On December 10, 2022 The Janssen Pharmaceutical Companies of Johnson & Johnson reported new results from a cohort of the Phase 1b MajesTEC-2 study of TECVAYLI (teclistamab-cqyv), a first-in-class, BCMAxCD3 bispecific T-cell engager antibody, in combination with DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) and lenalidomide (Press release, Janssen Biotech, DEC 10, 2022, View Source [SID1234625040]). According to the results, the immune-based triplet therapy regimen had a manageable safety profile with no unexpected safety signals observed. A very good partial response (VGPR) or better was achieved by 90.3 percent of patients with relapsed or refractory multiple myeloma who had received one to three prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug, with responses deepening over time.1 These data were presented during the 2022 American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting (Abstract #160).

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"These results show the potential of the combination of the bispecific BCMA-directed antibody teclistamab with the anti-CD38 antibody daratumumab and lenalidomide in the treatment of patients with relapsed or refractory multiple myeloma," said Emma Searle, M.D., Ph.D., Consultant Hematologist and Honorary Senior Lecturer, The Christie Hospital and University of Manchester, England, and study investigator.† "This is the first presentation of data from a teclistamab-based triplet regimen and we are eager to better understand how this combination may benefit patients through ongoing clinical studies."

At a median follow-up of 8.4 months (range, 1.1 to 12.9), the overall response rate (ORR) was 93.5 percent.1 Among all patients in the trial, VGPRs or better were achieved by 90.3 percent of patients, and 54.8 percent of patients achieved a complete response (CR) or better.1 Median time to response was one month, and responses deepened.1 The median time to CR or better was three months (range, 1 to 10.4).1 At data cut-off, 80.6 percent of patients remained progression-free and on treatment.1 Responses deepened over time, and median duration of response had not been reached.1

"Following the recent regulatory approvals of TECVAYLI in the U.S. and EU, as well as its inclusion in the NCCN Clinical Practice Guidelines in Oncology as a recommended treatment option for certain patients with multiple myeloma, we are encouraged by its potential to improve outcomes in combination regimens and for earlier lines of treatment," said Sen Zhuang, M.D., Ph.D., Vice President, Clinical Research and Development, Janssen Research & Development, LLC. "We remain committed to addressing the unmet needs of patients with multiple myeloma through off-the-shelf immunotherapies like TECVAYLI and where we can bring together novel therapeutic approaches in the treatment of complex blood cancers."

The primary objective of this cohort of the MajesTEC-2 study (NCT04722146) was to understand if the immunomodulatory effects of daratumumab and lenalidomide could enhance the function of TECVAYLI, resulting in enhanced antimyeloma activity in a broader population of patients.1 The MajesTEC-7 study (NCT05552222) will examine the potential of this combination in patients newly diagnosed with multiple myeloma.

The most frequent hematological adverse events (AEs) observed in the study included neutropenia (84.4 percent any grade, 78.1 percent grade 3/4) and thrombocytopenia (25 percent any grade, 15.6 percent grade 3/4).1 The most frequent non-hematological AE was cytokine release syndrome (CRS) (81.3 percent, all grade 1/2); 97 percent of CRS events occurred during cycle 1.1

Other common non-hematological AEs included fatigue (46.9 percent any grade, 6.3 percent grade 3/4); diarrhea (46.9 percent any grade, none grade 3/4); cough (40.6 percent any grade, 3.1 percent grade 3/4); COVID-19 (37.5 percent any grade, 12.5 percent grade 3/4); insomnia (37.5 percent any grade, 3.1 percent grade 3/4); hypophosphatemia (31.3 percent any grade, 6.3 percent grade 3/4); pyrexia (31.3 percent any grade, 3.1 percent grade 3/4); upper respiratory tract infection (31.3 percent any grade, none grade 3/4); increased alanine aminotransferase (ALT) (28.1 percent any grade, 9.4 percent grade 3/4) and pneumonia (25 percent any grade, 15.6 percent grade 3/4).1 Two patients discontinued therapy due to an AE (COVID-19), considered to be unrelated to the study by investigator assessment.1 Infections were common among patients in the study and the majority were low grade (90.6 percent any grade, 37.5 percent grade 3/4).1

New Data from the Phase 1/2 MajesTEC-1 Study Evaluating TECVAYLI in Relapsed or Refractory Multiple Myeloma Patients
New correlative analyses were also presented from the MajesTEC-1 study (NCT04557098). Data from these analyses may be used to help better understand baseline immune and tumor correlatives associated with outcomes in patients treated with TECVAYLI.2 The data were presented during an oral abstract session (Abstract #97). Additional pharmacokinetic data evaluating potential drug interactions with TECVAYLI were presented during a separate poster session (Abstract #3228), as well as analyses of serum teclistamab-cqyv concentrations after intravenous and subcutaneous administration (Abstract #1911), to improve understanding of the clinical pharmacological profile of TECVAYLI.3,4

About the MajesTEC-2 Study
MajesTEC-2 (NCT04722146); is Phase 1b multicohort study evaluating the safety and efficacy of TECVAYLI in combination with other anticancer therapies in patients with relapsed or refractory multiple myeloma who received at least one prior line of therapy.1 Patients were eligible for treatment if they had received 1-3 prior lines of therapy, including a proteasome inhibitor and immunomodulatory drug.1

In the presented study cohort, 32 patients received weekly doses of TECVAYLI (0.72 mg/kg or 1.5 mg/kg, with step-up dosing) plus the approved schedules of DARZALEX FASPRO 1800 mg and lenalidomide 25 mg.1 Responses were investigator assessed using International Myeloma Working Group criteria, and AEs were assessed by Common Terminology Criteria for Adverse Events (CTCAE) v5.0, except for CRS and immune effector cell-associated neurotoxicity syndrome (ICANS), which were graded per American Society for Transplantation and Cellular Therapy (ASTCT) guidelines.1

