Stem Cell Transplantation

Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis

Abstract

Transplant outcome was analyzed in 150 patients with myelodysplastic syndrome (MDS) or acute myelogenous leukemia transformed from MDS (tAML) conditioned with nonmyeloablative or myeloablative regimens. A total of 38 patients received nonmyeloablative regimens of 2 Gy total body irradiation alone (n=2) or with fludarabine (n=36), 90 mg/m2. A total of 112 patients received a myeloablative regimen of busulfan, 16 mg/kg (targeted to 800–900 ng/ml), and cyclophosphamide 120 mg/kg. Nonmyeloablative patients were older (median age 62 vs 52 years, P<0.001), more frequently had progressed to tAML (53 vs 31%, P=0.06), had higher risk disease by the International Prognostic Scoring System (53 vs 30%, P=0.004), had higher transplant specific comorbidity indices (68 vs 42%, P=0.01) and more frequently had durable complete responses to induction chemotherapy (58 vs 14%). Three-year overall survival (27%/48% (P=0.56)), progression-free survival (28%/44%, (P=0.60)), and nonrelapse mortality (41%/34%, (P=0.94)) did not differ significantly between nonmyeloblative/myeloablative conditioning. Overall (HR=0.9, P=0.84) and progression-free survivals (HR=1, P=0.93) were similar for patients with chemotherapy-induced remissions irrespective of conditioning intensity. Graft vs leukemia effects may be more important than conditioning intensity in preventing progression in patients in chemotherapy-induced remissions at the time of transplantation. Randomized prospective studies are needed to further address the optimal choice of transplant conditioning intensity in myeloid neoplasms.

Introduction

Myelodysplastic syndrome (MDS) comprises a spectrum of stem cell disorders characterized by peripheral cytopenias and variable risks of transformation into acute myeloid leukemia (tAML). The only currently known treatment for MDS with curative potential is hemopoietic cell transplantation (HCT). However, even with the availability of suitable donors, conventional HCT may not be an option for many patients either because of advanced age or comorbid illness. One recent advance in the field of HCT is the development of reduced intensity and nonmyeloablative conditioning regimens. These alternative regimens were developed to avoid the toxicities associated with myeloablative conditioning in older patients, and they rely on graft vs leukemia effects of donor cells for eradication of malignancy.1, 2, 3 Results in patients with MDS raised the possibility that the advantage gained with reduced nonrelapse mortality (NRM) might be offset by problems with graft failure and disease progression.4

Concurrently, advances have been made in modifying conventional myeloablative transplant regimens to allow for the treatment of older patients. However, regimen-related toxicities have remained problematic.5, 6 Therefore, the advantages and disadvantages of conventional and reduced-intensity conditioning must be weighed carefully when counseling patients. Oftentimes, the optimal strategy for a given patient is unclear. Here, we present results of a retrospective analysis that compared outcomes among concurrent patients with MDS or tAML prepared for allogeneic HCT with nonmyeloablative or myeloablative conditioning.

Materials and methods

Patients

This retrospective review included all patients over the age of 40 years with diagnoses of MDS or tAML, who were transplanted from HLA-matched donors at the Fred Hutchinson Cancer Research Center or Puget Sound VA in Seattle between January 1998 and December 2003. All patients with tAML had a documented diagnosis of MDS, which preceded the transformation to AML. Patient characteristics are summarized in Table 1. In all, 112 patients were conditioned with targeted busulfan and cyclophosphamide,5 referred to hereafter as ‘myeloablative patients’. Their median follow-up after HCT was 809 (range: 312–2339) days. Of these patients, 38 were conditioned with 2 Gy of total body irradiation (TBI) administered without (n=2), or with (n=36), fludarabine,3, 7 referred to hereafter as ‘nonmyeloablative patients’. Their median follow-up after HCT was 614 (range: 153–1564) days. Patients were selected for a nonmyeloablative over a myeloablative-conditioning regimen because of increased age or presence of comorbid diseases. For the nonmyeloablative protocols that were active during this time period, it was required that patients have <10% marrow myeloblasts at time of enrollment.

