Aims of this study were to verify whether reduction in transplant-related mortality (TRM) of children with acute lymphoblastic leukemia (ALL) in second complete remission (CR) given allogeneic hematopoietic stem cell transplantation (HSCT) from unrelated volunteers has occurred over time and to investigate the role of other variables on the probabilities of relapse, TRM and event-free survival (EFS). We compared results obtained in 26 children given HSCT before January 1998 with those of 37 patients transplanted beyond that date. In all donor–recipient pairs, histocompatibility was determined by serology for HLA-A and -B antigens and by high-resolution DNA typing for DRB1 antigen. High-resolution molecular typing of HLA class I antigens was employed in 20 of the 37 children transplanted more recently. Probability of both acute and chronic GVHD was comparable in the two groups of patients. In multivariate analysis, children transplanted before January 1998, those with T-lineage ALL and those experiencing grade II–IV acute GVHD had a higher relative risk of TRM at 6 months after transplantation. Relapse rate was unfavorably affected by a time interval between diagnosis and relapse <30 months. The 2-year probability of EFS for children transplanted before and after 1 January 1998 was 27% (10–44) and 58% (42–75), respectively (P = 0.02), this difference remaining significant in multivariate analysis. EFS of unrelated donor HSCT in children with ALL in second CR has improved in the last few years, mainly due to a decreased TRM. This information is of value for counseling of patients with relapsed ALL.
Current regimens cure up to 75% of children with acute lymphoblastic leukemia (ALL), disease recurrence remaining the main cause of treatment failure. Allogeneic hematopoietic stem cell transplantation (HSCT) is being increasingly used for pediatric patients with ALL in second complete remission (CR) after marrow relapse.1,2,3 Several studies have documented that allogeneic HSCT from matched family donors (MFD) offers high chances of rescuing these patients and the results in terms of event-free survival (EFS) are superior to those achieved with either a second course of chemotherapy or with an autologous transplant.4,5,6 Unfortunately, 70% of the children who might benefit from this therapy lack an HLA-identical family donor.
With the establishment of bone marrow donor registries now including more than 7 million unrelated volunteers worldwide, many patients who need an allogeneic HSCT have been able to locate a suitable unrelated donor. However, mainly because of HLA polymorphism and the limits of conventional techniques for HLA-typing, increased difficulties for engraftment and augmented incidence of both acute and chronic graft-versus-host disease (GVHD) have been reported in recipients of an unrelated donor allograft, which leads to results, in terms of EFS, inferior to those reported using a compatible sibling as donor.7,8,9,10,11,12,13 Recently, it has been demonstrated that a more precise characterization of HLA alleles using high-resolution typing for both class I and class II molecules may allow identification of the correlation between risk of developing immune-mediated complications or fatal events after the allograft and HLA disparity in donor–recipient pairs.14,15 Thus, better selection of unrelated donors, as well as refinements in both prophylaxis and treatment of GVHD, allow the hypothesis of improved outcome of patients given allograft from an unrelated volunteer over time. In order to test this hypothesis, we compared the outcome of allogeneic HSCT from unrelated donors for children with ALL in second CR, subdividing patients according to the year of transplant. We chose 1998, the year in which high-resolution molecular typing for both HLA class I and II antigens became available in most centers, for stratifying patients in to two groups: those transplanted before 1 January 1998 and those given the allograft beyond that date. Moreover, we evaluated the impact of other disease-, patient- and transplant-related factors on the probabilities of relapse, non leukemia-death and EFS.
Patients and methods
Between April 1992 and December 2000, 63 consecutive children (41 males and 22 females) with ALL in second CR after either an isolated or a combined marrow relapse were given allogeneic HSCT from an unrelated donor in one of the nine centers reporting data to the Registry of the AIEOP (Associazione Italiana di Ematologia e Oncologia Pediatrica). Information on these patients was collected through a data recording form about patient, disease, donor, number of cells infused, HLA typing and transplant outcome. Submitted data were reviewed by two physicians (AP and RR) and computerized error checks were performed to ensure data quality.
Twenty-six children were given HSCT before January 1998, whereas the remaining 37 patients were transplanted beyond that period. Details on patient and donor characteristics, pre-transplant disease history, conditioning regimen, GVHD prophylaxis, number of cells infused, as well as comparison between the two groups analyzed, are reported in Table 1. In all cases, children were transplanted with bone marrow cells.