About TECVAYLI
TECVAYLI (teclistamab-cqyv) received approval from the U.S. Food and Drug Administration in October 2022 as an off-the-shelf (or ready to use) bispecific antibody that is administered as a subcutaneous treatment for adult patients with relapsed or refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent and an anti-CD38 monoclonal antibody.5 In August 2022, TECVAYLI received approval from the European Commission as an off-the-shelf bispecific antibody administered as a subcutaneous treatment for adult patients with relapsed or refractory multiple myeloma who have received at least three prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 antibody.6 Teclistamab-cqyv (TECVAYLI) was recently recommended by the National Comprehensive Cancer Network (NCCN) as a treatment option for these patients. TECVAYLI is a first-in-class, bispecific T-cell engager antibody therapy which uses innovative science to activate the immune system by binding to the CD3 receptor expressed on the surface of T cells and to the B-cell maturation antigen (BCMA) expressed on the surface of multiple myeloma cells and some healthy B-lineage cells.7

About DARZALEX FASPRO
DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) received U.S. FDA approval in May 2020 and is approved for eight indications in multiple myeloma (MM), three of which are for frontline treatment in newly diagnosed patients who are transplant eligible or ineligible.8 It is the only subcutaneous CD38-directed antibody approved to treat patients with MM. DARZALEX FASPRO is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme’s ENHANZE drug delivery technology.

About Multiple Myeloma
Multiple myeloma is an incurable blood cancer that affects a type of white blood cell called plasma cells, which are found in the bone marrow.9 In multiple myeloma, these plasma cells change, spread rapidly and replace normal cells in the bone marrow with tumors.10 In 2022, it is estimated that more than 34,000 people will be diagnosed with multiple myeloma, and more than 12,000 people will die from the disease in the U.S.11 While some people diagnosed with multiple myeloma initially have no symptoms, most patients are diagnosed due to symptoms that can include bone fracture or pain, low red blood cell counts, tiredness, high calcium levels, kidney problems or infections.12

TECVAYLI IMPORTANT SAFETY INFORMATION
WARNING: CYTOKINE RELEASE SYNDROME and NEUROLOGIC TOXICITY including IMMUNE EFFECTOR CELL-ASSOCIATED NEUROTOXICITY SYNDROME
Cytokine release syndrome (CRS), including life-threatening or fatal reactions, can occur in patients receiving TECVAYLI. Initiate treatment with TECVAYLI step-up dosing schedule to reduce risk of CRS.
Neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) and serious and life-threatening reactions, can occur in patients receiving TECVAYLI. Monitor patients for signs or symptoms of neurologic toxicity, including ICANS, during treatment and treat promptly.
TECVAYLI is available only through a restricted program called the TECVAYLI Risk Evaluation and Mitigation Strategy (REMS).
WARNINGS AND PRECAUTIONS
Cytokine Release Syndrome: TECVAYLI can cause cytokine release syndrome (CRS), including life-threatening or fatal reactions. In the clinical trial, CRS occurred in 72% of patients who received TECVAYLI at the recommended dose, with Grade 1 CRS occurring in 50% of patients, Grade 2 in 21%, and Grade 3 in 0.6%. Recurrent CRS occurred in 33% of patients. Most patients experienced CRS following step-up dose 1 (42%), step-up dose 2 (35%), or the initial treatment dose (24%). Less than 3% of patients developed first occurrence of CRS following subsequent doses of TECVAYLI. The median time to onset of CRS was 2 (range: 1 to 6) days after the most recent dose with a median duration of 2 (range: 1 to 9) days. Clinical signs and symptoms of CRS included, but were not limited to, fever, hypoxia, chills, hypotension, sinus tachycardia, headache, and elevated liver enzymes (aspartate aminotransferase and alanine aminotransferase elevation).

Initiate therapy according to TECVAYLI step-up dosing schedule to reduce risk of CRS. Administer pretreatment medications to reduce risk of CRS and monitor patients following administration of TECVAYLI accordingly. At the first sign of CRS, immediately evaluate patient for hospitalization, manage per consensus guidelines, and administer supportive care based on severity; withhold or permanently discontinue TECVAYLI based on severity.

TECVAYLI is available only through a restricted program under a REMS.

Neurologic Toxicity including ICANS: TECVAYLI can cause serious or life-threatening neurologic toxicity, including Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS)

In the clinical trial, neurologic toxicity occurred in 57% of patients who received TECVAYLI at the recommended dose, with Grade 3 or 4 neurologic toxicity occurring in 2.4% of patients. The most frequent neurologic toxicities were headache (25%), motor dysfunction (16%), sensory neuropathy (15%), and encephalopathy (13%). With longer follow-up, Grade 4 seizure and fatal Guillain-Barré syndrome (one patient each) occurred in patients who received TECVAYLI.

In the clinical trial, ICANS was reported in 6% of patients who received TECVAYLI at the recommended dose [see Adverse Reactions (6.1)]. Recurrent ICANS occurred in 1.8% of patients. Most patients experienced ICANS following step-up dose 1 (1.2%), step-up dose 2 (0.6%), or the initial treatment dose (1.8%). Less than 3% of patients developed first occurrence of ICANS following subsequent doses of TECVAYLI. The median time to onset of ICANS was 4 (range: 2 to 8) days after the most recent dose with a median duration of 3 (range: 1 to 20) days. The most frequent clinical manifestations of ICANS reported were confusional state and dysgraphia. The onset of ICANS can be concurrent with CRS, following resolution of CRS, or in the absence of CRS.

Monitor patients for signs and symptoms of neurologic toxicity during treatment. At the first sign of neurologic toxicity, including ICANS, immediately evaluate patient and provide supportive therapy based on severity; withhold or permanently discontinue TECVAYLI based on severity and follow management recommendations.

Due to the potential for neurologic toxicity, patients are at risk of depressed level of consciousness. Advise patients to refrain from driving or operating heavy or potentially dangerous machinery during and for 48 hours after completion of TECVAYLI step-up dosing schedule and in the event of new onset of any neurologic toxicity symptoms until neurologic toxicity resolves.

