Recap…
As we have seen in Part I of this series, a lot has changed on the stem cell transplant scene. To recap what we have learned so far:
- Autologous transplants for CLL patients are a thing of the past.
- Full bore myeloablative transplants are reserved for special circumstances, and only in the case of very fit and young patients.
- Mini-all transplants (non-myeloablative transplants, also called reduced intensity conditioning or RIC transplants) have revolutionized transplant protocols, cutting by more than half the dreaded TRM (treatment related mortality).
- Fludarabine has gained importance as a pretreatment drug precisely because it does such a good job of immune suppression and killing T-cells. Campath in the same role has had mixed results and controversial. (See the Khouri paper we reviewed in Part I for more details on this subject).
- Formal consensus has been reached in Europe regarding when to initiate transplant procedures and which patients are most likely to benefit most from it. Based on the Khouri paper it seems a similar consensus is emerging in the USA as well, welcome news indeed.
- Younger patients with aggressive disease and poor prognostics (17p deletion) are encouraged to explore SCT sooner rather than later. The same is true of patients who get a partial remission at best or relapse soon after chemoimmunotherapy regimens such as FCR. Patients who undergo Richter’s transformation are also recommended to consider transplants at an early opportunity.
While the Khouri paper did not cover this aspect, finding a suitable donor (sibling or MUD) has been a huge problem for many patients who fit the selection criteria above. I strongly urge such patients to consider stem cells from umbilical cord as a viable alternative. This technology is coming up the curve fast and will soon catch up with transplants using adult donor stem cells.
Mini-allo SCT versus conventional salvage chemotherapy
We have seen hints here and there, in small scale studies (such as the M. D. Anderson study of life after FCR) that stem cell transplants are not only viable therapy option, they may in fact be the preferred approach when it comes to salvage therapy for patients who have aggressive disease or have relapsed soon after chemoimmunotherapy combinations. We also know now that patients with high level of 17p deletions just do not do well on any of the combinations such as FR, FCR etc. from the get-go.
But I have not seen anything concrete that compared head-to-head the results patients can expect if they choose salvage chemotherapy instead of SCT. This is of crucial importance. SCT is a tough decision, almost a leap of faith (less so now than it used to be). Patients rightly dither and agonize over this decision. Here is a paper that sheds some light on this comparison. The abstract is below, write to me personally if you want help locating a full text copy of the paper.
Ann Oncol. 2009 Jul 12.
Does reduced-intensity allogeneic transplantation confer a survival advantage to patients with poor prognosis chronic lymphocytic leukaemia? A case-control retrospective analysis.
Delgado J, Pillai S, Phillips N, Brunet S, Pratt G, Briones J, Lovell R, Martino R, Ewing J, Sureda A, Milligan DW, Sierra J.
Department of Haematology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain.
BACKGROUND: Reduced-intensity conditioning (RIC) allogeneic haemopoietic cell transplantation (allo-HCT) is increasingly considered as a therapeutic option for younger patients with poor-risk chronic lymphocytic leukaemia (CLL). In this retrospective analysis, we assessed the outcomes of CLL patients undergoing RIC allo-HCT compared with a group of matched controls that were candidates for transplantation but did not have a suitable donor or refused the procedure. PATIENTS AND METHODS: Cases comprised 37 patients who underwent RIC allo-HCT. Haemopoietic cell grafts were harvested from HLA-matched siblings (27) and unrelated donors (7). Controls consisted of 43 patients from the same institutions who received conventional therapy only. Matching variables were age at diagnosis and time to first CLL-specific therapy. RESULTS: Both patient groups were well balanced in terms of cytogenetics by FISH, CD38 and ZAP-70 expression, and immunoglobulin heavy-chain variable region mutational status. Median overall survival was 113 months for HCT patients and 85 months for controls when calculated from time of diagnosis (P = 0.072) and 103 and 67 months, respectively, when calculated from time of first therapy (P = 0.041). CONCLUSION: RIC allo-HCT is a reasonable option for patients with high-risk CLL. However, these results require confirmation before the procedure can be recommended outside clinical trials.
