Volume 12, Issue 10 , Pages 1047-1055, October 2006
Impact of Conditioning Regimen Intensity on Outcome of Allogeneic Hematopoietic Cell Transplantation for Advanced Acute Myelogenous Leukemia and Myelodysplastic Syndrome
Article Outline
Abstract
We reviewed 136 patients with advanced acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic transplantation to assess the impact of conditioning regimen intensity on outcome. Thirty-nine patients receiving nonmyeloablative stem cell transplantation (NST) were compared with 97 patients receiving myeloablative transplantation. Patients receiving NST were at high risk for treatment-related complications given that they were older, 57 vs 43 years (P < .001), and more likely had received previous or myeloablative transplantation (54% vs 2%; P < .0001). The cumulative risk of relapse was higher for patients after NST (61% vs 38%; P = .02). The 100-day mortality was less after NST (15% vs 32%) Overall survival (OS) at 2 years was 28% for NST and 34% for myeloablative transplantation (P = .89). Progression-free survival (PFS) at 2 years was 20% for NST and 31% for myeloablative transplantation (P = .31). Cox regression analysis showed that the intensity of the conditioning regimen had no effect on either OS or PFS. Despite the high-risk features of patients with advanced AML or MDS undergoing NST, OS and PFS in these patients was similar to those in patients receiving myeloablative transplantation. These results demonstrate that dose intensity plays a significant role in control of disease after transplantation, but that this benefit is negated by increasing treatment-related mortality. These results suggest that NST is a reasonable alternative for patients with advanced AML and MDS at high risk for complications after myeloablative transplantation.
Key Words: Acute leukemia, Myelodysplastic syndrome, Allogeneic, Graft versus leukemia
Introduction
The use of nonmyeloablative conditioning before allogeneic hematopoietic stem cell transplantation (HSCT) has increased dramatically over the past 5 years. This increase has been led in part by the recognition that engraftment of allogeneic hematopoietic cells can be achieved in many cases with less-intensive conditioning, and that such conditioning will be associated with reduced regimen-related toxicity. This approach has been adopted particularly for older patients and those who have previously undergone a fully myeloablative transplantation [1, 2, 3, 4].
The shift toward nonmyeloablative and away from ablative conditioning regimens is motivated by the observation that graft-versus-tumor (GVT) activity plays a significant role after allogeneic HSCT in some diseases and that the antineoplastic effects of chemotherapy and radiation may play a secondary role. The relative contributions of dose-intensive chemotherapy/radiotherapy and GVT activity to the cure of patients likely depends on disease type and disease stage at transplantation.
Acute myelogenous leukemia (AML) and myelodysplastic syndrome (MDS) are among the leading diagnoses for which nonmyeloablative HSCT is performed. However, the role of dose intensity in producing cures for these diagnoses is not clear, particularly in patients with advanced disease. The importance of dose intensity for patients with AML in first remission was demonstrated in a randomized study of high-dose versus intermediate- or low-dose cytosine arabinoside (ara-C) as postremission intensification therapy. In patients under age 60 years, high-dose ara-C produced superior long-term event-free survival and led to its routine use in first-remission AML patients [5].
Dose-intensive therapy has not benefited all patients, however. In contrast to patients under age 60, no improvement in outcome was observed for patients over age 60 receiving high-dose ara-c–based chemotherapy compared with less-intensive chemotherapy, and to date there remains no clear role for consolidation chemotherapy for older individuals [6, 7, 8]. Conflicting data also appear from studies of autologous HSCT for patients with AML. Supporting a role for dose-intensive therapy, studies have documented long-term remissions and cures for patients receiving high-dose chemotherapy and autologous HSCT for patients with AML beyond first remission, whereas standard chemotherapy alone in these settings is almost always insufficient to produce cure [9, 10]. In contrast, prospective randomized studies of autologous HSCT versus chemotherapy alone as postremission therapy for AML in first complete remission have not demonstrated a convincing advantage for high-dose therapy and autologous HSCT arms [11, 12, 13]. The underlying biology of the leukemia itself has significant influence. The benefit of high-dose therapy has been observed in patients with favorable-risk cytogenetics, but not in those with adverse karyotypic features [14].
