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© 2000 American Society for Clinical Oncology Partially Mismatched Related-Donor Bone Marrow Transplantation for Pediatric Patients With Acute Leukemia: Younger Donors and Absence of Peripheral Blasts Improve OutcomeFrom the Division of Transplantation Medicine, Palmetto Richland Memorial Hospital, University of South Carolina, Columbia, SC. Address reprint requests to Kamar T. Godder, MD, Division of Transplantation Medicine, University of South Carolina and Palmetto Richland Memorial Hospital, 7 Richland Medical Park, Suite 600, Columbia SC 29203; email kamar.godder{at}rmh.edu
PURPOSE: To extend access to bone marrow transplantation (BMT), we used partially mismatched related donors (PMRD) for pediatric patients with acute leukemia. In this report we sought to determine pretransplantation factors that might predict outcome. PATIENTS AND METHODS: Of 67 such patients, 43 had acute lymphocytic leukemia and 24 had acute myelogenous leukemia. At the time of transplantation, 41 patients were in relapse. Donors included 40 parents, 24 siblings, and three cousins. HLA disparity of two to three major antigens was detected in two thirds of the donor-recipient pairs. Conditioning therapy, including total-body irradiation and chemotherapy followed by graft-versus-host disease (GvHD) prophylaxis with partial T-cell depletion of the graft using T10B9 or OKT3, was combined with posttransplantation immunosuppression. RESULTS: Estimated probability (EP) of engraftment was 0.96 and was not affected by donor-antigen mismatch (AgMM; P = .732). EP of grades 2 to 4 acute GvHD was 0.24 and was not affected by recipient AgMM (P = .796). EP of disease-free survival was 0.26 at 3 years but improved to 0.45 when donors were younger than 30 years (P < .001). EP of relapse at 3 years was 0.41 and reduced with younger donors’ age. For patients who were in relapse at the time of transplantation, absence of blasts was associated with a lower relapse rate (0.46 v 0.84; P = .083), similar to that of patients in remission. CONCLUSION: PMRD-BMT in pediatric leukemia resulted in high engraftment and low GvHD rates. To improve outcomes, younger donors should be sought, and clinicians should attempt to reduce peripheral blasts in patients who are in relapse.
ALTHOUGH MOST pediatric patients with acute leukemia can be cured with chemotherapy, a subset of patients with advanced disease may benefit from allogeneic bone marrow transplantation (BMT). Matched sibling donor (MSD) BMT has been shown to improve disease-free survival (DFS) in such patients, 1-9 but unfortunately, this option is available to less than 30% of them. The rest might continue on conventional chemotherapy, but this offers little chance of cure. Over the past two decades, national and international registries have been established in which data on unrelated volunteers’ tissue typing are collected and are made available to patients in need of BMT. Although BMT from an unrelated donor has proven to be a feasible and effective treatment, 10,11 obtaining a marrow from these donors involves consideration of the donor’s convenience, coordinating and performing further testing, and collecting and shipping the marrow, all of which are time-consuming and costly. Moreover, with the increase in worldwide population migration, many children are of interethnic or interracial descent, which makes their HLA phenotype more difficult to match with an unrelated donor. Unrelated cord blood banks were recently explored as an alternative stem-cell source. 12,13 Data on this procedure is still limited, and the restricted access to donors remains a problem. Furthermore, many of the patients from racial or ethnic minorities may not find a donor because of insufficient representation of minorities in these registries. Partially mismatched related donors (PMRD) are available to almost all patients14-16; They are available immediately and many of the expenses related to the search are eliminated. In this report we describe the clinical course and outcome of 67 consecutive pediatric patients with acute leukemia who underwent PMRD-BMT (some of these were reported previously).17 We also sought to identify both patient and donor pretransplantation factors that may predict outcome.
Patients Between February 1993 and May 1997, 67 patients (  21 years old) with acute leukemia (acute lymphocytic leukemia [ALL] and acute myelogenous leukemia [AML]) who lacked an HLA-matched sibling underwent PMRD-BMT at the Center for Cancer Treatment and Research of Palmetto Richland Memorial Hospital and the University of South Carolina (Columbia, SC). Patients were treated on an institutional review board–approved protocol after signing an informed consent form. Patients’ diagnoses were verified according to French-American-British morphology guidelines before transplantation. Patients were classified according to whether they were in relapse or remission. Furthermore, patients in relapse were divided into two categories: those with presence and those with absence of blasts in the peripheral blood.
