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Journal of Clinical Oncology, Vol 22, No 14 (July 15), 2004: pp. 2816-2825 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.07.130 Outcome of Allogeneic Hematopoietic Stem-Cell Transplantation in Adult Patients With Acute Lymphoblastic Leukemia: No Difference in Related Compared With Unrelated Transplant in First Complete RemissionFrom the Clinic for Bone Marrow Transplantation and Hematology/Oncology, Idar-Oberstein; German Clinic for Diagnostics, Wiesbaden; Medizinische Hochschule, Hannover; University Hospital Eppendorf, Hamburg; Westfaelische Wilhelms University, Muenster; Carl Gustav Carus University, Dresden; University Hospital, Frankfurt; University Hospital, Cologne, Germany; Center for Allogeneic Stem Cell Transplantation, Huddinge, Sweden Address reprint requests to Michael G. Kiehl, MD, Clinic for Bone Marrow Transplantation and Hematology/Oncology, Dr-Ottmar-Kohler-Str 2, 55743 Idar-Oberstein, Germany; e-mail: mkiehl{at}bmt-center-io.com
PURPOSE: The role of unrelated allogeneic stem-cell transplantation in acute lymphoblastic leukemia (ALL) patients is still not clear, and only limited data are available from the literature. We analyzed factors affecting clinical outcome of ALL patients receiving a related or unrelated stem-cell graft from matched donors. PATIENTS AND METHODS: The total study population was 264 adult patients receiving a myeloablative allogeneic stem-cell transplant for ALL at nine bone marrow transplantation centers between 1990 and 2002. Of these, 221 patients receiving a matched related or unrelated graft were analyzed. One hundred forty-eight patients received transplantation in complete remission; 62 patients were in relapse; and 11 patients were refractory to chemotherapy before transplant. Fifty percent of patients received bone marrow, and 50% received peripheral blood stem cell from a human leukocyte antigen–identical related (n = 103), or matched unrelated (n = 118) donor. RESULTS: Disease-free survival (DFS) at 5 years was 28%, with 76 patients (34%) still alive (2.2 to 103 months post-transplantation), and 145 deceased (65 relapses, transplant-related mortality, 45%). We observed an advantage regarding DFS in favor of patients receiving transplantation during their first complete remission (CR) in comparison with patients receiving transplantation in or after second CR (P = .014) or who relapsed (P < .001). We observed a clear trend toward improved survival in favor of B-lineage ALL patients compared with T-lineage ALL patients (P = .052), and Philadelphia chromosome–positive patients had no poorer outcome than Philadelphia chromosome–negative patients. Total-body irradiation–based conditioning improved DFS in comparison with busulfan (P = .041). CONCLUSION: Myeloablative matched related or matched unrelated allogeneic hematopoietic stem-cell transplantation in ALL patients should be performed in first CR.
As clearly shown by the recently published Surveillance, Epidemiology, and End Results analysis, the incidence of acute lymphoblastic leukemia (ALL) is increasing, especially in children and adults up to 64 years of age.1 Advances in the chemotherapeutic treatment of adult ALL have improved patient outcome in the last decade.1 Multicenter trials demonstrated complete remission (CR) rates of 75% to 89% and leukemia-free survival rates of 33% due to intensified chemotherapeutic regimens.2–7 The favorable results of allogeneic stem-cell transplantation (SCT) for standard-risk ALL patients in first CR (1.CR) have been already shown by the United Kingdom Medical Research Council ALL XII/European Cooperative Oncology Group E2993 trial.8 For those patients relapsing or with high-risk ALL allogeneic SCT, a related or unrelated donor is able to improve disease-free survival (DFS).9 A recently published French study demonstrated a benefit of allografting with a DFS for allograft recipients of 46% compared with 31% in the control group.9 This effect was more pronounced in high-risk ALL patients with a DFS of 44% in the allograft group compared with 11% in the control group. After relapse, allogeneic SCT should be performed, and International Bone Marrow Transplant Registry (IBMTR) data show a DFS of 42% for patients receiving transplantion in second CR (2.CR).10 Beyond 2.CR, or in patients with primary induction failure, the outcome of transplantation worsens considerably, with only 5% to 15% of long-term survivors.11 Although the donor of choice is a matched sibling, this is the case in less than 30% of patients. Thus, transplantation from an unrelated donor should be considered, especially in younger patients. The IBMTR reports a DFS of 44% in patients receiving an unrelated transplant for ALL in 1.CR.10 We analyzed factors affecting clinical outcome of patients with ALL treated with related or unrelated donor marrow or peripheral blood stem-cell (PBSC) transplants at eight transplant centers in Germany and one center in Sweden, over a period of 12 years (1990 to 2002).