Because allogeneic HSCT using nonmyeloablative conditioning regimens depends almost entirely on the GVL effect for success, comparing the outcome of patients after myeloablative and nonmyeloablative HSCT may help elucidate the relative contribution of dose-intensive conditioning to the outcome of HSCT for patients with advanced AML or MDS. We examined our experience with nonmyeloablative transplantation using low-dose intravenous busulfan and fludarabine as conditioning in patients with advanced AML or MDS and compared outcome and reasons for treatment failure with those in patients with a similar diagnosis receiving conventional high-dose preparative regimens followed by allogeneic transplantation at our institution. The retrospective analysis included 136 patients with advanced AML or MDS receiving either nonmyeloablative HSCT (n = 39) or myeloablative HSCT (n = 97).
Patients and methods
Patient Population
Patients with advanced AML or advanced MDS receiving unmanipulated HLA-matched allogeneic transplantation from 1997–2002 at our institution were included in the analysis. All patients had advanced disease at the time of transplantation, as defined by AML beyond first remission or MDS with excess blasts or secondary MDS. Eligibility requirements for myeloablative transplantation included Eastern Cooperative Oncology Group performance status 0–2, absence of active infection at the time of study entry, left ventricular ejection fraction > 40%, and normal or near-normal kidney and liver function values. Eligibility requirements for nonmyeloablative transplantation were similar to those for ablative transplantation, except for an ejection fraction >
30%.
All patients receiving nonmyeloablative conditioning were evaluated for myeloablative transplantation and considered to have contraindications to that approach. Relative contraindications to myeloablative transplantation included previous myeloablative transplantation, age >50 years, or significant organ dysfunction. Between May 2000 and December 2002, 39 patients underwent transplantation using a nonmyeloablative approach. The decision to pursue nonmyeloablative as opposed to myeloablative conditioning during this period was based on patient and physician preference. A subset of patients over age 50 was previously reported in an analysis of outcome of elderly patients after transplantation [3].
The Human Subjects Protection Committee of the Dana-Farber Cancer Institute approved all investigational protocols. Written informed consent was obtained in all cases.
Donors
All donors included in this analysis were HLA-matched at A, B, and DR loci. Unrelated donors were required to match recipients at HLA-DR loci by molecular analysis. Class II typing was performed with sequence-specific oligonucleotide probes. The majority of patients (87%) in the nonmyeloablative cohort received filgrastim-mobilized peripheral blood stem cells (PBSCs). In the myeloablative group, 24 (25%) patients received filgrastim-mobilized PBSCs and 73 (75%) received bone marrow. PBSC donors in both groups were mobilized with filgrastim at 10 μg/kg/day for 5 days. Stem cell collection was initiated on the fifth day of filgrastim administration and continued until a sufficient number of CD34+ stem cells were obtained. The target stem cell dose was >6 × 106 CD34+ cells/kg. Bone marrow was obtained in the operating room under general or epidural anesthesia, and the targeted cell count was >2 × 108 nucleated cells/kg.
Conditioning Regimens
Patients undergoing nonmyeloablative transplantation received fludarabine 30 mg/m2/day on days −6, −5, −4, and −3 and intravenous busulfan 0.8 mg/kg/day on days −6, −5, −4, and −3. The patients receiving myeloablative transplantation were treated with either high-dose cyclophosphamide 1800 mg/m2 × 2 days and fractionated total body irradiation 1400 cGy in 7 fractions over 4 days (in 91 patients [94%]) or oral busulfan 16 mg/kg divided over 4 days) and cyclophosphamide 1800 mg/m2 × 2 days (in 6 patients [6%]).
GVHD Prophylaxis
All patients included in the analysis received immunosuppressive therapy as GVHD prophylaxis. The nonmyeloablative transplant recipients were treated on sequential protocols with defined GVHD prophylaxis. Thirty patients received GVHD prophylaxis consisting of cyclosporine plus corticosteroids; 9 patients received tacrolimus or cyclosporine combined with methotrexate. Of the 97 patients who underwent myeloablative conditioning, 91 received GVHD prophylaxis consisting of tacrolimus and methotrexate or cyclosporine and methotrexate; 6 patients with a contraindication to methotrexate administration received a corticosteroid or rapamycin in addition to a calcineurin inhibitor.
