Ivosidenib and Azacitidine for IDH1-Mutated AML

There has been another significant advance in the treatment of Acute Myeloid Leukemia (AML) at least for the small subset of patients (6-10%) who have a mutation in one of their genes called IDH1 (isocitrate dehydrogenase 1).   

Until 5-7 years ago, the typical initial treatment (called induction) for patients with AML consisted of relatively high doses of cytarabine (Ara-C) and another chemotherapy called an anthracycline (usually either daunorubicin or idarubicin).  Cytarabine is given as a continuous infusion for seven days and a daunorubicin or idarubicin is given on the first 3 days (this is commonly referred to as “7 + 3“regimen). There are other regimens that are sometimes used although most contain cytarabine.  This regimen is effective, but quite toxic and usually reserved for healthier fitter patients (generally under 65 without comorbidities like diabetes, or certain heart conditions). 

In 2018, the Food and Drug Administration (FDA) approved venetoclax and azacitidine for use in older patients or those with comorbidities.  Earlier this year, FDA approved Iivosidenib (used in combination with azacytidine) for newly diagnosed AML patients an IDH1 mutation.  The approval was for “adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy”.  This was based on a clinical trial reported in the New England Journal of Medicine (NEJM): Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia,.  Ivosidenib is not a brand new drug, it was approved in 2018 for relapsed or refractory AML. 

The current approval was based on a global, double-blind, randomized, placebo-controlled trial comparing AML patients with an IDH1 mutation treated with ivosidenib and azacytidine with patients treated with azacytidine alone.  The primary end point of the trial was event-free survival (EFS), defined as the time until treatment failure (i.e., the patient did not have complete remission by week 24), relapse or death.  The first group of patients, who received ivosidenib had an EFS at 12 months of about 37% versus 12% in the placebo group.  In addition, the median overall survival (that is half of the patients lived at least this long) was 24.0 months with ivosidenib and azacitidine versus 7.9 months with azacytidine alone.  This is a big difference, although there is still a lot of room for improvement.  In addition, there were fewer infections in the ivosidenib, group although there were more incidences of low white blood counts (neutropenia) and bleeding in that group. 

While this is good news, showing ivosidenib and Azacytidine is better than Azacytidine alone, most patients with AML with an IDH1 mutation who are not good candidates for intensive induction chemotherapy during the time period of the trial would likely have been treated with azacytidine and venetoclax.  The combination has been shown to be much more effective than Azacytidine alone.  My guess is that Azacytidine alone was chosen as the comparison, since the ivosidenib trial started enrolling patients in March 2018 (presumably the protocol for the trial was completed several months before that) and venetoclax was not approved until November, 2018.  The question remains, which is better ivosidenib and azacytidine or azacytidine and venetoclax.  I believe we will probably never know.  Given that AML is already a rare disease and no more that 10% of AML patients have an IDH1 mutation, it is not likely such a trial would be done.  Instead, it seems more likely that trials will look at the 3-drug combination of Ivosidenib, Venetoclax and Azacytidine.  Perhaps a trial with 3 arms may be done, comparing Azacytidine with Ivosidenib, or Venetoclax or both.  I hope the 3-drug combination will be more effective than either Ivosidenib or Venetoclax combined with Azacytidine.  If the side effects are not much worse, then standard therapy for AML patients with an IDH1 mutation who are not good candidates for intensive chemotherapy would become the 3-drug combination.  This would happen faster than first comparing ivosidenib to venetoclax and then comparing the better of those two to the 3-drug combination.   For younger healthier patients, ivosidenib is being combined with intensive chemotherapy in clinical trials.


Further reading: 

Ivosidenib and Azacitidine in IDH1-Mutated Acute Myeloid Leukemia, the original article from the New England Journal of Medicine (N Engl J Med 2022; 386:1519-1531). 

Ivosidenib and Azacitidine for IDH1-Mutated AML, mostly a repeat of the abstract of the above NEJM article, but also includes some commentary. 

