Cogent Biosciences Announces Submission of New Drug Application for Bezuclastinib in Gastrointestinal Stromal Tumors (GIST)

Cogent Biosciences, Inc. (Nasdaq: COGT), a biotechnology company focused on developing precision therapies for genetically defined diseases, announced the completion of the submission of its New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for bezuclastinib in patients with Gastrointestinal Stromal Tumors (GIST) who have received prior treatment with imatinib. Based on the positive results from the PEAK trial, the bezuclastinib NDA was submitted under the FDA’s Real-Time Oncology Review (RTOR) program, which is intended to enable a more streamlined review process. Bezuclastinib was also granted Breakthrough Therapy Designation as a treatment for GIST earlier this year.

Bezuclastinib NDA submitted under the FDA’s RTOR program based on positive results from Phase 3 PEAK trial; bezuclastinib previously granted Breakthrough Therapy Designation in GIST

Bezuclastinib combination demonstrated 16.5 month mPFS and 46% ORR in imatinib-resistant GIST patients, dramatically improving upon the current standard of care

“We are excited to complete our PEAK NDA submission which marks a significant step toward bringing a new therapy to patients with second-line GIST,” said Andrew Robbins, President and Chief Executive Officer. “Based on the strength of the PEAK data, we believe the bezuclastinib combination has the potential to meaningfully change the treatment landscape for these patients. We are grateful to the patients, investigators, and study teams who made this possible.”

Pivotal data from PEAK, a global, randomized Phase 3 clinical trial evaluating bezuclastinib in combination with sunitinib vs. sunitinib monotherapy in patients with GIST who have received prior treatment with imatinib, were reported in November 2025. As disclosed in the top-line results, the bezuclastinib combination demonstrated a substantial and highly statistically significant clinical benefit on the primary endpoint of progression free survival (PFS), reducing risk of disease progression or death compared to the current standard of care by 50% (hazard ratio of 0.50, 95% CI: 0.39 – 0.65). mPFS, as assessed by blinded independent central review, was 16.5 months for the bezuclastinib combination vs. 9.2 months for sunitinib monotherapy. Additionally, the bezuclastinib combination demonstrated an unprecedented ORR in imatinib-resistant patients, with 46% of patients treated with the bezuclastinib combination achieving an objective response compared to 26% of patients treated with sunitinib. The bezuclastinib combination was generally well tolerated, and no unique risks were observed with the novel combination when compared to the known safety profile of sunitinib. Data for overall survival remains immature.

At the time of data cutoff, based on the number of ongoing patients receiving treatment on the bezuclastinib combination arm, the estimated mean duration of treatment for the bezuclastinib combination is projected to exceed 19 months.

Cogent plans to present full results from the PEAK trial at a major medical meeting during the first half of 2026. Additionally, Cogent is on track this quarter to initiate a Phase 2 trial investigating the benefit of the bezuclastinib plus sunitinib combination for first-line GIST patients with exon 9 mutations who are naive to, or recently initiated treatment with, imatinib. The NDA submission with bezuclastinib in Advanced Systemic Mastocytosis (AdvSM) also remains on track for the first half of 2026.

Bezuclastinib - Expanded Access Program

Working with the FDA, Cogent has established active Expanded Access Programs (EAPs) for U.S. patients with GIST or SM who meet disease-specific criteria and could benefit from treatment with bezuclastinib or the combination of bezuclastinib and sunitinib. A growing number of sites now offer access to the bezuclastinib EAPs. For more information please visit: https://www.cogentbio.com/bezuclastinib-program-development/#our-expanded-access-policy

Inducement Grants Under Nasdaq Listing Rule 5635(c)(4)

Cogent also announced today that, on March 30, 2026, the Compensation Committee of Cogent’s Board of Directors, made up entirely of independent directors, approved the grants of “inducement” equity awards to six new employees under the company’s 2020 Inducement Plan with a grant date of March 30, 2026. The awards were approved in accordance with Listing Rule 5635(c)(4) of the corporate governance rules of the Nasdaq Stock Market. The employees received, in the aggregate, (i) nonqualified options to purchase 21,100 shares of Cogent common stock and (ii) 15,700 restricted stock units (RSUs). Each option has a 10-year term, an exercise price equal to the closing price of Cogent’s common stock on the grant date, and a 4-year vesting schedule with 25% vesting on the 1-year anniversary of the grant date and the remainder vesting in equal monthly installments over the subsequent 36 months, provided such employee remains employed through each such vesting date. The RSUs vest annually in equal installments over 4 years from the grant date, provided such employee remains employed through each such vesting date.