Chimerism Analysis
The presence of donor-derived hematopoiesis was assessed in the patients undergoing nonmyeloablative transplantation. Unfractionated donor chimerism was assessed from bone marrow aspirates at approximately day +30 and day +100 posttransplantation. Genotypes of donor and recipient were determined using DNA extracted from pretransplantation samples. Nine short tandem repeat loci were typed using the ABI Profiler Plus Kit and ABI 310 Genetic Analyzer (Applied Biosystems, Foster City, CA) to resolve alleles. “Informative” alleles that were present only in the donor or recipient were used in the chimerism calculations. In cases of sex- mismatched donor–recipient pairs for which molecular chimerism analysis was not available, assessment of donor chimerism was based on fluorescent in situ hybridization for X and Y chromosomes or on cytogenetic analysis.
Statistical Considerations
Descriptive statistical analysis was performed to assess patient baseline characteristics, disease, disease status at conditioning, GVHD prophylaxis, and source of progenitor cells. The 2-sided Fisher’s exact test was used for 2 × 2 table analysis, and the 2-sided Wilcoxon’s rank-sum test was used for 2-sample comparison of continuous variables.
Cumulative incidence curves for nonrelapse death and relapse with or without death were constructed reflecting time to relapse and time to nonrelapse death as competing risks. The difference between cumulative incidence curves in the presence of a competing risk was tested using the Gray method [15]. Time to relapse and time to nonrelapse death were measured from the date of stem cell infusion. Patients who were alive without relapse were censored at the time last seen alive and relapse-free. Overall survival (OS) and progression-free survival (PFS) were calculated using the Kaplan-Meier method. The log-rank test was used for comparisons of Kaplan-Meier curves. PFS was defined as the time from stem cell infusion to relapse or death from any cause. OS was defined as the time from stem cell infusion to death from any cause. Potential prognostic factors for OS, PFS, relapse, and nonrelapse death were examined using the proportional hazards model and the competing-risks regression model. The competing-risks regression model is a semiparametric proportional hazards model for subdistribution of relapse (or nonrelapse death) in the presence of a competing risk [16]. All interaction terms, including interaction with time, were examined in the proportional hazards regression model.
Results
Patient Characteristics
The characteristics of all patients are detailed in Table 1. AML was present in 59% of the recipients of nonmyeloablative conditioning and in 61% of the recipients of myeloablative conditioning, with the remainder in each group having MDS. Active disease was present at the time of transplantation in 83% of the patients with AML receiving nonmyeloablative transplantation and in 68% of the patients with AML receiving myeloablative transplantation. All patients received unmanipulated marrow or PBSCs with immunosuppressive medication as GVHD prophylaxis. The patients receiving nonmyeloablative transplantation were significantly older than those receiving myeloablative transplantation (median age, 56 years [range, 21–70 years] vs 43 [21–65], respectively; P < .0001); 26% of those receiving nonmyeloablative transplantation were over age 60, compared with only 3% of myeloablative transplantation recipients (P = .0002). Patients receiving nonmyeloablative conditioning were more likely to have had previous myeloablative transplantation (54% vs 2%; P < .0001). The donor source was similar in both groups, with 59% of those receiving nonmyeloablative conditioning and 43% of those receiving myeloablative conditioning having unrelated donors (P = .13). The primary indications for patients receiving nonmyeloablative transplantation are outlined in Table 2. The median follow-up for those still alive is 35 months (range, 16–49 months) for patients receiving nonmyeloablative transplantation and 40 months (range, 21–82 months) for those receiving myeloablative transplantation.
