B-cell Chronic Lymphocytic Leukemia: the “Good” Cancer?

Carl learned this year that he has the “good” kind of cancer. Carl knows a contradiction when he hears one. Although Chronic Lymphocytic Leukemia (CLL) isn’t the automatic death sentence that many of its relatives are, the “good” lies more in the leaps and bounds that research is taking toward effective treatments rather than any good feeling Carl might have had when his doctor told him “if you have to have cancer, this is the good one to have.” The war waged by medical researchers upon the slowly-progressing yet wily disease of Carl's immune system is far from won, but doctors have developed a new arsenal in the past ten years that is rapidly increasing their options for treatment. In this article, we will follow Carl through his diagnosis and treatment options to provide an overview of CLL, how it progresses, a history of treatments and how they work, and new clinical research.

What is CLL?

CLL begins with one mutation in a B-lymphocyte, a white blood cell that fights infection. This cell multiplies, replacing and crowding out normal lymphocytes with CLL cells that can't fight infection (Figure 1). A routine blood test which showed high lymphocyte count, and additional blood tests which showed low immunoglobulin levels and extra lymphocytes with particular antigens or epitopes on their surface brought Carl into the company of 100,760 Americans—most aged 50 and above--living with the most common form of blood cancer.

“CLL progresses very slowly,” his oncologist told him. “While there's no cure, if it does start to act up we can do a lot to treat it. You'd be more likely to die of old age before this one will take you out.”

His physician pointed out that while some people with early stage disease can live with it for twenty years, as the disease advances it decreases quality of life and survival time which prompts the ultimate puzzle: when do you treat CLL? How do you do it?

CLL Staging and Treatment History

Leukemia researcher Dr Kanti Rai developed a staging system (see Table 1) to predict CLL prognosis and determine when to treat patients. It's been accepted in the U.S. and worldwide since 1975. However, the past ten years have brought on board CT scans and flow cytometry techniques—reflecting laser beams off streams of cells and chromosomes suspended in a stream of fluid to provide information about each particle's structure--which tell doctors about patient-specific DNA or the genetic profile of the individual cancer cells so they can better predict the course of the disease (see Table 2).

Carl's high lymphocyte count and a slightly enlarged spleen first prompted diagnosis as low-risk, but his low platelet count is a high-risk prognostic factor.  Actual numbers of CLL cells in the blood and bone marrow are an important prognostic factor, along with the cells' physical appearance under a microscope. So a CLL specialist recommended “watchful waiting” until a rapid change occurred. When lymph nodes started to swell in his neck and white blood cell counts increased, she advised chemotherapy to put the CLL into remission and regain normalcy in blood counts, thus prolonging Carl's life and maintaining its quality. The CLL will eventually come back, but multiple treatments could keep it in check for years.

Twenty years ago, Carl would probably have been given a prescription for the “gold-standard” drug, Chlorambucil, to keep his symptoms in check and then been sent on his way. It achieves 51% partial remission rate for 18 months, but rarely sees complete remission [2]. Combined with other drugs, it could yield higher response, but not longer survival rates. Were Carl a lot younger, physicians might have suggested a bone marrow transplant to stop production of the CLL cells and to let the donor stem cells produce mutation-free lymphocytes. But now, Carl has other, safer options for long-lasting treatments thanks to research that has flourished in the past decade.

The Past 10 Years

The three types of drug now used to treat CLL are alkylating agents which damage the DNA in cancer cells; purine analogues which mimic structures in DNA in order to inhibit enzymes in DNA replication; and monoclonal antibodies which bind to particular structures called antigens or epitopes on the CLL cell to identify it for destruction by the immune system.  Combining them is most effective.