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

FDA Approves Romvimza (vimseltinib) for the Treatment of Symptomatic Tenosynovial Giant Cell Tumor

Ono Pharmaceutical Co., Ltd. (Headquarters: Osaka, Japan; President: Toichi Takino; “Ono”) announced  the U.S. Food and Drug Administration (FDA)  approval of  Romvimza (vimseltinib), a kinase inhibitor, for adult patients with symptomatic tenosynovial giant cell tumor (TGCT) for which surgical resection will potentially cause worsening functional limitation or severe morbidity. The FDA previously granted Fast Track designation and Priority Review for Romvimza, which was developed by Deciphera Pharmaceuticals, Inc. (“Deciphera”), a wholly owned subsidiary of Ono.

“The approval of Romvimza provides a new, much-needed, well-tolerated, and effective treatment option for people suffering from TGCT,” said Hans Gelderblom, M.D., Ph.D., Chair of the Department of Medical Oncology at Leiden University Medical Center. “TGCT adversely affects the lives of patients, causing significant pain, limited mobility, and stiffness. The MOTION Phase 3 study demonstrated Romvimza’s ability to shrink tumors along with being the first well-tolerated agent to demonstrate significant improvement in a number of other important quality-of-life measures without any observed liver injury as seen with other approved TGCT treatment. Romvimza is a differentiated treatment that has the potential to address the significant unmet needs of the TGCT community.”

“The FDA approval of Romvimza for TGCT is a crucial advancement for the TGCT community and we believe Romvimza has the potential to become the new standard of care for people with TGCT for which surgical resection will potentially cause worsening functional limitation or severe morbidity. This is also an important milestone for our organization, as it is the second approved therapy discovered using Deciphera’s proprietary switch-control kinase inhibitor platform,” said Ryota Udagawa, President and Chief Executive Officer of Deciphera Pharmaceuticals. “I’d like to extend my gratitude to the patients, families, caregivers, and healthcare providers who contributed to the success in Romvimza’s clinical studies. Their commitment, along with the dedication of the Deciphera and Ono teams, enabled us to advance this impactful new treatment, which we look forward to delivering to patients.”

TGCT is a rare, non-malignant tumor that forms within or near joints. TGCT arises from the dysregulation of the CSF1 gene, resulting in an overproduction of CSF1. If left untreated or if the tumor repeatedly recurs, it can lead to damage and degeneration in the affected joint and surrounding tissues, potentially causing significant disability.

The FDA approval was based on the efficacy and safety results from the pivotal Phase 3 MOTION study of Romvimza in patients with TGCT not amenable to surgery with no prior anti-CSF1/CSF1R therapy (prior therapy with imatinib or nilotinib allowed), compared to placebo, as well as the Phase 1/2 study of Romvimza. In MOTION, Romvimza demonstrated a statistically significant and clinically meaningful ORR at Week 25 in the intent-to-treat (ITT) population, as assessed by blinded independent radiologic review (IRR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), versus placebo (40% in Romvimza arm vs 0% in placebo arm, p <0.0001). The primary endpoint was supported by statistically significant and clinically meaningful improvements in active range of motion, patient-reported physical functioning, and patient-reported pain observed in the vimseltinib arm compared to the placebo arm at week 25. The safety profile of Romvimza is manageable and consistent with results previously disclosed in the Phase 1/2 clinical trial.

Deciphera Pharmaceuticals plans to make Romvimza commercially available in the U.S. next week. Learn more at www.Romvimza.com.

In July of 2024, the Company announced the marketing authorization application (MAA) for Romvimza for the treatment of patients with TGCT was accepted and is under review by the European Medicines Agency (EMA).

Deciphera is committed to supporting TGCT patients and providers in navigating coverage and access to Romvimza. As part of that commitment, Deciphera AccessPointTM, a patient support program, is available to provide comprehensive access and financial assistance programs for eligible patients. For more information, visit DecipheraAccessPoint.com or call 1-833-4DACCES (1-833-432-2237), Monday-Friday, 8:00 AM to 8:00 PM Eastern Time (ET).

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

FDA Approves Romvimza (vimseltinib) for the Treatment of Symptomatic Tenosynovial Giant Cell Tumor

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

FDA Approves Ayvakit (avapritinib) for the Treatment of Adults with Unresectable or Metastatic PDGFRA Exon 18 Mutant Gastrointestinal Stromal Tumor

Blueprint Medicines Corporation (NASDAQ: BPMC), a precision therapy company focused on genomically defined cancers, rare diseases and cancer immunotherapy,  announced that the U.S. Food and Drug Administration (FDA) has approved Ayvakit (avapritinib) for the treatment of adults with unresectable or metastatic gastrointestinal stromal tumor (GIST) harboring a platelet-derived growth factor receptor alpha (PDGFRA) exon 18 mutation, including PDGFRA D842V mutations. Ayvakit is the first precision therapy approved to treat a genomically defined population of patients with GIST.

