Lenalidomide Clinical Trial

[Data]

I was offered the opportunity to participate in a Phase I clinical trial today. The consent form states:
________________________________________________________________________________
The purpose of this research study is to evaluate the safety and maximum tolerated dose of a drug called lenalidomide in patients with acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS), with minimal residual disease (MRD) following allogeneic hematopoietic stem cell transplant (allo-HSCT). This study will look at: any side effects that occur, the effectiveness of the study drug, and how your disease reacts to lenalidomide. This study will try to find the highest tolerated dose of this drug without causing serious side effects. This study will also look to see how your cancer responds to the drug using laboratory tests. Allogeneic HSCT is an effective treatment for high risk AML and MDS, however relapse following transplant continues to be a major obstacle to treatment success and cure. Treatment of relapsed disease is more successful if started earlier when disease levels are lower. This study will use a laboratory test called CD34+ donor chimerism to detect MRD following your allogeneic HSCT. MRD is the name given to small numbers of leukemic cells that remain in your body during and after treatment, even when you are considered to be disease free. The CD34+ donor chimerism test may be able to detect relapsed disease earlier than traditional methods and allow us to treat you sooner.
________________________________________________________________________________

Has anyone heard of using lenalidomide in this manner? I believe this particular trial is only being conducted at UF Health, Gainesville, FL. My dose would be 2.5 mg once daily orally on Days 1-21 of repeated 28-day cycles ( the study would only consist of two cycles). One aspect of the trail that intrigued me was the CD34+ donor chimerism because it might give me a better indication of my chances of relapsing.


Any comments are greatly appreciated!!

Cheers

Data

[Neil Cuadra]

As you probably know, lenalidomide (better known to most of us by its trade name Revlimid) has been a successful drug for the subset of MDS patients with "deletion 5q" syndrome. Researchers want to know the other circumstances where Revlimid can be beneficial, such as patients without deletion 5q, or in this study post-transplant patients.

The higher the clinical trial phase, the more likely that participants in the study will benefit themselves, not just contribute to scientific knowledge. Usually a Phase I trial is studying safety, side effects, and how a drug is metabolized and excreted, a Phase II trial is studying effectiveness against a disease (compared to "standard treatment" or no treatment), and a Phase III trial is studying dosages, but these aren't always the case. This trial seems to be combining these goals.

I think it's worth a frank discussion with the study sponsors about what they expect to learn from the trial and what the benefits vs. risks are likely to be for you.

[DanL]

Data,

Although cd34+ is a measurement of how well you are engrafting, it does not necessarily correlate closely to relapse. Also, getting the donor chimerism numbers can and usually is done periodically after transplant without going through the trial.

As Neil stated, the safety and efficacy of revlimid is pretty well documented in MDS as it is one of only 3 drugs currently approved for the treatment of MDS, but its approval is limited to the -5q patients. In non -5q patients, it has about a 25-30% improvement rate in lower risk patients primarily. One interesting note is that even when it does not work from a clinical perspective - ie improvement in blood counts - it sometimes has the effect of removing chromosomal abnormalities.

Revlimid typically helps RBC, but benefits are also seen in patients in the platelet and wbc lines as well. If I recall, revlimid may also have some positive benefit in patients with fibrosis. I know that many years back I read a study that showed this as a potential benefit.

Revlimid is known as an immune modulatory drug, but its actual mechanism of action isn't really clearly understood at this point from what I know.

Like Neil, I think that it is very much worth a discussion with your doctor as a potential option, especially since I think you were considered high risk at transplant. The 21 day dosing cycle sounds like the standard cycle for Revlimid, but I don't know anything about the dosing level.

Please share any information you can about the trial when you get more information, and as always, good health and strong recovery to you!

Dan

[bailie]

My experience with Revlimid (lenalidomide) is that I took it along with Vidaza for my last three cycles before SCT. I felt zero side effects from it. I took it 90 days straight before the transplant.

[Data]

All,
The consent form clearly stated there was no direct benefit to me but the indirect benefit is I am learn whether I am likely to relapse or not and the lenalidomide could stall that for a while.

As far as the chimerism test, this isn't the one that is done routinely after a transplant. It was one that was developed at UF Health and is supposed to be much more accurate and predict relapse.


Cheers

Data

[DanL]

that is odd. we ran chimerism tests every three months for me.

[PaulS]

Hi Data - hope your faring well and the GVHD is getting better...

For what its worth... We discussed using Vidaza as a post transplant maintenance drug - I was skeptical since I didn't respond prior to transplant ... but in any event my platelets were low - and still are only around 100 - so my Dr. didn't want to do something that would lower my platelets even more.. now at 8 months he said that by the time my platelets rose high enough to consider Vidaza it'd be so long post transplant that the risk of relapse would be low in any event - so it looks like no Vidaza for me. He also thought the GVHD I had might also help prevent relapse...