Table 1. Patient Characteristics
| Nonmyeloablative | Myeloablative | P | |
|---|---|---|---|
| n | 39 | 97 | |
| Age (years) | 56(21–70) | 43(21–65) | <.0001 |
| >50 | 24(62%) | 26(27%) | .0001 |
| >60 | 10(26%) | 3(3%) | .0002 |
| Disease type | |||
| AML | 23(59%) | 59(61%) | .85 |
| Second complete remission | 4(17%) | 14(17%) | |
| Relapse | 19(83%) | 19(32%) | |
| Induction | — | 21(36%) | |
| Failure/untreated | |||
| MDS | 16(41%) | 38(39%) | |
| RA/RARS | 5(31%) | 1(3%) | |
| RAEB/CMML | 11(69%) | 37(97%) | |
| Type of transplant | .13 | ||
| MRD | 16(41%) | 55(57%) | |
| URD | 23(59%) | 42(43%) | |
| Transplant conditioning regimen | |||
| Flu/Bu | 39(100%) | 0 | |
| CTX/TBI | 0 | 91(94%) | |
| Bu/CTX | 0 | 6(6%) | |
| GVHD prophylaxis | |||
| Cyclosporine/prednisone | 30 | 6 | |
| Tacrolimus or Cyclo/MTX | 9 | 91 | |
| Stem cell source | <.0001 | ||
| PBSC | 34(87%) | 24(25%) | |
| BM | 5(13%) | 73(75%) | |
| Previous myeloablative transplantation | 21(54%) | 2(2%) | <.0001 |
Table 2. Primary Indications for Nonmyeloablative Transplantation
| Indication | n (%) |
|---|---|
| Advanced age (>50 yrs) | 13(33%) |
| Previous myeloablative transplantation | 21(54%) |
| Other medical condition/organ dysfunction | 5(13%) |
GVHD and Treatment-Related Mortality
The incidence of grade 2–4 acute GVHD was similar in patients receiving nonmyeloablative transplantation and those receiving myeloablative transplantation: 26% and 27%, respectively (Table 3). The incidence of extensive chronic GVHD was increased in patients receiving nonmyeloablative transplantation (33%) compared with those receiving myeloablative transplantation (18%) (P = .04).
Table 3. Incidence of Acute GVHD
| Grade of GVHD | Nonmyeloablative | Myeloablative |
|---|---|---|
| 0 | 26(67%) | 46(47%) |
| 1 | 3(8%) | 25(26%) |
| 2 | 2(5%) | 13(13%) |
| 3–4 | 8(21%) | 13(13%) |
Day 100 mortality was lower for patients receiving nonmyeloablative conditioning than for recipients of myeloablative conditioning (15% vs 32%). Despite the difference in 100-day mortality, the cumulative incidence of nonrelapse mortality was similar: 26% for patients receiving nonmyeloablative conditioning, compared with 33% for those receiving myeloablative conditioning (P = .28) (Figure 1). Nonrelapse death and relapse were considered competing risks in this analysis. The major causes of nonrelapse mortality for patients receiving nonmyeloablative transplantation were GVHD and infection (Table 4).
Figure 1.
Cumulative incidence of TRM (P = .28) and risk of relapse (P = .02) after nonmyeloablative or myeloablative transplantation for patients with advanced AML or MDS.
Table 4. Causes of Treatment Failure
| Nonmyeloablative | Myeloablative | |
|---|---|---|
| GVHD | 4(13%) | 3(5%) |
| Infection | 4(13%) | 4(6%) |
| VOD | 0 | 5(8%) |
| Other | 1(3%) | 6(9%) |
| Pulmonary | 1(3%) | 14(21%) |
| Relapse | 20(67%) | 35(52%) |
Relapse
Disease relapse was the primary cause of treatment failure in patients receiving nonmyeloablative transplantation. The cumulative incidence of relapse in the presence of treatment-related mortality (TRM) as a competing risk was 61% for patients receiving nonmyeloablative conditioning and 38% for those receiving myeloablative conditioning (P = .02) (Figure 1). However, this difference was no longer significant at the 0.05 level when other prognostic factors were adjusted in a competing-risks regression analysis (P = .06; data not shown).
OS and PFS
Despite the adverse characteristics of the patients receiving NST, no difference in OS or PFS was seen in patients receiving nonmyeloablative or myeloablative HSCT. Estimated OS at 2 years was 28% for nonmyeloablative transplantation recipients and 34% for myeloablative transplantation recipients (P = .89) (Figure 2; Table 5). Estimated PFS at 2 years was 20% for nonmyeloablative transplantation recipients and 31% for myeloablative transplantation recipients (P = .31) (Figure 3; Table 5).
Figure 2.
OS in patients receiving nonmyeloablative transplantation and patients receiving myeloablative transplantation (P = .89).
