib.

95% of patients with CML have an abnormality known as the Philadelphia chromosome. This chromosome produces a type of protein called Bcr-Abl, which is responsible for the overproduction of the cancerous white blood cells that are the main feature in Ph+ CML. Nilotinib is a potent and selective inhibitor of the Bcr-Abl protein, thereby inhibiting the production of these cancerous cells.

Ref : http://www.novartis.com/newsroom/media-releases/en/2009/1359764.shtml

Dasatinib Tops Imatinib for Ph+ Acute Lymphoblastic Leukemia

In continuation of my update on dasatinib and imatinib

Dasatinib is associated with improved survival for pediatric patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL), according to a study published online Jan. 16 in JAMA Oncology.

Shuhong Shen, M.D., Ph.D., from the Shanghai Jiao Tong University School of Medicine, and colleagues conducted an open-label randomized trial at 20 hospitals in China involving patients aged 0 to 18 years with Philadelphia chromosome-positive ALL. Patients were randomly assigned to either daily dasatinib or imatinib (92 and 97 patients, respectively) in the context of intensive chemotherapy without prophylactic cranial irradiation.

The researchers found that the four-year event-free and overall survival rates were 71.0 and 88.4 percent, respectively, in the dasatinib group and 48.9 and 69.2 percent, respectively, in the imatinib group. The four-year cumulative risk for any relapse was 19.8 and 34.4 percent in the dasatinib and imatinib groups, respectively; the four-year cumulative risk for an isolated central nervous system relapse was 2.7 and 8.4 percent, respectively. There was no difference between the treatment groups in the frequency of severe toxic effects.

"The present study provides promising early outcome data supporting the use of a dasatinib-based regimen for Philadelphia chromosome-positive ALL," write the authors of an accompanying editorial. "It also highlights some key challenges that remain in the management of this disease."

Several authors disclosed financial ties to pharmaceutical companies, including Bristol-Myers Squibb, which manufactures dasatinib.

https://en.wikipedia.org/wiki/Dasatinib

Imatinib for the treatment of Scleroderma ?

We know that Imatinib (its mesylate salt, Novartis) is a drug used to treat certain types of cancer. It is used in treating chronic myelogenous leukemia (CML), gastrointestinal stromal tumors (GISTs) and a number of other cancers. It is the first member of a new class of agents that act by inhibiting particular tyrosine kinase enzymes, instead of non-specifically inhibiting rapidly dividing cells.

More over the discovery of this compound itself is interesting & its one drug obtained via, High Throughput Screening (HTS). Chemists used a HTS of chemical libraries to identify the molecule 2-phenylaminopyrimidine. This lead compound was then tested and modified by the introduction of methyl and benzamide groups to give it enhanced binding properties, resulting in imatinib. More interesting part of this drug is a recent discovery, i.e., GLEEVEC^® (imatinib mesylate) can be used to treat Scleroderma. As per the claim by the researchers, until now no drug has been shown to be effective in treating scleroderma in a clinical trial. Several years ago, a small study provided some evidence that a chemotherapy drug called cyclophosphamide may help scleroderma patients, but the benefit was minimal and this drug causes side effects including infertility and secondary cancers.

The investigators reported an interim analysis of their results, although the study is ongoing. At one year, the investigators saw a 23 percent improvement in skin scores. The researchers also saw an improvement in forced vital capacity scores by 9.6 percent and diffusion capacity scores by 11 percent in the 18 patients who had completed one year of treatment. The lung function data was really exciting,” Dr. Spiera said. “In patients with scleroderma, you usually see lung function tests getting worse over time, and if doctors try a therapy for a year and a patient doesn’t get any worse, we get pretty excited. What is amazing to me in this study is that we actually saw improvements in both lung function tests. Congrats for this remarkable achievement.....

Ref : http://www.hss.edu/newsroom_drug-provide-treatment-scleroderma.asp

Bafetinib demonstrates significant inhibition of glioblastoma multiforme cell lines (preclinical trials)..

The treatment of chronic myeloid leukemia (CML)  changed  dramatically with the emergence of the ABL tyrosine kinase inhibitor (TKI) imatinib mesilate. However, primary and secondary imatinib resistance has been frequently reported, particularly in patients with advanced-stage disease. To override imatinib resistance, three second-generation ABL TKIs, i.e., dasatinib, nilotinib and bosutinib, were developed. Bafetinib (see structure source : Chemblink :INNO-406, NS-187) is a dual ABL/Lyn inhibitor developed by the team at Kyoto University Hospital in collaboration with Nippon Shinyaku. 