Here are a couple questions you might consider asking:

1. There has been some research using Vidaza post transplant - and I think at least some transplant centers are starting to use it, at least in some cases - but I think it still is experimental -- I'd ask your doctor's their feeling about Vidaza v. Revlimid post transplant - and why they think Revlimid would be as or more effective? Is there any data yet from trials using Vidaza? Since Vidaza seems to work best with most MDS it makes more sense to me to try that drug first...

2. If they have a better test for chimerism/relapse - why don't they use it on all patients?

Did you discuss the abnormal blood morphology? Does that make your doctor more interested in trying the Revlimid?

Revlimid does seem to be well tolerated from what I have read - so you'd probably be OK trying it ... but not necessarily an easy call.

Stay strong!

Paul

[bailie]

My chimerism has been at 100 percent donor from +30 days until now except for a couple of months at about Day+210 when I relapsed and chimerism dropped to 85 percent.

[Data]

Originally Posted by DanL

that is odd. we ran chimerism tests every three months for me.

Dan,
This is the not the normal chimerism test. It is one developed at UF Health and is supposed to be much more accurate.

Data

[Data]

Originally Posted by PaulS

Hi Data - hope your faring well and the GVHD is getting better...

For what its worth... We discussed using Vidaza as a post transplant maintenance drug - I was skeptical since I didn't respond prior to transplant ... but in any event my platelets were low - and still are only around 100 - so my Dr. didn't want to do something that would lower my platelets even more.. now at 8 months he said that by the time my platelets rose high enough to consider Vidaza it'd be so long post transplant that the risk of relapse would be low in any event - so it looks like no Vidaza for me. He also thought the GVHD I had might also help prevent relapse...

Here are a couple questions you might consider asking:

1. There has been some research using Vidaza post transplant - and I think at least some transplant centers are starting to use it, at least in some cases - but I think it still is experimental -- I'd ask your doctor's their feeling about Vidaza v. Revlimid post transplant - and why they think Revlimid would be as or more effective? Is there any data yet from trials using Vidaza? Since Vidaza seems to work best with most MDS it makes more sense to me to try that drug first...

2. If they have a better test for chimerism/relapse - why don't they use it on all patients?

Did you discuss the abnormal blood morphology? Does that make your doctor more interested in trying the Revlimid?

Revlimid does seem to be well tolerated from what I have read - so you'd probably be OK trying it ... but not necessarily an easy call.

Stay strong!

Paul

Paul,
The chimerism test they have developed is in clinical trial. It is also supposedly very expensive. Have not talked to the Doc about the morphology yet.

Data

[Data]

I enrolled in the clinical trial. I will have the blood drawn for the first (of three) "CD34+ mixed chimerism analysis" on Tuesday, 7 June. The results are supposed to be back in approximately 1 week. If the chimerism is less that 90% the study literature (consent form) says I will start the Lenalidomide at 2.5 mg for a 28 day cycle (taking the drug for 21 days and then skipping 7 days till the next cycle begins) within 5 days.

This is not the normal chimerism test that is routinely done and not "standard of care". It is a test that was developed at Shands at the University of Florida. I have been told it is expensive.

Cheers

Data

[bailie]

I had lenalidomide for three months before SCT and had zero side effects from it.

[Data]

Originally Posted by bailie

I had lenalidomide for three months before SCT and had zero side effects from it.

Bailie,
Thanks for the info.
What dose were you taking?
Also, lenalidomide is typically used for MDS/Del 5Q. If you don't mind me asking, why were you getting lenalidomide if your MDS was RAEB-2?


Data

[bailie]

I can't remember the dosage. The reason, "We want to add Revlimid to your chemo regimen to deepen the response and get the blast count even lower prior to considering transplant." At that time my blast count was less than 5 percent.

There have been several studies the positive effects from the combination of Vidaza and lenalidomide in higher-risk myelodysplastic syndromes and AML.

[DanL]

Data,

I do recall seeing a study that Bailie was referencing that showed a response rate of up to 70% when Vidaza was used in conjunction with Revlimid in RAEB - 2 patients.

Revlimid trials in non-5q patients have had overall improvement in 25-30% of participants, with almost all of the success coming from patients that fell in the intermediate and lower risk categories - almost no positive response in high-risk patients without the -5q.


All of this from memory, so I wouldn't quote it as gospel, but I believe my memory to be correct here.

Also, I was curious as to what additional information they were trying to obtain by having a more accurate chimerism test. It seems like you are pretty much 100% donor, or you are not, and you are either trending toward it or away from it, so what is the benefit of knowing down to a more precise percentage? When I have seen other members post a chimerism that was falling or rising, it was usually pretty precipitous in decline, and firmly upward when rising.

