How come we get no respect?
A few years ago, Campath (alemtuzumab) won across the board FDA approval for treating CLL – as a frontline drug, single agent therapy, in combination with other drugs, the whole enchilada. They were the first to discover the fine art of doing straw-man comparisons with low dose chlorambucil, thereby “demonstrating” the impressive efficacy of their drug. Any number of CLL experts were touting the use of Campath as a consolidation regimen, something to do after completion of regimens like FCR, R+HDMP etc, as a way of getting more people into the coveted MRD (minimum residual disease) negative status. I got a lot of push-back because I was not sold on this concept. I thought the toxicity of Campath as a consolidation drug after prior chemoimmunotherapy was too high, a case of the reward not being worth the risk. Campath kills T-cells, and keeps T-cell counts very low for months after completion of therapy. This means higher risk of opportunistic infections, even secondary cancers.
Talk about irony. Campath is no longer available as a commercial drug to treat CLL patients. What caused this massive change of heart on the part of the drug company that owns this monoclonal? Simple. Money. Lots of it. You see, the very thing that made Campath so immune suppressive in CLL patients – its well documented ability to kill off T-cells and keep T-cell counts low for a long time thereafter – proved to be useful in treating multiple sclerosis. MS is an autoimmune disease, caused by T-cells gone berserk and attacking the myelin sheath of nerves. For these patients, reduced T-cell counts is a blessing, since it gets them much desired remission.
Why not market Campath both for CLL and MS? Aha. That is the billion dollar question. You see, MS patients need very small amounts of Campath. If it is marketed at the present price Campath commands to treat CLL, the company would be selling the drug to MS patients at a significantly cheaper price than other MS therapies. Oy vey! If the drug was available in the marketplace at the present price it gets for CLL, doctors and patients would be buying it at that price, even if they were actually going to use it for treating MS. What to do? Stop selling Campath to CLL patients! Genius! Now the company can jack up the price several times over, sell it only to the MS patient community. I wonder how much they pay the guy who came up with this idea. And how he sleeps at night.
Oh yes, in an attempt to avoid scathing public opinion, the company says they will give away Campath free of charge to CLL patients in this country. However, doctors cannot prescribe it in the usual manner, hospital pharmacies cannot supply it, physicians have to call a special phone number and the physician has to go through a lot of hoops and hassles to justify why a given patient needs Campath.. The Campath website hosted by Genzyme for this purpose is suddenly very stark in the list of potential dangers of this drug for CLL patients. How long will the company continue the compassionate use program? No one knows. Is this only for USA patients? How about CLL patients elsewhere? I do not know.
Meanwhile, all the CLL experts who were ecstatic about using Campath in prior years are doing a fast back step. Suddenly no one likes Campath anymore. Sour grapes, anyone?
Pity of it is that while Campath was hardly the wonder drug its supporters claimed it was a few years ago, it was nevertheless an important drug for CLL patients. It was one of few options for patients with the dreaded 17p deletion. If you were not cynical about drug company agendas before, this story might be enough to push you over the edge.
Secondary cancers in CLL
We have discussed this issue in many previous articles. A detailed ASCO2012 abstract from the prestigious Moffitt Cancer Center brought this subject up again – coupled with deeply troubling news that a couple of friends have been identified with solid cancers secondary to their CLL diagnosis (one non-small cell lung cancer and one colorectal cancer) just this last week – made it necessary for me to bring up this subject once again. There are a couple of lessons that all of us can learn from this latest information. First, the abstract. Then the discussion.
Incidence of second and secondary malignancies in patients with CLL: A single institution experience.
J Clin Oncol 30, 2012 (suppl; abstr 6568)
Author(s): Samir Dalia, Julio C. Chavez, Gelenis Domingo, Estrella M. Carballido, Paibel I. Aguayo-Hiraldo, Kendra Lynn Sweet, Robert M. Crescentini, Lubosh Sokol, Celeste M. Bello, Jennifer L. Cultrera, Bijal D. Shah, Jeffrey E. Lancet, Rami S. Komrokji, Eduardo M. Sotomayor, Javier Pinilla-Ibarz; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL
Background: Patients with chronic lymphocytic leukemia (CLL) have a higher incidence of second malignancies than the general population with one study showing the risk at 2.2 times the general popualtion. The increased incidence is thought to be due to immunosupression which results in decreased cell surveillance and proliferation of malignant cells. Our study aims to present the rate of second malignancies by cancer type in patients with CLL at our institution.
