|
|
 Previous Article | Table of Contents | Next Article 
Blood, 1 March 2002, Vol. 99, No. 5, pp. 1873-1874
CORRESPONDENCE
To the editor:
Different clinical value of minimal residual disease after
autologous and allogeneic stem cell transplantation for chronic
lymphocytic leukemia
The clinical significance of minimal residual disease (MRD)
after treatment for chronic lymphocytic leukemia (CLL) has recently been addressed by Rawstron et al1 in an analysis of 25 patients in complete remission (CR) after autologous stem cell
transplantation or treatment with alemtuzumab (CAMPATH-1H). In
this study the authors emphasized the applicability of a
multiparametric flow cytometry strategy for a sensitive detection of
CLL residual population using a 2-step acquisition protocol and a
4-color combination, and they observed that the persistence of MRD
after treatment correlated with a shorter duration of the response and
survival compared to patients achieving MRD CR. We would like to comment on this important issue on the basis of
updated results in 32 patients with CLL who received stem cell
transplants at our institution.2 The results show that the
predictive value of MRD depends on the type of stem cell
transplantation (autologous or allogeneic). MRD was detected by the cytofluorometric analysis of peripheral blood
and bone marrow samples using a triple combination strategy (CD20/CD5/CD19, CD22/CD23/CD19, and kappa/lambda/CD19), with a level of
sensitivity of 5 × 105 and performed in
parallel with nonspecific allele CDR3 polymerase chain reaction (PCR)
analysis (data not shown). Results are summarized in Table 1. In the
group of patients autografted (n = 18) MRD persisted in 7 patients
(39%) at first assessment, performed 3 months after transplantation,
and a clinical relapse was observed in 6 patients after a median
follow-up of 15.5 months (range, 9-20 months). Of note, a steady
increase in the MRD level was observed in all MRD+
patients, although the rate of increase varied among patients. In
contrast, only 1 of the 11 patients achieving a MRD
status after transplantation has progressed (median follow-up, 28 months; range, 5-62 months), thus translating into a
significantly lower risk of relapse (P < .01; Figure
1). In addition, reappearance of MRD has
been observed in 3 patients (at 11, 31, and 43 months after
transplantation), although only 1 of these patients has relapsed (at 36 months from transplantation). Therefore, MRD status after
autotransplantation anticipates clinical progression in most patients,
with an 87% (SE ± 12%) actuarial risk of relapse at 25 months after MRD detection.
View larger version (11K):
[in this window]
[in a new window]
| Figure 1.
Clinical outcome and MRD response.
Patients in CR but are MRD+ have a higher risk of
progression than those in CR with no detectable MRD (log-rank test;
P < .01).
|
|
In the allografted group of patients (n = 14), MRD was observed in 4 of 10 responding patients surviving for at least 3 months. Remarkably,
disease progression has not been observed in any of these patients
after a median follow-up of 38 months (range, 6-79 months). Among these
patients, a delayed clearance of MRD was observed in 1 patient, up to
12 months after transplantation, whereas in 2 patients an intermittent
detection of MRD has been observed during follow-up (47 and 79 months,
respectively) and the remaining patient died due to a
transplantation-related cause more than 6 months afterward without
evidence of disease at the necropsy. Quantification of MRD positive
samples after allotransplantation showed a low level of detectable CLL
in all 4 patients, below 1 cell/µL in peripheral blood and less than
0.5% of total bone marrow cellularity. On the other hand, none of 6 patients achieving a MRD status after allogeneic
transplantation have presented MRD relapse (median follow-up, 59 months; range, 8-120 months). In summary, the persistence of MRD in CLL patients appears to have
different implications depending on the type of transplantation, autologous or allogeneic. Thus, while persistence of MRD after autologous transplantations is highly predictive of clinical
progression, the detection of MRD after allogeneic transplantations
does not necessarily predict clinical relapse. Moreover, delayed
responses or persistently low-level MRD can be observed in some
patients, thus indicating a possible graft-versus-leukemia
effect.3-6 Therefore, sequential quantitative strategies
such as real-time PCR7 or multiparametric flow cytometry
analysis are required to define more accurately the clinical
significance of MRD status in CLL patients undergoing intensive
treatments, particularly stem cell transplantations. Finally, this type
of study might be useful for designing posttransplantation therapy
based on MRD status.
