9 replies to this topic

[RJF]

I assume some of you have read about this, but I have not see anything posted on this site.

In brief:  Researchers in France conducted a study where CML patients who had achieved CMR (and maintained for two years), where taken off Imatinib.   60% of the patients relapsed (most within 6 months) and returned to Imatinib with success.  The other 40% remained PCRU for one full year / 38% for 2 years (and counting I assume).  See linked article for full story, there are many other articles if you search "cml leukemia" in google news.

http://www.businessw...day/644666.html

Does anyone know if there are similar studies in the US?  I would be interested to hear opinions, concerns, etc.

RJF

[CallMeLucky]

Dr. Talpaz at University of Michigan is currently doing a combnation trial with Gleevec and Peg Interferon.  The goal is for people to come off and see if they can hold the remission.  I believe in the French study,the large majority of the individuals who held their response were treated at one point with Interferon.

[tallsandwich]

I'm on this French trial (in fact I beleive it is a European trial called SPIRIT which has been executed in onther countries)

I understand there are 3 Branches in the trial, one of which involves PEG Interferon weekly, for up to one year in combination with daily Gleevec 400. After stopping the PEG you must complete another 2 years on Gleevec with no incidents and then you are can try to stop taking the Gleevec. This is what my haemotologist told me. I am being treated in Toulouse Purpan. I understood that about 10% maintain their MMR or PCU state once having stopped Gleevec in these conditions, but I am not fully up to date so please check with correct sources about exact details.

Incidently, I read that in the UK the PEG/Gleevec branch of the SPIRIT trial was stopped as they had so much trouble getting candidate patients to take Interferon Alpha.

I don't have any info on people stopping Gleevec who have not taken PEG, I only know about the protocol that I follow, so there may be more to the story :-)

I managed 14 months of PEG before I had had enough of the side effects!

[CallMeLucky]

TS,

Your information is very interesting, thanks for sharing it.  I was very interested in doing this at some point, when I first heard about it, but as time goes on, I have had mixed feelings about it.  I initially heard the amount of Interferon was very small and there were very few side effects.  When I discussed it with my doctor, she said "you know Interferon is no walk in the park, right?"  Now I hear your experience and some of the others on the trial and it makes me wonder about trying it.  I mean if I knew for sure it would work, I would be willing to tolerate two years of hell, but if they are only coming up with results like 10%, that is a big hit to quality of life for a 90% chance it is not going to work.  I still have the mindset that I don't have that many years left so to "waste" them feeling really bad with such a low chance of success makes me think it might not be worth it.

I guess we'll have to see what the results really turn out to be over the next few years.  So far I have only read limited information.  I also assume that like Gleevec side effects, Interferon probably effects everyone a little differently.  Some people seem to tolerate it okay, but most say the effects are pretty rough.

[Trey]

Those who stop TKI therapy relapse within a year or so at a fairly high rate (about 50%).  For those who have stopped TKI drugs and have not relapsed (so far), both the numbers of people and  length of time involved (2 - 3 years now) are too short to prove a cure.  It is  conjecture that the study participants are actually free of all CML stem  cells (the only true definition of a cure).  At initial PCRU, there are  still possibly 1 million CML cells in the body.  As long as there is one  leukemic CML stem cell hiding, the person is not cured.  And since CML  stem cells have shown the ability to go dormant for long periods, hiding  deep in the marrow stromal layer next to the bone, we need to respect  their ability to survive for long periods.  This is a problem with  proving any CML cure, not just this one.

The most recent study data shows that nearly equal numbers of PCRU  patients took only Gleevec as took Gleevec+Interferon.  That is not very  convincing that Interferon had any part in the results.  QUOTE: "Of  these 69 patients, 27 patients have relapsed; 13 were pretreated with  IFN, and 14 were only treated with Gleevec."  Other data showed that  Gleevec+Interferon patients were 53% of the total remaining in PCRU.   The data is statistically insignificant.

