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Cladribine and Fludarabine - compared head to head in major randomized clinical trial

Research just published in the Journal of Clinical Oncology reports on a large randomized clinical trial of 423 patients in the Polish Adult Leukemia Group, PALG-CLL3 Study.

This study compared the purine analog Cladribine (2CDA) combined with Cyclophosphimide with the first line treatment for CLL, Fludarabine and Cyclophosphimide.

Up until this point Cladribine (Leustatin) has been used to treat hairy cell leukemia (leukemic reticuloendotheliosis) and multiple sclerosis.

While Cladribine is a purine analogue and in the same family as Fludarabine it works in a different manner. Chemically, it mimics the nucleoside adenosine and thus inhibits the enzyme adenosine deaminase, which interferes with the cell's ability to process DNA. Cladribine has similar side effects to Fludarabine, like T4 cell reductions, a decline in blood cell counts, increases the risk of herpes virus infections and so on.

This study reported: "Of 423 randomly assigned patients (211 to CC and 212 to FC), 395 were evaluated in the final analysis. The CR and ORR reached 47% and 88% in the CC arm and 46% and 82% in the FC arm (P = .25 and P = .11, respectively). The median PFS was 2.34 years with CC and 2.27 years with FC (P = .51). OS and grade 3/4 treatment-related toxicity were also comparable. Moreover, we did not observe any significant differences in CC and FC efficacy across different patient prognostic subgroups that included patients with 17p13 (TP53 gene) deletion who had poor survival in both study arms."

This study concluded: "Cladribine and fludarabine in combination with cyclophosphamide are equally effective and safe first-line regimens for progressive CLL. Both combinations have unsatisfactory activity in patients with 17p13 (TP53 gene) deletion."

Abstract: Click Here

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Are CLL patients exposed to too much radiation?

A recent paper published by the FDA's Center for Devices and Radiological Health has started an initiative to reduce unnecessary radiation exposure from medical imaging. The two largest emitters of radiation currently are from computed tomography (CT) 'CAT' scan and fluoroscopy.

Medical imaging procedures are vital for modern medicine and offer important clinical information to the physician. In CLL, CT scans can provide information on node and spleen involvement with the disease. But it must ask if the same or similar information can not be obtained by simple 'hands on' palpation of the spleen and lymph nodes?

Certainly, palpation does not offer a high tech image of the node system or spleen, but this is not needed for most CLL patients at diagnosis. What is needed to be known is by how much the nodes and spleen are swollen.

Even in treated of relapsed patients CT scans may not be of added benefit.

A report in relapsed CLL patients in The Journal of Clinical Oncology, 2007, stated;
"Current CLL response criteria are a significant predictor of PFS in previously treated CLL patients, with no additional benefit from the inclusion of CT scans. Although retrospective, these results highlight the importance of prospective validation of CT scans before routine inclusion in CLL response criteria." Read More Here

The 2008 revision National Cancer Institute–Working Group's CLL Treatment Guidelines by Michael Hallek states;

3.5.2.2. CT scans generally are not required for the initial evaluation or follow-up. Moreover, the staging of CLL does not use CT scans but relies on physical examination and blood counts.

In clinical trials, in which the treatment intent is to maximize complete remission (CR), chest, abdominal, and pelvic CT scans are recommended to evaluate the response to therapy. One CT scan should be performed before the start of therapy and another CT scan at the first re-staging after therapy if previously abnormal.

It is important to look at the dose of radiation CLL patients get during each scan. According to the FDA report "The adult effective dose from a CT exam of the abdomen is roughly equivalent to the adult effective dose from roughly 400 chest x-rays". (8 mSv) (Mettler, Jr. FA, et al., July 2008.)

Considering this dosage, would you have 400 chest x-rays in a row?

The American National Council on Radiation Protection and Measurements (NCRP) states that the U.S. population’s total exposure to ionizing radiation has nearly doubled over the past two decades. NCRP estimates that 67 million CT scans, 18 million nuclear medicine procedures, and 17 million interventional fluoroscopy procedures were performed in the U.S. in 2006, and the authors predict that these figures will continue to grow.

Clearly, CT Scans have a benefit and a risk. It is a personal decision between you and your doctor, but it may make very good sense to have one CT scan shortly after diagnosis to set a baseline of the spleen and node involvement and a second after treatment.

However, since CLL patients are at a 2.2 times greater risk for all secondary cancers according to a MD Anderson Study (2009) each patient must question the over use of diagnostic radiation, particularly CT scans, which may increase risk of cancer.

Like most diagnostics, CT scans are an important medical tool, but many feel they are over used. The FDA recognizes the importance of empowering patients with information and tools to help them and their physicians manage their exposure to radiation from medical imaging in the short term, even before longer-term changes take effect.

It is highly recommended that CLL patients keep a record of your radiation exposure.
To this end, an X-ray Report Card is available in .pdf format: HERE

FDA Paper - Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging

More Information on CT Scans:

Click Here and
Click Here

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Transgenic goats make a better anti-CD20 monoclonal antibody

An announcement today from GTC Biotherapeutics states that it has achieved high-level production of TG20; an anti-CD20 monoclonal antibody (MAb). The TG20 MAb, which is produced in the milk of transgenic goats, is being co-developed by GTC and LFB (a French Company) as part of the LFB-GTC joint venture. (The LFB Group is the leading manufacturer of plasma-derived medicinal products in France and 6th worldwide and is also among the leading European companies for the development of monoclonal antibodies and new-generation proteins based on biotechnologies.)

