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Campath Therapy

 

Campath - Looking Better and Better

February 3, 2004

by Chaya Venkat

I have just been reading all the past articles we have on our website on the subject of Campath.  The articles are listed chronologically, and I was struck by the gradual shift in my own perspective of this monoclonal antibody, earlier comments such as "Campath scares me" gradually morphing into "Campath is a good drug to have available as an option". I think it is time to re-visit the subject of Campath, see what has changed in the past couple of years.

Background on Campath

Campath (sometimes referred to as Campath-1H) is a fully humanized monoclonal antibody. For comparison, Rituxan is a chimeric monoclonal antibody, part human and part mouse. Where as Rituxan targets CD20 marker on mature B-cells, Campath is directed against CD52. The big advantage for Campath is that just about 100% of CLL patients have CD52 expression on their B-cells, at a high (bright) intensity. As you may remember from our many articles on Rituxan therapy, the CD20 target of Rituxan is not always expressed by all the CLL cells and even when it is expressed by CLL cells, in the case of many patients the expression is of low (dim) intensity. In sharp contrast, there are as many as half a million of the Campath target CD52 markers per each B-cell! At that level of intensity, it is next to impossible for a Campath molecule to swing by a B-cell and resist. The other good news is that hematopoietic stem cells do not have CD52 marker (nor CD20, for that matter), so they are left alone and not harmed during monoclonal therapy by Campath or Rituxan.

While it is good to know that almost all CLL patients will respond to some degree to Campath because of the high prevalence of the CD52 marker, the other side of the coin is that this marker is a little too available - it is also exhibited by T-cells, monocytes and macrophages, all of which are therefore fair game for Campath's targeting. Each of these are important components of the immune system and wiping them all out as well as the dysfunctional CLL B-cells in one fell swoop is a huge hit. It leaves the patient unprotected from opportunistic infections that might use this window of opportunity to score a few points off you. Experts have come up the learning curve on how to manage this risk, how to administer the drug in the first place and how to protect the patients during the period of vulnerability. Eventually your bone marrow will replace the cell lines wiped out during therapy, because the stem cells themselves are not destroyed. But this can take some time to happen and there are lingering concerns that the full repertoire of T-cells take a long time to be replaced.

Here is a small snippet of information that you may not have heard. Did you know that Campath is a male infertility drug (through inhibition of sperm mobility)? Hard to imagine how the same drug can be both an infertility drug and a cancer drug, but there it is. Do sperm express CD52 marker? Casually drop that little piece of information at the right time and impress the heck out of your oncologist.

Campath as Frontline Therapy in Untreated ("Chemo-naive") CLL Patients

A well conducted and well-documented phase 2 multi-center clinical trial in Sweden gives us some of the latest information on the use of Campath for previously untreated CLL patients. The PubMed abstract is quoted below. If you are interested in reading the whole article (or any of the other articles referenced here), write to us at identifying the article by title.

The Administration Protocol:

  • The 30-mg dose was given 3 times weekly for a maximum of 18 weeks.

  • The first couple of weeks the Campath was given in smaller doses, gradually building up to the 30 mg level.

  • After the dose-escalation phase and the disappearance of “first-dose” skin reactions, almost all patients were able to administer the subcutaneous shot themselves.

  • Allopurinol was given for the first four weeks (to protect against tumor lysis damage to the liver, etc.). Tylenol, Benadryl (or European versions of these drugs) were used in the first few weeks, while the "first dose" flu-like reactions were present. This now seems to be pretty standard procedure and  the same set of drugs are used prior to Rituxan therapy as well.

  • Opportunistic infections were one of the major problems with early Campath studies. Now it is almost mandatory to use pre-emptive drugs to protect against this risk. This study used valacyclovir, fluconazole and cotrimoxazole throughout the 18 week period of the therapy, and for an additional 8 weeks thereafter. If you tend to have unpleasant side-effects associated with antibiotics and antivirals etc, this point is worth considering carefully. We are talking about a full six months of pretty heavy duty dosing here, and you are well advised not to skip taking the medications.

