Consumer Watch Dog
One of the roles of the FDA is to be a good watch dog and keep track of additional information regarding adverse effects that comes to light during post-marketing surveillance. Manufacturers and physicians are supposed to notify the FDA when they come across hitherto unsuspected toxicity information. Unfortunately, this process does not work as well as it should. Pharmaceutical companies do not exactly chomp at the bit when it comes to reporting bad news. And the amount of paperwork and hassle involved in reporting adverse effects means most physicians just don’t bother. In any case, the trickle down of information from the FDA to your local guy can take many moons and not soon enough to be of value to you.
I try to keep an eye out for new warnings from the FDA about drugs that are important to us. I don’t always catch them ASAP. Several pairs of eyes watching out are much better than just my one pair of cataract inflicted eyes. If you come across any warnings that you think are important, write to me and let me know.
Treanda (Bendamustine) warnings
Back in Oct 2008 there were changes announced by the FDA on several safety issues related to Treanda. I am sorry to say I just came across the changes. You can read these recent changes and the full prescribing information document by clicking on the links. Basically, Section 5 relating to “Warnings and Precautions” is the one that has been modified. Kind of important stuff, I wish I had seen it earlier. The italicized bits below are direct quotes fromt he FDA site.
- Myelosuppression: in the two NHL studies, 98% of patients had Grade 3-4 myelosuppression. Three patients (2%) died from myelosuppression-related adverse reactions. (FYI: blood cells are broadly classified as either “myeloid” or “lymphoid”. Lymphoid cell lines include B-Cells and T-cells. Myeloid cell lines include red blood cells, neutrophils (granulocytes) and platelets. Myelosuppression can therefore mean reduced red blood cells (anemia), neutrophils (neutropenia) or platelets (thrombocytopenia))
- Infection including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports. Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. The pneumonia part is what worries me most, especially as we head into a bad flu season this year.
- Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in post-marketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, close monitoring of blood chemistry, particularly potassium and uric acid levels, and the use of allopurinol during the first few weeks of TREANDA therapy in patients at high risk. TLS is a dangerous beast people. Make sure your doctor keeps an eye out for it, especially if you are a high risk patient – as in you already have kidney problems, history of kidney stones or gout.
- A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. After watching my husband PC develop skin rashes due to Rituxan hypersensitivity, I became a lot more aware of potentially dangerous skin reactions such as Steven-Johnson syndrome and TEN (toxic epidermal necrosis).
- Other Malignancies : There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined.
This is the second shoe I have been dreading. As we pointed out in our earlier article “Treanda: facelift for bendamustine“, this drug hails back from vintage second world war East Germany. It has an interesting chemical structure. One end of it looks like a purine analog (examples of well known purine analogs are fludarabine, pentostatin) and the other end looks like an alkylating agent (examples are cyclophosphamide, chlorambucil). It has been suspected for some years that combination of purine analogs with alkylating agents packs a particularly powerful wallop, with increased risk of myeloid cancers. I wondered if bendamustine too is at risk of triggering myeloid malignancies because of its two-for-one chemistry. Looks like I was not far off the mark, sorry to say. Below is an article from 2002 Journal of clinical Oncology where a high pedigree list of authors (including no less than Kanti Rai) discuss the risk of myeloid cancers in CLL patients treated with purine analog + alkylating agent combinations.
J Clin Oncol 2002 Sep 15;20(18):3878-84
Therapy-related myeloid leukemias are observed in patients with chronic lymphocytic leukemia after treatment with fludarabine and chlorambucil: results of an intergroup study, cancer and leukemia group B 9011.
Morrison VA, Rai KR, Peterson BL, Kolitz JE, Elias L, Appelbaum FR, Hines JD, Shepherd L, Larson RA, Schiffer CA.
Section of Hematology/Oncology, Veterans Affairs Medical Center, Minneapolis, MN 55417
PURPOSE: Patients with chronic lymphocytic leukemia (CLL) may have disease transformation to non-Hodgkin’s lymphoma or prolymphocytic leukemia; however, development of therapy-related acute myeloid leukemia (t-AML) is unusual. A series of patients enrolled onto an intergroup CLL trial were examined for this complication.
