LLC hypo-gammaglobulinémie

– Très fréquent (10 – 15 % au diagnostic)
– Source d’infection par des bactéries à multiplication extracellulaire (souvent encapsulées (streptococcus pneumoniae, haemophilus influenzae). Mais sont aussi impliqués staphylococcus, streptococcus et entérobactéries
– Pas de corrélation entre la profondeur du déficit, le type d’Ig impliquée et la survenue d’infections

LLC espérance de vie muté ou pas muté

source atelier V Leblon
   Les cellules cancéreuses peuvent chez le malade être "mutées" ou "non mutées" cela est un élément important sur le pronostique de survie....


autre article
the presence or absence of somatic mutations in the immunoglobulin variable region (IgV_H ) genes in chronic lymphocytic leukemia (B-CLL) identifies subtypes with very different prognoses
Median survival time in patients whose cells had unmutated IgV_H genes and expressed CD38 was 8 years;
in those with mutated IgV_H genes not expressing CD38, it was 26 years

LLC espérance de vie est réduite sauf pour les plus de 75 ans

 Les auteurs montrent aussi que la survie des patients avec une LLC est significativement plus courte que la survie observée dans une population normale contrôle de même âge et ce pour tous les sous groupes de patients, excepté les patients de plus de 75 ans.
La survie des patients avec un stade 0 dans la classification de Rai est aussi plus courte que celle observée dans la population contrôle, sauf chez les patients de plus de 75 ans.

source :2010 Age at diagnosis and the utility of prognostic testing in patients with chronic lymphocytic leukemia.

Department of Medicine, Division of Hematology, Mayo Clinic, Rochester, Minnesota 55902, USA

Survival of CLL patients aged <75 years is shorter than the age-matched general population regardless of disease stage. Among patients aged <75 years, the simple combinations of stage and IGHV or stage and FISH identifies those with excess risk of death relative to the age-matched population. Although useful for predicting time to first treatment independent of stage for patients of all ages, prognostic testing had little utility for predicting OS independent of stage among patients aged ≥75 years.

LLC abréviation utilisés dans les documents médicaux

Adénopathie  = état pathologique d'un ganglion lymphatiqueSplénomégalie = une augmentation de volume  de la rate .
MRD = maladie résiduelle indétectable (MRD)
RC = rémission complète clinique
W&W = watch-and-wait = on regarde et on attend (pas de traitement stade A)

la présence ou l'absence d'un marqueur sur une population, par exemple « CD34+CD31− » signifie que la population exprime le CD34, mais pas le CD31.

Anglais
IGVH = immunoglobulin variable region heavy chain
OS =  overall survival =  survie total
PFS =  progression free survival = survie médiane sans progression

LLC traitement pas traitement quel traitement

Ceci est une réflexion personnelle pour mon propre cas

Tous les traitements aggravent l'immunodeficience.
"You are also right to say that all treatments of CLL make the immunodeficiency worse, but whether this is a big issue depends very much on the individual patient. For those who start out with a very poor immune system, it obviously is a very important factor, but for other patients, even a big hit on their immune system leaves them better off than are some patients before they start treatment." DR T Hambling.

For those who start out with a very poor immune system, it obviously is a very important factor, but for other patients, even a big hit on their immune system leaves them better off than are some patients before they start treatment. DR T Hambling.

LLC adverse events évenement indésirable pendant la chimio

quand on test un médicament on ananlyse les événements indésirable (AE adverse events)  et on les classifie 
Grade 1 Mild AE
Grade 2 Moderate AE
Grade 3 Severe AE
Grade 4 Life-threatening or disabling AE
Grade 5 Death related to AE
Pour le NCI dans la norme v3.0 (CTCAE)

LLC lymphocyte B leur vie

Je ne suis pas médecin ni biologiste j'essaie de comprendre et je peux me tromper:
   -les cellules de la moelle osseuse se divisent et peuvent donner des cellules différentes entre autre des cellules qui seront les lymphocytes B

   Pour devenir un lymphocyte B une partie des gènes de cette cellule doit muter (cette mutation est normale et lui permet de fabriquer a sa surface des immunoglobulines adaptés a des antigenes)

    Avant devenir lymphocyte B la cellule se mature dans la moelle osseuse.
                                                la cellule circule dans le circuit lymphatique c'est une "cellule naive "(non muté - ce qui est normal).
                                                la cellule va dans un ganglion lymphatique
                                                La cellule mute les genes IGVH (ou récepteur B Cell Receptor BCR) ce qui a pour conséquence la fabrication a sa surface d' immunoglobuline spécifique d'un antigene: la cellule devient un lymphocyte B mémoire (muté -ce qui est normal)
                                                 la cellule Lymphocyte B mémoire circule, se multiplie a l'identique, meurt
                                                 Si  la cellule rencontre l’antigène qui lui est spécifique, elle augmente sa rapidité de multiplication pour répondre a ce qui est considéré comme une attaque.

Le probleme des cellules lymphotcytes B c'est que:
                                                  ce sont des Lymphocytes B mémoire ou naive qui se multiplient anormalement et ne meurent pas.  Donc on retrouve des leucocytes B tous identiques (clones) qui n'ont pas d'utilité contre un antigène. et qui diminuent la capacité du processus normal des autres cellules du sang....
                                                 



                                                
                     

   

Dr. Terry Hamblin la LLC dans son blog, Critères de début de traitement

*2006*mutations of mortality: Other prognostic factors - doubling time: "Doubling time. This is a simple measurement of how rapidly the CLL is growing. A lymphocyte count doubling every six months is an indicatio..."

Dr. Terry Hamblin la LLC dans son blog: But du traitement

2006*mutations of mortality: What is the aim of treatment? (part 3): "If the aims of treatment are to live as long as possible and as well as possible, it may be that these aims are not compatible. We can make ..."
*2006*mutations of mortality: What is the aim of treatment? (Part 2): "What about a long remission? There are lots of cases of acute leukemia that we can’t cure. Most people over 40 for a start. Does that mean ..."
*2006*mutations of mortality: What is the aim of treatment? (Part 1): "Is it to cure? We want to cure cancer. That was my ambition when I became a cancer doctor. Can cancer be cured? Clearly some cancers can. I..."