The Punch Line - Results

Considering the mixed bag of patients, some of them with pretty heavy duty tumor loads, the overall response rates are pretty good. Campath has a very easy time of clearing the peripheral blood of CLL cells, but then, so does Rituxan. As I am fond of pointing out, cancer cells in your blood are no more than the tip of the iceberg. Patients tend to focus on their CBC numbers because that is what they get to see each month when they get their blood tests done. Unfortunately, the real home of CLL is the bone marrow, as well as lymph nodes and spleen in patients with more advanced or aggressive disease. As you can see from the table below, while a whopping 95% of the patients in the study had squeaky clean blood at the end of the study (well, for a short while anyway), far fewer (45%) had their bone marrow cleaned out. The worst response was in the lymph nodes, where less than a third of the patients obtained the coveted grade of CR (Complete Response). This point is driven home even more clearly if you read the full article: there was a further distinction between people with bulky lymph nodes (anything larger than a Ping-Pong ball) versus the people with small grape size nodes. If you have large lymph nodes (massive "lymphadenopathy") or swollen spleen ("splenomegaly"), chances are slim you will get a complete response with Campath alone.

Response (%) in relation to disease site

Site

Overall
Response

Complete
Response

Blood

97

95

Bone Marrow

79

45

Lymph Nodes

87

29

Spleen

90

36

The Side Effects

Compared to the scary stuff we all heard regarding intravenous administration of Campath in some of the earlier trials, the subcutaneous ("sq") method of administration seems to have been much better tolerated by almost all of the patients. In fact, patients were able to give themselves the shot without having to make the trip to the clinical center. As you can see from the table below, many of the usual side-effects such as fever, rigor, nausea, etc., were mild or absent. Most side-effects disappeared after 1 to 2 weeks AND ONLY 3 patients withdrew from the study due to side-effects. No one is quite sure why there is such a big difference between the intravenous and subcutaneous modes of administering Campath. If I were to guess, my money would be on the fact that sq administration allows the drug to seep into the blood circulation slowly over time, not in one sharp spike as is the case with intravenous administration. Frankly, I wonder why no one has tried subcutaneous administration of Rituxan too, it would seem to me this is a no-brainer. Maybe no one has thought to do it since it is assumed patients don't suffer too much with Rituxan, so why bother. Right. Tell that to the patients.

“First-dose” reactions following subcutaneous Campath in CLL patients

Event

NCI Grade
I/II,  %

NCI Grade
III,  %

Fever

68

2

Rigor

15

2

Rash

0

0

Hypotension

0

0

Nausea/vomiting

0

0

Diarrhea

0

0

Headache

0

0

Fatigue

5

2

Injection Site Reaction

88

2

NCI Grade I/II: Not so bad
Grade III: Something to write home about
Grade IV: The pits.

Patients tend to focus on their aches and pains during the actual drug administration. But again, this is just the tip of the iceberg. More important is the toxicity to the bone marrow and the depletion of other cell lines. This is one area of concern where Campath suffers by contrast to Rituxan. Since Rituxan targets the CD20 marker present only on mature B-cells, other cell lines such as neutrophils, T-cells etc are spared. Not so with Campath. It is also not obvious why either Campath or Rituxan therapy should cause reduction in red blood cells and platelets, giving rise to anemia and thrombocytopenia. The short answer is that platelets and red blood cells also participate in the process of clean-up after all the murder and mayhem. The cellular and other debris resulting from cancer cell-kill has to be carted away. Many of the messy fragments are picked up by these hard working cells, carted away to the spleen and liver for final disposal. In the process of doing garbage duty, many of the red blood cells and platelets also get chewed up. The detailed answer is more complicated, but this will do to get you through the pop quiz.