Bafetinib was 25-55 times more potent than imatinib in blocking BCR/ABL autophosphorylation, while otherwise retaining specificity for ABL and Lyn. Bafetinib had antiproliferative effects against cells bearing wild-type or most mutated BCR/ABL proteins, except T315I, and also inhibited BCR/ABL-positive leukemic cell growth in the central nervous system. A phase I study on bafetinib was completed and the agent was well tolerated and demonstrated clinical activity across a range of doses. Responses occurred even in the setting of a heavily pretreated population, thus making bafetinib a viable option for CML therapy.

Recently  CytRx Corporation, announced that its drug candidate bafetinib (formerly known as INNO-406) demonstrated statistically significant inhibition of glioblastoma multiforme cell lines in a preclinical trial. The company believe that bafetinib could be efficacious in several hematological cancers and  it is  preparing to begin evaluating bafetinib in a Phase 2 proof-of-concept clinical trial in high-risk B-cell chronic lymphocytic leukemia (B-CLL) this quarter, as well as a Phase 2 clinical trial in advanced prostate cancer next quarter.... 

Ref : http://www.cytrx.com/inno_406.html

Bosutinib shows 'low' vascular, cardiac event risk profile

 In continuation of my update on Bosutinib

Third-generation tyrosine kinase inhibitor (TKI) study findings suggest that bosutinib is associated with a low risk of vascular and cardiac events in patients undergoing first-line or subsequent treatment for chronic myeloid leukaemia (CML).

"The results of this analysis suggest that the vascular and cardiac toxicity profile of bosutinib is distinct relative to other TKIs", write Jorge Cortes, from University of Texas MD Anderson Cancer Center in Houston, USA, and co-authors in the American Journal of Hematology

.

The team collated information on treatment-emergent adverse events (TEAEs) in 570 patients who received second-, third- or fourth-line bosutinib treatment for Philadelphia chromosome-positive CML as part of a phase I/II study.

In addition, the researchers determined the incidence of TEAEs in a phase III study comparing first-line bosutinib in 248 patients with first-line imatinib in 251 patients.

Trial participants were all followed up for at least 2 years and the overall incidence of vascular TEAEs was low, with all-grade and grade 3 or more severe side effects affecting 6.8% and 3.7% of patients given bosutinib, respectively.

First-line bosutinib was associated with a lower rate of vascular TEAEs than second-line or subsequent bosutinib therapy, affecting 4.8% versus 7.7%. First-line imatinib had comparable incidence of both overall and grade 3 and more severe vascular TEAEs to that of first-line bosutinib.

Cerebrovascular TEAEs were reported in 1.8% of patients given bosutinib, again being less common in those given primary bosutinib relative to second-line or later treatment (0.8 vs 2.3%). All-grade and grade 3 or more severe cardiovascular TEAEs occurred in 3.7% and 2.3% of bosutinib-treated patients, occurring at a lower rate in first-line than later treated patients (2.4 vs 4.2%).

Serious vascular TEAEs were reported in 4.2% of bosutinib-treated patients, with grade 3 or more severe events occurring in 3.1%, most commonly coronary artery disease (0.9%) and acute myocardial infarction (0.6%).

Events were less common in newly diagnosed patients than those with refractory or relapsed disease (2.0 vs 5.1%), and there was no significant difference in the incidence or exposure-adjusted rate between the first-line bosutinib and imatinib groups.

Ref : http://onlinelibrary.wiley.com/doi/10.1002/ajh.24360/abstract

Bosutinib shows 'low' vascular, cardiac event risk profile: Third-generation tyrosine kinase inhibitor study findings suggest that bosutinib is associated with a low risk of vascular and cardiac events in patients undergoing first-line or subsequent treatment for chronic myeloid leukaemia.

Beta-catenin shows treatment target potential for TKI-resistant CML

Nuclear β-catenin could be a treatment target for patients whose chronic myeloid leukaemia (CML) is resistant to tyrosine kinase inhibitors (TKIs) independent of additional BCR–BL1 mutations, US researchers suggest.