TECVAYLI is available only through a restricted program under a REMS.

TECVAYLI REMS: TECVAYLI is available only through a restricted program under a REMS called the TECVAYLI REMS because of the risks of CRS and neurologic toxicity, including ICANS.

Hepatotoxicity: TECVAYLI can cause hepatoxicity, including fatalities. In patients who received TECVAYLI at the recommended dose in the clinical trial, there was one fatal case of hepatic failure. Elevated aspartate aminotransferase (AST) occurred in 34% of patients, with Grade 3 or 4 elevations in 1.2%. Elevated alanine aminotransferase (ALT) occurred in 28% of patients, with Grade 3 or 4 elevations in 1.8%. Elevated total bilirubin occurred in 6% of patients with Grade 3 or 4 elevations in 0.6%. Liver enzyme elevation can occur with or without concurrent CRS.

Monitor liver enzymes and bilirubin at baseline and during treatment as clinically indicated. Withhold TECVAYLI or consider permanent discontinuation of TECVAYLI based on severity.

Infections: TECVAYLI can cause severe, life-threatening, or fatal infections. In patients who received TECVAYLI at the recommended dose in the clinical trial, serious infections, including opportunistic infections, occurred in 30% of patients, with Grade 3 or 4 infections in 35%, and fatal infections in 4.2%. Monitor patients for signs and symptoms of infection prior to and during treatment with TECVAYLI and treat appropriately. Administer prophylactic antimicrobials according to guidelines. Withhold TECVAYLI or consider permanent discontinuation of TECVAYLI based on severity.

Monitor immunoglobulin levels during treatment with TECVAYLI and treat according to guidelines, including infection precautions and antibiotic or antiviral prophylaxis.

Neutropenia: TECVAYLI can cause neutropenia and febrile neutropenia. In patients who received TECVAYLI at the recommended dose in the clinical trial, decreased neutrophils occurred in 84% of patients, with Grade 3 or 4 decreased neutrophils in 56%. Febrile neutropenia occurred in 3% of patients.

Monitor complete blood cell counts at baseline and periodically during treatment and provide supportive care per local institutional guidelines.

Monitor patients with neutropenia for signs of infection.

Withhold TECVAYLI based on severity [see Dosage and Administration (2.4)].

Hypersensitivity and Other Administration Reactions: TECVAYLI can cause both systemic administration-related and local injection-site reactions. Systemic Reactions – In patients who received TECVAYLI at the recommended dose in the clinical trial, 1.2% of patients experienced systemic-administration reactions, which included Grade 1 recurrent pyrexia and Grade 1 swollen tongue. Local Reactions – In patients who received TECVAYLI at the recommended dose in the clinical trial, injection-site reactions occurred in 35% of patients with Grade 1 injection-site reactions in 30% and Grade 2 in 4.8%. Withhold TECVAYLI or consider permanent discontinuation of TECVAYLI based on severity.

Embryo-Fetal Toxicity: Based on its mechanism of action, TECVAYLI may cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment with TECVAYLI and for 5 months after the last dose.

Adverse Reactions: The most common adverse reactions (≥20%) were pyrexia, CRS, musculoskeletal pain, injection site reaction, fatigue, upper respiratory tract infection, nausea, headache, pneumonia, and diarrhea. The most common Grade 3 to 4 laboratory abnormalities (≥20%) were decreased lymphocytes, decreased neutrophils, decreased white blood cells, decreased hemoglobin and decreased platelets.

Please read full Prescribing Information including Boxed Warning for TECVAYLI.

DARZALEX FASPRO IMPORTANT SAFETY INFORMATION
INDICATIONS
DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) is indicated for the treatment of adult patients with multiple myeloma:

In combination with bortezomib, melphalan, and prednisone in newly diagnosed patients who are ineligible for autologous stem cell transplant
In combination with lenalidomide and dexamethasone in newly diagnosed patients who are ineligible for autologous stem cell transplant and in patients with relapsed or refractory multiple myeloma who have received at least one prior therapy
In combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant
In combination with pomalidomide and dexamethasone in patients who have received at least one prior line of therapy including lenalidomide and a proteasome inhibitor
In combination with carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy
In combination with bortezomib and dexamethasone in patients who have received at least one prior therapy
As monotherapy in patients who have received at least three prior lines of therapy including a proteasome inhibitor (PI) and an immunomodulatory agent or who are double-refractory to a PI and an immunomodulatory agent
CONTRAINDICATIONS
DARZALEX FASPRO is contraindicated in patients with a history of severe hypersensitivity to daratumumab, hyaluronidase or any of the components of the formulation.

WARNINGS AND PRECAUTIONS
Hypersensitivity and Other Administration Reactions
Both systemic administration-related reactions, including severe or life-threatening reactions, and local injection-site reactions can occur with DARZALEX FASPRO. Fatal reactions have been reported with daratumumab-containing products, including DARZALEX FASPRO.

Systemic Reactions

In a pooled safety population of 898 patients with multiple myeloma (N=705) or light chain (AL) amyloidosis (N=193) who received DARZALEX FASPRO as monotherapy or in combination, 9% of patients experienced a systemic administration-related reaction (Grade 2: 3.2%, Grade 3: 1%). Systemic administration-related reactions occurred in 8% of patients with the first injection, 0.3% with the second injection, and cumulatively 1% with subsequent injections. The median time to onset was 3.2 hours (range: 4 minutes to 3.5 days). Of the 140 systemic administration-related reactions that occurred in 77 patients, 121 (86%) occurred on the day of DARZALEX FASPRO administration. Delayed systemic administration-related reactions have occurred in 1% of the patients.

Severe reactions included hypoxia, dyspnea, hypertension and tachycardia. Other signs and symptoms of systemic administration-related reactions may include respiratory symptoms, such as bronchospasm, nasal congestion, cough, throat irritation, allergic rhinitis, and wheezing, as well as anaphylactic reaction, pyrexia, chest pain, pruritis, chills, vomiting, nausea, and hypotension.