As you can see from the table below, just about all the patients got mild-to-middling level of one or more hits on anemia, neutropenia or thrombocytopenia. The only one that would cause me serious concern is the fact that about one out of every five patients had grade IV neutropenia. I guess they are not kidding when they insist on the 6 months of bug pills to try and prevent any opportunistic infections. Even with the precautions, 4 patients (roughly 10%) had CMV (cytomegalovirus) reactivation, but none of these CMV infections were considered dangerous. One patient developed pneumonia. Shingles was not mentioned specifically, but I would be willing to bet that if you skipped on the anti-viral pills (valcyclovir), and had been exposed to chicken pox as a kid, you would come down with shingles. I have not had shingles myself, but I think I believe the folks who tell me it hurts like hell, so be good and remember to take your medications if you are going to try Campath.

 

Hematologic toxicity (%) after sq Campath

NCI Grade

0-I

II-III

IV

Anemia

61

39

0

Neutropenia

26

53

21

Thrombocytopenia

84

11

5

So, where does all this leave us?

I guess if I were newly diagnosed CLL patient, rather young and of a relatively impatient nature that cannot deal with the long term chess game that CLL can become, I might be tempted to consider an up-front and early intervention with Campath. Patients achieving a complete response with no detectable CLL cells by MRD flow cytometry have an extremely good outcome, with a 65% 5-year event-free survival (personal observation, Dr. Ben Kennedy, Department of Hematology and Oncology, Leeds General Infirmary, Leeds, United Kingdom).

This is tempting, no doubt about it. If I had just the early phase of the disease with no discernable lymph nodes, and a bone marrow biopsy said I had only a small amount of bone marrow involvement, it can be argued that I could go for broke, look for a deep and PCR negative response with just Campath. I like this option better than the current "gold standard" of fludarabine as a single agent therapy. Unlike fludarabine, Campath is not a DNA damaging agent, and recent studies have shown that even patients with poor cytogenetics (11q or 17p deletions) do well with Campath. The same cannot be said for purine analogs such as fludarabine and pentostatin. Unlike the other earlier gold standard chlorambucil ("Leukeran"), where percentage CRs were in the low single digits, Campath is potent and does a terrific job on blood, and a pretty decent job on bone marrow. Just don't expect Campath to clear large lymph nodes or spleen, all by itself.

Abstract:

Blood. 2002 Aug 1;100(3):768-73.

Phase II trial of subcutaneous anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) as first-line treatment for patients with B-cell chronic lymphocytic leukemia (B-CLL).

Lundin J, Kimby E, Bjorkholm M, Broliden PA, Celsing F, Hjalmar V, Mollgard L, Rebello P, Hale G, Waldmann H, Mellstedt H, Osterborg A.

Department of Hematology, Karolinska Hospital, and Huddinge University Hospital, Stockholm, Sweden.

This phase II study determined the efficacy and safety of alemtuzumab, a humanized anti-CD52 monoclonal antibody, delivered subcutaneously as first-line therapy, over a prolonged treatment period of 18 weeks in 41 patients with symptomatic B-cell chronic lymphocytic leukemia (B-CLL). Injections were administered subcutaneously 3 times per week, from week 2 to 3 onward. An overall response rate (OR) of 87% (95% CI, 76%-98%; complete remission [CR], 19%; partial remission [PR], 68%) was achieved in 38 evaluable patients (81% of intent-to-treat population). CLL cells were cleared from blood in 95% patients in a median time of 21 days. CR or nodular PR in the bone marrow was achieved in 66% of the patients and most patients achieved this after 18 weeks of treatment. An 87% OR (29% CR) was achieved in the lymph nodes. The median time to treatment failure has not yet been reached (18+ months; range, 8-44+ months). Transient injection site skin reactions were seen in 90% of patients. Rigor, rash, nausea, dyspnea, and hypotension were rare or absent. Transient grade IV neutropenia developed in 21% of the patients. Infections were rare, but 10% patients developed cytomegalovirus (CMV) reactivation. These patients rapidly responded to intravenous ganciclovir. One patient, allergic to cotrimoxazole prophylaxis, developed Pneumocystis carinii pneumonia. Alemtuzumab is highly effective as first-line treatment in patients with B-CLL. Prolonged treatment is important for maximal bone marrow response. Subcutaneous administration induced very few "first-dose" flulike symptoms and may reduce health care costs in comparison with the intravenous infusions.

