Seeing Early Results within 5 Days of Starting Trial Drug

Todd holds up the AG-221 Trial Study Drug

We are so excited that Todd finally got to start the Trial Drug AG-221 on Monday, April 20, 2015, at the Cleveland Clinic. We had to be there from Sunday night April 19, through Thursday morning, April 23.  My mom graciously stayed with the kids.  Monday was a long day, beginning with testing at 7:15 a.m.  He took the first dose of the drug:  200 mg or 2- 100 mg tablets with food  around 9:00 a.m. with hourly tests of EKGs and blood draws for 10 hours beginning shortly after.  His blood counts were low that day with his hemoglobin at 7.6; whites .47; platelets 34,000; and ANCs/neutrophils too low to count.  So, once they checked the protocol to make sure it was alright to give him blood during the testing, they ordered him two units of blood to be transfused while he was there.  We finished that day around 7:00 p.m.

The next morning, Tuesday, April 21, we had to be there around 8:30 a.m. for lab work and testing.  No drug was given this day.  The protocol called for one dose on Day -3, which was Monday, then to do testing and evaluations for the next 72 hours.  So, we had to go back Wednesday for another easy day of morning testing and no medication.  Thursday, April 22, 2015 (my mom's birthday!) was considered the official first day or Day 1 of the trial drug.  It too was a relatively easy day.  We were able to finish up early and head home.  For all the months and preparation leading up to beginning the trial, three out of the four days we were relatively uneventful!

Overall, we are pleased with how everything went at Cleveland Clinic.  Todd got to see his bone marrow transplant doctor on Monday and Thursday.  I love the research nurses Ashley, Samantha, and Chad.  They were very good to us.  The Cleveland Clinic was able to fund our hotel stay for this initial visit at a nearby hotel between downtown Cleveland and the Clinic; mainly because we were on the waiting list for the Hope Lodge, but were unable to get in.   We were able to submit travel expenses including Todd's meals and gas/mileage for reimbursement.  On all other trips, we have to pay for our hotel stay, unless a room becomes available at the Hope Lodge, but we can submit those expenses also.  God continues to provide for us!

While we were there, we visited our friend Rick, from the Transplant Floor.  He had been admitted to the Leukemia floor trying to fight his relapsed AML since March.  The chemo has taken the toll on him.  His hands and feet were peeling and yellow from jaundice.  He wasn't as responsive like normal. He has a bowel blockage and hasn't been able to eat solid foods; unfortunately, he can't control his bowels at all, they believe that is also a side-effect of the additional chemo.  He has to have platelets and blood transfusions every day!  They are also giving him potassium for his brain.
As a follow-up, I talked his wife on Wednesday, April 29, and they were in the process of moving him to hospice closer to home.  The doctor said he may have 2 weeks to 2 months to live.  He has 50% blast cells in his blood stream, and does not have the same gene mutation Todd does, which makes him ineligible for AG221 drug study.  Please pray for him in his last days and for his family as they go through this difficult time.  

Todd had to have routine blood work done on the following Monday, April 27, 2015.  We were afraid he was going to need a transfusion, because he had been feeling fatigued the day before and spent most of the day in the bed resting.  To our surprise, his numbers were good!  He needed no transfusion since his hemoglobin count was at 8.8. His white count went up to 1.0 which hasn't been that high in weeks or months! His neutrophils were still low at .700, but at least he was above the neutropenia threshold of .500 and his platelets were at 60,000! We were praising God for these very early results. He had only taken 5 doses of the trial drug by this day and we want to believe that the increase was the result of the medication beginning to work.

The weekend we got back home, we started working on the house again, trying to get it ready to sell.  We both worked a little too hard and too much, but not without help.  That day, I had my good friend Dana come over and she went to work on helping clean out my bedroom closet, so it didn't look cramped or cluttered.  We got a lot done! Monday, I spent finishing cleaning the closet and taping up boxes and moving them out to the garage with the help of my good friend Darsie.  Tuesday, we were blessed with the help of our great friends Chris and Lynda; the guys worked outside in the yard and Lynda and I cleaned and straightened up the Piano Room and Dining Room.  We got so much done! 