Preparative regimens varied mainly according to patient age and transplant center protocols (Table 1). Fifty-eight patients received a preparative regimen containing total body irradiation (TBI), whereas in the five remaining children a chemotherapy-based myeloablative therapy was employed. In 47 children, TBI was associated with thiotepa and cyclophosphamide, as previously reported.3 Cyclosporine (CsA) and short-term methotrexate (MTX) were used for GVHD prophylaxis in 11 children, whereas the combination of CsA, MTX and either anti-lymphocyte globulin (ALG, 3.75 mg/kg from day −4 to day −2) or the monoclonal antibody Campath1-G (20 mg/day or 10 mg/day on days −3 and −2 for patients with a body weight greater or lower than 25 kg, respectively) was employed in 43 and 9 children, respectively. The two groups were comparable for all variables analyzed, with the exception of first-line chemotherapy protocol and GVHD prophylaxis. In fact, a higher number of children given HSCT before 1998 was treated with the combination of CsA, MTX and the monoclonal antibody Campath-1G as GVHD prophylaxis.
First-line chemotherapy was administered according to the AIEOP protocol for children with ALL (see also Table 1 for further details).16,17,18,19 Treatment for obtaining a second remission after relapse was heterogeneous, even though patients relapsing within 30 months after transplantation had more intensive therapies (data not shown).
Supportive therapy, as well as prophylaxis and treatment of infections was similar among centers participating in this study. Fifty out of the 63 patients were given recombinant human granulocyte colony-stimulating factor (rHuG-CSF) after transplantation. This growth factor was usually started 7 days after HSCT. A comparable number of subjects in the two groups received rHuG-CSF (data not shown). Cytomegalovirus (CMV) serological status was studied before transplantation in all donor–recipient pairs (see Table 1 for details). In all patients, the expression of pp65 human CMV matrix protein (antigenemia) was monitored in order to detect CMV reactivation.20 Patients experiencing reactivation of CMV infection were treated according to a strategy of pre-emptive therapy with ganciclovir or foscarnet at conventional dosage until antigenemia became negative.20
Unrelated donors were located through a network of national and international bone marrow donor registries as previously described.13 The median time between activation of donor search and HSCT was 4.8 months (range 2–14), with no difference between children transplanted before or beyond 1998 (data not shown). Twenty-four out of the 63 children were transplanted with donors of the Italian Bone Marrow Donor Registry (IBMDR). Two investigators (NS and FL) reviewed all data on HLA typing; queries concerning patient and donor typing were verified through the database of the IBMDR. In all donor–recipient pairs, histocompatibility was determined by serology for HLA-A and -B antigens and by DNA typing for DRB1 antigen and we defined this characterization of HLA antigens as conventional typing. In all cases, DRB1 typing was performed by high-resolution allelic technique. Since 1998, high resolution molecular typing has also been performed for HLA class I antigens in 20 of the 37 children transplanted beyond that date and we defined this characterization as high-resolution typing. High-resolution molecular typing of both class I and class II antigens was employed for prospectively choosing the best donor in these 20 cases. Transplants were classified as HLA-mismatched if the donor did not share HLA-A, -B or -DRB1 antigens or alleles of the recipient. Details on the distribution of patients according to the period of transplant, conventional or high-resolution HLA typing and HLA disparity are reported in Table 2.
Acute GVHD was diagnosed and graded by investigators at each transplant center according to previously reported criteria.21 All patients surviving more than 14 days after transplant were considered at risk for developing acute GVHD. Children alive 100 days post transplant with sustained donor engraftment were considered to be evaluable for chronic GVHD, which was classified according to previously reported criteria.22 Tissue biopsy samples were obtained to confirm diagnosis of GVHD whenever clinically indicated and feasible. Treatment of both acute and chronic GVHD was administered according to the protocols in use at each single institution.
Myeloid engraftment was defined as the first of 3 consecutive days when neutrophils were >0.5 × 109/l and platelet engraftment as the first of 7 consecutive days with an unsupported platelet count >50 × 109/l.