PMID: 12130484
______________

Early Prediction of Outcome in Campath Therapy

True, the subcutaneous administration of Campath and the prudent use of prophylactic drugs to prevent opportunistic infections have made a huge difference. But lower risk is not the same as zero risk. There are real benefits if it were possible to predict soon after start of therapy which patients are likely to respond well and which ones are not going to make the grade. For example, patients who are not likely to do well may decide to stop the therapy mid-stream, save themselves the additional toxicity, CMV reactivation and the like. Or they could "upgrade" for the more aggressive fludarabine plus Campath therapy, and hope this will put them over the top. If nothing else, it makes sense from a public policy perspective, since monoclonal antibody therapy is very expensive, and there is no point in throwing away good stuff down the rat hole, if it is not going to do the patient much good anyway.

Until very recently, therapy was monitored by means of very frequent bone marrow biopsies looking for CLL cells. Ouch. Also, this is not very useful since most patients, even the ones that are eventually going to get a full CR at the end of therapy, have substantial levels of CLL cells in their bone marrow until the very end of the 18 weeks of therapy. Thus BMBs were no good in telling apart the star students from the ones who were going to flunk the course.

The abstract below describes a clever way of getting around this issue. The authors came up with an improved and very sensitive flow cytometry technique for CLL cells in the peripheral blood. It was observed that Campath first cleans out the peripheral blood, and only after this job is done does it go after the CLL cells in the bone marrow and lymph nodes. Patients who had very, very low levels of CLL cells in their blood by week 4 of the 18 week therapy could be safely expected to get CRs at the end of 18 week therapy period. Those that had even small amounts of CLL cells left over in their blood by end of week four were probably not going to make it, and had best revisit their therapy options.

Accurate measurements and being able to make predictions based on the measurements is at the heart of all improvements. These researchers were able to develop a dependable relationship between the absolute number of CLL cells circulating in the blood and the degree of bone marrow infiltration in patients. This is painstaking and not very glamorous work, I suppose, but many CLL patients will be better off knowing relatively early in the Campath therapy if they should stick with their original game plan or make some changes. All this while avoiding repeated bone marrow biopsies. Well done, gentlemen!

Abstract:

Blood. 2003 Nov 20 [Epub ahead of print]

Early prediction of outcome and response to alemtuzumab therapy in chronic lymphocytic leukemia.

Rawstron AC, Kennedy B, Moreton P, Dickinson AJ, Cullen MJ, Richards SJ, Jack AS, Hillmen P.

Academic Unit of Haematology and Oncology, HMDS, Leeds General Infirmary, Leeds, United Kingdom.

Alemtuzumab therapy is effective for some refractory CLL, but identifying responders requires at least eight weeks of therapy. Early identification of non-responders would minimize toxicity and/or facilitate more effective strategies. The aim of this study was to identify a minimally-invasive method for early prediction of response and relapse. Flow cytometric monitoring was performed in 887 blood and 201 marrow samples from 43 patients undergoing intravenous alemtuzumab therapy. Although the absolute lymphocytosis resolved in all patients by week four, significant depletion of bone marrow tumor only occurred if circulating B-lymphocytes were persistently <0.001 x10(9)/L, which was rare in non-responders. The majority of patients (16/28) who did not benefit from a full course of therapy were identified with 100% positive predictive value using the algorithm: peripheral B-cell count >0.001 x10(9)/L at week two with <1 log depletion of circulating B-cells between weeks two and four. Monitoring CLL levels post-treatment identified patients at risk of early disease progression and could potentially improve patient management. During alemtuzumab therapy, bone marrow CLL depletion only occurs after abrogation of circulating tumour, requiring close monitoring of circulating B-cell levels. If validated in prospective studies, blood monitoring at two and four weeks may be used to optimize therapy.

