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TAGRAXOFUSP

TAGRAXOFUSP (also known as Elzonris or SL-401) is a specialized medication being studied in clinical trials for various blood cancers, including acute myeloid leukemia (AML), blastic plasmacytoid dendritic cell neoplasm (BPDCN), chronic myelomonocytic leukemia (CMML), and myelofibrosis (MF). This unique drug works by targeting CD123, a protein marker found on certain cancer cells. TAGRAXOFUSP combines a targeting component (interleukin-3) with a toxin (truncated diphtheria toxin) to specifically kill cancer cells while potentially sparing healthy cells. Clinical trials are evaluating this drug alone and in combination with other therapies to determine its safety, optimal dosing, and effectiveness in various blood cancer settings.

Table of Contents

What is Tagraxofusp?

Tagraxofusp (also known by the brand name Elzonris, or formerly SL-401) is a targeted therapy used in the treatment of certain blood cancers[1]. It belongs to a class of medications called CD123-directed cytotoxins, which means it specifically targets a protein called CD123 that is found on the surface of certain cancer cells[2].

Tagraxofusp is a protein-drug conjugate that consists of two parts: a targeting portion (interleukin-3) that binds to CD123, and a toxic portion (truncated diphtheria toxin) that kills the cells once the drug is taken up[3]. The U.S. Food and Drug Administration (FDA) has approved tagraxofusp for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN) in both adult and pediatric patients[4].

How Does Tagraxofusp Work?

Tagraxofusp works through a targeted approach to kill cancer cells. Here’s how it works:

  1. The medication targets a specific protein called CD123 (also known as the interleukin-3 receptor alpha chain) that is found in high amounts on certain cancer cells[5].
  2. Once tagraxofusp binds to CD123, the cancer cell absorbs the drug[5].
  3. Once inside the cell, the diphtheria toxin portion of tagraxofusp is released, which prevents the cell from making new proteins[3].
  4. Without the ability to make new proteins, the cancer cell dies[3].

What makes tagraxofusp different from conventional chemotherapy is that it directly targets CD123, which is present on tumor cells but is expressed at lower levels or absent on normal hematopoietic stem cells (the cells in your bone marrow that give rise to all blood cells)[12]. Additionally, tagraxofusp’s killing mechanism is not dependent on cell division, making it effective against both highly proliferative tumor cells and quiescent (inactive) tumor cells[12].

What Conditions Does Tagraxofusp Treat?

Tagraxofusp is FDA-approved for the treatment of blastic plasmacytoid dendritic cell neoplasm (BPDCN), which is a rare and aggressive type of blood cancer that affects the bone marrow and multiple organs[4].

Additionally, clinical trials are investigating its use in several other conditions:

  • Acute Myeloid Leukemia (AML) – A type of cancer that affects the blood and bone marrow, characterized by rapid growth of abnormal white blood cells[1][2].
  • Chronic Myelomonocytic Leukemia (CMML) – A type of cancer that starts in blood-forming cells of the bone marrow and invades the blood[1].
  • Myelofibrosis (MF) – A rare type of bone marrow cancer that disrupts the body’s normal production of blood cells[1][4].
  • Various other CD123-positive hematologic malignancies – These include certain types of lymphomas and mixed phenotype acute leukemias[12].

Researchers are particularly interested in tagraxofusp for these conditions because they typically express high levels of CD123, the protein that tagraxofusp targets[2].

How is Tagraxofusp Administered?

Tagraxofusp is administered as an intravenous (IV) infusion, which means it’s given directly into your vein. Here are the key points about its administration:

  • It’s typically given as a 15-minute infusion[1].
  • The standard dose is 12 micrograms per kilogram of body weight (μg/kg), though clinical trials may test different doses (7-16 μg/kg)[3].
  • It’s usually administered for 3-5 consecutive days in each treatment cycle[1][2].
  • Cycles are typically 21 or 28 days long, depending on the specific treatment protocol[2][3].
  • The first cycle often requires hospitalization for monitoring, while subsequent cycles may be done on an outpatient basis[1].

Your healthcare provider will determine the appropriate dosing schedule based on your specific condition, response to treatment, and any side effects you may experience[1].

