Originally published as JCO Early Release 10.1200/JCO.2005.02.0057 on November 28 2005

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Allogeneic Stem-Cell Transplantation Using a Reduced-Intensity Conditioning Regimen Has the Capacity to Produce Durable Remissions and Long-Term Disease-Free Survival in Patients With High-Risk Acute Myeloid Leukemia and Myelodysplasia

From the Department of Hematology, Queen Elizabeth Hospital, Edgbaston, Birmingham, United Kingdom

Address reprint requests to Charles Craddock, MD, Department of Hematology, Queen Elizabeth Hospital, Edgbaston, Birmingham B15 2TH, United Kingdom; e-mail: charles.craddock{at}uhb.nhs.uk

	ABSTRACT

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PURPOSE: The toxicity of allogeneic stem-cell transplantation can be substantially reduced using a reduced-intensity conditioning (RIC) regimen. This has increased the proportion of patients with myeloid malignancies eligible for allogeneic transplantation. However, the capacity of RIC allografts to produce durable remissions in patients with acute myeloid leukemia (AML) and myelodysplasia (MDS) has not yet been defined, and consequently, the role of RIC allografts in the management of these diseases remains conjectural.

PATIENTS AND METHODS: Seventy-six patients with high-risk AML or MDS received an allograft using a fludarabine/melphalan RIC regimen incorporating alemtuzumab. The median age of the cohort was 52 years (range, 18 to 71 years).

RESULTS: The 100-day transplantation-related mortality rate was 9%, and no patient developed greater than grade 2 graft-versus-host disease. With a median follow-up of 36 months (range, 13 to 70 months), 27 patients were alive and in remission, with 3-year actuarial overall survival (OS) and disease-free survival (DFS) rates of 41% and 37%, respectively. The 3-year OS and DFS rates of patients with AML in complete remission at the time of transplantation were 48% and 42%, respectively. Disease relapse was the most common cause of treatment failure and occurred at a median time of 6 months after transplantation. All but one patient destined to relapse did so within 24 months of transplantation.

CONCLUSION: The extended follow-up in this series identifies a high risk of early disease relapse but provides evidence that RIC allografts can produce sustained DFS in a significant number of patients with AML who would be ineligible for allogeneic transplantation with myeloablative conditioning.

	INTRODUCTION

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The incidence of acute myeloid leukemia (AML) and myelodysplasia (MDS) in adults increases sharply with age.¹ Despite improvements in chemotherapy and supportive care, the outlook for patients 50 years and older is dismal, and new treatment strategies are needed.^2-4 In younger patients, allogeneic stem-cell transplantation (SCT) has been shown to decrease the risk of disease relapse when compared with chemotherapy and is now established as the treatment of choice in eligible patients with high-risk AML and MDS.⁵ Until recently, a myeloablative conditioning regimen has been considered a prerequisite for successful allogeneic SCT both because of its antitumor activity and also because of its perceived role in securing durable donor stem-cell engraftment.⁶ However, the toxicity of myeloablative preparative regimens has precluded the extension of the potentially curative effect of allogeneic SCT to older patients with myeloid malignancies, limiting treatment options even further in this population of patients at high risk of disease relapse.⁷

Accumulating evidence that the donor-derived immune system exerts a potent antileukemic effect after allograft has led to the development of reduced-intensity conditioning (RIC) regimens that are designed to produce durable donor engraftment of allogeneic stem cells and provide a platform for an immunologically mediated graft-versus-leukemia (GVL) effect with less attendant toxicity.^8-10 RIC regimens have been remarkably successful in reducing transplantation-related mortality (TRM), permitting allogeneic SCT to be performed in older patients in whom it was previously contraindicated. However, although a number of reports have confirmed that such regimens allow older patients with high-risk AML or MDS to receive an allograft with relative safety, the follow-up in these studies has been short.^11-14 Thus, it has not been possible to assess whether RIC regimens have the capacity to produce long-term disease-free survival (DFS) in patients with high-risk AML and MDS, and consequently, the role of RIC regimens in patient management remains controversial.