“Collectively, our data implicate nuclear β-catenin in intrinsic BCR-ABL1 kinase-independent TKI resistance, but argue against a direct role for β-catenin in BM [bone marrow]-mediated (extrinsic) TKI resistance”, write Michael Deininger, from the University of Utah in Salt Lake City, and co-investigators.

However, writing in Leukemia, they add “the caveat that even primary CML cells cultured ex vivo on primary MSCs [mesenchymal stromal cells] may not fully recapitulate persistent leukemia cells in patients on long-term imatinib therapy, including heterogeneity across patients.”

The team demonstrated that imatinib therapy reduced β-catenin levels in TKI-sensitive cell lines but had no impact on β-catenin in cells lines with either intrinsic or extrinsic BCR-ABL1 kinase-independent TKI resistance, indicating that “imatinib-resistant cells have uncoupled β-catenin expression from BCR-ABL1 activity.”

Beta-catenin shows treatment target potential for TKI-resistant CML

New drug holds potential for treating advanced mastocytosis

In continuation of my update on Midostaurin 

Most people have never heard of mastocytosis. It's a rare, sometimes deadly, immune disorder. Now new research may help those with advanced mastocytosis and possibly many more people, too. "This is the first drug that's shown to be effective in this very rare disease," says Tracy George, MD, at the University of New Mexico Comprehensive Cancer Center. George was part of the international team that recently published the results of its study on mastocytosis in the New England Journal of Medicine.

"Mast cells are normal cells in the body that mediate the body's allergic and inflammatory responses," says George. "But people with mast cell disease have too many mast cells and they're abnormal." Too many abnormal mast cells can cause allergic reactions and inflammation. Different subtypes of the disease differ in the how serious these responses are.

People with indolent mastocytosis may have mild symptoms and lead normal lives. Others with indolent mastocytosis may have flushing and diarrhea and other symptoms severely enough that they can't hold a job or do things that most people can do. People with other subtypes of the disease can have life-threatening reactions, such as anaphylactic shock and organ damage. And people with advanced mastocytosis — the most deadly subtype is called mast cell leukemia — live less than six months after their diagnosis.

The Food and Drug Administration has approved only one drug, called imatinib, to treat advanced mastocytosis. Imatinib blocks the action of a cellular protein called a tyrosine kinase receptor. But people with a mutation in a gene called D816V KIT do not respond to imatinib. The D816V KIT gene codes for a tyrosine kinase receptor, says George. And, she says, most people with advanced mastocytosis have the D816V KIT mutation.

Research on the new treatment began at Stanford University, where George worked with a colleague, Jason Gotlib, MD, whose patient had mast cell leukemia. They gave that woman a drug called midostaurin under the FDA's compassionate use policy. "Midostaurin is a multi-kinase inhibitor," says George. "Midostaurin was being evaluated in a clinical trial for a different disease, acute myeloid leukemia. And this lady with mast cell leukemia remarkably improved within weeks, within days."

 Midostaurin 

Gotlib and George began a small clinical trial to test midostaurin in people with advanced mastocystosis. That clinical trial expanded into an international clinical trial after Gotlib and George shared their preliminary results at an international conference. George brought the clinical trial to UNM when she joined the Pathology department and the UNM Comprehensive Cancer Center.

The clinical trial included treatment for three subtypes of advanced mastocytosis. Still, it took years to enroll enough people because the disease is so rare. Mastocytosis affects only about one person in 10,000. In comparison, breast cancer affects more than 12 times as many people and prostate cancer affects more than 13 times as many, according to the American Cancer Society. But even though the clinical trial was small, the results were astounding.

People with advanced mastocytosis on the clinical trial lived an average of 28 months longer. This average includes the 40 percent of people who did not respond to midostaurin. The 60 percent who did respond, though, responded within two or three months of starting treatment. Responders had mild side effects like diarrhea, vomiting and nausea, if they had any at all.

Sixteen people in the clinical trial had mast cell leukemia. "For those patients who did respond," says George, "their median survival has not been reached. So that means [some are] still living, which is unbelievable."

The clinical trial has spurred more research. Scientists around the world are now studying how midostaurin affects mast cells and how to combine it with other drugs to create an even more potent treatment. Novartis, the maker of midostaurin, and other drug companies are investing in research on multi-kinase inhibitors. Clinical trials to test midostaurin for controlling symptoms in people with indolent mastocytosis have opened. And more research into using midostaurin to treat asthma, skin diseases and allergies is in the planning stages.