Dr. Terry Hamblin la LLC dans son blog: Les traitements

*2011*mutations of mortality: FCR as salvage therapy: "What is the best treatment for relapsed CLL? The MDACC group makes a plea that it is still FCR. In the Blood of 17th March a final report of..."

*2007*mutations of mortality: Treatment of CLL: "I am in the midle of writing a review of CLL for the Lancet Oncology. Here is a first draft of the section on treatment. The finished articl..."

Dr. Terry Hamblin la LLC dans son blog: CT scans CAT scan

*2007*mutations of mortality: CT scans: "When should a CLL patient have a CT scan? The first thing to say is that for the past 30 years the staging of CLL has been carried out very..."

*2006*mutations of mortality: CAT scans: "Should you have a CAT scan as part of your diagnostic work up? A CAT scan uses a computer to produce pictures of what thin slices through y..."

Dr. Terry Hamblin la LLC dans son blog: Groupe de patient

*2007*mutations of mortality: Late treatment in CLL: "I have been looking at a group of patients with who manage to go a long time before requiring treatment, and comparing them with patients wh..."

*2007*mutations of mortality: Borderline mutated: "Although the difference between CLL with mutated and unmutated immunoglobulin variable region heavy chain (IgVH) genes is well established a..."

*2006*mutations of mortality: Consultation document 2: "This is the mangled paragraph unmangled. In the original paper describing Rai staging, stage 0 patients were reported to have an overall su..."

Dr. Terry Hamblin la LLC dans son blog: Immunodeficience Vaccins

*2008*mutations of mortality: Immunodeficiency 6: "Vaccines Patients commonly ask whether they should receive vaccinations. Their enquiries have two purposes; they want to know if vaccinatio..."
*2008*mutations of mortality: Immunideficiency 5: "Potential remedies for the immunodeficiency As has already been seen just treating the CLL does not restore immunity and guidelines do not ..."
*2008*mutations of mortality: Immunodeficiency 4: "It should be noted that stimulation of the T-cell receptor without interaction between CD28 and CD80/CD86 leads to T cell anergy [4] CTLA-4..."
*2008*mutations of mortality: Immunodeficiency in CLL 3: "Another prominent and important factor in the suppression of lymphocyte and monocyte function and thus the occurrence of opportunistic infec..."
*2008*mutations of mortality: Immunodeficiency in CLL 2: "In most patients with CLL T cell numbers are increased. This increase mainly affects CD8+ cells, but CD4+ cells are also increased, though t..."
*2008*mutations of mortality: The immunodeficiency of CLL: "Introduction Patients with chronic lymphocytic leukaemia (CLL) are all to a degree immunodeficient. The most obvious and well-known abnorma..."
*2007*mutations of mortality: Vaccination against pneumonia: "People keep asking about vaccination against pneumonia and although I have been able to give some advice, it hasn't been very encouraging ad..."

Dr. Terry Hamblin la LLC dans son blog :MBR monoclonal B-cell lymphocytosis

*2008*mutations of mortality: Monoclonal B-cell lymphocytosis: "We have known about monoclonal B-cell lymphocytosis (MBL) for some time now. In order to have CLL you need to have two things; a lymphocyte ..."

*2009*mutations of mortality: MBL: what does it mean for you?: "The quite different criterion for diagnosing CLL - namely a B lymphocyte count of 5000/mictrolitre will make a big impact on how we see CLL...."

*2009*mutations of mortality: MBL with the characteristics of indolent CLL: "We have known for many years that many people (about 6% of the over-60s) have a monoclonal protein in their serum, reminiscent of multiple m..."

Dr. Terry Hamblin la LLC dans son blog Molecules pour traiter

Les molécules courantes pour traiter
**2011* mutations of mortality: A closer look at Bendamustine in CLL: "Have I been too hard on Bendamustine? This alkylating agent is more than 30 years old and was discovered in communist East Germany, where it..."
**2011*mutations of mortality: Bendamustine: is it better?: "Bendamustine or Treanda is being seen as the new player on the block by many oncologists and is often regarded as the place to go when the p..."

*2009*mutations of mortality: Bendamustine trial: "A paper has appeared in the J Clin Oncol comparing Bendamustine with Chlorambucil in untreated patients with CLL. It shows Bendamustine to b..."
*2008*mutations of mortality: Bendamustine: Hype or Hope?: "A lot of fuss is being made about bendamustine (also known as Treanda). Because it is an alkylating agent with some of the properties of ..."


**2011*mutations of mortality: fludarabine v cladribine: "A new look at Cladribine has been published in Blood. It is perhaps a neglected drug, being very similar to fludarabine, which is usually pr..."
*2007*mutations of mortality: Fludarabine and prednisolone: "This is the comparison of two phase II trials at MDACC showing no benefit from adding prednisolone to fludarabine."
*2006*mutations of mortality: Fludarabine Combinations: "Today I want to evaluate an important new paper published in Cancer by Bill Wierda. http://www3.interscience.wiley.com/cgi-bin/abstract/1122..."


*2006*mutations of mortality: More on chlorambucil: "Although in the latest British CLL4 trials fludarabine and the higher dose of chlorambucil were indistinguishable in efficacy, fludarabine w..."
*2009*mutations of mortality: Chlorambucil rituximab for CLL: "This is an Open-Label Phase II Study to Investigate the Safety and Efficacy of Rituximab Plus Chlorambucil in Previously Untreated Patients ..."

*2009*mutations of mortality: Alemtuzumab at ASH: "Alemtuzumab is thought to be a superior monoclonal to rituximab for the treatment of CLL. The question ought then to be asked as to whether ..."
*2007*mutations of mortality: Consolidation therapy with Alemtuzumab: "This is another section on consolidation therapy to follow on from the section on bone marrow transplantion. An alternative approach with p..."

*2007*mutations of mortality: Campath: "I have been meaning to write something about Campath for some time. I first started using this monoclonal antibody before it had been humani..."