PATIENTS AND METHODS: A total of 544 previously untreated B-cell CLL patients were enrolled onto a randomized intergroup study comparing treatment with chlorambucil, fludarabine, or fludarabine plus chlorambucil. Case report forms from 521 patients were reviewed for t-AML.
RESULTS: With a median follow-up of 4.2 years, six patients (1.2%) to date have developed therapy-related myelodysplastic syndrome (t-MDS; n = 3), t-AML (n = 2), or t-MDS evolving to t-AML (n = 1), from 27 to 53 months (median, 34 months) after study entry. This included five (3.5%) of 142 patients treated with fludarabine plus chlorambucil and one (0.5%) of 188 receiving fludarabine; no chlorambucil-treated patients developed t-MDS or t-AML (P =.007). At study entry, the median age among these six patients was 56 years (range, 44 to 72 years); three were male; the CLL Rai stage was I/II (n = 4) or III/IV (n = 2). Response to CLL therapy was complete (n = 4) or partial remission (n = 1) and stable disease (n = 1). Marrow cytogenetics, obtained in three of six cases at diagnosis of t-MDS or t-AML, were complex, with abnormalities in either or both chromosomes 5 and 7. Other abnormalities involved chromosomes X, 1, 8, 12, 17, and 19. Median survival after diagnosis of t-MDS/AML was 3.5 months (range, 0.5 to 10.1 months).
CONCLUSION: Our findings raise the possibility that alkylator-purine analog combination therapy may increase the risk of therapy-related myeloid malignancies, which is of particular relevance with regard to ongoing trials using these combination therapies.
PMID: 12228208
Once again for the record, let me highlight the need to balance risk and reward when making therapy decisions. Do the new FDA warnings mean you should never use bendamustine? No, it does not. A time may come when it is your best choice in controlling this incurable cancer and in that case you should be glad to have this choice available to you. Should you use bendamustine straight out of the gate because it is so – ahem – “triendy”? Not on your life. CLL patients often face devil and the deep blue sea choices. The smart money is on patients and doctors who weigh the odds carefully and make the right choices at the right time.
Information is our very life blood. Accurate and credible information, that is. I will do my best to keep you up to date. You can help by keeping your eyes peeled as well and alerting the rest of the community when you come across important drug alerts.
19 comments on "Recent FDA warnings about Treanda (bendamustine)"
Chaya:
Thanks again for keeping us informed!
Brian
Chaya,
I have been on chemo for about 6 months. I had rituxan in february and the rest of the time chlorambucil.
I have had my ups and downs including anemia and now a platelet count of 43, that is increasing. As you know, I refused treanda because of drug interaction and fludara because of previous problems.
I am now thinking, the old girl, me, made the right choices. That is, because of updates, warnings from you Chaya. Thank you so much for keeping us informed.
Rita
Dear Chaya, I read todays warning and article re: combinations of cytoxin and retuxamab.I will be at Sloan Kettering in NY for an exam on July 30th, and having just completed six months of PCR,( two of the mentioned drugs) I will open the discussion with my doctor and see what their thinking is and advise you.
Bob
Bob:
For some reason that I don’t quite understand, combination of purine analogs with alkylating agents along with Rituxan seem to present fewer problems. Notice the Rai article I quote is just purine analog + alkylating agent, no Rituxan.
Along the same lines, single agent fludarabine is contraindicated for patients at risk of AIHA. But R+F and R+FC seem to present less risk.
In other words, P+C+R is a safer combination than just P+C it seems.
Chaya:
Diagnosed in November. Served incountry Vietnam 1969 to 1970 running a swift boat in the Mekong Delta. VA has been good – presumed agent orange exposure awarded 100% disability.
I read and reread late into the night your articles and updates. Your web site along with the other contributors, gives me confidence to face my own future.