Current Clinical Use and Research

Tagraxofusp is being studied in various clinical settings, including:

  • First-line treatment for newly diagnosed patients with certain blood cancers[3].
  • Treatment for relapsed or refractory disease (cancer that has returned after treatment or doesn’t respond to treatment)[2].
  • Maintenance therapy after stem cell transplant to help prevent relapse[1].
  • Bridge to stem cell transplantation – helping patients achieve remission so they can undergo a potentially curative stem cell transplant[3].
  • Treatment for measurable residual disease (MRD) – targeting small numbers of cancer cells that remain after treatment and can lead to relapse[11].

Clinical trials have shown promising results in certain patient populations. For example, in first-line BPDCN, tagraxofusp has shown high rates of complete response, which means all signs of cancer have disappeared with treatment[3].

Tagraxofusp in Combination Therapies

While tagraxofusp can be used alone (as monotherapy), many clinical trials are investigating its use in combination with other cancer treatments to potentially improve outcomes. Some combination approaches being studied include:

  • Tagraxofusp with venetoclax and azacitidine – This three-drug combination is being studied for AML. Venetoclax is a targeted therapy that blocks a protein called BCL-2, while azacitidine is a hypomethylating agent that can help restore normal function to certain genes[9][11].
  • Tagraxofusp with pacritinib – This combination is being studied for myelofibrosis. Pacritinib is a JAK2 and IRAK1 inhibitor that can help with symptoms and splenomegaly (enlarged spleen)[4].
  • Tagraxofusp with gemtuzumab ozogamicin – This combination is being investigated for relapsed/refractory AML. Gemtuzumab ozogamicin is another targeted therapy that delivers a toxic substance to cancer cells[10].
  • Tagraxofusp with cladribine and cytarabine – This combination is being studied for CD123-positive relapsed or refractory AML[13].

These combination approaches aim to target cancer cells through multiple mechanisms simultaneously, potentially increasing effectiveness and reducing the chance of treatment resistance[9].

Potential Side Effects

Like all medications, tagraxofusp can cause side effects. The most significant side effect is capillary leak syndrome, a condition in which fluid and proteins leak out of small blood vessels into surrounding tissues[3].

Other potential side effects may include:

  • Nausea and vomiting[1]
  • Fever[1]
  • Fatigue[3]
  • Decreased appetite[3]
  • Headache[3]
  • Increased liver enzymes[1]
  • Low blood counts (which can lead to increased risk of infection, bleeding, or anemia)[3]

During clinical trials, researchers carefully monitor for these side effects and may adjust the treatment schedule or provide supportive care as needed[1]. The safety profile of tagraxofusp, both alone and in combination with other therapies, continues to be studied[4].

Ongoing Research and Future Applications

There are numerous ongoing clinical trials investigating tagraxofusp in various settings and combinations. Some key areas of research include:

  • Dose optimization – Finding the most effective and safest dose for different patient populations[2].
  • Novel combinations – Testing tagraxofusp with other therapies to potentially enhance effectiveness[4][9].
  • Biomarker identification – Determining which patients are most likely to benefit from tagraxofusp based on specific characteristics of their cancer[11].
  • Treatment sequencing – Understanding the optimal timing of tagraxofusp in relation to other therapies[1].
  • Long-term outcomes – Assessing the durability of responses and long-term survival of patients treated with tagraxofusp[3].

Researchers are particularly interested in the potential of tagraxofusp to target measurable residual disease (MRD), which refers to a small number of cancer cells that remain after treatment and can lead to relapse. By targeting these residual cancer cells, tagraxofusp might help prevent disease recurrence[11].

Tagraxofusp in Pediatric Patients

Tagraxofusp is approved for pediatric patients with BPDCN, and research is ongoing to expand its use in children with other blood cancers[12].

A Phase I study is investigating tagraxofusp, both alone and in combination with chemotherapy, in pediatric patients with relapsed or refractory CD123-expressing hematologic malignancies[12]. This study includes children and young adults with various types of blood cancers, including AML, acute lymphoblastic leukemia (ALL), BPDCN, myelodysplastic syndromes (MDS), and certain lymphomas[12].

The study is designed to determine the recommended phase 2 dose of tagraxofusp in pediatric patients, as well as to describe its toxicities and pharmacokinetic properties (how the drug moves through the body)[12]. Notably, the study includes patients with Down syndrome, a population that is often excluded from clinical trials despite having a higher risk of developing certain types of leukemia[12].