*2008*mutations of mortality: Do Statins make Rituximab ineffective?: "A few years ago a revolution took place in medical publishing with the introduction of open access journals freely available on line. Of cou..."
*2008*mutations of mortality: Rituxin and high white counts: "Many people are confused over why some doctors recommend reducing the white count before starting rituximab. Remember that rituximab was ori..."
*2006*mutations of mortality: Chlorambucil plus rituximab: "Don't read this if you are squeamish. As readers will know I have long been an advocate of chlorambucil plus rituximab as a logical regimen..."
*2006*mutations of mortality: Beta Glucan to enhance rituximab: "How rituximab kills CLL cells is not known for certain. It could do it by invoking direct apoptotic mechanisms. (Apoptosis = programmed cell..."

*2008*mutations of mortality: CLL: Immunochemotherapy: "Rituximab—the chimeric monoclonal anti-CD20—is only moderately active as a first-line agent in chronic lymphocytic leukaemia,[131] with an o..."
*2008*mutations of mortality: CLL Treatment: Purine analogues: "With the introduction of purine analogues, a class of drug better able to achieve complete remission in chronic lymphocytic leukaemia, the p..."
*2006*mutations of mortality: Steroids 3: "After a long interval, I want to complete this subject with an essay on how steroids are used in CLL. First, it goes without saying that wh..."
*2006*mutations of mortality: Monoclonal antibodies in CLL: "On May 4th this year the UKCLL Forum held a meeting in London. The topic was 'Monoclonal Antibodies in the Treatment of CLL' I have written ..."


Les molécules "en cours d'étude" pour traiter
*2009*mutations of mortality: OFAR: "I have been asked about OFAR (combined oxaliplatin, fludarabine, cytarabine and rituximab) There is one paper at ASH from MDACC on OFAR used..."
 
*2009*mutations of mortality: TRU016: "TRU-016 is described as “a single chain anti-CD37 Fc fusion molecule that displays pro-apoptotic and Fc-dependent cellular cytotoxicity acti..."

*2009*mutations of mortality: Ofatumumab at ASH: "Those expecting a load of new information on Ofatumumab (O) from ASH are likely to be disappointed. Only three papers have been accepted and..."

*2008*mutations of mortality: Hsp90 again: "Several people have asked about the status of heat shock protein 90, inhibition of which was thought of as a new way of treating the most ag..."

*2008*mutations of mortality: CLL: New agents: "A whole range of new therapeutic agents is in development, some of which are already in the clinic. Lenalidomide [163] might act by interfer..."

*2006*mutations of mortality: PARP inhibitors: "PARP inhibitors may offer the first really targeted therapy for CLL. Although monoclonal antibodies are thought of as targeted therapies th..."

*2006*mutations of mortality: Revlimid: "Revlimid is an analogue of thalidomide that has been developed as part of a research programme to separate the evil effects of thalidomide f..."

Dr. Terry Hamblin la LLC dans son blog Pronostiqueurs

Pronostiqueurs
*2011*mutations of mortality: TP53 again: "WE know that TP53 problems are about the worst you can have with CLL, but we also know that 17p deletion is very rare in newly diagnosed pat..."
*2008*mutations of mortality: TP53: is it such a big deal?: "Everyone knows that p53 abnormalities bode ill for patients with CLL. Generally such leukemias are resistant to fludarabine, cyclophosphamid..."
*2009*mutations of mortality: P53 explored: "Of all the malign features of CLL, damage to the p53 pathway is the most serious. Most drugs used in CLL work by invoking the p53 pathway to..."
*2007*mutations of mortality: Hope for p53 mutants: "The worst cases of CLL are those with reduced or absent p53 function. There are two reasons for this. p53 is known as ‘the guardian of the g..."

*2011*mutations of mortality: ZAP-70 again: "As readers know I am less than enthusiastic about ZAP-70 as a surrogate for IGHV mutations. I came across this conversation on the web which..."
*2010*mutations of mortality: ZAP-70 changes: "In order to make this paper available to all. ZAP-70 levels do change in CLL but not very often.Terry J Hamblin Abstract Evidence is accum..."
*2007*mutations of mortality: ZAP-70 again.: "One of the most pressing topics to come up in Canada was the usefulness or otherwise of ZAP-70 as a prognostic factor. In fact John Byrd sai..."
*2007*mutations of mortality: ZAP-70: "ZAP-70 is a molecule used to transmit a signal from the T-cell receptor to downstream pathways. Most B cells lack ZAP-70 and instead use a r..."


*2010*mutations of mortality: More on 13q14: "I have been promising to write something more about the 13q14 deletion in CLL. I have already visited this subject several times and claim s..."
*2010*mutations of mortality: A del 13q anomaly explained: "After Carlo Croce stressed the importance of the miR-15 and 16 genes in del 13q14 CLL we had a bit of problem because the smallest minimally..."
*2010*mutations of mortality: Del 13q14 - the Bournemouth background: "I feel a sort of ownership for del 13q14, since it was on some of my patients that the first cases in both CLL and myeloma that it was disco..."

*2011*mutations of mortality: Alkylating agents for del 11q: "I am sure you will recognise the Dohner et al hierarchical model for FISH results in CLL. This graph has been published hundreds of times. ..."
*2007*mutations of mortality: Del 11q23: "I am responding to one of my correspondents up front because not everybody reads the 'comments' on this blog. 'Anonymous' has misinterpreted..."



*2008*mutations of mortality: CD38 polymorphisms: "Why are we all so different? The plain answer is genetic polymorphisms. Perhaps the best known example is sickle cell anemia. Most people ha..."
*2007*mutations of mortality: Up to date on CD38: "Readers may have noticed that I have not yet delivered my promised summary of the IWCLL meeting. This is because I have been working on one ..."
*2005*mutations of mortality: CLLs discordant for VH mutations and CD38 have an ...: "CLLs discordant for VH mutations and CD38 have an intermediate prognosis "
*2005*mutations of mortality: This was the original graph from the Chiorazzi pap...: "This was the original graph from the Chiorazzi paper showing that CD38 was a useful prognostic factor "
*2005*mutations of mortality: CD38: "Somebody recently asked on the ACOR List CD38 and VH genes interalate. Let's first think about CD38. It has been mentioned in well over 1000..."