PMID: 19596701
The Barcelona experience
Among the European centers of CLL excellence is the Barcelona group and this paper’s author list is impressive. I am picky in choice of papers I review for you. I look for credible papers from acknowledged experts in good journals, cutting edge information that can help you. This paper meets all the criteria.
This paper compares the outcome of two well matched groups of patients. It is important to note this was not a computer randomized study where patients are put into two groups at random and in that sense it is not a classic two arm study. Nevertheless, since the researches took pains to match the two groups on a long laundry list of patient characteristics and I think the study provides a useful comparison.
Please note the years when the patients were treated. The transplants were between 1992 and 2003. Given how fast things have been changing (improving) in transplant technology, this is a huge chasm between 1992 and 2009. We will have to take that into account when interpreting the results. Since both the transplant group and the salvage chemo group are equally ‘antiquated’, the comparison is valid. But please be aware that the survival statistics for transplants today are a whole lot better than they used to be in the 1992-2003 vintage.
Study Design
37 patients who underwent mini allo transplants at Barcelona (this paper calls them reduced intensity conditioning allogeneic hematopoietic stem cell transplants .. RIC allo-HCT for short. Same deal as mini- allo, a rose is a rose etc) between the years 1992 – 2003 made up the study group. 33 of these were sibling donor transplants, 4 were MUD (matched unrelated donor) transplants.
In order to define a good control group the investigators looked at their database of 673 consecutive CLL patients between 1990 and 2005 at the same institution. These were all patients who were eligible candidates for transplants but could not find a suitable donor (95%) or refused the procedure (5%). Out of this group 43 patients were identified that closely matched the transplant group on a huge list of demographic, clinical and prognostic indicators.
Not a bad design, given that we are not likely to get a true randomized double arm trial to study this question. It would not be ethical to conduct such a trial.
Patient Characteristics
Below is a table that summarizes the patient characteristics of the transplant and “control” groups.
As you can see, the match between the two groups is excellent on a detailed list of parameters, including modern prognostic indicators such as FISH abnormalities, CD38 and ZAP-70 expression, and IgVH gene mutational status for the majority (but not 100%) of the patients.
Results
The researchers compared and contrasted the data in many different ways. You will get the full details only by reading their paper. What I give below is a summary of the findings. Remember these findings represent 1992- 2003 technology and also that statistically derived median results may not be exactly what individual patients will see in their situations. In other words, your individual mileage may vary.
- Median overall survival was 113 months for the mini-allo group and 85 months for the control group, calculated from the time of CLL diagnosis. That is 28 extra months. You have to decide whether it is worth living on average another extra two years + with your Sweetie, another two plus years to watch grandkids grow.
- The median overall survival calculated from date of first therapy is 103 months for the transplant group and 67 for the control group. Three extra years.
- Looking at how the patients fared from the time they entered the study (start of transplant or start of salvage chemotherapy respectively), there was higher early mortality in the transplant group but with better long term survival for the transplant group compared to the control group.
- How about a full CURE? Even in these early transplant protocols the trend becomes clear at the 4 year mark. Little more than 20% of the transplant patients were alive and free of CLL, they were in “Progression free survival mode” and continued to be so even 10 years after the transplant.
- Looking at the control group on the other hand, the sad news is that every single one of the patients died with no let up. Salvage chemotherapay did not cure a single patient. The graph below makes these trends clear. The dark line represents transplant group, the blue-green line represents the control group.
Cause of death
Without question the percentage of patients who did not survive is far too high in both groups. Here is how the causes of death broke down.
Patients dying from CLL relapse after transplant is one third of the rate in the control group (11% versus 33%). Remember, these were very early days for mini-allo technology. Improved transplant protocols to harness more potent graft-versus-leukemia effect and new approaches such as DLI (donor lymphocyte infusion) to kick start more robust GVL, the 11% death due to CLL relapse after mini-allo transplant has been whittled down.
I also suspect that in those days patients getting SCT (and the new fangled mini-allo version at that!) were very far gone cases. Most experts (including Khouri) recommend earlier intervention while patients are still chemo-sensitive and can be transplanted when they are in reasonable remission. Results from the “Hutch” report relapse risk (and therefore death due to relapse) becoming close to zero when patients are transplanted in full CR.