But I do not rule out anything, since this cannot be proven either way.  Some transplant patients have relapsed as many as 14 years later.  Time will tell.  Those who are PCRU for several years could likely stay PCRU for a long time without drugs.  Some other strategies for long term PCRU patients could someday be "pulsed therapy" (take drugs every other day, or every few days, or once a week) or possibly a low maintenance dosage.  These need to be investigated to before they could potentially become approved treatments.

[tallsandwich]

I read that mid-study, those who took IFN+Gleevec had a slightly higher chance of being able to succesfully stop Gleevec, but I agree that it is only a small percentage of the patients and offers no tangible benefit except for perhaps the chance to stop Gleevec for a while. I would not recommend Peg Interferon to anyone unless there was a high probability that it would have a significant impact on future prospects. I took it in order to contribute to the trial and in the hope that it might be beneficial (certainly, with the exception of the side effects it did not seem to have any negative effects on my track to a MMR etc). I read that the response was deeper and longer for those who had had some Interferon treatment, either in the past, or at the time that they started Gleevec, than those who just took Gleevec, but I don't think the results are overwhelming.

[cherylannes]

Lucky, Tallsandwich and Trey,

Interesting topic and conversation.

The Talpaz/Michigan protocol differs slightly from the SPIRIT trial.  The Protocol in Michigan looks for patients who have been on GLeevec for at least two years and are not PCRU.  They are given PEG INF at a dose range of about 180 ug of Peg IFN once a week along with the 400mg of Gleevec.  However, from talking with patients on the trial, my understanding is that the 180 ug of Peg IFN once a week is the highest dose and that this dose can be lowered to accommodate where necessary.  One patient that I know of is on 90 ug Peg IFN once every two weeks.  This is rather interesting because at a recent conference someone asked what is the lowest dose one could have PEG IFN and still find good efficacy, and my understanding was that you could go as low as 45 UG once a week.  The trick is to stay on the treatment for at least 18 to 24 months.  Anyway, the Talpaz trial requires that you maintain PCRU for two years on this combination and then you can stop the GLeevec and continue on PEG IFN or stop both, and be closely monitored.

At this years ASH there will be a presentation on Interferon from a Doctor in Helsinki,  Dr. Satu Mustjoki.  She has been looking into the immunoresponse mechanisms, or at least determining if there are indeed immune responses and trying to determine other markers that may indicate when IFN therapy has been successful enough to allow a patient to stop.

Below is an abstract to the paper and a link to the abstract.

Additionally, one of the really successful trials with combining Gleevec and PEG INF was the one done by Dr. Hochhaus in Germany.  Newly diagnosed patients were started for one month on standard Gleevec therapy, 400 mg, then the following month they added 135 UG of Peg IFN once every two weeks.  After two full years of treatment the patients were allowed to drop GLeevec, even if they were not PCRU, and continue on the maintenance therapy of Peg IFN.  5 patients relapsed and went back on Gleevec and achieved excellent results.  20 patients did not relapse and in fact, many of these patients were not PCRU but did reach PCRU after continuing with just the maintenance of Peg IFN.  I actually know one of these patients and he has been on PEG IFN maintenance for over 5 years with very minimal side effects, such as slight fatigue and irritability a day or two after injecting, which clears away in a day or two...

Because of my own situation, I have just completed over two years of treatment with reduced Sprycel (50mg) and 90 ug of PEG IFN once a week.  In my particular case this did not interfere with full time university courses and full time commitment to the running and leadership of the CML Society of Canada.  All of this whil enjoying an active healthy personal life which includes hiking, SCUBA diving and traveling...

http://ash.confex.com/ash/2010/webprogram/Paper26735.html

1201 Interferon Alpha Treated Patients with Chronic Myeloid Leukemia (CML) In Prolonged

Complete Remission Have Increased Numbers of NK-Cells and Clonal Gamma-Delta T-Cells, and a

Distinct Plasma Cytokine Profile

Oral and Poster Abstracts

Poster Session: Chronic Myeloid Leukemia - Biology and Pathophysiology, excluding Therapy: Poster I

Saturday, December 4, 2010, 5:30 PM-7:30 PM

Hall A3/A4 (Orange County Convention Center)

