Leukemia (2005) 19, 504–506 & 2005 Nature Publishing Group All rights reserved 0887-6924/05 $30.00 www.nature.com/leu
DEBATE ROUND TABLE Full donor chimerism by day 30 after allogeneic peripheral blood progenitor cell transplantation is associated with a low risk of relapse in pediatric patients with hematological malignancies A Lassaletta1, M Ramı´rez1, JM Montero1, M Gonza´lez-Vicent1, A Balas2, L Madero1 and MA´ Dı´az1 Servicio de Oncohematologı´a y Trasplante Hematopoye´tico, Hospital Infantil ‘Nin˜o Jesu´s’, Madrid, Spain; and 2Centro de Trasfusio´n Comunidad de Madrid, Madrid, Spain 1
Leukemia (2005) 19, 504–506. doi:10.1038/sj.leu.2403692 Published online 24 February 2005
Despite the many reports available on chimerism status after allogeneic hematopoietic transplantation, few studies have focused on chimerism using peripheral blood progenitor cell (PBPC) alone as source of hematopoietic stem cells, either adult or children.1–3 We conducted a retrospective study in 39 children with leukemia assessing whether the achievement of early (day þ 30 after allogeneic PBPCT) full donor chimerism status would allow us to separate children at high or low risk of relapse. The main characteristics of patients, donors and transplantation are shown in Table 1. Informed consent was obtained according to institutional guidelines for all procedures. The clinical protocols for mobilization, apheresis and transplantation were approved by the Institutional Review Board. Details of mobilization, apheresis and transplantation procedures have been reported elsewhere.4 Chimerism studies were carried out on genomic DNA obtained from peripheral blood (PB) or bone marrow (BM) samples, taken at the time of neutrophil engraftment, on day þ 30, and 3, 9 and 12 months after transplantation. In addition, PB or BM samples were taken depending on clinical events following transplantation. Samples were amplified by polymerase chain reaction (PCR) with a panel of six single tandem repeat (STR) and variable number of tandem repeat (VNTR) markers.3 Patients were closely followed and clinically evaluated daily. Time to neutrophil and platelet engraftment were recorded. Acute and/or chronic graft-versushost disease (GVHD) were diagnosed clinically and by pathology examination of a skin biopsy when required. Complete donor chimerism (CC) was defined as the presence of 99% or higher donor DNA as detected by the PCR-STR assay. Mixed chimerism (MC) was defined as at least 1% recipient DNA as detected by the PCR-STR assay. PBPC provided a rapid acquisition of full donor chimerism early after transplantation. In all, 27 patients (69.2%) showed CC by day 30 after transplantation. The median time to achieve CC was 15 days (range 8–750) (Figure 1a). CC was documented in 33 patients (84.6%) sometime during the follow-up. In 6 patients (15.4%), CC was never reached. The median donor cell percentage in MC patients was 97% (range 80–98%). The only one variable that had a significant influence on chimerism status was the number of CD34 þ cells infused, either in univariate or in multivariate Correspondence: Dr MA Dı´az, Servicio de Oncohematologı´a y Trasplante Hematopoye´tico, Hospital Infantil ‘Nin˜o Jesu´s’, Mene´ndez Pelayo 65, Madrid 28009, Madrid, Spain; Fax: 34-91-5035902; E-mail:
[email protected] Received 28 June 2004; accepted 23 December 2004; Published online 24 February 2005
analysis (P ¼ 0.02). Moreover, when the CD34 þ cell dose was analyzed dichotomously above or below 5 106/kg recipient body weight, this influence was more significant (P ¼ 0.009). The high numbers of CD34 þ cells infused in our series are likely responsible for the lack of statistical significance of other classical variables. We used unmanipulated PBPC, but a similar finding has been observed using CD34 þ selected PB cells.2 Table 1
Patients, donor and graft characteristics
Patients Number of patients Age (years) Sex (male/female)
39 8 (1–16) 22/17
Donors Age Sex (male/female)
13 (1–40) 12/27
CMV serologic status Patient seronegative with negative donor Other combinations
3 36
Diagnosis Acute lymphoblastic leukemia 25 Acute myeloid leukemia/myelodisplastic syndrome 8 Chronic myelogenous leukemia 6 Disease status at transplantation Early Intermediate Advanced
19 10 10
Conditioning regimen TBI-based Non TBI-based
17 22
GvHD Prophylaxis CsA CsA+MTX CsA+MP
15 18 6
Number of CD34 106/Kg infused Median (range) Number of CD3 108/Kg infused Median (range) Follow-up for survivors (months) Median (range)
5.9 (2.01–19.3) 5.34 (1.2–12.1) 36 (1.5–108)
CMV, cytomegalovirus; TBI, total body irradiation; CsA+MTX, cyclosporine A and short methotrexate; GvHD, graft-versus-host disease. Disease status: Early; first complete remission or first chronic phase, Intermediate; second complete remission, Advanced; beyond second complete remission, persistent disease, blast crisis or second chronic phase.
