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Musculoskeletal Pain on Stopping Imatinib: Should We Worry?
#1
Posted 10 August 2016 - 05:13 PM
#2
Posted 10 August 2016 - 05:18 PM
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#3
Posted 11 August 2016 - 04:23 AM
Discontinuation of therapy is being explored in patients with chronic myelogenous leukemia (CML) who experience deep molecular responses after treatment with a tyrosine kinase inhibitor (TKI) such as imatinib (Gleevec). However, for the first time, a report indicates that some patients can experience musculoskeletal pain associated with imatinib even after stopping therapy.
In the Europe Stop TKI (EURO-SKI) trial, researchers found that 30% of patients who stopped imatinib treatment experienced pain in various parts of the body, according to a letter published online July 28 in the Journal of Clinical Oncology.
"This is nothing to be alarmed about, but something to be aware of. Patients who stop therapy should continue to be followed for adverse events," researcher Johan Richter, MD, PhD, from the Skåne University Hospital in Lund, Sweden, toldMedscape Medical News.
Dr. Richter and his colleagues were prompted to write their letter after reading results from the According to Stop Imatinib (A-STIM) study, evaluating clinical responses in patients with CML who had stopped imatinib treatment, which failed to mention possible adverse effects related to this strategy (J Clin Oncol. 2014;32:424-430).
In an accompanying reply to the letter, Philippe Rousselot, MD, from Hôpital Mignot, Université Versailles Saint-Quentin-en-Yvelines, in Le Chesnay, France, and his A-STIM colleagues explain that although French investigators have been examining the cessation of treatment strategy since 2007, none of the studies was designed to collect data on low-grade adverse events.
However, after reading the letter by Dr. Richter's team, the A-STIM investigators went back to their patient files and found that 4 of 80 patients reported similar symptoms on discontinuation. "Because of the retrospective nature of the collection of these data, we believe that the proportion may be underestimated," Dr. Rousselot and colleagues write in their response.
"We are currently conducting the Stop Imatinib 2 (STIM2) study for patients treated only with imatinib and are prospectively recording events of all grades at the time of discontinuation and after discontinuation," they add.
Reporting Adverse Events After Treatment Cessation
Dr. Richter and colleagues explain that they were intrigued when some patients of the EURO-SKI patients complained of musculoskeletal pain.
As a follow-up, the team initiated a substudy in which information on musculoskeletal adverse events was collected in a structured manner on specific-case report forms. Typically, such information is not collected in imatinib cessation trials, Dr. Richter told Medscape Medical News.
Of the 50 EURO-SKI patients involved in the 6-month follow-up substudy, 15 reported pain in various parts of the body, including the shoulders, hips, and extremities. The pain, which can start within 1 week of stopping treatment and evolve over 6 weeks, sometimes resembles polymyalgia rheumatica, Dr. Richter reported.
After personal communication with other investigators, he reported that these events have been observed "in other Stop trials, but have never been recorded in a structured manner. Our results suggest that even after cessation of treatment, patients may experience adverse events."
Although Dr. Richter and his colleagues say that theirs is the first publication of this withdrawal syndrome, in fact, Koreanresearchers reported, at the recent European Hematology Association congress, that in the early stages of imatinib cessation, approximately 25% of patients experience aggravation of joint pain.
Treating Musculoskeletal Pain
Of the 15 EURO-SKI patients reporting pain, 8 had grade 2 pain and 7 had grade 1 pain, measured on the Common Terminology Criteria for Adverse Events scale (version 4.0).
The pain was not associated with an increase in inflammatory markers, such as C-reactive protein, and it was not indicative of whether patients would experience molecular relapse. "The rate of molecular relapse in the first 6 months after imatinib discontinuation did not differ between patients presenting with musculoskeletal adverse effects and those without," said Dr. Richter.
Grade 1 pain was managed with nonprescription nonsteroidal anti-inflammatory drugs. In some cases, grade 2 pain required prednisone 10 to 20 mg daily, which was tapered within weeks. Prednisone could not be tapered in 1 patient, and 1 patient did not respond, but 3 patients did respond. After 2 years, 1 patient is still on low-dose (2.5 mg) prednisone, Dr. Richter reported.
TKI Withdrawal Syndrome May Not Be Universally Observed
Medscape Medical News asked several experts in the United States whether they had seen the TKI withdrawal syndrome.
At the University of Texas M.D. Anderson Cancer Center in Houston, Hagop M. Kantarjian, MD, said he had not seen it in patients who discontinued imatinib, and Jorge E. Cortes, MD, explained that very few of his patients have stopped taking the drug.
B. Douglas Smith, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins in Baltimore, Maryland, said he has not observed the phenomenon, but cautioned that only looking for certain characteristics is likely to overestimate prevalence rates. It is atypical to think that the discontinuation of treatment is associated with adverse events, he noted.
