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Autotransplantation versus HLA-matched unrelated donor transplantation for acute myeloid leukaemia: a retrospective analysis from the Center for International Blood and Marrow Transplant Research

  1. Hillard M. Lazarus1,
  2. Waleska S. Pérez2,
  3. John P. Klein2,
  4. Craig Kollman3,
  5. B. Bate-Boyle4,
  6. Christopher N. Bredeson5,
  7. Robert Peter Gale6,
  8. Robert B. Geller7,
  9. Armand Keating8,
  10. Mark R. Litzow9,
  11. David I. Marks10,
  12. Carole B. Miller11,†,
  13. J. Douglas Rizzo2,
  14. Thomas R. Spitzer12,
  15. Daniel J. Weisdorf4,
  16. Mei-Jie Zhang2,
  17. Mary M. Horowitz2

Article first published online: 20 JAN 2006

DOI: 10.1111/j.1365-2141.2005.05947.x

Issue

British Journal of Haematology

British Journal of Haematology

Volume 132, Issue 6, pages 755–769, March 2006

Additional Information

How to Cite

Lazarus, H. M., Pérez, W. S., Klein, J. P., Kollman, C., Bate-Boyle, B., Bredeson, C. N., Gale, R. P., Geller, R. B., Keating, A., Litzow, M. R., Marks, D. I., Miller, C. B., Douglas Rizzo, J., Spitzer, T. R., Weisdorf, D. J., Zhang, M.-J. and Horowitz, M. M. (2006), Autotransplantation versus HLA-matched unrelated donor transplantation for acute myeloid leukaemia: a retrospective analysis from the Center for International Blood and Marrow Transplant Research. British Journal of Haematology, 132: 755–769. doi: 10.1111/j.1365-2141.2005.05947.x

Author Information

  1. 1

    University Hospitals of Cleveland, Ireland Cancer Center, Cleveland, OH, USA

  2. 2

    Center for International Blood and Marrow Transplant Research (CIBMTR), Health Policy Institute, Medical College of Wisconsin, Milwaukee, WI, USA

  3. 3

    Jaeb Center for Health Research, Tampa, FL, USA

  4. 4

    Division of Haematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA

  5. 5

    CancerCare Manitoba, University of Manitoba, Winnipeg, MB, Canada

  6. 6

    Center for Advanced Studies in Leukemia, Los Angeles, CA, USA

  7. 7

    Arizona Cancer Center, Scottsdale, AZ, USA

  8. 8

    Princess Margaret Hospital, University of Toronto, Toronto, ON, Canada

  9. 9

    Mayo Clinic and Foundation, Rochester, MN, USA

  10. 10

    Bristol Children's Hospital, Bristol, England

  11. 11

    Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins School of Medicine, Baltimore, MD, USA

  12. 12

    Massachusetts General Hospital, Boston, MA, USA

  1. †

    Currently at St. Agnes Health Care Baltimore, MD, USA.

*Mary M. Horowitz MD, MS, Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, 8701 Watertown Plank Road, PO Box 26509, Milwaukee, WI, 53226 USA. E-mail: marymh@hpi.mcw.edu

Publication History

  1. Issue published online: 13 FEB 2006
  2. Article first published online: 20 JAN 2006
  3. Received 29 August 2005; accepted for publication 21 November 2005

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Keywords:

  • autograft;
  • unrelated allograft;
  • acute myeloid leukaemia;
  • bone marrow transplantation;
  • haematopoietic stem cell transplant

Summary

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

Most acute myeloid leukaemia (AML) patients lack human leucocyte antigen-identical sibling donors for transplantation. Autotransplants and unrelated donor (URD) transplants are therapeutic options. To compare autologous versus URD transplantation for AML in first (CR1) or second complete remission (CR2), we studied the outcomes of 668 autotransplants were compared with 476 URD transplants reported to the Center for International Blood and Marrow Transplant Research. Proportional hazards regression adjusted for differences in prognostic variables. In multivariate analyses transplant-related mortality (TRM) was significantly higher and relapse lower with URD transplantation. Adjusted 3-year survival probabilities were: in CR1 57 (53–61)% with autotransplants and 44 (37–51)% URD (P = 0·002), in CR2 46 (39–53)% and 33 (28–38)% respectively (P = 0·006). Adjusted 3-year leukaemia-free survival (LFS) probabilities were: CR1 53 (48–57)% with autotransplants and 43 (36–50)% with URD (P = 0·021), CR2 39 (32–46)% and 33 (27–38)% respectively (P = 0·169). Both autologous and URD transplantation produced prolonged LFS. High TRM offsets the superior antileukaemia effect of URD transplantation. This retrospective, observational database study showed that autotransplantation, in general, offered higher 3-year survival for AML patients in CR1 and CR2. Cytogenetics, however, were known in only two-thirds of patients and treatment bias cannot be eliminated.