This article reports the outcome of patients with high-risk AML and MDS who underwent allogeneic transplantation using a RIC regimen incorporating alemtuzumab. Extended follow-up of this cohort has identified that durable remissions are achievable in a significant proportion of patients with high-risk AML. Disease relapse remains the major cause of treatment failure and occurs in the first year after transplantation in the majority of patients. These data demonstrate that RIC allografts possess the capacity to deliver long-term DFS in patients with high-risk AML.

	PATIENTS AND METHODS

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Patient Characteristics
This article reports the outcome of 76 patients who received an alemtuzumab-containing RIC allograft for high-risk AML or MDS at one of 12 transplantation centers in the United Kingdom from 1998 to 2004. Of the 76 patients in this study, 11 were reported previously and are now included here with extended follow-up.^15,16 Detailed characteristics are listed in Table 1. The median age was 52 years (range, 18 to 71 years). There were 46 men and 30 women; 41 patients received an allograft from an unrelated donor, and 35 received an allograft from a matched sibling donor. Twenty-four patients younger than 45 years old received an RIC regimen rather than a myeloablative regimen because of poor performance status (n = 16), previous SCT (n = 7; autologous SCT in five patients and myeloablative allograft in two patients), or patient preference (n = 1). At the time of transplantation, 42 patients with AML were in complete remission (CR), of whom 22 were in first CR (CR1) and 20 were in second CR (CR2) or greater. Patients who received an allograft in CR1 were classified as being at a high risk of treatment failure after conventional chemotherapy because of a diagnosis of therapy-related or secondary AML, the presence of an adverse karyotype at diagnosis,⁴ or the development of prolonged aplasia after chemotherapy.¹⁷ In patients who underwent transplantation in CR2, the median duration of CR1 was 21 months (range, 18 to 60 months). Of the remaining patients, 14 had relapsed/refractory disease AML, and 20 had MDS (refractory anemia, n = 8; refractory anemia with ringed sideroblasts, n = 2; and refractory anemia with excess of blasts, n = 10).

Transplantation Details and Monitoring
The RIC regimen and supportive care have been described previously.^15,16 In brief, patients received in vivo alemtuzumab (20 mg/d for 5 days), fludarabine (30 mg/m²/d for 5 days), and melphalan (140 mg/m² for 1 day). Twenty-five patients received a lower dose of alemtuzumab (10 mg/d for 5 days). Cyclosporine was used as graft-versus-host disease (GVHD) prophylaxis. The source of stem cells was peripheral-blood stem cells (PBSC), which were collected after treating donors with granulocyte colony-stimulating factor (10 µg/kg/d for 4 days), in 52 patients or bone marrow mononuclear cells in 24 patients (volunteer unrelated donor, n = 22; and sibling donor, n = 2). The median CD34⁺ cell dose in patients who received an allograft with PBSC was 5.2 x 10⁶ cells/kg body weight (range, 1.7 to 15.8 x 10⁶ cells/kg body weight). The median mononuclear cell dose in recipients of bone marrow cells was 4.9 x 10⁸/kg body weight (range, 1.5 to 11.4 x 10⁸/kg body weight). Antimicrobial prophylaxis was determined by local protocols, but all patients received prophylactic trimethoprim/sulfamethoxazole or nebulized pentamidine as prophylaxis against Pneumocystis carinii pneumonia. If either patient or donor was seropositive for cytomegalovirus (CMV) before transplantation, plasma specimens were monitored weekly for evidence of CMV reactivation by polymerase chain reaction analysis after transplantation until 100 days after transplantation. Patients with evidence of CMV reactivation received pre-emptive therapy with ganciclovir. Chimerism studies were performed on whole blood or marrow at 3-month intervals by fluorescence in situ hybridization or variable tandem repeat single nucleotide polymorphism analysis by polymerase chain reaction. Donor lymphocytes were administered in a number of patients as management of mixed hematopoietic chimerism or at disease relapse.