Methods: The Moffitt Cancer Center Total Cancer Care (TCC) database was used to identify patients who had a diagnosis of CLL between January 1993-December 2009. Individual charts were reviewed to confirm the diagnosis of CLL, collect demographic data, and to assess for the presence of a second malignancy under an IRB approved protocol. A second malignancy was defined as another malignancy or transformation of CLL reported in the medical record. Second malignancy data was placed in three categories; skin cancers, solid tumor malignancy, and hematologic malignancy. Results: 546 CLL patients were included in the study. Median age was 62.5 years. 84 (43%) were Stage 0 and 62 (32%) were Stage 1 RAI at diagnosis indicating earlier disease. 266 (49%) patients had a second or secondary malignancy. A total of 304 cancers were identified. 14% of patients had more than one malignancy. Melanoma was identified in 44 (16.5%) patients and non-melanoma skin cancer was identified in 54 (20%). Lung cancer was identified as the most frequent solid tumor malignancy with 36 (13.5%) cases, followed by prostate (35), breast (21), colorectal (15), and bladder (14). 10 patients had a Richter’s transformation of their CLL. 26 patients developed either myelodysplastic syndrome or acute myelogenous leukemia. Conclusions: Second malignancies are frequent in CLL patients. Immunosupression, increased UV light exposure, longer life expectancy in low risk CLL, and tertiary cancer center referral bias are likely reasons for these increased rates. Further research is needed to identify the precise mechanism which cause patients with CLL to have higher rates of second malignancies and to identify if there is an increased risk of a specific type of malignancy in patients with CLL.
No responsible CLL expert questions the increased likelihood of secondary cancers in CLL patients. Here is the short version of why that is the case. One of the jobs of our immune system is to keep on the look out for cancer. T-cells are particularly good at it. They troll the blood circulation highways and the nooks and crannies of the tissues of the body, looking for trouble. And even in perfectly healthy individuals, there are always microscopic clusters of cancer cells, in the lungs, gut, skin, breast, prostate etc. Fortunately for us, most of the time T-cells are able to identify these cancerous cells and kill them on the spot, before they have a chance to make a lot more cancerous babies and become a full fledged problem. How about CLL patients? By now you should know CLL is a cancer of the very immune system that is supposed to protect you from these random cancers. True, CLL is cancer of the B-cells. But B-cells and T-cells are buddies, each group influences the other a great deal. CLL patients have less than effective T-cell surveillance on the look out for cancer clusters. This is particularly true if the patient has been treated by T-cell killing drugs such as Campath, fludarabine etc. You get the picture.
That said, this article from the reputable Moffitt Center was stunning in the statistics reported. A whopping 49% of the 546 CLL patients Moffitt saw between 1993- 2009 developed secondary cancers. 14% were doubly blessed, with more than one secondary cancer on top of the CLL. As you would expect skin cancer topped the list, with 36.5% developing melanoma or non-melanoma skin cancer. Lung cancer came in second, with 13.5% of the patients. You can read the rest of the statistics in the abstract, I tried to highlight the scary bits.
I confess I was blown away by these statistics, these risks were far higher than I expected. What gives? One small ray of hope for the general run of CLL patients is identified by the researchers themselves: “tertiary cancer center referral bias”. That is a fancy way of saying higher risk folks than the run of the mill CLL patient are more likely to be referred to an expert center such as Moffitt. A “smoldering” CLL patient with no other health issues or secondary cancers is likely to stick with his locally convenient oncologist. I can see why places like Moffitt, M. D. Anderson, Mayo etc see more of the tough cases, and these guys are also likely to be more at risk of secondary cancers of all sorts. Let us hope that is the reason for these frighteningly high secondary cancer statistics. But all the same, it is sobering news and I hope it provides a much needed kick in the butt for those of our members who (1) indulge in excessive UV exposure (2) smoke (3) skip regular prostate, breast and colorectal screenings.
Chew your way to fewer ear and upper respiratory infections
OK, here is a more upbeat and fun little factoid.
Vaccine. 2000 Dec 8;19 Suppl 1:S144-7.
Xylitol in preventing acute otitis media.
Uhari M, Tapiainen T, Kontiokari T.
Department of Paediatrics, University of Oulu, FIN-90220 Oulu, Finland. firstname.lastname@example.org
Xylitol is a polyol sugar alcohol and is referred to as birch sugar, because it can be produced from birch. Natural sources of xylitol include plums, strawberries, raspberries and rowan berries. Xylitol inhibits the growth of Streptococcus pneumoniae and it inhibits the attachment of both pneumococci and Haemophilus influenzae on the nasopharyngeal cells. In two clinical trials xylitol was found efficient to prevent the development of acute otitis media with a daily dose of 8.4-10 g of xylitol given in five divided doses. The efficacy in these 2-3 months follow-up trials was approximately 40% when chewing gum was used and approximately 30% with xylitol syrup. The need to use antimicrobials reduced markedly when using xylitol. In a high-risk group of children with tympanostomy tubes xylitol was ineffective in preventing otitis. Xylitol appears to be an attractive alternative to prevent acute otitis media. A more practical frequency of doses should be found before its use can be widely recommended.