Thank you
Dave
Docs are currently combining Rituxan with Bendamustine and that may also influence the effects of this drug. Nothing is simple …
Dave,
I too was exposed to the organophosphate pentachloraphenol,(same family of chemicals as agent orange)sprayed in our house as a wood preservative in 1991. This has sinced been banned by the WHA. I developed a phlegmy cough, flu like symptoms and rinitus.Then, 14 years later I was diagnosed with CLL.The trouble is, the effects of these chemicals come 14-18 years later, so very hard to prove a causal link.
Molly
Thanks for this update, Chaya.
My father has just completed his six rounds of Treanda treatments at the Louisville VA hospital this week. It is a comfort to have this information at hand as we wait and see how long this treatment will hold his CLL at bay.
Thanks again for all you do in this regard!
Christine
Chaya,
My father has completed his second round of Treanda with Allopurinol (in Louisville, KY. as well, Christine – KCI) and was hospitalized first time (as you know) with fever/neutropenia….took 12 days for his numbers to come back up….they lowered his dosage this time and switched from one Neulasta injection to 14 Neupogen (sp?) in a row…thankfully he has been able to skip 2 of the injections this week due to good numbers…this was the only combo his dr. put before us and said he had had the best luck with Treanda and older patients. I am so thankful to have this information even though I don’t regularly discuss things with his dr. It’s still good to be informed and know what to watch out for. THANK YOU for your work on this site!
Dear Chaya,
I can’t tell you enough how much I appreciate the information you provide to us with CLL. My doc said the other day that he hadn’t been getting good results with Bendamustin, but that was all that was said. I now can be more informed. Thanks,
Murre
As you know, there is no “smoking gun” research that demonstrates a dose related linkage between alylating agents, purine analogs and secondary malignancies such as MDS (myelodysplastic syndrome) and AML (acute myeloid leukemia), but for many years there has been a consensus that chemotherapeutic agents do likely cause such malignancies.
To make matters worse, the incidence of such secondary malignancies is almost certainly greater in patients who have received therapy for lymphomas (especially for Hodgkins disease) than it is for many solid tumors such as breast cancer. Some solid tumors (eg, testicular carcinoma treated with epipodohllotoxins) also have been associated with such secondary malignancies.
Although the incidence overall is low, the consequences are certainly devastating for the individuals involved, as these secondary malignancies usually carry an especially poor prognosis.
We all must remember that CLL to date has not been cured by the various combinations of purine analogs and alkylating agents with or without monoclonal antibodies.
It is intuitive (though unproven) that the incidence of such secondary malignancies will likely rise over time as people undergo multiple such therapies for CLL. For this reason we have to hope that studies such as Dr. Foon’s study of so-called “FCR Lite” prove to be efficacious for CLL and simultaneously result in a lower incidence of such secondary malignancies. It will, however, be a long time before this information is known.
Following the advice of a good CLL specialist is of paramount importance, but we must recall that therapy for therapy’s sake is not always in a person’s best interest and the overall goals and long term picture must be considered. Such decisions are never easy which is why the input of good CLL specialists is vital.
Al Sullivan
Thanks for the update, Chaya.
Like Cristine’s father (above) I completed 6 rounds (12 infusions) of Bendamustine at the end of Jan. 09. This treatment (100mg/m^3, reduced to 70mg/m^3 after 2nd round) was recieved over a 7 month period (averaged 5 weeks between rounds). I had great success with this regimen and essentually no side effects—minor skin reactions. My WBC—once over 500k—was at normal levels after the 6th round and remains in the normal range as of Jul. 10, 2009. My Dr. pronounces me in chemical remission with barely palpable lymphnodes.
How long remission will last is another matter, but for now I’m very pleased with the action of this bi-functional molecule.
(Chaya, I share your bent for Chemistry. Bendamustine’s unique sturcture was a factor in my choice of this treatment drug.)