In addition to working on the house, we have been selling our furniture and other items as we go.  I take photos and then we post the items online and usually spend the next day or two taking emails, texts, calls, and arranging pick-up times.  This has been a good strategy, since we are getting things removed now before showing the house and before I attempt a garage sale (which is so much work in relation to how little people are willing to pay). 

By Wednesday we needed a break! We had to pack for our trip to The Cleveland Clinic, but at least I was able to help Ellie pack up some keepsakes in her room before leaving late that night.   Thanks to Todd's mom Ann and our former neighbors Joni and Raymond, for all the boxes and packing materials!

We arrived around in Cleveland around 11 pm last night and hit the bed, since we had to be at the hospital the this morning, Thursday, April 30 before 7:30 a.m.  The day's appointments went well.  Todd saw his doctor and the research nurses got busy asking their questions, doing the EKG and blood work for the trial study.  He was scheduled to have a transfusion today if his hemoglobin was below 8.5, but we learned that it was at exactly 8.5, so everyone was in agreement that since Todd was feeling pretty good, they were going to hold off on transfusing him for today.  The rest of his numbers were down slightly, his whites went down to .830; his platelets down to 41,000; and the nurse contacted us later with the other numbers, namely his neutrophils, which have dropped to .530 making his nearly neutropenic again.

What's Next?
He is scheduled for routine blood work every Monday at the local oncologist's office, so we will see how his counts are on Monday, May 4, 2015.  If he needs transfused, the local oncologist will make arrangements for him at Miami Valley  Hospital before his next appointment at the Cleveland Clinic on Thursday, May 7, 2015.  This is going to be another long day of tests, because it is Day 15, or about the half-way point of the Cycle 1 of his drug trial.  In addition to hourly blood draws for 10 hours, he will have EKGs, and a bone marrow biopsy (his 15th? I think, he has had so many, I have lost count). They have also scheduled a treatment appointment for transfusion, if he hasn't had one by then and needs one. The protocol of taking the drug with food will also change at this point.  Instead, he will have to fast for 2 hours before taking his scheduled dose at 9:00 a.m. and then wait for 1 hour after taking it before he can eat.

The only concern so far is his bilirubin levels, which were elevated, however, even this is expected in the beginning.  The research nurse assured me that these levels typically come down as time goes on.  They are not concerned about these levels because his liver numbers and the direct bilirubin numbers both looked good.  They only thing that I noticed today, was a slight yellowing in the corners of his eyes; the nurse agreed that there was a slight bit of yellowing, but that this is a known side-effect of the drug.  If it gets too high, they will interrupt the dose or decrease it, but that his current levels are no where near needing any of those adjustments now.

On a personal note, we will continue to work on getting our house ready to sell.  Which means, I will be enlisting another round of volunteers to help me inside get things de-cluttered and cleaned for showing.  Todd won't need much more help outdoors, but mainly indoors, with a bit of painting projects, changing light bulbs inside and outside (some days I don't want him on a ladder), and repairing a bit of drywall.  Tomorrow, I'm going to help our oldest daughter Abby finish moving things out of her dorm room.  I can't believe she is done with her Freshman Year of college already!  I need to work on preparing a graduation party for Hannah Lewis, including buying decorations, ordering food, etc.  Ellie's last club volleyball tournament is this Saturday: yahoo!  And track season should be ending soon too.

Please pray: 

• That we can get our house on the market in about two weeks.  The market is still hot and we can't really buy or write a contract on anything til we have ours sold.
• That Abby and Hannah Lewis find jobs soon.
• That I can get get the majority of packing and selling done before I start summer classes in June.  I also have to turn in my application for a fall practicum by June 6 or so, and I don't have one lined up yet.  If I can't do this, I won't be able to graduate by the end of the year. 
• Continued improvement of Todd's health and stamina; namely, that the drug will begin to help his counts go up and the need for transfusions go down.
• Family issues and dynamics as we continue to undergo weekly family counseling
• That the transition of moving to go smoothly.  That God would open and close doors: find the right buyer for our house and the right house for us to buy.  We have been struggling to find  a house that isn't too big or too small that will give us enough financial breathing room while Todd is on disability and I finish my degree.  The physical demands of moving and the emotions of giving up our home and most of our belongings is traumatic, even though we understand they are just material.  This is the only home Ellie has really known and both of her siblings will be gone at college this fall; all this will be a big adjustment for her. 