*2008*mutations of mortality: SNIPs: "The prognostic factors of CLL are well established and include clinical stage, IgVH mutational status, CD38 expression, ZAP-70 expression (w..."

*2008*mutations of mortality: CD20 and trisomy 12: "In advice that I have been giving over the past 5 years I have been stressing that CD20 is brighter in patients who have trisomy 12. Indeed ..."

*2006*mutations of mortality: Soluble CD23: "CD23 is the low affinity receptor for IgE. When it appears on eosinophils and macrophages it helps these cells to kill and eat structures th..."

*2008*mutations of mortality: FISH and mutations: "I have recently been asked whether del 11q is also influenced by the mutational status of IgVH genes. As you can see by these two survival..."
*2006*mutations of mortality: Del 17p: "One of the most feared findings in CLL is a loss of the short arm of chromosome 17. It is usually found by FISH testing and the technical te..."

*2008*mutations of mortality: FCRL2; a new prognostic marker for CLL: "In a forthcoming issue of Blood there will be an article on FCRL2, a new prognsotic factor for CLL. The discovery that patients with chroni..."
*2005*mutations of mortality: One picture is worth a thousamd words. This surviv...: "One picture is worth a thousamd words. This survival curve shows the difference between having mutated and unmutated VH genes. "
*2005*mutations of mortality: VH mutations: "I well remember a meeting in Italy when VH gene mutations were the hot topic. I was in the camp that believed that CLL was frozen in time as..."

*2007*mutations of mortality: Beta-2 microglobulin: "I am beginning to have a different view of beta-2 microglobulin as a prognostic factor in CLL. Hitherto, I have been suspicious of its value..."
*2005*mutations of mortality: Beta-2 microglobulin: "Beta-2 microglobulin is used by some centers as a prognostic factor and is particularly favored by the MD Anderson Cancer Center in Houston...."

*2008*mutations of mortality: CLL; Assessment of prognosis: "In chronic lymphocytic leukaemia, a third of patients never need treatment and have long survival; in another third, an initial indolent pha..."

*2007*mutations of mortality: How many mutations are you allowed?: "Legend of figure. Figure 1. Comparison of survival in months of patients with CLL with different degrees of sequence homology for IgVH g..."

Dr. Terry Hamblin la LLC dans son blog: La Greffe

La greffe *2009*mutations of mortality: Transplants - a conclusion: "So, what is the conclusion? Who should have a transplant and when. As usual, the best results are achieved in people who don't need one, and..."
 
*2009*mutations of mortality: Specific transplant problems in CLL: "Transplants are more likely to be rejected in CLL than in other conditions. The rejection rate in follicular lymphoma is between 3 and 6%. F..."

*2009*mutations of mortality: What are the alternatives to transplantation?: "In patients who are fludarabine refractory or have a p53 dysfunction the available treatments are limited. The first drug that comes to mind..."

*2009*mutations of mortality: Transplants: ablative or non-ablative?: "Continuing from yesterday. Should one go for an ablative or non-ablative transplant? Ablative means using sufficient chemotherapy to destroy..."

*2009*mutations of mortality: Who needs a transplant?: "I think another article about bone marrow transplants is due. A paper has appeared in Blood detailing the European experience in CLL, so it ..."
*2009*mutations of mortality: Should I have a transplant 2?: "Here is the attraction of stem cell transplants: they cure people. Here is the problem with stem cell transplants in CLL: they kill people. ..."

*2009*mutations of mortality: Should I go for a transplant?: "Should I go for a transplant or not? This is often a difficult question for patients with CLL. Until recently the answer was, “Not if you ca..."

*2008*mutations of mortality: 1000 transplants: "I spent yesterday at the celebration in London of the Kings College Hospital's one thousandth stem cell transplant. Although not rivalling S..."

*2008*mutations of mortality: stem cell transplants - a personal history: "I was first involved in a bone marrow transplant (BMT) in 1970. We attempted to transplant bone marrow into a toddler with aplastic anemia f..."

*2008*mutations of mortality: Transplants in CLL: "I thought you might be interested in this provisional guideline for when to do a transplant in CLL. 1. Very high risk CLL defined as CLL wi..."

*2007*mutations of mortality: Stem cell transplant - a lifelong committment: "Some people think I am against transplants. Not at all, I regularly attend a ward round at the biggest transplant center in Britain. Ther..."

*2007*mutations of mortality: Bone marrow transplantation for CLL: "This is the next section in the article that I am writing in the Lancet. In leukemia, remissions are traditionally consolidated with high d..."

Dr. Terry Hamblin la LLC dans son blog: Conseils et traitement

Conseil initiaux
*****mutations of mortality: Why experts do better.: What has got the CLL world talking at the moment is a paper in Cancer from the Mayo Clinic which suggests that patients treated by the CLL t...
       En deux mots faites vous suivre par des spécialistes de le LLC...

*****mutations of mortality: Your first reaction to having CLL: "What do you do first when confronted with a diagnosis of CLL? The first thing is don't panic. Three quarters of cases are diagnosed because..."

*2006*mutations of mortality: What questions shall I ask the doctor?: "One of the commonest questions that I am asked is 'What questions should I ask when I see my doctor about CLL?' This is quite a difficult o..."

*2007*mutations of mortality: CLL Guidelines: "Guidelines for the management of CLL were issued in 1988 and 1996 and these are about to be replaced by a new set of guidelines produced by ..."
*2006*mutations of mortality: Who needs treatment?: "It seems a strange question to ask; surely everybody with cancer needs treating? Let me tell you a story about prostate cancer. This has sud..."


****2010*mutations of mortality: survival curves: "Despite having had cancer for more than two years now, I never look at survival curves for my type of cancer. Why not? Because they are not ..."

*****mutations of mortality: Where are we with prognostic markers today?:  "Who should have their prognostic markers done? When I first started working in this area, I was motivated by the fact that many people were..."
*2005*mutations of mortality: What is chronic lymphocytic leukemia?: "Almost every review begins 'CLL is the commonest leukemia in the western world'. I wonder who first wrote that sentence? And is it true? Tr..."


