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CLL Complications

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Secondary Cancers

Date: May 7, 2003

by Chaya Venkat

Risks Are Higher for CLL Patients

Related Article:
Dying to Get a Tan?

Transplantation of stem cells in the bone marrow (SCT) is considered to be one of the few ways in which a "cure" is possible for CLL. I am not sure that opinion is still 100% valid, what with the high percentage of deep, PCR negative responses being obtained with chemoimmunotherapy combinations. Since these therapies are relatively new on the horizon, not enough time has passed for us to have solid and reliable survival statistics. Only time will tell if the PCR negative patients of today will live out their natural life spans free of CLL and any therapy related secondary cancers.

Stem Cell Transplants have a lot longer track record, but even there you must take the statistics with caution. A lot has changed in the pre-transplant procedures, as well as the actual SCT itself. I am pretty sure the statistics for today's patients will be a lot better than they were back in 1974. With that caveat, it is worth looking at this retrospective study.

3372 patients (from 1974 through 2001) who had SCTs were in this study. 137 of these patients (roughly 4%) developed new cancers after the SCT. Some of these new secondary cancers were skin cancer, AML, NHL, Hodgkin's disease, and several types of solid tumors. There was roughly an 8-fold increase in cancers of various sorts in this post-SCT group of patients, compared to a "normal" population of the same age and sex. You can read the detailed statistics in the abstract below. And the second abstract describes the secondary cancers possibly attributable to combination of chemotherapy agents such as fludarabine and cyclophosphamide.

There are a number of theories in vogue for explaining chemotherapy and transplant related secondary cancers. The obvious one is that many of the drugs used in chemotherapy are mutagenic, they can sometimes cause mutations in the DNA which may, in a few cases, go on to develop into full blown cancers.

The second theory has to do with the concept of immune surveillance. This concept underscores the fact that there is a constant barrage of individual cells somewhere in your body developing a dangerous mutation, and this is happening all the time. But an active and effective immune system takes care of the problem right away, by killing the malignant cell before it has a chance to establish a toe-hold in the body. Think of this along the lines of law enforcement. There will always be crooks and criminals in any given population, but as long as there is an effective police force to enforce the laws of the land, crime rate will not get out of hand. The problem arises when there is a prolonged period of immune deficiency, when no one is minding the store, so to speak. This is one of the reasons why there is a high incidence of rare types of cancer such as Kaposi Sarcoma in AIDs patients, who have badly damaged immune systems. By the way, non-Hodgkin's lymphoma, a kissing cousin of our favorite CLL, is also very common in AIDs patients. Is there a connection between higher incidence of cancers, especially the rare types that are infrequent in normal population, in immune compromised individuals, such as AIDs and CLL patients? Researchers who subscribe to the theory of immune surveillance as a natural protection against cancer think there is a connection here.

More recently, there has been a great deal of interesting research pointing to the link between viruses and cancer. There have been clearly documented cases where viruses such as EBV (Epstein-Barr Virus) have been strongly implicated in post-transplant secondary cancers. HPV (human papillomavirus) has been shown to be the cause of a good percentage of cervical cancers. So much so that there has been announcement of a breakthrough development of a vaccine that may prevent these specific cancers driven by HPV, which targets the virus and not the cancer itself. Just last year we reported on a study where an astonishing percentage of splenic lymphoma patients who also happened to be positive for HCV (Hepatitis C virus) and were treated with anti-virals for the HCV also got unexpected and deep remissions from their cancers as well. In all these cases, one school of thought is that these different viruses, many of which are present in the vast majority of the population, bide their time and stay dormant in healthy individuals. A window of opportunity, where the individual's immune system is not working at peak efficiency, may be seized by the viruses to proliferate. In the process of their proliferation they seize control of the machinery of the cells they infect, subverting the fail-safes that are built into the system. The end result may, in some instances, be cancer. Once again, like the ever present criminal element in any population, all most all of us have one or more of these viruses present in us since childhood. The trick is to keep them under constant control, and even if they flare up, as in the case of an innocent Herpes Simplex cold sore, regaining control soon enough to prevent mischief. Below are some links you can browse to learn more about the viral connections of some cancers.

BBC News Article on Cervical Cancer Vaccine;
NEJM Article on SLVL and Hepatis C Virus;
JNCI Artice on Connecting Viruses to Cancer: How Research Moves From Association to Causation.

All forms of chemotherapy we are likely to encounter play the percentages: does the particular drug have a high percentage of success in killing the cancer cells, but a low percentage of risk of killing or mutating normal cells needed for proper functioning of the body, especially the immune system? Does the risk increase if a patient is in an immune-deficient state for a long period of time? How proactive should doctors be to catch and nip in the bud incipient neutropenia? There are no hard and fast rules on these issues. We are still on the learning curve in many of these areas and to make the situation even more complex, different patients seem to react very differently to periods of neutropenia. It is always a good idea to discuss with your doctor your options if you are prone to frequent and persistent infections and take the necessary precautions to avoid infections through prophylaxis and behavior modification, especially if you are going through a phase of immune suppression.


J Clin Oncol 2003 Apr 1;21(7):1352-8

New malignancies after blood or marrow stem-cell transplantation in children and adults: incidence and risk factors.

Baker KS, DeFor TE, Burns LJ, Ramsay NK, Neglia JP, Robison LL.

Departments of Pediatrics and Medicine, Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN.

Purpose: To determine the incidence and risk factors for the development of new malignancies occurring after stem-cell transplantation (SCT).

Patients: Between January 1, 1974, and March 31, 2001, 3,372 patients underwent SCT at the University of Minnesota. From these transplants, 147 posttransplant malignancies (PTMs) were identified in 137 patients.

Results: Excluding nonmelanoma skin cancers (n = 19) and carcinoma-in-situ (n = 5), the remaining 123 cases represented an 8.1-fold (95% confidence interval [CI], 6.7 to 9.6) increased risk of a PTM, an excess risk of 102.7 cases/10,000 persons/yr (age and sex adjusted). This includes a significantly elevated risk for developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML; standardized incidence ratio [SIR] = 300; 95% CI, 210 to 406), non-Hodgkin's lymphoma including posttransplant lymphoproliferative disorder (PTLD; SIR = 54.3; 95% CI, 39.5 to 41.1), Hodgkin's disease (SIR = 14.8; 95% CI, 3.9 to 32.9), or solid tumors overall (SIR = 2.8; CI, 2.0 to 3.7) and in specific for melanoma, brain, and oral cavity tumors. The cumulative incidence for the development of any PTM was 6.9% (95% CI, 5.2 to 8.6) at 20 years post-SCT. For PTLD (n = 43), the cumulative incidence plateaued at 1.4% (95% CI, 1.0 to 1.8) by 10 years post-SCT. For MDS or AML, the cumulative incidence plateaued at 1.4% (95% CI, 0.9 to 1.9) by 10 years post-SCT. The cumulative incidence of developing a solid tumor did not plateau and was 3.8% (95% CI, 2.2 to 5.4) at 20 years post-SCT.

Conclusion: These data reveal that the risk of PTMs, especially solid tumors, continues to increase even 20 years after transplant, necessitating long-term close follow-up for these patients.

PMID: 12663726

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




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