Pre-medicate patients with histamine-1 receptor antagonist, acetaminophen and corticosteroids. Monitor patients for systemic administration-related reactions, especially following the first and second injections. For anaphylactic reaction or life-threatening (Grade 4) administration-related reactions, immediately and permanently discontinue DARZALEX FASPRO. Consider administering corticosteroids and other medications after the administration of DARZALEX FASPRO depending on dosing regimen and medical history to minimize the risk of delayed (defined as occurring the day after administration) systemic administration-related reactions.

Local Reactions

In this pooled safety population, injection-site reactions occurred in 8% of patients, including Grade 2 reactions in 0.7%. The most frequent (>1%) injection-site reaction was injection site erythema. These local reactions occurred a median of 5 minutes (range: 0 minutes to 6.5 days) after starting administration of DARZALEX FASPRO. Monitor for local reactions and consider symptomatic management.

Cardiac Toxicity in Patients with Light Chain (AL) Amyloidosis
Serious or fatal cardiac adverse reactions occurred in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO in combination with bortezomib, cyclophosphamide and dexamethasone. Serious cardiac disorders occurred in 16% and fatal cardiac disorders occurred in 10% of patients. Patients with NYHA Class IIIA or Mayo Stage IIIA disease may be at greater risk. Patients with NYHA Class IIIB or IV disease were not studied. Monitor patients with cardiac involvement of light chain (AL) amyloidosis more frequently for cardiac adverse reactions and administer supportive care as appropriate.

Neutropenia
Daratumumab may increase neutropenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Monitor patients with neutropenia for signs of infection. Consider withholding DARZALEX FASPRO until recovery of neutrophils. In lower body weight patients receiving DARZALEX FASPRO, higher rates of Grade 3-4 neutropenia were observed.

Thrombocytopenia
Daratumumab may increase thrombocytopenia induced by background therapy. Monitor complete blood cell counts periodically during treatment according to manufacturer’s prescribing information for background therapies. Consider withholding DARZALEX FASPRO until recovery of platelets.

Embryo-Fetal Toxicity
Based on the mechanism of action, DARZALEX FASPRO can cause fetal harm when administered to a pregnant woman. DARZALEX FASPRO may cause depletion of fetal immune cells and decreased bone density. Advise pregnant women of the potential risk to a fetus. Advise females with reproductive potential to use effective contraception during treatment with DARZALEX FASPRO and for 3 months after the last dose.

The combination of DARZALEX FASPRO with lenalidomide is contraindicated in pregnant women, because lenalidomide may cause birth defects and death of the unborn child. Refer to the lenalidomide prescribing information on use during pregnancy.

Interference with Serological Testing
Daratumumab binds to CD38 on red blood cells (RBCs) and results in a positive Indirect Antiglobulin Test (Indirect Coombs test). Daratumumab-mediated positive indirect antiglobulin test may persist for up to 6 months after the last daratumumab administration. Daratumumab bound to RBCs masks detection of antibodies to minor antigens in the patient’s serum. The determination of a patient’s ABO and Rh blood type are not impacted. Notify blood transfusion centers of this interference with serological testing and inform blood banks that a patient has received DARZALEX FASPRO. Type and screen patients prior to starting DARZALEX FASPRO.

Interference with Determination of Complete Response
Daratumumab is a human IgG kappa monoclonal antibody that can be detected on both the serum protein electrophoresis (SPE) and immunofixation (IFE) assays used for the clinical monitoring of endogenous M-protein. This interference can impact the determination of complete response and of disease progression in some DARZALEX FASPRO-treated patients with IgG kappa myeloma protein.

ADVERSE REACTIONS
The most common adverse reaction (≥20%) with DARZALEX FASPRO monotherapy is upper respiratory tract infection. The most common adverse reactions with combination therapy (≥20% for any combination) include fatigue, nausea, diarrhea, dyspnea, insomnia, pyrexia, cough, muscle spasms, back pain, vomiting, upper respiratory tract infection, peripheral sensory neuropathy, constipation, pneumonia, and peripheral edema.

The most common adverse reactions (≥20%) in patients with light chain (AL) amyloidosis who received DARZALEX FASPRO are upper respiratory tract infection, diarrhea, peripheral edema, constipation, fatigue, peripheral sensory neuropathy, nausea, insomnia, dyspnea, and cough.

The most common hematology laboratory abnormalities (≥40%) with DARZALEX FASPRO are decreased leukocytes, decreased lymphocytes, decreased neutrophils, decreased platelets, and decreased hemoglobin.

Please see full Prescribing Information for DARZALEX FASPRO.

On December 10, 2022 Servier, a leader in oncology committed to bringing the promise of tomorrow to the patients we serve, reported new data at the 64th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) characterizing clonal evolution and relapse mechanisms in patients with newly-diagnosed IDH1-mutated acute myeloid leukemia (AML) who are 75 years of age or older or have comorbidities that preclude use of intensive induction chemotherapy treated with TIBSOVO in combination with azacitidine (Press release, Servier, DEC 10, 2022, View Source [SID1234625039]).

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Results from the study reinforce that TIBSOVO in combination with azacitidine leads to deep, durable remissions associated with clearance of IDH1-mutated AML, with no second-site IDH1 mutations observed to date amongst the patients enrolled in the TIBSOVO plus azacitidine study arm with both baseline and longitudinal DNA sequencing available (46/72 patients). Amongst patients who relapsed (n=22), mutations in other genes, including IDH2, can emerge and provide an opportunity for relapse. Further study is needed to better characterize mechanisms of relapse for patients treated with TIBSOVO plus azacitidine combination therapy.