TG20 has enhanced antibody-dependent cell-mediated cytotoxicity (ADCC), a key feature useful in the treatment of cancer and auto-immune diseases, and it has been shown to have 10-fold enhanced ADCC when compared side by side with rituximab in assays performed with B-cell chronic lymphocytic leukemia, or B-CLL, patient cancer cell isolates.

Under their joint venture, GTC and LFB are developing TG20, a MAb that targets the CD20 receptor of the immune system with target specificity similar to the rituximab MAb (Rituxan®, MabThera®). This antibody has demonstrated a significantly higher ADCC than rituximab. ADCC is one of the mechanisms that the immune system uses to kill cells targeted by a specific antibody. Therapeutic MAbs with increased ADCC are believed to offer more potent treatments for oncology indications. Rituximab has received marketing approval in both the EU and the U.S. for rheumatoid arthritis. Worldwide sales of rituximab were approximately $5.6 billion in 2009.

Article

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ATM gene - not the machine

The genetic basis for CLL is partly known. It has been demonstrated by FISH test that the ATM gene is mutant in approximately 20% of samples from CLL patients and that some patients have heterozygous germ line mutations.
The ataxia telangiectasia-mutated gene (ATM) encodes a protein kinase that acts as a tumour suppressor. (Kinase enzymes modify other proteins by chemically adding phosphate groups to them). The ATM protein coordinates DNA repair by activating enzymes that fix the broken double strand breaks (DSBs) of DNA that it finds, rather like glue. The ATM protein is found to be missing on the long arm of 11q chromosome at position 22.3 (aka - 11q:22.3) of CLL patients and is also associated with many other types of cancers as well, like breast cancer. The ATM gene is extremely important to cell repair and survival and it works in conjunction with TP53, found of 17p chromosome (17p:13), to achieve cell death (apoptosis).

The primary function of ATM is to check cells for defects due to radiation damage and repair them if it can be done. Without any functional ATM protein cells are hypersensitive to radiation and do not respond normally to DNA damage. Instead of activating DNA repair, the defective ATM protein allows mutations to accumulate in other genes, which may cause cells to grow and divide in an uncontrolled way.

ATM tries its best to repair cell damage but at some point p53 (protein) assesses the repair process and if it is not going as expected, then TP53 actually sets up the cell death.

In some CLL patients parts of the 11q:22.3 chromosome and the 17p:13 chromosome are damaged or missing. This prevents two important things from occurring. The first failure is the inability to repair damaged genes with ATM, and second failure is to kill defective cells with TP53 (the gene).

Both 11q and 17p deletions are considered the most aggressive forms of CLL, probably because cell repair is blocked by no ATM and cell death fails without the TP53 gene.

ATM Genetics: ATM

More than you ever want to know about ATM: Venture Here

More Information of CLL Genetics (.pdf): Click Here

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Familial CLL study in Norway & Denmark

This is a new study looking at approximately 800 cases of CLL. In 56 (7%) out of 800 CLL patients with hematological diseases of all kinds, 51 families and 141 cases of CLL were determined.

Of the total 141 cases of all malignant hematological disease, 107 or 75% were CLL.

Researchers in this study found that paternal (father's side) CLL disease, was transmitted primarily to the youngest sons, but maternal (mother's family side) showed equal distribution of CLL to all siblings. This was demonstrated by means of matrix conjugation and confirmed with Cox regression on parity and birth order.

In this study, researchers found that B-cell expression was exactly the same in familial CLL and sporadic CLL. They also concluded that paternal genomic imprinting is pointed out as one possible mechanism behind this non-Mendelian genomic output.

Source: In Vivo. 2010 Jan-Feb;24(1):85-95., Pay Per View Article

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Cutaneous Richter’s syndrome ~ Extremely Rare

Richter’s syndrome (RS) corresponds to the transformation of chronic lymphocytic leukemia (CLL) into high-grade lymphoma. RS can involve extranodal sites including the gastrointestinal tract, lungs and skin. Cutaneous RS is rare. In this study researchers describe 4 cases with clinical manifestations, histological and immunohistological patterns, and outcome.

Methods: Clinical data was analyzed and all patients’ skin biopsy samples stained with HE for the CD20, CD5, CD3 and CD30 antigens. Epstein-Barr-virus (EBV)-encoded early RNA and clonal rearrangements were also analyzed.

Results: The patients’ mean age at CLL diagnosis was 57 years (53–62 years), with a male/female sex ratio of 3:1. The transformation to cutaneous RS occurred between 8 and 75 months after initial diagnosis and progressed to a fatal systemic disease in 3 cases, between 24 and 129 months. Cutaneous CLL was associated with earlier transformation in our series and could not be distinguished from RS on clinical grounds alone. All patients in the study had a large-cell infiltrate and clonal rearrangements.

Conclusions: The precise mechanism of RS is unclear, but a role of EBV has been suggested in fludarabine-treated CLL. For all patients, the diagnosis of transformation was made on the basis of cutaneous localizations and led to intensified CLL treatment.

Abstract Link: Dermatology (DOI: 10.1159/000269737)

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Information on the CLL CANADA website (www.cllcanada.ca) is intended to be used for general information and educational purposes and should not replace consultation with healthcare professionals.
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