Donors
Clinical Protocol
Marrow Graft Preparation Donor marrow was harvested by aspiration of 4.5 to 6.0 x 108 nucleated cells/kg of recipient weight. Grafts initially were depleted of mature T lymphocytes using T10B9.1A-31 (T10B9 courtesy of John Thompson, MD, University of Kentucky, Lexington, KY), which is directed against the alpha and beta chains of the T-cell receptor heterodimer, along with rabbit complement, as described previously.18 Another T-cell receptor–targeted antibody, OKT3, (Orthoclone OKT3 or muromonab-CD3; Ortho Biotech Inc, Raritan, NJ) was subsequently used.19 Quality control assays included same-day flow cytometry for T-cell depletion estimate, limiting dilution analysis for the actual enumeration of T cells,20 granulocyte-macrophage colony-forming units to determine hematopoietic potential, and microbial assessment.
Posttransplantation Evaluation
Statistical Methods
For the multivariate analysis, AML and ALL patients were combined. Cox proportional hazards multivariate regression was used to investigate potential prognostic variables, including patient’s age (< 10 years v
Univariate Analysis Patient characteristics. Forty-three of the patients had ALL and 24 had AML. Patient characteristics are listed in Table 1. At the time of transplantation, 23 (53%) of 43 patients with ALL and 18 (75%) of 24 patients with AML were in relapse. Patients for whom induction failed were included in the relapse group. Two thirds of the relapse patients had blasts in the peripheral blood. All nine patients who underwent transplantation in first remission had poor prognostic features: (1) unfavorable cytogenetics (n = 5, one of whom was still positive at time of transplantation) consisting of: Philadelphia chromosome (n = 3), near-full haploid (n = 1), and 7q- (n = 1), (2) secondary AML (n = 1), (3) M6 morphology (n = 1), and (4) more than two courses required to achieve remission (n = 2). Most of the patients who were experiencing relapse underwent treatment in an attempt to induce remission before transplantation, which was unsuccessful. One patient died during conditioning therapy.
Donor characteristics. Donors were family members as follows: the majority were parents (n = 40) and full siblings (n = 21); others were half siblings (n = 3) and cousins (n = 3). Donor characteristics are listed in Table 2. For purpose of analysis, donors were also divided according to those who were younger than 30 years (n = 33) or older (n = 34). Median ages of the two donor groups (younger and older) were 12 years (range, 4 to 28 years) and 37 years (range, 30 to 55 years), respectively. HLA disparity between the donors and recipients is listed in Table 3.
Graft characteristics. As listed in Table 4, the nucleated cell count and T-cell dose were significantly higher (P = .007 and .028, respectively) and log depletion was significantly lower (P < .001) when T-cell depletion was performed using T10B9 as compared with OKT3.
Engraftment. The estimated probability of engraftment was 97% (CI, 92 to 100) at a median of 17 days (range, 12 to 26 days; Fig 2). Two patients failed to engraft and received a marrow boost, which resulted in a successful engraftment in one. The treatment protocol significantly affected engraftment. Median time to engraftment was 19 days on protocol 93-14 and 15 days on 94-65 (P = .002). In univariate analysis, the estimated probability of engraftment was improved with younger patient age (P = .017), younger donor age (P = .035) and nonparent donor compared with parent donor (median, 15 v 17 days; P = .047). Time to engraftment was not significantly affected by type of acute leukemia (AML v ALL; P = .972), remission status (P = .820), rejection (donor) antigen mismatch (P = .451; Fig 3), and sex mismatch (P = .793).