PMID: 14630811
______________

Campath for the Tough (Bucket C) Cases

I hope you have had a chance to read "What Type of CLL Do You Have?". I am rapidly becoming convinced that it is impossible to make intelligent decisions regarding when to start therapy and what therapy to chose, without having a good fix on your cytogenetics. Interphase FISH is now becoming available as a commercial test that can be done for not more than a few hundred dollars, and very often you do not have to trek to a major CLL center to get this done. Check ahead of time to make sure you got the details right. It is possible to get blood drawn at one of your local labs and have it sent by overnight to the testing lab that does this test. Most insurance companies will cover the cost, but again you are well advised to get your ducks in a row first.

Here is the single biggest reason for getting your FISH (cytogenetics) information: CLL patients with deletions or mutations in the 11q22 or 17p53 gene progress rapidly, require treatment sooner than patients with more benign chromosomal aberrations, and frequently have major lymph nodes as well as spleen and liver involvement. These two chromosomal aberrations focus on the ATM and TP53 genes respectively, both of which are involved in cell repair and tumor suppression. You can see why it is bad news if these keepers of the sanctity of your genome are not doing their job right. You can read more about how these two genes work and why they are important in other articles on our website.

Probably the single most important feature of our poor prognosis "Bucket C" group is the presence of 11q or 17p abnormalities. Not only does the CLL progress faster in this group of patients, it is harder to treat. Recently, several studies have demonstrated that conventional chemotherapy agents such as chlorambucil, fludarabine and cyclophosphamide do not work well in this high risk group. Of the two cytogenetic abnormalities, I get the sense that 17p deletion or mutation is the more dangerous one, but neither one is something you would wish on your worst enemy. If you go back to the article "What Type of CLL Do You Have?",  do look up the stark and frightening statistics for 11q and 17p mutated cases. Look at the scary charts of survival statistics and then thank you lucky starts that we now have drugs that do work on these hard to treat cases, drugs that were not available just a few years back when Dohner and Stilgenbauer collected their retrospective data. The age of monoclonals is here, and it has given hope to these "Bucket C" round-headed kids in our midst. Since this article is all about Campath, I will restrict my discussion in this section to the use of Campath for this group of patients.

Below is the abstract of an article hot off the presses (it has not even issued in print - I am reporting from the electronic version that issues ahead of the printed version. We are truly at the cutting edge of things on CLL Topics!). The author list is of blue-blood pedigree. If you wish to read the whole article, and I hope at least a few of you will want to make the effort, write to us at .

Abstract:

Blood. 2004 Jan 15 [Epub ahead of print]

Alemtuzumab is an Effective Therapy for Chronic Lymphocytic Leukemia with p53 Mutations and Deletions.

Lozanski G, Heerema NA, Flinn IW, Smith L, Harbison J, Webb J, Moran M, Lucas M, Lin T, Hackbarth ML, Proffitt JH, Lucas D, Grever MR, Byrd JC.

Pathology, The Ohio State University, Columbus, OH, USA.

The presence of p53 mutation or deletion predicts for poor response to conventional therapy in chronic lymphocytic leukemia (CLL). We sought to determine if the humanized anti-CD52 antibody alemtuzumab was effective in this patient group. Thirty-six patients with fludarabine refractory CLL were treated with alemtuzumab, fifteen (42%) of which had p53 mutations or deletions. Clinical responses in patients with p53 mutations and/or deletions were noted in 6 of 15 (40%) versus 4 of 21 (19%) of patients without. The median response duration for this subset of patients was 8 months (range 1-17 months). These data suggest that alemtuzumab may be an effective therapy for CLL patients with p53 mutations or deletions.

