Will a “Min-Allo” let you live longer?

Let us agree, right up front, even the “kinder and gentler” mini-allo transplants are not fun, and they are not for the faint of heart.  There is significant risk of morbidity (think quality of life) and mortality (as in death).  You would not do it if there were better options.  So, here is the million dollar question: do mini-allo stem cell transplants save lives? 

Two recent excellent articles address this question. The first one from M. D. Anderson gives us a historical perspective.  The second one gives the latest survival results and compares them against conventional (non transplant) approaches. I have summarized the salient points from both articles along with my own explanations of the science & jargon where I thought it necessary.  Since the review got a bit too long I decided to publish it in two parts.  Here is the first installment.

The only CURE

None, I repeat none, of the chemotherapy regimens we have available are capable of producing a CURE for this incurable cancer.  No matter how deep the remission, it will end and often it will end sooner than you want.  For a lucky percentage of patients it may be possible to run out the clock, string along a series of temporary remissions until your natural life span runs out.  If this is possible for you, it is surely the way to go.  If you have good prognostics backed up by real life slow progressing or smoldering variety of CLL, if you are already at an age when you did not expect to live several more decades in any case, running out the clock is a terrific strategy.  Kick back, enjoy, wish the rest of us chickens good luck.

But for younger patients with families to raise, jobs to go to and mortgages to pay, running out the clock is not an option. If their CLL also happens to be an aggressive variety, serial chemotherapy quickly becomes a losing game with diminishing results.  We desperately need better therapy options for this set of our patient population.  For now, the only therapy potentially capable of curing CLL is a stem cell transplant (SCT) from a matched donor. So, here are the million dollar questions: is it worth it?  Should you consider a stem cell transplant?

M. D. Anderson experience

The article (abstract below) from M. D. Anderson gives a very nice overview of the whole stem cell transplant (SCT) field, by a man who has been in the forefront of it.  I strongly urge you to read the whole article, not just the abstract.  Write to me (personally) if you need help locating it. 

 Hematol Oncol. 2009 Jun;27(2):53-60.

The role of stem cell transplantation in the management of chronic lymphocytic leukaemia.

Tam CS, Khouri I.

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

The majority of patients diagnosed with chronic lymphocytic leukaemia (CLL) will ultimately die of their disease. Stem cell transplantation (SCT) remains the only treatment modality capable of cure, but has traditionally been associated with very high morbidity and mortality. We review the results of myeloablative autologous and allogeneic SCT in CLL, discuss the evolution of the new non-myeloablative approaches, and make recommendations for when SCT should be considered in patients with CLL.

PMID: 19358149

CLL is the “good” cancer to have, right? So why should we even think about risky stuff like transplants? Experts have been pussyfooting around this question long enough. It is good to have someone of Dr. Khouri’s stature to finally say the emperor is buck naked.  For too many patients CLL is an incurable cancer, a killer. Here is a direct quote from the paper, one of many good ones.

“The reality is that a substantial proportion of patients with CLL are diagnosed prior to the age of 60 and 70% of patients diagnosed with CLL will die either directly or indirectly of their disease”. 

 Wow, how is that for a swift kick in the gut.  Sorry, but some of us (and some of our doctors too) need that little wake-up call.  A “good” cancer does not need a stem cell transplant.  A killer cancer that is incurable by any other means - now that is an entirely different ballgame and we need to think about stem cell transplants.

“Among patients with progressive CLL, those who eventually develop disease resistance to currently available drugs have a dismal survival of less than 12 months.  As SCT is the only treatment modality capable of cure in CLL, it is likely that a discussion regarding its use will arise at some point during the disease course in a majority of patients”.

Do autologous SCT work?

Like with all things CLL you have to learn the lingo of transplants.  Autologous SCT are when stem cells are harvested from the patient himself and give back at a later time.  There is no second party involved, no matched donor giving the gift of his / her healthy stem cells to replace your damaged immune system. 

Autologous stem cell transplants have been used in two settings: first as salvage therapy in patients who have relapsed after conventional chemotherapy, and second in an attempt to go for broke and try to eradicate all traces of CLL in younger patients with early stage disease. 

Disappointingly, even when auto SCT was attempted early in the ball game, low tumor burden, a chemo-sensitive CLL and all the technology we have to “clean” the patient’s own harvested stem cells (to try and prevent any contaminating CLL cells from sneaking back into the patient’s body) before giving them back to him, there was a continuous pattern of relapse.  No one was cured; it was once again a matter of when the remission ended.  Khouri et al cite chapter and verse in their seminal paper, vital statistics from many reputable institutions.  Same pattern, same disappointing story. No cure.

Think of an auto SCT as very aggressive chemotherapy to treat the CLL and you would not be far off the mark.  Yes, the remission may be long (or not), as you would expect with any aggressive combination - say, FCR or CFAR.  But like these heavy duty approaches, life after remission ends may become difficult with few good choices. 

By now I hope all of our readers are savvy enough to tell the difference between one or two patients who are still in long term remission after an auto SCT and robust, statistically valid data such as presented in the Khouri article.  We wish the lucky patients continued good health, but it is foolish to draw comfort from their one-of-a-kind situation.  Auto SCT for CLL patients are now discredited and except in rare circumstances they are no longer the recommended for CLL patients in this country or Europe.