aGvHD. The estimated probability of grade 2 to 4 aGvHD was 0.24 (CI, 0.13 to 0.35) and grade 3 to 4 was 0.10 (CI, 0.02 to 0.17). Grade 1 to 4 aGvHD occurred in 22 of 66 assessable patients. Eight patients had grade 1, eight had grade 2, two had grade 3, and four had grade 4 disease. Altogether, four patients died of aGvHD (two with ALL and two with AML); two died after DLI. Donor age and relation to the patient (parent v nonparent) were the only covariates that significantly affected probability of aGvHD in the univariate analysis. The estimated probability of grade 2 to 4 aGvHD was 0.10 (CI, 0.00 to 0.20) in patients whose donors were younger than 30 years, compared with 0.37 (CI, 0.19 to 0.55) in patients whose donors were  30 years of age (P = .022). Patients whose donor was a parent were more likely to have grade 2 to 4 aGvHD than patients whose donor was a related nonparent (P = .033). Patients who were a full haplotype-mismatch with their donor had similar probability of aGvHD as those who received grafts from donors with 0 to two antigen mismatches in the GvHD direction (0.26 v 0.22; P = .796; Fig 4). Neither disease diagnosis nor patient age, treatment protocol, sex mismatch, T-cell dose of the graft, or CMV seropositivity of donor or recipient were shown in a univariate analysis to affect probability of aGvHD.
cGvHD. cGvHD occurred in 14 (37.8%) of 37 assessable and was extensive in only one of those 14 patients. Median time to cGvHD was 7.5 months (range, 3.2 to 22.5). cGvHD was not affected by disease diagnosis, GvHD (host) antigen mismatch, or BMT protocol. In addition, in the 17 patients who received grafts from their full siblings, there was no statistically significant difference in development of cGvHD by whether the shared haplotype was the father’s or the mother’s (data not shown). Regimen-related toxicity and VOD. Forty-eight patients (72%) developed grade 3 to 4 toxicity in the gastrointestinal tract, primarily severe mucositis that was of short duration. Also, the majority (67%) of patients developed hypertension that was controlled with antihypertensive medications. Only 10 patients (15.2%) developed VOD of the liver, five with AML and five with ALL, although mild liver toxicity (not fitting Jones’ criteria for VOD) was seen in 30% of patients. Patients on protocol 94-65 were more likely to develop this complication (P = .037), but no patient developed fatal VOD. Other toxicities seen were kidney (14%), lung (13%), and CNS (9%). Primary causes of death are listed in Fig 5.
Survival and DFS. Twenty-one of 67 patients are surviving at a median of 28.5 months (range, 3.1 to 46.3 months). The estimated probability of survival at 3 years is 0.26% and is similar for patients with ALL and AML. Most (86%) of the survivors have Karnofsky/Lansky scores greater than 80. As seen in Figs 6 and 7, probability of DFS and overall survival were significantly superior when the donor was younger than 30 years (0.45 v 0.13, P < .001, and 0.40 v 0.12, P < .001, respectively). Similar results were observed when the donor was a nonparent compared with a parent (probability of survival was 0.36 v 0.18 [P = .011] and probability of DFS was 0.37 v 0.19 [P = .018]). Regarding the effect of disease status on survival, the only significant variable was the absence of blasts in the peripheral blood. In both AML and ALL patients who were in relapse at the time of transplantation, the absence of blasts in peripheral blood was associated with significantly higher DFS (0.54 absent v 0.08 present; P = .004; Fig 8). Other pretransplantation variables that did not affect DFS in univariate analysis included donor (rejection) HLA-antigen mismatch (P = .147), CMV status of recipient/donor (0.17 positive recipient v 0.27 negative recipient with positive donor; P = .262), and conditioning therapy (P = .605).
Relapse. Seventeen patients (39.5%) with ALL experienced relapse within the first 8 months, and nine patients (39.1%) with AML relapsed within 16 months of transplantation. As expected, disease state at time of transplantation predicted relapse rate posttransplantation. The estimated probability of relapse at 3 years was 0.41 in remission patients and 0.69 in relapse patients (P = .056). Of interest, no patient has had a late relapse (after 16 months), and patients with cGvHD seem to have a lower relapse rate (three of 13 patients) compared with those without cGvHD (14 of 22 patients). When 40 patients in relapse were analyzed separately, the absence of circulating blasts at the time of transplantation (regardless of their number in the marrow) was associated with a relatively decreased probability of relapse (0.46 v 0.84, respectively; P = .083). Again, the use of younger donors showed a trend toward a decreased relapse rate (P = .063).
Multivariate Analysis
For patients who were in relapse at the time of transplantation, donor relationship significantly affected outcome. A patient whose donor was a parent was 3.1 times more likely to experience relapse and 3.6 times more likely to experience treatment failure than a patient whose donor was a nonparent (P = .033 and .004, respectively). Moreover, patients who had blasts in peripheral blood at the time of transplantation were much more likely to experience relapse (RR = 3.4; CI, 1.1 to 10.1) or treatment failure (RR = 5.1; CI, 1.9 to 14.3).