Good luck on the trial and keep us posted on your progress.

[bailie]

REVLIMID® and VIDAZA® Combination Therapy Achieves Nearly 30 Percent Complete Response in Untreated Elderly Patients with Acute Myeloid Leukemia

In the phase II investigator-initiated study, patients received azacitidine 75 mg/m2/day, days 1-7 followed by lenalidomide 50 mg/day, days 8-28 of 42-day cycles. Treatment was continued until disease progression, unacceptable adverse event or completion of 12 cycles.

With 42 patients enrolled in the study, the overall response rate was 41%, with 28% of patients achieving a complete response (CR/CRi). The median time to CR and CRi was 12 and 6 weeks, respectively; the median duration of response (CR/CRi/PR) was 28 weeks (range 6 to >104 weeks). Median overall survival for all patients in the study was 20 weeks (range 1 to >121 weeks) and 69 weeks (range 10 to >121 weeks) for patients who responded to therapy. Additionally, median overall survival for responders was superior to non-responders (69 vs. 15 weeks p<0.01).


http://ir.celgene.com/releasedetail....leaseid=795214

[bailie]

Another,

Phase 2 study of the lenalidomide and azacitidine combination in patients with higher-risk myelodysplastic syndromes



Lenalidomide and azacitidine each have activity in myelodysplastic syndromes (MDS) patients, where both microenvironment and cell-regulatory mechanisms contribute to disease pathogenesis.

The overall response rate (per modified MDS International Working Group criteria) was 72%: 16 patients (44%) achieved a complete response(CR),and 10 (28%) had hematologic improvement. Median CR duration was 17 months (range, 3-39); median overall survival was 37months (range,7-55)for CR patients, and 13.6months for the entire cohort (range, 3-55). TET2/DNMT3A/IDH1/2 mutational status was associated with response in a limited number of patients. The lenalidomide/azacitidine combination is well-tolerated and highly active in treating greater-risk MDS. This study is registered at http://www.clinicaltrials.gov as NCT00352001. (Blood. 2012;120(25): 4945-4951)

http://www.bloodjournal.org/content/...o-checked=true

[Data]

Originally Posted by DanL

Also, I was curious as to what additional information they were trying to obtain by having a more accurate chimerism test. It seems like you are pretty much 100% donor, or you are not, and you are either trending toward it or away from it, so what is the benefit of knowing down to a more precise percentage? When I have seen other members post a chimerism that was falling or rising, it was usually pretty precipitous in decline, and firmly upward when rising.

Dan,
I think anytime you can have a more accurate test, it is to your advantage. I think that is the idea behind the test in this study. Their idea is a that a chimerism of less that 90% or one that is falling is indicative of a higher chance of relapse. If the test is more accurate, it would follow that the prognosis of relapse would be more accurate.

Cheers

Data

[bailie]

It is interesting that I was 100 percent donor (chimerism) from Day+30 until Day+210 when I relapsed. At Day+210 I had a lung infection/lung surgery and 160 mg/day of prednisone. I really think I was totally vulnerable (perhaps short telomeres) at Day+210 and that caused the relapse. My relapse was completely different in personality than my previous status before SCT. Since Day+210 I have come back to 100 percent chimerism and have remained 100 percent for about 18 months.

[PaulS]

Hi Data - good luck with the clinical trial - when do you start?

How are you feeling now? How are your counts? How's the GVHD fight going?

This was a tough period for me - hope you're doing well.

Paul

[Data]

Originally Posted by PaulS

Hi Data - good luck with the clinical trial - when do you start?

How are you feeling now? How are your counts? How's the GVHD fight going?

This was a tough period for me - hope you're doing well.

Paul

Paul,
I did start the trial. They took the blood sample yesterday and I should know within a week if I will be getting the lenalidomide or not. They pretty much have the GVHD under control - it isn't getting any worse and it is vastly improved from when I first had it. My platelets took a nose dive and the doc is working on that - he said he will probably adjust my meds on Friday. I currently have two viruses - CMV and BK - that they are working on. I am still just incredibly tired. I wish I had never opted for the transplant.

Cheers

Data

[DanL]

Data,

I am sorry about the trials that you are facing. I had BK for several months which wasn't pleasant. I have been fortunate enough to avoid CMV thus far, but from what I hear, it is exceptionally common in MDS patients, and from what I read, about 62% of the population tests CMV positive by the age of 50 - meaning that they have CMV antibodies present.

Try to stay positive. It is said that the night is darkest just before the sun rises. I am about 27 months since transplant. I have relapsed, had acute and chronic GVHD, had 1 hip replaced and will do the other one next month due to avascular necrosis - shoulder will probably follow. I have had cataract surgery on the left eye, the right eye is next week. I was hospitalized for 85 or so days last year after not being hospitalized for a single day during the first year after transplant. I had PCP (pneumocystis pneumonia) cellulitis, random infections, and was put on so much oxycontin and oxycodone, that I was told that most elephants would not survive the dosage.