Therapy for acute myeloid leukaemia (AML) results in complete remission (CR) in 70–80% of newly diagnosed patients (Leith et al, 1997; Lowenberg et al, 1999). Consolidation therapy after attaining remission is necessary to prevent relapse (Cassileth et al, 1988). Even with intensive consolidation, the disease recurs in 50–70% of patients; the risk is higher in patients with antecedent haematological disorders, older age and unfavourable cytogenetic abnormalities (Cassileth et al, 1988; Dillman et al, 1991; Phillips et al, 1991; Wiernik et al, 1992; Leith et al, 1997). For younger patients, dose-escalation using allogeneic haematopoietic stem cells to repopulate ablated bone marrow, and to provide immune-mediated antileukaemia effects, is often undertaken (Copelan et al, 1991; Schiller et al, 1992; Zittoun et al, 1995; Harousseau et al, 1997; Cassileth et al, 1998). Despite the morbidity and mortality of graft-versus-host disease (GVHD) after allogeneic transplantation, human leucocyte antigen (HLA)-identical sibling transplantation in first complete remission (CR1) appears to improve long-term outcome (Copelan et al, 1991; Schiller et al, 1992; Zittoun et al, 1995; Harousseau et al, 1997; Cassileth et al, 1998) although some investigators have questioned this tenet (Wheatley, 2002). Patients achieving a second complete remission (CR2) after relapse also appear to benefit from HLA-identical sibling transplantation (Gale et al, 1996). More than two-thirds of patients; however, do not have a suitable sibling donor. For these patients, autotransplantation or an unrelated donor (URD) transplant are often considered.

Despite the hazards of reinfusing leukaemia cells, several studies demonstrated that autotransplantation provided long-term disease-free survival rates comparable or superior to intensive chemotherapy without stem cell reinfusion when performed in CR1 (Gorin et al, 1991; Cassileth et al, 1993; Laporte et al, 1994; Sierra et al, 1996; Stein et al, 1996; Burnett et al, 1998; Breems & Lowenberg, 2005). Autotransplantation has also been used successfully in patients with more advanced disease, i.e. second or subsequent remission (Selvaggi et al, 1994; Mehta et al, 1996; Linker et al, 2002).

With more than 6 million HLA-typed volunteers available worldwide, suitable unrelated bone marrow donors may be found for as many as 50–85% of patients who do not have an HLA-identical sibling (Anasetti et al, 2000). Registry data showed a steady increase in number of URD transplants for AML (Gratwohl et al, 1999). Analyses of these and other data indicate that some patients attain long-term disease-free survival after URD transplantation for AML (Kernan et al, 1993; Busca et al, 1994; Ringden et al, 1995; Sierra et al, 1997). We conducted a risk-adjusted comparison of autologous and URD transplantation for AML in CR1 or CR2. We used data from the Center for International Blood and Marrow Transplant Research (CIBMTR).

Patients and methods

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

Data sources

The CIBMTR is a research affiliation of the International Bone Marrow Transplant Registry (IBMTR), Autologous Blood and Marrow Transplant Registry (ABMTR) and the National Marrow Donor Program (NMDP), which comprises a voluntary working group of more than 450 transplantation centres worldwide that contribute detailed data on consecutive allogeneic and autologous haematopoietic stem cell transplants to a Statistical Center at the Health Policy Institute of the Medical College of Wisconsin in Milwaukee or the NMDP Coordinating Center in Minneapolis. Participating centres are required to report all transplants consecutively; compliance is monitored by on-site audits. Patients are followed longitudinally, with yearly follow up.

The CIBMTR collects data at two levels: registration and research. Registration data include disease type, age, sex, pretransplant disease stage and chemotherapy responsiveness, date of diagnosis, graft type (bone marrow, blood-derived stem cells or cord blood), pretransplant conditioning regimen, post-transplant disease progression and survival, development of a new malignancy and cause of death. All CIBMTR teams contribute to the registration data. Research data are collected on selected subsets of registered patients and include comprehensive pretransplant and post-transplant clinical information. Computerised checks for errors, doctor reviews of submitted data and on-site audits of participating centres ensure the quality of data.

Transplant procedures were performed under institutional guidelines with consent for treatment approved at each transplant centre. Confirmation of individual consent for central data submission to the NMDP was requested of all surviving patients using communication methods and procedures reviewed and approved by the NMDP Institutional Review Board (IRB) and by the Federal Office for Human Research Protection. Statistical adjustments were made within the evaluable data set to account for a minority of surviving patients who either declined consent for central data submission or in whom the consent could not be verified. Unrelated donor transplants in the NMDP database performed prior to 2002 were required in 2003 to be consented. A massive effort was made to find all patients and receive their consent to have their data used. All patients who died prior to the date of this consent effort were automatically consented. Approximately 15% of the survivors did not give consent for the use of their data or could not be found to obtain their consent. If only ‘consented’ patients (survivors and deaths) were included in the study the sample would be biased towards the deaths. Using all the NMDP data a model called the Corrective Action Plan (CAP) was developed that gave the probability that a survivor would be consented. This probability was used to randomly select deaths in the same proportion as the survivors to prevent bias. This CAP modelled data set was used in this study. No further statistical adjustments or adjustments to the statistical methods was needed. The CAP was reviewed and approved by the NMDP IRB.

Patients

This study included patients with AML in CR1 or CR2, defined using previously published criteria, receiving a first autologous (n = 668) or URD (n = 476) bone marrow transplant between 1989 and 1996 reported to the CIBMTR (Cheson et al, 1990). The median follow up of survivors was 81 (3–174) months for autotransplant recipients and 95 (5–177) months for URD transplant recipients.