Time of relapse was calculated as interval between HSCT and disease recurrence, with censoring at death in complete remission. Transplant-related mortality (TRM) was defined as all causes of non-leukemia deaths. Overall survival was the time between transplantation and death due to any cause, whereas EFS was defined as the time interval from HSCT to first event (either relapse or death in complete remission whichever occurred first).
Since the BFM group has classified ALL relapses into four different groups of risk according to site of relapse, time from diagnosis to relapse and immune-phenotype, documenting a prognostic significance of this stratification,23 we also subdivided our children into three subgroups, namely S2, S3 and S4. Patients with T-lineage ALL experiencing marrow relapse, irrespective of the time interval between diagnosis and recurrence, as well as children with marrow relapse of B-lineage ALL occurring in the first 18 months after diagnosis belonged to the S4 group (17 cases). Patients with isolated marrow relapse of B-lineage ALL occurring after 18 months from diagnosis and within 6 months from treatment discontinuation were assigned to the S3 group (14 cases). The remaining 32 children belonged to the S2 group, which includes children with: (1) isolated or combined marrow relapse of B-lineage ALL occurring after 6 months from treatment discontinuation; and (2) combined marrow relapse of B-lineage ALL occurring after 18 months from diagnosis and within 6 months from treatment discontinuation. None of our children belonged to the S1 group of the BFM classification, which is associated with the best prognosis and includes patients with isolated extramedullary relapse occurring more than 6 months from treatment discontinuation.
Data were analyzed as of 30 June 2001. Patient-, disease- and transplant-related variables of the whole study population and of the two subgroups of patients (transplants performed before 1 January 1998 vs transplants performed after that date) were expressed as median and range or as percentage, as appropriate, and were compared using the Fisher exact test for categorical variables and the non parametric Mann–Whitney rank-sum test for continuous variables.
The following patient or graft characteristics were analyzed for their potential impact on outcome: sex, age, WBC count at diagnosis and relapse, immunophenotype, response to steroids (patients with less than 1000 blasts/mm3 after the first intrathecal injection of MTX and the first 7 days of prednisone treatment were defined as good responders and those with more than 1000 blasts/mm3 were considered poor responders), first line chemotherapy protocol, interval diagnosis–first relapse, interval first relapse–second remission, interval second remission–BMT, year of transplantation (transplants performed before 1 January 1998 vs those performed after 1 January 1998), conditioning regimen (TBI vs chemotherapy), number of mononuclear cells infused, donor–recipient pair HLA compatibility (HLA-identical vs 1 antigen-mismatched), BFM stratification for relapses, acute and chronic GVHD occurrence.
For this analysis, continuous variables were categorized as follows: each variable was first divided into four categories at the 25th, 50th and 75th percentiles. If the relative event rates (ratio of the observed number of events to the expected number of events in the category, assuming no variation across categories) in two or more adjacent categories (and the median times-to-events) were not different, these categories were grouped. If no clear pattern was observed for the primary outcomes, the median was taken as the cut point.24
Patients were censored at time of relapse or of last follow-up.25 The probability of EFS was estimated by the Kaplan–Meier method and expressed as percentage and 95% confidence limits (95% CL),26 while relapse incidence (RI) and TRM were expressed as cumulative incidence curves, in order to adjust the analysis for competing risks.27,28,29 The significance of differences between curves was estimated by the log–rank test (Mantel–Cox). All variables with a P value less than 0.05 in univariate analysis were included in a multivariate analysis performed using the Cox proportional hazard regression model and a backward selection procedure.30,31
Statistical analysis was performed using the SAS System (SAS, Cary, NC, USA) and the SPSS computer program (SPSS, Chicago, IL, USA).
Median follow-up for survivors in the two groups of patients transplanted before or beyond January 1998 is 63 (range 41–80) and 18 (range 7–38) months, respectively (P < 0.001). Median follow-up for deceased patients in the groups is 3.5 (range 1–41) and 3.5 (range 2–12) months, respectively (P = NS).
Engraftment and GVHD occurrence
All patients engrafted and the median time for neutrophil recovery was 17 days (range 12–34) and 15 days (range 10–24) for patients transplanted before and after 1998, respectively (P = 0.07); there was a trend for faster myeloid recovery in patients given rHuG-CSF (data not shown). Platelet engraftment was reached in 52 out of the 63 patients analyzed, the remaining 11 patients having died before achieving platelet recovery. No significant difference for platelet recovery was observed between the two groups, the median time for a self-sustained platelet count >50 × 109/l being 32 days (range 14–184) and 33 days (range 11–414) for patients given transplantation in the early and late period, respectively.