*2008*mutations of mortality: Surgery in CLL patients: "CLL mpatients have to have operations just like anybody else. Are they at particular risk? The answer is no, not unless they have reduced pl..."

*2008*mutations of mortality: High White Counts: "Patients and doctors get very worried about high white counts. Need they be? I remember one holiday weekend spending days at the hospital w..."

*2007*mutations of mortality: Why should I get my prognostic markers done?: "I think that this is a genuine dilemma for patients with CLL. In one sense whether you know what your prognostic markers say or not is not g..."

Quand commencer a traiter?
*2008*mutations of mortality: CLL: when to start treatment: "Most patients with chronic lymphocytic leukaemia present without symptoms or signs; they are identified simply because a blood test has been..."
2007*mutations of mortality: To treat or not to treat: that is the question.: "This is a point that confuses a lot of people so I need to spell it out clearly. It has become an accepted fact that the new treatments for ..."

*2007*mutations of mortality: Watching and waiting too long: "There is no evidence that early treatment improves survival in CLL compared to watching and waiting until symptoms arrive. Because the poten..."

*2006*mutations of mortality: Weight loss in CLL: "One of the criteria for treatment of CLL is weight loss. The criterion has been lifted straight from the criteria identified for the Ann Arb..."


S'aider a maintenir sa santé
*2008*mutations of mortality: Immunodeficiency 6: "Vaccines Patients commonly ask whether they should receive vaccinations. Their enquiries have two purposes; they want to know if vaccinatio..."

*2009*mutations of mortality: Vaccination for the coming winter.: "We are entering the flu vaccination period and I have been asked for advice for CLL patients. The first thing to say is that CLL patients a..."

**2010* mutations of mortality: Exercise for fatigue.: "I have just signed up for an exercise programme similar to this one reported from the University of Alberta, Canada The video is worth watch..."

*2008*mutations of mortality: Polyphenols: natural products to treat leukemia: "I was asked a question today about polyphenols which reminded me of an editorial I wrote about them a year or so ago. I don't think this has..."

Effets secondaires réels ou supposés
*2006*mutations of mortality: Fatigue in CLL: "Many patients with CLL complain about fatigue. It is also true that many patients without CLL complain about fatigue. The commonest reason..."
*2009*mutations of mortality: Leg cramps and CLL: "Back in 1972 when I was still a trainee hematologist, my boss, Jeremy Lee Potter, told me that leg cramps were a feature of CLL. I couldn't ..."
*2007*mutations of mortality: Quality of life: "It is becoming essential that clinical trials include estimates of quality of life improvements in their assessments. Recently published is ..."

Traitements
***2010/10/9*mutations of mortality: The ultimate FCR advice: "After all those sleepless nights fueled by dexamethasone working on CLL8 I think it right that I should put FCR into context. In this I am h..."

***2010/09/04*mutations of mortality: Update on FCR: "There has been a great kerfuffle about FCR recently. I have to admit that I was very dubious about this drug combination when it first came ..."

*2009*mutations of mortality: Who now should get FCR?: "The German CLL8 trial continues to give us useful information. For the first time one treatment arm has lead to an improvement in overall su..."
*2008*mutations of mortality: FCR: No country for old men: "Outcome of treatment for chronic lymphocytic leukemia (CLL) depends more upon the nature of the disease than the type of treatment given. De..."
*2008*mutations of mortality: A good look at FCR: "Although fludarabine, cyclophosphamide and rituximab (FCR) has long been standard treatment for CLL in America, there has hitherto been no e..."

**mutations of mortality: Splenic irradiation for CLL: "Splenic irradiation is the forgotten treatment for CLL. Perhaps it is because there is no profit to be made from it by the drug companies, b..."

*2009*mutations of mortality: Side Effects in easier language: "After Paul's comment I have rewritten the last piece to make it more understandable by patients. Recently, there has been some discussion a..."
*2009*mutations of mortality: Side effects: "Recently, there has been some discussion among CLL patients about the side effects of drugs used to treat the disease. Are there any treatme..."

*2006*mutations of mortality: CLL mistakes: "How much do general haematologists know about CLL? I have just been consulted about a patient who died of complications of treatment and I i..."

Dr. Terry Hamblin la LLC dans son blog Etudes Scientifiques

Etudes scientifiques *2011*mutations of mortality: PARP again: "I have already written about PARP inhibitors here so this will be a follow up for some. A paper in the November 25th Blood tells of the pre-..."

*2011*mutations of mortality: RIC allografting in CLL: "A long time ago I promised to review the German experience with reduced intensity conditioning allograft in CLL which was published in the O..."

*2011*mutations of mortality: Gleevec for CLL: "Mcl-1 is one of those anti-apoptotic proteins that belong to the bcl-2 family. It may well be the most important in CLL. A paper from Liverp..."

*2010*mutations of mortality: UK CLL Trials meeting: "Although I wasn't well enough to attend the last Clinical Trials meeting of the UK CLL sub-group I did receive the agenda. I was impressed b..."

*2010* mutations of mortality: German CLL8 Part 1: "The German CLL8 trial by Hallek et al in today's Lancet is the most important CLL paper published for a decade. Why? Like most chronic lym..."

*2010* mutations of mortality: German CLL8 trial 2: "What sort of trial is the German CLL8 trial? It is an open label, randomized phase III trial. First it is 'open label'. This means that bot..."

*2010*mutations of mortality: German CLL8 Part 3: "This is a trial designed to see whether adding the anti-CD20 antibody, rituximab, to the previous gold-standard regimen of fludarabine and c..."

etc aller sur le site de Dr Terry Hamblin et faire une recherche avec code CLL8
*2009*mutations of mortality: ASH 2009: "It is now possible to view the ASH abstracts for 2009. Although I have already broken the news that for the first time a first line treatmen..."

*2009*mutations of mortality: Other trials in CLL: "I managed to attend my first Committee meeting yesterday. I went to London to meet with other CLL experts to discuss the forthcoming British..."

*2008*mutations of mortality: ASH 1 - The German CLL8 trial: "For CLL patients and doctors alike, the main event at ASH was the German CLL8 trial comparing FC with FCR. We already knew from the Roche we..."