Table 1 Patient and disease characteristics

The patients' diagnoses had been established and categorized prospectively according to the French–American–British (FAB) classification. Modifications according to the WHO criteria were made retrospectively. Since many patients received induction chemotherapy before HCT, the highest pretransplant FAB and WHO categorizations (before induction chemotherapy) were used for risk assessment regarding post-transplant outcomes such as disease progression and NRM. The risks and prognosis according to the International Prognostic Scoring System (IPSS) were determined at diagnosis and immediately pretransplant (Table 1). However, for the purpose of risk assessment in this analysis, the immediate pretransplant IPSS categories were used.8 The IPSS criteria were used to characterize good, intermediate, and poor risk cytogenetics. HCT-specific comorbidity Index Scores (HCT-CI) were used to quantify the comorbidities and assess risks of NRM.9 Nonmyeloablative patients were older, had higher HCT-CI scores, had higher peak IPSS categories, higher disease stages by FAB, and higher cytogenetic risks compared to myeloablative patients. Nonmyeloablative patients were also more likely to have received pretransplant induction chemotherapy in attempts to achieve responses and become eligible for nonmyeloablative conditioning. There were no significant differences between the two cohorts with regards to gender distribution, donor cytomegalovirus (CMV) status, recipient CMV status, duration of disease before HCT, primary or secondary etiology of MDS, or source of stem cells. All patients were matched at HLA antigens A, B, C, DR, and DQ with their donor by intermediate or high-resolution HLA typing.

Induction chemotherapy

In total, 25 (22%) of 112 myeloablative patients, and 24 (63%) of 38 nonmyeloablative patients received pretransplant induction chemotherapy. Cytarabine and an anthracycline given on a seven plus three schedule were used in 20 of the myeloablative and 19 of the nonmyeloablative patients. Other regimens used included topotecan or fludarabine with cytarabine. The median time that elapsed between induction chemotherapy and HCT was 3 (range: 1–19) months for the myeloablative patients, and 4 (range: 1–14) months for the nonmyeloablative patients. For the purposes of this study, ‘complete responses’ following induction chemotherapy were defined as a marrow myeloblast percentage of <5% but did not require the absence of dysplasia or clonal cytogenetic abnormalities or the recovery of normal hemopoietic parameters.

Conditioning regimens and post-transplant immunosuppression

Myeloablative patients received a regimen of targeted busulfan and cyclophosphamide.5 The starting dose of oral busulfan was 1 mg/kg, given every 6 h for 16 doses. Plasma levels were measured sequentially, and doses were adjusted to maintain steady-state plasma levels of 800–900 ng/ml. Cyclophosphamide was given intravenously at 60 mg/kg/day for 2 consecutive days following the completion of oral busulfan. Prophylaxis for graft-versus-host disease (GVHD) consisted of methotrexate (MTX) and cyclosporine (CSP) in 82 patients, CSP, MTX, and antithymocyte globulin in 17 patients, CSP and mycophenolate mofetil (MMF) in eight patients, CSP, MTX, and sirolimus in four patients, and CSP, MTX, and tacrolimus (FK-506) in one patient.

The nonmyeloablative patients received one of two conditioning regimens. The first consisted of 2 Gy TBI administered either by a linear accelerator or dual cobalt 60 sources at a rate of 0.07 Gy/min on day 0 in two patients.3 As nonfatal graft rejections were observed in several patients with other diagnoses prepared with this regimen, the second regimen added fludarabine at 30 mg/m2/day on days −4, −3, and −2 to 2 Gy TBI in 36 patients.7 All patients transplanted from related donors received MMF 15 mg/kg orally twice a day from day 0 to day 27 with no taper, and CSP 5–6.25 mg/kg orally twice a day from day –3 to day 35 or 56 with tapers in the absence of GVHD to days 56, 77, or 180 based upon disease risk. All unrelated transplant recipients received MMF 15 mg/kg orally two or three times a day from day 0 to day 40 with a taper to day 96, and CSP 5–6.25 mg/kg orally twice a day from day –3 to day 100 with a taper to day 180 in the absence of GVHD.

