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Welcome...

CLL CANADA.ca is for patients, caregivers, families and companions of CLL patients. The information contained here is from the experiences of CLL patients and should never be considered expert medical information or opinion.

Here is an excellent overview of CLL Treatment Options from 2006. It is important to note that some of the treatments mentioned are still not available in Canada and/or the drug is available, but not paid for under provincial drug plans. These drugs can easily run tens of thousands of dollars - out of pocket. Further, many transplants mentioned in the article are based on age and physical condition, and many CLL patients are too old (generally 55 yrs or more) or unfit to qualify after standard drug treatments, which are used first, because of lower risks and expense.

Possibly the most important document you can read is the 2008 CLL Treatment Guidelines (.pdf file) by Michael Hallek et al.

British Journal of Haematology, 2004: Guidelines on the diagnosis and management of CLL

ASCO - Cancer.Net - CLL Overview

Diagnosing and Treating CLL in 2009 in .pdf
New Menus for CLL Treatment .pdf
Interesting Times in the Diagnosis and Treatment of CLL .pdf

~chris

DX 2000, W&W Stage 1, WBC September 2009 -93K, January 2010 -47K

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Is MDR your treatment goal?

It has been known for a number of years that the eradication of Minimal Residual Disease (MRD) is associated with longer progression free survival (PFS). While fludarabine based therapies coupled with monoclonal antibodies have been shown to produce high rates of overall response in CLL, very long term survival is still illusive.

Part of the problem in the past has been the ability in the clinic to determine the amount of residual disease that a patient has after treatment. In the past few years however, new types of tests have become available, like 4 colour Flow Cytometry or Polymerase Chain Reaction (PCR) that are now capable of finding a single CLL B-cell in 10,000 leukocytes in peripheral blood. More - Genzyme MRD Flow Cytometry

Getting a CLL patient to be negative (-MDR) should be the goal of treatment according to the GCLLSG - CLL8 study. They randomized 817 previously untreated patients to FC and FCR. The importance of eradicating minimal residual disease was confirmed by this trial, which demonstrated that progression free survival (PFS) depended upon the ability to eradicate MRD.

In addition to reaffirming the importance of eradicating MRD, the GCLLSG CLL8 study demonstrated that MRD can be determined from peripheral blood and that bone marrow biopsies are not necessary to gain MRD information, eliminating an intrusive patient procedure and opening the way for better testing at the clinical level.

A paper present at ASH 2009 stated about MDR that; "achieving MRD negativity in CLL is an independent predictor of survival in multivariate even when a variety of different treatment approaches are considered and regardless of the line of therapy. This is the strongest evidence yet that achieving MRD negativity is the most appropriate aim of therapy in CLL for patients who are fit enough for such an approach. Furthermore patients who achieve MRD negativity after their first therapy have a 5 year PFS of 89% and a 5 year overall survival of 95% suggesting that the optimal time to attempt to achieve MRD negativity is with first line therapy."

But in 2010 is eradication of Minimal Residual Disease (MRD) a treatment goal?

CLL207 MRD Eradication Study has just ended and will publish later this year. The study looked at using Campath-H (alemtuzumab) to eliminate MDR. Link Here

CLL207 Study .pdf

CLL207 Interim Report

See More Here about MDR and Campath-H

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Treanda®, (Bendamustine, Ribomustin) in Canada? It is rumoured...

There have been some indications that Bendamustine may be available if your doctor makes a request to the Special Access Programme (SAP) of Health Canada.

Requests are assessed on a case by case basis, and require the co-operation of the drug company (Cephalon).

The huge Catch-22 for many is that you must pay for it yourself at about $8000 for a single dose, it is rumoured. Based on infusions day 1 and day 2 (this is a single cycle) on a 28 day, 6 cycle treatment, then the cost would approach $96,000.

Clinical Trials in Canada: Here

More Information on Treanda: Here

Average Wholesale Cost in USA 2008 (Murray L. Red Book: Pharmacy’s Fundamental Reference. Montvale, NJ: Thomson PDR; 2008): See Here

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TP53 Gene

Note: Often TP53 and p53 are used interchangeably. We have opted to call the gene TP53 and the cellular tumour antigen, p53.