*2008*mutations of mortality: Leukemia Research: "When I attend a committee that awards grants to researchers, I am of course sworn to secrecy about what goes on there, but I can blog about ..."

*2008*mutations of mortality: New Trials: "No blogging yesterday as I was at the UK CLL group's clinical trials meeting. This was a good chance to review what was happening in the UK...."

*2008*mutations of mortality: More from EHA on CLL: "At the recent EHA meeting at Copenhagen, Michael Hallek reported on current therapeutic options for CLL. He emphasised that most patients en..."

*2008*mutations of mortality: CLL latest news from EHA: "I have just listened to a podcast by Jesper Jurlander from the recent EHA meeting from Copenhagen. Remember that he was the man who introduc..."

*2008*mutations of mortality: ERIC: how to understand CLL little by little: "The EHA meeting is on just now in Copenhagen. I went to Copenhagen on Thursday but only to attend the European Research Initiative on CLL (E..."

*2008*mutations of mortality: Drug-resistant chronic lymphocytic leukaemia: "After successful induction therapy, relapse is almost inevitable if no consolidation takes place and is still possible if consolidation has ..."

*2008*mutations of mortality: New Clinical Trials: "I was at the UKCLL Forum Clinical Trials Meeting yesterday. Here are some of the trials up and running or in development in the UK. CLL6 is..."

*2006*mutations of mortality: Chemotherapy combinations: "Whenever an oncologist finds two drugs that are both effective in a particular cancer, his natural inclination is to combine them. It makes ..."

*2006*mutations of mortality: Outcomes in clinical trials: "A recent paper in the New England Journal of Medicine has given us all something to think about. It did not concern CLL; rather it was about..."

Dr. Terry Hamblin la LLC dans son blog

Outils de diagnostique
*2011*mutations of mortality: CT scanning in CLL: "Because CT scanning is the only way to follow what is happening in lymphoma, oncologists assume that it should be done in CLL. Nothing could..."

*2009*mutations of mortality: Elements of Danger - Medical Imaging: "An article in today's New England Journal of Medicine needs to be considered by everyone with CLL. It is probably true that patients with CL..."

*2009*mutations of mortality: Diagnosing CLL: "The diagnosis of CLL is easy, but the criteria for the diagnosis have recently changed. The first thing that is necessary is a raised lympho..."

*2005*mutations of mortality: How do you know if you have CLL?: "December 14th 2005 Three-quarters of all cases of CLL are discovered by accident. The patient has a blood test for some other reason or, th..."

Divers
*2011*mutations of mortality: Picking up on Richter's Syndrome: "What makes a CLL patient more prone to develop Richter's syndrome? This is an important question since early recognition and treatment are t..."

*2011*mutations of mortality: Leukostasis and thrombosis in CLL: "The highest white count that I have seen in CLL is 800,000/cu mm though Tom Kipps told me of a patient with 1,400,000/cu mm. The odd thing i..."

*2011*mutations of mortality: Splenic lymphomas: "My source for this article is Iannitto & Tripido, Blood 2011; 17:2585. The causes of splenomegaly are many. Infections can cause (usually t..."

*2011*mutations of mortality: The Mayo vitamin D paper: "I have now had a chance to study the paper from the Mayo Clinic that found an association between low levels of vitamin D and poor prognosis..."

*2010*mutations of mortality: vitamin D and CLL: "I wrote about vitamin D in January this year, but I am prompted to write about it again by the recent announcement by the Institute of Medic..."

** mutations of mortality: Vitamin D and cancer, particularly CLL:  "When I started my series on vitamins I intended to deal with the question of vitamin D and CLL, but I got sidetracked. I have seen a number ..."

**mutations of mortality: T-CLL: "There are a lot of people who have been told that they have T-CLL. Many years ago this was a proper diagnosis. Indeed, it was taught that th..."

*2009*mutations of mortality: The cause of CLL: "The extreme differences in geographical variation worldwide ought to give us a clue as to the etiology of CLL. Prevalence rates show a 40-fo..."

*2009*mutations of mortality: More of the CLL Chapter: "I have been gradually improving since the weekend and I have put some work in on the chapter that is due next month. Diagnosis The diagnosi..."

*2009*mutations of mortality: CLL: Introduction: "Sorry to have been silent for so long. Two things: the side effects lasted longer this time than usual; that in itself would not have stoppe..."

*2009*mutations of mortality: CLL: differential diagnosis part II: "B-PLL B-PLL is a very rare disease and some people think that it doesn’t exist as a single entity. The picture shows what it looks like do..."

*2009*mutations of mortality: CLL differential diagnosis: "The diagnosis of CLL is easy. The cells are very characteristic on the blood film. They have dark staining nuclei that takes up most of the..."

*2009*mutations of mortality: What is leukemia?: "I am in the process of writing a chapter on CLL for a new textbook and I thought I would take the opportunity to write a guide to CLL for pa..."

*2009*mutations of mortality: What is a CR?: "I spent yesterday wrestling with the CLL Guidelines - both the 1996 and the 2008 versions - trying to evaluate a clinical trial results as p..."

*2008*mutations of mortality: Merkel Cell Carcinoma: "About one third of cases of Merkel cell carcinoma occur in patients with CLL. Although second cancers reputedly occur more commonly in patie..."

*2008*mutations of mortality: CLL - MBL - IWCLL: "Earlier this year new guidelines on CLL were published by the IWCLL. I have to admit that despite being consulted about the paper before pub..."

*2008*mutations of mortality: Non Hemic Autoimmunity in CLL: "Although everyone is familiar with the autoimmune complications of chronic lymphocytic leukemia (CLL), a clear understanding of their pathog..."

*2008*mutations of mortality: Is CLL a lymphoma?: "This is one of the most frequently asked questions by patients, and the answer is yes and no. It depends on what you understand by the word ..."

*2008*mutations of mortality: CLL - is treatment getting better?: "The SEER database is a wonderful tool for understanding cancer and the recent release of hematological data from 1973 to 2004 has prompted s..."

*2008*mutations of mortality: CLL: Consolidation therapy: "Consolidation of remission aims to eliminate all detectable disease from the patient. In assessing the success of such attempts, the sensiti..."