Death due to other reasons (infections, secondary cancers, heart attacks etc) was 22% in the transplant group and 33% in the control group. Interestingly, secondary cancers were seen only in the control group, none in the transplant group.
PTLD (post transplant lymphoproliferative disease) was responsible for 5% of the patients dying in the transplant group. Once again it is important to remember this study was conducted at a time when it was not clearly established that simple Rituxan (or ofatumumab, another anti CD20 monoclonal) infusions halt PTLD in its tracks. Death due to PTLD after transplant is now becoming a thing of the past. One more bridge crossed safely.
That leaves GVHD (graft versus host disease) as the tough nut to crack. 19% of the patients in the transplant group died due to this frustrating complication. When we have figured out how to improve the desired GVL (graft versus leukemia) and reduce or better still eliminate GVHD we would have truly learned to cure CLL.
Fortunately we have come a long way since 1992-2003 in understanding and treating GVHD. In the next two days I will publish the third review of this series, highlighting a brand new cellular approach to controlling GVHD that is getting rave reviews. It is already fast tracked for pediatric transplants and the FDA is bending over backwards for use of this technology in adult patients as well.
Editorial
I wish we had the latest, state of the art properly randomized mini-allo transplant versus conventional salvage chemotherapy study to look at. We do not, and we are not likely to see any such study. So, let us do a thought experiment, a little imaginary experiment where we plug in reasonable statistics from today and see what pops out for CLL patients considering mini-allo SCT today. I will be on the conservative side of things so as not to paint too rosy a picture.
Putting our best foot forward, let us imagine our cohort of patients were advised by physicians aware of modern expert consensus recommending patients opt for a state-of-the-art mini allo as soon as they met the European consensus guidelines (also similar to the guidelines suggested by Khouri in his paper).
In our imaginary cohort of SCT patients we are talking of younger patients with bad prognostics (17p deletion) or patients soon after their FCR (or similar combo) relapse. We stipulate these patients have not waited until the last bitter moment, gone through every chemo protocol known to man and therefore they remained reasonably chemo-sensitive. This in turn means they were able to get disease de-bulking thanks to new drugs such as Revlimid, even if they had the dreaded 17p deletion. I am thinking of PC as I write this. He did not get much joy after Humax + FC, but Revlimid was able to get him into a pretty good remission with just a few very small nodes left over. Not quite a CR but close to it.
What can we expect for this ideal patient group by way of results after a mini-allo transplant with a well matched graft? (Don’t get me started on the subject of enormous difficulty faced by a large percentage of patients who need a mini-allo SCT but cannot find a suitable sibling or MUD donor. Patients coming from ethnic minorities have a specially hard time finding MUD donors. Cord blood as a source of stem cells is a ray of hope in this otherwise bleak situation).
As has been shown at the Hutchinson Cancer Center, patients who go into transplants with nodes less than 5cm in diameter have much lower risk of CLL relapse, and this goes down to almost zero if the patient is in a full CR when transplanted. It is reasonable to cut that 11% relapse risk in the Barcelona paper down to say 5% or lower, if transplant centers start seeing better quality of patients and not just the basket cases looking for a Hail Mary transplant.
As I wrote above, PTLD related death is now history and we can reduce that 5% death to zero.
GVHD is already getting easier to handle, institutions such as the Hutch and M. D. Anderson report death rates much less than the 19% in this paper. With the advent of cellular GVHD therapy options (hold your horses! I promise I will write about it in the next 2-3 days), I am optimistic death due to GVHD can be reduced into small single digits.
With better understanding of how patients need to be protected from opportunistic infections (interesting that there were no secondary cancer deaths in the transplant group in the Barcelona study, only in the control group that had salvage chemotherapy), it is not unrealistic to drop that death toll from a whopping 22% down to 10%. How does all this stack up?
- Death due to CLL relapse: 5%
- Death due to PTLD: 0%
- Death due to GVHD: 10%
- “Other” causes of death: 10%
This compares well with the statistics quoted by the Hutch in 2005 for mini-allo transplants for CLL patients. Their co-morbidity index study showed patients with no additional health issues (other than CLL) had far better survival chances than folks fighting wars on multiple fronts.