Myeloablative allogeneic SCT

I agree, it is mouthful - but not all that hard to understand, if you break it down into little bits.  Let me show you how.

Myeloablative”  is full strength conditioning using high does of chemotherapy and full body radiation to rid the patient’s body of as many CLL cells as possible - think of it as the mother of all chemo / radiation combinations to get patient into best possible remission ahead of receiving the precious stem cells gifted by a matched donor. No attempt is made to spare the patient’s own hematopoietic stem cells - they too are killed in hordes.  Not to worry, they will soon be replaced by a healthy bunch of donor stem cells.

That is where the “allogeneic” bit comes in.  The root words “Auto” means self, and “Allo” means other.  By definition, an allogeneic stem cell transplant (sometimes abbreviated to “allo SCT“) involves finding a suitable donor, one who is healthy, willing and able to donate blood stem cells matched to your own cell type. 

The first place to look for a matched donor is in your own family, your brothers and sisters (not your parents, not your kids.  They would not match).  The more sisters and brothers you have, the better the chance that at least one of them is a good match.

Sibling donor matches are the first choice, followed by generous donors who are not related to you but who happen to be a good match.  These are called MUD (matched, unrelated donors).  Not everyone can find MUD donors as needed, especially if they are from ethnic minorities.  Umbilical cord blood is a recent option that became available for such patients.  Details of donor selection are described in an earlier article “Matching made simple“.

A small dog-leg in the universal preference of sibling donors is the small risk of getting a second dose of CLL from your donor!  How nasty is that?!  We know now that CLL is a familial disease, your blood relatives are at significantly higher risk of getting / having CLL themselves compared to the general public.  Roughly 13.5% of your first degree blood relatives may have the tell-tale signs of a CLL clone, even if it is so small it has not been clinically diagnosed (and may never grow up and show fangs, may never become clinically relevant).  Dana Farber reported in their study 7 sibling donors were excluded because they themselves were at hitherto undiagnosed risk.  Going one step further, you will understand it is not a good idea to have your identical twin as a stem cell donor, not without extensive testing to make sure there is no sign of MBL or undiagnosed blood disorder in the donor as well.

The enthusiasm for doing a thorough house-cleaning with full strength myeloablative preconditioning becomes muted when we consider very high treatment related mortality (TRM) statistics.  It is a case of the cure being almost as bad as the disease.  TRM rates quoted by Khouri for myeloablative allo SCT are in the range of 38-50%.  Statistics show approximately roughly 2 out of 3 patients treated with myeloablative allo SCT die either due to TRM, recurring CLL or other complications, but approximately one third will be CURED of their disease.  This is a case of 2/3 empty glass and 1/3 full glass

The aggressive nature of full strength myeloablative conditioning also meant there was very strict age and fitness restrictions placed on who is eligible to go this route.  Patients who are young, fit, still in early stage of CLL which is therefore chemosensitive do well with this approach. It gets a little hard to quote firm survival statistics since each institution has its own recipe, its own cocktail of chemo and radiation combinations for the high impact preconditioning and the results vary accordingly.  But the bottomline is pretty clear. 

Non-myeloablative allogeneic SCT

Now we come to the present day standard of stem cell transplantation technology. Pulling apart the tongue-twisting moniker once again, this too is an allogeneic stem cell transplant, and therefore by definition it involves finding a suitable matched donor willing to donate his / her blood stem cells.

We have already discussed myeloablative approach, heavy handed chemo + radiation combination to eradicate as many CLL cells as possible with an equally impressive treatment related mortality to pay for it.

Non-myeloablative approach takes a slightly lower impact approach to preconditioning.  Don’t have any illusions about it, even non-myeloablative approach is pretty strong medicine, it is kinder and gentler only by comparison to its more dangerous myeloablative big brother.  Street name for non-myeloablative allogeneic SCT is “mini-allo“.  Not so mini, but you get the drift.

Here is the logic of a mini-allo transplant.  The preconditioning regimen is used to achieve two goals.  One goal is to kill off as many CLL cells as possible in order to reduce the number of the enemy before the new immune system comes in.  There is no expectation that every single last CLL cell is eradicated, no attempt to achieve this goal.

The second and equally important goal is to kill of the patient’s own T-cells, NK cells etc, cell lines that are the defense troops whose function is to protect against foreign invaders.  Why is this important?  Well, if these defenders are still around when the precious new stem cells from the donor come in, they are seen as invaders and promptly killed off.  Result is a disaster, the dreaded graft failure.  So, it is important that the preconditioning is strong enough to kill host T-cells and the like, to give the new donor cells a chance of surviving.

