Developing frontiers, brighter tomorrow
The main point of this article is to review an important paper recently published by Fred Hutchinson Cancer Center (“Hutch”) researchers in “Blood” titled “Who is fit for allogeneic transplantation?” As the premier stem cell transplant center in the USA (and perhaps the world), when the Hutch speaks, physicians and patients listen.
Stem cell transplant technology is a rapidly developing field. The good news is that survival statistics and cure rates are increasing slowly but surely, year by year. The bad news is that as with most cutting edge technology, there is a bewildering thicket of jargon and acronyms that patients have to wade through before they can come up the learning curve. I can’t do much about the survival statistics besides report them. But I can try to make the jargon and acronyms less intimidating. Before we get to the main course, please bear with me while I give a quick cheat-sheet for the newly diagnosed members in our community.
Cheat Sheet: what is a “mini-allo stem cell transplant”?
Let us take the two most important words in that phrase, “stem cells”. If you were a stickler for total accuracy you would say “hematopoietic stem cells”. You see, we are not talking about the real grand-daddies (and grand-mommies) of all stem cells, the embryonic stem cells created when a human egg is fertilized by human sperm. Embryonic stem cells can grow, specialize, divide, and when everything is working just right, eventually make a complete human baby. Embryonic stem cells are the ultimate jacks of all trades, they can do the whole gamut of tasks needed to make a very complex human being.
As embryonic stem cells go about doing their job, some of them make an irrevocable decision to change into more specialized kinds of stem cells. One of the many kinds of specialized stem cells are hematopoietic stem cells (HSC). These blood stem cells (hematopoietic = blood) are able to do only one thing. They can make all the different varieties of cells present in your blood. HSC can make red blood cells, platelets, lymphocytes, macrophages etc. But that is all they do, they make blood. HSC cannot make babies.
HSC needed for transplants are obtained from two sources and only these two sources (1) willing and healthy adult donors who are doing it for no other reason than generosity and desire to save lives (2) Umbilical cord-blood, a “waste” product that is generally thrown away after a baby is born. Fortunately for us, this means there are no political or ethical controversies out there surrounding research having to do with HSC transplantation.
In contrast to allogeneic hematopoietic stem cell transplants , autologous stem cell transplants involve harvesting the patient’s own stem cells first, then treating the patient with very heavy dose chemotherapy, followed by giving him back his own stem cells. Auto stem cell transplants are no longer recommended for CLL patients (except under special circumstances) since they are not able to cure even a percentage of patients undergoing them.
Earlier in the development of stem cell transplants, patients went through full strength “myeloablative” pre-conditioning prior to receiving the precious healthy stem cells from their donor. This pre-conditioning generally involved chemotherapy plus high dose full body radiation. The idea was to kill off the patient’s own immune system thoroughly, as well as do a thorough job of killing as many cancer cells as possible, before introducing the new donated immune system. Good idea, except that the process of myeloablative conditioning was very hard to tolerate. Only quite young and fit patients could hope to tolerate full strength myeloablative conditioning, and even then the mortality was quite high. This was a case of transplant perhaps curing the original cancer, but killing the patient as well in the process – death by therapy.
We now have non-myeloablative pre-conditioning. It still uses massive amounts of chemotherapy, and many institutions still use low dose radiation as part of the protocol. But it is nowhere as high impact as earlier myeloablative procedures. The result has been that older patients are now eligible for transplantation, as well as those who are not quite marvels of good health and fitness. The word “mini” (as opposed to “maxi”, I suppose) is just a catch word to describe the fact that the pre-conditioning is not quite as tough as it used to be. But don’t make the mistake of thinking mini-allo transplants as the equivalent of a friendly walk in the park. They are still pretty daunting procedures, there is still mortality and morbidity, people still die from therapy related causes, some people still relapse with their original cancer. But there is also no question that things are getting better, older patients can benefit, survival statistics are improving and there is every reason to hope this trend will continue.
“Who is Fit for Allogeneic Transplantation?”
The abstract of this important paper published in August edition of “Blood” is given below. If you are ever likely to be in the market for a transplant, this is a must read paper. Send me a personal email if you want to read the full text article and I will try and point you in the right direction.
Blood. 2010 Aug 11.
Who is fit for allogeneic transplantation?
Deeg HJ, Sandmaier BM.
Fred Hutchinson Cancer Research Center and the University of Washington School of Medicine, Seattle, WA, United States.