Several well respected CLL transplant experts have quoted to me 75% or better progression free survival, if they are given a chance to transplant the patient with a well matched graft, at a time when the patient is chemosensitive and does not have bulky disease. I can think of a simpler word that describes “Progression free survival” over the long haul. It is called a CURE. Modern mini-allo SCT can yield CURE rates of 75% or higher, if the patient selection was more favorable. How do you like them apples?
Yes, there is risk involved in transplants, even the min-allo variety. It will be many moons and probably not in our lifetimes before all the risk factors are taken out. No one in their right mind would go the transplant route if there were better and safer alternatives. But if you have a lot of life left to live and you have an aggressive variety of CLL with poor prognostic indicators, if you fit the consensus transplant selection criteria Khouri and other experts have identified, I hope you will do yourself a favor and discuss your options with a good transplant team, sooner rather than later.
I want to make sure you get this point. Mini-allo SCT is now a viable therapy option for CLL patients. It is no longer just one last gasp, a straw to clutch before you give up. Learning as much as you can about it and maximizing your chances of transplant success will pay off big time.
We have come a long way baby, this is no longer your father’s transplant. Dr. Khouri’s paper (discussed in Part I of this series) is seminal and we finally have a highly regarded transplant expert telling it like it is.
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19 comments on "Stem Cell Transplants – Are They Worth It? (Part II)"
Wow. Impressive summary (as usual). Attentive to why this is the best evidence one can get, given that a randomized clinical trial is not feasible. Ditto to the difference b/w 1992-2003 and today in terms of physicians’ ability to manage the bad stuff that follows the big T (for transplant). We patients lack patience: We don’t usually sing “Time is on my side, yes it is.” This mini allo transplant procedure may be a case in which the advance of medical knowledge and technique has moved fast enough to matter here and now for the lucky — and for younger patients entering pipeline of CLL.
A tangential question: I do not recall CLL Topics addressing what constitutes optimum fitness for a CLL patient. My doctor said “Get enough sleep, exercise, eat a healthy diet.” My reading of the literature (observational and epidemiological studies) is that higher body mass index is associated w/ higher incidence of blood cancers and, more important, higher premature mortality for those with blood cancers. So I went on Weight Watchers and lost 25+ lbs.
But is it enough to be at the top of one’s BMI range for height and sex? What about overall lean body mass? (Is fat, as someone put it, “a little engine of hormones”?) What about the relative merits of cardiovascular vs. strength exercises? Is it possible to strengthen our capacity to generate the good blood cells that CLL’s crabgrass leukocytes generally crowd out?
Of course, hope that exercise, diet, nutritional supplements, etc. will fight CLL are typicall part of the continuum of the patient’s hope that something — even shining a green light on one’s skin for a half hour daily — will turn off CLL’s motor or strengthen our immune systems. I have read review articles and individual studies on exercise and premature mortality from cancer — and sometimes, from blood cancer. The literature exists but is not vast. Nor is it of high quality (issues include small sample size, lack of randomization, imperfect controls for selection effects b/w treatment and control, imperfect control variables for confounding factors in nonexperimental designs, etc.) Still, the few good articles I find still point to lower BMI as a plus for CLLers. But evidence on exercise that’s credible re: blood cancers is skimpier.
Chaya and others knowledgeable about the science — is the literature on fitness of any sort (vis a vis blood cancers) fit for human consumption? Inquiring minds want to know.
Many thanks, Chaya, for your energy and dedication, your intelligence and your (sometimes dark) humor. Keep it up! (So say your loyal fans.) — J.
JonNoVa
What defines a fit CLL patient?
Simply put, whatever definition of health you accept for the general population is right for CLL patients as well.
Getting into specifics, I would look for lack of chronic disease (other than CLL) such as diabetes, hypertension, cardiac insufficiency, obesity, chronic liver or kidney disease, pulmonary insufficiency or autoimmune disease such as COPD and asthma, secondary cancers etc.
A long laundry list of stuff that is of importance to all people, not just CLL patients.
