Tag Archive for: Art Flatau

FLT3 Inhibitors for AML Update

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Introduction

Mutations in the FLT3 (fms-like tyrosine kinase 3) gene are the most common mutations seen in Acute Myeloid Leukemia (AML) patients. FLT3 mutations are seen in about 30% of AML patients. There are 2 different FLT3 mutations, FLT3-ITD (internal tandem duplication) mutation and tyrosine kinase domain mutations (TKD) mutation. Here I report some newer results of treatments with FLT3 inhibitors, that I have come across in the last several months.

There are quite a few drugs that target the FLT3 gene, including:

First generation drugs:

  • Sorafenib (Nexavar)
  • Midostaurin (Rydapt)
  • Lestaurtinib clinical development of lestaurtinib has been discontinued as it did not provide significant clinical benefit.

Second generation drugs, which tend to have fewer and less severe side effects and are more effective include:

  • Gilteritinib (Xospata)
  • Quizartinib (Vanflyta) – Only for ITD mutations.
  • Crenolanib – Not FDA approved.

FLT3 inhibitors are effective treatments for AML with a FLT3 mutation. However, there are still a number of open questions. How should FLT3 inhibitors be used, with induction chemo, with consolidation chemo and/or for maintenance after a stem cell transplant (SCT) or chemo? Can they be used as a single agent for treating patients who are not good candidates for chemotherapy? Do they work well with newer treatments, specifically with azacitidine and ventoclax regimens? There have not been a lot of comparison between the different drugs. Finally, there is the question of why all these drugs have names that are barely pronounceable!

Gilterinib

There is a new study looking at the use of gilterinib as maintenance after SCT. This was a multi-national randomized study, comparing maintenance with gIlterinib against placebo. The result was overall the patients who received gilterinib had better relapse-free survival (RFS) compared to patients who received placebo. However, this difference was not considered statically significant.  However, the trial had a pre-specified secondary objective to look at the subgroup of patients who had measurable residual disease (MRD), that is they were MRD+.

About half of the patients were MRD+ either before SCT or after (or both). In this group, the RFS survival in the patients receiving gilterinib was significantly greater than the placebo group. Unfortunately, there were more side effects in the gilterinib group. It is likely that, because of this study, patients who are FLT3+ and undergoing a transplant will get gilterinib as maintenance if they are MRD+ and not if they are MRD-. The use of gilterinib or other FLT3 inhibitors as maintenance therapy will continue to be a subject of active research.

Quizartinib

I wrote a post on quizartiinb: Quizartinib in FLT3-ITD-Positive AML that was an overview of a trial of this drug along with induction and consolidation chemo and as maintenance after chemotherapy. In July, 2023, Quizartinib was approved for treatment of FLT3-ITD AML in the United States by the FDA.

Crenolanib

Crenolanib is a second-generation FLT3 agent that works for both FLT3-ITD and FLT3-TKD mutations. In Crenolanib and Intensive Chemotherapy for Adults With Newly Diagnosed FLT3-Mutated AML, crenolanib was given with “7+3:” induction and then with consolidation chemotherapy and as maintenance therapy after consolidation chemo and after a SCT. About 2/3 of patients were younger than 60, but patients as old as 75 were included. Although this was not a randomized trial and was fairly small (44 patients), it seemed that Crenolanib added to chemotherapy and as maintenance improved survival compared to midostaurin (the first drug approved for FLT3 AML) and quizartiinb (described above).

Sorafenib

While sorafenib is an FLT3 inhibitor, this first study is on its use in AML patients even if they did have a FLT3 mutation. Previous studies had shown sorafenib improved survival when given with standard “7+3” induction for AML. This study (Sorafenib Plus Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone for Untreated AML) looked at sorafenib with cladribine, high-dose cytarabine, granulocyte colony–stimulating factor, and mitoxantrone (CLAG-M). The first part of the study (Phase I) tried increasing doses of sorafenib and mitoxantrone. The Phase II part of the study used the recommended phase 2 dose (RP2D) to treat more patients. When compared with historical controls who received CLAG-M without sorafenib, the patients who received the RP2D had improved survival.

Finally, there is a report on the long term follow-up of a trial looking at using sorafenib as maintenance therapy after a transplant (Sorafenib Maintenance After Allogeneic HSCT in Patients With AML With FLT3 Internal Tandem Duplications). The use of sorafenib as maintenance reduced relapse which improved survival in patients with FLT3-ITD AML. The non-relapse mortality and the incidence of chronic Graft-Versus-Host Disease (GVHD) in those who had a transplant was similar in patients who received sorafenib and those who did not. This result was sustained long-term (with a median follow-up of about 5 years).

