“Just Right” Goldilocks Scenario

goldilocksBy now most of us know that single agent or chemotherapy combinations are rarely given all on one day. Most often they are given over a few days and the process is repeated over a number of cycles. For example, each cycle of FCR is given over three days and the cycle is repeated every month for six months. This standard protocol was developed at M. D. Anderson in their pioneering clinical trials involving many hundreds of patients.

Now that FCR is accepted as the present day gold standard by most CLL practitioners, you are likely to be treated with this regimen as a front-line therapy outside of clinical trials. Come to think of it, you and your oncologist are no longer rigidly locked into the FCR clinical trial protocol. It is possible to consider tweaking the protocol to customize it for individual patients. How much chemo is just right for you?

CLL is such a diverse disease, how is it possible that standardized and rigid protocols defining drug dosage and number of cycles are right for all patients? In this article I would like to discuss the pros and cons of finishing all six cycles of the therapy protocol, as opposed to calling it quits part way through. It is a tricky question and there is plenty of grey area. But a new technology is rapidly gaining acceptance that might make it just a bit easier to make the decision.

Risks and Rewards

Let us all agree on one point: just about every single cancer drug out there has some level of toxicity. Chemotherapy dosages and number of cycles are designed to kill cancer cells – while sparing the healthy cells in your body. Think of it as a window of opportunity, where the drug dosage and its toxicity is enough to kill cancer cells with gusto, but has relatively low toxicity to the healthy cells of your body. The word “relative” is important. It is once again a question of judging whether you get sufficient bang for the buck, without going over the top in terms of toxicity and loss of quality of life.

The problem with CLL is that it presents so differently in different people. Folks with good prognostic indicators, chemo naïve patients who have never had a whiff of chemotherapy earlier on, these guys are likely to respond very well to therapy, getting deep reduction in the number of cancer cells in their bodies right away before they have gone through many cycles. Not so lucky are the patients with refractory disease, poor prognostic indicators and / or prior history of having been around the chemotherapy block a couple of times. So, what is the logic of having the same fixed drug dosage and the same fixed number of cycles no matter which of these two extreme groups you belong to? You don’t want to scald your mouth with too hot porridge, but you don’t want to eat a cold and congealed mess either. You want it just right, thank you very much.

Some Common Reasons Why Patients Do Not Finish All Cycles

With the best of intentions some patients are not able to finish all the cycles prescribed in a given protocol. For them the toxicity becomes too much; important blood counts such as neutrophils, red blood cells and platelets take a dive; or their liver, heart or some other important organ takes too much of a hit; or they are plain unable to tolerate the regimen. For these guys there is no choice, they drop out when they can not handle the therapy any longer. Most of the time they do not get the full benefit of the therapy and have to make-do with less than stellar remissions.

Another subset of patients discontinue therapy before finishing all cycles because they are clearly not responding well.  They are not getting much benefit from the therapy in question and there is not much point in beating a dead horse. They are better off regrouping and figuring out what to do next, whether some other therapy option is likely to serve them better.

When You Actually Have A Choice

Let us now focus on patients who have a choice in the matter. Let us assume you are among the lucky ones with good prognostics and this is the first time you are being treated with any kind of chemotherapy. You have completed four of the prescribed six cycles of FCR. Lymph nodes have melted away.  A physical exam by your oncologist cannot find any swollen nodes of spleen, no matter how hard he poked around. WBC and ALC are in normal range. But as expected there has been some toxicity and as you went through each cycle your red blood cell counts have taken a hit. Your neutrophil counts have fallen below 1.0K and you are officially neutropenic, increasing your risk of infections and viral reactivations.

Here is the million dollar question: for all practical purposes you are in clinical “CR” (“complete response”), at least once your other blood counts have had a chance to recover. Should you tighten your belt and complete the remaining 2 cycles, or should you quit at this point to avoid further toxicity?

Not All “CR” Responses Are Created Equal

And that is what makes it difficult in deciding when to call it a day and not undergo additional cycles of therapy. The problem is that “complete response” or CR does not mean what you expect it to mean in plain English. It is not complete. Not by a long shot. It just means within the detection capabilities of your oncologist’s trained fingers, there are no swollen lymph nodes, and within the capabilities of the garden variety CBC, the WBC and ALC are within normal ranges, and other blood counts are not too far from normal ranges (or expected to recover reasonably quickly once therapy is completed).

A picture is worth a thousand words. Below is a pictorial representation of the kinds of results we can expect using single agent chlorambucil, or fludarabine, or one of the modern combos such as FCR.