Grade II to IV acute GVHD developed in 35 (56%) patients. The cumulative incidence of developing grade II–IV acute GVHD in the two cohorts of children was 42% (15–68) and 65% (49–82), respectively (P = NS), whereas that of developing grade III–IV acute GVHD was 30% (4–56) and 27% (12–43), respectively (P = NS). Children given GVHD prophylaxis including CsA, short-term MTX and Campath-1G had a lower incidence of grade II–IV acute GVHD (20% (0–46)) as compared to children given CsA + short-term MTX (73% (47–100)) or CsA + short-term MTX + anti-lymphocyte globulin (60% (43–77)) (P = 0.04).
Seventeen (38%) out of the 45 patients at risk developed chronic GVHD, which was limited in 11 cases and extensive in the remaining six. The cumulative incidence of chronic GVHD occurrence was 35% (7–63) and 39% (20–58) for children transplanted before and beyond 1998, respectively (P = NS). In all cases, chronic GVHD followed acute GVHD.
Twenty patients (32%) died of transplant-related causes at a median of 3.5 months after transplantation (range 1–41). Details on the causes of death are reported in Table 3. The 100-day TRM probability was 36% (17–55) and 11% (1–22) for children transplanted before and after 1998, respectively (P = 0.01). Figure 1 shows that the 6-month TRM cumulative incidence was 38% (19–57) and 16% (4–29) for children transplanted before and after January 1998, respectively (P = 0.03). As four more patients died beyond 6 months after HSCT, ultimately, the probability of dying for transplant-related complications was 42% (20–62) and 24% (9–40) for patients belonging to the early and late transplant groups, respectively (P = 0.05). Table 4 lists probabilities of 6-month TRM, RI and EFS, calculated in univariate analysis. The 6-month TRM cumulative incidence for patients transplanted with a high-resolution 0–1 antigen/allele disparate donor was 11% (7–15), while it was 31% (17–45) for subjects transplanted with donors having a higher degree of mismatch or for whom high-resolution typing was not available (P = NS) (see Figure 2). Other variables, which influenced 6-month TRM were BFM class at relapse, time interval between diagnosis and relapse, immunophenotype of ALL and occurrence of grade III–IV acute GVHD. From the Cox model, we found that children transplanted before January 1998, those with T-lineage ALL and those experiencing grade III–IV acute GVHD had the highest probability of TRM (see Table 5 for further details).
Leukemia relapse after the allograft occurred in 14 patients (22%) at a median time of 7.5 months (range 1.8–18). There was no difference in the time of relapse between the two groups. Leukemia progression was the direct cause of death in 12 cases (also see Table 3 for further details). The cumulative incidence of leukemia relapse for children transplanted before and after January 1998 was 40% (15–64) and 15% (1–29), respectively (P = 0.09). In univariate analysis, the following variables predicted an increased risk of leukemia recurrence after the allograft: time interval between diagnosis and relapse less than 30 months (Figure 3), GVHD prophylaxis with CsA, short-term MTX and Campath-1G and S3 + S4 BFM classes at relapse (also see Table 4 for further details). Only an interval between diagnosis and relapse less than 30 months remained a predictive variable for an increased risk of relapse in multivariate analysis (also see Table 5).
Overall, 31 children remain alive after HSCT, the 5-year Kaplan–Meier estimate of survival being 41% (25–57). Twenty-nine out of the 63 patients (46%) are alive and leukemia-free. The 3-year cumulative probability of EFS is 40% (25–56) for the whole cohort of patients studied, while it is 58% (42–75) for patients given HSCT after January 1998, a value significantly better than the 27% (10–44) estimate for patients transplanted before 1998 (P = 0.02, see also Figure 4a). Univariate analysis of other factors related to patient, leukemia and transplant influencing EFS (Table 4) shows that a time interval between diagnosis of ALL and relapse <30 months, a WBC count at diagnosis greater than 100 × 109/l, T-lineage ALL and groups S3+S4 according to the BFM classification (Figure 4b) were associated with a worse outcome. Children experiencing grade II acute GVHD enjoyed a better outcome as compared to patients with either grade 0–I or grade III–IV acute GVHD (P = 0.04). The Kaplan–Meier estimante of EFS of patients transplanted with high-resolution 0–1 antigen/allele disparate donor was 60% (37–83), while it was 36% (20–52) for subjects transplanted with donors having a higher degree of mismatch or for whom high-resolution typing was not available (P = NS) (see Figure 4c).