Graft failure and graft rejection

For myeloablative patients, the day of engraftment was defined as the first of 3 consecutive days on which the absolute neutrophil count remained greater than 0.5 × 109/l. Graft failure was suspected in surviving patients who failed to reach 0.5 × 109 neutrophils/l by day 28. Graft rejection was suspected in patients with progressive declines in peripheral blood counts after initial recovery. When possible, bone marrow aspirations were performed to confirm graft failure and graft rejection.

For nonmyeloablative patients, engraftment was confirmed by chimerism analyses of flow cytometrically sorted peripheral blood granulocytes and T cells, and marrow nucleated cells. Analyses were performed on days 28, 56, 84, 180, 365, and then yearly after HCT. Graft failure was defined as <5% CD3+ donor T cells on day 28. Graft rejection was defined at the time point when donor T-cell chimerism declined to <5% after initial evidence of engraftment.10

Disease progression

All patients had marrow evaluations on days 28, 56, and 84 for cytogenetic, flow cytometric, and morphologic analyses. Subsequently, studies were performed annually and as clinically indicated. Progression in the myeloablative cohort was defined as the presence of dysplastic cells by flow cytometry and morphology, or the recurrence of previously identified cytogenetic abnormalities. Progression in the nonmyeloablative cohort was defined as increases in marrow or peripheral blood myeloblast percentages over baseline pretransplant values.

Causes of death

In patients with disease progression, progression was listed as their primary cause of death regardless of other associated events. In patients with GVHD requiring immunosuppressive therapy who subsequently died from infections, GVHD and infection were listed as their causes of death. Infections were listed as causes of death when they occurred in the absence of progression or clinically significant GVHD. Multiorgan failure was identified as the cause of death when it occurred in the absence of progression and was thought not to be primarily due to preceding GVHD or infection. Graft failure and graft rejection (as defined above) were only considered the cause of death if there was no evidence of concurrent disease progression or GVHD, and only if patients survived beyond day 28 post-transplant.

Statistical analysis

The primary end point of this retrospective comparison was progression-free survival among myeloablative and nonmyeloablative patients. Secondary end points included: overall survival, NRM, and progression.

Overall survival and progression-free survival were estimated using the Kaplan–Meier method. Deaths were treated as competing events in the analyses of graft failure, GVHD, and progression. Graft rejection was treated as a competing event in the analysis of GVHD. Hazard ratios were estimated using Cox regression models and adjusted for FAB group, IPSS group, and HCT-CI.

Results

Response to pretransplant induction chemotherapy

Among the 25 myeloablative patients who received pretransplant induction chemotherapy, 16 achieved complete responses (as defined under Methods), which were durable until the time of HCT. There were two additional patients who responded, but progressed before HCT as evidenced by increases in the marrow myeloblasts to more than 5% of nucleated cells by morphology. Seven myeloablative patients had no responses to pretransplant induction chemotherapy.

Among the 24 nonmyeloablative patients who received pretransplant induction chemotherapy, 20 obtained durable complete responses. An additional two nonmyeloablative patients responded, but progressed before HCT (as defined above). Two nonmyeloablative patients had no responses to pretransplant induction chemotherapy. As a result of the responses to pretransplant chemotherapy, IPSS risk categories at the time of HCT were comparable for myeloablative and nonmyeloablative patients.

Graft failure and graft rejection

Among the 112 myeloablative patients, five died before day 28 without evidence of GVHD and were not evaluable for engraftment. The median time to engraftment in the remaining 107 myeloablative patients was 17 (range: 10–35) days. One myeloablative patient developed graft rejection on day 266 after HCT.