 Three blood tests, Jan 2009, pcr test

Chlorambucil reduces the total number of CLL cells in your body a hundred-fold, from a trillion cancer cells to a mere ten billion or so, give or take a few. Fludarabine does a better job, taking down the remaining tumor load to just one billion CLL cells. There is no free lunch, you pay for this ten-fold improvement in reduction of remaining cancer cells – in terms of increased toxicity of fludarabine compared to chlorambucil.

Notice what happens to the number of cancer cells in your body over time, once the chlorambucil or fludarabine treatments are finished. Gradually over time the numbers creep back up and pretty soon you are back where you started. End of remission, time to think of your next option. Compared to chlorambucil the fludarabine response lasts a bit longer since you got a slightly deeper clean-out of cancer cells.

Modern therapy combinations such as FCR get much deeper responses, going all the way from a trillion cancer cells to begin with to a mere handful, a couple of million or so CLL cells. That is a 100,000 fold reduction! No wonder experts are excited about this and similar chemotherapy combinations. This is the first time in history we are seeing such deep remissions.

What can happen over time to folks who get such deep remissions? We project three possible scenarios. The grey line shows gradual but inexorable increase in cancer cell count, eventual relapse baked in the cake for this scenario. True, even in this bleak scenario the remission lasts a lot longer than the remissions possible with chlorambucil or fludarabine singe agent therapy.

The green line and red line are more interesting. The remaining CLL cell count in the body waffles up and down a bit, the survivors having difficulty regrouping and getting back to full fledged strength. Perhaps your immune system is lending a hand as well, keeping the badly beaten army of cancer cells under control. Our experience to date has been that just about all patients will eventually relapse, even after getting deep cancer cell clearance. But it is reasonable to expect that truly deep remissions are likely to last longer since it will take that much longer for the enemy to regroup. Longer duration remissions are what every patient wants from therapy.

There are two horizontal lines on the graph. The first (higher one) gives us the definition of the NCI “CR”. Even the fludarabine folks get a “CR” by this ‘easy’ criterion. This criteria cannot tell the difference between a ho-hum “CR” after fludarabine or a really deep “CR” after FCR therapy. The second horizontal line is the level of detection accuracy possible with PCR (polymerase chain reaction) technique. It is a hundred times more sensitive. The present day holy grail in response is a “PCR negative remission” – which means that even the most sensitive testing method at our disposal cannot see any CLL cells in your body. It does not mean there are truly no CLL cells left behind in your body. Just that we cannot see any, no matter how hard we looked.

Lessons learned Thus Far

  • Not everyone responds the same way to therapy. We need to have customized protocols (outside clinical trials).
  • Deeper clean-out of CLL cells is likely to give us longer remission – something that we all desire.
  • While higher dosages and longer duration of therapy may yield deeper responses and possibly longer remissions, there is a clear cost to this in terms of toxicity and loss of quality of life.
  • We need some way of telling when we have reached the break-even point, when more therapy is not going to improve response but might add to the toxicity side of the equation.
  • CT scans with contrast can help look more closely for tell-tale swollen nodes hidden deep in the abdomen. Bone marrow biopsies can look at the level of infiltration. Both of these are invasive procedures that many patients are justly reluctant to undertake. PCR testing is a blood test. But it is expensive, not easy to do and there is not 100% consensus on how exactly to do it.
  • We need a simple blood test that does not cost an arm and a leg, that can go much further than the standard CBC in its sensitivity and ability to detect traces of CLL cells, that can shed some light on the status of the bone marrow.

Below are two abstracts of important papers that describe a flow cytometry method that is gaining approval from many experts. As we described in an earlier article, flow cytometry is a blood test. What makes this one special is that it focuses on four crucial markers on CLL cells – hence its name of “Four color flow cytometry”. More and more, it is being used to test for minimum residual disease.

Blood. 2001 Jul 1;98(1):29-35.

Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy.

Rawstron AC, Kennedy B, Evans PA, Davies FE, Richards SJ, Haynes AP, Russell NH, Hale G, Morgan GJ, Jack AS, Hillmen P.