Clinical Trial Focus Treatment Approaches Patient Populations Dosing Information Key Outcome Measures
Post-transplant maintenance therapy TAGRAXOFUSP after allogeneic stem cell transplant Patients with CD123+ AML, MF, and CMML who have undergone transplant IV infusion over 15 minutes on days 1-3 of cycles 1-4, then days 1-2 of subsequent cycles Safety, relapse prevention, survival, graft-versus-host disease
Treatment of CD123+ blood cancers TAGRAXOFUSP as monotherapy Patients with CD123+ or BPDCN-like AML 12 μg/kg/day for 5 days, for at least 4 cycles (21-day cycles) Objective response rate, survival, disease-free survival
First-line and relapsed/refractory treatment TAGRAXOFUSP at various dose levels Patients with BPDCN and AML Dose levels of 7, 9, 12, 16 μg/kg/day Maximum tolerated dose, CR rate, duration of response
Combination therapies TAGRAXOFUSP with other drugs (venetoclax, azacitidine, pacritinib, etc.) Various blood cancer patients including those with AML, MF, and others Typically 12 μg/kg/day for 3-5 days per cycle with partner drugs on specific schedules Safety of combinations, response rates, survival metrics
Pediatric applications TAGRAXOFUSP alone or with chemotherapy Children with relapsed/refractory CD123+ blood cancers Various dose levels being tested Dose-limiting toxicities, safety profile, responses
Measurable residual disease TAGRAXOFUSP to eliminate remaining cancer cells Patients with minimal residual disease after initial treatment Usually combined with other therapies in specific schedules MRD conversion rate, relapse-free survival

FAQ

  • What is TAGRAXOFUSP and how does it work? TAGRAXOFUSP (also known as Elzonris or SL-401) is a CD123-directed cytotoxin. It works by targeting the CD123 protein that appears on the surface of certain cancer cells. The drug combines two parts: a targeting component (interleukin-3) that seeks out CD123-positive cancer cells, and a toxic component (truncated diphtheria toxin) that enters these cells and kills them by stopping their ability to make proteins. This targeted approach aims to destroy cancer cells while minimizing damage to healthy cells that don't express CD123.
  • What types of cancer is TAGRAXOFUSP being tested for? TAGRAXOFUSP is being tested in clinical trials for several types of blood cancers, including: Acute Myeloid Leukemia (AML), Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN), Chronic Myelomonocytic Leukemia (CMML), and Myelofibrosis (MF). It has already received FDA approval for treating BPDCN, but researchers are exploring its potential benefits in other blood cancers that express the CD123 protein marker.
  • How is TAGRAXOFUSP administered in clinical trials? In most clinical trials, TAGRAXOFUSP is administered as an intravenous (IV) infusion over approximately 15 minutes. Depending on the specific trial protocol, it may be given for 3-5 consecutive days in each treatment cycle. The dosage ranges from 7 to 12 micrograms per kilogram (μg/kg) of body weight per day. Treatment cycles typically last 21-28 days, and patients may receive multiple cycles based on their response and tolerance to the treatment.
  • What are the common side effects of TAGRAXOFUSP in clinical trials? While side effects vary between patients, common ones observed in TAGRAXOFUSP clinical trials include capillary leak syndrome (a serious condition where fluid leaks from blood vessels), fever, nausea, and changes in blood counts. Researchers carefully monitor for dose-limiting toxicities (DLTs), which are side effects serious enough to prevent increasing the dose further. The trials include safety measures like starting with lower doses and monitoring patients closely, especially during the first cycle of treatment.
  • Is TAGRAXOFUSP being tested alone or in combination with other drugs? TAGRAXOFUSP is being tested both as a single agent (monotherapy) and in combination with other cancer drugs. Many current trials are exploring combinations with drugs like venetoclax, azacitidine, gemtuzumab ozogamicin, pacritinib, cladribine, and cytarabine. These combination approaches aim to improve effectiveness by targeting cancer cells through multiple mechanisms simultaneously. Researchers are carefully evaluating which combinations provide the best outcomes while maintaining acceptable safety profiles.