As you can tell, there is just so much uncertainty in our future.  We are doing our best to take things a day at a time, but with such upheavals and the constant concern for Todd's health, me and the kids are feeling a bit anxious and emotional. (Not Todd, he is in a different place than we are!). We understand the wisdom of asking God to give us just what we need for that day, and not to worry or be anxious about everything else, but we need reminded!  We also understand that we need to take these feelings to God through prayer and that he will supply all of our needs.  Please pray with us.

As always, we appreciate your love and outpouring of concern and support.  It means so much, to see our friends and family helping us through all of this day by day.

AG-221 Trial Study: The Recommended Treatment

First, allow me to apologize for the delay in getting this post written.  At first, we needed time to take everything in.  Second, I began to suffer a severe migraine and ear ache for several days now, and was out for the count.  I couldn't focus on a computer, phone, or any reading the first few days.  I broke down and went to the doctor and got a message on my head, neck, and shoulders.  I am being treated for possibly TMJ (from clenching my jaw in stress) and a possible sinus infection, although the doctor thinks that my symptoms are mainly the result of stress.  (You think!) 

We received a call from Todd's BMT doctor Wednesday evening about 5:30 pm, February 25, 2015.  She called our home phone, which is unusual, and I walked in while Todd was on the phone with her.  He put the call on speaker so I could hear. 

She told me that she had conferred with her colleagues, the other bone marrow transplant doctors, and they came to the consensus that they were NOT in favor of doing a second stem cell transplant at this time.  We were a little shocked, knowing this had been her intent since December, 2014, once Todd's relapse was discovered.  Even now, she did not necessarily "agree" with this choice, but felt she needed to defer to the majority who would rather Todd pursue the trial study for the drug AG-221, because they felt like that would provide the best outcome for Todd, considering the aggressiveness of his disease. 

I knew from my own research, that the success rate for second transplants was not good, but I never wanted to discourage Todd, and after talking to his doctor back in December, we both agreed to be positive and hope for the best; that Todd was NOT a statistic, and that his case has not been textbook MDS from the beginning.  However, this ugly fact had to be considered now when determining his treatment options.

The doctors were not that impressed that his blast counts had been reduced from 7% at the time of relapse to his last biopsy which showed 3% blasts.  Because Todd relapsed within those critical 100 days post-transplant, and that after three rounds of Vidaza,  his disease was still present, they didn't think a second transplant would be successful.  This was devastating news all the same.  For the past three months, we had been pinning our hopes on this second transplant, and now they didn't think it had a good enough chance to work.  I asked why the change in that thinking.  She told us the success rates for second transplants with an aggressive disease was in the "teens."  I somewhat knew this, but had hoped Todd's case would be different.  He is younger and healthier than most of the patients who are in published studies; most are about 60 years old.  These odds are not very good, and they didn't want to set the transplant up for failure.  She said that with his chimerism at 75% of recipient cells (Todd's original bone marrow) and only 25% of his brother's bone marrow left, and with still have disease present (3% blast cells), they would have to do some type of intensive chemotherapy prior to the second transplant to suppress Todd's diseased bone marrow, for there to be any hope of success.  Then, he could get a bad case of Graft versus Host disease on top of the transplant not working, making his overall health condition even worse. 

