CLL Complications el pt

Infectious Complications in CLL

Date: June 10, 2024

by Chaya Venkat

Best Practices: How to Manage Infectious Complications

Index Page for Articles on
Best Practices

Here is a sound bite that you can take to the bank: “About 80% of CLL patients will sustain infectious complications at some point during their disease course, and 50% to 60% of patients will die due to infection.” No, the majority of CLL patients do not die of old age, nor do they get hit by the proverbial bus coming down the turnpike. How many local oncologists are familiar with this scary sound bite, and use it to counsel their patients, as opposed to the “good cancer to have” baloney?

Here are some questions you should be asking. The answers may well make the difference between life and death — and they will certainly influence your quality of life.

• What makes CLL patients so prone to infections?
• Do the drugs used to treat CLL make us more prone to infections?
• What are some of the major infections?
• Is there anything we can do protect against them?

Funny you should ask. Yes, there are things we can do to protect ourselves. There is an absolutely hot-off-the presses review article that spells out “Best Practices” in our understanding of this important issue. The abstract of this important paper and our “cheat-sheet” summary of the highlights are given below for your reading pleasure. The link provided gives you access to the full-text article in PDF form. If the link does not work for you, please do write to us to help you locate the document.

We hope lots of you print it out and take it with you to your next appointment with your local oncologist and make him a present of it. This is “Continuing Medical Education” with a modern twist appropriate for this internet era. Expert “Best Practices” that do not get sufficient publicity at the local healthcare level can be given a boost in visibility by patient advocacy and empowerment. We can take that extra step and help the process of knowledge trickle down - our very lives depend on it. Expert credibility and our grassroots reach is a match made in heaven.

Best Practices: How to Manage Infections in CLL

Article from Seminars in Oncology (PDF)

Semin Oncol. 2024 Apr;33(2):240-9.

Infectious complications of chronic lymphocytic leukemia.

Wadhwa PD, Morrison VA.

Section of Hematology/Oncology, Veterans Affairs Medical Center, University of Minnesota, Minneapolis, MN 55417

Infectious complications continue to be one of the major causes of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL). The pathogenesis of infections in these patients is multifactorial. Hypogammaglobulinemia is an important predisposing factor for infection in patients with early-stage disease and for those treated with conventional alkylating agents. However, the proportion of patients treated with purine analogs and monoclonal antibodies such as rituximab and alemtuzumab is increasing. As a result of this therapy, these patients often experience profound and sustained T-cell immunodeficiency. Consequently, the spectrum of organisms causing infections in these patients is changing from common bacterial organisms to less common opportunistic pathogens such as Pneumocystis, Listeria, mycobacteria, herpesviruses, and Candida. This review focuses on the pathogenesis and risk factors for infections in patients with CLL, the spectrum of infectious organisms associated with the newer agents, and the management of these infections with an emphasis on prophylaxis and vaccination strategies.

PMID: 16616071
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Highlights

I had trouble picking out the highlights of this article, since the whole review is one giant highlight! There is a treasure trove of information in this review. The only way you are going to get the full benefit of this excellent overview is to get out your highlighter, sit down with a full text hard copy of the article and mark it up to suit your personal situation. I strongly urge you to do it — someday, your life may depend on your familiarity with this subject.

What makes CLL patients so prone to infections?

• About 80% of CLL patients will fall prey to infectious complications at some point during their disease course, and 50% to 60% of patients will die due to these infections.
• Patients with hypogammaglobulinemia (this is just a long word that means the levels of gammaglobulins are too low) appear to be particularly vulnerable to recurrent bacterial infections, especially with encapsulated organisms. The incidence and severity of hypogammaglobulinemia increases the longer you have had CLL, and with advancing stage. People, it is important to get your immunoglobulin (the same thing as gammaglobulin) levels checked periodically, especially if you are experiencing frequent bacterial infections! There are three kinds of immunoglobulins: IgA, IgM and IgG. All three are measured by a simple blood test.
• The other major arm of our immune system is cell-based defenses. Chiorazzi, et. al., have demonstrated a functional defect in helper T cells in CLL patients. Obviously, therapy with T-cell unfriendly drugs such as fludarabine and Campath will make matters a whole lot worse. Steroid drugs (prednisone, prednisolone, dexamethasone, etc.) are also suppressive of T-cell counts. T-cells protect us against viral infections, as well as carry out surveillance against incipient new cancers (aggressive skin cancer is one of them). A marked decrease in NK (“Natural Killer”) cell activity in CLL patients has also been reported. Think of NK cells as the “swat team” of the immune system. They are ready to go fight invaders at a moment’s notice.
• The complement system plays a critical role in protection against infection by coating the surface of the offending invader with complement fragments (“opsonization”). This draws the immediate attention of neutrophils to the site, leading to the death of the invader. Multiple studies have demonstrated abnormal complement activity in CLL patients.
• Neutrophil counts are often normal in untreated and early stage CLL patients. But eventually most patients will experience neutropenia as a consequence of the bone marrow becoming progressively choked up with CLL cells and as a consequence of myelosuppressive (that just means unfriendly to neutrophils) chemotherapy. Neutropenia is very common in patients who have undergone combination therapies such as RF, RFC. RPC, etc.