George, who is the American expert in mastocytosis pathology, says, "I do think this [mastocytosis] is under-diagnosed. Even though patients with advanced mastocytosis are rare, indolent [mastocytosis] is more common. And there are lots of diseases for which unhappy mast cells are a pathogenesis." Now, with the potential for a treatment, people with unhappy mast cells may feel better.

New drug holds potential for treating advanced mastocytosis

Biotechdaily - Nilotinib Enhances Toxic Protein Removal from Parkinson's Disease Neurons

In continuation of my update on Nilotinib

The anticancer drug nilotinib induces clearance of the toxic protein alpha-synuclein from   neurons in a mouse model of Parkinson's disease and ameliorates symptoms of the disease.

Investigators at Georgetown University Medical Center (Washington DC, USA) worked with a mouse model of Parkinson’s disease. They reported in the May 10, 2013, online edition of the journal Human Molecular Genetics that lentiviral transfection of the gene encoding alpha-synuclein into the mouse SN lead to activation (phosphorylation) of the tyrosine kinase Abl and that lentiviral transfection of the gene encoding Abl increased alpha-synuclein levels, which exacerbated the disease. Administration of the tyrosine-kinase inhibitor nilotinib decreased Abl activity and increased autophagic clearance of alpha-synuclein into lysosomes in transgenic and lentiviral gene-transfer models.

The drug nilotinib was approved as Tasigna in the USA and the EU for drug-resistant chronic myelogenous leukemia (CML). In 2006, a Phase I clinical trial found that nilotinib had a relatively favorable safety profile and showed activity in cases of CML resistant to treatment with imatinib (Gleevec [USA]/ Glivec [Europe, Australia, and Latin America]), another tyrosine kinase inhibitor currently used as a first-line treatment. In that study, 92% of patients (already resistant or unresponsive to imatinib) achieved a normal white blood cell counts after five months of treatment.

In the current study, nilotinib, which enters the brain within [US] Food and Drug Administration approved doses, led to autophagic degradation of alpha-synuclein, protection of SN neurons and improvement of motor performance in the Parkinson’s disease mice.

 
"No one has tried anything like this before," said senior author Dr. Charbel E-H Moussa, assistant professor of neuroscience at the Georgetown University Medical Center. "This drug, in very low doses, turns on the garbage disposal machinery inside neurons to clear toxic proteins from the cell. By clearing intracellular proteins, the drug prevents their accumulation in pathological inclusions called Lewy bodies and/or tangles, and also prevents amyloid secretion into the extracellular space between neurons, so proteins do not form toxic clumps or plaques in the brain."

"The doses used to treat CML are high enough that the drug pushes cells to chew up their own internal organelles, causing self-cannibalization and cell death," said Dr. Moussa. "We reasoned that small doses—for these mice, an equivalent to 1% of the dose used in humans—would turn on just enough autophagy in neurons that the cells would clear malfunctioning proteins, and nothing else. We successfully tested this for several diseases models that have an accumulation of intracellular protein. It gets rid of alpha-synuclein and tau in a number of movement disorders, such as Parkinson's disease as well as Lewy body dementia."

Biotechdaily - Nilotinib Enhances Toxic Protein Removal from Parkinson's Disease Neurons

Second-line bosutinib offers ‘durable’ response for chronic phase CML patients

In continuation of my update on bosutinib

Four-year results for an ongoing study of second-line bosutinib indicate that the tyrosine kinase inhibitor (TKI) offers long-term efficacy with manageable side effects for patients with chronic phase chronic myeloid leukaemia (CP CML).

“Overall, these findings highlight the therapeutic potential of bosutinib as second-line therapy in IM-R [imatinib resistant] or IM-I [imatinib intolerant] CP CML patients”, say Tim Brümmendorf (Universitätsklinikum der RWTH Aachen, Germany) and co-investigators.

In the phase I/II trial, bosutinib 500 mg/day was given for a median of 24.8 months to 196 IM-R and 90 IM-I patients; 59% of 264 evaluable patients achieved or maintained a major cytogenetic response (MCyR) for at least 4 weeks, including 59% of the IM-R and 61% of the IM-I groups.

Of the 248 patients without a complete cytogenetic response (CCyR) at baseline, 57% achieved a MCyR and 47% a CCyR during bosutinib therapy. And 14 of the 16 patients with a baseline CCyR maintained this response for between 12 and 288 weeks; two discontinued bosutinib because of adverse events (AEs) and were not reassessed.