Most centers still use chemo + radiation (usually lower dose than in myeloablative procedures) in their mini-allo protocols.  Since one of the desired goals is to kill host T-cells before transplant, fludarabine is a huge favorite.  Ironic, isn’t it - fludarabine’s penchant for killing T-cells that is so dreaded under ‘normal’ therapy conditions is a huge asset in the context of transplant preconditioning.  Killing host T-cells is exactly what is needed in order to protect the graft when it is introduced into your body.  That is why most transplant centers would prefer if you have had your fair share of fludarabine before you even go to them.  That way the transplant team can be assured your T-cells are not frisky and looking for trouble.  Even if you have already had fludarabine, almost all transplant protocols will include additional amounts of this important drug to make doubly sure all of your own T-cells are dead and not likely to cause trouble for the graft. 

While different transplant centers have their own house blend of chemo + /- radiation recipes for mini-allo preconditioning, you can see that the kinder and gentler mini-allo can only go so far in the department of being kind, a certain amount of bloody murder is needed to make sure your original immune system is truly flat on its back and not likely to put up a fight when the graft comes in. No one wants to risk graft failure.

Graft versus Leukemia

As we mentioned above, the preconditioning in a mini-allo is not expected to eradicate every last CLL in your body, not even close.  So how can you expect a cure from this approach?  This is where the miracle of GVL (Graft Versus Leukemia) comes in. 

You see, a properly working immune system is supposed to hunt and destroy all cancer cells it sees in the body, a case of house to house search & destroy until the last enemy combatant is dead.  The reason why you have CLL is because your immune system (mostly T-cells and NK cells) has stopped recognizing the cancer cells as dangerous. 

What happens when you throw out the bums, get a new police force in?  The newly grafted immune system has no ties to the nepotism of the previous police force and once they are established the new donor T-cells and NK cells go on a dedicated mission of destroying every CLL cell they find.  This is the precious GVL effect that is capable of CURING the otherwise incurable CLL. The killing power of allogeneic T-cells and NK cells in destroying CLL cells wherever they hide is far superior to man-made chemotherapy drugs. No such GVL is possible in an autologous transplant since you are getting back your own lazy good for nothing immune system.  That is the single biggest reason for the failure of autologous transplants.

M. D. Anderson reported the first results from mini-allo transplants in lymphoid diseases back in 1998.  Six years later results from 17 CLL patients who had undergone sibling donor mini-allo transplants were reported by Dr. Khouri’s group. The preconditioning was FC (fludarabine + cyclophosphamide) or FCR (Rituxan was added in the case of patients recruited later in the program). The reduced intensity of the conditioning allowed recruitment of generally older and more heavily pre-treated patients.  All patients engrafted and treatment related mortality (TRM) was “only” 22% at 2 years.  It is still too high, but a whole lot better than the roughly 38-50% quoted for full bore myeloablative SCT, with the added advantage of younger and fitter patients to boot.

This was pretty impressive stuff, especially since the researchers were able to show significant Graft-versus-Leukemia effect along with the reduced death-due-to-therapy numbers.  Much has been learned since those early days, many fine touches added to preconditioning regimens, immune modulation to maximize GVL and minimize graft-versus-host disease (GVHD), better understanding of what constitutes a good match as far as donor selection is concerned, protecting patients from opportunistic infections and the like while their newly grafted immune systems were getting settled down and getting ready to do the heavy lifting.  You really need to read the full text article we are reviewing here to get all the interesting tidbits.

So, when is the right time to consider a transplant?

This is perhaps the most important question of all.  No one wants to transplant a newly diagnosed patient; SCT is not a valid frontline therapy.   On the other hand, should you put off transplant considerations for as long as possible, wait it out till the bitter end and nothing is working before doing a Hail Mary transplant?  We discussed some of these issues in our earlier article “Catch-22“. Dr. Khouri gives clear reasoning for his guidance:

“A key lesson learnt .. is that these procedures achieve their best outcomes if they are performed at a stage when the leukemia is still chemosensitive, particularly if the leukemia can be de-bulked to a low disease burden prior to transplantation”.

Makes sense.  Since mini allo SCT depends on the fine-tuned effects of GVL to eradicate the cancer and not the heavy handed approach of full strength myeloablative conditioning, it really helps if the ranks of the enemy are reduced ahead of time and the enemy is not a hardened variety that has learned every trick in the book.  In other words, if you go in to a transplant in a good remission with very little disease burden and your CLL is still sensitive to chemotherapy, you stand a good chance of coming out a winner.  Low TRM because of the reduced intensity conditioning, good GVL because your CLL is still easy to kill, and low risk of CLL relapse because the new graft does not have to face hordes of CLL cells right off the bat - that has all the hallmarks of a successful stem cell transplant.

Dr Khouri further identifies patients who are good transplant candidates, pretty much along the same lines as defined in the formal European consensus on the subject.

Here is a final quote from Dr. Khouri”

“Patients who relapse following first-line treatment with modern chemoimmunotherapy have a median survival of less than 3 years from the time of relapse, and those patients with the most favorable survival were those who eventually underwent allogeneic SCT. As the process of initiating sibling typing and/or unrelated donor search may take a considerable period of time, we recommend that a discussion regarding the potential need for transplantation be conducted at the time of first relapse from frontline therapy with FCR or equivalent regimen”.

Part Two of this two part article will focus on comparing mini-allo SCT versus standard chemotherapy in a just published 80 patient study.  Which group did better?  Who lived longer? Coming soon to a website on your computer..