Haematological Malignancy Diagnostic Service, Leeds General Infirmary, Leeds, United Kingdom. andy.rawstron@newscientist.net

Previous studies have suggested that the level of residual disease at the end of therapy predicts outcome in chronic lymphocytic leukemia (CLL). However, available methods for detecting CLL cells are either insensitive or not routinely applicable. A flow cytometric assay was developed that can differentiate CLL cells from normal B cells on the basis of their CD19/CD5/CD20/CD79b expression. The assay is rapid and can detect one CLL cell in 10(4) to 10(5) leukocytes in all patients. We have compared this assay to conventional assessment in 104 patients treated with CAMPATH-1H and/or autologous transplant. During CAMPATH-1H therapy, circulating CLL cells were rapidly depleted in responding patients, but remained detectable in nonresponders. Patients with more than 0.01 x 10(9)/L circulating CLL cells always had significant (> 5%) marrow disease, and blood monitoring could be used to time marrow assessments. In 25 out of 104 patients achieving complete remission by National Cancer Institute (NCI) criteria, the detection of residual bone marrow disease at more than 0.05% of leukocytes in 6 out of 25 patients predicted significantly poorer event-free (P =.0001) and overall survival (P =.007). CLL cells are detectable at a median of 15.8 months (range, 5.5-41.8) posttreatment in 9 out of 18 evaluable patients with less than 0.05% CLL cells at end of treatment. All patients with detectable disease have progressively increasing disease levels on follow-up. The use of sensitive techniques, such as the flow assay described here, allow accurate quantitation of disease levels and provide an accurate method for guiding therapy and predicting outcome. These results suggest that the eradication of detectable disease may lead to improved survival and should be tested in future studies.

PMID: 11418459

 OK, we buy that four color flow cytometry can tell us much more accurately how many CLL cells are floating around in the blood.  Aha, but what about the bone marrow?  How can we tell how many CLL cells are lurking there?  Do we still need to do a painful / invasive bone marrow biopsy to get a handle on this?  The good news is that the authors have shown a very nice correlation between the number of circulating CLL cells in the blood versus the percentage of bone marrow infiltration.  Nice correlation, but not perfect – good enough for government work as they say.

Four color flow cytometry vs bone marrow

The value of this approach was not lost on researchers and there is a rapidly growing consensus on its use.  As the abstract below points out, we are now developing international standardized approaches to using this technique with a view to judge MRD status of the patient at different points along the therapy protocol.

Leukemia. 2007 May;21(5):956-64. Epub 2007 Mar 15.

International standardized approach for flow cytometric residual disease monitoring in chronic lymphocytic leukaemia.

Rawstron AC, Villamor N, Ritgen M, Böttcher S, Ghia P, Zehnder JL, Lozanski G, Colomer D, Moreno C, Geuna M, Evans PA, Natkunam Y, Coutre SE, Avery ED, Rassenti LZ, Kipps TJ, Caligaris-Cappio F, Kneba M, Byrd JC, Hallek MJ, Montserrat E, Hillmen P.

HMDS, Leeds Teaching Hospitals, Leeds, UK. andy.rawstron@hmds.org.uk

The eradication of minimal residual disease (MRD) in chronic lymphocytic leukaemia (CLL) predicts for improved outcome. However, the wide variety of MRD techniques makes it difficult to interpret and compare different clinical trials. Our aim was to develop a standardized flow cytometric CLL-MRD assay and compare it toreal-time quantitative allele-specific oligonucleotide (RQ-ASO) Immunoglobulin heavy chain gene (IgH) polymerase chain reaction (PCR).Analysis of 728 paired blood and marrow samples demonstrated high concordance (87%) for patients off-therapy. Blood analysis was equally or more sensitive than marrow in 92% of samples but marrow analysis was necessary to detect MRD within 3 months of alemtuzumab therapy. Assessment of 50 CLL-specific antibody combinations identified three (CD5/CD19 with CD20/CD38, CD81/CD22 and CD79b/CD43) with low inter-laboratory variation and false-detection rates. Experienced operators demonstrated an accuracy of 95.7% (specificity 98.8%, sensitivity 91.1%) in 141 samples with 0.01-0.1% CLL. There was close correlation and 95% concordance with RQ-ASO IgH-PCR for detection of CLL above 0.01%. The proposed flow cytometry approach is applicable to all sample types and therapeutic regimes, and sufficiently rapid and sensitive to guide therapy to an MRD-negativity in real time. These techniques may be used as a tool for assessing response and comparing the efficacy of different therapeutic approaches.

PMID: 17361231

Strange Bed Fellows

I am generally not a big fan of “Managed Care Magazine”. You might say they have a bit of a slanted view of things, a tad more emphasis on saving dollars than me. But for a change their emphasis on dollar cost has a parallel in what is more important to me, toxicity cost to patients. More chemo cycles beyond the optimum point means more health-care dollars. It also means your body takes on more toxicity than is optimum. Hooray, we share a common agenda with the pencil pushers at Managed Care. I have given below some excerpts (highlighting is my contribution). You really should read the full article, it is well written and with little by way of medical jargon. It won’t hurt a bit, I promise.