Outcomes and Statistical Analysis
The main end points of the study were overall survival (OS), DFS, and time to relapse. Patients were last followed up in May 2005, with a median follow-up time of 36 months (range, 29 to 70 months for alive patients). Survival curves were constructed using the Kaplan-Meier method,¹⁸ and the log-rank test¹⁹ was used to assess differences between groups. OS was measured from the time of transplantation until death from any cause; DFS was measured from transplantation until disease relapse or death. Patients still alive at the time of the analysis were censored at the date of last follow-up. Time to relapse was calculated from date of transplantation to date of first relapse; patients who did not relapse were censored at either date of death or date of last follow-up, as appropriate. Minor end points were TRM (at day 100 and 1 year) and acute and chronic GVHD. TRM was defined as death in CR or death related to transplantation where it was not possible to assess disease status before death. Cox regression analyses²⁰ were performed to determine independent predictors of survival and DFS in patients who received an allograft for AML. All influential factors were included in a forward stepwise analysis (sex, age, disease status, source of stem cells, donor type, CMV status, GVHD, and previous transplantations). Patients who died from other causes were censored at the time of death. Data were analyzed using SAS statistical software (SAS Institute, Cary, NC).

	RESULTS

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Engraftment and Chimerism Analysis
Seventy-four patients demonstrated durable neutrophil and platelet engraftment. Neutrophil engraftment occurred at a median of 13 days after transplantation (range, 7 to 27 days), and platelet engraftment occurred at a median of 13 days (range, 6 to 66 days). Chimerism studies confirmed more than 95% donor engraftment by day 60 in the 19 patients in whom it was available. Primary graft failure occurred in two patients transplanted from an unrelated donor; one patient received bone marrow mononuclear cells, and one patient received PBSC (both patients received more than 2 x 10⁶ CD34⁺ cells/kg). Cryopreserved autologous marrow was used to rescue one patient who subsequently experienced disease relapse. The other patient received a second transplantation from a different unrelated donor but subsequently died of grade 4 GVHD.

Survival Analysis
At the time of analysis, 27 of 76 patients were alive and in remission, with 3-year OS and DFS rates for the whole group of 41% (95% CI, 29% to 53%) and 37% (95% CI, 25% to 48%), respectively (Figs 1 and 2). The 3-year OS and DFS rates of patients who received an allograft with AML in remission (CR1, CR2, or third CR) were 48% and 42%, respectively. In patients who underwent transplantation with AML in CR1, the 3-year DFS rate was 39%, and in patients who received an allograft with AML in CR2 or third CR, the 3-year DFS rate was 45% (Fig 3). For patients with relapsed/refractory AML, the 3-year DFS rate was 20%. The 3-year DFS rate for patients with MDS was 34% (Fig 3). Patients receiving an allograft from a volunteer unrelated donor had a 3-year DFS rate of 31% compared with 45% for patients who underwent transplantation using a sibling donor (P = .52; Fig 4). No difference was noted in outcome between patients receiving bone marrow or PBSC (3-year DFS rate, 32% and 37%, respectively; P = .97). Eight of 17 patients who received an allograft in CR2 demonstrated a duration of remission after transplantation that exceeded their CR1 duration consistent with remission inversion (Fig 5).

View larger version (10K): [in this window] [in a new window]   Fig 1. Overall survival of patients undergoing reduced-intensity conditioning allogeneic stem-cell transplantation for acute myeloid leukemia and myelodysplasia.

View larger version (10K): [in this window] [in a new window]   Fig 2. Disease-free survival of patients undergoing reduced-intensity conditioning allogeneic stem-cell transplantation for acute myeloid leukemia and myelodysplasia.

View larger version (17K): [in this window] [in a new window]   Fig 3. Disease-free survival of patients undergoing reduced-intensity conditioning allogeneic stem-cell transplantation by disease group. CR1, first complete remission; CR2, second complete remission; CR3, third complete remission; MDS, myelodysplasia.

View larger version (9K): [in this window] [in a new window]   Fig 4. Disease-free survival of patients undergoing reduced-intensity conditioning allogeneic stem-cell transplantation by donor type. VUD, volunteer unrelated donor.