Al
I have had R+T prescribed for me back in May and, but for the fact my hem/onc of 8-years was moving away, I’d be on it now. I decided to wait until his replacement arrived (due Aug 3) before I started a new (to me) treatment so your alert is timely. I’m somewhat concerned now because I haven’t recovered from the FCR-Lite I did in the second half of 2007. I fully believe the culprit was cytoxan. I feel I’ve never been in so great a need for TX as I am now but I’m barely able to drag around my body. I live alone and still manage somehow but I’ll be starting TX for the first time w/o much confidence. After 12 years of this game there aren’t many good options left. Thanks so much for the warning.
Fred, age 82, Arcata CA
My husband is currently on his third month of FCR with a once a month injection of Neulasta and a daily dose of Dapsone. He began his CLL fight eight years ago with chlorambucil (which did zip for him), moved on to Fludara, then F & R, then Rituxan alone for about a year and now FCR. He always responds wonderfully to his treatment but soon after it stops his WBC starts going up again and his lymph nodes enlarge by leaps & bounds. Nothing has put him in remission longer than a year. This time he was offered Treanda – I did my research on it (mainly on this site & a few others) and we requested to go with FCR first and keep Treanda for the future if necessary. I’m very glad we did.
As someone who is going to talk to her consultant about Bendamustine treatment on Monday (in 2 days time) this is timely information. I will take a copy with me for my doctor. Since reading as much as I could about Bendamustine, I have had grave reservations about it and if it was the best treatment for me. Now I’m sure it’s not. Thankyou so much Chaya. Have a wonderful break – I too wish I still had my mum – she died from CLL 16 years ago.
Sylvie
MJH I did 2 treatments of Treanda in Feb 09 but it wasn’t doing anything so my Dr put me on FCR. I ended up in the hospital for 10 days. I have been on Compath for 6wks with very good response. Of coarse I have no immune system working for me. They are preparing me for a mini-stem cell transplant this fall some time in Seattle. I don’t know if I have any damage from the Treanda but I have been told my bone marrow is scared. My whites were 295 thousand and now are 0.20. I feel great but have to get platelet replacement and units of blood. The treatment center here in Longview Wa. is wonderful. Myrna
My impression of Treanda, after talking with CLL experts at the April Conference in Niagara Falls, was that it hadn’t been in use long enough in the U.S. or Canada for our doctors to understand its benefits and drawbacks. One expert, whom I trust, told me to “avoid it like the plague”. Not enough clinical trial results comparing Treanda, either alone or in combo with Rituxan, to FCR, PCR, etc. Cephalon has been marketing Treanda to local oncologists to get them to use it more often. A local oncologist, who doesn’t see many CLL patients, might be more influenced by that type of marketing than a CLL expert. My doctor gave me a glossy brochure and DVD but later advised that although he has had good responses (in the few patients he treated with Treanda) they began to suffer anemia and other problems. He’s not so hot on the drug right now. So my thinking is, if I’m going to do chemotherapy, I will go with the “gold standard” (FCR or PCR), and save Treanda for the future, hopefully after its treatment role is more defined. It may be an option for the fludarabine refractory.
My husband has just completed 5 rounds of Treanda with this last being quite difficult with severe nausea, diarrhea, low blood pressure readings and weight loss. 2 weeks following his first treatment, he was hospitalized with critically low HGH, platelets, and hematocrit requiring transfusions. Continued low counts caused the second treatment to be delayed for a month past the scheduled date. Last week’s blood count levels, however, are looking pretty good with platelets rising to 94 – the highest by far in a year. Upon initial diagnosis 6 years ago, he was quite fortunate to see a top CLL specialist and was able to enter a late phase FCR clinical trial which put him into a complete remission for 4 years. (He definitely falls into the aggressive “bucket” of CLL and needed to begin treatment the same year of diagnosis.) Our CLL Specialist recommended Treanda or a second time around with FCR – we chose Treanda. These decisions are never easy and we pray that we made the right one.
As an update to my last comment of July 19th, my husband’s last round of treatment with Treanda was cancelled after he experienced a lot of difficulty and following a bone marrow biopsy which revealed continued CLL activity in the marrow. He’ll now be taking a break for the next month to recuperate while the next step in treatment is decided.
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