If you have read as many clinical trial results reports as I have, you would know that most of the time researchers measure the efficacy of their particular therapy in terms of patient responses right after completion of therapy. How many “CR” (complete responses) were there? How many patients got some sort of a response (“ORR”, overall response rate) and, wait for it, this is the biggie, drum roll please, how many patients got the coveted MRD Negative status?
For starters, “CR” does not mean what you think in means, if you are talking plain English. If you are new to the world of oncology research, you may be forgiven for thinking “complete” means – well, complete. Duh. And that if you get a “CR” remission, you are home free because your response to the therapy in question is complete. (Not!)
But those of us who have been round the block a few times know this is not quite true. “CR” just means that your blood counts look normal at the end of the therapy, you do not have any swollen lymph nodes bigger than 1.5 cm that can be felt by your doctor poking around. Here is the official word on how “CR”, “PR” etc are defined by the IWCLL (International working group on CLL). “ORR” (overall response rate) is the sum of CR + PR.
Notice, there is no mention of CT scans to determine level of response. So, it is entirely possible that someone who got a “CR” response has a lot of swollen lymph nodes about the size of a grape, tucked away deep in their chest, abdomen or groin, where their physician’s fingers cannot feel them. Same goes for judging swollen liver or spleen. What you don’t measure does not count, that is the name of the game.
If you do have residual CLL cells in deeply buried locations, irrespective of your “CR” or even MRD negative status, will these reservoirs of CLL cells grow back? Yes. How soon will they grow back? Aha. That, my friends, is the million dollar question and the central point of this article.
“MRD Negative Status”: The goal post keeps changing
We defined MRD negative status as a case where no CLL cells were detected, using our most state-of-the-art sophisticated techniques. Since science does not stand still and there are constant improvements in our ability to detect stuff, you can see this is a moving target.
Let me take this to a ridiculous extreme. A mere few decades ago, the best we could do was look at a smear of blood on a glass slide under a microscope. Lab tech looks at the blood, sees there are no obviously wonky “smudge” cells, returns the verdict – nope, no cancer cells to be seen. Doc prodded around, no swollen nodes to be felt. Put the two bits of information together, that would have been an MRD negative status response, back then.
Then we got a bit more fancy, invented a bunch of technical gizmos. We got stuff such as CT scans. we got flow cytometry machines that can target and look for specific CD marker patterns that are the equivalent of cancer cell fingerprints. We have even more complicated “pcr” (polymerase chain reaction) techniques that can look for cancer cells with ever greater precision. I have no doubt that this process will continue, we will invent newer and better ways in which we can look for and count the number of cancer cells present in the body. If you want to learn more about some of these techniques and what they mean, I refer you to an earlier article on our website : “Three important blood tests“.
What exactly are we talking about, how fancy have we gotten in our technical ability to detect and quantify CLL cells in the body? The diagram below is a pictorial representation only.
As you can see, we have come a long way, Baby. The old fashioned “CR” was bestowed on patients who still had as many as 10 billion CLL cells in their body, give or take a few. Chlorambucil, the drug of choice back then, often came up just short of meeting the CR definition of the day. Fludarabine was able to get deeper remissions, more patients got a “CR” response using fludarabine. But notice, at the nadir, at the point where they had the least amount of cancer in their body, there could still be as many as a billion CLL cells in their body.
Moving on to modern days and modern technology, MRD negative status is now defined as cases where the number of CLL cells left behind in the body are no more than a mere hundred million or so. And the good news is that several of our modern immunotherapy regimens such as FCR are able to meet this much more stringent criteria. After all, there is a huge difference between 100 million and 10 billion.
But where would we really like to be, if we had our way? We would like to be way at the bottom of the chart, where there are zero CLL cells left in the body. That would be a for real “Complete Response”, meaning the same thing as the English word “CURE“, don’t you think?
Are all MRD negative statuses equal?
Let us do a little “thought experiment”. We will consider two generic patients who both undergo the same therapy, get the coveted MRD negative status at the end of it. Patient A had high risk disease going in, perhaps he had bad cytogenetics that pointed to rapid growth of the CLL clone. Boy, was he happy to get that MRD negative result! Patient B had much less aggressive disease at start of therapy, in fact he was pretty sure he was going to get a good response. Which he did. At the end of therapy, both patients had the same level of CLL left over in their bodies, a mere 10 million of so of the cancer cells. At this point, the researchers write up the results, claim success with both patients and go home.
As you can see, it is what happens after the study is done and reported that is interesting. Since our patient A has more aggressive brand of CLL, one that likes to have a lot of babies quickly, the left over trace amounts of CLL cells in his body increase their numbers rather quickly. All too soon, he is no longer MRD negative, and shortly thereafter, he crosses the definition of old fashioned CR as well. He is at that point out of remission.