End points

Primary end points were transplant-related mortality (TRM), clinical leukaemia relapse (haematological and extramedullary), leukaemia-free survival (LFS), and overall survival. TRM was defined as death during a continuous CR. Relapse was defined as clinical or haematological leukaemia recurrence. For analyses of LFS, failures were clinical or haematological relapses or deaths from any cause; patients alive and in CR were censored at time of last follow up. For analyses of overall survival, failure was death from any cause; surviving patients were censored at the date of last contact.

Statistical analysis

Patient-, disease- and transplant-related variables for the autologous and URD transplant cohorts were compared using the chi-squared statistic for categorical variables and the Kruskal–Wallis test for continuous variables. Univariate probabilities of LFS and survival were calculated using the Kaplan–Meier estimator; the log-rank test was used for univariate comparisons. Probabilities of TRM and leukaemia relapse were calculated using cumulative incidence curves to accommodate competing risks (Gooley et al, 1999). Adjusted probabilities of LFS and survival were calculated using the multivariate Cox models described below, stratified on type of transplant and disease status prior to transplant and weighted by the pooled sample proportion value for each prognostic factor. 95% confidence intervals (CI) for adjusted LFS and survival probabilities and P-values of pairwise comparisons were derived from pointwise estimates and calculated using standard techniques (Klein & Moeschberger, 1997). These adjusted probabilities estimate likelihood of outcomes in populations with similar prognostic factors.

Transplant-related mortality, relapse, LFS and survival after URD versus autologous transplantation were evaluated in multivariate analyses using Cox proportional hazards regression to adjust for other potentially confounding differences between the cohorts (Klein & Moeschberger, 1997). Separate models for CR1 and CR2 transplants and a single model combining CR1 and CR2 transplants were evaluated. Results were similar and only the combined model is presented here. Variables considered in multivariate analysis were those demonstrated to have prognostic importance for transplant outcome in previous studies (Bennett et al, 1985; International Bone Marrow Transplant Registry, 1989; Dastugue et al, 1995); these variables are described in Appendix 1. Cytogenetics were grouped as good prognosis, including 16q; t(8;21); t(15;17); intermediate prognosis including: +8; +21; t(1;7); t(6;9); t(8;16); other abnormalities and poor prognosis including: −5/5q−; −7/7q−; −20/20q−; 3q; 11q; t(5;7); t(9;22). Not all factors affect autologous and URD transplant outcomes equally. For each outcome, we compared the likelihood from a model stratified on type of transplant to the likelihood from a model with different risk co-efficients for each transplant using the likelihood ratio test to determine if there was a statistically significant interaction between transplant type and the factor being examined. When the likelihood ratio test was significant (P < 0·05), an interaction term was added to the model to reflect differential effects in allogeneic and autotransplants. After determining interaction terms, we tested the proportional hazards assumption for each factor in the Cox model using time-dependent covariates. We only found an interaction for age when the outcome was relapse (P = 0·0294). All other interactions had P-values of >0·05. When this indicated differential effects over time (non-proportional hazards), models were constructed by splitting the post-transplant time course into two periods, using the maximised partial likelihood method to find the most appropriate breakpoint. After modeling time-varying effects, the final multivariate model was built using a forward stepwise model selection approach. Each model contained the main effect (type of transplant: URD versus autologous). Factors significantly associated with the outcome variable at a 5% level were kept in the final model. Examination for centre effects used a random effects or frailty model (Andersen et al, 1999). We found no evidence of correlation between centre and any of the outcomes. All P-values are two-sided.

Results

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

Patients

Subject-, disease- and treatment-related variables are shown in Table I. Although the median ages were similar, a higher proportion of autotransplant recipients were younger than 10 years. URD transplant recipients were more likely than autotransplant recipients to be male, to have a performance score <90%, to have unfavourable cytogenetics and to have required more than 8 weeks of therapy to achieve CR1. Recipients of URD transplants were also more likely to receive total body irradiation (TBI) for pretransplant conditioning and to be transplanted more recently.

Table I.  Characteristics of 668 patients receiving autotransplants and 476 subjects receiving unrelated donor transplants for acute myeloid leukaemia in first or second complete remission, 1989–96, and reported to the CIBMTR.
VariableType of transplantP-value*
AutologousUnrelated donor
N EvaluableN (%)N EvaluableN (%)

  1. CIBMTR, Center for International Blood and Marrow Transplant Research; BM, bone marrow; HLA, human leucocyte antigen; TBI, total body irradiation; FAB, French-American-British classification; WBC, white blood cell count; CR, complete remission; NA, not applicable; GVHD, graft-versus-host disease; CsA, ciclosporin; MTX, methotrexate; GF, growth factors; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; CMV, cytomegalovirus.

  2. *The chi-square test was used for discrete covariates; the Kruskal–Wallis test was used for continuous covariates.

  3. †Good prognosis included: 16q; t(8;21); t(15;17). Intermediate prognosis included: +8; +21; t(1;7); t(6;9); t(8;16); other abnormalities. Poor prognosis included: −5/5q−; −7/7q−; −20/20q−; 3q; 11q; t(5;7); t(9;22).