TP53 (aka p53) like the Rb gene is a tumour suppressor gene, located on chromosome 17p13.1, which stops cell division when DNA damage is present, thus allowing DNA repair to occur before cell division. It's product is a protein called p53. This protein is responsible for the death of DNA damaged cells and is thought to be brought about through its phosphorylation. [a common process where a protein's amino acids are changed by addition of a phosphate (PO₄) group]

This phosphorylation is mediated by ataxia telagiectasia mutated gene (ATM), found at 11q22-23. In the absence of TP53 activity, cells that cannot be repaired by ATM will continue to proliferate in their damaged state. In CLL patients with 11q deletion, the ATM gene is usually missing, so this repair process can not take place. Patients deleted for TP53 may be rendered resistant to alkylating chemotherapeutic agents as these are designed to damage the DNA in the cells that TP53 would have destroyed. When TP53 does not function normally due to gene mutations or a gene deletion, cancer cells can accumulate, as in CLL. In the cell, p53 protein binds DNA, which in turn stimulates another gene to produce a protein called p21 that interacts with a cell division-stimulating protein (cdk2). When p21 is complexed with cdk2 the cell cannot pass through to the next stage of cell division. Mutant p53 can no longer bind DNA in an effective way, and as a consequence the p21 protein is not made available to act as the 'stop signal' for cell division. Thus cells divide uncontrollably.

Over 10% of patients with B-CLL have a dysfunctional TP53 gene. Patients may have TP53 mutations, a TP53 deletion or both. Recent research, primarily from Creighton University, Omaha, Nebraska has found that CLL patients with 17p deletions may also have two mutated copies of TP53.

Mutations and deletions in TP53 predict poor survival in B-CLL patients (median survival 6-31 months) versus those patients without TP53 abnormalities (median survival of patients with normal karyotype >100 months).

Several studies have demonstrated that alkylating agents (Cyclophosphamide, Chlorambucil), purine analogs (Fludarabine, Pentostatin, Cladribine) and some monoclonal (Rituxan) therapies are ineffective in treating CLL patients with TP53 mutations and/or deletions. Finally, chemotherapy can cause TP53 gene alterations, such that even if not present at initial diagnosis, refractory CLL can exhibit new alterations of TP53.

Mutations or deletions of TP53 is seen in many cancers, not just CLL/SLL.

Main Source: Genzyme Genetics p53 Mutation Analysis in B-Cell

TP53 Website: Extensive Information

P53 Knowledgebase

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Canadian Cancer Charities

These figures are based on MoneySense Magazine (Dec/Jan 2010) Article Here


The figure for the Leukemia & Lymphoma Society (International 2008) is from their website. See Here

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Bendamustine ~ not a Treanda in Canada unfortunately!

Bendamustine (Ribomustin, Treanda, SDX-105) is NOT currently approved for use with CLL in Canada.

Bendamustine is the first drug approved for patients with CLL in the US since 2001. It is a mechlorethamine derivative with structural similarity to Chlorambucil and other drugs from the nitrogen mustard class, as well as a benzimidazole ring, which may act as an antagonist to purines and amino acids. So simply put it is similar to Fludarabine and Chlorambucil combined as one.

Synthesized in 1963 in East Germany (the former German Democratic Republic), it is a white, water soluble microcrystalline powder with amphoteric properties. Until 1990 it was available only in East Germany but is now licensed to Cephalon.

While Bendamustine does not seem to be as reactive in CLL as Fludarabine and Cyclophosphimide (FC), it also has little cross resistance to other alkylating agents and remains active even in extensively pretreated patients. This means it can work in situations where other drugs have become refractory. (Note: Cladribine also has this property) Like FC, Bendamustine can be used in combination with monoclonal antibodies like Rituxan or Ofatumumab which increases its effectiveness.

FDA approval for use in CLL was based on findings from a randomized, open-label, Phase III study comparing Bendamustine with Chlorambucil as single-agent therapy in treatment naive patients with CLL. But like all CLL treatment, Bendamustine has side effects, the most common being non-hematologic adverse events include fatigue, nausea, xerostomia, and pyrexia.

While Bendamustine has been used in Central Europe to treat CLL for years it is only now being studied in North America, however most clinical trials deal with Non-Hodgkin's Lymphoma. (NHL) There are currently two trials in Canada for Bendamustine, one for Mantle Cell Lymphoma, the other for NHL.

Bendamustine is being very actively studied in Europe, German and Austria and several locations in the USA. Regrettably, there are no Bendamustine - CLL trials available in Canada at this time.

