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.