Patients Patients and transplant characteristics are given in Tables 1 and 2. The analyzed study group consisted of 221 consecutive adult (  17 years of age) patients receiving an allogeneic SCT between September 1990 and January 2002 for ALL at nine European transplant centers (Idar-Oberstein: n = 47; Wiesbaden: n = 36; Hannover: n = 31; Huddinge, Sweden: n = 26; Hamburg: n = 25; Münster: n = 22; Dresden: n = 21; Frankfurt: n = 9; Cologne: n = 4) with a human leukocyte antigen (HLA) -A, -B, and -DRB1 matched related (n = 103) or unrelated (n = 118) donor. Most patients were male. One hundred seventy-two patients had B-lineage ALL, 40 had T-lineage ALL, and nine had other types of ALL. The Philadelphia chromosome (Ph) was present in 72 patients (33%). Most patients (67%) received transplantation in CR (1.CR: n = 94; 2.CR: n = 43; 3.CR: n = 11), whereas the other patients (33%) received transplantation in first (n = 32), second, or higher relapse (n = 30), or in primary refractory disease (n = 11).
Before 1997, HLA typing of class I was performed by serology only. Later, polymerase chain reaction–sequence-specific primer (PCR-SSP) low-resolution typing for class I was used. For HLA class II, genomic high-resolution DNA-based typing (PCR-SSP) was used. In the case of PBSC mobilization, all donors were treated with granulocyte colony-stimulating factor (Amgen, Thousand Oaks, California; Rhône-Poulenc Rorer, Lyon, France) for 4 to 6 days before apheresis. The total daily dose of granulocyte colony-stimulating factor ranged from 9 to 12.5 µg/kg per day, administered subcutaneously once or twice daily.
Conditioning As additional immunosuppressive treatment before transplantation, 82 patients (37%) received antithymocyte globulin (n = 77: ATG-Fresenius; Fresenius AG, Bad Homburg, Germany; Thymoglobulin; IMTIX-Sangstat, Lyon, France) or monoclonal antibodies (n = 4: Orthoclone OKT3; Ortho Biotech, Raritan, NJ; n = 1: Campath-1H; MedacSchering Onkologie GmbH, Munich, Germany) were given for 4 to 5 days. Most patients received cyclosporine A for graft-versus-host prophylaxis, combined with a short course of methotrexate (n = 118).
Engraftment
Graft-Versus-Host Disease (GVHD)
Risk Classification Standard risk. Standard risk was defined as achieving CR within 28 days after start of induction therapy, have leukocyte counts less than 30,000/µL (B-precursor ALL) or less than 100,000/µL (T-precursor ALL), and no pre T-ALL or pro B-ALL. High risk. Remission requires more than 28 days of induction therapy, leukocytes more than 30,000/µL (B-precursor ALL) or more than 100,000/µL (T-precursor ALL), pre T-ALL or pro B-ALL, and t(4;11)/ALL1-AF4–positive ALL. Very high risk. Very high risk was defined as t(9;22)/BCR-ABL positive ALL.
Statistics
Engraftment Leukocyte engraftment was observed in 191 patients 17.0 ± 5.8 days post-transplant. Mean time to engraftment was 19.2 ± 4.4 days in patients receiving bone marrow grafts and 15.2 ± 6.1 day in patients receiving PBSC grafts (P < .001). The number of patient without engraftment was 14 (10 bone marrow, four PBSC), and they consequently died (10 due to infection, three due to multiorgan failure, and one due to unknown cause). Engraftment data of 16 patients were not available for analysis.