Chimerism after Allo-PBPCT in children A Lassaletta et al
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Figure 1 (a) Probability of complete chimerism after allogeneic PBPC transplantation. Median time to CC was 15 days. In all, 27 patients (69.2%) achieved CC by day þ 30. (b). Probability of relapse after allogeneic PBPC transplantation according to donor chimerism status by day þ 30, for MC patients was 54.5715 vs 20.879.6% for CC patients (P ¼ 0.004).
Chimerism status at day þ 30 had a predictive value for relapse. We found that patients who were in CC by day þ 30 had a lower probability of relapse than those who were not (54.5715% vs 20.879.6%; HR: 4.98; 95% CI 2.04–43.57; P ¼ 0.004) (Figure 1b). Overall, 10 patients relapsed (25.6%), with a median time of 127 days (range 50–1290). Six of those 10 patients who relapsed did not achieve CC by day þ 30. The level of MC of relapsing patients was 5% (range 0–17%) on day þ 30, whereas it was 1% (range 0–7%) in patients who did not relapsed. Six patients who presented MC by day þ 30 achieved CC during the follow-up. Only one of these six patients did relapse, while only one patient that presented CC by day þ 30 developed MC during the follow-up, and then relapsed. The pattern of relapse was different depending upon whether patients had or did not have CC by day þ 30. All leukemic relapses among patients who were MC by day þ 30 occured during the first year post-transplant, whereas two patients with CC by day þ 30 relapsed during the first year and two relapsed in the fourth year after transplant (Figure 1b). MC by day þ 30, the number of CD34 þ cells infused and absence of chronic GVHD were significantly associated with a higher probability of relapse in univariate analysis. A trend toward higher relapse incidence was observed in patients transplanted in more advanced phase of disease (P ¼ 0.06). The multivariate analysis showed that MC by day þ 30, absence of chronic GVHD and the disease status at transplantation were significant risk factors for relapse. The predictive role of
chimerism status for detecting relapsing disease is one of the most debatable issues after hematopoietic stem cell transplantation in patients with leukemia.5 Some of the conflicting results may be due to the different methods used for chimerism analysis, the different type of stem cell sources and the use of T lymphocyte-depleted grafts among other factors. Many authors agree that the presence of increasing MC is strongly associated with leukemia relapse.5,6 MC might be due to the recurrence of the disease, something that could be clarified with concurrent MRD analysis. Unfortunately, specific molecular markers are not always available in these patients. So, patients at risk of relapse should be monitored in short periods of time, but this is expensive, time-consuming and not always rewarding. The median follow-up for survivors was 36 months (range 6– 108). In all, 14 patients (35.8%) died, 10 patients because of disease and four because of transplant-related toxicity. The status of CC by day þ 30 was significantly related with the development of chronic GVHD in our series. Patients who presented CC by day þ 30 had a probability of developing chronic GVHD of 80.878%, whereas the probability of patients with MC by day þ 30 was 48717% (P ¼ 0.04). Although patients with CC by day þ 30 had a lower probability of relapse, we did not find any statistical differences in the event-free survival between patients with CC and MC by day þ 30. In our work, the patients in CC by day þ 30 had a higher transplantrelated mortality (TRM) than those in MC, mainly due to GVHD. This fact explains that the fewer incidences of relapses did not result in a better survival. Patients who develop chronic GVHD have been related with a lower risk of relapse after allogeneic transplantation, either using BM or PBPC.6,7 This could be due to a protracted graft-versus-leukemia effect by donor cells in chronic GVHD. In fact, PBPC have been considered most appropriated than BM for transplantation in patients with advanced diseases because the higher incidence of chronic GVHD resulted in a better long-term survival.8,9 We may conclude that the analysis of chimerism kinetic would help clinicians in anticipating the post-day þ 30 major challenges: relapse for patients with MC or GVHD for patients with CC. This fact may be used to design a timely implementation of post-transplant measures in the group of patients with MC by day þ 30, such as faster tapering off immunosuppression, donor lymphocyte infusion and more frequent monitoring of chimerism. We are aware that the results of the present study should be taken with caution due to its retrospective nature, but further studies will clarify this interesting question.
References 1 Valcarcel D, Martino R, Caballero D, Mateos MV, Perez-Simon JA, Canals C et al. Chimerism analysis following allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning. Bone Marrow Transplant 2003; 31: 387–392. 2 Briones J, Urbano-Ispizua A, Lawler M, Rozman C, Gardiner N, Marin P et al. High frequency of donor chimerism after allogeneic transplantation of CD34+-selected peripheral blood cells. Exp Hematol 1998; 26: 415–420. 3 Dubovsky J, Daxberger H, Fritsch G, Printz D, Peters C, Matthes S et al. Kinetics of chimerism during the early post-transplant period in pediatric patients with malignant and non-malignant hematologic disorders: implications for timely detection of engraftment, graft failure and rejection. Leukemia 1999; 13: 2060–2069. 4 Diaz MA, Sevilla J, de la Rubia J, Verdeguer A, Espigado I, Vicent MG et al. Factors predicting peripheral blood progenitor cell collection from pediatric donors for allogeneic transplantation. Haematologica 2003; 88: 919–922. 5 Bader P, Niethammer D, Willasch A, Kreyenberg H, Klingebiel T. How and when should we monitor chimerism after allogeneic Leukemia
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