Patient B, as you would expect, has a better time of it. He too starts at the same point in his remission immediately after completion of therapy, with about 10 million or so CLL cells left over in his body. Starting from the same point as Patient A, the CLL clone in patient B behaves quite differently. His more indolent version of CLL grows slowly, takes a lot longer to come out of MRD negative status and even longer to come out of remission and full fledged relapse. It is not a huge stretch of our grey cells to predict that Patient A will need salvage therapy sooner than Patient B, that he is likely to need more such interventions to keep the CLL at bay and have shorter overall survival.
Both patients got MRD negative response,both earned their researcher the same level of accolade. Which one would you rather be?
ASH 2012 – the place to be
That is, if you like to see all the hematologists and CLL experts in one place. This conference of the American Society of Hematology is the annual industry event. I have attended a few of them. It is a bit overwhelming, the conference is packed solid with brilliant researchers – and industry reps, of course, marketing to them. I gave it a miss this year since I am still in India.
The abstract below got me thinking about MRD negative status and what it is worth.
1777 Minimal Residual Disease (MRD) Re-Growth Kinetics Are An Independent Predictor for Progression Free Survival (PFS) in Chronic Lymphocytic Leukemia (CLL) and Are Related to Biologically Defined CLL-Subgroups – Results From the CLL8 Trial of the German CLL Study Group (GCLLSG)
Sebastian Boettcher, Matthias Ritgen, Kirsten Fischer,, Stephan Stilgenbauer, Raymonde Busch, Gunter R. Fingerle-Rowson, Anna-Maria Fink, Andreas Buehler, Dirk Winkler, Michael K. Wenger, Myriam Mendila, Clemens Wendtner, Barbara Eichhorst, Hartmut Döhner, Michael Hallek, and Michael Kneba.
MRD single time point assessments during therapy and at the end of treatment have been identified as independent predictors of PFS and overall survival in CLL patients (pts) by our group and others. However, it is currently unknown whether MRD kinetics during follow-up (FU) also have prognostic significance and whether kinetics show associations with CLL risk features. We therefore investigated MRD during treatment-free FU within the CLL8 trial of the GCLLSG.
MRD kinetics were analyzed in 256 pts who had not progressed 1 year after completion of therapy and for whom at least 2 peripheral blood MRD assessments during the subsequent year were available. The slope of the common logarithm of MRD / time was calculated for 193 patients with at least 2 positive MRD measurements. Median MRD increase was 6.3fold during the observation period for the whole group (i.e. 0.80 log MRD unit increase / year). We compared groups of pts who (1) were always MRD negative (25% of all 256 pts), (2) had measurable disease with a slope below median (slow re-growth, 37% of pts), and (3) had measurable disease with a slope above median (fast re-growth, 39 %).
The medians of the first measurable MRD levels during observation did not differ significantly between groups 2 (4.3 x 10-3) and 3 (1.7 x 10-3, p=.16). Pts with faster MRD re-growth kinetics (group 3) experienced a shorter median PFS (40 months) than pts with slower re-growth (group 2, 66 months), whereas median PFS has not been reached in pts who were always MRD negative (group 1, log-rank p= 3 x 10-14). Compared to group 1, group 2 and 3 pts carried increasingly higher risks of progression (HR 3.1 and 7.7, resp.). Pts showing a slow re-growth pattern (group 2) had a 2.5fold lower risk of clinical progression than pts with a greater MRD slope (group 3, p=5 x 10-6).
The prognostic significance of MRD kinetics for PFS was also tested in Cox regression analysis together with clinical response, deletion 17p, IGHV mutational status, number of treatment cycles, treatment arm, thymidine kinase, beta2-microglobulin, pre-therapeutic WBC and MRD levels 1 year after completion of therapy. MRD kinetics (p=4×10-9), MRD levels (7×10-14), cycle number (8×10-5) and IGHV mutational status (1×10-3) remained independently significant for PFS in this multivariate analysis.
We next correlated MRD slopes during the second year of FU and prognostic features in 204 pts (groups 2 and 3 plus 11 pts with early clinical relapse but measurable MRD slope during second FU year). Pts who required treatment within 2 years from diagnosis experienced a faster re-growth after therapy (.92/a) than pts with a longer treatment-free interval (.68, p=.04). The slope was significantly lower in pts with Binet A disease prior to therapy (.43/a) than in Binet B (.77/a, p =.03) and Binet C (.88/a, p=.02) pts. Pts carrying a chromosomal deletion (del) 13q as single abnormality had a significantly slower MRD re-growth pattern (.58/a) than those with del(11q) (1.0/a, p=.0004) or without cytogenetic abnormalities (1.1/a, p=.001), while the difference to pts with 12q+ (.71/a) was not significant. Pts with a mutated IGHV gene progressed slower (.54/a) than those with unmutated IGHV (.96/a, p=.0002). A thymidine kinase of at least 10 U/L was associated with a steeper MRD slope (.82/a) than lower levels (.61/a, p=.03). MRD slopes were not significantly associated with gender, WBC prior to therapy, beta2-microglobuline levels, presence of B-symptoms, or treatment arm.