Jordi Esteve, Neus Villamor, Dolors Colomer, and Emili Montserrat
Correspondence: Jordi Esteve, Hematology Department, Hospital
Clínic, Villarroel 170, 08036 Barcelona, Spain; e-mail:
jesteve{at}clinic.ub.es
Acknowledgments
This work was partially supported by a grant from Fondo de
Investigaciones Sanitarias, Madrid, Spain (FIS 01/1581).
References
1.
Rawstron AC, Kennedy B, Evans PAS, et al.
Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy.
Blood.
2001;98:29-35[Abstract/Free Full Text].
2.
Esteve J, Villamor N, Colomer D, et al.
Stem cell transplantation for chronic lymphocytic leukemia: different outcome after autologous and allogeneic transplantation and correlation with minimal residual disease status.
Leukemia.
2001;15:445-451[CrossRef][Medline]
[Order article via Infotrieve].
3.
Mattsson J, Uzunel M, Remberger M, et al.
Minimal residual disease is common after allogeneic stem-cell transplantation in patients with B cell chronic lymphocytic leukemia and may be controlled by graft-versus-host-disease.
Leukemia.
2000;14:247-254[CrossRef][Medline]
[Order article via Infotrieve].
4.
Mehta J, Powles R, Singhal S, Iveson T, Treleaven J, Catovsky D.
Clinical and hematological response of chronic lymphocytic leukemia and prolymphocytic leukemia persisting after allogeneic bone marrow transplantation with the onset of acute-versus-host disease: possible role of graft-versus-leukemia.
Bone Marrow Transplant.
1996;17:371-375[Medline]
[Order article via Infotrieve].
5.
Rondon G, Giralt S, Huh Y, et al.
Graft-versus-leukemia effect after allogeneic bone marrow transplantation for chronic lymphocytic leukemia.
Bone Marrow Transplant.
1996;18:669-672[Medline]
[Order article via Infotrieve].
6.
Jarque I, Palau J, Sanz GF, et al.
Delayed complete response after allogeneic bone marrow transplantation in chronic lymphocytic leukemia.
Blood.
1993;82:1036-1037[Free Full Text].
7.
Pfitzner T, Engert A, Wittor H, et al.
A real-time PCR assay for the quantification of residual malignant cells in B cell chronic lymphatic leukemia.
Leukemia.
2000;14:754-766[CrossRef][Medline]
[Order article via Infotrieve].
Response:
Interpretation of sequential minimal residual disease
assessment in chronic lymphocytic leukemia
Esteve et al have presented interesting and informative
observations regarding the assessment of minimal residual disease (MRD)
following intensive therapy for chronic lymphocytic leukemia (CLL).
Their report is consistent with our own experience in that the
eradication of detectable disease in CLL is associated with prolonged
progression-free survival. We also agree that CLL patients who have
detectable MRD at any time following monoclonal antibody therapy or
autologous stem cell transplantation will experience progressively
increasing levels of CLL in their peripheral blood and will eventually
relapse clinically. To determine whether it is possible to predict the
time at which further therapy will be required, we have assessed
sequential samples in 45 patients for up to 5 years following treatment
with Alemtuzumab (MabCampath) for refractory CLL (manuscript in
preparation). In summary, following Alemtuzumab therapy the kinetics of
disease progression is biphasic in most (24 of 34) patients: there is a
rapid increase in peripheral blood CLL cells within 2 months of
stopping therapy, followed by a second phase characterized by more
gradual increase in CLL cells. It appears that the first phase, with
rapidly increasing peripheral CLL cells, is due to redistribution of
CLL cells from bone marrow or lymphoid tissue to peripheral blood,
while the second phase represents expansion of absolute numbers of CLL
cells. During this second phase it is possible to calculate a doubling time for the CLL cells (in this series it was a median of 30 days [range, 5-289 days]), which can be used to predict when an individual with CLL is likely to progress clinically. It is of considerable importance that Esteve et al have demonstrated
persistent but stable levels of CLL in patients after allogeneic
transplantation. This indicates that there must be continuing
suppression of the CLL clone following an allograft, and therefore that
graft-versus-leukemia is a clinically significant phenomenon in this
setting. We therefore agree that to understand the clinical implication
of detectable MRD after allograft in an individual patient requires
sequential studies and should not in itself be used to define therapy.