The median times to MCyR and CCyR were 12.3 and 24.0 weeks, respectively.

The 4-year cumulative incidences of MCyR and CCyR, at 59% and 49%, respectively, were similar to the previously reported 2-year figures of 59% and 48%, prompting the authors to suggest that “most initial responses occur within 2 years from bosutinib treatment initiation.”

The rate of cumulative progression or death during treatment was an estimated 19% at 4 years.

The Kaplan–Meier-estimated probability of maintaining MCyR at 4 years was found to be high for the whole population and the IM-R and IM-I groups, at 74.5%, 69.3% and 86.3%, respectively, and the median duration of this response had not yet been reached.

Second-line bosutinib offers ‘durable’ response for chronic phase CML patients

Chaetocin synergistic with TKIs against CML cells

Chaetocin (structure below), a mycotoxin that increases oxidative stress, can complement the activity of tyrosine kinase inhibitors (TKIs) in chronic myeloid leukaemia (CML) by overcoming innate resistance mediated by secreted bone marrow stromal cytokines and growth factors (BMSFs), researchers report.

The authors explain that CML–leukaemic stem cells (CML–LSCs), which exhibit innate resistance to TKIs, are crucial for the maintenance of CML. And add that BMSFs are implicated in this innate resistance, and are also known to increase the levels of reactive oxygen species (ROS).

“Higher ROS levels in CML-LSCs exposed to BMSFs might render them susceptible to ROS-mediated damage by exogenous ROS-generating agents”, hypothesises the team inOncogenesis.

Chaetocin significantly reduced the viability and colony forming capacity of CML–LSK cells, and increased apoptosis. These effects of chaetocin were enhanced in the presence of BMSFs.

Moreover, treatment with both chaetocin and imatinib overcame BMSF-mediated imatinib resistance, and resulted in increased cytotoxicity and apoptosis induction as well as a complete loss of colony formation.

Although treatment with either chaetocin or BMSFs resulted in increased ROS levels in CML–LSKs, when the two were used in combination, ROS levels were significantly higher than when either was used alone. Interestingly, chaetocin-mediated cytotoxicty was inhibited when the cells were pretreated with an antioxidant, N-acetyl-cysteine.

This “strongly suggested” that chaetocin activity against CML–LSKs, and its potentiation by BMSFs, was mediated by the increased ROS, say the researchers.

Chaetocin synergistic with TKIs against CML cells

FDA Approves Gleevec for Expanded Use in Patients with Rare Gastrointestinal Cancer

In continuation of my update on imatinib...

FDA Approves Gleevec for Expanded Use in Patients with Rare Gastrointestinal Cancer: The U.S. Food and Drug Administration today granted Gleevec (imatinib) regular approval for use in adult patients following surgical removal of CD117-positive gastrointestinal stromal tumors (GIST). Today’s action also highlights an increase in...

Novartis Drug Tasigna Approved by FDA to Treat Children with Rare Form of Leukemia

In continuation of my update on Nilotinib

Novartis announced today that the US Food and Drug Administration (FDA) expanded the indication for Tasigna (nilotinib) to include treatment of first- and second-line pediatric patients one year of age or older with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (Ph+ CML-CP)

In the United States, Tasigna is now indicated for the treatment of adult and pediatric patients one year of age or older with newly diagnosed Ph+ CML-CP. Tasigna is also indicated for the treatment of pediatric patients one year of age or older with Ph+ CML-CP resistant or intolerant to prior tyrosine kinase inhibitor (TKI) therapy, as well as adult patients with Ph+ CML in chronic phase and accelerated phase, resistant or intolerant to prior therapy that included imatinib.

This approval is the latest in a series of regulatory milestones that broadens the understanding and clinical use of Tasigna.

CML is a type of blood cancer where the body produces malignant white blood cells. Almost all patients with CML have an abnormality known as the "Philadelphia chromosome," which produces a protein called BCR-ABL. This protein aids the proliferation of malignant white blood cells in affected patients. Worldwide, CML accounts for approximately 3% of newly diagnosed childhood leukemia[1].

"Novartis' commitment to people living with CML is reinforced by today's FDA approval of Tasigna in children," said Liz Barrett, CEO, Novartis Oncology. "This expanded use, along with the other recent global regulatory Tasigna milestones, underscores our dedication to reimagining medicine and addressing the needs for people with CML, including children with this cancer."