Four-Color Flow Cytometry Detects Minimal Residual Disease in Leukemia

Should a new (and cheap) test for chronic lymphocytic leukemia be a component of prior-authorization protocols?

Thomas Morrow, MD

  • Most managed care decision-makers have focused on the cost of the new therapeutic regimes.
  •  Even when the polymerase chain reaction is negative, there are probably a number of malignant cells still alive that are undetectable, and sometimes referred to as minimal residual disease (MDR). These residual cells then repopulate, resulting in a relapse. If these few cells are eradicated, we may have a longer disease-free survival
  • Scientists have developed a new method to detect these small amounts of cancer cells in patients with B-cell chronic lymphocytic leukemia (B-CLL). This test utilizes a four-color flow cytometry (FC) technology that can detect even a single B-CLL cell in 10,000 white blood cells.
  • FC can be used to diagnose a disease as well as to follow post-therapy response.
  • FC can be used on peripheral blood, bone marrow aspirate
  • Overall, FC is less expensive and much faster (one to two lab hours) to process than IHC (immunohistochemistry)
  • Because this new technology detects very low levels of B-cell leukemic cells, it will enable clinicians to cease therapy with a level of clinical certainty unheard of in the recent past, thus potentially preventing unnecessary courses of expensive therapy.
  • Common current therapy includes Campath, costing about $64,000 for a three month course, and Rituxan and Fludara, costing about $20,000 for a six-month course. When FC is used to detect MRD, patients avoid the painful, invasive bone marrow biopsy.
  • This FC-MRD test retails for about $1,500.
  • FC will become a normal part of clinical practice rapidly. How will it be covered? Should FC become a requested component of the prior authorization protocols for various expensive drug regimes?

I am aware that Genzyme does the four color flow cytometry testing for minimum residual disease. Other companies may do so as well. Below is a link to their website and a bit of the information. Please visit their website to get the code numbers etc needed to order the test.

CLL-MRD (Minimal Residual Disease) Testing by Flow Cytometry

This process allows for the differentiation of 1 CLL cell in 10,000 normal B-cells and provides a quantitative measurement of the MRD status of patients with CLL who are undergoing therapy. Patients who achieve CLL-MRD-negative status have improved overall and progression-free survival. This test is not suitable for making primary diagnosis or monitoring untreated CLL patients with a high tumor load.

Specimen Requirements (Peripheral Blood) : 10-20 ml in sodium heparin (green-top) tube.

Turnaround Time: 24-48 hours

Editorial

This article was prompted by three separate cases that came to my attention last couple of weeks, one in the UK and two here in the USA. All three patients have completed some but not all of the six cycles prescribed in the protocols. All three have already achieved what appear to be “CR” responses. In each case, the supervising oncologist did not pro-actively raise the possibility of testing for MRD before going further. However, in the UK case, when requested by the patient his physician agreed to get a four color flow cytometry test done to check for minimum residual disease before progressing to cycles #5 and #6.

As I said, this is not an easy decision to make. The last thing I want is for you guys to chicken out of needed therapy and therefore fail to get full benefit from the chemotherapy option you and your physician have selected. Pulling your punches before you have reached the optimum point would be a shame.

At the same time, more chemo is not necessarily better either. Once again, it is a case of careful weighing of risks and rewards. For a change, technology has given us a great new tool that can help make this process easier. There is no radiation involved as in CT scans, no pain and suffering of a bone marrow biopsy. Just the usual needle prick for a blood sample and away it goes for a quick turn around (2 days!) four color flow cytometry test to evaluate your MRD status. Even your insurance company will be pleased with you, since using this test means dollar cost savings for them.

Will you get some push-back from your oncologist if you ask for a minimum residual disease test (four color flow cytometry) before moving on to remaining cycles?  You might, if the oncologist is not up to speed on latest Best Practices in the field. Four color flow cytometry is a new-fangled thing and some people have a built-in objection to new things.  It is also much easier to make slam dunk decisions without putting brain in gear first – it saves a whole few minutes of the consultation time!  But like the UK consultant I discussed above, most hematologists and oncologists who try to stay abreast of new developments will take your request seriously. 

However, if you are in a clinical trial things may be different.  There is a huge amount of vested interest in having as many patient – volunteers complete the full course, dot each “i” and cross each “t” of the clinical trial protocol as possible since it makes data interpretation that much easier. Once again we face the ugly possibility of conflict of interest – between that of the dedicated researcher trying to run a well controlled experiment and that of the ethical physician doing the best he can for the individual patient in front of him.  It is not always easy wearing two hats.

If you are in the middle of therapy, this is something you should discuss with your doctors with a view to customizing the number of cycles in your case. You agree?

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