Table 5. OS and PFS
| Median (95% CI) (Months) | 2 Years | 3 Years | P | |
|---|---|---|---|---|
| OS | ||||
| Nonmyeloablative | 9.1(6–16) | 28% | 22% | .89 |
| Myeloablative | 6.7(5–15) | 34% | 33% | |
| PFS | ||||
| Nonmyeloablative | 5.6(4–7) | 20% | 13% | .31 |
| Myeloablative | 5.7(4–12) | 31% | 29% |
Figure 3.
PFS in patients receiving nonmyeloablative transplantation and patients receiving myeloablative transplantation (P = .31).
Cox regression analysis was performed to identify the factors associated with OS and PFS for all patients. Factors analyzed included age, transplantation conditioning regimen (nonmyeloablative vs myeloablative), patient–donor sex mismatch, donor type (related vs unrelated), stem cell source (bone marrow vs peripheral blood), and previous transplantation. No factors, including the intensity of the conditioning regimen, influenced either OS or PFS. In a subset analysis of patients over age 50 years, estimated OS at 2 years was 25% for nonmyeloablative transplantation recipients and 12% for myeloablative transplantation recipients (P = .06), and estimated PFS at 2 years was 13% and 12%, respectively, for these 2 groups (P = .31).
For patients for whom cytogenetic data were available (n = 100), as expected, patients with favorable or intermediate-risk cytogenetics had a better 2-year OS and PFS than those with unfavorable cytogenetics (OS, 43% favorable/intermediate vs 18% unfavorable, P = .02; PFS, 41% favorable/intermediate vs 13% unfavorable, P = .006). The intensity of the conditioning regimen did not influence outcome for patients with favorable/intermediate risk cytogenetics (OS, 46% NST vs 42% myeloablative, P = .87; PFS, 38% NST vs 42% myeloablative, P = .64). Similarly, the intensity of the conditioning regimen did not influence outcome for patients with unfavorable cytogenetics (OS, NST 20% vs myeloablative 17%, P = .45; PFS, 7% NST vs 17% myeloablative, P = .89).
Effect of Early Donor Chimerism on Outcome after Nonmyeloablative Transplantation
Hematopoietic chimerism was assessed at approximately 1 month after nonmyeloablative transplantation. Thirty-four of 39 patients had samples available for analysis and could be evaluated. The median donor-derived chimerism was 92% (range, 0–100%). Patients with donor chimerism ≥90% at 1 month had a significantly improved OS at 1 year (72% vs 31%) and 2 years (44% vs 19%) compared with those with donor chimerism <90% (P = .02). Similarly, patients with ≥90% donor-derived hematopoiesis had an improved PFS at 1 year (44% vs 19%) and 2 years (33% and 13%) compared with those with <90% donor-derived hematopoiesis, although this difference did not reach statistical significance (P = .10) (Figure 4). There was no association between the degree of donor chimerism achieved early after transplantation and the development of acute GVHD or TRM.
Figure 4.
OS for patients with AML or MDS after nonmyeloablative transplantation comparing patients achieving ≥90% donor-derived hematopoiesis with patients with <90% donor-derived hematopoiesis 1 month after transplantation (P = .02).
Discussion
This retrospective comparison of patients with advanced AML and MDS receiving either a nonmyeloablative or a myeloablative conditioning regimen before allogeneic HSCT suggests that the less toxic fludarabine/intravenous busulfan–based nonmyeloablative regimen produces results similar to those of the myeloablative conditioning regimen. Although retrospective analysis such as this are open to criticism regarding the comparability of patients in each cohort, the patients in the nonmyeloablative group were a higher-risk population by virtue of being older and were more likely to be undergoing their second transplantation procedure. Therefore, the finding that nonmyeloablative conditioning with fludarabine/low-dose busulfan was associated with comparable OS and PFS with a conventional myeloablative regimen is worthy of attention.