The new indications, granted under the FDA's Priority Review designation, are based on two studies evaluating the efficacy and safety of nilotinib in pediatric patients (two years to less than 18 years of age) with Ph+ CML-CP. A total of 69 Ph+ CML-CP pediatric patients, either newly diagnosed (first-line) or who were resistant or intolerant to prior TKI therapy (second-line), received nilotinib[2]. In newly diagnosed pediatric patients, the major molecular response (MMR; BCR ABL/ABL <=0.1% International Scale [IS]) rate was 60.0% (95% confidence interval [CI]: 38.7, 78.9) at 12 cycles, with 15 patients achieving MMR[2]. The cumulative MMR rate among newly diagnosed pediatric patients was 64.0% by cycle 12, and the median time to first MMR was 5.6 months (range: 2.7 to 16.6). In pediatric patients with resistance or intolerance to prior TKI therapy, the MMR rate was 40.9% (95% CI: 26.3, 56.8) at 12 cycles, with 18 patients being in MMR[2]. The cumulative MMR rate among pediatric patients with resistance or intolerance was 47.7% by cycle 12, and the median time to first MMR was 2.8 months (range: 0.0 to 11.3)[2].

Adverse reactions observed in these pediatric studies were generally consistent with those observed in adults, except for laboratory abnormalities of hyperbilirubinemia (Grade 3/4: 13%)-a condition where there is too much bilirubin in the blood-and transaminase elevation (AST Grade 3/4: 1%, ALT Grade 3/4: 9%), which were reported at a higher frequency than in adult patients. One resistant or intolerant pediatric CML patient progressed to advance phase/blast crisis (AP/BC) after about 10 months on treatment.

FDA panel votes in favour of Sunitib (Sutent) for pancreatic tumors....

In continuation of my update on sutent/sunitib....

 Pfizer Inc. announced this Tuesday that its oral multi-kinase inhibitor "Sutent" (see structure)  was determined as having a favourable benefit-risk profile by an oncology advisory committee of the FDA for the treatment of unresectable pancreatic neuroendocrine tumors. The panel voted 8-2 in favour of Sutent – generically called Sunitib malate.

Advanced pancreatic neuroendocrine tumour or NET, is a rare, life-threatening and difficult-to-treat form of cancer that accounts for approximately 22-28 percent of all neuroendocrine tumours. Nearly 90 percent of patients are initially diagnosed with locally advanced or metastatic disease, or cancer that has spread to other organs. An unresectable tumour is one that cannot be removed or resected by surgery.

 More...

Sutent or sunitinib malate targets vascular endothelial growth factor receptor or VEGFR and platelet-derived growth factor receptor or PDGFR, both of which are expressed by many types of solid tumours. The two targets are involved in tumours acquiring blood vessels, oxygen and nutrients needed for growth. 

Sunitinib was approved in 2006 in the United States for treating locally advanced or metastatic renal cell carcinoma and for imatinib-refractory or -intolerant gastrointestinal stromal tumour (GIST). It was approved for treating PNET in 2010 in Europe. A decision on approval is expected by the end of 2011, according to a company spokesperson....

Novartis announces FDA approval of its first and only CML therapy with TFR data in product label

In continuation of my update on nilotinib

Novartis announced today that the US Food and Drug Administration (FDA) approved the inclusion of Treatment-free Remission (TFR) data in the Tasigna® (nilotinib) US product label. Tasigna is now the first and only BCR-ABL tyrosine kinase inhibitor (TKI) to include data about attempting treatment discontinuation in eligible adult patients with Philadelphia chromosome-positive chronic myeloid leukemia in the chronic phase (Ph+ CML-CP) after achieving sustained deep molecular response of MR4.5 (BCR-ABL1 International Scale [IS] <= 0.0032%) in its FDA-approved prescribing information. TFR is the ability to maintain a sustained molecular response* after stopping TKI therapy in patients with Ph+ CML-CP. TFR requires scheduled monitoring of BCR-ABL1 levels to identify possible loss of molecular response.

"It has long been our ambition at Novartis to make it possible for some people with CML to discontinue therapy," said Bruno Strigini, CEO, Novartis Oncology. "We are proud that Tasigna is now the first and only TKI with TFR data in its labeling in the US and several countries around the globe. This achievement would not have been possible without the partnership of patients around the world who participated in our groundbreaking TFR trials, helping Novartis to once again reimagine what is possible for people living with CML."