"Combination therapy consisting of TIBSOVO in combination with azacitidine for newly-diagnosed patients with acute myeloid leukemia and an IDH1 mutation has shown significant clinical effectiveness, but it’s important that we analyze patient response throughout their treatment to better understand mechanisms of resistance," said Susan Pandya, M.D., Vice President Clinical Development and Head of Cancer Metabolism Global Development Oncology & Immuno-Oncology, Servier. "We are committed to our exploratory translational efforts and will continue to update the data, as available, to contribute to a better understanding of how to improve outcomes for patients living with this aggressive hematologic malignancy."

These data presented today at ASH (Free ASH Whitepaper) 2022 represent continued clinical evidence on the effectiveness of TIBSOVO amongst newly-diagnosed AML patients with an IDH1 mutation who are 75 years of age or older or have comorbidities that preclude use of intensive induction chemotherapy, and follows the expanded approval of TIBSOVO in AML supported by data from the AGILE study. Data from the global Phase 3 AGILE study showed TIBSOVO as the first IDH1 mutation-specific targeted therapy to demonstrate improved event-free survival (EFS) and overall survival (OS) in combination with azacitidine compared to azacitidine plus placebo.

"These new data reinforce the original results from the AGILE trial, showing TIBSOVO in combination with azacitidine as an effective, first-of-its kind combination treatment option for patients with newly-diagnosed, IDH1-mutated acute myeloid leukemia," said Eytan Stein, M.D., Chief of the Leukemia Service in the Division of Hematologic Malignancies at Memorial Sloan Kettering Cancer Center (MSKCC). "Given the rapid progression of acute myeloid leukemia, it’s important to have a targeted therapeutic option that provides significant event-free survival and overall survival alongside a favorable safety profile, and that’s what we’ve seen clinically with TIBSOVO plus azacitadine."

About the NCT03173248 AGILE Phase 3 AML Triali

The AGILE trial is a global, Phase 3, multicenter, double-blind, randomized, placebo-controlled clinical trial designed to evaluate the efficacy and safety of TIBSOVO in combination with azacitidine compared with placebo in combination with azacitidine, in adults with previously untreated IDH1-mutated acute myeloid leukemia (AML) who are not candidates for intensive chemotherapy (≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy). The study’s primary endpoint is event-free survival (EFS), defined as the time from randomization until treatment failure, relapse from remission, or death from any cause, whichever occurs first. Treatment failure is defined as failure to achieve complete remission (CR) by Week 24.

Key secondary endpoints include CR rate, defined as the proportion of participants who achieve a CR; overall survival (OS), defined as the time from date of randomization to the date of death due to any cause; CR and complete remission with partial hematologic recovery (CRh) rate, defined as the proportion of participants who achieve a CR or CRh; and objective response rate (ORR), defined as the rate of CR, CR with incomplete hematologic recovery (CRi) (including CR with incomplete platelet recovery [CRp]), partial remission (PR), and morphologic leukemia-free state (MLFS).

About Acute Myeloid Leukemia

Acute myeloid leukemia (AML), a cancer of blood and bone marrow characterized by rapid disease progression, is the most common acute leukemia affecting adults, with approximately 20,000 new cases in the U.S., and 43,000 cases in Europe each year.ii,iii AML incidence significantly increases with age, and the median age of diagnosis is 68.ii The five-year survival rate is approximately 30.5%.iv For 6 to 10 percent of AML patients, the mutated IDH1 enzyme blocks normal blood stem cell differentiation, contributing to the genesis of acute leukemia.v

About TIBSOVO (ivosidenib tablets)

TIBSOVO (ivosidenib tablets) is approved in the U.S. in combination with azacitidine for the treatment of patients with newly-diagnosed IDH1-mutated acute myeloid leukemia (AML) in adults 75 years of age or older, or who have comorbidities that preclude use of intensive induction chemotherapy. TIBSOVO is the first therapy targeting cancer metabolism approved in combination with azacitidine for patients with newly-diagnosed IDH1-mutated AML.

TIBSOVO is also approved in the U.S. as monotherapy for the treatment of adults with IDH1-mutant relapsed or refractory AML, and for adults with newly-diagnosed IDH1-mutated AML who are ≥75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy. Last year, TIBSOVO garnered its first approval in a non-hematologic malignancy for patients with previously treated IDH1-mutated cholangiocarcinoma.

Please see the TIBSOVO indications and Important Safety Information with a link to the full Prescribing Information below.

On December 10, 2022 Sumitomo Pharma Oncology, Inc., a clinical-stage company focused on novel cancer therapeutics, reported new data from the ongoing Phase 1/2 study evaluating TP-3654, an investigational selective oral PIM1 kinase inhibitor, in patients with myelofibrosis (MF) previously treated with or ineligible for JAK inhibitor therapy (Press release, Sumitomo Pharmaceuticals, DEC 10, 2022, View Source;exposition-301699788.html [SID1234625038]). These results were presented during an oral presentation at the American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting & Exposition, being held Dec 10-13, 2022, in New Orleans, LA.

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Preliminary findings from the Phase 1 dose escalation study indicated TP-3654 is well tolerated with limited myelosuppressive adverse events. TP-3654, as a single agent, showed preliminary signs of clinical activity in the study, including spleen volume reduction, symptom improvement, and broad cytokine reduction, in patients previously treated with JAK inhibitors.1

"We are pleased by these preliminary clinical data and are encouraged by the safety and tolerability data seen in the ongoing TP-3654 dose escalation study. We remain committed to progressing this program, including expanding our clinical sites, and contributing to the advancement of possible treatment options which may improve outcomes for patients with myelofibrosis," said Patricia S. Andrews, Chief Executive Officer and Global Head of Oncology, Sumitomo Pharma Oncology, Inc.

The dose escalation portion of the study has enrolled 9 patients at the time of the analysis. To date, five dose levels of TP-3654 were evaluated, including once-daily and twice-daily regiments. No dose-limitation or related serious adverse event was observed up to the time of the analysis.