The results demonstrate that there is a moderate GVL effect mediated after nonmyeloablative transplantation in patients with advanced AML or MDS, resulting in a 20% PFS at 2 years after transplantation. The relapse rate after nonmyeloablative transplantation is high compared with that after myeloablative transplantation, suggesting that dose intensity contributes to improved disease control. With respect to patients over age 50, dose intensity appears to play a minimal role, with an essentially identical PFS seen in both groups. An European Bone Marrow Transplantation Group retrospective comparison of nonmyeloablative and myeloablative transplantation of patients over age 50 with AML reached a similar conclusion, with similar leukemia-free survival between the 2 approaches [17]. De Lima et al [15] compared regimens of different dose intensities in patients with AML. They evaluated the moderately intensive fludarabine/cytosine arabinoside/idarubicin and the more highly intensive fludarabine/melphalan. Although the difference in intensity in that comparison was not as marked as in our fluarabine/low-dose intravenous busulfan versus cyclophosphamide/total body irradiation, they reported superior survival in the more intensive fludarabine/melphalan group, but only in patients who were in complete remission at the time of transplantation. Another retrospective analysis focusing on patients with MDS or AML with multilineage dysplasia demonstrated similar OS and PFS for patients receiving either nonmyeloablative or myeloablative transplantation [18].
The lack of significant benefit from high-dose chemotherapy is not surprising, especially in older patients with advanced disease. The leukemia in older individuals is relatively resistant to chemotherapy, with lower initial complete remission rates, and these patients are not cured using standard chemotherapy regimens [19]. Similarly, patients with relapsed AML are relatively chemotherapy resistant, as demonstrated by a low rate of complete response to salvage chemotherapy and a short duration of response. It is likely that both of these patient populations rely largely on GVL effects for long-term responses. In these patients, the conditioning regimen still plays an important role, perhaps not for its antineoplastic effects, but rather for its ability to induce lymphohematopoietic donor chimerism or to achieve sufficient cytoreduction, thereby controlling the disease long enough to allow the GVL response to develop.
Longer follow-up could reveal that myeloablative transplantation may be associated with improved PFS, although most relapses for patients with advanced AML or MDS occur within the first 2 years of transplantation. Dose-intensive chemotherapy and radiation certainly contribute directly to cure in some patients; however, increased treatment-related toxicity is also noted. This trade-off between increased risk of relapse and lower TRM associated with nonmyeloablative transplantation has been noted in other studies comparing outcome in patients receiving nonmyeloablative transplantation and those receiving myeloablative transplantation. Consequently, for the individual patient, careful consideration of the potential benefits of dose intensity must be counterbalanced by the patient’s risk for transplantation-related complications. Comorbidity indices, which assess the impact of other medical conditions, may help quantify a patient’s risk of transplantation-related complications and allow for a better estimate of the risk associated with myeloablative transplantation [20, 21]. If significant risk factors for TRM from dose-intensive therapy are not present, then myeloablative transplantation may be preferred. However, our data suggest that dose-intensive therapy is of no benefit in patients over age 50 with advanced AML or MDS. Keep in mind, however, that our results shed no light on the role of nonmyeloablative transplantation for patients in first remission or early-stage MDS, in whom dose-intensive chemotherapy/radiotherapy may be important.
In the current study, patients who achieved ≥90% donor-derived hematopoiesis early after nonmyeloablative transplantation had better OS than those who achieved <90% donor-derived hematopoiesis. Another study by Baron et al [22] demonstrated that patients achieving full T-cell donor chimerism after nonmyeloablative transplantation had a decreased risk of progression or relapse [22]. That study demonstrated that donor chimerism had the greatest impact on outcome in patients with AML, MDS, and myeloproliferative disorders. These findings may indicate that perhaps achieving a high degree of donor-derived chimerism after nonmyeloablative transplantation is a surrogate marker for the GVL effect, and that the GVL effect is not leukemia-specific but rather is directed against hematopoietic antigens that are shared with hematopoietic stem cells and progenitors. If this supposition is correct, then attempting to achieve higher degrees of donor chimerism by administering more-intensive chemotherapy may not lead to improved outcome. In the current study, multivariate analysis did not identify any specific factor (including donor–recipient sex mismatch, development of acute GVHD, or number of CD34+ cells infused) that influenced chimerism after transplantation. It is not clear whether attempting to enhance donor chimerism for patients with a low degree of donor chimerism by immunologic manipulation, such as prophylactic donor lymphocyte infusion, will influence outcome.