  4. ‡For patients transplanted in second remission.

  5. §Serological method for A and B and molecular typing for DR.

Number of patients 668 476 
Age [years, median (range)]66825 (1–50)47627 (1–58)0·043
Age at transplant (years)668 476 0·003
 <10 152 (23) 66 (14) 
 10–19 125 (19) 97 (20) 
 20–29 106 (16) 99 (21) 
 30–39 144 (21) 112 (24) 
 ≥40 141 (21) 102 (21) 
Male sex667337 (51)476276 (58)0·013
Karnofsky score pretransplant <90%64195 (15)474109 (23)0·001
Remission status pretransplant668 476 <0·001
 CR1 489 (73) 203 (43) 
 CR2 179 (27) 273 (57) 
FAB subtype668 476 <0·001
 M1 or M2 274 (41) 180 (38) 
 M3 79 (12) 48 (10) 
 M4 160 (24) 86 (18) 
 M5 or M6 or M7 120 (18) 71 (15) 
 Other/unknown 35 (5) 91 (19) 
Cytogenetics†668 476 0·004
 No abnormalities 181 (27) 104 (22) 
 Good prognosis 96 (14) 46 (10) 
 Intermediate prognosis 96 (14) 98 (21) 
 Poor prognosis 68 (11) 50 (10) 
 Unknown 227 (34) 178 (37) 
WBC at diagnosis, median (range) × 109/l57314 (0·1–690)39312 (0·4–428)0·06
TBI in conditioning regimen668112 (17)476384 (81)<0·001
Time to achieve CR1 >8 weeks641196 (31)435204 (47)<0·001
Duration of first CR1 ≥1 year‡15674 (47)23490 (38)0·08
Time from remission to transplant (d)616102 (8–1406)450104 (2–769)0·85
High-dose cytarabine for induction or consolidation of first remission666223 (33)383160 (42)0·007
Donor age [years, median (range)]NA 41736 (19–56)–
Donor–recipient gender match  472 –
 Male–male   174 (37) 
 Male–female   105 (22) 
 Female–male   100 (21) 
 Female–female   93 (20) 
CMV status donor/recipientNA 463 –
 −/−   156 (34) 
 +/−   68 (14) 
 −/+   143 (31) 
 +/+   96 (21) 
Donor–recipient HLA-match§NA 476 –
 Known allele level match   243 (51) 
 Serological match (no DNA typing)   138 (29) 
 Allele mismatch   33 (7) 
 Major mismatch   62 (13) 
Positive CMV status612304 (50)471241 (51)0·63
Graft type for autotransplants660 NA –
 Purged BM 174 (26)   
 Unpurged BM 443 (67)   
 Peripheral blood 43 (7)   
Year of transplant668 476 <0·001
 1989 62 (9) 15 (3) 
 1990 67 (10) 26 (5) 
 1991 92 (14) 44 (9) 
 1992 98 (15) 48 (10) 
 1993 104 (16) 50 (11) 
 1994 100 (15) 80 (17) 
 1995 83 (12) 94 (20) 
 1996 62 (9) 119 (25) 
GVHD prophylaxisNA 472 –
 CsA ± other (not MTX)   45 (10) 
 MTX ± other (not CsA)   35 (7) 
 CsA + MTX ± other   275 (58) 
 T-cell depletion ± other   105 (22) 
 Other   12 (3) 
GF post-transplant: G-CSF or GM-CSF593178 (30)14943 (29)0·78
Median follow up of survivors, (range; months)33881 (3–174)16195 (5–177)–

Univariate analyses

Univariate comparisons of transplant outcomes are shown in Table II and Figs 1 and 2. The probability of attaining a neutrophil count of at least 0·5 × 109/l by 100 d after transplantation was similar. 100-d TRM was significantly higher with URD transplantation compared with autotransplantation: 30% (95% CI: 24–37%) vs. 6% (4–9%) in CR1 (Fig 1, pointwise P < 0·001) and 31% (25–37%) vs. 7% (4–11%) in CR2 (Fig 1, pointwise P < 0·001). Five-year relapse rates were significantly lower with URD transplantation: 13% (8–18%) vs. 40% (35–45%) in CR1 (Fig 2, pointwise P < 0·001) and 15% (11–20%) vs. 50% (42–58%) in CR2 (Fig 2, pointwise P < 0·001). These competing risks did not completely offset one another. Five-year LFS rates were lower after URD transplantation than after autotransplantation: 36% (30–43%) vs. 50% (46–55%) in CR1 (P = 0·001) and 32% (26–38%) vs. 35% (28–43%) in CR2 (P = 0·46). Similarly, overall survival at 5 years was lower with URD transplantation than with autotransplantation: 39% (32–46%) vs. 55% (50–59%) in CR1 (P < 0·001) and 33% (28–39%) vs. 40% (33–48%) in CR2 (P = 0·13).

Table II.  Univariate analysis of transplant outcomes after autologous versus unrelated donor transplants for acute myeloid leukaemia.
Outcome eventType of transplantP-value†
AutotransplantsUnrelated donor
N EvaluableProb (95% CI)*N EvaluableProb (95% CI)*

  1. TRM, treatment-related mortality; LFS, leukaemia-free survival; Prob, probability; CI, confidence interval.

  2. *Probabilities of leukaemia-free survival and overall survival were calculated using the Kaplan–Meier product limit estimate. Engraftment, TRM and relapse were calculated using the cumulative incidence estimate.