Ongoing Clinical Trials on TAGRAXOFUSP

  • Study on the Effectiveness and Safety of Tagraxofusp and Venetoclax for Adults with Untreated Blastic Plasmacytoid Dendritic Cell Neoplasm

    Recruiting

    1 1 1
    Investigated drugs:
    France

  • Study of Azacitidine, Venetoclax, and Tagraxofusp for Patients with Higher-Risk Chronic Myelomonocytic Leukemia

    Recruiting

    1 1 1
    Investigated drugs:
    Germany Italy Spain

Glossary

  • Acute Myeloid Leukemia (AML): A type of cancer that affects the blood and bone marrow, characterized by the rapid growth of abnormal white blood cells that build up in the bone marrow and interfere with normal blood cell production.
  • Allogeneic Stem Cell Transplant: A procedure where a patient receives healthy blood-forming stem cells from a donor to replace their diseased bone marrow. The donor stem cells can grow into new, healthy blood cells.
  • Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): A rare and aggressive type of blood cancer that affects cells called plasmacytoid dendritic cells. It often presents with skin lesions and can spread to the bone marrow and other organs.
  • CD123: A protein marker (also known as interleukin-3 receptor alpha) found on the surface of certain cancer cells, particularly in blood cancers. TAGRAXOFUSP targets cells that express this marker.
  • Chronic Myelomonocytic Leukemia (CMML): A type of cancer that affects blood-forming cells in the bone marrow, resulting in too many monocytes (a type of white blood cell) in the blood and bone marrow.
  • Complete Remission (CR): A treatment response where there is no evidence of disease, typically defined as less than 5% blasts (immature blood cells) in the bone marrow, normal blood counts, and no signs of leukemia elsewhere in the body.
  • CR with incomplete hematologic recovery (CRi): A state where the cancer appears to be in remission but blood cell counts have not completely returned to normal levels.
  • Cytotoxin: A substance that is toxic to cells, often used in cancer treatments to kill cancer cells. TAGRAXOFUSP contains a cytotoxin (diphtheria toxin) to kill targeted cancer cells.
  • Dose-Limiting Toxicity (DLT): Side effects severe enough to prevent increasing the dose of a drug in a clinical trial. These are carefully monitored to determine the maximum tolerated dose.
  • Dose Escalation: A clinical trial approach where the dose of a drug is gradually increased to determine the optimal dose that balances effectiveness and safety.
  • Event-Free Survival (EFS): The length of time after treatment during which a patient remains free of certain complications or events that the treatment was designed to prevent or delay.
  • Hematopoietic Cell Transplant (HCT): A procedure that replaces damaged or diseased blood-forming cells with healthy ones. Also known as a bone marrow transplant or stem cell transplant.
  • Minimal Residual Disease (MRD): Small numbers of cancer cells that remain after treatment, which may not be detected by standard tests but could eventually cause the cancer to return.
  • Maximum Tolerated Dose (MTD): The highest dose of a drug that can be given without causing unacceptable side effects. This is determined during the dose escalation phase of clinical trials.
  • Myelofibrosis (MF): A rare type of blood cancer where abnormal blood cells and fibers build up in the bone marrow, disrupting the body's normal production of blood cells.
  • Objective Response Rate (ORR): The percentage of patients whose cancer shrinks or disappears after treatment. This typically includes those with complete and partial responses.
  • Overall Survival (OS): The length of time from either the date of diagnosis or the start of treatment that patients are still alive.
  • Partial Response (PR): A decrease in the size or extent of cancer that meets certain criteria but falls short of a complete response. In blood cancers, this often means a significant reduction in cancer cells.
  • Recommended Phase 2 Dose (RP2D): The dose of a drug determined from Phase 1 trials to be appropriate for further testing in Phase 2 trials, based on safety and preliminary efficacy data.
  • Relapsed/Refractory (R/R): Cancer that has returned after a period of improvement (relapsed) or has not responded to treatment (refractory).

References

  1. https://clinicaltrials.gov/study/NCT05233618
  2. https://clinicaltrials.gov/study/NCT04342962
  3. https://clinicaltrials.gov/study/NCT02113982
  4. https://clinicaltrials.gov/study/NCT06414681
  5. https://clinicaltrials.gov/study/NCT07007052
  6. https://clinicaltrials.gov/study/NCT02268253
  7. https://clinicaltrials.gov/study/NCT02270463
  8. https://clinicaltrials.gov/study/NCT05442216
  9. https://clinicaltrials.gov/study/NCT06456463
  10. https://clinicaltrials.gov/study/NCT05716009
  11. https://clinicaltrials.gov/study/NCT07148180
  12. https://clinicaltrials.gov/study/NCT05476770
  13. https://clinicaltrials.gov/study/NCT06561152