Monday, February 12, 2007

Bone marrow transplantation for CLL

This is the next section in the article that I am writing in the Lancet.

In leukemia, remissions are traditionally consolidated with high dose chemotherapy, sometimes with autologous stem cell rescue. Using this approach the German group were able to eliminate minimal residual disease (MRD) and produce prolonged remissions in patients whose CLL had mutated VH genes, but for those with unmutated VH genes molecular relapse was inevitable and clinical relapse almost so by 4 years follow-up [1]. However, even this, less-than-encouraging, outcome may be better than what is achievable with more conventional chemotherapy according to a comparison with matched historical controls [2]. Moreover, a stem cell harvest is only possible in about two thirds of cases [3] and there is a worryingly high incidence of secondary myelodysplastic syndrome [3, 4]

In an attempt to gain immunological control over the CLL by using the graft-versus-leukemia effect, stem cell allografts have been employed. As might have been expected with a largely elderly population, myeloablative conditioning leads to an unacceptably high treatment-related mortality of between 40% and 50% [4, 5]. To combat this toxicity, allotransplantation with reduced intensity conditioning, often followed by donor lymphocyte infusion, has become popular. However, early results do not yet show an improvement in event-free survival compared to myeloablative transplants [6-8]. In every series there is a high incidence of chronic graft-versus host disease. Nevertheless, in patients with poor risk prognostic markers, and especially those with 17p13 deletions, sustained remissions without molecular relapse are achievable [9].

1. Ritgen M, Lange A, Stilgenbauer S et al. Unmutated immunoglobulin variable heavy-chain gene status remains an adverse prognostic factor after autologous stem cell transplantation for chronic lymphocytic leukemia. Blood. 2003;101:2049-53.
2. Dreger P, Stilgenbauer S, Benner A et al. The prognostic impact of autologous stem cell transplantation in patients with chronic lymphocytic leukemia: a risk-matched analysis based on the VH gene mutational status. Blood. 2004103:2850-8.
3. Milligan DW, Fernandes S, Dasgupta R et al. Results of the MRC pilot study show autografting for younger patients with chronic lymphocytic leukemia is safe and achieves a high percentage of molecular responses. Blood. 2005;105:397-404.
4. Gribben JG, Zahrieh D, Stephens K et al. Autologous and allogeneic stem cell transplantations for poor-risk chronic lymphocytic leukemia. Blood. 2005;106:4389-96.
5. Paneesha S, Milligan DW. Stem cell transplantation for chronic lymphocytic leukaemia. Br J Haematol. 2005;128:145-52..
6. Dreger P, Brand R, Milligan D et al. Reduced-intensity conditioning lowers treatment-related mortality of allogeneic stem cell transplantation for chronic lymphocytic leukemia: a population-matched analysis. Leukemia. 2005;19:1029-33.
7. Brown JR, Kim-HT, Li S et al. Predictors of improved progression-free survival after nonmyeloablative allogeneic stem cell transplantation for advanced chronic lymphocytic leukemia. Biol Blood Marrow Transplant. 2006;12:1056-64.

That is very much a brief summary because I have limited space, but here are the figures in detail for allos and mini-allos:

John Gribben et al (Dana Farber)Blood 2005;106:4389-96. 25 sibling donor myeloablative allotransplants aged 28-55. Treatment related mortality was 24%. Overall survival at 6 years was 58%. Median progression free survival 2 years. 6 year progression-free survival was 24%.

Peter Dreger et al. (EBMT) Leukemia 2005; 19:1029-33. 82 myeloablative allografts (MA) and 73 with reduced intensity conditioning (RIC). At 2 years actuarial follow up there was no significant difference between MCA and RIC transplants in terms of treatment related mortality, event-free survival and overall survival, but there were fewer relapses in those receiving full dose conditioning (28% v 11%); but when other adverse prognostic factors were taken into consideration, treatment related mortality was less for the RIC patients by a factor of 0.4. Significantly, relapse was more likely if chronic graft-versus-host disease (GVHD)did not occur.

Jennifer Brown et al. (Dana Farber) Biol Blood Marrow Transplant. 2006;12:1056-64. 46 patients RIC allografts either sibling or matched unrelated donors. Age 35-67. Treatment related mortality was 17%, relapse at 2 years was 48%, 1 year progression-free survival was 44% and 2-year progression-free survival was 34%. One-year overall survival was 66% and two-year overall survival was 54%. This was a mixed bag of patients who had mostly relapsed after both chlorambucil and fludarabine therapy, although very few had p53 deletions. Better results were obtained in patients who entered their transplant with fewer than 5% CLL cells in their marrow, but only 11% of those with poor risk cytogenetics were still in remission at 2 years.

Julia Delgado et al. (UK transplant group). Blood 2006; 107:1724-30. 41 Campath-based mini-allos in patients aged 37-67. Transplant-related mortality 26%. Overall survival at 2 years 51%. Acute GVHD in 41%, chronic GVHD in 33%. Of 11 patients refractory to fludarabine, 2 remain alive in CR, one alive with molecular relapse, one alive with graft failure and 7 are dead. Donor lymphocyte infusions were tried in 9 relapsing patients but produced a sustained response in only 3.

Mohamed Sorror et al (Seattle) J Clin Oncol 2005; 23:3819-29. 64 patients received RIC allografts. Mortality at 2 years was 40%, half due to treatment; half due to relapse; 2-year relapse free survival was 52% and overall survival 60%. Chronic GVHD occurred in 39%.

Dolores Caballaro et al (Spain). Clin Cancer Res 2005; 11:7757-63. 30 patients aged 35-67 receiving RIC allos. Of the 30 patients, 2 died early, 6 more died in the first 2 years without relapsing, 22 patients (72%)remain alive and in remission at 4 years. These results are better than in other series; are there any factors that explain this? Eight patients had del 11q and 6 has del 17p. These patients seem to have done as well as the others. Having had more than two lines of treatment before transplant was an adverse factor. The conditioning regimen was fludarabine 150mg plus melphalan 140 mg (both per sq meter) in the majority of cases.

My conclusions on bone marrow transplantation for CLL are as follows: All transplant procedures on CLL patients are experimental procedures. Granted that it is only applied to patients with the poorest risk, but in most series 40% of patients are dead within 2 years of receiving the transplant. Stem cell autografting works well with patients with mutated VH genes (who may not really need it) but poorly in patients with unmutated VH genes (though perhaps better than conventional chemotherapy would. For these patients an immunological approach might be better.

Originally, allografting was restricted to very young patients so that it had little application in CLL. However, reduced intensity conditioning has extended the age range (up to 67) and made unrelated donor transplants feasible. Nevertheless the mortality associated with the procedure is still around 40% at two years, and in those patients who survive there is a high incidence of chronic GVHD. If it is restricted to patients who are refractory to other treatments, the outcome is even worse, but still probably better than with most other treatments. Were it used earlier in the disease would the outcome be better? That is one of the questions that needs to be tested in clinical trials.


Anonymous said...

One wonders if it would be ethical to perform an allo transplant early in the disease when other treatment that can give remission are available.

It would also be interesting to see the overall survival rates at five years; that is one benchmark for cancer patient studies.

Terry Hamblin said...

Exactly. Allotransplantation is an experimental technique. We need long term follow up.