Do the drugs used to treat CLL make us more prone to infections? What are some of the major infections?

• Bacteria account for the majority of infections in patients treated with drugs like chlorambucil and cyclophosphamide. The infections often occur at mucosal sites, especially the respiratory tract. Other common sites of involvement include the urinary tract, skin and soft tissues, especially in patients with severe neutropenia.
• Fungal and viral infections such as Candida (“thrush”) and Aspergillus are not commonly seen, except in patients with therapy-related neutropenia, or with steroid use.
• Purine analogs such as fludarabine and pentostatin have made a major impact on the treatment of CLL. But these improved results come at the cost of not only an increased incidence but also a changing spectrum of infections. We are seeing a lot more opportunistic infections. Patients remain at an increased risk for infection for up to 1 year after completing treatment.
• Infectious complications are more commonly observed in those patients treated with fludarabine than with chlorambucil or cyclophosphamide based therapy.
• Fludarabine does a real nasty number on all T-cells, with a decrease in CD4 T-cells persisting for as long as 11 months after completion of treatment. Keating, et. al. reported on 174 CLL patients who received fludarabine as frontline therapy. The median CD4 T-cell count decreased from a pretreatment level of 1,562 cells/L to 172 cells/L after three cycles and 163 cells/L after six cycles of treatment. That is one tenth of the amount the patients started with — and in the same league as people with HIV and AIDS! No wonder these patients are so much more at risk of viral infections.
• The spectrum of infections after fludarabine includes not only bacterial infections but also opportunistic infections caused by Listeria, Nocardia, and mycobacteria. Fungal infections are most often caused by Candida and Aspergillus and may be spread throughout the body. The risk of pneumonia is greater in patients treated with combinations of fludarabine plus steroid drugs. Viral infections are common, especially shingles, adenovirus, cytomegalovirus (CMV), and reactivation of hepatitis B.
• The increased risk of infection with Campath therapy is a consequence of the prolonged and profound depression in all lymphocyte counts, including T-cells, neutrophils, macrophages, etc.
• Patients are at risk for opportunistic infections beginning 3 to 4 weeks after the start of Campath therapy and lasting at least 12 to 16 weeks following completion of therapy. Other researchers have shown a much longer window on this. T-cell counts are a mere shadow of their former selves even one year later.
• There is a high frequency of bacterial and opportunistic infections after Campath therapy whether administered by an IV or sub-cutaneous route. As with fludarabine, the infections are more common in heavily pretreated patients. CMV reactivation is particularly frequent but the good news is it usually responds to prompt antiviral (ganciclovir) treatment.
• Best Practices recommendation: antimicrobial prophylaxis (that just means preventive and ahead of time) with Bactrim, acyclovir, or famciclovir and fluconazole during Campath therapy. Prophylaxis should be continued for at least 8 to12 weeks following completion of treatment.

Strategies for Prevention of Infection

• In CLL patients at high risk for infections (history of low immunoglobulins and/or infections) intravenous immunoglobulin (IVIg) reduced moderately severe bacterial infections by 50%. But there was no subsequent reduction in the incidence of nonbacterial infections or mortality in these patients once they stopped getting the IVIg.
• The number of infection-related hospital admissions and fevers was significantly lower during the IVIg treatment period.
• But IVIg therapy just gets you a boost in IgG levels, it does not replace IgA and IgM. Reduced levels of IgA and IgM have been implicated in some studies as the cause of increased incidence of infection.
• IVIg is extremely expensive and the immunoglobulins are in chronic short supply. Several studies have shown that IVIg is not cost-effective in preventing infections in CLL patients. You may have trouble convincing your doctor or your insurance company to let you get regular IVIg therapy.
• Additionally, in the era of fludarabine and Campath therapy, most of the serious and opportunistic infections are due to T-cell defects, and IVIg will not help you in that context.
• Vaccination strategies have often been disappointing in these patients, especially in those with advanced refractory disease, because these patients do not mount a satisfactory response to the vaccination.
• "Further novel strategies are needed to enhance the immunogenic potential of vaccines or to augment the host response to vaccines in this patient population.” Yeah, tell us about it! This is why we launched our recent "Low Hanging Fruit” clinical trial (see Improving Immunizations). Improving vaccinations for flu and pneumonia will save many patient lives. This project needs patient participation. There is no money to be made in this project folks. If we as a patient community don’t get around to doing it, no one else will either. Business as usual means we can continue dropping dead of flu and pneumonia, as always.
• Antimicrobial protection ahead of therapy is probably neither needed nor cost-effective in early-stage CLL patients, especially if they have normal immunoglobulin levels.
• Prophylaxis against infections is probably not required during conventional therapy with chlorambucil or cyclophosphamide. It might very well be appropriate if fludarabine is the drug of choice.
• With late stage or very high-risk patients, protection with either amoxicillin/clavulunic acid or Bactrim may be considered. If prophylaxis is initiated, it should be continued for at least 2 months after completion of treatment.
• Pneumonia and Listeria infections are common only in patients who are receiving fludarabine and corticosteroids. These patients should be considered for prophylaxis with TMP/SMX. Antiviral prophylaxis might benefit patients with a low initial CD4 counts, less than 50/L.
• CMV reactivation continues to be a problem with Campath use. Weekly surveillance for CMV infection by qualitative PCR-based assays should be considered during the treatment period, as well as Bactrim, famciclovir and fluconazole prophylaxis, especially in heavily pretreated patients who have also received fludarabine in the past.