View larger version (19K): [in this window] [in a new window]   Fig 5. Comparison between duration of remission after reduced-intensity conditioning (RIC) allograft and first complete remission (CR1) duration in patients who underwent transplantation for acute myeloid leukemia in second complete remission.

GVHD, TRM, and Death
Acute GVHD was graded according to standard criteria.²¹ Twenty-one of the 74 assessable patients (two patients with primary graft failure were excluded from this analysis) developed grade 1 to 2 acute GVHD (sibling transplantations, n = 9; unrelated donor transplantations, n = 12). No patient developed grade 3 or 4 acute GVHD. Eight patients (sibling transplantation, n = 3; volunteer unrelated donor transplantations, n = 5) developed chronic GVHD (six patients with limited and two patients with extensive GVHD). The TRM at day 100 was 9%; the TRM increased to 19% at 1 year. The TRM for sibling and volunteer unrelated donor allografts were 6% and 13%, respectively, at day 100 and 13% and 24%, respectively, at 1 year, but the differences were not statistically significant. Of the 58 patients at risk of CMV reactivation, 26 developed evidence of CMV reactivation. One patient died of CMV pneumonitis.

Disease Relapse
Disease relapse occurred in 27 patients and accounted for 59% of all deaths. Of the 27 patients who experienced relapse, the median time to relapse after transplantation was 6 months (interquartile range, 3 to 10 months). Fourteen (52%) of 27 patients, 23 (85%) of 27 patients, and 26 (96%) of 27 patients experienced relapse within 6, 12, and 24 months of transplantation, respectively (Fig 6). No significant difference in the kinetics of disease relapse was detected between the different disease groups.

View larger version (10K): [in this window] [in a new window]   Fig 6. Time from transplantation to relapse in patients undergoing reduced-intensity conditioning allogeneic stem-cell transplantation.

	DISCUSSION

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Patient age is one of the most important determinants of outcome in adults with AML. Less than 25% of patients with AML older than 50 years old treated with chemotherapy alone survive long term.^2,4,22 The outlook for patients with relapsed disease is equally poor, and remissions achieved using chemotherapy in relapsed AML are rarely durable.^23,24 Therefore, the opportunity provided by RIC regimens to extend the curative potential of allogeneic SCT to this population of patients is of considerable interest. However, although a number of studies have confirmed that RIC regimens permit transplantation of sibling or unrelated donor stem cells with acceptable toxicity in patients up to the age of 70 years,^11-14 the ability of RIC regimens to confer long-term DFS in patients with high-risk AML or MDS has not previously been demonstrated. In this series, the 3-year DFS rates observed for patients undergoing transplantation for AML in CR1 or CR2 using an RIC regimen are comparable with the rates obtained using a myeloablative regimen.^5,25 Of note, the 3-year survival rate for comparable patients treated with chemotherapy alone would be expected to be in the range of 15% to 25%.^4,22-24 Relapse was the major cause of treatment failure after RIC allograft and occurred early. All but one of the patients who experienced relapse did so within 24 months of transplantation. Thus the kinetics of disease relapse after a RIC allograft are similar to those observed when patients are transplanted using a more intensive myeloablative conditioning regimen, in which patients are exposed to the combined antileukemic effect of myeloablation and a GvL effect.^26,27 Therefore, it is reasonable to conclude that the probability of relapse is low for patients in this series who are alive and free of leukemia more than 2 years after an RIC allograft. Taken together, our data demonstrate that RIC regimens have the capacity to deliver long-term DFS in a proportion of patients with high-risk AML. Consequently, a prospective comparison of RIC allogeneic SCT is now warranted in older patients (and patients with significant comorbidities) with AML in first CR.