Ivosidenib with Chemotherapy New Option for Some People with AML an article on Ivosidenib and Azacytidine from Cancer Currents: An NCI Cancer Research Blog. 

This AML Treatment Option is an Alternative to Induction Therapy an article on Ivosidenib and Azacytidine from PatientPower. 

FDA approves ivosidenib in combination with azacitidine for newly diagnosed acute myeloid leukemia an article about the drug approval, from Practice Update (registration may be required). 

Ivosidenib or enasidenib combined with intensive chemotherapy in patients with newly diagnosed AML: a phase 1 study, an article in Blood (Volume 137, Issue 13, April 1 2021) about a preliminary study of Ivosidenib and Enasidenib (for patients who have a mutation in IDH2) along with intensive chemotherapy (“7+3” induction, Ara-C consolidation). 

FDA grants regular approval to venetoclax in combination for untreated acute myeloid leukemia, an article from the FDA on the approval of Venetoclax for treating AML (October, 2020). 

FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation, an article from the FDA on the initial approval of Ivosidenib for treating AML (July, 2018).FDA approves first targeted treatment for patients with relapsed or refractory acute myeloid leukemia who have a certain genetic mutation, an article from the FDA on the initial approval of Ivosidenib for treating AML (July, 2018). 

Naïve T-cell Depletion in Donor Blood Stem Cell Transplant Patients 

Introduction 

T-cell depletion is a strategy to remove T-cells from bone marrow or peripheral stem cells taken from a donor before they are given to a patient. T-cell depletion (TCD) has been around for quite some time, at least since the early 1980s. TCD decreases the risk of graft-versus-host disease (GVHD) and, in particular, deaths from GVHD. The goal is to also have similar survival to non-T-cell depleted transplants (sometimes referred to T-cell replete or T replete). This would be a significant advance. Removing only the naïve T-cells from the graft looks like a promising approach to achieve these goals. The recent article Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease reports on a trial looking at the use of naïve T-cell depletion and comparing the results to historical controls.  

What are Naïve T-cells? 

I had not heard of naïve T-Cells before. According to an article from the National Cancer Institute (NCI) Can Chronic Graft-Versus-Host Disease Be Prevented? 

T cells are among the many types of immune cells that can attack cancer cells. But there are several subsets of T cells. Naive T cells have never encountered an antigen—a protein or other molecule that can provoke an immune response. For reasons that are not yet fully understood, they are more likely to react to healthy cells in the transplant recipient. 

I don’t know how naïve T-cells can be distinguished from other T-cells, but apparently this is possible. 

Problems with T-Cell Depletion 

TCD does significantly reduce the risk of GVHD and deaths from GVHD, however it is not without drawbacks.    There have been many attempts at T-cell depletion over the years, first removing all T-cells and more recently selectively removing some of the T-cells. However, most of the problems listed below have persisted to some degree: 

  1. Graft failure is generally higher in TCD transplants than in non TCD transplants  
  2. Epstein-Barr virus–associated lymphoproliferative disorders (LPD). This is a rare side effect of T-replete transplants, but is much more common in TCD transplants (as well as solid organ transplants) Generally, the decrease in deaths acute GVHD are about equivalent in the increase in deaths LPD  
  3. There is a much higher rate of disease recurrence after TCD transplants. It is well established that patients who experience GVHD have a lower rate of relapse (this was known at the time of my transplant, almost 30 years ago). This is because of what is known as a graft-versus-leukemia (GVL) effect (or more generally as a graft-versus-tumor, GVT effect). The T-cells are causing GVHD by attacking the host cells in the patients.  Since any residual cancer cells are also recognized as foreign by the T-cells, they are destroyed as well.