Dr. Smith said he concurs with Dr. Richter that there is no cause for concern, but added that it would be good to know if this syndrome is observed in other imatinib cessation studies.
"This is an area we don't know much about," said Michael J. Mauro, MD, leader of the myeloproliferative diseases program at the Memorial Sloan Kettering Cancer Center in New York City.
"We'd like to know the positive and negative effects of long-term treatment and withdrawal of TKIs," he told Medscape Medical News. He noted that TKI withdrawal is typically done in the setting of clinical trials.
Collecting data on low-grade adverse events is not written into protocols of TKI cessation trials, but this could soon change. Dr. Mauro reported that TKI discontinuation trials being initiated in the United States are designed to collect data on adverse events and quality of life.
A different perspective was offered by Bruce D. Cheson, MD, from the Lombardi Comprehensive Cancer Center in Washington, DC, who posts the Medscape Cheson on Oncology blog.
"Clearly, imatinib is one of the great advances in modern hematology-oncology," he told Medscape Medical News. "Nevertheless, the indefinite use of the drug is financially problematic. The fact that most patients can be safely taken off the drug, with a few experiencing a transient musculoskeletal syndrome, indicates that the benefits of stopping the treatment outweigh the problems."
#4
Posted 11 August 2016 - 12:08 PM
Not sure why the cessation pain is a surprise. Since the TKI causes changes in bone remodelling when started, that will be reversed when it is stopped resulting in new pain from the reversal. Sometimes I am surprised at the lack of insight from people who supposedly know a lot about this stuff.
#5
Posted 11 August 2016 - 01:45 PM
FISH 92%
BMB 9:22 translocation
1/19/15 began 400 mg gleevec
1/22/15 bcr 37.2 IS
2/6/15 bcr 12.5 IS
3/26/15 bcr 10.3 IS
6/29/15 bcr 7.5 IS
9/24/15 bcr 0.8 IS
1/4/16 bcr 0.3 IS
Started 100 mg dasatinib, mutation analysis negative
4/20/16 bcr 0.03 IS
8/8/16 bcr 0.007 IS
12/6/16 bcr 0.002 IS
Lowered dasatinib to 70 mg
4/10/17 bcr 0.001 IS
Lowered dasatinib to 50 mg
7/5/17 bcr 0.004 IS
8/10/17 bcr 0.001. Stopped TKI in prep for September surgery.
9/10/17 bcr 0.006
10/10/17 bcr 0.088
#6
Posted 11 August 2016 - 04:59 PM
But if they could work out which bits of the gleevec do what and drop the other bits that cause rhe side effects I might consider it, if it was an option.
#7
Posted 11 August 2016 - 05:06 PM
I asked the tfr group who was on sprycel and was having the redrawal issues with their joints. I only had one "positive" response. That could be because we have fewer sprycel TFRers currently as opposed to gleevec and tasigna people. Or is it because sprycel is different to gleevec and tasigna, hence less bone remodelling.
#8
Posted 11 August 2016 - 08:35 PM
Not sure why the cessation pain is a surprise. Since the TKI causes changes in bone remodelling when started, that will be reversed when it is stopped resulting in new pain from the reversal. Sometimes I am surprised at the lack of insight from people who supposedly know a lot about this stuff.
#9
Posted 11 August 2016 - 08:40 PM
#10
Posted 13 August 2016 - 02:03 PM
I'm hopeful that the intense and enduring physical pain suffered during Gleevec dosage reduction is mostly behind me. Only time will tell. If I had abruptly terminated Gleevec, going from 400mg to 0mg, and experienced everything at once, it is likely that heavy-duty pain meds would have been required. Age and prior major injury (C4 through T-1 damage) are a contributing factor to my Gleevec withdrawal experience. I think about exercising but so far it's mostly only a thought.
For the benefit of yourself and others please add your CML history into your Signature
02/2010 Gleevec 400mg
2011 Two weakly positives, PCRU, weakly positive
2012 PCRU, PCRU, PCRU, PCRU
2013 PCRU, PCRU, PCRU, weakly positive
2014 PCRU, PCRU, PCRU, PCRU (12/07 began dose reduction w/each continuing PCRU)
2015 300, 250, 200, 150
2016 100, 50/100, 100, 10/17 TFR
2017 01/17 TFR, 04/18 TFR, 07/18 TFR 0.0012, 08/29 TFR 0.001, 10/17 TFR 0.000
2018 01/16 TFR 0.0004 ... next quarterly PCR 04/17
At the earliest opportunity, and whenever possible, lower your TKI dosage; TKIs are toxic drugs and the less we take longterm the better off we are going to be ... this is especially true for older adults.