Fortunately Carl's health insurance will cover him for the current recommended first-line treatment: a cocktail called “FCR.” Purine analogue Fludarabine (“F”) on its own was hailed as the gold standard as it achieved an overall response rate — complete and partial remission— of 80% over the past decade [3]. But overall response further increased when combined with alkylating agent cyclophosphamide (“C”) and increased again with the addition of monoclonal antibody Rituximab (“R”). Rituximab resulted in a huge step forward, as it targets one of the most common antigens ( ‘CD20’ where the cluster designation number, CD, identifies a specific protein) on CLL cells without killing as many normal cells as Fludarabine would. This is pretty potent stuff, so it's a good thing that Carl worked to maintain his level of fitness; he should, therefore, be able to handle the side effects better than a weaker patient who would have to be given a less potent combination.

Ill patients, or those in whom standard treatment is useless due to a specific CLL gene mutation or other poor prognostic factors (see Table 2), have other options. Cambridge University researcher Herman Waldmann led the development of Campath (alemtuzumab, a monoclonal antibody that targets heavily-expressed CD52 antigen), which, administered on its own, yields results in patients with one high-risk mutation form of CLL that renders FCR useless. The risk? Lots of other good cells express CD52 and can get wiped out in the process. And Campath can be deadly when combined with fludarabine and cyclophosphamide [6].

Unfortunately, even the most potent treatment won't cure CLL—the mutated cells will gradually grow back and might be nonresponsive to a repeat of the original treatment.  If it comes back before 6 – 12 months or the treatment just didn't work, treating with alemtuzumab alone, a combination of alkylator bendamustine with Rituximab that has fewer side effects than FCR, or one of many clinical trials can send CLL into another, albeit likely shorter, remission.  Additionally, cancer cells can mutate and lead to worse prognoses over time or even to other types of cancers.

Current Developments

Carl hoped that he could wait to start CLL treatment, because the rate of developing clinical trials is soaring and a new drug might further increase overall response rate and progression free survival time. But waiting to treat can make it harder to control the disease. The key to longer-lasting treatments may lie in eliminating minimal residual disease, traces of CLL leftover after chemotherapy that can then be singled out and cleaned up with monoclonal antibodies. Minimal residual disease is said to be “none” when blood counts show less than one CLL cell per 100,000 lymphocytes [3].

Bring on the radiation. Tositumomab, branded as Bexxar and conjugated with radioactive iodine, binds to CD20 antigen in relapsed or refractory CLL, then delivers radiation to kill the tumor cells that weren't already killed [9]. Carl hopes for longer-lasting effects from the very specifically tailored dose. But he's not going to wait until his CLL no longer responds to therapy. His physician has suggested he volunteer to participate in a Bexxar clinical trial just a few months after his last FCR treatment.

And, in the unlikely event that Carl doesn't respond well to FCR and Bexxar, he'll probably participate in another clinical trial of a potent drug that's been shown useful in relapsed and refractory CLL (that is, CLL that has returned after the last treatment): flavopiridol inhibits the cell reproduction cycle at a key step; lenalidomide helps raise immune response, and oblimersen blocks the production of a protein that makes cancer cells live longer [7]. Additionally, monoclonal antibody Ofatumumab was granted approval by the US Federal Drug Administration in 2009 for use when Rituximab is ineffective as it has a higher affinity for CD20.

If things get really bad, adding Rituximab to a combination of cytotoxins is a salvage treatment for refractory CLL that doesn't respond to fludarabine [8]. But Mayo Clinic's experimental treatments include replacing fludarabine with pentostatin in the classic FCR cocktail to see if the remission will occur and be maintainable with Campath treatment. The duration of cycles of treatments is also under analysis, as lower doses and fewer cycles may make room for other innovative agents [3].

What happens next

With forward-thinking doctors and doing his part to maintain good health, Carl has every chance of having a long progression-free survival. He knows it's not good to have CLL, but good questions are being asked: Are there treatments that are better than the current standards? Can treatments be better tailored to individual prognoses? Can novel anti-CD20 antibodies enhance treatments?

“CLL patients can now reap the benefits of the years of exciting research ” he comments, “but the complexity of tailoring a specific treatment to an individual makes one appreciate that medicine is a combination of art and science.”