PMID: 14726385
______________

The table below spells out the details of the 36 patients who volunteered for this study. As you can see, just about all of them were tough nuts, high risk candidates who have already been through the wars of chemotherapy as it were. Most of them were fludarabine refractory, which is bad news by all accounts. Almost all of the patients had cytogenetic abnormalities to match, bad news all around. These patients were treated with intravenous Campath, 30 mg three times weekly for a total of 12 weeks. I wish the monoclonal administration had been done by subcutaneous mode, but it was not the case.

Clinical Features of Patients

Features

Number

Total Number of Patients

36

Age (Years)

47-74

Number of Male Patients

29

Rai Stage - Intermediate Risk

9

Rai Stage - High Risk

27

Number of Prior Therapies

1-12

Fludarabine Refractory Patients

29

Interphase FISH Cytogenetics

 

Mutation(17p) 

11

Deletion(17)(p13.1) 

12

Deletion(11)(q22.3)

16

Trisomy 12 

3

Deletion(13)(q14)

23

Deletion(6)(q21)

4

Normal interphase cytogenetics 

3

How did Campath perform in this very tough crowd? Table below spells out the details. Not every one went home happy with a perfect CR, but these results are extraordinarily good, given the tough situation most of these patients were in, good enough to change the survival statistics projected by Dohner, Stilgenbauer et. al., I would bet.

Response to Campath by Patient Characteristics

Characteristics

Number with CR or PR

Age: Less than 60 years

5 out of 17

Age: More than 60 years

6 out of 19

Rai Stage - Intermediate Risk

4 out of 9

Rai Stage - High Risk

7 out of 27

Three or Fewer Prior Therapies

6 out of 18

More than Three Prior Therapies

5 out of 18

Fludarabine Refractory Patients

7 out of 29

Fludarabine Non-Refractory Patients

4 out of 7

Interphase FISH Cytogenetics

 

Mutation/Deletion (17p) 

6 out of 15

Deletion (11q)

3 out of 11

Commentary:

Can one improve on these statistics, get a better deal for our round-headed kids in Bucket C? I am going out on a limb here with this commentary, but not too much. I think there is a window of opportunity for these folks that must be explored and nailed down. Conventional "Watch & Wait" until the disease gets to be a full grown monster may be the kiss of death, literally, for folks with 11q and 17p deletions. Below is a direct quote from the Byrd, Flinn, Grever et al, three names most of us long timers will recognize.

"If our collective findings are confirmed in larger prospective cohorts of patients, it would appear that alemtuzumab (aka Campath), as opposed to fludarabine, chorambucil, .... would be a more rational initial treatment choice for patients with p53 mutations and/or del(17)(p13.1). In addition, these data would provide preliminary evidence for screening all patients at time of initial and subsequent therapies for the presence of del(17)(p13.1) and p53 mutations to avoid administration of otherwise ineffective therapy for this disease".

Let us take it from the top. Let us say you are newly diagnosed, and you were smart enough to go get yourself a solid and irrefutable diagnosis of CLL, and you went the extra 9 yards and got the FISH test done as well. The news is bad, you have the dreaded ATM (11q) or TP53 (17p) deletions. You are early stage, the monthly CBC does not look so scary yet, you have no B-symptoms and feel generally quite healthy. Should you wait, watching the WBC creep up slowly, and this is even more important, watch the lymph nodes start popping up along your jaw line and elsewhere? Not a smart move, it appears. Since you have the dreaded 11q and/or 17p deletions, standard chemotherapy drugs such as fludarabine, chlorambucil and cyclophosphamide may not work as well, and if you let the lymph nodes and spleen get too large, you may have also shot yourself in the foot in terms of Rituxan and/or Campath. According to the statistics in the first paper reviewed above, only about one out of three patients with bulky disease get a CR with Campath therapy.