Conclusion

The best way to use FLT3 inhibitors in patients with FLT3 mutation is still an area of active research. Newer agents promise better results – fewer side effects and better survival.

Further Reading

FLT3 Tyrosine Kinase Inhibitors for the Treatment of Fit and Unfit Patients with FLT3-Mutated AML: A Systematic Review, Int J Mol Sci. 2021 Jun; 22(11): 5873.

Molecular Mechanisms of Resistance to FLT3 Inhibitors in Acute Myeloid Leukemia: Ongoing Challenges and Future Treatments, Cells 2020, 9(11), 2493.

Gilteritinib as Posttransplant Maintenance for AML With Internal Tandem Duplication Mutation of FLT3, Practice Update (registration required, free), March 26, 2024.

Gilteritinib as Post-Transplant Maintenance for Acute Myeloid Leukemia With Internal Tandem Duplication Mutation of FLT3, Medscape, June 21, 2023.

Gilteritinib as Post-Transplant Maintenance for Acute Myeloid Leukemia With Internal Tandem Duplication Mutation of FLT3, Journal of Cinical Oncology. March 12, 2024..

Quizartinib Approval Adds New Treatment Option for AML, Including in Older Patients , National Cancer Institute, Cancer Currents Blog , August 15, 2023.

Crenolanib and Intensive Chemotherapy for Adults With Newly Diagnosed FLT3-Mutated AML, Practice Update (registration required, free), March 4, 2024.

Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML (JCO article) Journal of Clinical Oncology February 07, 2024.

Sorafenib Plus Cladribine, High-Dose Cytarabine, G-CSF, and Mitoxantrone for Untreated AML Practice Update (registration required, free), July 25, 2023.

Phase 1/2 study of sorafenib added to cladribine, high-dose cytarabine, G-CSF, and mitoxantrone in untreated AML, Blood Adv (2023) 7 (17): 4950–4961.

Sorafenib Maintenance After Allogeneic HSCT in Patients With AML With FLT3 Internal Tandem Duplications, Practice Update (registration required, free), July 25, 2023.

Sorafenib maintenance after allogeneic haemopoietic stem-cell transplantation in patients with FLT3-ITD acute myeloid leukaemia: long-term follow-up of an open-label, multicentre, randomised, phase 3 trial, The Lancet, Volume 10, ISSUE 8, e600-e611, August 2023

Rezafungin for the Treatment of Candidemia and Invasive Candidiasis in Adults

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Introduction 

I was the patient representative on the FDA Advisory Antimicrobial Drugs Advisory Committee (AMDAC) that met on January 24, 2023, to consider whether to recommend the approval of a new anti-fungal drug Rezafungin. The indication was the treatment of candidemia (an infection of a fungus, Candida in the blood) and invasive candidiasis (a systemic infection with Candida). This is a summary of my thoughts on the meeting and Rezafungin.

I have to say that I was a little bit out of my element at this meeting. I originally thought that the topic of the meeting was going to be fungal infections after a transplant or chemotherapy or preventing fungal infections. However, patients with quite a few underlying conditions (including having had chemo and/or a transplant) who had Candidemia or Invasive Candidiasis were included in this indication. There is a separate, ongoing trial looking at preventing fungal infections in transplant patients using Rezafungin. 

Overview of the Rezafungin Trials 

The first-line treatment for Candida is with antifungal drugs in the echinocandin class. The existing echinocandins are Micafungin (Mycamine), Eraxis (Anidulafungin) and Canicidas (Caspofungin). Rezafungin is an addition to that class, derived from Anidulafungin, but modified so it can be given weekly instead of daily. 

There were two clinical trials that formed the basis of the evidence for Rezafungin. The trials compared Rezfungin to Caspofungin. The first trial called STRIVE (which I think stands for something, although I am not sure what) was a Phase II (smaller) trial that compared two dosages of Rezafungin (both had a 400 mg initial dose, followed by weekly doses of either 400 mg or 200 mg) against Casofungin. After the first part of the trial, it was determined that 400/400mg dosing was no more effective than the 400/200 dosing, so the latter was used for the rest of the trial.  The trial enrolled 76 patients in the 400/400 Rezafungin group, 46 in the 400/200 group and 61in the caspofungin group.