With this label update, Tasigna is the only TKI that provides defined, approved criteria to attempt and monitor TFR. This approval follows a priority review for a supplemental New Drug Application (sNDA) for Tasigna seeking the addition of TFR information and is based on safety and efficacy results from the 96-week analyses of two open label trials, ENESTfreedom and ENESTop. These trials evaluated the potential to maintain MMR (BCR-ABL1 <= 0.1%) after stopping Tasigna therapy among eligible adult patients with Ph+ CML-CP. Patients in the trials had achieved a sustained MR4.5 with Tasigna in both the first-line setting or after switching from Glivec® (imatinib). The trials demonstrated that almost half of the Ph+ CML-CP patients who discontinued Tasigna remained in TFR approximately two years after stopping treatment[1]. Among patients who did lose molecular response during the TFR phase of the trials, nearly all regained MMR when Tasigna therapy was promptly reinitiated[1]. The safety data are consistent with previously published studies and the known safety profile of Tasigna.

The TFR data in the Tasigna label approved by the FDA included the use of the MolecularMD MRDxTM BCR-ABL test, a FDA-authorized companion diagnostic validated to measure BCR-ABL transcript levels down to MR4.5. Discontinuation of Tasigna should only be attempted under the close supervision of a physician. Frequently scheduled patient monitoring after Tasigna discontinuation is required so that possible loss of MMR and MR4.0 (BCR-ABL1 IS <= 0.01%) is quickly identified and treatment re-initiation is started promptly.

Ref : https://www.novartis.com/news/media-releases/novartis-drug-tasignar-approved-fda-first-and-only-cml-therapy-treatment-free-remission-data-its-label

Novartis announces FDA approval of its first and only CML therapy with TFR data in product label

FDA Expands Approval of Sprycel (dasatinib) to Include Treatment of Children with Philadelphia Chromosome-Positive Chronic Myeloid Leukemia in Chronic Phase

In continuation of my update on Sprycel(dasatinib)

Bristol-Myers Squibb Company (NYSE:BMY) announced the U.S. Food and Drug Administration (FDA) has expanded the indication for Sprycel(dasatinib) tablets to include the treatment of children with Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase (CP). This approval for Sprycel in pediatric patients with Ph+ CML in chronic phase was granted under priority review, and the indication received orphan drug designation from the FDA. The safety and efficacy of Sprycel in pediatric patients was evaluated in two pediatric studies of 97 patients with CP-CML: an open-label, non-randomized, dose-ranging trial (NCT00306202) and an open-label, non-randomized, single-arm trial (NCT00777036). Among the 97 patients in the two studies, 51 patients (exclusively from the single-arm trial) had newly diagnosed CP-CML, and 46 patients (17 from the dose-ranging trial and 29 from the single-arm trial) were resistant or intolerant to previous treatment with imatinib.

Sprycel is associated with the following Warnings and Precautions: myelosuppression, bleeding-related events, fluid retention, cardiovascular events, pulmonary arterial hypertension, QT prolongation, severe dermatologic reactions, tumor lysis syndrome, embryo-fetal toxicity and effects on growth and development in pediatric patients.¹.

“While chronic myeloid leukemia is rare in children, accounting for less than three percent of all pediatric leukemias, it is often more aggressive in younger patients than in adults and until recently, there have been few available treatment options,”^2,3 said Vickie Buenger, President, Coalition Against Childhood Cancer. “The FDA’s decision to approve the expanded use of Sprycel in children with Philadelphia chromosome-positive chronic myeloid leukemia in chronic phase may bring new hope to these patients and their families.”

“Our decision to pursue an expanded indication for Sprycel is indicative of our commitment to exploring pediatric applications within our broad development program,” said Johanna Mercier, head, U.S. Commercial, Bristol-Myers Squibb. “We are pleased this option is now available for appropriate pediatric chronic phase CML patients and their physicians.”

As part of its commitment to children and adolescents with cancer, Bristol-Myers Squibb continues to explore pediatric applications for investigational oncology agents within its broad development program. In addition, Bristol-Myers Squibb supports organizations and initiatives focused on pediatric patients and their families.

Sprycel (Dasatinib) for ovarian cancer ?