The use of allogeneic hematopoietic cell transplantation (HCT) has expanded progressively, facilitated by the increasing availability of unrelated donors and cord blood, and the inclusion of older patients as transplant candidates. Indications remain diagnosis-dependent. As novel non-transplant modalities have been developed concurrently, many patients come to HCT only when no longer responding to such therapy. However, patients with refractory or advanced disease frequently relapse after HCT, even with high-dose conditioning, and more so with reduced-intensity regimens as used for patients of older age or with co-morbid conditions. Thus, patients with high-risk malignancies who have substantial co-morbidities or are of advanced age, are at high risk of both relapse and non-relapse mortality, and should probably not be transplanted. Being in remission or at least having shown responsiveness to pre-HCT therapy, is generally associated with increased transplant success. In addition, to handle the stress associated with HCT, patients need a good social support system, and a secure financial net. They need to be well informed, not only about the transplant process, but also about expected or potential post-HCT events, including graft versus host disease and delayed effects that may become manifest only years after HCT.
What makes for a good risk transplant candidate?
Here is how the Hutch defined good risk and poor risk candidates for hematopoietic stem cell transplants.
This paper does a good job of examining each of these criteria in detail and how they impact stem cell transplant success. Please remember Hutch is not talking about just CLL cases in this paper. The discussion is more general and includes all the various types of blood cancers. This is something you should keep in mind as you read the full text article.
Younger, healthier patients who have no other medical problems will do better. Switching from full strength myeloablative transplants to “kinder and gentler” mini-allo transplants has meant that patients well into their seventies can now be eligible for transplantation. Age at transplant time has been going up every year. Over the last ten years, one in every five transplant patients is in his/her 7th or 8th decade of life.
But the other side of the coin is that waiting until the bitter last moment (either in terms of age or disease progression or general overall health) may make the whole transplant decision moot, irrelevant. So, besides the “who” part of the question, here is the million dollar question: when is it the right time to opt for a mini-allo transplant? One again we face the Goldilocks’ dilemma. We don’t want to do it too early in the game, but we don’t want to wait too long either. We explored this search for the perfect decision time in an earlier article titled “Catch 22”. The Hutch criteria reinforce the decision points. Consider a transplant before your CLL becomes truly refractory, before it grows fangs and starts “ROFL” (laughing) at standard chemotherapy. Do it while you are still in relative good health.
Since mini-allo transplants depend upon “graft-versus-leukemia” (GVL) effect to track down and kill the remaining CLL stragglers in your body after the transplant, it makes sense that patients with very low levels of cancer cells in their body just ahead of the transplant will fare much better. The idea is to go into a transplant while still in a very deep remission, with no more than trace amounts of CLL cells that need to be tackled by the curative action of GVL. Relapse rates (return of the CLL even after transplant) are very much dependent on the level of remission prior to transplant and whether or not the patient’s cancer was still response to chemotherapy. Waiting too long can quickly become a sucker’s game.
Finding the right donor
It is very important to have a well matched donor. That is sort of the ante you have to have before you get in the transplant game. The first choice is to look at your own brothers and sisters. A well matched sibling donor is still the best choice. Next best choice is unrelated but well matched adult donors from the stem cell donor banks around the world. Tough luck on this one if you are an ethnic minority; your chances of finding an adult donor in the donor banks is much poorer if you are of mixed ethnicity or your particular brand of ethnicity is not well represented in the donor banks. The next choice is stem cells from umbilical cord blood. This opton has rapidly become a life line to patients who need a transplant and do not have sibling or unrelated matched adult donors.
There were more than 26,000 hematopoietic stem cell transplants worldwide last year. 6,500 of them were done in Northern America. People ask me why there are “only” six or seven thousand hematopoietic stem cell transplants in North America. A major stumbling block to stem cell transplants is the ability to find a suitable stem cell donor. Large families with many brothers and sisters are no longer the norm, sibling donors are much harder to find today. We are a melting pot here in America, representing just about every ethnic minority there is in the face of the world. Since transplant candidates are getting older on average, their brothers and sisters are getting older too – possibly with health conditions themselves that prevent them from being good donors for their CLL sibling.
We desperately need better funded stem cell donor banks. We also need a motivated and determined cadre of advocates to drive stem cell donor registration, especially in minority populations. Cord blood banks are such a “gimme” that it breaks my heart how little they are used in this country. Rather than throwing the umbilical cord into the trash after the baby is born, or letting unscrupulous hucksters con you into saving the cord “for your own use” in private banks, each and every healthy baby born to a healthy mother should be blessed with the good karma of possibly saving a life – by donating the baby’s umbilical cord to the voluntary cord blood donor banks.