TRM and Acute GVHD
The overall incidence of acute GVHD (194 patients were available for analysis, and the data of 27 of the very first patients are excluded because of misleading documentation) grade 1 to 4 was 58% (grade 2 to 4, 30%; grade 3 to 4, 11%). We observed a trend for a higher incidence of severe grade acute GVHD in matched unrelated transplants in comparison with matched related transplants (P = .055; ie, 7% of the patients receiving a matched related and 15% receiving a matched unrelated transplant suffered from grade 3 to 4 GVHD; Table 3). Analyzing influence of severity of GVHD on DFS (Fig 2) demonstrated a clear improvement in DFS for patients with grade 1 to 2 acute GVHD in comparison with patients without grade 1 to 2 GVHD (P = .018) or severe grade 3 to 4 GVHD (P < .001).
Overall and Disease-Free Survival After a median follow-up of 7.1 months (range, 0.03 to 103 months), 76 (34%; 41 related, 35 unrelated) of 221 patients were still alive, and 69 of them were free of leukemia; 145 patients died due to relapse (n = 65), infection (n = 43), multiorgan failure (n = 12), GVHD (n = 19), or other non–relapse associated complications (n = 6). The Kaplan-Meier estimates (Fig 3) for DFS of all patients at 3 years and 6 years were 29% and 24%, respectively, with a clear tendency in favor of patients with B-lineage ALL (inserted figure) in comparison with patients with T-lineage ALL (P = .052). Univariate Kaplan-Meier analyses of DFS and TRM are shown in Table 4 for subsets of patients undergoing transplantation in different remission or disease status. DFS is significantly better in patients receiving transplantation during 1.CR (n = 94); 62 patients (79% were high- and very-high risk) received a matched related transplant, and 32 patients (94% high- and very-high risk; P was not significant) received a matched unrelated transplant. Median observation time (mot) was 13.2 months (range, 0.13 to 95.5 months) in comparison with patients receiving transplantation in 2.CR (n = 54; mot, 7.2 months; range, 0.4 to 103 months; P = .014) or in relapse (first relapse: n = 32; mot, 3.6 months; range, 0 to 34.5 months; P < .001; second relapse: n = 30; mot, 3.5 months; range, 0 to 72 months; P < .001). Outcome of transplantation in primarily refractory patients is similar to that of patients receiving transplantation in 1.CR of the disease (1.CR see number of patients, mot, and range data; primarily refractory: n = 11; mot, 6.5 months; range, 0.04 to 87 months; P = .39). When considering donor type and remission status, there is no difference in DFS for related and unrelated transplant patients in 1.CR.
Factors Affecting DFS Analyzing risk factors on DFS in a univariate analysis, donor status, patient age group, diagnosis, disease status, conditioning regimen, and stem-cell source were identified as prognostic parameters with a positive impact (Table 5). Other risk factors are shown in Table 5 but neither a single nor a combination had a significant influence on DFS.
In the multivariate analysis, we observed a tendency toward improved DFS in patients 17 to 26 years of age, whereas patients 27 to 40 years of age, and patients aged 41 and older demonstrated similar DFS (Table 6). DFS at 5 years was 35% in patients aged 17 to 26 years, 22% in all those aged 27 to 40 years, and 24% in patients age 41 and older (Fig 4). Furthermore, B-lineage ALL, CR at transplant, a TBI-containing conditioning regimen, and bone marrow as stem-cell source are favorable factors for DFS (Table 6). Differences between bone marrow and PBSCs on DFS are only significant if transplant was performed before January 7, 1998, demonstrating a clear improvement in apheresis techniques and immunosuppressive therapy over time (data not shown).
Comparing DFS in patients with a matched related donor (n = 103; mot 10.4 months) with patients with a matched unrelated donor (n = 118; mot, 6.0 months), there was a statistically significant difference (P = .015) in favor of patients receiving transplantation with a graft from a related donor. However, analyzing effects of disease status at transplantation and donor on DFS, we did not observe any differences comparing matched related and matched unrelated donors (Fig 5) in patients receiving transplantation in 1.CR. DFS at 5 years in patients receiving transplantation in 1.CR from a matched unrelated donor is 45%, and in patients receiving a graft from a matched related donor, it is 42%. DFS of patients receiving transplantation in 2.CR, relapse or refractory disease did not show any significant differences comparing related or unrelated transplantation. Only patients receiving transplantation in 2.CR from a related donor showed improved DFS (40% at 4 years) compared with grafts from an unrelated donor (DFS, 17% at 4 years), but this was not statistically significant (P = .10).