Dasatinib, is a cancer drug produced by Bristol-Myers Squibb and sold under the trade name Sprycel. Dasatinib is an oral dual BCR/ABL and Src family tyrosine kinases inhibitor approved for use in patients with chronic myelogenous leukemia (CML) after imatinib treatment and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). It is also being assessed for use in metastatic melanoma. Its named after Jagabandhu Das, who was a member of the large discovery and development team at Bristol Myers Squibb.

Recently, researchers with UCLA's Jonsson Comprehensive Cancer Center found that Sprycel, significantly inhibited the growth and invasiveness of ovarian cancer cells and also promoted their death. The drug, when paired with a chemotherapy regimen, was even more effective in fighting ovarian cancer in cell lines in which signaling of the Src family kinases, associated with the deadly disease, is activated. The researchers are excited because of the fact that "recent gene expression studies have shown that about one-third of women have ovarian cancers with activated Src pathways", so the drug could potentially help 7,000 ovarian cancer patients every year. Gottfried Konecny (lead researcher) said, it also inhibits the focal adhesion kinase and ephrin receptor, (drug is known to inhibit in many pathways) also associated with ovarian cancer. Though clinical trials are still to be established , its a remarkable achievement. More details .....

Blueprint Medicines Announces FDA Acceptance of New Drug Application for Avapritinib for the Treatment of PDGFRA Exon 18 Mutant GIST and Fourth-Line GIST

Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy, today announced that the U.S. Food and Drug Administration (FDA) has accepted the company's New Drug Application (NDA) for avapritinib for the treatment of adult patients with PDGFRA Exon 18 mutant gastrointestinal stromal tumors (GIST), regardless of prior therapy, and fourth-line GIST. The FDA granted Priority Review and set an action date of February 14, 2020 under the Prescription Drug User Fee Act (PDUFA). At this time, the FDA is not planning to hold an advisory committee meeting to discuss this application. Avapritinib, an investigational therapy, is a potent and highly selective KIT and PDGFRA inhibitor for patients with advanced GIST.

"Patients with PDGFRA Exon 18 mutant GIST and fourth-line GIST are in need of new treatment options that address the underlying drivers of the disease," said Andy Boral, M.D., Ph.D., Chief Medical Officer at Blueprint Medicines. "The FDA's acceptance of our application for Priority Review brings us closer to our goal of delivering avapritinib to patients with GIST, and we look forward to working closely with the FDAduring the review process."

The FDA's acceptance of the NDA indicates the application is sufficiently complete to permit a substantive review. A Priority Review designation accelerates the FDA's review time from 12 months to a goal of eight months from the NDA submission date, and is granted to drugs that may offer a significant improvement in the safety or effectiveness of the treatment, prevention or diagnosis of a serious condition. Previously, the FDA granted avapritinib Breakthrough Therapy Designation for the treatment of patients with unresectable or metastatic GIST harboring the PDGFRα D842V mutation.

In July 2019, the European Medicines Agency validated Blueprint Medicines' Marketing Authorization Application for avapritinib in adult patients with PDGFRα D842V mutant GIST, regardless of prior therapy, and fourth-line GIST.

About GIST

GIST is a sarcoma, or tumor of bone or connective tissue, of the gastrointestinal (GI) tract. Tumors arise from cells in the wall of the GI tract and occur most often in the stomach or small intestine. Most patients are diagnosed between the ages of 50 to 80, and diagnosis is typically triggered by GI bleeding, incidental findings during surgery or imaging and, in rare cases, tumor rupture or GI obstruction.

Most GIST cases are caused by a spectrum of clinically relevant mutations that force the KIT or PDGFRA protein kinases into an increasingly active state. Because currently available therapies primarily bind to the inactive protein conformations, certain primary and secondary mutations typically lead to treatment resistance and disease progression.

In unresectable or metastatic GIST, clinical benefits from existing treatments can vary by mutation type. Mutational testing is critical to tailor therapy to the underlying disease driver and is recommended in expert guidelines. Currently, there are no approved therapies for patients with KIT-driven GIST whose disease progresses beyond imatinib, sunitinib and regorafenib. In patients with metastatic PDGFRα D842V-driven GIST, progression occurs in a median of approximately three to four months with available therapy.

https://pubchem.ncbi.nlm.nih.gov/compound/Avapritinib#section=2D-Structure