She said that the only reason they do second transplants, even though the odds of success are so low, is that up until now it has been the only main option, apart from the Donor Lymphocyte Infusion (DLI), which Todd wouldn't be considered for, since his disease is still present (not an aggressive enough treatment).  But, now they have another option: The drug AG-221 in phase 1 trial studies.  The doctors at Cleveland collectively agreed that this drug would be Todd's best chance of controlling his disease.  It would NOT be the "curative" treatment, like the second stem cell transplant, but they have  had success with it controlling the disease and achieving "complete or partial responses."  This is the reason that his doctor was not in favor of the drug versus the transplant, because she said that knowing us so intimately, she wanted to go for the curative treatment. 

Todd asked her if she had been "overruled" by the other doctors in the department, and she said she didn't want to use that word, but that the other doctors were in a position to be much more objective than her.  They all felt it was a better option, to get the most bang for the buck, and help further research in the field, which made us feel like the other doctors just wanted to "guinea pig" Todd by enrolling him in the study.   This didn't sit well with us. The lack of confidence that she had in this decision troubled me.

She encouraged us to get a second opinion and that she would refer us to another physician at another research and BMT hospital.  In addition, they would still consider doing a second transplant at some point, if they could continue to "prove" that he can fight the disease, gaining more time between his last transplant and a future transplant: translation, that he can stay alive long enough and his condition improve enough to justify the second transplant.  Which, they feel is a good possibility if he could start taking the trail study drug: AG-221.  A good number of patients, most 60 years or older, who have not been candidates for a bone marrow transplant have sustained complete or partial responses to the drug since they have been on it.  More about this later.

As to pursuing the study, we would have to wait for the rest of the bone marrow results to come back, which includes cytogenics and the test confirming that Todd still has the gene mutation, IDH2 which is required to be enrolled in the drug study.  After suggesting this study to his doctor a while back, she investigated and found that Todd did have this gene mutation prior to transplant, when he was enrolled in a study with his oncologist at Cleveland Clinic after his diagnosis.  So, the study hospital  needs an official confirmation of this before Todd could be enrolled.  We all agreed that it would do us no good to pursue a second opinion or seek to enroll until we got these results back, which would take another week. 

We also needed to consider where he would enroll in the trial.  The Cleveland Clinic has applied to participate in the study, but it has not yet been approved.  Of course, there a multi-step process that the hospital must go through to obtain this approval.  She said it could take a month, or even longer to get this approval.  In light of this, she suggested that Todd could do another round of Vidaza, to keep his blast counts down, and then revisit the status afterwards.  The only problem with this, they still may not have the approval by then, which would put us in the same situation we are in now.  The closest hospitals that are enrolling patients are in Chicago and Nashville (Vanderbilt), both about six hours away.  We would not be required to stay during the entire trial, but we would have to return for tests at designated points in the study. 

Cleveland would obviously be closer at 3-4 hours away, but I hate to think about delaying treatment for another month or more with Todd's low counts, low energy levels, susceptibility to infections, and requiring blood transfusions every week. 

Concluding the conversation, this was the plan:
1.  Wait until next week, when all the test results were in, including the genetic test confirming the IDH2 gene mutation.  Without this confirmation, Todd would not be eligible for the study at all.  Then would have to go for the second transplant.
2.  If the results show he still has the IDH2 mutation, we will be seeking a second opinion at Vanderbilt Hospital in Nashville.  The BMT doctor will refer us to a doctor there.  We decided if we were going to get a second opinion, that we might as well have it done at a place where they are currently conducting the trial drug study, so that we could get feedback about how well it has been working.  If I had the money to fly often, I would rather go to Memorial Sloan Kettering in New York where the lead doctor and investigator, Dr. Eytan Stein is at.  He has been working with the drug the most.

So, with all this thrown at us in a matter of minutes, we were overwhelmed, sad, and heart broken.

We kept discussing the conversation that evening, questioning their recommendation.  We refuse to allow Todd to be a guinea pig.  I got up the next morning and decided that WE were going to make the final decision about what treatment he would do.  If we wanted to go for the second transplant, we would tell them that was our choice, and if they refused to do it, then we would go somewhere else.  

Still feeling like I needed more information about this decision, I began a further investigation into the drug and the trial study.  I'm so glad I did. 