Current Study 

For the most part the current study did not show the problems listed above. There were 138 patients with acute leukemia treated in this trial. There were 2 patients who experienced graft failure (< 2%). The incidence of Epstein-Barr virus (EBV) reactivation was rare, only 3 patients (2.3%) experiences this.  Only 1 required treatment with rituximab (Rituxan, which is one of the more effective therapies for EBV related LPD).  The overall incidence of relapse was 23%, which is in line with the expected relapse rate from T-replete transplants. The incidence of acute GVHD was low and most patients who experienced acute GVHD were treated successfully with steroids.  Only 7% of patients developed chronic GVHD (much lower than T-replete transplants), which also largely responded to steroids. 

Future Reading 

  1. Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease, the full article from the Journal of Clinical Oncology, from April 2022 (registration may be required). 
  2. A blog article from the National Cancer Institute (NCI) Can Chronic Graft-Versus-Host Disease Be Prevented? This is quite interesting and not nearly as technical as the journal articles. 
  3. An older abstract (2020) from the same author, Marie Bleakley: Naive T-cell depletion in stem cell transplantation 
  4. Naive T Cell Depletion for Preventing Chronic Graft-versus-Host Disease in Children and Young Adults with Blood Cancers Undergoing Donor Stem Cell Transplant, the clinical trial description from the National Cancer Institute 
  5. The history and future of T-cell depletion as graft-versus-host disease prophylaxis for allogeneic hematopoietic stem cell transplantation  from the journal Blood.  A technical and older (2001) article but may be interesting to some. 
  6. Does GVHD Ever Resolve in Acute Myeloid Leukemia Patients?

References

Naive T-Cell Depletion to Prevent Chronic Graft-Versus-Host Disease Marie BleakleyAlison SehgalStuart SeropianMelinda A. BiernackiElizabeth F. KrakowAnn DahlbergHeather PersingerBarbara HilzingerPaul J. MartinPaul A. CarpenterMary E. FlowersJenna VoutsinasTheodore A. GooleyKeith LoebBrent L. WoodShelly HeimfeldStanley R. Riddell, and Warren D. ShlomchikJournal of Clinical Oncology 2022 40:111174-1185

Low Testosterone in Cancer or Transplant Survivors

I was one of the authors (out of more than 50) of a review article on male specific late effects in stem cell transplant patients [1]. The article looked at many late effects in male transplant survivor. This post is a summary on one late effect, hypogonadism (that is low testosterone) as well as my opinion about the recommendations on screening for low testosterone.

We do not know much about low testosterone in cancer survivors or transplant survivors. There is a significant increase in the incidence of low testosterone but the size of the increase in transplant survivors is not well understood. Symptoms related to low testosterone include: “loss of body hair, small testes, and ED (Erectile Dysfunction)”. Other symptoms that may be signs of low testosterone but may be signs of other problems include: “loss of libido, anemia, fatigue, lack of motivation, reduced muscle mass, and increased fat mass” (I don’t really know what “lack of motivation” means). The article recommends: “testing and consideration of hormone replacement therapy based on symptoms”. This is similar to what has been recommended in the past [2].

In 2016, some 23 years after my bone marrow transplant (BMT) I was diagnosed with low testosterone. I had finally asked one of my doctors to get tested and my testosterone level was 192 (my free testosterone was also low, and this is useful for the doctors, but I won’t mention it anymore). The normal level of testosterone is between 300 and 1000 nanograms per deciliter (ng/dL). [3] While I had symptoms, low libido, loss of muscle mass and fatigue primarily, no doctor had asked about those symptoms, and I had not thought about them as more than getting old.

I started on testosterone replacement, and it has made a huge difference. The biggest difference in my mind is less fatigue. One of the more common side effects of testosterone replacement is it can raise your red blood count (I like to call this an “effect”). Since a year or two after my transplant, my hemoglobin was on the low side (typically 12-13, normal for men is 13.2-16.6) and my hematocrit was generally between 37 and 40% (normal for men is 38.3-48.6%) [4]. A few years ago, at my annual exam my hematocrit was close to 35%. I went to see an oncologist (the oncologist who treated me is no longer seeing patients in the office). A whole bunch of tests were run, but not a testosterone test and nothing abnormal other than my red blood values was found. After starting testosterone replacement, my hematocrit is 43-45% and my hemoglobin is 14-15. The biggest change for me is that I have far less fatigue presumably because I have more red blood cells.

