Role of Allogeneic Hematopoietic Stem-Cell Transplantation in Chronic Lymphocytic Leukemia

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Journal of Clinical Oncology, Vol 26, No 30 (October 20), 2008: pp. 4864-4865

Role of Allogeneic Hematopoietic Stem-Cell Transplantation in Chronic

Lymphocytic Leukemia

G. Gribben

Institute of Cancer, Barts and The London School of Medicine, London, United

Kingdom

The use of combination chemotherapy and chemoimmunotherapy for the treatment of

chronic lymphocytic leukemia (CLL) has resulted in dramatically improved

complete remission (CR) rates and prolongation of remission of disease. However,

there is no evidence to date that these treatments are curative; all patients

invariably experience relapse and subsequently develop resistance to

chemotherapy.1 CLL is an indolent disease, but once patients become fludarabine

refractory, their prognosis is dismal, with a median survival time of less than

1 year.2

In other hematologic diseases, the rational for hematopoietic stem-cell

transplantation (SCT) has been demonstrated in randomized clinical trials

demonstrating a survival advantage after SCT compared with chemotherapy. To

date, no such studies have been performed in CLL, but a number of phase II

studies have been performed in CLL to determine whether SCT has curative

potential. High-dose therapy with autologous SCT is feasible in CLL but does not

seem to be curative, and the major problem remains relapse of disease and late

toxicities.3,4 Myeloablative allogeneic SCT is associated with a high morbidity

and mortality; registry data demonstrate that treatment-related mortality (TRM)

is unacceptably high, with rates of up to 50% reported.5 Despite the high TRM,

patients who do survive can have long-term disease control, with actuarial

overall and event-free survival rates of almost 40% at 5 years. The major

advantage of the use of allogeneic SCT seems to be the potential for a

graft-versus-leukemia (GVL) effect. A strong GVL effect has been noted, with

patients developing acute or chronic graft-versus-host disease (GVHD) having

near complete protection from relapse.6

Most patients with CLL are too elderly to consider high-dose therapy and SCT

because the median age of presentation is between 65 and 70 years. More than 90%

of younger patients will die as a result of their CLL,7 unlike older patients

who often die of comorbidity not associated with CLL. Therefore, there has been

considerable interest in the use of reduced-intensity conditioning SCT

approaches, which may be more suitable to allow the use of SCT in older patients

with CLL. The approach could allow the use of SCT in older patients, decrease

the TRM,8 and still allow exploitation of the GVL effect to induce long-term

remission or even cure. Despite encouraging initial results, the follow-up of

most clinical trials of reduced-intensity conditioning SCT has been too short to

assess whether this approach could cure CLL.

In the current issue of Journal of Clinical Oncology, long-term follow-up is

reported in 82 CLL patients who underwent reduced-intensity conditioning SCT

using total-body irradiation (2 Gy) with or without fludarabine, with 52

patients using related donors and 30 patients using unrelated donors.9 At 5

years, 50% of patients were alive and 39% were free of disease, but this success

did not come without a high price. The nonrelapse mortality rate remains high at

23%, and GVHD remains a considerable problem. Almost 50% of patients developed

chronic extensive GVHD. The median duration of immunosuppressive treatment for

GVHD was 25 months, with some patients requiring more than 5 years of treatment,

and one patient in four remains on immunosuppressive therapy. In the present

study, presence of bulk disease and presence of comorbidity were risk factors

for poor outcome.9

Although there are always concerns regarding some degree of patient selection in

nonrandomized clinical trials comparing SCT with alternative therapy, 87% of the

patients in the study by Sorror et al9 had documented fludarabine-refractory

disease, so it seems highly unlikely that such durable responses could have been

obtained in this patient population without the use of SCT. There is still

plenty of room for improvement, and longer follow-up is required to determine

whether there really is a plateau on the overall and event-free survival curves.

Questions remain regarding appropriate patient selection for consideration of

SCT and the timing of SCT in the clinical course of the disease, the ideal

conditioning regimen, optimal post-transplantation immunosuppressive therapy,

and how best to exploit the GVL effect without concomitant morbidity from GVHD.

Whereas improved disease control might be achieved by increasing the intensity

of the conditioning regimen, this might also lead to increased TRM and increased

GVHD. Specific immune manipulation of the donor cells to engender more GVL is

currently under investigation but remains experimental. In all hematologic

disorders, improved outcomes after allogeneic SCT are seen when patients undergo

transplantation earlier in their disease course and before their disease has

become refractory. It is intriguing to speculate whether results could be

improved by judicious selection of high-risk patients before the disease becomes

fludarabine refractory, so that patients could undergo SCT without bulk disease.

In CLL, as in all other diseases, the role of SCT must always be considered by

comparing the risk of undergoing SCT with the risk from the underlying disease.

SCT is clearly not an appropriate option for patients with indolent disease, but

relatively younger patients with poor prognosis can be identified for whom SCT

may offer a chance of cure. Recently, major advances have been made in

establishing prognostic factors that help to identify patients who are likely to

follow an aggressive course or in whom chemotherapy resistance will reduce the

likelihood of durable responses to chemotherapy. It remains unclear whether a

GVL effect can overcome these poor prognostic biomarkers of disease. Whereas

patients with unmutated immunoglobulin gene rearrangements have poorer outcome

after autologous SCT, this adverse event can be overcome by the GVL effect.10 In

the present report,9 expression of high levels of CD38 and presence of high-risk

cytogenetic factors were not associated with poor outcome, but further study

will be required to assess this. A working party has established European Group

for Blood and Marrow Transplantation guidelines outlining the indications for

SCT in CLL.11 The guidelines conclude that there is evidence for the efficacy of

allogeneic SCT in CLL and that this is indicated in high-risk CLL patents. The

consensus of the working group was that allogeneic SCT is recommended early in

the disease course for young patients with CLL who do not achieve CR or who

experience progression within 12 months after purine analogs and in patients who

experience relapse within 24 months after having achieved a response with purine

analog-based combination therapy or autologous transplantation. Precisely what

other factors are defined as high risk remains unclear, but patients with p53

deletions or mutations are considered candidates in first remission. Ongoing

prospective clinical studies will be required to determine the specific risk

factors that identify patients at sufficiently high risk to merit use of

allogeneic SCT in first CR. The Cancer and Leukemia Group B and the Blood and

Marrow Transplant Clinical Trials Network plan to examine the role of

reduced-intensity conditioning SCT in patients with relapsed disease, as well as

in high-risk patients in first response. Inherent in this approach is the

correlative science that is planned in collaboration with the CLL Research

Consortium.

Future approaches to the management of this disease must always take into

account the balance between the increased morbidity and mortality of SCT in CLL

and the curative potential that these approaches potentially offer. In the

absence of any other treatment modalities currently capable of improving outcome

in this disease, the treatment of choice for younger patients with poor risk CLL

may indeed be allogeneic SCT. Therefore, continued enrollment of appropriate

patients into well-designed clinical trials is vital for further progress.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following

author(s) indicated a financial or other interest that is relevant to the

subject matter under consideration in this article. Certain relationships marked

with a " U " are those for which no compensation was received; those relationships

marked with a " C " were compensated. For a detailed description of the disclosure

categories, or for more information about ASCO's conflict of interest policy,

please refer to the Author Disclosure Declaration and the Disclosures of

Potential Conflicts of Interest section in Information for Contributors.

Employment or Leadership Position: None Consultant or Advisory Role: None Stock

Ownership: None Honoraria: G. Gribben, Roche, Celgene Research Funding:

None Expert Testimony: None Other Remuneration: None

NOTES

published online ahead of print at www.jco.org on September 15, 2008

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