Data on the conditioning regimens used are provided in Table 2. The Kaplan-Meier estimate for overall DFS was 26% (30% at 5 years) in patients receiving TBI-based conditioning and 17% (17% at 5 years) in patients receiving busulfan-based conditioning (Fig 6A; P = .041). Looking at stem-cell source, we observed no difference comparing bone marrow and PBSC grafts (Fig 6B; P = .076).
Investigating whether time of transplantation has any influence on donor selection (related or unrelated), we divided patients in cohorts receiving transplantation before and after January 7, 1998. Here we observed a trend toward increased acceptance of unrelated donors in patients receiving transplantation after January 7, 1998, which is not statistically significant. In this connection, it is important to investigate whether DFS improved over time, and we observed an improvement in DFS comparing patients receiving transplantation before and after January 7, 1998 (P = .087, Wilcoxon-Peto test), which is in line with other investigations.
To our knowledge, this is the largest published report to date on adult patients with ALL receiving a hematopoietic SCT from either a matched related or a matched unrelated donor including standard as well as high- and very high-risk patients. In adult patients, chemotherapy improved during the last 10 years, and different study groups report CR rates of 76% to 91% and leukemia-free survival of 17% to 38% after 5 to 9 years.6,7,9,22 SCT is generally accepted as the therapy of choice in 2.CR and, if a compatible related donor is available, in high- and very high-risk patients in 1.CR.7,23,24 Recently presented data demonstrated a benefit of SCT from a related donor even in standard-risk patients in 1.CR.8 For unrelated transplantation, the most extensive study so far reported an overall survival of 40% after 2 years in 64 patients.24 In this analysis, most patients were Ph positive and therefore considered high-risk. We report on 221 patients, 72 of whom (36 unrelated and 36 related transplants) were Ph positive; 48 of them received transplantation in 1.CR, and 19 of these (40%) patients are still alive and free of leukemia. Of the other 24 patients receiving transplantation in 2.CR, relapse, or refractory disease, five (21%) are still alive and free of leukemia. It is important to note that of four patients receiving transplantation in refractory disease, two are still alive and free of leukemia. As standard chemotherapy studies achieve a 5-year survival rate of 7% in Ph positive patients, these ALL patients should be considered for allogeneic transplantation as soon as possible after diagnosis.24 It is interesting to note that in contrast to the results of the chemotherapy trials, the DFS after transplant in B-lineage ALL is significantly better in comparison to T-lineage ALL.6,22 A further risk factor is patient age. Bunin et al23 recently published the outcome of unrelated transplantation for ALL in children, and they could clearly demonstrate that an age greater than 15 years is associated with inferior outcome compared to younger patients, with a TRM of 60% in comparison to 38% for younger patients. We could confirm the relevance of age even in adult patients as patients 17 to 26 years of age showed a significantly better overall DFS (35%) in comparison with patients of 27 to 40 years or older than 41 years. Thus, increased age worsens DFS; on the other hand, we do not observe any difference in DFS comparing patient cohorts of 27 to 40 years of age and older than 41 years of age. Consequently, in those older than 27 years, an increase of age does not influence DFS.