More than two thirds of children who may benefit from allogeneic BMT lack an MSD. Our group has recognized the immediate accessibility of mismatched family members as potential marrow donors and has used them primarily for patients with advanced disease.17 In this study, we examined the role of PMRD-BMT in a group of pediatric patients with high-risk acute leukemia and have shown it to be an effective therapy when using partial T-cell depletion along with posttransplantation immunosuppression. We also showed that the outcome is mostly affected by peripheral-blood blast count of the patient and by the age of the donor. Haploidentical BMT was used beginning in the late 1970s but was abandoned because of the serious posttransplantation complications that were encountered, including graft failure, GvHD, and other nonrelapse complications.14,26 Graft failure has been associated with increasing major HLA disparity in the donor, as well as T-cell depletion10,11,14,27-30 of the graft. We and others have shown that HLA barriers can be overcome when aggressive immuno- and myeloablative therapies are used.31-33 Indeed, once immunoablative therapy was intensified by increasing TBI dose and adding pretransplantation ATG (RMH-IRB protocol 94-65), graft failure declined significantly.34 The probability of engraftment in our current pediatric study was similar to that reported by Davies et al30 in recipients of non–T-cell–depleted grafts from unrelated donors. Engraftment rates using unrelated donors was inferior in a report from the Seattle group35 and in a larger analysis from the National Marrow Donor Program10 (93% and 94%, respectively). Our engraftment rates also compared favorably with that reported from studies of cord blood, the newly developed alternative source of hematopoietic stem cells. Engraftment rates in unrelated cord-blood transplantation range from 70% to 81%,13,36 and successful engraftment is highly dependent on the cell dose that is delivered to the patient. Time to engraftment, another measurement of graft function, was not affected in our study by donor HLA disparity, unlike that which was previously reported in mismatched donor BMT14,28 and in unrelated cord-blood transplantation.13 This finding further demonstrates the efficacy of our intensive conditioning therapy combined with sequential immunomodulation of donor and host. Many transplantation physicians choose not to use PMRD because of the well-recognized risk of GvHD,14,37,38 the severity of which increases with the degree of mismatch.11,26,38,39 Because GvHD in MSD-BMT and matched unrelated donor (MUD)-BMT is independently associated with patient age, we compared our results with those of other pediatric series only. Davies et al,30 reporting on T-cell–replete unrelated grafts, showed an incidence of 27% to 30% for grade 3 to 4 GvHD, which was the primary cause of death in 41% of patients who died posttransplantation. Similar results demonstrating severe aGvHD after unrelated donor transplantation are reported from Seattle (37% in the matched and 62% in the mismatched MUD-BMT)35 and from Italy (38% in patients who received a variety of GvHD prophylaxis regimens).40 Depleting the graft of T-cells in the Milwaukee41 and St Jude Children’s Research Hospital series42 resulted in decreased incidence of GvHD and abolished the effect of HLA disparity on severity of GvHD, similar to our findings. More recently, a report on haploidentical transplantation from the Perugia group43 indicated that the use of intense T-cell depletion along with enrichment of the graft with peripheral-blood stem cells could result in engraftment. Although results are promising in regard to elimination of GvHD, there is still a very high nonleukemic mortality rate. Another approach to prevention of GvHD involves the coincubation of recipient and donor cells with an antibody that blocks the costimulatory pathway, resulting in specific anergy to mismatched HLA.44 This novel method of creating tolerance warrants further study. Many investigators had turned their attention to the use of cord blood as an alternative source of hematopoietic stem cells in hopes of avoiding severe GvHD through the naivety of infantile lymphocytes. Reports on the incidence of acute GvHD in unrelated cord-blood transplantation vary widely. Although Kurtzberg et al,12 from a single institute, report that only two of 21 patients developed grade 3 GvHD, registry data from the Pediatric Blood and Marrow Transplant Consortium and from the New York Blood Bank show that 23% developed grade 3 to 4 GvHD36,45 and up to 31% developed grade 2 to 4 GvHD, as reported from the European collective analysis.46 A large number of the patients in our series did suffer from cGvHD, but most of them had limited disease, and Karnofsky/Lansky score of most of the patients was higher than 80%. Although the numbers are small, patients with cGvHD in our series tended to have decreased incidence of relapse, which is similar to results reported with MSD-BMT.47,48 Retrospective studies have