More here: Bendamustine mono-therapy in advanced and refractory CLL

and here: Bendamustine ~ Drug Portal with many Links

Full Prescribing Information .pdf

Treanda Website ~ Patient Information

Old and New Alkylating Agents - Presentation (Bendamustine - Mostly NHL but some CLL references)

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Deletion 13q14 - Much more complex

For a number of years it has been the view that patients with 13q14 deletion have a favourable outcome. But this may be changing.
A recent study published in Haematologica looked at 350 Cll cases and found that 109 people (31.1 %)had a 13q deletion as a single genetic defect. In this subgroup they took a subset of 18 patients with greater than 80% of 13q deletion in their cells. Read Article Here

The conclusions state; "Patients with B-cell chronic lymphoid leukemia with a high number of losses in 13q14 as the sole cytogenetic aberration at diagnosis display different clinical and biological features: short overall survival and time to first therapy as well as more proliferation and less apoptosis. A quantification of the number of cells showing a genetic abnormality should, therefore, be included in the study of the prognostic factors of B-cell chronic lymphoid leukemia." (Haematologica, Vol 94, Issue 3, 364-371 doi:10.3324/haematol.13862)

Genetic markers are analysed by tests like FISH (Fluorescent in situ hybridization) and more recently by the newer and more inclusive comparative genomic hybridization arrays.(CGH) See: Hemescan Research

In 2008, Dr. Malek et al at the University of Michigan, Ann Arbor, found that 13q14 was far more complex than first considered. They realized that 13q14 deletion could be subdivided into two subgroups, type I and type II. Broadly these two types are separated by having (type I) or not having (type II) the retinoblastoma gene (Rb), a prototype tumour-suppressor gene.

Recent work at the Mayo Clinic Abstract Here is finding that some CLL patients not only have a 13q deletion but also additional deletions, like 1q22.3, 17p13.1, or trisomy 12. They concluded that "The clinical implications of 13q- in CLL appear more complex than originally appreciated".

Just this month, Malek has published a paper looking not only 13q14, but also patients having multiple DNA deletions. In conclusion, Makel et al states; "Our quantitative analysis links multiple molecular defects, including for the first time del11q and large 13q14 deletions (type II), to elevated genomic complexity in CLL, thereby suggesting mechanisms for the observed clinical aggressiveness of CLL in patients with unstable genomes." Read Abstract Here

Clearly, the genetic damage in CLL is not nearly as simple as once thought and genetic testing is absolutely essential to the proper management and treatment of this cancer.

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LD Barometer in CLL

Lactate dehydrogenase (LD aka LDH) is an enzyme found in many cells of the body. There are 5 types numbered from LDH1 to LDH5. These are very specific:

• LDH-1 (4H) - in the heart
• LDH-2 (3H1M) - in the reticuloendothelial system
• LDH-3 (2H2M) - in the lungs
• LDH-4 (1H3M) - in the kidneys
• LDH-5 (4M) - in the liver and striated muscle

There is a daily turnover of cells in the body and as cells die the LD enzyme is released into the blood stream. This constant turnover of cells means we always have a measurable amount of LD in our blood.

In times of trauma to the body, like a heart attack or perhaps a car accident, cells die at an increased rate. The LD levels in the body are like a barometer to cell activity and tumour load. It is not so important to know the level of LD, but rather to observe the changes in LD levels. There have been some attempts to link LD levels and clinical staging in CLL, but nothing concrete has come of it to date. There have been some indications that patients with 17p deletions and poor prognosis have raised levels of LD, when compared with patients with good genetic markers 13q. LDH levels and genetic markers

In CLL, rising LD levels may indicate a progressive disease stage or perhaps a transformation while falling levels could mean the cancer is less aggressive. In HIV patients LD levels may indicate the onset of pneumonia for example. Often in CLL, elevated LD levels may signal hemolytic anemia. This is especially true after treatment. Also, over 50% of CLL to Richter's transformation cases have elevated LD levels.

Some treatment for CLL will cause LD levels to jump as will tumour lysis syndrome sometimes occurring with Revlimid (Lenilidomide) treatments.

Any significant rise in LD levels of unknown cause should be carefully investigated by a hematologist. It could be as simple as improper handling or storage of blood samples in the lab. Whatever the cause, it needs thorough investigation.

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Refractory to Fludarabine?