Among the 38 nonmyeloablative patients, four patients died before day 28 without evidence of GVHD and were not evaluable for engraftment. Three failed to achieve sustained engraftment. One nonmyeloablative patient rejected his graft on day 84 after HCT. Of the four patients with documented graft failure or graft rejection, three died of infectious complications before donor lymphocyte infusions (DLI) or a second transplant could be performed. One patient had DLI performed twice without engraftment and subsequently died from infectious complications. The remaining 30 nonmyeloablative patients achieved sustained engraftment based upon chimerism studies.

GVHD

Five myeloablative and four nonmyeloablative patients were not evaluable for GVHD because of death before day 28 without evidence of engraftment. In agreement with prior studies,11 the incidence of grades II–IV acute GVHD was lower in patients who received a nonmyeloablative regimen (54%) compared to patients who received a myeloablative regimen (78%). There was no difference between nonmyeloablative and myeloablative conditioning for grades III–IV acute GVHD (22 vs 21%). The 2-year incidence of clinically extensive chronic GVHD was 55% in the nonmyeloablative cohort and 64% in the myeloablative cohort.

Disease progression

Disease progression was the single most common cause of death among both myeloablative and nonmyeloablative patients. Of 112 myeloablative patients, 26 progressed 29–1441 (median 147) days after HCT, and 22 died secondary to progression. Four patients were alive and in remission after withdrawal of immunosuppression, and one of these had received a donor lymphocyte infusion. In all, 11 nonmyeloablative patients had progressive disease 28–523 (median 82) days after HCT. Of them, 10 patients died secondary to disease progression, and one was alive and in remission after withdrawal of immunosuppression. Overall, 23% of the myeloablative and 31% of the nonmyeloablative patients had disease progression at 3 years (P=0.43) (Figure 1a). The higher proportions of patients with tAML, higher IPSS, and poor cytogenetic risk among the nonmyeloablative cohort, might have accounted for the non-significant increase in progression rates, although a less intense antileukemic effect with the nonmyeloablative regimen must also be considered. Given the higher proportion of patients with more advanced disease in the nonmyeloablative cohort, we also examined post-transplant progression based upon FAB classification. In RA/RARS patients (Figure 1b), none of whom had received induction chemotherapy, there was a non-significant increase in progression rates among nonmyeloablative patients (P=0.22). No significant difference in progression rates was found for patients with RAEB or tAML between myeloablative and nonmyeloablative cohorts (Figure 1c and d, respectively). However, more nonmyeloablative than myeloablative patients had achieved complete responses to induction chemotherapy prior to HCT, which could potentially bias the nonmyeloablative cohort favorably. Therefore, we also examined the risk of progression in patients who obtained a durable complete response to pre-HCT induction chemotherapy. Among patients with <5% marrow blasts at time of HCT following pretransplant induction chemotherapy progression rates were similar in the two cohorts (Figure 2).

Figure 1
figure1

Incidence of progression in patients conditioned with myeloablative or nonmyeloablative regimens. (a) All patients. (b) Patients with RA/RARS. (c) Patients with RAEB. (d) Patients with tAML.

Figure 2
figure2

Incidence of progression in patients with RAEB/tAML who had durable complete responses to induction chemotherapy with <5% marrow myeloblasts at the time of HCT.

Causes of death

Causes of death are summarized in Table 2. Among 112 myeloablative patients, 36 (32%) died from nonrelapse causes, and among 38 nonmyeloablative patients, 15 (39%) died from non-relapse causes. There was no significant difference in NRM between the two cohorts (P=0.94) (Figure 3).

Table 2 Causes of death
Figure 3
figure3

Overall nonrelapse mortality in patients conditioned with myeloablative or nonmyeloablative regimens.

Overall survival and progression-free survival

At 3 years, overall survival for the myeloablative cohort was 48%, with a median follow-up of 789 days, compared to 28% for the nonmyeloablative cohort, with a median follow-up of 614 days (P=0.56). (Figure 4a).

Figure 4
figure4

Probability of overall survival (a) and progression-free survival (b) in patients conditioned with myeloablative or nonmyeloablative regimens.