  3. †Pointwise P-value was used for univariate comparisons between groups.

ANC >0·5 × 109/l at100 d65195 (93–96)47593 (90–95)0·22
TRM at 100 d
 All patients6586 (5–8)45431 (26–35)<0·001
 CR14826 (4–9)19330 (24–37)<0·001
 CR21767 (4–11)26131 (25–37)<0·001
TRM at 5 years
 All patients65811 (9–13)45452 (47–57)<0·001
 CR148210 (7–12)19351 (43–59)<0·001
 CR217615 (10–21)26153 (46–60)<0·001
Relapse at 5 years
 All patients65843 (39–47)45414 (11–18)<0·001
 CR148240 (35–45)19313 (8–18)<0·001
 CR217650 (42–58)26115 (11–20)<0·001
LFS at 5 years
 All patients65846 (42–50)45434 (29–38)<0·001
 CR148250 (46–55)19336 (30–43)0·001
 CR217635 (28–43)26133 (26–38)0·46
Overall survival at 5 years
 All patients66851 (47–55)47636 (31–40)<0·001
 CR148955 (50–59)20339 (32–46)<0·001
 CR217940 (33–48)27333 (28–39)0·13

Figure 1. Cumulative incidence of transplant-related mortality (TRM) for patients transplanted in first (CR1) or second complete remission (CR2) for acute myeloid leukaemia (AML), by type of transplant.

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Figure 2. Cumulative incidence of relapse patients transplanted in first (CR1) or second complete remission (CR2) for acute myeloid leukaemia (AML), by type of transplant.

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image

Multivariate analyses

In multivariate analyses, the risk of TRM after autotransplantation was significantly lower than after URD transplantation (Table III, P < 0·001). The risk of relapse was significantly higher with autologous versus URD transplantation, by nearly twofold for patients younger than 20 years (P = 0·003) and by more than fourfold for older patients (P < 0·001; Table III). Autotransplant recipients were significantly more likely to survive leukaemia-free for the first 3 months after transplant (P < 0·001); risks of treatment failure did not differ after this 3-month period (Table IV). Similarly, autotransplant recipients had lower overall mortality in the first 5 months after transplant (P < 0·001), but after this time, autotransplant and URD transplant recipients had similar survivals (Table IV). Adjusted (for the other prognostic variables identified in multivariate analyses) 3-year probabilities of LFS were 53 (48–57)% and 43 (36–50)% after autologous and URD transplants in CR1 (P = 0·021); adjusted probabilities in CR2 were 39 (32–46)% and 33 (27–38)%, for autologous and URD transplants respectively (P = 0·169; Fig 3). There was a statistically significant (95% CI excluded zero) LFS advantage for autologous transplants over URD transplants in patients transplanted in CR1 for much of the study period, but not for those transplanted in CR2. Adjusted 3-year probabilities of survival were 57 (53–61)% after autologous and 44 (37–51)% after URD transplants in CR1 (P = 0·002); adjusted probabilities in CR2 were 46 (39–53)% and 33 (28–38)% for autologous and URD transplants respectively (P = 0·006; Fig 4). Figure 5 shows the 95% CI for the absolute difference in survival between autologous and URD transplants over time. Again, for most of the study period there was a survival advantage for autotransplants in CR1 but this was statistically significant only for the early post-transplant period in CR2.

Table III.  Multivariate analysis comparing treatment-related mortality and relapse after autologous versus unrelated donor transplants for acute myeloid leukaemia.
VariablesRelative risk (95% CI)P-value

  1. CR, complete remission; FAB, French-American-British classification; CMV, cytomegalovirus.

  2. *Reference group.

  3. †Four degrees of freedom.

  4. ‡Two degrees of freedom.

  5. P12, probability of testing (1) = (2); P13, probability of testing (1) = (3).

Treatment-related mortality
Type of transplant
 Unrelated donor1·00* 
 Autologous0·18 (0·13–0·24)<0·001
Other significant covariates
Age (years)
 <201·00* 
 ≥201·58 (1·25–1·99)<0·001
Disease status pretransplant
 CR11·00* 
 CR21·28 (1·00–1·63)0·044
FAB classification
 M1, M21·00*Poverall = 0·059†
 M30·64 (0·41–0·98)0·040
 M40·86 (0·62–1·18)0·342
 M5, M6, M70·84 (0·59–1·20)0·338
 Other/unknown1·23 (0·89–1·69)0·199
Patient CMV status
 Negative1·00* 
 Positive1·57 (1·24–1·99)<0·001
Relapse
Type of transplant
Age <20 years
 Unrelated donor1·00* 
 Autologous1·83 (1·23–2·73)0·003
Age ≥20 years
 Unrelated donor1·00* 
 Autologous3·65 (3·37–3·95)<0·001
Other significant covariates
Remission status pretransplant
 (1) First complete remission1·00*Poverall < 0·001‡
 Second complete remission
 (2) CR1 duration <1 year2·04 (1·53–2·70)P12 < 0·001
 (3) CR1 duration ≥1 year1·05 (0·74–1·49)P13 = 0·778
FAB classification
 M1, M21·00*Poverall = 0·010†
 M30·43 (0·27–0·70)<0·001
 M40·93 (0·70–1·22)0·571
 M5, M6, M71·01 (0·75–1·36)0·935
 Other/unknown0·76 (0·48–1·20)0·239
Cytogenetics
 No abnormalities1·00*Poverall < 0·001†
 Good0·45 (0·28–0·73)0·001
 Intermediate1·03 (0·73–1·43)0·878
 Poor0·79 (0·52–1·20)0·265
 Unknown1·18 (0·91–1·55)0·219
Table IV.  Multivariate analysis comparing leukaemia-free survival and overall survival after autologous versus unrelated donor transplants for acute myeloid leukaemia.
VariableRelative risk (95% CI)P-value