Our current challenge is to determine how to best augment these GVL effects without inducing disabling acute or chronic GVHD, conditions accounting for much of the morbidity and mortality of nonmyeloablative HSCT. It would be ideal if we could generate specific immune responses independently of GVHD, perhaps through the development and administration of whole cell or peptide vaccines [23, 24]. At this juncture, it remains unclear what level of dose intensity should be used in conditioning regimens for patients with AML or MDS. For now, our data suggest that it is reasonable to treat patients with advanced AML or MDS with conditioning regimens that are less toxic but still sufficiently potent to promote donor lymphohematopoietic engraftment. Given that dose intensity may be important in some patients, myeloablative transplantation may be preferred unless significant risk factors for treatment-related complications are present.
Acknowledgments
This work was supported in part by the National Heart, Lung, and Blood Institute (grant PO1 HL070149) and the Ted and Eileen Pasquerello Leukemia Research Fund.
References
- Comparing morbidity and mortality of HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative and myeloablative conditioning: influence of pretransplantation comorbidities. Blood. 2004;104:961–968
- Morbidity and mortality with nonmyeloablative compared with myeloablative conditioning before hematopoietic cell transplantation from HLA-matched related donors. Blood. 2004;104:1550–1558
- Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood. 2005;105:1810–1814
- Treatment for acute myelogenous leukemia by low-dose, total-body, irradiation-based conditioning and hematopoietic cell transplantation from related and unrelated donors. J Clin Oncol. 2006;24:444–453
- Intensive postremission chemotherapy in adults with acute myeloid leukemia. N Eng J Med. 1994;331:896–903
- Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia (Cancer and Leukemia Group B). N Engl J Med. 1995;332:1671–1677
- Postremission therapy in older patients with de novo acute myeloid leukemia: a randomized trial comparing mitoxantrone and intermediate-dose cytarabine with standard-dose cytarabine. Blood. 2001;98:548–553
- . Postremission therapy in adults with acute myeloid leukemia. Semin Hematol. 2001;38:17–23
- Acute myelogenous leukemia in first relapse treated with two consecutive autologous bone marrow transplantations: a pilot study. Eur J Haematol. 1989;42:441–444
- BAVC regimen and autograft for acute myelogenous leukemia in second complete remission. Bone Marrow Transplant. 1996;18:693–698
- Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. N Eng J Med. 1995;332:217–223
- . Autologous bone marrow transplantation in first remission AML using nonpurged marrow: update. In: Hagenbeek A, Lowenberg B editor. Minimal Residual Disease. Dordrecht, The Netherlands: Martinus Nijhoff; 1986;p. 211
- Chemotherapy compared with autologous or allogeneic bone marrow transplantation in the management of acute myeloid leukemia in first remission. N Engl J Med. 1998;339:1649–1656
- Karyotypic analysis predicts outcome of preremission and postremission therapy in adult acute myeloid leukemia: a Southwest Oncology Group/Eastern Cooperative Oncology Group Study. Blood. 2000;96:4075–4083
- . A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat. 1988;16:1141–1154
- . A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc. 1999;94:496–509
- Comparative outcome of reduced intensity and myeloablative conditioning regimen in HLA-identical sibling allogeneic haematopoietic stem cell transplantation for patients older than 50 years of age with acute myeloblastic leukaemia: a retrospective survey from the Acute Leukemia Working Party (ALWP) of the European group for Blood and Marrow Transplantation (EBMT). Leukemia. 2005;19:2304–2312
- Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis. Leukemia. 2006;20(1):128–135
- Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. N Eng J Med. 1995;332:1671–1677
- Hematopoietic cell transplantation (HCT)-specific comorbidity index: a new tool for risk assessment before allogeneic HCT. Blood. 2005;106:2912–2919
- Comorbidity indices in hematopoietic stem cell transplantation: a new report card. Bone Marrow Transplant. 2005;36:475–479
- Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol. 2005;23:1993–2003
- Targeted T-cell therapy for human leukemia: cytotoxic T lymphocytes specific for a peptide derived from proteinase 3 preferentially lyse human myeloid leukemia cells. Blood. 1996;88:2450–2457
- . GM-CSF–based cancer vaccines. Immunol Rev. 2002;188:147–154
PII: S1083-8791(06)00407-1
doi:10.1016/j.bbmt.2006.06.003
© 2006 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 12, Issue 10 , Pages 1047-1055, October 2006