This is the first time I have seen doctors go beyond the medical requirements and address financial and social support systems in their analysis. As you can imagine, discussions of money, social and cultural background, race, haves and have-nots etc. are incredibly sensitive and divisive in the political environment of today. We steer clear of politics on this website. I ask you to do the same. Just consider this: CLL is a non-discriminatory cancer. It really does not care about all these differences that separate us. Take away the unimportant details and we are all brothers and sisters fighting a common enemy. That is all I care about. I hope you do too.
Getting a successful transplant depends on many factors, not just medical factors. Do you have good medical insurance? Transplants are expensive business. They can cost anywhere from several hundred thousand dollars for a straightforward and no complication transplant to a couple of million dollars for a complicated case needing lots of hospitalization etc. Is your insurance up to the challenge? I am no expert on insurance and Medicare issues – but I do know they play a huge role in the lottery of life that our guys face.
How about family and care givers? Transplant patients need 24/7 devoted caregivers for several months after completion of the transplant. I know, I was there. Taking care of my husband PC while he was going through his (cord blood) stem cell transplant was no easy matter for me and our daughter. Here is where the investments made in developing strong family ties and community support will help the patient, big time.
Are you fighting a multi-front war with cancer as only one of a set of medical problems? Older patients are more likely to have co-morbidities such as cardiac and pulmonary issues, diabetes, high blood pressure. Last but not least, how is your emotional stability and intestinal fortitude? Do you still have the cojones to handle the emotional and physical roller-coaster that a transplant can be? Only you can answer that question.
Impact of prognostics on transplant decisions
The Hutch paper does not discuss the specifics of CLL prognostics and how they impact transplant decisions. But an earlier very important European consensus document addressed that particular question. CLL is an indolent disease. In a significant lucky minority, the disease “smolders” and goes no where fast. It would be a terrible mistake to put these people through the risk and dangers of stem cell transplants.
But not everyone is so lucky. There are patients whose CLL gallops ahead from day one, who burn through every chemotherapy option there is and face grim prognosis. The good news is that with modern prognostic indicators we have a chance of identifying these people ahead of time. They are good candidates to get into a transplant program sooner rather than later. They may not get too many good remissions and should be aware that putting off transplant decision may close the window of opportunity for them. This is particularly true of younger patients with aggressive disease. They do not have the luxury of running out the clock. For them CLL is very much a killer cancer – where the only cure is a mini-allo stem cell transplant.
As we adopt ever more aggressive therapy options as frontline gold standards, choices remaining to patients who relapse after these chemoimmunotherapy options are not all that good. Some of these issues were discussed in our article “Life after FCR“. Only patients who did well after FCR relapse are those that chose transplant as their choice of salvage therapy.
Leukemia. 2007 Jan;21(1):12-7.
Indications for allogeneic stem cell transplantation in chronic lymphocytic leukemia: the EBMT transplant consensus.
Dreger P, Corradini P, Kimby E, Michallet M, Milligan D, Schetelig J, Wiktor-Jedrzejczak W, Niederwieser D, Hallek M, Montserrat E
Chronic Leukemia Working Party of the EBMT.
Department of Medicine V, University of Heidelberg, Heidelberg, Germany
The aim of this project was to identify situations where allogeneic stem cell transplantation (allo-SCT) might be considered as a preferred treatment option for patients with B-cell chronic lymphocytic leukemia (CLL). Based on a MEDLINE search and additional sources, a consented proposal was drafted, refined and approved upon final discussion by an international expert panel. Key elements of the consensus are (1) allo-SCT is a procedure with evidence-based efficacy in poor-risk CLL; (2) although definition of ‘poor-risk CLL’ requires further investigation, allo-SCT is a reasonable treatment option for younger patients with (i) non-response or early relapse (within 12 months) after purine analogues, (ii) relapse within 24 months after having achieved a response with purine-analogue-based combination therapy or autologous transplantation, and (iii) patients with p53 abnormalities requiring treatment; and (3) optimum transplant strategies may vary according to distinct clinical situations and should be defined in prospective trials. This is the first attempt to define standard indications for allo-SCT in CLL. Nevertheless, whenever possible, allo-SCT should be performed within disease-specific prospective clinical protocols in order to continuously refine transplant indications according to new developments in risk assessment and treatment of CLL.
This Hutch article is not restricted to CLL; it considers all the major blood cancers. Please keep this in mind as you read the full text article. But one telling paragraph about CLL response statistics caught my eye.
- In CLL patients undergoing stem cell transplants after relapsing from fludarabine and cyclophosphamide containing regimens, Hutch projects 60% of the patients achieved “progression free survival”. What does that mean? 60% of the patients lived, without relapse of their CLL. I don’t know about you, I call that a CURE.