The low nonrelapse mortality using this preparative regimen is notable because all patients were considered ineligible for a myeloablative allograft on the grounds of comorbidity or age, more than half received an unrelated donor transplantation, and a number had undergone a previous SCT. This study confirms previous reports that the incorporation of alemtuzumab into the preparative regimen is associated with a low incidence of severe acute and chronic GVHD.^12,15,16 Strategies that reduce the risk of GVHD play a major role in limiting the toxicity of reduced-intensity allografts because T-cell–replete RIC transplantations have been reported to be associated with a substantial rate of GVHD-related mortality and morbidity, particularly in recipients of unrelated donor grafts.^13,14,29 CMV reactivation remains a significant complication of allogeneic SCT using this conditioning regimen. Because stem-cell dose is an important determinant of immune reconstitution after allogeneic SCT, it will be important to assess whether the increased availability of PBSC harvests from unrelated donors reduces the incidence of CMV viremia.³⁰

The major cause of treatment failure after allogeneic SCT for AML using an RIC regimen is disease relapse. This parallels results achieved using the myeloablative conditioning regimen in high-risk AML, in which relapse rates range from 30% to 60%.^25,31,32 It might be expected that the intense degree of T-cell depletion achieved using alemtuzumab would increase the risk of disease relapse, particularly in patients receiving an RIC regimen. However, at present, the relapse rates observed in this study do not seem to be substantially higher than the rates in patients receiving T-cell replete RIC allografts.^{13,14,29,33,34} In addition, remission inversion was produced in a significant number of patients who received an allograft in CR2 using this alemtuzumab-containing regimen. Although pharmacokinetic data from patients treated with in vivo alemtuzumab have indicated delayed recovery of the T-cell compartment after transplantation,³⁶ our results imply the persistence of a potent GVL effect. Recent data are consistent with the presence of a significant GVL effect in AML exerted by both alloreactive T and natural killer (NK) cells,⁹and rapid reconstitution of the NK cell repertoire is now known to occur after transplantation in the HLA-matched setting.³⁵ In addition, early withdrawal of cyclosporine after an RIC allograft may also play a role in permitting the rapid expansion of both T lymphocytes and NK cells.

Further elucidation of the mechanisms underlying eradication of the leukemic clone after an RIC allograft will be important to develop strategies to reduce the risk of disease relapse. The observation in this article that the great majority of patients who are destined to relapse do so in the first 12 months after transplantation defines the period when regular monitoring for evidence of disease recurrence is warranted and also identifies a relatively narrow window in which intervention aimed at reducing the risk of relapse should be targeted. The serial use of lineage-specific chimerism to monitor the proportion of donor T cells after allograft may identify patients at risk of relapse and allow the early use of prophylactic DLI with the aim of securing full donor T-cell chimerism. Because the incidence of GVHD with this regimen is low, such a strategy is feasible, although the risk of severe GVHD after DLI, particularly when it is administered in the first few months after transplantation, may limit the effectiveness of this approach. Combining biologically targeted therapies, such as flt-3 or farnesyltransferase inhibitors, with an RIC allograft may be an attractive strategy, allowing DLI administration to be delayed in certain biologically defined patient subgroups. Alternatively, the use of technology, such as radioimmunotherapy, to intensify the antileukemic activity of the preparative regimen without increasing toxicity may be of value.³⁷ Our study and other studies indicate that RIC allografts are of little value in patients with a significant disease burden at the time of transplantation,²⁸ and by extension, it is possible that the relapse risk in patients who received an allograft in CR may be determined by levels of occult residual disease at the time of transplantation. The use of newer techniques, such as multiparametric flow cytometry, to study minimal residual disease will help explore this hypothesis further and may identify a role for more intensive cytoreduction before transplantation in patients in morphologic CR. In summary, the ability of allogeneic SCT using an alemtuzumab-containing RIC regimen to produce sustained remissions in patients with AML represents a potential advance in the curative options available in this disease and provides a basis for the further development of immunotherapeutic strategies in patients currently not eligible for myeloablative transplantations.

	Authors' Disclosures of Potential Conflicts of Interest

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The author or immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Stephen MacKinnon Schering AG (C)

Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) $100,000 (N/R) Not Required

	Acknowledgment

 
We thank the data managers at participating transplantation centers for their contribution to this work.

	NOTES

 
S.T. and C.C. contributed equally to this article.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted March 22, 2005; accepted August 16, 2005.

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