Poster Board I-181

Anna Kreutzman, MSc1*, Peter Rohon, MD2*, Edgar Faber, MD, PhD2*, Karel Indrak, MD, PhD2*, Vesa Juvonen, PhD3*, Veli

Kairisto, MD, PhD3*, Jaroslava Voglova, MD4*, Marjatta Sinisalo, MD, PhD5*, Emilia Flochova, MD, PhD6*, Petteri Arstila, MD,

PhD7*, Kimmo Porkka, MD, PhD1 and Satu Mustjoki, MD, PhD1

1 Hematology Research Unit, Biomedicum Helsinki, Helsinki University Central Hospital (HUCH), Helsinki, Finland

2 Department of Hemato-oncology, University Hospital Olomouc, Olomouc, Czech Republic

3 Turku University Central Hospital, Department of Clinical Chemistry and TYKSLAB, Turku, Finland

4 2nd Department of Internal Medicine, University Hospital Hradec Králové, Hradec Králové, Czech Republic

5 Department of Hematology, Tampere University Hospital, Tampere, Finland

6 Department of Hematology and Transfusiology, University Hospital in Martin, Martin, Slovak Republic

7 Department of Bacteriology and Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland

Background. Before the era of tyrosine kinase inhibitors (TKIs), interferon alpha (IFN-!) was the treatment of choice in CML

and prolonged survival of responding patients. Recent studies suggest that combination of IFN-! with TKI improves therapy

outcome. Significantly, a proportion of IFN-! treated patients in prolonged complete cytogenetic remission (CCyR) have

been able to discontinue treatment without disease relapse (Mahon et al. JCO 2002). The mechanism of action of IFN-!

therapy is incompletely understood; the drug exerts both direct cytotoxic and immunomodulatory effects on leukemic cells.

The aim of this project was to study the immunomodulatory effects of IFN-! in CML patients in prolonged remission and

isolate biological markers predicting response.

Patients and methods. The study population consisted of CML patients treated with IFN-! monotherapy (n = 10, median

therapy time 146 months, range 63-231 months) and CML patients who had discontinued IFN-! therapy but remained in

remission for >2 years (n = 9, median therapy time 120 months, range 80-184; median time without therapy 53 months,

range 24-96). None of the patients were previously treated with TKI therapy. In addition, non-CML patients (3 patients with

essential trombocythemia and one patient with polycythemia vera) treated with IFN-! and healthy volunteers (n = 43) were

included as controls. Lymphocyte populations in all four groups were characterized with comprehensive

immunophenotyping panels. The clonality of T-cells was analyzed by a TCR "/# rearrangement assay by PCR. Lymphocytes

were further sorted into CD3+ TCR !$+ and CD3+ TCR "#+ populations (n = 8). Additionally, plasma levels of 25 cytokines

were measured with a multiplex bead-based cytokine assay (Luminex®).

Results. The proportion of NK-cells from lymphocytes was significantly increased in IFN-! discontinued patients (median

26%, range 18-51%) compared to healthy volunteers (11%, 5-21%) or patients on IFN-! therapy (12%, 6-31%)

(P=0.0005). Similarly the proportion of CD8+ cells from T-cells was significantly increased in both CML IFN-! groups (55%

in IFN-! discontinued patients, 44% in IFN-! treated patients vs. 31% in healthy volunteers; P<0.05 for both groups). Also

a larger proportion of T-cells expressed the long-term memory antigen CD45RO in IFN-! patients (74%, 58% vs. 44% in

healthy controls, P<0.01). The proportion of regulatory T-cells (CD4+CD25+FoxP3+) was increased in IFN-! groups (6.1%,

5.2% vs. 3.8% in healthy volunteers, P=0.01). Similar changes in immunoprofile were not observed in IFN-treated non-CML

patients.

