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A New Lease on Life for "Bucket C" Patients

Date: July 16, 2024

CLL does not much feel like an indolent disease for folks with poor prognostics. For “Bucket C” kids, therapy becomes necessary all too soon after diagnosis and the kicker is that most conventional therapies do not work as well for them. This is particularly true for those with deletion of the all important “17p” region, home of an important tumor suppressor gene. Patients with unmutated IgVH are also at risk of rapid disease progression and poorer response to therapy. These grim facts are baked in the cake, built into most of the survival statistics developed prior to the advent of the monoclonal antibodies.

Now we get solid confirmation that the landscape has changed, we finally have a drug that doesn’t seem to care about IgVH gene mutation status or 17p deletion status. And that is big news. Even if you presently enjoy a "good" chromosomal abnormality such as the 13q deletion, bear in mind that clonal evolution is a documented fact of life with CLL. This can happen all by itself, since CLL cells have unstable genome and can develop new aberrations. Therapy with mutagenic drugs (that is just about most of the chemotherapy drugs in our arsenal) can increase the probability of gaining additional and more dangerous aberrations. Bottom line, a very significant percent of CLL patients may "graduate" to Bucket C status over the years, even if they did not start there at the time of diagnosis.

If all of this sounds like so much jargon to you, it is time to get yourself an education. Believe me it is not all that hard, if you are willing to take the time. Here are a few links you can look up if you are new to the CLL scene, or you need a refresher course:

1. What Type of CLL Do You Have?;
2. What You and Your Oncologist Need to Know about CLL;
3. Prognosis at Diagnosis;
4. Shopping for Therapies;
5. Prognostic and Monitoring Test Packages.

The German Study Group reporting the latest Campath findings has my highest respect for the quality of their work, especially when it comes to careful statistical analysis of the data. When Prof. Stilgenbauer speaks, I listen. When the full length article is available, I will review it in detail. For now, here are the highlights of his presentation at a recent international conference:

• This was a very tough patient cohort, 46 folks who had already flunked fludarabine.
• The patients received subcutaneous Campath (“alemtuzumab” is the technical name, Campath is the brand name. Same thing.)
• Overall response was 37%.
• The most interesting thing is that patients with 17p deletions or unmutated IgVH, the Bucket C folks, responded just as well as patients without these dangerous prognostic indicators. There was also no difference in time to relapse or overall survival.
• This truly sets Campath apart from all the other drugs used to treat CLL. This also means all the older survival statistics go out the window.

These results have a couple of other implications as well. First, it is really, really important for you to get a good handle on your own prognostics. Knowing the lay of the land is going to make all the difference when it comes to making therapy choices. Second, if Campath continues to the only drug that works equally well with all prognostic groups, you might want to stay within the window of opportunity of this drug. Campath does not work very well on large lymph nodes. It can handle CLL in the blood, even the bone marrow, but it does not do lymph nodes. So, if you are a Bucket C patient, chances are that conventional therapy is not going to work well for you and Campath therapy is in your near future; you may not want to dither while the nodes get bigger and bigger. Gone are the days “watch and wait”, therapy initiated only when the tumor load got so high that “B-symptoms” kicked in. Now we know the decision of “when and what” should be made in the context of your individual prognostic factors, and the chosen drug administered at a stage when it is likely to be of highest benefit.

I have no illusion that this change in the CLL landscape will percolate down to the local oncologist level soon enough to suit us. On a weekly basis I hear from patients who were treated with yesterday’s “gold standard” fludarabine, with no attempt made to obtain the patient’s prognostics ahead of time. I know of several that failed to respond to fludarabine and later found they had the 17p deletion, a variety of CLL that does not respond to fludarabine at all. All that pain and toxicity of chemotherapy, all for nothing. I also hear from patients who know their Bucket C status, and dither while their lymph nodes grow progressively larger, because their oncologists show no urgency and they continue to feel fine. Watch out! Campath does not do lymph nodes!

Should you wait for your local guy to come up the learning curve and make the right calls for you? It may be safer for you if you make an effort to learn some of this stuff, so that you can at least ask the right questions next time you get your 15 minutes with the doc. I know, it is unfair, it is hard to read all this jargon and there should be a better way of handling all this new fangled stuff. But until that happens, I suggest you get busy and learn as much as you can about this disease. The life you save will be your own.

Be well,

Chaya
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Press Report

Alemtuzumab effective in poor-genetic-risk chronic lymphocytic leukaemia

17 Jun 2024

Subcutaneous alemtuzumab (MabCampath) is as effective in the genetically hard-to-treat patients with refractory chronic lymphocytic leukaemia (CLL) as in all patients with refractory CLL.

This was the preliminary conclusion of the CLL2H trial of the German CLL Study Group, based on an interim analysis of 46 patients. Professor Stephan Stilgenbauer, Department of Internal Medicine, University of Ulm, Ulm, Germany, presented these findings during the 9th International Conference on Malignant Lymphoma (8-11 June, 2024) at Lugano, Switzerland.

The German CLL Study Group had set out to evaluate the application of subcutaneous alemtuzumab in a genetically high-risk population of fludarabine-refractory CLL patients after intravenous dose escalation. Median age of patients in the cohort was 62 years and three out of four were male.

The overall response rate in the 46 patients was 37%. Professor Stilgenbauer showed an analysis of the response rates of the different genetic subgroups. He said, ‘There is no major variation in response rates. In other words, the 17p- subgroup, which appears to pose a particular clinical problem, appears not to have an inferior response rate to the overall cohort. The same holds true for patients with un-mutated VH states - they also appear to respond to treatment'.

With respect to survival, the picture was the same. The median overall survival time was 17.4 months, and the median time to progression free survival time was 10.8 months. Said Professor Stilgenbauer, ‘There is no clear separation of the 17p- curve, showing that these patients do not only respond, but retain their response and show the same survival time as compared with other genetic subgroups'. He showed a similar pattern with the VH un-mutated status subgroup.

Professor Stilgenbauer concluded, ‘This trial shows that the subcutaneous administration of MabCampath shows similar efficacy as the intravenous application. Most importantly alemtuzumab is active in high risk CLL as defined by the presence of 17p- deletion.'

Stratification by prognostic indicators like 17p- and VH states are now held to be a vital part of the structure of clinical trials. The traditional staging systems are of limited use as prognostic systems. For instance, almost 50% of patients with early-stage disease develop more advanced disease quickly and die of its complications. New laboratory tests can identify some patients with early-stage CLL at high risk of progression. A key method is chromosomal analysis by Interphase Fluorescence In Situ hybridization (FISH). The median survival by FISH category after a median follow-up of 70 months is: for ‘abnormality 17p-‘ median survival 2.5 years; for ‘no abnormality' median survival 9 years; and for ‘abnormality 13q-‘ median survival 11 years. Also, the median survival for patients with early stage disease with non-mutated IgVH gene - detected by flow cytometric analysis of peripheral blood - have been reported to be about 8 years, whereas patients with early-stage disease with mutated-type clones have a median survival of greater than 24 years. (See Shanafelt TA, Call TG. Mayo Clin Proc. 2024;79:388-398).

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