The data showed an early signal of clinical activity with spleen volume reduction (SVR). Six of 8 evaluable patients on treatment for at least 12 weeks experienced SVR, including 2 of 8 patients having at least 35% SVR. Additionally, a reduction in the symptom burden, measured by change in treatment score symptom (TSS), was experienced by 7 of the 8 evaluable patients, with 5 out of 8 patients having greater than 50% reduction. TP-3654 treatment was associated with reduced levels of cytokines associated with MF as early as 4 weeks, with cytokine reductions correlating with improved TSS.

Overall, TP-3654 appears to be well tolerated with no dose limiting toxicity (DLT) to date. The most common adverse events are Grade 1 gastrointestinal toxicities, which resolved in 1-2 weeks. Additionally, patients showed stable blood counts and no cytopenia with extended time on treatment. Currently, there are no discontinuations due to adverse events.

"These preliminary data presented at ASH (Free ASH Whitepaper) 2022 Annual Meeting & Exhibition are encouraging as we learn more about how TP-3654’s inhibition of PIM1 kinase may lead to reductions in bone marrow fibrosis and splenomegaly, and improved overall survival in patients with myelofibrosis," said Jatin J. Shah, M.D., Chief Medical Officer and Global Head of Development, Sumitomo Pharma Oncology (SMP Oncology). "We look forward to continuing to advance this study to evaluate the potential role of TP-3654 as a monotherapy, in addition to exploring combination opportunities with JAK inhibitors, for patients with myelofibrosis." Below are the details for the SMP Oncology presentation:

Abstract Title

Details

Presenter

Preliminary Data From the Phase I/II Study of TP-3654, a Selective Oral PIM1 Kinase Inhibitor, in Patients With Myelofibrosis Previously Treated with or Ineligible for JAK Inhibitor Therapy

Presentation #240 Saturday, December 10 at 3:15 p.m. CST
Oral Podium Presentation

Firas El Chaer, MD, Division of Hematology/Oncology, University of Virginia Health System, Charlottesville, VA

To view the full presentation, please visit to our website here.

About TP-3654
TP-3654 is an oral investigational inhibitor of PIM kinases, which has shown potential antitumor and anti-fibrotic activity through multiple pathways, including induction of apoptosis in preclinical models.2,3 TP-3654 was observed to inhibit proliferation and increased apoptosis in murine and human hematopoietic cells expressing clinically relevant JAK2V617F mutation.3 TP-3654 alone and in combination with ruxolitinib also showed normalized WBC and neutrophil counts, and reduced spleen size and bone marrow fibrosis in JAK2V617F and MPLW515L murine models of myelofibrosis.3 TP-3654 is currently being evaluated in a Phase 1/2 study of oral TP-3654 in patients with intermediate and high-risk myelofibrosis (NCT04176198).

On December 10, 2022 Tessa Therapeutics Ltd. (Tessa), a clinical-stage cell therapy company developing next-generation cancer treatments for hematological malignancies and solid tumors, reported that enhanced clinical data from an ongoing Phase 1 study (NCT04288726) of TT11X, an allogeneic "off the shelf" CD30 (Press release, Tessa Therapeutics, DEC 10, 2022, View Source [SID1234625033]).CAR-modified Epstein-Barr virus-specific T-cell (EBVST) therapy being co-developed by Baylor College of Medicine and Tessa. The results, detailed in an oral podium presentation at the 64th Annual Meeting of the American Society of Hematology (ASH) (Free ASH Whitepaper) on December 10, demonstrated TT11X to be well-tolerated at all dosing levels, eliciting a 79% overall response rate and complete disappearance of tumor in six patients.

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The podium presentation, entitled, "Evaluating Safety and Clinical Efficacy of Off-the-Shelf CD30.CAR-Modified Epstein-Barr Virus-Specific T cells in Patients with CD30+ Lymphoma," reported data from 14 heavily pre-treated patients with advanced CD30-positve Hodgkin lymphoma who were administered TT11X across three dosing levels (4 × 107 CD30.CAR EBVSTs, 1 × 108 CD30.CAR EBVSTs, and 4 × 108 CD30.CAR EBVSTs). An overall response rate of 79% (11/14 patients) was observed across all three dose levels, including six complete responses and six partial responses. The strongest responses were achieved in patients treated at the higher dose levels with additional infusions resulting in increasing effectiveness.

TT11X was demonstrated to be well tolerated with no dose limiting toxicities observed, including no evidence of graft-versus-host disease (GVHD) and only two patients having reversible grade 4 cytopenia.

"The data reported at ASH (Free ASH Whitepaper) suggest that allogeneic CD30.CAR EBVSTs provide a potentially safe and efficacious treatment for CD30-positive lymphomas and affirm previously reported data indicating the technology may avert GVHD and immediate rejection even after multiple infusions," stated David H. Quach, Ph.D., Instructor at Center for Cell and Gene Therapy, Baylor College of Medicine, USA. "Importantly, CD30.CAR EBVSTs elicited a clinical response in 11 of 14 patients with advanced CD30-positve Hodgkin lymphoma including six complete responses. Based on these results, CD30.CAR EBVSTs appear to be a promising platform for off-the-shelf cancer immunotherapy."

Tessa is currently advancing a pipeline of products that utilize CD30.CAR-modified EBVSTs, including its lead allogeneic cell therapy, TT11X, which is being co-developed with the Baylor College of Medicine for the treatment of relapsed or refractory CD30-positive lymphomas. Tessa’s proprietary "off-the-shelf" CD30.CAR EBVST allogeneic cell therapy platform is based on decades-long research and development by researchers at Baylor College of Medicine into the unique properties of virus specific T-cells (VSTs). These highly specialized T cells have the ability to recognize and kill infected cells while activating other parts of the immune system for a coordinated response. CD30 Allogeneic VSTs without genetic modification have demonstrated a strong safety profile and efficacy in early trials with minimal risk of GVHD.