  1. CR, complete remission; FAB, French-American-British classification; CMV, cytomegalovirus.

  2. *Reference group.

  3. †Two degrees of freedom.

  4. ‡Four degrees of freedom.

  5. §Recipients of autologous transplantation were more likely to survive leukaemia-free for the first 3 months after transplant (RR = 0·47; 95% CI: 0·36–0·62); risks of treatment failure did not differ after this 3-month period.

  6. ¶Autotransplants recipients had lower overall mortality in the first 5 months after transplant (RR = 0·33; 95% CI: 0·26–0·43), but recipients had similar survival beyond 5 months after autotransplant or URD transplant.

  7. P12, probability of testing (1) = (2); P13, probability of testing (1) = (3).

Leukaemia-free survival
Type of transplant
 (1) Unrelated donor§1·00* 
 Autologous
 (2) First 3 months post-transplant0·47 (0·36–0·62)P12 < 0·001
 (3) >3 months post-transplant0·89 (0·73–1·10)P13 = 0·280
Other significant covariates
Disease status pretransplant
 (1) First complete remission1·00*Poverall < 0·001†
 Second complete remission
 (2) CR1 duration <1 year1·53 (1·25–1·86)P12 < 0·001
 (3) CR1 duration ≥1 year1·18 (0·94–1·49)P13 = 0·157
FAB classification
 M1, M21·00*Poverall = 0·004‡
 M30·55 (0·39–0·75)<0·001
 M40·88 (0·72–1·08)0·217
 M5, M6, M70·94 (0·73–1·13)0·392
 Other/unknown1·06 (0·82–1·37)0·675
Cytogenetics
 No abnormalities1·00*Poverall < 0·001‡
 Good0·55 (0·39–0·77)0·001
 Intermediate1·00 (0·78–1·27)0·994
 Poor1·02 (0·77–1·36)0·902
 Unknown1·21 (0·99–1·48)0·062
Patient CMV status
 Negative1·00*Poverall = 0·001†
 Positive1·36 (1·16–1·59)<0·001
 Unknown1·46 (1·03–2·08)0·036
Overall survival
Type of transplant
 (1) Unrelated donor¶1·00* 
 Autologous
 (2) First 5 months post-transplant0·33 (0·26–0·43)P12 < 0·001
 (3) >5 months post-transplant0·98 (0·78–1·23)P13 = 0·829
Other significant covariates
FAB classification
 M1, M21·00*Poverall = 0·008‡
 M30·55 (0·39–0·77)0·001
 M40·87 (0·70–1·07)0·182
 M5, M6, M70·94 (0·75–1·17)0·567
 Other/unknown1·08 (0·83–1·41)0·579
Disease status pretransplant
 (1) First complete remission1·00*Poverall < 0·001†
 Second complete remission
 (2) CR1 duration <1 year1·54 (1·26–1·89)P12 < 0·001
 (3) CR1 duration ≥1 year1·18 (0·93–1·50)P13 = 0·179
Cytogenetics
 No abnormalities1·00*Poverall = 0·008‡
 Good0·50 (0·35–0·71)<0·001
 Intermediate1·01 (0·79–1·29)0·958
 Poor1·02 (0·76–1·36)0·909
 Unknown1·22 (0·99–1·50)0·060
Patient CMV status
 Negative1·00*Poverall = 0·002†
 Positive1·33 (1·13–1·57)0·001
 Unknown1·40 (0·97–2·02)0·074

Figure 3. Adjusted probability of leukaemia-free survival (LFS) for patients transplanted in first (CR1) or second complete remission (CR2) for acute myeloid leukaemia (AML), by type of transplant.

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Figure 4. Adjusted probability of overall survival for patients transplanted in first (CR1) or second complete remission (CR2) for acute myeloid leukaemia (AML), by type of transplant.

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image

Figure 5. Absolute difference of adjusted survival probabilities with 95% confidence interval (CI) for patients transplanted in (A) first (CR1) or (B) second complete remission (CR2) for acute myeloid leukaemia (AML; Difference = Survival with autotransplant − Survival with URD transplant).

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image

We also undertook an analysis for patient outcome stratifying further donor–recipient HLA-match into match versus mismatch. No statistical differences were noted for TRM, relapse, LFS and overall survival at 1, 3 and 5 years after transplant (data not shown).