My advice to patients is quite simple. We all know what good health is and what we need to do to improve our health. Eat a variety of good food that is heavy on fruits and vegetables, eat moderately to avoid the problems associated with obesity, exercise regularly to the level you are able (including weight bearing exercsie to strengthen bones), sleep well, stay well hydrated and avoid stress to the extent you can.
In otehr words, all the things your mother told you to do because they are good for you.
One last bit: it really is of no use trying to fight for every extra year of life after CLL diagnosis if you do not enjoy the time you do have. Life is meant for living. Don’t get fixated on the CLL to the level where living becomes a chore.
I am about to find out if the Mini Allo works…..set to go into the hospital at MD Anderson tomorrow – Wed the 12th…..Dr. Khouri is my physician. Diagnosed at 43 – just turned 50 two weeks ago. FCR in the Fall of 2007 – Partial Remisson……then relapsed in Fall of 2008 -with 17p deletion…….saw Dr. Mike Keating at MD Anderson in Jan of 2009 — no question in his mind when he did my exam — do chemo to get de-bulked… then do SCT as soon as donor was found. Did three rounds of OFAR (clinical trial) and one round of HYPER-C-Vad……..which did the trick….not a CR but good enough to go…….got a 10 of 10 match from the MUD bank after both brothers turned out to be 9 of 10 — not good enough. I was very lucky to find several 10 of 10 matches. Now in Houston just waiting to go into the hospital and get this show on the reoad!!
Thanks so much for the information…….its straight forward and thats what I need!!
To au1981 .. Best of luck to you. I’m sure all of us in Chaya’s flock are beaming you healing thoughts.
Chaya, Your clear and excellent articles have been so very helpful to us. Please continue your wonderful work!
Chaya,
As usual, your timing is impectible… you are the best.
God Bless,
au1981, prayers for your safe recovery. Mike
Krazyleggs
Hello Chaya, I recall a while back a comment you made regarding anti-oxidants and the jury still being out, with the thinking that boosting the immune system (vit c, etc) could actually be promoting B cll lymphacyte growth?? I could be wrong, but ever since cutting out many foods with high vitamin C, my ALC levels have actually dropped. Do you have any info on this subject??
Gratefully
Au1981,
God bless you and have a safe journey thru, to a healthy and wonderful life on the other side. May you feel the freedom, that each and everyone of us hopes to feel one day. My prayers are sincere!!!
With Kindest Regards!!
Raymond Parker
Chaya,
This was a most helpful article and analysis and gives us hope, something we have been short on. Thank you for these articles.
I am thinking that where you choose to have your transplant is very important, is this so? Is one better off by going to the Hutch or MD Anderson where they have much experience and keep up on all the latest procedures and tx.?
Chris R.
I have just completed cycle one of concurrent RF protocol at Dr. Byrd’s Clinic at OSU. Though I have “good” markers my disease is marked by aggressive accumulation of cancer in all three areas of bone marrow, peripheral blood and nodes(internal and external).
Although my response has proven so far to be a very good one, the big unknown is whether my remission after cycle 5 will be deep and enduring.
It is reasonable for patients who have bad markers or clinical characteristics like mine (multiple node cluster involvement and aggressive accumulation) to begin to think about “plan B” to include HSCT. This should not be thought of as pessimistic but a potential reality that one can more easily transition to by familiarizing yourself with questions like, “where would I have to go if I needed an HSCT?” and of course absorbing the fruits of Chaya’s articles. I actually chose an oncologist/hematologist who is a transplanter/researcher to give my 2nd through 5th RF cycles of treatment, in part to cover this contingency should it arise.
There is much valuable insight and discoveries that are being worked on like the discovery of adipocyte (fat cells) in the bone marrow and the effect it may have on outcome from chemo TX and HSCT by Dr. George Daley.
Chaya’s coverage of this pressing topic is really great – Thanks Chaya,
WWW
Thanks Chaya. Outstanding info, as usual. I had one of those “Hail Mary” transplants in April ’05. No longer tx responsive, and “CLL loaded”, I went for it at age 64. The transplant was looking good for a year then I aggressively relapsed. The good news is I became tx responsive again. I received a good one year-plus remission from subQ campath. I am now in my final couple weeks of subQ campath again, and it looks like I’m again responding well. Some might say, “gee those are short remissions”. I’m savoring every moment. I feel very blessed that the “Hail Mary” SCT delivered some goodies, even though it was not the remission hoped for.