My point here is that transplant can be a rough process. My circumstances are admittedly different than yours, but there is not a day that I regret my decision to have the transplant, and there is not a day that I wake up that I am unable to appreciate the opportunity to live that I have been given.

Know that you are going to get through the difficulty and that you are going to live out a strong healthy life when you are done. Do the best that you can each day, accept the limitations that you have for now, push the boundaries as far as you can without putting yourself in danger.

Please know that my intent is not to be preachy, but to hopefully provide some encouragement during the challenges you face. You can win each day, and sometimes that means getting out of bed, enjoying breakfast or lunch (depending on when you woke up) and then watching some tv, hopefully laughing a bit. Other days you make it to the gym, exercise, sweat a bit, and then go golfing afterwards.

You can do this and make the disease sorry that it picked you to torment.

Dan

[Data]

Dan,
I appreciate your thoughtful post. I think I have a fundamentally different outlook on life. I value quality more than quantity. I would rather have two years of quality time than five years of just being alive. My outlook is in contrast to others that influenced my decision to have the transplant. Please don't get me wrong - I made the decision and I am the one responsible for it. I just should not have based my decision on what others wanted. I rarely ever give advice to anyone but if I were to, I would just simply say "make your decision based on your desires and objectives and stick with it". If the other people don't like the decision that is their problem.

Again, I appreciate your thoughts and admire you for your courage. You have been through a lot and to have such a positive attitude is admirable. I wish you well.

Data

[bailie]

Well said, Dan. Data, as you realize, we are all different in our situations. My situation (RAEB II) was that without a SCT I would be lucky to live seven or eight months and it would not have been a "quality" seven or eight months. I can understand your thoughts if someone would have told me that I would have had a quality two years, but all of the information I read that would have been impossible to guarantee. I was a math major in college and the numbers just weren't there to accept a short period of "quality" for the possibility of longer term of life. From what I determined that "short term" quality" could be anything but "quality". As it has turned out, these last two years have produced more quality than I thought possible. I have learned more about things from a totally different perspective than I have ever been exposed during my previous life. I will admit that I am not a "glass is half full" person. I don't develop false positives just because, but at the same time I don't let negatives diminish the effort.

I wish you all the strength to work your way through this. It is a challenge. Most of all, I appreciate the difficulties of your decisions and hope for the very best for you.

[PaulS]

Hi Data - you are going through a very difficult time in the recovery process - it was for me - I really had to learn patience - recovery takes a long time and is not a straight line. As my doctor says you did the transplant to live - not just to be kept alive - but it will take some time - recognize the milestones along the way - you lived through the transplant - you got GVHD (which will help prevent relapse) under control - your numbers are pretty good. That's all awesome. Not everyone does so well.

What helped me was setting ambitious goals for myself - six months to be skiing - then take my wife to a beach - then go to my son's graduation. With each one accomplished I felt stronger and better - next goal is to climb Mt. Whitney (highest peak in the continental US) in September and summit on the anniversary of my transplant. It keeps me focussed and forces me to notice progress - and to appreciate the ability to do things I wouldn't have been able to do without the transplant. Tell people what you want to do - makes it harder for you to not achieve them - I really didn't feel like skiing at six months and was afraid of traveling - but I had to do it or I'd let myself and everyone down - and it was great that I went. Not sure I really want to climb Mt. Whitney - but I can't back out now...

Going into transplant feeling good I'm sure was a difficult decision - but the idea of two good years and then death is probably not necessarily what would have happened - I had one good year post diagnosis and then two of slow and steady decline - gradually losing the ability to do the things I loved - hiking, biking, skiing - all got harder and then impossible - I became transfusion dependent - going to an infusion center weekly - barely able to do anything - walking to the kitchen was a chore. A steady decline filled with despair and sadness. With high risk MDS I suspect the decline would have been faster and maybe more brutal.

You did the transplant to live - not just stay alive- you are near the bottom now and should start to get better and stronger - try and stay positive and focus on your goal of being cured and healthy - try not to focus on the things that can go wrong or have gone wrong.

I really suggest you set goals for yourself - when do you want to start riding a bike - take an extended bike ride? travel somewhere - do something fun and physical that you couldn't have done if you were a professional patient dying of MDS ?? Tell yourself and everyone else what you plan to do - maybe its a long fun bike ride -The transplant Is like a long ride with some serious uphills - but trust you will get to the top and how good that will feel.

Believe me I know what its like to worry and live with depression and despair - but try and stay positive and focused on being strong and healthy and the end of all this. Attitude is really important.

I'm thinking you don't really like pep talks - but there it is anyway!

Stay strong
Paul