Clonal TCR "/# rearrangements were observed in 18 of 19 (95%) IFN-treated CML patients as compared to 3 of 22 (14%)

in healthy volunteers (P<0.01). In both IFN-! CML patient groups a unique rearrangement pattern was observed: 14/19

(79%) of patients had the V"9 gene clonally rearranged. This clonal rearrangement resided in CD3+ "#+ T-cell population,

as assessed by cell sorting. Two of four non-CML patients treated with IFN-! had the same clonal rearrangement, as well as

one healthy control (1/22; 5%). Similar clonality patterns have not been observed in dasatinib or imatinib treated CML

patients (Kreutzman et al. Blood 2010).

IFN-! treatment was associated with a distinct plasma cytokine profile in CML patients. IP-10, IL-6, IL-12, eotaxin, MCP-1,

and IFN-" levels were significantly increased in IFN-! treated CML patients. In particular, eotaxin and MCP-1 levels differed

significantly between healthy controls and IFN-! patients who had successfully discontinued IFN-! therapy (428 vs. 1173pg/ml,

P<0.0001 and 107 vs. 459 pg/ml, P=0.0003, respectively). In IFN-! treated non-CML patients, eotaxin or MCP-1

levels were not increased.

Conclusions. Our results show that IFN-! treatment induces distinct changes in the immunoprofile of CML patients. Patients

who had successfully discontinued IFN-! therapy differed markedly from healthy controls. IFN-! therapy was associated

with increased numbers of NK-cells and clonal "#+ T-cells. These cells possess potent anti-leukemic activity and may

contribute to the prolonged therapy responses in this group of patients. Furthermore, plasma cytokine profile could be a

helpful biomarker when considering which patients can discontinue the IFN-! treatment without imminent disease relapse.

Disclosures: Faber: BMS, Novartis: Consultancy, Honoraria. Porkka: BMS, Novartis: Consultancy, Honoraria, Research

Funding. Mustjoki: BMS, Novartis: Honoraria.

[cherylannes]

Lucky,

Do you really believe what you said : "I still have the mindset that I don't have that many years left so to "waste" them feeling really bad with such a low chance of success makes me think it might not be worth it."

On the contrary, you have lots of years left....It seems to me that your early reports show a very good response to Gleevec.  I have been managing this disease on either IFN alone, GLeevec alone, Sprycel alone or a mix of both Sprycel and IFN since 2000.  I do not plan on going anywhere too soon either.  In other words, you should still keep paying into your pension plan, regardless of what your age is...

There will be interesting things like JAK2 inhibitors, Hedgehog inhibitors and a few other molecules going into trials shortly, all of these are aimed at getting rid of the last leukemic stem cell....

Long and prosperous life to all of us...

Cheers!

[CallMeLucky]

Hey Cheryl,

You know my mood changes from day to day.  The cognitive side of my brain feels pretty good about things.  I know the majority do well and even of the ones who don't do "well" many of them are able to plug along.  I recently read about a CML'r who is going on 12yrs and has never been able to reach CCR yet she manages to keep going trying different things.  Still the emotional side of me still goes to dark places from time to time as I am still adjusting to this.  At only about 5 months, I feel I have learned a lot (although what I don't know is still significantly more) and so far I am responding pretty well.  I recognize I am fortunate, but I still feel like the rug can be pulled out from under me at any minute.  Plenty of people were cruising along just fine only to find their counts to suddenly drop, or FISH/PCR to increase, to any number of other things.  I try not to focus on the negative possibilities, but I also am not one to fantasize about the positive possibilities.  I believe this will play out how ever it will play out.  I know I am fortunate to have the treatment options I have and hopefully they will work for me and everyone else.  As time goes on I worry less about dying, but it still pops into my head frequently and subconsciously I think it is still very much front and center.  I'm still adjusting.

[reedgirl]

Very well said Lucky.  I feel the same way about my husband, I'm afraid to hear good news, I'm afraid to get my hopes up for fear the rug will be yanked out from under me!  I'm sure there are lots on here feeling the same. Not sure how to avoid the thoughts, probably not possible. You put words to the thoughts that enter my mind, thanks for having the courage to speak it.

Hope you can avoid the dark places in your mind and stay positive and focused

All the best,

Audrey