"The safety and efficacy data presented at ASH (Free ASH Whitepaper) were very compelling and indicate that our "off-the-shelf" CD30.CAR EBVST allogeneic cell therapy platform could provide a potential leap forward in the treatment of CD30 positive lymphomas," stated Ivan Horak, M.D., Chief Medical Officer and Chief Scientific Officer of Tessa Therapeutics. "We look forward to continuing the development of TT11X as a potential treatment for CD30-positive lymphomas, while exploring opportunities to extend the EBVST platform to other cancer indications, including solid tumors where there is significant unmet medical need."

Details of the podium presentation are as follows:

Presentation Title: Evaluating Safety and Clinical Efficacy of Off-the-Shelf CD30.CAR-Modified Epstein-Barr Virus-Specific T cells in Patients with CD30+ Lymphoma

Presenting Author: David H. Quach, PhD, Center for Cell and Gene Therapy, Baylor College of Medicine, Houston, TX

Session Date: Saturday, Dec. 10, 2022, at 1:00 PM CT; Ballroom AB

A second oral podium presentation scheduled for Monday, December 12 at 5:45 PM CT p.m. and a poster presentation scheduled for Sunday, December 11 will highlight data from the Phase 2 CHARIOT trial evaluating the safety and efficacy of TT11, Tessa’s autologous CD30.CAR-T-cell therapy in patients with relapsed or refractory classical Hodgkin lymphoma (cHL).

On December 10, 2022 Syndax Pharmaceuticals, Inc. (Nasdaq: SNDX), a clinical-stage biopharmaceutical company developing an innovative pipeline of cancer therapies, reported updated positive data from the Phase 1 portion of the ongoing Phase 1/2 AUGMENT-101 trial of revumenib in patients with nucleophosmin mutant (mNPM1) and KMT2A rearranged (KMT2r) relapsed/refractory (R/R) acute myeloid or acute lymphoid leukemias (ALL or AML) (Press release, Syndax, DEC 10, 2022, View Source [SID1234625031]). Revumenib is the Company’s highly selective, oral menin inhibitor. The data were featured during two oral sessions today at the 64th American Society of Hematology (ASH) (Free ASH Whitepaper) Annual Meeting.

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"Both AUGMENT-101 data presentations featured today at the ASH (Free ASH Whitepaper) Annual Meeting highlight revumenib’s compelling clinical profile and continue to support the potential for revumenib to be a first-in-class and best-in-class therapy for both KMT2Ar and NPM1 acute leukemias," said Michael A. Metzger, Chief Executive Officer. "We previously announced that revumenib received Breakthrough Therapy Designation for the treatment of adult and pediatric patients with R/R acute leukemia (AML or ALL) harboring KMT2A rearrangements, further emphasizing the compelling data that we have generated in the Phase 1 portion of the trial that included 46 R/R KMT2Ar acute leukemia patients as well as the unmet need that exists in this population. We remain on track to report top-line data from at least one of the cohorts from the pivotal Phase 2 portion of the trial beginning in the third quarter of 2023, followed by a potential New Drug Application filing by the end of 2023."

"Patients with genetically-defined acute leukemias, including those harboring NPM1 mutations and KMT2A-rearrangements, have a limited number of effective treatment options and face a particularly poor prognosis," said Ghayas C. Issa, M.D., Assistant Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center. "The deep, durable responses and manageable safety profile observed continue to support the potential for revumenib to serve as a meaningful new addition to the treatment armamentarium for this patient population. I look forward to contributing to the continued advancement of this promising therapeutic option."

The oral presentation titled "The Menin Inhibitor Revumenib (SNDX-5613) Leads to Durable Responses in Patients with KMT2A-Rearranged or NPM1 Mutant AML: Updated Results of a Phase 1 Study" featured updated results from the Phase 1 portion of the AUGMENT-101 trial. As of the March 2022 data cutoff date, 60 patients with R/R mutant NPM1 or KMT2Ar acute leukemia were efficacy evaluable. In the efficacy evaluable population, the ORR was 53% (32/60) with a CR/CRh rate of 30% (18/60), and 78% (14/18) of patients with CR/CRh attaining minimal residual disease (MRD) negativity. Additional analyses from the trial indicate that at doses which met the protocol defined criteria for a recommended Phase 2 dose (RP2D), the CR/CRh rate was 27% in both the KMT2Ar (10/37) and the mutant NPM1 (3/11) patient populations. A total of 38% (12/32) of responders proceeded to transplant. The median time to response in the trial was 1.9 months, and the median duration of CR/CRh response was 9.1 months in the efficacy evaluable population as of data cutoff.

Additional results included:

Best Response

Efficacy Population

(N=60)

Efficacy Population

Doses Meeting Criteria for
RP2D

(n=48)

Response

Overall response rate1, n, (%)

32 (53 %)

25 (52 %)

CR/CRh

18 (30 %)

13 (27 %)

CR

12 (20 %)

8 (17 %)

CRh

6 (10 %)

5 (10 %)

CRp

5 (8 %)

5 (10 %)

MLFS

9 (15 %)

7 (15 %)

MRDneg rate2

18/32 (56%)

14/25 (56%)

within CR/CRh MRDneg, n, (%)

14/18 (78%)

10/13 (77%)

within CR/CRh/CRp MRDneg, n, (%)

18/23 (78%)

14/18 (78%)

KMT2Ar (MLLr)

Overall response rate1, n, (%)

27/46 (59%)

20/37 (54%)

CR/CRh

15/46 (33%)

10/37 (27%)

mNPM1

Overall response rate1, n, (%)

5/14 (36%)

5/11 (46%)

CR/CRh

3/14 (21%)

3/11 (27%)

1. Overall Response Rate = CR+CRh+CRp+MLFS; 2. MRD status assessed locally by PCR or MCF

Revumenib was well-tolerated, and no new safety signals were identified in the trial, including in patients who proceeded to stem cell transplant. There were no discontinuations due to treatment-related adverse events. The only dose limiting toxicity was asymptomatic Grade 3 QT prolongation, observed in 10% of patients treated at the RP2D and 13% of patients treated at all doses tested. No ventricular arrythmias or other clinical sequelae related to QTc prolongation were reported. Differentiation syndrome occurred in 16% of patients, and all cases of differentiation syndrome were Grade 2, and responded to standard management of steroids with or without hydroxyurea.