The analysis by Cornelissen et al24 demonstrated a highly significant difference in DFS in patients receiving transplantation in 1.CR versus patients doing so at The most important finding of our study is that we did not observe any difference in DFS comparing patients receiving a graft from a matched related or matched unrelated donor in 1.CR of the disease. One should remember that only the high-risk patients received an unrelated transplant in 1.CR. This raises the question, what will be DFS if even standard risk patients receive an unrelated transplant in 1.CR? We could further demonstrate that in ALL patients TRM with regard to a related matched or an unrelated matched donor is not different. Thus, in the case of an available matched unrelated donor, transplantation should be considered in high- and very high-risk patients early in CR.1. In conjunction with the data published by Cornelissen et al24 our data indicate a strong graft-versus-leukemia (GVL) effect in ALL patients as DFS is improved in the presence of grade 1 to 2 GVHD in comparison with patients without GVHD. This is in keeping with a study from the European Group for Blood and Marrow Transplantation, in which the best DFS was seen in patients with acute GVHD of grade 1.25 The significant GVL effect by acute GVHD was also seen in ALL patients in a study performed by the IBMTR.26 Patients with severe GVHD of grade 3 to 4 died mostly due to infectious problems as a consequence of the increased immunosuppression as well as due to refractory GVHD. Especially patients with B-lineage ALL seem to be susceptible for GVL as we found fewer relapses in these patients in comparison to all other ALL patients. This observation in combination with the data published for the response to donor leukocyte infusion suggest that new conditioning regimens with reduced intensity of chemotherapy or radiotherapy focusing on GVL effects might be effective in ALL patients and might be capable of reducing TRM.27–30 A further still unanswered question is the relevance of conditioning with regard to DFS. Some studies in myeloid leukemia as well as in myeloid and lymphoblastic leukemia demonstrated some advantages for TBI with regard to alopecia, veno-occlusive disease, or cystitis, but not regarding relapse incidence.31,32 We were able to show a significant benefit of TBI-based conditioning in comparison with busulfan-based regimens which is expressed by a DFS of 30% in TBI-conditioned patients and of only 17% in busulfan-conditioned patients at 5 years. Thus, conditioning should include TBI if possible. This is in line with a study from the European Group for Blood and Bone Marrow Transplantation (EBMT) showing that patients with ALL undergoing autografts receiving busulfan-containing conditioning had an increased incidence of relapse and a decreased DFS compared with those treated with TBI.33 It is important to note that in our study, busulfan was mainly used due to logistic problems and not because of medical contraindications to TBI.
The authors indicated no potential conflicts of interest.
We thank Axel Hinke (Wissenschaftlicher Service Pharma GmbH) for the excellent statistical care, the staff of the bone marrow transplantation units for providing excellent care of our patients, and the medical technicians for their excellent work in the bone marrow transplantation laboratories.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
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26. Horowitz MM, Gale RP, Sondel PM, et al: Graft-versus-leukemia reactions after bone marrow transplantation. Blood 75:555–562, 1990 27. Yazaki M, Andoh M, Ito T, et al: Successful prevention of hematological relapse for a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia after allogeneic bone marrow transplantation by donor leukocyte infusion. Bone Marrow Transplant 19:393–394, 1997[Medline] 28. Keil F, Kalhs P, Haas OA, et al: Relapse of Philadelphia chromosome positive acute lymphoblastic leukaemia after marrow transplantation: Sustained molecular remission after early and dose-escalating infusion of donor leucocytes. Br J Haematol 97:161–164, 1997[CrossRef][Medline] 29. Storb RF, Champlin R, Riddell SR, et al: Non-myeloablative transplants for malignant disease. Hematology 1:375–391, 2001[CrossRef] 30. Esperou H, Boiron JM, Cayuela JM, et al: A potential graft-versus-leukemia effect after allogeneic hematopoietic stem cell transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Results from the French Bone Marrow Transplantation Society. Bone Marrow Transplant 31:909–918, 2003[CrossRef][Medline]
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32. Ringden O, Remberger M, Ruutu T, et al: Increased risk of chronic graft-versus-host disease, obstructive bronchiolitis, and alopecia with busulfan versus total body irradiation: Long-term results of a randomized trial in allogeneic marrow recipients with leukemia—Nordic Bone Marrow Transplantation Group. Blood 93:2196–2201, 1999 33. Ringden O, Labopin M, Tura S, et al: A comparison of busulphan versus total body irradiation combined with cyclophosphamide as conditioning for autograft or allograft bone marrow transplantation in patients with acute leukaemia: Acute Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol 93:637–645, 1996[CrossRef][Medline] Submitted July 17, 2003; accepted April 23, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test, Fisher's exact test, or Mantel-Haenszel test. Engraftment with regard to stem-cell source was analyzed by the t test. Event-related data were measured from the date of transplantation to that of disease relapse or death from any cause in the case of DFS, of death from any cause in case of overall survival, and of transplant procedure–related death in the case of treatment-related mortality (TRM). At the date of last follow-up in patients without the respective event, the data were censored. Survival functions were estimated by the Kaplan-Meier method and compared by the log-rank test