Progression-free survival at 3 years was 44% for the myeloablative cohort, and 27% for the nonmyeloablative cohort (P=0.10) (Figure 4b).

Comparative analysis

Three-year outcomes are summarized at the top of Table 3. Hazard ratios were used to compare outcomes of myeloablative patients and nonmyeloablative patients (bottom of Table 3). A ratio of less than one indicated a superior outcome for nonmyeloablative HCT, and a ratio of greater than one indicated a superior outcome for myeloablative HCT. The hazard ratios were adjusted for FAB classification, IPSS category at time of transplant, and HCT-CI. There were no significant differences in overall survival, progression-free survival, progression, or nonrelapse mortality between the myeloablative and nonmyeloablative patients.

Table 3 Comparisons of outcomes for patients after nonmyeloablative vs myeloablative conditioninga

Discussion and conclusion

The ideal transplant regimen, characterized by lack of toxicity, complete and sustained donor cell engraftment without GVHD, and low risk of disease progression, has remained elusive. While concerns about engraftment and relapse or progression apply to all age groups, regimen-related toxicity is of particular concern in older patients and in patients with comorbid conditions. Transplant strategies that employ reduced intensity or nonmyeloablative conditioning have expanded the patient population eligible for HCT. Since MDS and tAML primarily occur in older individuals, these considerations are of particular relevance for patients with these disorders.

Our retrospective analyses revealed no significant differences in progression, progression-free survival, NRM, or overall survival between patients with MDS given nonmyeloablative or myeloablative conditioning. An inclusion criterion for patients who received nonmyeloablative transplants was <10% marrow myeloblasts at the time of transplant. Conversely, the myeloablative cohort included only patients who were deemed eligible for myeloablative transplantation based on their relatively good health status, as illustrated by their significantly lower HCT-CI comorbidity indices. Based on the higher peak IPSS risk, a higher incidence of disease progression might not have been surprising among nonmyeloablative patients. However, most had received induction chemotherapy (IPSS scores at HCT were not different from myeloablative patients), and, indeed, progression rates were comparable for the two cohorts. The fact that the hazard ratio for relapse among patients with RA/RARS who had not received induction chemotherapy favored myeloablative patients supports the conclusion that induction chemotherapy before nonmyeloablative HCT had a beneficial effect. Despite all the shortcomings of retrospective data, these results are intriguing when considering that nonmyeloablative patients were older, had higher peak IPSS scores, had worse comorbidities (higher HCT-CI) which are known to be associated with higher NRM, and were at higher risk of relapse following HCT based upon FAB/WHO classification.5, 6

When considering only patients who had durable complete responses to pretransplant chemotherapy, progression-free survival and progression rates did not differ between myeloablative and nonmyeloablative cohorts. This finding suggested that the intensity of transplant conditioning was not the decisive factor in preventing post-transplant progression among patients with tAML and RAEB who had responded to treatment and had less than <5% marrow myeloblasts at the time of HCT. Presumably, the pretransplant induction chemotherapy substituted for a more intensive conditioning regimen by reducing the disease burden before HCT, and the use of myeloablative conditioning offered no additional gain in progression prevention but added regimen-related toxicity. Alternatively, response to pretransplant induction chemotherapy may have selected for treatment sensitive patients who might also be more responsive to an allogeneic graft vs leukemia effect.

In contrast to patients with tAML and RAEB, patients with RA/RARS received no pretransplant chemotherapy, and there was a suggestion of a higher progression incidence with nonmyeloablative conditioning. This observation suggests that pretransplant chemotherapy may not only reduce the disease burden, as measured by pre-HCT marrow morphology in patients with advanced MDS, but may also have effects not measurable by morphology that facilitate donor cell engraftment in the nonmyeloablative cohort and decrease risk of disease progression.10

A retrospective analysis from the Dana-Farber Cancer Institute compared outcomes with nonmyeloablative and myeloablative conditioning in patients over the age of 50 years with a range of diagnoses (NHL, AML, acute lymphocytic leukemia, chronic myelogenous leukemia, CLL, MDS, chronic myelomonocytic leukemia).12 That analysis showed a trend towards improvement in overall survival with nonmyeloablative vs myeloablative conditioning (39 vs 29%, P=0.056) at 2 years. While NRM was significantly reduced with nonmyeloablative conditioning (32 vs 50%, P=0.01), there was an increase in relapse incidence (46 vs 30%, P=0.052), and no significant differences were seen in relapse-free survivals (27 vs 25%, P=0.24).