References

[1] Byrd, J., A new twist for CD38 antigen expression in CLL. Blood 105:3002 (2005).

[2] Eichhorst, B.F. Et al., First line therapy with fludarabine compared to chlorambucil does not result in a major benefit for elderly patients with advanced chronic lymphocytic leukemia. Blood 114.16:3382-3391 (2009)

[3] Hallek, M., State-of-the-art treatment of chronic lymphocytic leukemia. American Society of Hematology 440-449 (2009).

[4] Jurisic, V. et al, Analysis of CD23 antigen expression in B-chronic lymphocytic leukaemia and its correlation with clinical parameters. Med Oncol 25:315-322 (2008).

[5] Klatt et al., Blood (1994).

[6] Lepretre, S. et al., Immunochemotherapy with Fludarabine (F), Cyclophosphamide ©, and Rituximab ® (FCR) Versus Fludarabine (F), Cyclophosphamide (C) and MabCampath (Cam) (FCCam) in Previously Untreated Patients (pts) with Advanced B-Chronic Lymphocytic Leukemia (B-CLL). American Society of Hematology 51^st Annual Meeting Abstracts (2009).

[7] Maddocks, K.j. And Lin, T.S., Update in the management of chronic lymphocytic leukemia. Journal of Hematology & Oncology 2.29 (2009).

[8] Tonino, S.H., R-DHAP is effective in fludarabine-refractory chronic lymphocytic leukemia. Leukemia 24:652-654 (2010).

[9] Vose, J.M., Bexxar: novel Radioimmunotherapy for the Treatment of Low-Grade and Transformed Low-Grade Non-Hodgkin's Lymphona, The Oncologist 9.2:160-172 (2004).

Tables and Figures

Figure 1: Purple-stained leukemia B cells under a microscope (photo: Klatt 1994)

Table 1: Rai CLL Staging

STAGE	CHARACERISTICS	RISK
0	High lymphocyte count (>15,000/mm^3) only	Low
I	High lymphocyte count and enlarged lymph nodes	Intermediate
II	High lymphocyte count and enlarged spleen or liver with our without enlarged lymph nodes	Intermediate
III	High lymphocyte count and low red blood cell count (hemoglobin <11g/dL), with our without enlarged spleen or liver or lymph nodes	High
IV	High lymphocyte count and low platelet count (<100,000/mm^3), with our without enlarged lymph nodes, liver, spleen, or low red blood count	High

Table 2: CLL Prognostic Indicators

TEST	WHAT IT IS	POSSIBLE OUTCOMES	PROGNOSIS
Flourescence in situ hybridization (FISH)	An antibody is attached to a flourescent dye and mixed with population of cells; cells with the anigen that can bind to the antibody will flouresce. This picks up abnormalities in chromosomes.	Deletion in long arm chromosome 13 [del(13q)]	Normal
		Trisomy chromosome 12	Slightly worse than del(13q)
		Deletion in long arm of chromosomes 11 or 6 [del(11q)] or [del(6q)]	Worse than del(13q) and trisomy 12
		Deletion in short arm of chromosome 17 [del(17p)]	Inferior: resistant to standard therapy
		Mutation of 53p	Inferior, resistant to therapy
Imunoglobulin variable-region heavy chain (IgVH) mutation status	Whether or not the gene controlling the shape of immunoglobulin on the B-cell has undergone the mutation that lets it fight a specific antigen	Unmutated	Inferior
		Mutated	Superior
ZAP-70 expression	Expression of zeta-chain associated protein kinase 70 on CLL cells; indicator of IgVH mutation status, more viable test than IgHV sequencing	Positive	Inferior
		Negative	Superior
Immunophenotype	Expression of surface antigens—proteins that recognise certain antibodies and can defend against them--compared to normal B cells	CD20, CD19, CD79b low expression	Normal diagnostic
		CD23 low expression	Poor: decreased in advanced stages [4]
		CD38 expression	Poor: drug-resistant [1]