Frontline FCR, not in Canada yet

Patients that use purine analogs like Fludarabine, Pentostatin and Cladribine or combination therapies like Fludarabine plus Cyclophosphimide (FC) and Rituxan (FCR)(PCR) etc. can become refractory to them. This simply means that the treatment no longer works, or works very slowly. Martinelli states, " These (refractory) patients are characterized by a very poor prognosis, with a median survival of 10-13 months." (Giovanni Martinelli, Oncoematologia, Istituto Europeo di Oncologia, Milano, Italy, 2007)

For the past few years, FCR has been considered the frontline treatment for CLL in much of the world. While Fludarabine and Cyclophosphimide are available under healthcare plans in Canada, the Rituxan portion is not yet paid for in most provinces. It will cost you about $15,000 out of pocket, should you decide to use this treatment 'add-on'.

Based on CLL4 and CLL8 (Phase III) trials (See More Here), FCR is the best treatment for CLL. This view has been further supported by the work at MD Anderson. Unfortunately, the trials at MD Anderson were neither randomized nor controlled. They were for the most part Phase II trials, where unconscious bias could influence the outcome, which leads to controversy.

How does this happen - selection by treatment?

Dr. Terry Hamblin, a renowned British CLL researcher, stated in 2005, "It seems likely that patients with CLL often have small numbers of cells that are missing p53, but these are kept under control by the presence of the other CLL cells. After effective treatment, even if there is a complete remission and no evidence of minimal residual disease by a sensitive test, there are always some CLL cells left behind. These are the resistant ones; often the ones that lack p53. When they grow back most of the cells will lack p53 and be resistant, and only sensitive to Campath or high dose prednisolone. Campath is even more immunosuppressive than fludarabine and high dose prednisolone not much better." More Here

Refractory to Fludarabine in Canada

The hard truth is our selection of available treatments for refractory Fludarabine patients in Canada is very poor compared to the U.S. Currently, the best hope for further treatment is probably to enter a clinical trial or perhaps try Campath-H or high dose Methylprednisolone and Rituxan when available. (I recommend you read the article about Campath-H (alemtuzumab) below on this page ~chris)

Refractory to Fludarabine ~ Now What

There was a study done in 2003 that Cladribine will work on Fludarabine refractory patients LINK HERE. While Cladribine is similar to Fludarabine, it uses different signal pathways. Other options are Treanda (Bendamustine) and Revlimid (Lenilidomide) . These can also be combined with monoclonal antibodies in some cases.

A final word

It is important to understand that becoming refractory to a treatment can happen with most current CLL therapies. Unfortunately treatments just stop working. This is true for Campath-H or Rituxan as well. The only treatment that appears not to have this failing is Bendamustine. It seems to work repeatedly and it may also work well on patients refractory to FCR.

For some high risk patients that become refractory, there may also be the option of a bone marrow or hematopoietic stem cell transplantation (HSCT) autologous or allogeneic. HSCT are a high risk procedure that may buy you 3-5 years, perhaps longer. It is not a cure and CLL will return in time. Your age, finding a suitable donor, overall health and ability to pay a portion of the costs are the major determining factors. Total costs can run well over $800,000 ++. Generally HSCT are only considered for patients under 55 years old with no comorbilities. The average age from the European BMT Registry is 53 years old. Allo-HSCT from Related and Unrelated Donors for CLL from the EBMT Registry

For a comprehensive overview of HSCT and its use in CLL by Dr. John Gribben, Institute of Cancer, Barts and The London School of Medicine, London, United Kingdom ~ Link Here

For an excellent and critical overview of FCR by Thomas S. Lin, Michael R. Grever, John C. Byrd ~ Link Here

And an informed opinion by another CLL patient on FCR ~ Link Here

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German study sheds light miR-34

The study "The miR-34 family in cancer and apoptosis", starts to explain the association between p53, ATM and miR-34.These are all involved in CLL.

Mutations in the p53 tumour suppressor gene are found in nearly all types of cancers. The transcription factor encoded by the p53 tumour suppressor gene is post-transcriptionally activated by DNA damaging agents/radiation, oxidative stress or activation of oncogenes. The critical signals induced by these events are presumably DNA double-strand (ds) breaks, which activate ATM kinase that in turn phosphorylates p53. In 17p deleted CLL patients, DNA section is missing where the p53 gene should be located. 11q CLL deleted patients are missing the ATM gene. Both the ATM and the TP53 genes are known to control cell death. (apoptosis)

The region encoding miR-15 and miR-16 has been found deleted in 65% of chronic lymphocytic leukemia (CLL). As miR-15/16 targets the anti-apoptotic factor, Bcl-2, the loss of miR-15/16 may explain the up-regulation of Bcl-2 in these tumours. See the work of (Carlo M. Croce, 2006)

About CLL the study states; "Zenz et al. found that the expression of miR-34a is decreased in CLL. This was associated with p53 mutations, chemotherapy (fludarabine)-refractory disease, impaired DNA damage response and decreased apoptosis. Mraz et al. also found that miR-34a is consistently down regulated in CLL with p53 mutations. This implies that the detection of miR-34a expression may potentially be used as a predictor of therapy response. Furthermore, the restoration of miR-34a activity may be useful to prevent chemotherapy resistance."