The favorable influence of the period of transplantation was also evident in the subgroups of patients identified according both to BFM class at relapse and to the time interval between diagnosis and leukemia relapse (see Table 4 for details). Table 5 shows the variables associated with an increased risk of treatment failure in multivariate analysis; they were: S3+S4 BFM classes at relapse and transplant performed before January 1998. Three patients of this cohort had Ph+ ALL and two of them are alive and disease-free 14 and 27 months after transplantation, respectively. No child had t(4;11) translocation.
Median Karnofsky score of our patients surviving leukemia-free is 100%, only three children having a value below 90%.
Our study provides evidence that outcome of patients with ALL in second CR given HSCT from an unrelated donor is improving over time. In particular, the 58% 2-year EFS of our cohort of unrelated HSCT recipients transplanted after January 1998 is significantly better compared with the 27% 2-year EFS of children given the allograft in the early study period and compares favorably with the results reported in the studies by Balduzzi et al8 and Davies et al,9 who analyzed the outcome of children with acute leukemia given an unrelated, unmanipulated bone marrow transplantation. In the report of Balduzzi and colleagues,8 probabilities of disease-free survival and relapse of 15 patients with ALL in first or second CR analyzed together were 47% and 20%, respectively, whereas in the study of the Minneapolis group9 the 2-year EFS of 19 patients with ALL in either first or second CR was 21%. The EFS of our patients transplanted beyond January 1998 is also comparable to those obtained in single center studies on children with ALL given a T cell-depleted unrelated donor HSCT.32,33
Our results on the cohort transplanted more recently suggest that, in terms of ultimate outcome, using matched unrelated donors offers minimal or possibly no significant disadvantage as compared to employing an HLA-identical sibling. Support for this speculation is also provided by a study recently reported by the Nordic Pediatric Cooperative Group, which, in a comparative analysis on 65 children with ALL in second CR, documented a 39% and 54% 5-year EFS in the 37 recipients of sibling HSCT and in the 28 children given an unrelated donor allograft, respectively.34 Accordingly, it is reasonable to envisage that the same indications for HSCT may be applied regarding both HLA-identical sibling donors and matched unrelated volunteers.
Several factors may have contributed to the improved outcome of our children transplanted in the second part of the study. The possibility of selecting a donor using high-resolution molecular typing for both class I and class II HLA alleles has been suggested potentially to be able to decrease the risk of graft failure, GVHD and TRM.14,15 Although the outcome of our children in whom high-resolution molecular typing of both class I and class II HLA antigens was performed is not statistically different from that of patients not analyzed in this manner, there is a favorable trend for the former cohort of patients (see Figures 2 and 4c). Noteworthy is that none of the nine patients resulting HLA-identical using high-resolution typing of both class I and class II HLA alleles with their donor died of transplant-related causes. Moreover, matching with high-resolution typing of the other HLA alleles may allow selection of unrelated donors who really have a single disparity for class I or even class II HLA molecules. Donors with a single HLA class I disparity have been reported by Petersdorf et al15 to provide results in terms of ultimate outcome comparable to those obtained using fully matched donors and their use can both increase the number of patients given HSCT and shorten the time needed to locate a suitable donor in a setting where disease progression might not allow an extended period of time for finding a donor. In fact, a long time interval between initial search still represents one of the major limitations of unrelated donor HSCT, since during the search process a relevant proportion of patients experience further relapse or loose their eligibility for an allograft. The issue of a prolonged period of time between initiation of donor search and HSCT has caused the use of unrelated donor cord blood hematopoietic stem cells, in view of the prompt availability of this source of hematopoietic progenitors.31,32 However, the ultimate outcome of cord blood transplant recipients does not seem to be better than that of children given HSCT from unrelated donors.35,36