suggested that GvHD is accompanied by graft versus leukemia (GvL) effect.47,48 In addition, studies in MUD-BMT have shown a relatively low relapse rate in high-risk patients without evidence of clinical GvHD,49,50 which suggests that minor antigen mismatch in this scenario may contribute to the GvL effect. To determine whether T-cell depletion51 and posttransplantation immunoablation and subsequent elimination of GvHD abrogated GvL effect, or whether major antigen mismatch has a role in GvL regardless of GvHD, we also compared our results with other studies on acute leukemia. First, we adjusted for state of disease. Most of our patients were in relapse at the time of transplantation. Relapse patients who received MSD-BMT had DFS of 10% to 23% in the Seattle52 and in the Memorial Sloan-Kettering Cancer Center53 cohorts (the latter analyzed children in fourth remission together with patients in relapse). Other groups had included relapse patients in a high-risk group that varies between studies and report DFS of 12% to 34%30,41,42,50,54,55 in patients who received transplants from MUDs or MSDs. When strictly comparing pediatric cohorts of 50 patients or more who received unrelated donor BMT, DFS in the high-risk patients was 10% to 34%.30,35,41,42 Overall incidence of relapse was 16% to 60%,30,35,41,42 depending on the definition of a high-risk patient and the presence of cGvHD (although this is not statistically significant).30 Our results showing DFS of 28% at 2 years are comparable to those achieved with the well-accepted MUD-BMT. As expected, we have observed a higher relapse rate among patients who were experiencing relapse at the time of transplantation; not surprisingly, this was the primary cause of death in our series. We believe that the high relapse rate in our series is a result of the state of disease rather than the T-cell depletion, because it is similar to that reported with MUD-BMT in the Seattle series,35 in which grafts were T-cell repleted. To clarify whether major antigen mismatch contributes to GvL effect, better-risk patients need to be studied. In our next largest group of patients, those with ALL in second remission, five of 14 are surviving at a median of 3 years after BMT. Although patient number is small, results are similar to those of other transplantation reports2-5,56-59 and as such are superior to those of patients treated with chemotherapy only. It is well established that patients with advanced leukemia are at increased risk of transplantation failure.11 Because the majority of our patients were in relapse at the time of transplantation, we tried to identify unique pretransplantation features that were associated with improved outcome. Absence of blasts in the peripheral blood (regardless of their number in the marrow) was found to be the most significant factor associated with survival. The Seattle group reported similar findings in a study of patients with secondary AML in which a higher number of blasts in the peripheral blood before BMT was associated with higher incidence of relapse.60 Interestingly, patients with peripheral blasts had also higher nonleukemia mortality.61 One may speculate that blasts in the peripheral blood serve as either a biologic marker for the aggression of the disease or alternatively as a reflection of tumor burden. In either regard, reducing blasts in the peripheral blood and consequently inducing aplasia in those with refractory leukemia may increase the feasibility of eradicating leukemia through the utilization of myeloablation combined with the alloreactivity of the graft. Once haploidentical donors are identified, they are often abundant. To choose the best donor, factors other than HLA were considered, and age was by far the most significant factor to affect outcome. Donor age of more than 30 years was earlier reported to affect outcome in MSD-BMT61 and age of more than 20 years in PMRD-BMT,11 but this was mostly in young patients whose parents were the donors. We have shown in our multivariate regression analysis that age of the donor was more significant than consanguinity and that it affected engraftment, GvHD, survival, and DFS. Similar results were recently reported also using MUDs.62 This finding should be considered in clinical management of children who have no full siblings, when half-sibling and cousin donors may be superior to parents. We have shown that the major problems with the use of PMRDs (ie, engraftment and GvHD) were overcome, and consequently, we were able to find a bone marrow donor for every child with a need for transplantation. Because PMRD-BMT was shown to be as effective as other sources of hematopoietic stem-cell transplantation, it should be incorporated into national pediatric leukemia trials, along with other transplantation options, to treat patients early in their disease process. For patients with refractory disease, further studies aimed at decreasing tumor load before transplantation are warranted.
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ABSTRACT
INTRODUCTION