- Patients going into the transplant with bulky disease had higher risk of their CLL coming back even after the transplant. Moral of the story, be kind to your new immune system, try and not ask it to lift too heavy a burden right away. Going into the transplant with lower level of CLL cells still lurking around gives the Graft versus leukemia effect a chance to succeed. You do not want to be in an out-gunned and out-numbered armies situation here.
These statistics look backwards, results obtained over the last decade or so. Technology has not stopped moving forward. Each month I read new reports, new transplant procedures explored to minimize pesky graft-versus-host disease (where the new graft attacks its host, namely the patient) while increasing the oomph of life saving graft-versus-leukemia.
Transplant technology is not quite a cut-and dry technical procedure. There is a lot of room for expertise and that makes it all the more important to make your transplant center and transplant team choices with care. Below is a very recent example of what I am talking about. In this clinical trial using a novel transplant approach, the overall progression free survival rate at 4 years was 76%. But if we look at only those patients who had sibling donors, the progression free survival was a whopping, wonderful 90%. How do you like them apples? Hunh? True, these are not CLL patients, but they are follicular lymphoma (non-Hodgekin’s lymphoma) patients – kissing cousins as it were. I will be happy to review this particular article if enough of you are interested.
J Clin Oncol. 2010 Aug 10;28(23):3695-700.
T-cell-depleted reduced-intensity transplantation followed by donor leukocyte infusions to promote graft-versus-lymphoma activity results in excellent long-term survival in patients with multiply relapsed follicular lymphoma.
Thomson KJ, Morris EC, Milligan D, Parker AN, Hunter AE, Cook G, Bloor AJ, Clark F, Kazmi M, Linch DC, Chakraverty R, Peggs KS, Mackinnon S.
Department of Haematology, University College Hospital, London, UK. Kirsty.email@example.com
PURPOSE: Follicular lymphoma (FL) is an indolent disorder that is treatable but considered incurable with chemotherapy alone. The curative potential of allogeneic transplantation using conventional myeloablative conditioning has been demonstrated, but this approach is precluded in the majority of patients with FL because of excessive toxicity. Thus, reduced-intensity conditioning regimens are being explored.
PATIENTS AND METHODS: This study reports the outcome of 82 consecutive patients with FL who underwent transplantation using fludarabine, melphalan, and alemtuzumab for in vivo T-cell depletion. Patients were heavily pretreated, having received a median of four lines of prior therapy, and 26% had experienced treatment failure with previous autologous transplantation. Median patient age was 45 years, and 52% of patients received stem cells from unrelated donors.
RESULTS: With a median follow-up time of 43 months, the nonrelapse mortality was 15% at 4 years (8% for sibling and 22% for unrelated donor transplantations), acute grade 2 or 3 graft-versus-host disease (GVHD) occurred in 13%, and the incidence of extensive chronic GVHD was only 18%. Although relapse risk was 26%, this was significantly reduced where mixed chimerism had been converted to full donor chimerism by the use of donor lymphocyte infusion (DLI; P = .03). In addition, 10 (77%) of 13 patients given DLI for relapse after transplantation experienced remission, with nine of these responses being sustained. Current progression-free survival at 4 years was 76% for the whole cohort (90% for those with sibling donors and 64% for those with unrelated donors).
CONCLUSION: The excellent long-term survival with associated low rates of GVHD and the frequency and durability of DLI responses make this an extremely encouraging strategy for the treatment and potential cure of FL.
Coming up the learning curve
Below are several articles from our archives. I strongly urge you to read these and other sources before you make transplant decisions. This is not an easy process, either in terms of money or risk. I am not exaggerating when I say your life hangs in the balance. You can search PubMed for related articles and read the original research publications for yourself. If that is your cup of tea, I strongly support it. Or you can read our more patient friendly reviews of cutting edge research. Your call. Either way, you need to learn this stuff.
Besides all the other reasons, another reason why there are so few transplants done (as a percentage of CLL patients who can benefit from transplants), one sad reason is that local oncologists are not very familiar with up-to-date transplant statistics and fail to counsel their patients on their therapy choices in this regard. What you and your doctor don’t know can truly kill you.
It is with great personal sadness that I acknowledge “Richard” of Catch-22 fame and “Harvey” the Round-headed Kid are no longer with us. One was a good friend and supporter. The other was my beloved husband of 38 years. Both were heroes who died while participating in clinical trials that contributed to the improvement of transplant statistics for the next generation of CLL patients. I salute these two special guys, as I do every patient who ever participated in clinical trials.