Does the new information regarding standard chemotherapy drugs (purine analogs and alkylating agents) not working as well in 11q and 17p deleted or mutated cases apply to combinations including them? In other words, does the famous FRC (fludarabine, Rituxan, cyclophosphamide) combo therapy popularized by M. D. Anderson work equally well in these poor prognosis patients as well? I have not seen compelling break-out of response statistics by cytogenetic risk factors. Yes, FRC has impressive statistics by way of overall response but we are still waiting to see if this has a clear survival advantage as well. Impressive, but not 100%. Who are the patients that do not respond, or even if they responded and even get a sufficiently deep response to get the coveted "PCR negative" status, relapse disappointingly soon after? Do these non-responders or too-soon-relapsers have 11q or 17p mutations more often than not? Did they enter the clinical trial with bulky lymph nodes, a tell-tale signal they may have one of the worse cytogenetic abnormalities? It seems to me this is the kind of detailed work we need, in order to make sensible therapy decisions. For now, I think we can put a question mark next to the FRC type combo therapies.

It boils down to this. If you are unfortunate enough to have poor cytogenetics, thank your lucky stars you were smart enough to find out this crucial piece of information soon enough to act upon it. Dithering is not for you. You are well advised to consider therapy early, before the lymph nodes become bulky enough to give you the chipmunk look, and the swollen spleen starts making you look like you have a beer belly or a 7-month pregnancy. Monoclonal therapy may be your best bet. Should it be Rituxan, or should it be Campath? As single agents or in combination with other drugs? Obviously, if your flow cytometry results indicate that your particular version of CLL has good expression of the CD20 marker on most of the CLL cells, Rituxan may be a good choice for you. Rituxan has the advantage of lower infusion-related side effects and a lower incidence of opportunistic infections. On the other hand, Campath has a tremendous advantage in that almost all CLL patients have a high percentage of their cancer cells exhibiting CD52, the target for Campath, and at a sufficiently high intensity. Chances are better that you will respond to Campath.

Recent work suggests that Campath researchers are coming up the learning curve rather quickly, understanding how to administer this important monoclonal (subcutaneous versus intravenous) and with enough prophylactic medications to keep away the opportunistic infections. Some of the recent Campath studies I have seen insist upon weekly monitoring of the patients' blood for markers of the CMV virus, so that they can hit it with heavy duty anti-virals well before full-blown CMV re-activation has taken place. Measuring viral load titers is something we have learned from the AIDs epidemic, and we are getting pretty good at it. Furthermore, the so-called demerit for Campath, that it is not as selective as Rituxan because it destroys T-cells as well as CLL B-cells, may be not such a bad thing after all. True, it leads to a deeper level of immune suppression. But on the other hand, it is gradually becoming clear that in CLL it is not just the cancerous CLL B-cells that are a problem. There is so much chit-chat going on between the B-cells and T-cells, such a cozy relationship of shared cytokines and mutual paracrine loops feeding each other, that the cancerous B-cells often corrupt the T-cells as well. Many of the autoimmune diseases that CLL patients develop are driven by subverted and corrupted T-cells. It may not be such a bad idea to get rid of not just the cancerous B-cells, but their partners in crime, the T-cells, as well.

This is the type of research that makes for gradually improved survival statistics for CLL patients, hard-won victories. The work is not as "sexy" as finding a cure for CLL that comes in the form of a neat little pill, or therapies that have catchy names and breathless sound-bites reported on the TV or tabloids, the latest miracle drug that will cure you, just trust the guy in the white coat with charm and charisma oozing from every pore. Me, I am a hard sell. I want to understand the details, ask the tough questions, walk around and kick the tires. It is no guarantee against things that go bump in the night, but it sure beats the alternative.

My next article, as soon as I review some of the published articles on the subject, will deal with use of Campath as a mop up agent, to get rid of MRD (Minimum Residual Disease). Below are the abstracts, just so you can get a quick peek. The use of Campath in MRD and bone marrow transplant settings are both extremely important subjects, and I want to do them justice.