About the Drug
The drug AG-221, is a pill that is taken over the course of 28 days per cycle.  Tests to check progress would include bone marrow biopsies, blood work, liver tests, etc.  After talking to the doctor that night, I was under the impression that the drug would work similarly to Vidaza, in regards to still producing low blood counts, but after further research, I don't believe that this is the case. 

After going on various websites, I found where Dr. Stein had presented his findings at the most recent ASH convention in December, 2014 on the drug company's website (Agios).  When I heard him say that patients taking the drug were responding in as little as one cycle, and that their blood counts had come up while blast counts had been reduced, I jumped for joy.  He cites one case where a patient's blast counts had gone done from 44% to 12%; Hemoglobin increased from 10.9 to 11.2; Platelets increased from 29,000 to 106,000; and ANCs went from .1 to 1.3!  (Stein, 2014, slide 28).  He even goes on to explain that even partial responses had to have platelets over 100,000 for it to be considered a partial response. This is so much better than what Todd is living with now (Platelets running 10,000-25,000)!    Here is the link if you are interested in this brief presentation.  Start at slide 18 and end at slide 29.  It does take a Shockware plug-in I believe to watch, but it shouldn't be an issue for most.
http://edge.media-server.com/m/p/s4b9a35f/lan/en

Key information: 

• Patients even on the lowest doses have received some response. Many have had relapse of their disease after a bone marrow transplant. 
• This Phase of the trial is to help determine the amount of the drug patients can take with minimal toxicity and still receive a response.  So, Todd would receive increased doses over time to "help determine the MTD or maximum tolerated dose and/or the recommended Phase II dose."  (U.S. National Institutes of Health. Purpose. 2015)  Retrieved from: 
  https://www.clinicaltrials.gov/ct2/show/NCT01915498?term=AG221&rank=3
• We are guaranteed certain rights, like they have to tell us which amount he will be given, he can stop or quit the study at anytime, and if they prove that a certain amount is the most beneficial, they can stop the trial and give him the appropriate amount.  (Memorial Sloan Cancer Center, 2015)  Retrieved from: http://www.mskcc.org/print/cancer-care/clinical-trials/how-decide-whether-clinical-trial-right-you  They have yet to reach a maximum tolerated dose yet. 
• The drug company runs the study at the designated hospital, under the care of a primary investigator (doctor) and co-investigators (other doctors), which can be a bit scary, but on the positive side, all of the costs of the drug, tests, and hospital expenses are paid by the drug company.   
• The job of the drug is to block the enzyme that allows the cells to mutate.  Therefore, it allows a good number of the blood cells to mature to healthy functioning cells. Thus, higher blood counts and lower blast counts.  Here is another great article that features information from Dr Stein.  http://www.targetedonc.com/conference/ash-2014/ag-221-sparks-durable-remissions-in-idh2-mutated-aml/2

 Of course, with any study, there are bad results too.  There have been some that have died from disease progression, or other causes and some that have not had any response.  But, a majority have done well.  With every treatment comes risks, but also the hope of remission.

In conclusion:

At this point, the only other step to the above discussed treatment plan, would be another addition:

3.  If the second opinion is the same, to pursue the trial drug study, then I think we will likely enroll soon thereafter at Vanderbilt, instead of waiting for the Cleveland Clinic to get approved.

Of course, all this is subject to change, in light of further information.

Thanks for your patience in waiting for me to get this posted and for the length of the post.  I will give another update when we have further information.  In the meantime, I expect that Todd will need another transfusion before Wednesday of this week.

We covet your prayers and support,
Kimberley

Other information about AG-221:
On YouTube:
https://www.youtube.com/watch?v=Pnkr2gZfr64

http://ashclinicalnews.org/trial-roundup-december-2014/

http://www.agios.com/pipeline-idh.php

http://investor.agios.com/phoenix.zhtml?c=251862&p=irol-newsArticle&ID=1916041&highlight=

Bone marrow biopsy and results

Todd and I went to the Cleveland Clinic on Wednesday, February 18, 2015 for treatment, a bone marrow biopsy, and to see his BMT doctor. We left Dayton around 5:45 am driving through thick snow and slick roads. 