Bob Larkin
Chaya,
Well said. You do good work, as always.
i would add 1-2% primary graft failure (my rare misfortune due to lack of ATG) to the list of risks, though in a mini, it is not usually a fatal complication. Just a big waste effort in most cases. Later graft failure is usually from relapse.
GVH is the killer, in every sense of the word, because the immunosuppressive drugs used to control it predispose to life threatening infections are other serious complications.
If my CT scan next week shows my mesenteric nodes have grown, I am pushing for standard FCR and a redo transplant, same donor ( after a BMB and repeat FISH of course) Maybe a few months of GVL will have done the trick. That’s my hope.
Have been there and done that, I remain open to helping those who I can through my blog bkoffman.blogspot.com or email.
Brian:
I am truly sorry about the graft failure in your case. But as you know, I have been concerned that the preconditioning had been too light, too mini, in your case. Graft failure could be the result of that. Too many of the host T-cells survive wimpy preconditining and they in turn kill off the donor graft before it can establish it self. But most centers now use ATG (especially in patients who have not had boat loads of fludarabine) and that takes care of the problem.
Unlike ATG (anti-thymocyte globulin – which kills host T-cells with great efficiency and then leaves the host body in short time), Campath as a pre-conditioning drug has become controversial. It too helps kill the host T-cells as needed, but unlike ATG it lasts in the host body for too long and may contribute to the killing of donor T-cells down the road. Net result, patients who have had Campath preconditionig are at greater risk of inadequate GVL and that in turn increases risk of CLL relapse.
M. D. Anderson was a big proponent of Campath preconditioning. But based on Khouri’s comments in his latest paper, it seems they too are having second thoughts about it.
All in all, graft failure is a diminishing risk; especially since we now have the option of DLI (donor lymphocyte infusion) to boost the graft’s potency.
Chaya:
Thank you so much for your information that serves as a great tool in all of our CLL journies.
Chaya,
Thanks again for giving an excellent and hopeful summary of a very tricky and frightful topic. I will be having a fully ablative cord blood transplant at the Hutch in a couple of weeks. I can only hope that the doctors there have done half the homework that you have!
Regards,
Jon
Dx Feb 08 CLL/SLL (age 37)
FCR x3 Aug – Oct 08
OFAR x5 Dec 08 – April 09
Transformation detected May 09
RCHOP x3 June 09 – Aug 09
Chaya,
Once again, excellent information that we can all use, or store away for future use. One quick off topic question: does anyone know what effect a cortisone injection 2+ weeks prior to a CBC would have on your WBC count, and how tendonitis might effect your labs, specifically WBC’s and lymphs. Any input would be appreciated. Thanks, Nancy
Single doses of corticosteroids used to treat acute inflammatory processes have variable and unpredictable, but essentially inconsequential effects on CLL.
Here is one reference: http://www.bloodjournal.org/cgi/reprint/49/5/719.pdf
11qRick & Chaya,
I sincerely appreciate the time you took to answer my question and send the link to the cortisone reference, which I read. Chaya, it’s the responses we receive from fellow CLLers that make your website so valuable to us. This network made up of professionals and lay people provides support and understanding in a way non-CLLers can’t, including placing valuable information at our fingertips. Many of us have educated ourselves to a level we thought impossible prior to our diagnosis, but usually have questions along the way. I had exhausted all of my searches on the web for the cortisone information and couldn’t come up with anything definitive. I didn’t have anywhere else to turn. The information given to me by my oncologist didn’t make sense to me (I must tell you I am an RN), and when I got home yesterday I started doing my research. That’s where I got stuck. After getting help on your site this morning, I was able to get the information I needed. Turns out my suspicions were right. ANYWAY….. My point is – THANK YOU – for this and everything else you do for us. With heartfelt appreciation, Nancy
ps: hope you are enjoying India and all it’s beauty with your mother.
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