A retrospective disease specific study from the MD Anderson Cancer Center compared results with two conditioning regimens of different intensity.4 In total, 94 patients with MDS or AML were transplanted after conditioning with fludarabine, 100–150 mg/m2, and melphalan, 140–180 mg/m2, (FM) (n=62) or fludarabine, 120 mg/m2, cytarabine, 4 gm/m2, and idarubicin, 36 mg/m2 (FAI) (n=32). Patients, who received FM, had a significantly higher cumulative incidence of NRM (39 vs 16%, respectively, P=0.036), which was counterbalanced, however, by a significantly lower cumulative incidence of relapse-related mortality (26 vs 53%, respectively, P=0.029, respectively). In the present analysis, the differences in progression-free survival and NRM between myeloablative and nonmyeloablative conditioning were not significant. However, besides the obvious differences in conditioning regimens, several aspects differed between these two retrospective analyses. First, none of the MD Anderson study patients who received the lower intensity regimen (FAI) were transplanted from unrelated donors which could limit potential graft vs leukemia effects.13 Secondly, the study did not distinguish between de novo and secondary AML. It is known that patients with secondary leukemia have a worse post-transplant prognosis than patients with de novo leukemia.14 Also, we characterized stage of disease not by remission status at time of HCT, but rather by highest FAB/WHO classification before HCT.

Thus, the data from the present analysis and from other reports indicated that NRM after HCT was reduced with nonmyeloablative/reduced intensity conditioning. However, there was also evidence of increased progression rates with lower intensity regimens, though confounded by higher risk patient categories. The optimum regimen will likely depend on disease type and stage, and patient characteristics. As in any retrospective analysis, selection bias is introduced when comparing different treatment regimens. One such selection bias in our study was the fact that most patients who received a nonmyeloablative HCT were treated with induction chemotherapy. A subset analysis in patients who had <5% marrow myeloblasts at time of HCT following prior induction chemotherapy, showed progression rates were similar regardless of conditioning intensity. However, there was no overall survival benefit with nonmyeloablative conditioning in this selected population because there was no significant reduction in NRM. A potential explanation for the lack of reduction in NRM in the nonmyeloablative cohort may be the advanced age and more severe comorbidities in these patients. If conditioning intensity is not an important factor in preventing progression in patients in remission at the time of HCT, then the use of nonmyeloablative conditioning may result in superior survival when comparable patient populations are examined. To address this issue, prospective randomized trials comparing myeloablative vs nonmyeloablative conditioning for patients with MDS and tAML will be required.

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Acknowledgements

We thank the transplant teams at the Seattle VA Puget Sound Health Care System and the Fred Hutchinson Cancer Research Center for their contributions; all patients for their participation in these trials, the research nurses Steve Minor, Mary Hinds, and John Sedgwick; Joanne Greene and Deborah Bassuk for maintaining the patient database; and Bonnie Larson and Helen Crawford for help with manuscript preparation. Supported by PHS Grants HL36444, CA78902, CA18029, and CA15704, NIH, Bethesda, MD.

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Correspondence to H J Deeg.

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Scott, B., Sandmaier, B., Storer, B. et al. Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis. Leukemia 20, 128–135 (2006). https://doi.org/10.1038/sj.leu.2404010

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Keywords

  • myelodysplastic syndrome
  • hemopoietic cell transplantation
  • nonmyeloablative transplantation
  • secondary leukemia

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