In hindsight I should have started my dosage reduction two years earlier; it might have helped minimize some of the longterm cumulative toxic effects of TKIs that I am beset with.
longterm side-effects Peripheral Artery Disease - legs (it's a bitch); continuing shoulder problems, right elbow inflammation. GFR and creatinine vastly improved after stopping Gleevec.
Cumulative Gleevec dosage estimated at 830 grams
Taking Gleevec 400mg an hour after my largest meal of the day helped eliminate the nausea that Gleevec is notorious for.
Trey's CML Blog - Stopping - The Odds - Stop Studies - Discussion Forum Cessation Study
Big PhRMA - Medicare Status - Social Security Status - Deficit/Debt
#11
Posted 13 August 2016 - 04:29 PM
Scuba has mentioned on a few occasions about tumeric helping his oesteo arthritis. Just wondering if that might be something that could help with the withdrawal as it is an anti inflammatory.
#12
Posted 13 August 2016 - 06:45 PM
Buzz,
Scuba has mentioned on a few occasions about tumeric helping his oesteo arthritis. Just wondering if that might be something that could help with the withdrawal as it is an anti inflammatory.
I take Curcumin, the active ingredient in Turmeric. It eliminated my arthritis onset (which runs in my family). Curcumin is a strong anti-inflammatory. When I stopped Sprycel for nine months last year, I had the TKI withdrawal syndrome in my hand/finger joints. No pain, just stiffness that I had to work out in the morning. It was slowly going away, but I resumed 20mg. Sprycel at the nine months mark. Within days, the joint stiffness disappeared. I suspect it will return when I next try cessation.
Diagnosed 11 May 2011 (100% FiSH, 155% PCR)
with b2a2 BCR-ABL fusion transcript coding for the 210kDa BCR-ABL protein
Sprycel: 20 mg per day - taken at lights out with Quercetin and/or Magnesium Taurate
6-8 grams Curcumin C3 complex.
2015 PCR: < 0.01% (M.D. Anderson scale)
2016 PCR: < 0.01% (M.D. Anderson scale)
March 2017 PCR: 0.01% (M.D. Anderson scale)
June 2017 PCR: "undetected"
September 2017 PCR: "undetected"
#13
Posted 13 August 2016 - 08:28 PM
I did start taking curcumin, Scuba. Nothing traditional medicine offered me was helping. I do feel a bit better.
#14
Posted 14 August 2016 - 05:09 PM
I take Curcumin, the active ingredient in Turmeric. It eliminated my arthritis onset (which runs in my family). Curcumin is a strong anti-inflammatory. When I stopped Sprycel for nine months last year, I had the TKI withdrawal syndrome in my hand/finger joints. No pain, just stiffness that I had to work out in the morning. It was slowly going away, but I resumed 20mg. Sprycel at the nine months mark. Within days, the joint stiffness disappeared. I suspect it will return when I next try cessation.
Thanks Scuba, trying to think of things that might help. I took glucosamine all the time I was on Gleevec and since I have been off, helps stop my knee pain, not sure if that might help the withdrawal pain. I started to get pain in my fingers just prior to stopping, perhaps that was the start of the bone remodeling that Trey talks about.
How long to go until you attempt cessation again?
#15
Posted 14 August 2016 - 07:41 PM
Gerry - My next PCR test is in September. If it is the same as it is now (near or at PCRU), I will cut my dose from 20 mg every day to 20mg every other day.
Diagnosed 11 May 2011 (100% FiSH, 155% PCR)
with b2a2 BCR-ABL fusion transcript coding for the 210kDa BCR-ABL protein
Sprycel: 20 mg per day - taken at lights out with Quercetin and/or Magnesium Taurate
6-8 grams Curcumin C3 complex.
2015 PCR: < 0.01% (M.D. Anderson scale)
2016 PCR: < 0.01% (M.D. Anderson scale)
March 2017 PCR: 0.01% (M.D. Anderson scale)
June 2017 PCR: "undetected"
September 2017 PCR: "undetected"
#16
Posted 14 August 2016 - 08:14 PM
As reported a couple of weeks ago, I restarted Gleevec at 300mg after stopping for 10 months. Just trying to find some relief from the pain of withdrawal that wasn't there before I stopped. Results so far are inconclusive though I feel fatigue may be a bit improved. Thankfully there has not been any noticeable bad effects of the Gleevec either. Will continue with the Gleevec awhile to see what happens.
#17
Posted 14 August 2016 - 10:55 PM
Thanks Alajazz.
Predisone appears to control it, but you can't keep taking that forever.
Question is why isn't it an issue for everyone. Have to figure it will be something they will look into, as it has the potential to put some people off the idea of trying cessation.
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