Discussion

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

Few studies have compared the efficacy of alternative donor and autologous transplants in AML. In this analysis, we noted that URD transplants were associated with a markedly enhanced antileukaemic effect compared with autotransplants, a finding also reported in chronic myeloid leukaemia (Hessner et al, 1995). TRM after URD transplants, however, was fivefold greater than observed with autotransplants, offsetting any potential benefit against recurrent leukaemia. Autotransplants were associated with higher 3-year LFS than URD transplants in CR1 and higher overall survival than URD transplants in both CR1 and CR2. This difference resulted entirely from survival differences in the first few months after transplantation. Among patients surviving the first 5 months, subsequent survival was similar in the autotransplant and URD transplant cohorts.

Previous studies have shown that the CIBMTR collect results of ≥50% of transplants conducted in North America, while the NMDP facilitates nearly all URD transplants in the US. Consequently, this study uses data which are broadly representative of clinical practice in the United States during the study period (Graves, 1991; National Hospital Discharge Survey, 1992, 1993; Silberman et al, 1994; Curtis et al, 1997). However, this was a non-randomised study in which the decision to perform an autologous versus URD transplantation was made by individual doctors, not by experimental design. A significantly greater percentage of autotransplant recipients were younger than 10 years and a lower percentage had poor Karnofsky performance scores at transplant (Table I). Additionally, URD recipients were more likely to have higher risk cytogenetic abnormalities (Table I). Cytogenetic findings are the most important prognostic factor in conventional therapy for AML, with a dismal outcome for patients in high-risk groups (Bloomfield et al, 1998). Once patients attain CR, unfavourable cytogenetics may lose prognostic significance, especially for URD transplants. In the largest study reported, cytogenetics did not influence outcome in AML patients undergoing URD transplants (Sierra et al, 2000). Adverse cytogenetics are associated with worse outcome of HLA-identical sibling transplants for AML; effects on URD transplantation are uncertain (Gale et al, 1995; Ferrant et al, 1997). Patients receiving URD grafts also took a longer time to attain CR1, a factor recently reported to influence outcome (Estey et al, 2000). Although statistical models were used to adjust for these factors, cytogenetic data were missing for many patients; differences in these and other less well-characterised prognostic factors may have led to selection of better risk patients for autotransplantation, which may account, in part, for their higher LFS. Even if the data were complete, adjustments for confounding cannot guarantee removal of bias (Deeks et al, 2003). We also compared autologous versus URD transplants separately for each cytogenetics risk group (good, intermediate and poor prognosis and unknown). The results were similar to those in Table IV. A formal test of an interaction between these risk groups and transplant type was not statistically significant.

Most URD transplants used a conditioning regimen that included TBI. Most AML studies have not demonstrated a superiority of TBI versus non-TBI regimens in CR1 or CR2 (Ringden et al, 1996; Hartman et al, 1998; Litzow et al, 2002). In addition, URD recipients were more likely to have received high-dose cytarabine therapy during induction or consolidation for CR1. Use of this agent was recently shown by the IBMTR to have no significant influence on outcome of HLA-identical sibling transplants for AML in CR1 and prior cytarabine was not significantly associated with any outcome in this study (Tallman et al, 2000).

More than one-quarter of autografts in this study were treated in vitro to remove leukaemia cells (purged). Prior studies suggest that purging of autografts may lead to significantly slower marrow recovery, higher TRM and lower relapse rates (Gorin et al, 1990; Cassileth et al, 1998). In this study, purging was not significantly associated with any of these outcomes. However, many autotransplant recipients received multiple courses of consolidation prior to bone marrow harvest, which may lead to in vivo purging and could favourably reduce the risks of relapse.

In the largest single-centre trial, Sierra et al (2000) reported their experiences in 161 AML patients in various disease states who received non-T-cell depleted URD transplants after cyclophosphamide/fractionated TBI (1320–1575 cGy). Sixteen patients were treated in CR1 (all considered high risk) and 40 in CR2 (28 considered high risk). For the entire group of 161 patients, transplant in remission, a marrow nucleated cell dose of at least 3·5 × 108/kg, and cytomegalovirus seronegative patient and donor status were favourable prognostic factors. Probabilities of LFS and non-relapse mortality in CR1 were 51% and 31%, respectively; corresponding probabilities in CR2 were 28% and 49%. These results are similar to our data.

Few studies have compared the results of alternative donors to autotransplantation. A report from the European Blood and Marrow Transplant Group (EBMT) compared autotransplantation, HLA-identical sibling transplantation and URD transplantation; this publication restricted the analysis to patients with secondary AML and is not reviewed herein (de Witte et al, 2000). In a study by Ringden et al (1997), which utilised a matched-pair analysis, autotransplantation appeared to provide superior overall survival at 2 years in CR1 patients. These analyses were limited by their retrospective nature, small sample size, patient heterogeneity and other selection factors. The EBMT is currently conducting a prospective, multicentre, non-randomised comparison of URD transplantation versus autotransplantation in AML (L. Fouillard, O. Ringdén and N. C. Gorin, personal communication).