*2008*mutations of mortality: CLL: apoptosis and proliferation: "Accumulation of mature B cells that have escaped programmed cell death and undergone cell-cycle arrest in the G0/G1 phase is the hallmark
of..."

*2008*mutations of mortality: CLL: Diagnosis and Pathophysiology: "Clinical diagnosis of chronic lymphocytic leukaemia is defined by absolute lymphocytosis of at least 5×109/L mature-appearing lymphocytes an..."

*2008*mutations of mortality: Genetic abnormalities in CLL: "Although multiple instances of chronic lymphocytic leukaemia in some families, and low frequency of the disease in individuals of Japanese o..."

*2007*mutations of mortality: Early stage treatment: "What follows is an early draft of a paper I am writing that makes the case for new trials of whether early treatment might benefit some pati..."

*2007*mutations of mortality: Leukemic Stem Cells: "The question is often asked as to whether there are leukemic stem cells for CLL. The theory goes like this. Most of the cells in a cancer ar..."

*2007*mutations of mortality: IWCLL 2007: "This week I have been at the IWCLL meeting in London. This meeting began many years ago in Paris and I have been to most of them. We were sh..."
*2006*mutations of mortality: Consultation document: "This is a draft of a paper that I am writing. I would appreciate comment from the CLL community. I have corrected some of the errors that cr..."


Théorie
*2011*mutations of mortality: More on Stereotypy: "ASH 2010 abstract 43 summarizes a collaboration between 16 different laboratories in which a total of 7596 patients with CLL who had had the..."

*2011*mutations of mortality: Autoimmunity and CLL: "Emili Montserrat's group in Barcelona has just published its experience with autoimmune phenomena in CLL over the past 28 years Blood 2010, ..."

*2011*mutations of mortality: CD14 raised in CLL: "It has long been known that CLL cells need help to be able to survive. Several studies have shown that it is what goes on in the tissues rat..."

*2011*mutations of mortality: T-depleted transplants - the UK experience: "The point about RIC transplants is that they use the transplanted immune system to attack the host's leukemia. This graft-versus-leukemia (G..."

*2011*mutations of mortality: CMV and immunosuppression: "A herpes virus isn't just for Christmas; you have it for life. This is particularly true for cytomegalo virus (CMV) which about 85% of us ge..."

*2011*mutations of mortality: LEF1: the Wnt pathway in CLL: "A paper from Neil Kay's group at the Mayo looks at LEF-1 which I mentioned in the last article as being part of the canonical Wnt signaling ..."

*2011*mutations of mortality: siRNA knockdowns of ROR1 and FMOD: "Small interfering RNAs (siRNAs) are a useful tool in finding out what genes do. Previously it was necessary to produce genetically engineere..."

*2011*mutations of mortality: array CGH: "When I started as a hematologist, I worked for a guy, who though a hematologist by name, was not much interested in patients with leukemia, ...

*2011*mutations of mortality: CCL3 - a VH surrogate: "It is now very clear that signaling through the B-cell receptor (BCR) is extremely important in determining how active CLL is. My original o..."

*2011*mutations of mortality: The cell of origin for CLL: "One of the great mysteries about CLL is what the cell of origin is. Based on its CD5 positivity it was originally thought to be derived from..."

**mutations of mortality: How does rituximab work?: "There is no doubt that rituximab was the drug of the decade as far as sufferers from lymphoid malignancies are concerned, but the big questi..."

*2009*mutations of mortality: MRD now: "In the previous article I mentioned the value of becoming MRD negative. I should stress that the method used to determine MRD negativity is ..."

*2009*mutations of mortality: The TCL1 story: "For the past couple of weeks I have been seeking to understand the TCL1 story. This is the result, though I have to confess that it is very ..."

*2009*mutations of mortality: MBL v CLL: "I have beavering away at the chapter I promised to write and have completed this section on monoclonal B-cell lymphocytosis. The references ..."

*2009*mutations of mortality: Just how common is CLL?: "Just exactly how common is CLL? Most articles about CLL begin with the sentence, “CLL is the commonest type of leukaemia in the Western wor..."

*2009*mutations of mortality: Prolymphocytes: "There has been quite a lot of discussion lately about prolymphocytes. A prolymphocyte is a lymphocyte that looks different down the micro..."

*2008*mutations of mortality: Dasatinib and CLL: "Figure from Src-family kinases in the development and therapy of Philadelphia chromosome-positive chronic myeloid leukemia and acute lympho..."

*2008*mutations of mortality: The B cell receptor: "The B-cell receptor The B-cell receptor is a multimeric complex formed by the assembly of a surface immunoglobulin homodimer and a non-cova..."

*2007*mutations of mortality: Chromosomes at IWCLL: "In my first report from the IWCLL I want to focus on chromosomes. FISH - fluorescent in-situ hybridization is the mainstay of chromosomal ex..."
*2005*mutations of mortality: Immunophenotyping: "All these CD numbers are confusing. It has nothing to do with compact discs. CD stands for clusters of differentiation. In the 1980s labora..."

Terry Hamblin Chlorambucil plus rituximab

9 septembre 2006 
http://mutated-unmuated.blogspot.com/2006_09_01_archive.html
Don't read this if you are squeamish.

As readers will know I have long been an advocate of chlorambucil plus rituximab as a logical regimen to study in CLL.

Trying to cure CLL is a forlorn hope in many cases. The most successful regimens at producing molecular remissions - remissions in which the most sophisticated tests available cannot detect a single CLL cell in the body - are achieved with drugs like fludarabine and Campath which are very good at killing CLL cells, but also very good at killing T cells. What no-one has shown yet is that such intensive regimens have ever cured anyone, nor even whether the overall survival with such treatment is better than starting with chlorambucil.

It may be possible to cure people with a transplant, but this is a very high risk strategy. Most people's experience is that you kill more than you cure, and the follow up of mini-transplants, which are less toxic, is too short to know how successful they are.