Testosterone levels naturally decrease with age. The folklore is that the testosterone level decreases about 1% per year from age 30 or so. [5] Other sources say from age 20. I believe this means that if you level is 800 at age 30 (there seems to be little data for a “normal” level at different ages), it will go down about 8 units per year (1% of 800). So, at age 80, the level would be around 400 (if this actually means a decrease of 1% of the current level every year, it will go down to about 480 at age 80). If the level was 600 at age 30, then it would be about 300 at age 80 (or around the low end of the normal range, which I imagine is about the average level for 80-year-old men). What if a 30-year-old had a testosterone level of 800 and then was diagnosed with AML and had chemotherapy and a transplant? Perhaps 2 years post-transplant is now 500, which is normal. There seems to be no data on testosterone levels in long term transplant survivors. However, if this goes down 8 units a year (this seems to be as good a guess as any), then after 25 years the level would be 320 and after 30 years it would 280, which is less than the 80-year-old man without cancer. It is important to state that there appears is no data to support or refute this scenario. Still my belief is that this is essentially what happened to me. My guess is that quite a few male transplant survivors have a testosterone level in the normal range 1 or 2 years post-transplant (although most will not have it tested) but will eventually have hypogonadism and likely not realize it.

While there is a lot we do not know about testosterone levels in transplant survivors (or for that matter healthy men), there is one thing we do know. “The majority of health care professionals do not address [sexual dysfunction]” [1]. In my mind this calls into question the recommendation to test testosterone levels “based on symptoms”. Most doctors do not seem to ask about symptoms specific to low testosterone and the other symptoms are non-specific. It seems to me that not testing testosterone levels at say 1 or 2 years post-transplant is likely causing harm to some male long term survivors. A better guideline would be to routinely test 1 or 2 years post-transplant and then again if symptoms warrant.

The BMT Infonet as part of their Celebrating a Second Chance at Life Symposium had a really good workshop on Sexual Concerns in Men after Transplantation by John Mulhall MD, from Memorial Sloan Kettering Cancer Center. You will have to register before viewing the replay of this workshop. While it covered other topics, there was a lot of information about low testosterone 

Contact Art Flatau, flataua@acm.org

Bibliography

[1] Phelan, R et. al., “Male-Specific Late Effects in Adult Hematopoietic Cell Transplantation Recipients: A Systematic Review from the Late Effects and Quality of Life Working Committee of the Center for International Blood and Marrow Transplant Research and Transplant Complica,” Transplantation and Cellular Therapy, 2021.

[2] Navneet, Majhail S.; et. al., “Recommended Screening and Preventive Practices for Long-Term Survivors after Hematopoietic Cell Transplantation,” Biology of Blood and Marrow Transplantation, vol. 18, no. 3, pp. 348 – 371, 2012.

[3] Icahn School of Medicine at Mount Sinai, “Testosterone,” [Online]. Available: https://www.mountsinai.org/health-library/tests/testosterone

[4] Mayo Clinic, “Complete Blood Count,” [Online]. Available: https://www.mayoclinic.org/tests-procedures/complete-blood-count/about/pac-20384919

[5] Mayo Clinic, “Testosterone therapy: Potential benefits and risks as you age,” [Online]. Available: https://www.mayoclinic.org/healthy-lifestyle/sexual-health/in-depth/testosterone-therapy/art-20045728

[6] WebMd, “Is Testosterone Replacement Therapy Right for You?,” [Online]. Available: https://www.webmd.com/men/guide/testosterone-replacement-therapy-is-it-right-for-you

Introducing Art Flatau, AML Empowerment Lead

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.