We demonstrate for the first time the independent prognostic significance of MRD kinetics during FU in CLL. MRD kinetics improve the prediction of PFS even when single time point MRD assessments during FU and other major risk features in CLL are additionally considered. MRD kinetics classify known CLL risk factors into two groups. IGHV, cytogenetics, thymidine kinase, stage, and time to treatment distinguish CLL subgroups with different re-growth kinetics, likely characterizing the relationship of proliferation to spontaneous apoptosis of the CLL clone itself. Other risk features did not show an association with kinetics in spite of proven significance in the CLL8 trial. Those features likely identify differences in responsiveness to therapy. We hypothesize that maintenance strategies will chance the course of the disease most effectively in patients who are responsive to therapy but relapse early due to fast CLL re-growth.
OK, the ASH abstract said pretty much the same thing, but in significantly more impressive language, as our discussion above. People with more aggressive disease are likely to come out of remission sooner, relapse more quickly, and have overall shorter survival – even if they got an MRD negative response. It all depends on the type of CLL you have going into therapy in the first place.
Here is the million dollar question. Should you try to get an MRD negative response, even if it means tagging a maintenance regimen of some sort at the end of the initial therapy? We have discussed Campath consolidation approaches before, as well as Rituxan maintenance at the end of FCR Lite. When does it make sense to go the extra mile or two to get as squeaky clean remission as possible? The answer, as always, is that it depends.
Please allow me to paint a really silly parable for you. I am in that kind of a mood today.
Three guys go out to get a much needed new car ….
First guy is stinking rich. And he loves to brag, he wants the best of everything. He cannot bear to take second place to anyone or anything. He goes directly to the Porsche showroom in town, buys their newest and shiniest model with all the bells and whistles. It costs an ungodly amount, but what he heck, he can afford it. He gets a good car in return, his neighbors are satisfyingly jealous of him and since he is very good at taking care of his automobiles, it will last him a long, long time. May even get him a good resale value down the road.
The second guy too would love to get a top of the line new car. Problem is, he really cannot afford it. All the same, he opts for the same model as his friend the rich guy above, paying for his expensive tastes by robbing his kid’s college tuition funds. Stealing from the future to pay for the present fancy, as it were. He is not all that good about taking care of cars either. Chances are, the very expensive and shiny new car will not stay shiny for very long. His buddies think he is a fool for trying to impress them and his kids stop talking to him.
Third guy is no different. He too wants the brand new Porsche. It seems chicks dig’em. He is no where as rich as our first guy. But he has an advantage. The car dealer is his brother-in-law, and he is able to cut him a real sweetheart deal. He gets the shiny new car, same as the other two guys, but ends up not having to pay as much for it. Best of both worlds, he gets to swank around in his new car and he did not have to rob the bank to do it either.
Same shiny new red Porsche. Its personal cost is different to the three buyers, it gets them different value after the purchase.
The first guy is the equivalent of a young, fit and otherwise healthy CLL patient. He can afford the extra ‘hit’ of aggressive therapy. And since he has good prognostic indicators, the MRD negative response is likely going to last him a nice long time. In his case, the “cost” of aiming for a deeper remission is worth it. It will most likely get him a long and trouble free remission.
Second guy is the equivalent of a foolish patient who has a boatload of other medical problems from the get go. Aggressive therapy is probably contra-indicated for him in any case, let alone the extra bit of toxicity involved in aiming for MRD negative status. (I am assuming the MRD negative remission is to be had only by tagging along something like Campath as a chaser to the original therapy). Since he has pretty poor prognostic indicators to start with, even the hard won MRD negative remission is not going to last very long. He will not have much to show for the additional toxicity, his remission is likely to be short. Since he fired all his ammo right upfront in aiming for the MRD negative status, he is likely to have more refractory disease that responds poorly to second and third round of salvage therapy – leading to poor quality of life as well as shorter overall survival.
Third guy is the lucky one. Whether or not his MRD remission holds for very long, the fact that he got there without having to pay an arm and a leg for it, that gives him a huge advantage. We would all like to be in his shoes: get decent remissions, perhaps even MRD negative remissions or better, without having to face the huge costs involved. And I am not talking about dollar costs, even though they are nothing to sneeze at. I am talking about the cost of increased toxicity, damage to the vital organs of the body, poorer quality of life for a good while after completion of therapy, no guarantee that the MRD negative status will hold for a long time. If these costs were not there, if we got new drug therapies that are both effective and low in toxicity, by all means each and every patient should aim for the deepest remission he or she can get.
Once again, we face the same issue. Balancing risks and rewards. Your doctors can (hopefully) give you good guidance on your chances of getting an MRD negative remission by going the extra distance. They can point out the type of adverse effects you are likely to encounter by going this route. They can read the tea leaves and make an educated guess whether you are in good enough shape for more aggressive therapy.
But only you can decide whether this option is right for you. How far are you willing to go? How much chemo is enough chemo? Listen to your body, talk to your family and friends, listen to your own heart. Then make your decision. It is the only RIGHT decision.