The current study was hampered by limitations in defining the degree of match between unrelated donor–recipient pairs. Serological, rather than DNA typing data were used in most instances. Recent improvements in the precision of HLA-typing methodologies have resulted in the identification of more closely matched donors, which are associated with a lower incidence and severity of GVHD and improved survival (Petersdorf et al, 1998; Sasazuki et al, 1998). In some disease settings, such as chronic myeloid leukemia, HLA-identical URD transplant results approach those of HLA-identical sibling transplants (Lamparelli et al, 1997).

These data indicate that autologous and URD transplants can extend survival for some patients that are unlikely to be cured by chemotherapy. The increased toxicity and TRM observed with URD transplants are partially counterbalanced by improved protection against relapse. It remains to be determined whether improved HLA-matching and advances in supportive care for URD transplants, including use of peripheral blood rather than bone marrow as the graft source, will further improve upon these results. Correspondingly, the addition of targeted chemotherapeutic agents, such as gemtuzumab, in the autotransplant group may reduce relapse rates without adding substantial toxicity (Sievers et al, 1999). This retrospective comparison indicates that the results following autotransplantation are superior for TRM and 3-year survival in patients with AML in CR1 and CR2. Prospective studies addressing additional clinical variables are needed to better guide clinical decision-making, i.e. risk-adjusted therapy, for patients with AML.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

Supported by Public Health Service Grant U24-CA76518 from the National Cancer Institute, the National Institute of Allergy and Infectious Diseases, and the National Heart, Lung and Blood Institute; Office of Naval Research; Health Resources Services Administration (DHHS); and grants from AABB, Aetna; AIG Medical Excess; American Red Cross; Amgen, Inc.; Anonymous donation to the Medical College of Wisconsin; AnorMED, Inc.; Berlex Laboratories, Inc.; Biogen IDEC, Inc.; Blue Cross and Blue Shield Association; BRT Laboratories, Inc.; Celgene Corp.; Cell Therapeutics, Inc.; CelMed Biosciences; Cubist Pharmaceuticals; Dynal Biotech, LLC; Edwards Lifesciences RMI; Endo Pharmaceuticals, Inc.; Enzon Pharmaceuticals, Inc.; ESP Pharma; Fujisawa Healthcare, Inc.; Gambro BCT, Inc.; Genzyme Corporation; GlaxoSmithKline, Inc.; Histogenetics, Inc.; Human Genome Sciences; ILEX Oncology, Inc.; Kirin Brewery Company; Ligand Pharmaceuticals, Inc.; Merck & Company; Millennium Pharmaceuticals; Miller Pharmacal Group; Milliman USA, Inc.; Miltenyi Biotec; National Center for Biotechnology Information; National Leukemia Research Association; National Marrow Donor Program; NeoRx Corporation; Novartis Pharmaceuticals, Inc.; Novo Nordisk Pharmaceuticals; Ortho Biotech, Inc.; Osiris Therapeutics, Inc.; Pall Medical; Pfizer, Inc.; Pharmion Corp.; QOL Medical; Roche Laboratories; StemCyte, Inc.; Stemco Biomedical; StemSoft Software, Inc.; SuperGen, Inc.; Sysmex; The Marrow Foundation; THERAKOS, a Johnson & Johnson Co.; University of Colorado Cord Blood Bank; Valeant Pharmaceuticals; ViaCell, Inc.; ViraCor Laboratories; WB Saunders Mosby Churchill; and Wellpoint Health Network.

The contents of this article are solely the responsibility of the authors and do not necessarily represent the official views of the National Cancer Institute.

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  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix
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Appendix

  1. Top of page
  2. Abstract
  3. Patients and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  8. Appendix

Appendix 1

Table Appendix1..  Variables tested in Cox proportional hazards regression models.

  1. CR, complete remission; FAB, French-American-British classification; WBC, white blood cell count; CMV, cytomegalovirus; HLA, human leucocyte antigen.

  2. *Included in all models.

Main effect variable*
 Type of transplant: unrelated donor versus autologous
Patient-related variables
 Age at transplant: <20 years vs. ≥20 years
 Gender: female versus male
 Karnofsky performance status pretransplant: <90% vs. ≥90%
Disease-related variables at diagnosis
 FAB subtype: M1, M2 versus M3 versus M4 versus M5, M6, M7 versus other/unknown
 WBC at diagnosis
 Cytogenetics: good prognosis versus intermediate prognosis versus poor prognosis versus no abnormalities versus unknown
Disease-related variables at transplant
 Remission status at transplant: CR1 versus CR2
 Time to achieve CR1: ≤8 weeks vs. >8 weeks
 Duration of first CR: <1 year vs. ≥1 year
 Time from remission to transplant
 High-dose cytarabine for induction or consolidation of first remission: yes versus no
Treatment-related
 Donor age: <30 years vs. ≥30 years
 Donor–recipient gender match: male–male versus female–male versus male–female versus female–female
 Donor–recipient CMV status: −/− vs. +/− vs. −/+ vs. +/+
 Recipient CMV status: + vs. −
 Donor–recipient HLA-match: known match versus potential match versus allele mismatch versus major mismatch
 Graft type for autotransplants: purged BM versus unpurged BM versus peripheral blood
 Year of transplant: ≤1993 vs. >1993
 Growth factors post-transplant: yes versus no
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