The full text of this research can be found Here

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Lumiliximab and FCR - Complete Research Paper Available

Dr. Byrd's LUCID trial called "Phase 1/2 study of Lumiliximab combined with fludarabine, cyclophosphamide, and rituximab in patients with relapsed or refractory chronic lymphocytic leukemia" has just been published by Blood Journal today (Jan 23rd, 2010).

This is an important clinical trial and indicates that Lumiliximab, an anti-CD23 monoclonal antibody gives the FCR combination greater anti-tumour effect.

The paper states, "Treatment with lumiliximab combined with FCR was well tolerated, resulted in a high number of patients with a durable CR, and was not associated with increased infectious risk or prolonged cytopenias compared with historical controls."

In conclusion they stated "Overall, these data combined with the preclinical data provide a rationale for further investigation of lumiliximab in combination with FCR, as part of a randomized trial to determine the true added benefit of lumiliximab combined with FCR as a combination therapy for patients with CLL."

Lumiliximab is an immunoglobulin G1, anti-(human immunoglobulin E receptor type II) (human-Macaca irus monoclonal IDEC-152 γ1-chain), disulfide with human-Macaca irus monoclonal IDEC-152 κ-chain, dimer immunomodulator.

Source: Full Article Here

Further research: Here

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High cost of CLL drug - GSK/Genmab's - Arzerra™

Rumours have been circulating for a few months that the FDA approved Arzerra (Ofatumumab, aka Humax-CD20) was going to be expensive.

According to Oncology Business Review a 6 month course of treatment for CLL will run about $98,000. The article states,

"Drug makers have primarily defended the cost of these expensive drugs for rare cancers, and other high-priced cancer treatments, by saying that they fulfill an unmet need for patients who have either few or no treatment options. But critics say that the therapies don’t provide enough benefits to patients to merit the high prices."

An similar article in the New York Times in December 2009 adds; "About $60,000 of the cost would be incurred in the first eight weeks, when the drug (Arzerra™) is given more frequently."

Arzerra™ is a fully human, CD20 cytolytic monoclonal antibody. The question is, how much better is Arzerra than Rituxan? Does it extend life longer in combination with other treatments? Hopefully a head to head trial will settle this issue, but nothing is on the horizon yet. Hoffman-La Roche has RO5072759 going in to clinical trials soon in Canada which is a fully human CD20 monoclonal similar to Arzerra™. If successful in CLL trials it will probably come to replace Rituxan in time.

Source: Article Link
NY Times Article: More Here
More Info: ARZERRA .pdf LINK

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Revlimid approved for CLL in Canada?

No, Revlimid (Lenalidomide, formerly - Thalidomide) was approved on March 27, 2008 by Health Canada, but the use is very specific.

In October 2008, Health Canada approved Revlimid in combination with Dexamethasone for the treatment of Multiple Myeloma patients who have received at least one other treatment regimen.

Currently it is NOT approved for the treatment of CLL.
Access to Revlimid is controlled by RevAid^SM, due to the fact that it is a derivative of thalidomide.

The full decision document can be found here in .pdf : NOTICE OF DECISION for Pr-REVLIMID®

No price for Revlimid is available for Canada, but one 5 mg cap was costing about $348.00
on average in Europe in June 2008. SEE HERE

Note that Revlimid is currently in clinical trials in Canada in St. John and Halifax for CLL see:
THE CONTINUUM TRIAL

Find other Canadian CLL trials here

Articles on Lenalidomide:

Read more HERE ~ Alan G. Ramsay, John G. Gribben

Read more HERE ~ Adrian Wiestner

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UCSD Moores Cancer Center gets $20 million research grant

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Scotland Approves Rituxan for CLL

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GSK to cut research jobs

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Dr. Hamblin discusses SLL

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Copyright 2000~2010 CLL CANADA ~ Designed by ~chris
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.
The information on this site is provided by CLL patients and caregivers.
Consult a qualified healthcare professional before making any medical decisions or if you have questions about your individual medical situation.
Please, do not self medicate.