Other factors may have played a role in promoting improved outcome. Although detailed information with regards to this is not available, we cannot exclude that patients transplanted more recently had more stable remission, due to the use of more effective therapies before HSCT. A learning and experience effect in handling recipients of unrelated donor HSCT, as well as better strategies for both prevention and treatment of GVHD, are variables for which it is reasonable to hypothesize a relevant role. In this regard, children given the combination of CsA, MTX and Campath-1G in vivo had the highest incidence of leukemia relapse. Since this subgroup of patients also had the lowest risk of developing acute GVHD, it can be concluded that use of this monoclonal antibody was associated with a marked in vivo T cell depletion, as already reported,37 which is able to reduce the risk of post-transplant immune complications, at the price, in our cohort, however, of an impaired graft-versus-leukemia effect (GVL). In view of the high relapse rate observed in children given Campath-1G in vivo, all children but one given serotherapy as part of GVHD prophylaxis beyond January 1998 were treated with ALG, which caused neither an increased incidence of leukemia recurrence nor a higher risk of infectious complications. The role of ALG for prevention of GVHD when high-resolution molecular techniques are employed for typing of donor–recipient pair HLA alleles remains to be proved in a controlled study. However, recently published studies seem to suggest that this type of serotherapy can both prevent occurrence of severe acute GVHD and maintain GVL effect.13,38 Recently, Bacigalupo and colleagues39 documented that the use of ALG as GVHD prophylaxis for patients transplanted from an unrelated volunteer was able to reduce the incidence of chronic GVHD. The low incidence of chronic GVHD observed in our cohort could be, at least partially, attributed to the fact that 43 out of the 63 patients were given ALG before the allograft. In multivariate analysis, grade III–IV acute GVHD was associated with an increased risk of 6-month TRM in our cohort of patients, whereas in univariate analysis patients with grade II acute GVHD had the best outcome. These findings provide further support for the concept that effective pharmacological strategy for prevention of severe GVHD, albeit able to spare partially the GVL effect, should be employed.
The main factors reported to influence the probability of obtaining a second sustained remission in children with ALL given a second course of chemotherapy were the site of relapse and the length of first remission, children with an isolated marrow recurrence, especially when it occurred during the first 24–30 months from diagnosis, having the worst prognosis.5,23,40,41,42 Other variables associated with a poor outcome in children with relapsed ALL given chemotherapy alone were older age, male sex and T-lineage ALL.23,38 In all previously published studies, the reported EFS after chemotherapy for relapses involving the bone marrow and occurring within 24–30 months from diagnosis ranges between 5 and 15%.5,23,40,41,42 In our cohort of patients, the probability of EFS for the 37 children with a time interval between diagnosis and relapse less than 30 months was 27% (11–43), a value comparable with those previously reported for children with the same prognostic characteristics given HSCT from a compatible relative.5
As mentioned above, on the basis of site of recurrence, length of first remission and immunophenotype, the BFM study group identified four different subgroups of children with relapsed ALL, each of them characterized by different prognosis.23 This stratification proved also to be of value in our study population for predicting prognosis, since children belonging to the S2 subgroup had a better chance of being alive and disease-free in comparison to those of S3 and S4 subgroups.
In conclusion, this study shows that outcome of children given an unrelated donor transplant for ALL in second CR has significantly improved over time and that nowadays results achievable with this type of transplant may be comparable to those of HSCT from a compatible relative. In view of these data, indications for an allograft from either a related or an unrelated donor can be considered the same. Identification of factors influencing TRM, relapse rate and EFS of unrelated donor HSCT can be of help in counselling patients with ALL experiencing bone marrow recurrence and lacking an HLA-identical sibling.
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This work has been partly supported by grants from AIRC (Associazione Italiana Ricerca sul Cancro), CNR (Consiglio Nazionale delle Ricerche), MURST (Ministero dell'Università e della Ricerca Scientifica e Tecnologica) and IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Policlinico S Matteo to FL. We are indebted to Geoff Hale for having kindly provided the monoclonal antibody Campath-1G.
About this article
- unrelated donor stem cell transplantation
- unrelated donor registries
- acute lymphoblastic leukemia
- leukemia relapse
- HLA typing
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