Editorial:

Continuing Medical Education (CME) is supposed to be the mechanism for bringing local physicians up to speed and keep them informed about new research findings. One can see thousands of oncologists and hematologists wandering around like lost souls at the annual ASCO (American Society of Clinical Oncology) and ASH (American Society of Hematology) convention centers. They are exposed to literally hundreds of presentations, many times more poster presentations, all of them thick and heavy with jargon. You can hardly blame our poor, over-worked and out-of-date oncologist for feeling intimidated and overwhelmed. The bars and restaurants around the convention centers are jammed each evening with doctors – lost souls trying to get rid of the migraine resulting from a full day of information overload.

How Much Do Local Oncologists Know about CLL and Its Complications?

Let us take a typical case, an oncologist in a small town or rural area, someone who went to medical school about 20 years ago, long before the era of molecular understanding of what makes CLL tick. We will assume this individual is a hard-working, well-intentioned practitioner who is trying to cope with ever increasing work load and complexity. Perhaps this physician belongs to an HMO and must satisfy the requirements of that organization in terms of costs and efficiency. He takes care of dozens of different types of cancer. The majority of his patients have the “big” cancers, such as breast cancer, prostate cancer, lung cancer and colorectal cancer. He may even have a smattering of patients with blood cancers, such as the acute leukemias and lymphomas. Each and every one of these cancers is a different beast, with its own explosion of new research findings. How many CLL cases is our hypothetical oncologist likely to see in a year? I doubt most local guys see more than one or two a year. Even hematologists who specialize in blood cancers may see no more than a handful of CLL cases in as many years.

Our typical physician faces constraints at every turn. He lives in an era of information overload. There are not enough hours in the day for him to bone up on all the stuff he needs to know. He must be efficient in his time management: he cannot spare more than the mandated 15 minutes for each patient. He must be cost conscious — the HMO is not going to react kindly to expensive diagnostic testing, not unless it has the backing of experts as necessary part of cutting edge prognostics. His medical malpractice insurance is going through the roof and he might feel the only way to protect himself is to do the slam dunk “gold standard” conventional therapies. No one gets sued for being boring, unimaginative or conventional; blazing a new path can be dangerous, it may hurt. If he spends any time worrying about his patients over and beyond the required 15-minute consultation, chances are he will spend it worrying about his “really sick” cases, not about his rare CLL patient. After all, CLL patients hang around for a long time and it is the "good" cancer to have, right? CLL patients do not die of CLL, they are more likely to get run over by a truck, right? How many of us have heard these ghastly conventional half-truths?

In the absence of rigorous truth, sound bites rule. There is no doubt in my mind that the slow trickle down of “Best Practices” is standing in the way of prompt and effective treatment of our patients. The theme of my recent talk at the UK CLL Forum (click here for a pdf version of Chaya's presentation) was that while researchers and experts are learning a great deal about CLL — what makes it tick at the molecular level, how best to treat it, what prognostics to use to make therapy decisions, what are the risk factors, etc. — this precious, life saving information is not trickling down fast enough to the local level. A small subset of our patient community gets the benefit of the hard won wisdom from cutting edge research — patients who are fortunate and able to go to experts at world class cancer centers, or patients who are just plain lucky and find a doctor that bothers to keep up with the latest information. For the rest of us the story is a whole lot bleaker. We are getting short-changed on all fronts. Having access to a knowledgeable and up-to-date physician is one of the most important prognostic indicators for managing your CLL over the long haul.

Most CLL patients in the United States are diagnosed and treated by local oncologists. Even though most insurance companies cover the cost of a second or even a third opinion, the majority of patients do not use this available resource. Why is that? Perhaps the patient has unbounded faith in his or her particular doctor or perhaps he or she is afraid of offending the local guy by asking to get a second opinion. Many patients feel intimidated in the doctor-patient relationship and the mere mention of a cancer diagnosis knocks the stuffing out of even the most intrepid. Bravado is checked in at the door and we meekly submit without any effort at taking charge. Sometimes trivial details show up as road-blocks. One patient who received less than optimal therapy from her local guy, and who happened to live within a hundred miles of the world-class CLL group under Dr. John Byrd at Ohio State University, told me that she did not want to spring for the cost of gasoline for the 100-mile drive each way. At the risk of sounding unsympathetic, I will ask how much does she spend each month on going out to eat or splurging on lattes at the local Starbucks or getting her hair and nails done at the beauty parlor? People, get your priorities right! If you cannot be bothered to take care of your health, how can you expect anyone else to do so?