But we believe that both our own data and the data of Esteve et al
indicate that after Alemtuzumab and/or after autograft, the presence of
detectable MRD is always indicative of progressive disease and that the
tumor burden at the end of therapy is predictive of outcome.
Andy C. Rawstron and Peter Hillmen
Correspondence: Andy C. Rawstron, HMDS, Academic Unit of
Haematology and Oncology, Algernon Firth Building, University of Leeds,
Leeds LS1 3EX, United Kingdom; e-mail:
andy.rawstron{at}hmds.org.uk
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
-
Quantitation of minimal disease levels in chronic lymphocytic leukemia using a sensitive flow cytometric assay improves the prediction of outcome and can be used to optimize therapy
- Andy C. Rawstron, Ben Kennedy, Paul A. S. Evans, Faith E. Davies, Stephen J. Richards, Andy P. Haynes, Nigel H. Russell, Geoff Hale, Gareth J. Morgan, Andrew S. Jack, and Peter Hillmen
Blood 2001 98: 29-35.
[Abstract]
[Full Text]
[PDF]
This article has been cited by other articles:
|
|
|
|
 
M. C. Bene and J. S. Kaeda
How and why minimal residual disease studies are necessary in leukemia: a review from WP10 and WP12 of the European LeukaemiaNet
Haematologica,
August 1, 2009;
94(8):
1135 - 1150.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Farina, C. Carniti, A. Dodero, A. Vendramin, A. Raganato, F. Spina, F. Patriarca, F. Narni, F. Benedetti, A. Olivieri, et al.
Qualitative and quantitative polymerase chain reaction monitoring of minimal residual disease in relapsed chronic lymphocytic leukemia: early assessment can predict long-term outcome after reduced intensity allogeneic transplantation
Haematologica,
May 1, 2009;
94(5):
654 - 662.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. W. L. Yee and S. M. O'Brien
Chronic Lymphocytic Leukemia: Diagnosis and Treatment
Mayo Clin. Proc.,
August 1, 2006;
81(8):
1105 - 1129.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Moreno, N. Villamor, D. Colomer, J. Esteve, E. Gine, A. Muntanola, E. Campo, F. Bosch, and E. Montserrat
Clinical significance of minimal residual disease, as assessed by different techniques, after stem cell transplantation for chronic lymphocytic leukemia
Blood,
June 1, 2006;
107(11):
4563 - 4569.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Caballero, J. A. Garcia-Marco, R. Martino, V. Mateos, J. M. Ribera, J. Sarra, A. Leon, G. Sanz, J. de la Serna, R. Cabrera, et al.
Allogeneic Transplant with Reduced Intensity Conditioning Regimens may Overcome the Poor Prognosis of B-Cell Chronic Lymphocytic Leukemia with Unmutated Immunoglobulin Variable Heavy-Chain Gene and Chromosomal Abnormalities (11q- and 17p-)
Clin. Cancer Res.,
November 1, 2005;
11(21):
7757 - 7763.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Moreno, N. Villamor, D. Colomer, J. Esteve, R. Martino, J. Nomdedeu, F. Bosch, A. Lopez-Guillermo, E. Campo, J. Sierra, et al.
Allogeneic Stem-Cell Transplantation May Overcome the Adverse Prognosis of Unmutated VH Gene in Patients With Chronic Lymphocytic Leukemia
J. Clin. Oncol.,
May 20, 2005;
23(15):
3433 - 3438.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. Dreger, S. Stilgenbauer, A. Benner, M. Ritgen, A. Krober, M. Kneba, N. Schmitz, and H. Dohner
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,
April 1, 2004;
103(7):
2850 - 2858.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
