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.