The FDA granted a full approval to Ayvakit based on efficacy results from the Phase 1 NAVIGATOR clinical trial, as well as combined safety results from multiple clinical trials for avapritinib. In patients with PDGFRA exon 18 mutant GIST, Ayvakit had an overall response rate (ORR) of 84 percent (95% CI: 69%, 93%), and a median duration of response (DOR) was not reached. The most common adverse reactions (≥20 percent) were edema, nausea, fatigue/asthenia, cognitive impairment, vomiting, decreased appetite, diarrhea, hair color changes, increased lacrimation, abdominal pain, constipation, rash and dizziness. Blueprint Medicines plans to make Ayvakit available in the U.S. within a week.

GIST is a rare, genomically driven sarcoma of the gastrointestinal (GI) tract. Approximately 6 percent of patients with newly diagnosed GIST have PDGFRA exon 18 mutations. The most common PDGFRA exon 18 mutation is the D842V mutation, which is resistant to all other approved therapies. A retrospective study showed that when these patients were treated with imatinib, they had an ORR of 0 percent.2

"Today's approval of Ayvakit brings forward a new standard of care for patients with PDGFRA exon 18 mutant GIST, a genomically defined population that previously had very limited treatment options. For the first time, we can offer these patients a highly effective treatment that targets the underlying genetic cause of their disease," said Michael Heinrich, M.D., Professor of Medicine at Oregon Health & Science University and an investigator on the NAVIGATOR trial. "Building on our growing understanding of the molecular basis of GIST, this milestone ushers in a new era of precision medicine in this disease. The FDA approval represents a call to action to conduct mutational testing in all patients with GIST before initiating kinase inhibitor therapy, as recommended by clinical guidelines, so appropriate patients may realize the benefits of this promising new medicine."

"The full approval of Ayvakit based on robust data from our Phase 1 NAVIGATOR clinical trial is an incredibly exciting milestone for our company and, more importantly, for GIST patients with a PDGFRA exon 18 mutation, who have been waiting for a new treatment option," said Jeff Albers, Chief Executive Officer at Blueprint Medicines. "Ayvakit is the first of what we hope will be many approved medicines enabled by our research platform. Now, as we begin to deliver Ayvakit to patients and their healthcare providers, we aim to fortify our leadership in the field of precision medicine and build a foundation for our broader portfolio by pairing our strong research and development capabilities with an equally talented commercial organization focused on addressing patient needs, accelerating diagnostic testing and enabling access."

Blueprint Medicines is dedicated to helping patients with PDGFRA exon 18 mutant GIST access treatment with Ayvakit and providing robust support throughout their treatment journey. As part of this commitment, Blueprint Medicines is introducing YourBlueprint™, a patient support program that offers access and affordability solutions for individuals receiving Ayvakit. For more information, visit YourBlueprint.com or call 1-888-BLUPRNT (1-888-258-7768), Monday to Friday, 8:00 a.m. to 8:00 p.m. ET. Healthcare providers who prescribe Ayvakit can fill out an enrollment form at YourBlueprint.com/HCP to help patients access Blueprint Medicines' support services.

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

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

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.

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.

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

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.

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.

Gleevec could be novel therapeutic agent for type 2 diabetes

The cancer treatment drug Imatinib, otherwise known as Gleevec is approved to treat various forms of cancer, mostly notably chronic myeloid leukemia (CML). However, researchers have stumbled onto another possible use for it, curing type 2 diabetes.

The team--made up of scientists from the Scripps Research Institute in United States, South Korea-based company Hyndai Pharm Co., Ltd., the Seoul National University, and Ulsan National Institute of Science and Technology (UNIST)--has identified for the first time that, through control of PPARγ, Gleevec lowers the level of insulin resistance, thereby reducing the risk of both hyperglycemia and obesity.

Acording to the team, led by Prof. Jang Hyun Choi (School of Life Sciences) of UNIST, "Although TZD-based medicines work effectively at improving glucose uptake by skeletal muscle and other peripheral tissues, due to increased risk of adverse effects they have been withdrawn from the market ." He continues, "In order to develop new type of medication that have fewer side effects, we have have discovered a new compound that can maintain stable blood sugar levels."

Among insulin-sensitizing drugs, TZDs are a therapeutic class that are selective agonists for PPARγ, which plays a central role in how the body metabolizes glucose, stores fat, and controls immune and inflammatory responses.

In the study, the team observed that the phosphorylation of PPARγ is closely related to developing diabetes. They also discovered that the removal of phosphoric acid from PPARγ shows anti-diabetic effects. To determine whether phosphoric acid is bound to PPARγ, the team developed a new chemical screening procedure. Using high throughput phosphorylation screening, the team discovered that Gleevec blocks CDK5-mediated PPARγ phosphorylation devoid of classical agonism as a PPARγ antagonist ligand.

Prof. Choi states, "Although studies have shown that Gleevec treatment may show improved insulin sensitivity and decrease blood glucose in patients with known diabetes, the exact cause hasn't been proven yet." He continues, "Through this research, we discovered Gleevec, which is used in leukemia medications, can inhibit the phosphorylation of PPARγ."

Gleevec could be novel therapeutic agent for type 2 diabetes

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.

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

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

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