His counts were in the pits, needing another blood transfusion, less than a week since his last one. His hemoglobin was at 7.3; white count was .300 and his ANCS were too low to count. His platelets were hanging in there at 29,000. 

The bone marrow biopsy went fine, but it took hours to get the blood he needed from the blood bank. Apparently, there was an emergency in the ER in which a lot of blood was needed. So all non-life threatening requests had to be stayed. He didn't get to start his first unit of blood until after 4:00 pm. 

Meanwhile, the doctor had to come down to his treatment room for his appointment. There wasn't a lot to discuss until the bone marrow biopsy results were back. We discussed possible scenarios for treatments speculating with what the results could be. We were told to expect her to call with preliminary results by Friday evening, but not to expect a definite treatment regimen until she had a chance to confer with the other BMT doctors at their Monday conference session. 

We got home after 10 pm. Exhausted from the long day. The weather was so bad school had been cancelled back home for our daughters that day. It was cancelled for Thursday too, due to the extremely low temperatures. Our daughter, Abby, at the University of Cincinnati came home to visit since her classes had also been cancelled all week. 

Friday morning we mustered all of our energy and headed to Savannah, GA for a college visit for our daughter Hannah. 

We got the call from his BMT doctor while on the road about 5:30 pm. She told us the preliminary results showed that the chemotherapy Vidaza treatments were able to get his blast counts down from 7% after the transplant to 3% now. We were pleased to hear that even though his counts weren't lower (>1-2%), that they could still proceed with further treatment, most likely a second stem-cell transplant. The possibility of just doing the Donor Lymphocyte Infusion (DLI)  of white T cells would likely not be an option. Instead his doctor is leaning towards the second transplant using some chemotherapy to suppress his original diseased bone marrow, so his brother's additional cells can gain the upper hand. 

She also brought up the trial study option  we talked about earlier, the drug AG 221.  She said that the Cleveland Clinic has been in the process of getting registered to do the study, and that they were hoping to have it available soon enough to treat Todd there. So, needless to say, I'm going to do some more research about this study. 

Overall, I was encouraged by this news and I can't wait to hear the other results of the biopsy as they come in. They are checking his genetics again for the trial criteria, his cytogenetics, and chimerism. I'm anxious to hear her final recommendations too. I'm assuming that if they do the transplant, that it will happen in the next 2-4 weeks. 

Todd reacted to the news differently. The day we were at the hospital and his doctor brought up the trial study, he said it bothered him to hear talk of enrolling him in a trial.  He feels trials are for patients with no other options. Today, his first reaction was to express a desire to do another round of Vidaza. But, I explained that I had read that the sooner a patient has a second stem cell treatment after relapse, the more success they have.  So, I really feel like time is of the essence here. His doctor, I think feels that Vidaza has done what it was meant to do, but that for now they need to proceed to the next treatment. 

I reassured Todd that there are a few options left. The second transplant, another medication Revlimid if he continues to have just the 5q deletion, and the trial. Although the trial sounds scary, many patients have been fortunate to be cured or put into remission by having the advantage of being in one. 

I asked about whether the multiple transfusion would interfere with his treatment options and her answer was no. That most MDS patients need transfusions like this. Todd had just been fortunate enough to not need them early on. The only detriment of the many transfusions is that Todd will accumulate iron in his blood that maybe over heathy limits. I asked about using chelation therapy to remove the excessive iron but she said that most doctors have found that it doesn't help and that at the Cleveland Clinic they don't even monitor his iron levels. It is a concern, because excessive iron can build up over time causing damage to vital organs. I guess, in the BMT doctor's mind though, this is a lesser priority than trying to get rid of the Cancer and/or staying out of danger from the detriments of low blood counts. 

There is so much more to write but I'm already behind in getting this posted. I will try to post again soon about the trial drug, our current financial situation, and other concerns. 

Thanks for your continued support.