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Abstracts:

Cancer. 2003 Dec 15;98(12):2657-63.

Alemtuzumab as treatment for residual disease after chemotherapy in patients with chronic lymphocytic leukemia.

O'Brien SM, Kantarjian HM, Thomas DA, Cortes J, Giles FJ, Wierda WG, Koller CA, Ferrajoli A, Browning M, Lerner S, Albitar M, Keating MJ.

Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.

BACKGROUND: The objective of this study was to investigate the efficacy and safety of alemtuzumab, the humanized anti-CD52 monoclonal antibody, in patients with B-cell chronic lymphocytic leukemia and residual disease after chemotherapy.

METHODS: Forty-one patients received alemtuzumab 3 times weekly for 4 weeks. The first 24 patients received 10 mg per dose, and the next 17 patients received 30 mg. All patients received infection prophylaxis during therapy and for 2 months after treatment.

RESULTS: The overall response rate was 46%, including 39% of patients who received the 10 mg dose and responded versus 56% of the patients who received the 30 mg dose. The major reason for failure to respond was the presence of adenopathy. Residual bone marrow disease cleared in most patients, and 11 of 29 patients (38%) achieved a molecular disease remission. The median time to disease progression had not been reached in responders with a median follow-up of 18 months. Six patients remained in disease remission between 24-38 months after therapy. Infusion-related events were common with the initial doses, but all such events were NCI Common Toxicity Criteria Grade 1-2. Infections were reported to occur in 15 patients (37%), and 9 of these infections were reactivation of cytomegalovirus. Three patients developed Epstein-Barr virus positive, large cell lymphoma. Two patients had spontaneous resolution of the lymphoma and, in one patient, the lymphoma resolved after treatment with cidofovir and immunoglobulin.

CONCLUSIONS: Alemtuzumab produced significant responses in patients with residual disease after chemotherapy. Bone marrow disease was eradicated more frequently than lymph node disease, and molecular disease remissions were achieved. A randomized trial comparing alemtuzumab with observation after chemotherapy is indicated. Copyright 2003 American Cancer Society.

PMID: 14669286
______________

Bone Marrow Transplant. 2002 Dec;30(12):797-804.

Alemtuzumab (Campath-1H) for treatment of lymphoid malignancies in the age of nonmyeloablative conditioning?

Hale G, Slavin S, Goldman JM, Mackinnon S, Giralt S, Waldmann H.

Sir William Dunn School of Pathology, University of Oxford, Oxford, UK.

The anti-CD52 (Campath-1) monoclonal antibodies (Mabs) have a substantial history of use for controlling graft-versus-host disease in allogeneic bone marrow transplantation. Now, with the availability of a humanised form, alemtuzumab (Campath-1H), and the demonstration that this agent can reduce the tumour burden in B-CLL, a new niche may be found - as a potentially curative agent in which its tumour purging ability in vivo combines with its role as a conditioning agent in nonmyeloablative transplantation. Review of the literature shows that alemtuzumab has unique advantages as a method of depleting malignant lymphocytes, including those in patients resistant to conventional chemotherapy. Alemtuzumab can also be used in BMT for depletion of normal T and B lymphocytes of both the recipient and donor for prevention of graft rejection and GVHD. It allows good stem cell recovery with resultant rapid engraftment, has a low risk of EBV-triggered secondary malignancy and does not interfere with blood stem cell mobilisation. As a method of eliminating the malignant clone in B-CLL, alemtuzumab has shown remarkable efficacy in heavily pre-treated patients, a number of whom have progressed to autologous or allogeneic transplantation. Efficacy data are shown within the context of other transplantation data for B-CLL. These results indicate that the combination of tumour-depleting and immunosuppressive properties of alemtuzumab should be explored, with the hope of providing improved treatment options for elderly patients with advanced B-CLL or indolent lymphoma whose prognosis is too poor currently to allow treatment with traditional regimens of high-dose myeloablative chemotherapy.

PMID: 12476271
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