The second trial was a larger Phaee III mutli-center, randomized double blind trial, called ReSTORE (I am also not sure what this stands for). It was designed to show that Rezafungin was non-inferior (i.e. at least as good as) Caspofingin. This trial used the 400/200 mg dosing. This trial enrolled 93 patients in the Rezafungin arm and 94 in the Caspofungin arm. 

In both trials, patients in the Rezafungin arm received daily infusions, giving Rezafungin on the first day and a placebo (saline alone) infusion on the next 6 days. Patients in the Capofungin arm who responded well after 3 or more days from the start of the trial could be switched to oral fluconazole “stepdown” therapy (fluconazole is an antifungal in a different class that is available orally). Patients in the Rezafungin arm would receive a placebo pill if they were deemed to be appropriate for stepdown therapy.  

FDA generally requires 2 well done Phase III trials. Given that there is an “unmet need” for better antifungal drugs, FDA used a “flexible development program” that requires less evidence for an approval. In this case, the approval requested was for a “limited use indication”.  Although there were some questions about the quality of the data in some cases, overall, the committee agreed that there did not seem to be any significant safety concerns (at least compared to Caspofungin) and Rezafungin seemed to have similar efficacy. 

Interesting Notes from the Meeting 

If you are interested in the details of trials, you can dive into the briefing materials. I will point out some interesting bits in this section. 

One area of concern for echinocandins is infusion reactions. In the ReSTORE trial there were no infusion reactions in the Caspofungin arm while there were 4 patients who had reactions in the Rezafungin arm. However, 2 of the patients who had reactions, had them on Day 3, a day on which they would have been getting a placebo. Overall, while medical personnel who are prescribing and giving Rezafungin should be on the lookout for infusion reactions, I don’t think it is a major concern. 

There is some hope that Rezafungin would be useful for deep tissue (intraabdominal and peritoneal) invasive candidiasis. This is based in part on the fairly large initial (loading dose) as well as the long-lasting effects of the drug. However, there is little data to back that up as only a few patients have gotten the drug for deep tissue infections. 

The FDA noted that in the STRIVE study, the patients who were in the Rezafungin 400/200 dose arm had a higher chance of mycological eradication (that is cultures for Candida were negative) at day 5 (82.6%) compared to the patients in the 400/400 dose arm (71.7%). However, at day 5, patients in both arms had received the exact same amount of the drug (400 mg, in the first dose). I am not sure what to make of this anomaly. 

Conclusion 

We recommended 14-1 for approval. My opinion is that Rezafungin is a useful drug, comparable to the existing drugs in the echinocandins class, with a modest benefit – weekly dosing instead of daily. In the discussion, it was felt that the best candidates initially for this drug are patients who would likely have difficulty coming in for daily infusions, which was generally not a population treated in the trial, as all patients received daily infusions of one of the drugs or an infusion of a placebo. It will be interesting to see if Rezafungin does work better than the other drugs for deep tissue infections. 

Further Reading 

Note: The FDA documents (including the ones from the Cidara) seem to go away after a while (perhaps a year, I am not sure). 

Cidara Briefing Document for AMDAC meeting January, 24, 2023, the briefing document from Cidara on Rezafungin.(accessed March 12, 2023) 

FDA Briefing Document for AMDAC meeting, January 24, 2023, the FDA’s briefing on Rezafungin, there is a minor errata to the document. 

January 24, 2023: Antimicrobial Drugs Advisory Committee Meeting Announcement, more information about the meeting, as well as other documents (the FDA slides, the committee members, the above briefing documents). 

Echinocandins, a listing of the existing Echinocandins from drugs.com 

Cidara Therapeutics and Melinta Therapeutics Announce FDA Advisory Committee Recommends Approval of Rezafungin for the Treatment of Candidemia and Invasive Candidiasis, a press release from Cidara on the recommendation to approve Rezafungin or treatment of candidemia and invasive candidiasis 

30-Year Acute Myeloid Leukemia Survivor Shares His Journey

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30-Year Acute Myeloid Leukemia Survivor Shares His Journey from Patient Empowerment Network on Vimeo.

What might acute myeloid leukemia (AML) patients experience for symptoms, treatment, and coping with AML? AML patient and Empowerment Lead Art Flatau shares the experience of his AML journey from diagnosis, through treatment and AML survival, and advancements in AML treatments.