The oral presentation titled "Outcomes After Transplant in Relapsed/Refractory KMT2Ar (MLLr) and mNPM1 (NPM1c) Leukemia Patients Achieving Remissions After Menin Inhibition: Revumenib (SNDX-5613) Ph1 Experience" describes outcomes after transplant in patients achieving remissions in the Phase 1 portion of the AUGMENT-101 trial. Across evaluable patients with mNPM1 (n=14) or MLLr (n=46) acute leukemia who received revumenib, 12 (20%) patients proceeded to stem cell transplant, 11 (92%) of whom were MRD negative prior to transplant. Nine of the 12 patients (75%) who received a stem cell transplant remained in remission as of the data cutoff date, with a median follow-up of 12.3 months, and four patients experienced remission for longer than one year without additional maintenance therapy.

A copy of today’s presentations will be available in the Publications and Meeting Presentations section of Syndax’s website.

Conference Call and Webcast

The Company will host a conference call and webcast to discuss the ASH (Free ASH Whitepaper) data update tomorrow, Sunday, December 11, 2022 at 8:00 a.m. CT/ 9:00 a.m. ET. Joining the call will be members of the Syndax management team as well as two of the Primary Investigators on the AUGMENT-101 trial [Eytan M. Stein, M.D., Assistant Attending Physician and Director, Program for Drug Development in Leukemia, Department of Medicine at Memorial Sloan Kettering Cancer and Ghayas C. Issa, M.D., Assistant Professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center].

The live audio webcast and accompanying slides may be accessed through the Events & Presentations page in the Investors section of the Company’s website. Alternatively, the conference call may be accessed through the following:

Conference ID: SYNDAX12
Domestic Dial-in Number: 800-225-9448
International Dial-in Number: 203-518-9708
Live webcast: https://www.veracast.com/webcasts/OpenEx/General/p08Np3.cfm

For those unable to participate in the conference call or webcast, a replay will be available on the Investors section of the Company’s website at www.syndax.com approximately 24 hours after the conference call and will be available for a limited time.

About Revumenib

Revumenib is a potent, selective, small molecule inhibitor of the menin-MLL binding interaction that is being developed for the treatment of KMT2A rearranged, also known as mixed lineage leukemia rearranged or MLLr, acute leukemias including acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), and NPM1 mutant AML. Revumenib is currently being evaluated in several clinical trials, including the Company’s pivotal AUGMENT-101 Phase 1/2 open-label clinical trial for the treatment of relapsed/refractory (R/R) acute leukemias. Robust clinical activity with durable responses have been reported in the Phase 1 portion of AUGMENT-101. Revumenib was granted Orphan Drug Designation by the U.S. Food and Drug Administration (FDA) and European Commission for the treatment of patients with AML, and Fast Track designation by the FDA for the treatment of adult and pediatric patients with R/R acute leukemias harboring a KMT2A rearrangement or NPM1 mutation. Revumenib was also granted Breakthrough Therapy Designation by the FDA for the treatment of adult and pediatric patients with R/R acute leukemia harboring a KMT2A rearrangement.

About AUGMENT-101

AUGMENT-101 is a Phase 1/2 open-label trial designed to evaluate the safety, tolerability, pharmacokinetics, and efficacy of orally administered revumenib. The Phase 1 dose escalation portion of AUGMENT-101 was separated into two cohorts based on concomitant treatment with a strong CYP3A4 inhibitor. Arm A enrolled patients not receiving a strong CYP3A4 inhibitor, while Arm B enrolled patients receiving a strong CYP3A4 inhibitor. The Phase 2 pivotal portion of AUGMENT-101 is currently underway. Patients will be enrolled across each of the following trial populations: patients with NPM1 mutant AML, patients with KMT2Ar (MLLr) AML, and patients with KMT2Ar (MLLr) ALL. Discussions with the FDA have confirmed that AUGMENT-101 may potentially serve as the basis for regulatory filings in each patient population. The primary endpoint for each of the trials will be efficacy as measured by complete remission rate (CR + CRh), with key secondary endpoints including duration of response (DOR) and overall survival (OS).

About KMT2A (MLL) Rearranged Acute Leukemia

Rearrangements of the KMT2A (mixed lineage leukemia or MLL) gene give rise to KMT2Ar acute leukemia known to have a poor prognosis, with less than 25% of adult patients surviving past five years. KMT2A genes produce fusion proteins that require interaction with the protein called menin to drive leukemic cancer growth. Disruption of the menin-KMT2Ar interaction has been shown to halt the growth of KMT2Ar leukemic cells.

KMT2Ar acute leukemia can phenotypically appear as AML, ALL, or mixed phenotype acute leukemia (MPAL) and is routinely diagnosed through currently available cytogenetic or molecular diagnostic techniques. The median overall survival (OS) after standard of care first-line treatment, including intensive chemotherapy and transplant, is less than 1 year and the majority of patients suffer relapse within 5 years. Most R/R patients treated with second-line therapy relapse within the first year. With third line treatment or beyond, only a small percentage of patients achieve complete remission (CR), and the median OS is less than 3 months.

About NPM1 Mutant Acute Myeloid Leukemia

NPM1 mutant acute myeloid leukemia (AML), which is distinguished by mutations in the NPM1 gene that drive the leukemic phenotype, is the most common type of cytogenetically normal adult AML and represents approximately 30% of all adult AML cases. This subtype of AML has a five-year overall survival rate of approximately 50%. Similar to mixed lineage leukemia rearranged (MLLr) leukemias, NPM1 mutant AML is highly dependent on the expression of specific developmental genes shown to be negatively impacted by inhibitors of the menin-MLL interaction. NPM1 mutant AML is routinely diagnosed through currently available screening techniques. There are currently no approved therapies indicated for NPM1 mutant AML.