CLL should not be thought of as just another cancer. As a cancer it is usually not much of a player. Very few CLL sufferers are ravaged by their tumor the way that melanoma attacks you. Melanoma is no respecter of territory it careers about the body setting up colonies wherever it lands. Great black tumors appear in the lungs, the liver, the bowel wall, the muscles, the heart, the spleen, the brain - it knows no bounds. CLL cells in most people obey the rules. They keep to the highway where lymphocytes are supposed to be. They rest in lymph nodes the liver and the spleen, causing traffic jams to be sure, but seldom spilling out into adjacent fields. This is why some doctors talk about a 'good cancer'. But CLL is more than just another cancer.

CLL is the tumor that causes the greatest disruption of the immune system. Until AIDS came along it was the only disease in adults that affected the immune system in a major way. The earliest work that I did on CLL showed that even the mildest cases, stage 0 with a lymphocyte count of less than 10, had impaired immunity. They were not able to respond to a new vaccine that they had not met previously. Everybody thinks that this is an antibody problem; after all, hypogammaglobulinemia - low levels of immunoglobulin in the blood - is a characteristic finding in CLL which is a B cell disease, and the B cells are responsible for making the immunoglobulin. But it is the T cells that instruct the B cells how to make the antibodies and T cells are at fault in CLL.

So to treat CLL with drugs that further damage T cells, seems to me to be risky, if not perverse. When fludarabine or Campath are used, it is necessary to protect against the kinds of germs that T cells are there to protect you from. Pneumocystis carinii and Herpes zoster require prophylaxis with Bactrim and val- or fam- cyclovir respectively. But the story doesn't end there. After fludarabine it is extremely difficult to get a stem cell harvest for an autograft. After fludarabine autoimmune hemolytic anemia may be triggered and sometimes this is so severe as to be untreatable. After fludarabine Richter's syndrome is more likely, probably because of reactivation of EB virus. After Campath, and sometimes after fludarabine in combination reactivation of CMV occurs. After fludarabine the risk of second cancers, especially skin cancers, is increased. After fludarabine secondary myelodysplasia seems to be commoner. I strongly suspect that this is because of its effect on T cells.

The first time I lectured about fludarabine I rejoiced that here was a drug with a major effect on lymphoma that was only minimally marrow toxic. I was reminded at the time by Professor Grant Prentice that its effect on T cells might be more significant. He was right. Fludarabine, like marriage 'is not by any to be enterprised, nor taken in hand, unadvisedly, lightly, or wantonly'. No doubt there are some for whom it is the right thing, but for many we must, like the dentist in 'Marathon Man', ask the question, "Is it safe?"

Don't you find it surprising that despite producing more and better responses and longer remissions than chlorambucil, it does not lead to a longer overall survival? Fludarabine's supporters put it down to crossover, the fact that once they fail chlorambucil, patients can try fludarabine later. But if that were the cause you would expect some to fall by the wayside in the changeover, and although it might not be significant, I would expect a small gap to be opening up at 5 years showing a small benefit for fludarabine. In fact, the small, but still statistically insignificant gap seems to be opening up in favor of chlorambucil. One possible reason for the failure of fludarabine based regimens to show superiority is the occurrence of late complications.

Rituximab is a different matter. Although as a single agent it does not seem to be all that good in CLL, in combination with virtually any chemotherapy, it adds value. It is so non-toxic. Sure it gets rid of the B cells, but not for ever as they are rapidly replenished from a CD20 negative source. Sure it causes infusion reactions, but these can be abolished by giving it more slowly. So adding it to chemotherapy improves the response and the overall survival. CHOP-R is better than CHOP; CVP-R is better than CVP; FCR is better than FC.

I have noticed that physicians have started using CVP-R for CLL. The logic behind this is that in follicular lymphoma CVP-R is better than CVP in the Robert Marcus trial. To many oncologists one low grade lymphoma is very like another and CLL is regarded as just another low grade lymphoma. I have no doubt that CVP-R will work in CLL, but CVP has been trialed in CLL and been shown to be no better than chlorambucil in terms of responses and survival, but worse in two respects: cyclophosphamide is more likely to cause you to lose your hair, and vincristine causes peripheral neuropathy. Everybody on vincristine loses their ankle reflexes, and some, especially older patients, never walk again.

Chlorambucil has been around since 1951. There is no money in it for the pharmaceutical companies. It is one sixteenth the price of fludarabine. Before fludarabine came along it had beaten off CVP, CHOP and CEP. The trials that showed it to be worse in some respects than fludarabine used a sub-optimal dose of chlorambucil. The latest CLL4 trial in Britain actually shows no difference between chlorambucil and fludarabine, though FC is better in every respect, except in overall survival.

Chlorambucil is not the perfect drug. It is marrow toxic, especially in higher doses. CLL does become resistant to it in a proportion of cases. It causes a rash in about 2% of cases. It does suppress T cells to a degree, though nothing like as much as fludarabine or Campath.

So why has nobody tried chlorambucil plus rituximab? There has been a small phase II trial in low grade lymphoma (unlike the Robert Marcus trial, this did include some patients with CLL). This trial was encouraging.

FCR has captured so much of the market and is so impressive up front that we have not been paying enough intention to late complications. Furthermore, the way it has developed, with initial courses given in Houston and subsequent courses and follow up taking place elsewhere in the US (indeed elsewhere the world) militates against the detection of late complications. Why was it that Houston, the greatest user of fludarabine, did not pick up the complication of triggering autoimmune complications as early as others? Because the follow-up was scattered to the winds.

The slow movement towards trying chlorambucil plus rituximab has come from patients, especially those who pay attention to the internet.

Here is a prediction. Changes in Big Pharma will bring about chlorambucil plus rituximab trials. Schering AG, a relatively small German company which markets both fludarabine and Campath, has been taken over by Bayer, one of the giants of the industry. This makes it much more unlikely that there will be joint trials between the Rituximab manufacturers and the fludarabine manufacturers in the future. There was always the possibility that Roche would take over Schering, but Bayer is too big a mouthful. So Roche, which handles rituximab outside the US, will be looking for another drug to use with rituximab. I predict they will hit on chlorambucil.

About 40% of patients with mutated IgVH genes will require some sort of therapy. Many of them will be elderly. The last thing they want is their immune systems completely scuppered. I predict that it will be in this group that we see the first trials.