Art also shares his empowerment advice for patients and care partners to ensure optimal care and how he has found a sense of purpose in patient advocacy efforts.

See More from [ACT]IVATED AML

Related Resources:

Empowered AML Patient: Ask the AML Expert

Empowered AML Patient: Ask the AML Expert 

 How an AML Survivor’s Resilience Saved Her Life

How an AML Survivor’s Resilience Saved Her Life 

 Advice for Acute Myeloid Leukemia Patients Seeking a Clinical Trial

Advice for Acute Myeloid Leukemia Patients Seeking a Clinical Trial 

Transcript:

My name is Art, and I live in Austin, Texas. In 1992, I was 31 and married with two young children. I was in graduate school and working full-time. For a couple weeks, I had been feeling tired and had been running a low-grade fever. I also had a lot of bruises, probably because I was playing rugby at the time. I thought the fatigue was because I was overworked and getting  too little sleep.

On Saturday, I had a rugby game but was too tired to play more than a few minutes. The next day, I was too tired to do much. My wife and I decided that I would go to the doctor on Monday. 

Monday morning, I woke, and there was blood on my pillow as my gums were bleeding. My wife wanted to take me to the ER, but I convinced her to just call our doctor. I went to the doctor later that morning. She noted my symptoms, did a quick exam, and sent me for blood work. After lunch, she called and said I needed to go to the hospital and see a hematologist. I knew I was in trouble.

We talked to the doctor and he said, “We have to see what kind of leukemia you have.” What a shock.  I knew that I was sick with something I had not had before. The fact that it was cancer was a shock. I didn’t know that there were different types of leukemia but soon found out that I had acute myeloid leukemia (AML).

That evening, I received platelets and red blood transfusions. The next morning, I had a bone marrow biopsy, more platelets, and surgery to put in a central line. That afternoon, less than 24 hours after hearing the word leukemia in reference to me, I started chemotherapy. This was all overwhelming. We had no way to understand what our options were or to get a second opinion.

Three-and-a-half weeks later, I got out of the hospital with no hair, 25 pounds lighter, a lot weaker but alive. I had more chemotherapy in the next few weeks and more hospitalizations. A few months later, I was finished with chemo. I regained some strength, regrew my hair, and tried to get my life back to normal.

In early 1993, about 9 months after being diagnosed, we got another shock, I had relapsed. I needed to have a bone marrow transplant. Although we had a little time, a few days to figure out where to go for a transplant, we were again struggling to understand the process. We were also struggling to figure out how to move to Dallas for three more months for the transplant. The transplant was a long grind, a month or so in the hospital, a couple of months of going to the outpatient clinic two to three times a week, but we made it through. 

Now, 30 years later, I’m still around. My children graduated from high school, college, and graduate school and have successful careers. My wife and I are empty-nesters.  I am still working but hoping to retire in a few years. Although I consider myself very lucky to have survived and have had relatively few side effects, I do have some side effects to deal with, including low testosterone.

Some things that I’ve learned during my AML journey include: 

  • AML is a rare disease: The good news is that over the last several years a lot of new treatments have been discovered for AML. These new treatments are leading to more people surviving AML. However, these new treatments are evolving rapidly. It is important to find a cancer center and doctors who treat a lot of patients with leukemia. 
  • Consider volunteering: Advocacy work is an excellent way to help yourself and to support other patients and continued research efforts.
  • If something doesn’t feel right with your health, advocate for yourself and ask for further testing.

These actions (for me) are key to staying on my path to empowerment.

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Introducing Art Flatau, AML Empowerment Lead

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I have decided to try my hand at writing a regular blog.  I hope to write a post every month or so. This first post is something of an introduction.  You can read more of my background on my PEN Empowerment Lead page. I suppose I should mention that I am not a medical doctor and am not giving medical advice. I have in the past written a very occasional blog, largely summarizing conferences or meetings I have attended (Art Flatau’s Blog on Leukemia). My plan is to mostly write about new advances in AML treatment and stem cell transplants (including other cellular therapy like CAR T-cell).  However, I also want to write some about my own experience, particularly dealing with late effects. 

I am an AML and bone marrow transplant survivor. My interests are in new advances in AML treatment including stem cell transplants. As a long-term survivor (the 29th anniversary of my transplant was last month, February 2022) I am also interested in late effects. I have a few ideas currently on subjects I would like to explore further, including: 

Let me know if you have topics that you are interested in. I cannot promise to write about them there are lots of interesting topics in this area that I know little about.