Xylitol is a sugar substitute. You can find it in the forms of lozenges, chewing gum, syrup, nasal spray, mouthwash etc. The abstract above reports on a clinical trial done in Finland, using a large group of high risk pediatric patients. Lo and behold, it reduced the incidence of severe ear infections, to the tune of 40%, when children chewed gum containing xylitol.
Wikipedia has a very nice write-up on this interesting molecule, easily readable, so I won’t belabor the points made there. Basically, xylitol has half the calories of plain table sugar, no after taste and no known toxicity. Here are a few quotes, for those of you lazy enough not to click on the link:
- Xylitol is a “tooth-friendly”, nonfermentable sugar alcohol; dental health benefits in caries prevention; recent research confirms a plaque-reducing effect.
- Bacteria prefer fermentable six-carbon sugars (i.e., normal table sugar), or disaccharides such as sucrose, as opposed to the nonfermentable xylitol, whose antimicrobial properties then “starve” the bacteria, reducing their growth and reproduction.
- Xylitol also inhibits the growth of Streptococcus pneumoniae, as well as the attachment of Haemophilus influenzae on the nasopharyngeal cells. (since strep and flu cells find it harder to attach to the cells of of your nose and throat in the presence of xylitol, there is hope for reduced bronchitis, pneumonia etc. As I have told you on many previous occasions, the single biggest cause of death in CLL patients is lung infections in general, pneumonia in particular).
- Studies have shown xylitol chewing gum can help prevent ear infections.
- Xylitol has been found to increase the activity of neutrophils, the white blood cells involved in fighting many bacteria. This effect seems to be quite broad, acting even in cases such as general sepsis. (but please be aware this is from an animal study. I have not been able to find a similar study in humans).
So, how reliable is all this good news? Some of you may be aware of a group called the Cochrane Collaboration. This group does an excellent job of looking at clinical trial results and sorting out credible stuff from poorly done studies or results biased by ugly agendas. Well, we are fortunate that they have looked at the Finnish study and in their considered opinion, the results are valid. You can read the full chapter and verse of their findings here. While these studies were done with pediatric patients, I am reasonably convinced that the results are equally valid in the case of adults. Xylitol is quite safe (except to dogs, so please be careful), so the risk is minimal. Like chewing gum? Choose to chew xylitol containing gum. Use a mouthwash? Find a brand that contains xylitol. Frequent bronchial infections during the flu season? There are all kinds of nasal sprays available that contain xylitol.
Do you know what this is? It is also called coccidioidomycosis. Valley fever is a fungal infection most commonly seen in the desert regions of the southwestern United States. One can get it by breathing in fungal particles from soil. The infection starts in the lungs. While normal people can fight off the fungus, immune compromized people – yup, that is us guys – are at significant risk. Here is a PubMed write-up that gives all the necessary details. The map below shows the regions of the country where it is endemic.
Why am I suddenly talking about valley fever – surely it has been around for a long time? Well, the recent drought meant a lot more dry land and dust storms – prime conditions for spread of the fungal spores. Here is quote from the Arizona Department of Health:
The reported number of cases of Valley Fever in Arizona has been increasing since it became laboratory-reportable in 1997. In 2005 there were 3515 cases reported; only 958 cases were reported in 1997. Between January and April 2006, ADHS received over 2,000 case reports of Valley Fever. This is more than three times the five-year average for these months.
Not convinced CLL patients are at risk? Here is a link to an article that describes valley fever in a Swiss CLL patient.
What can you do, if you live in one of the high risk areas? Obviously, it is not always easy to move someplace else, on account of valley fever. But you can be more careful not to go out when there is a lot dust blowing around, wear a proper mask (N95 or better) if you do have to go out, break the habit of touching your nose, eyes and mouth with your hands (that might have picked up the viral particles by touching surfaces contaminated with dust), keep a careful eye out for potential symptoms and ask around to find who is the local expert on valley fever so that you have someone to contact if you get infected. There is a blood test to check people for exposure to valley fever fungus – something to discuss with your physician if you think you have been exposed. Please remember the fungal spores can lie dormant in your body for many years, making their presence felt during a period of vulnerability – say after you have been through immune suppressive therapy to control CLL. A valley fever advocacy organization does a terrific of debunking many of the myths surrounding valley fever. Suggest you read it, if you live or visit high risk areas.