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Durable Remissions of Myelodysplastic Syndrome and Acute Myeloid Leukemia After Reduced-Intensity Allografting

D.C. Taussig, A.J. Davies, J.D. Cavenagh, H. Oakervee, D. Syndercombe-Court, S. Kelsey, J.A.L. Amess, A.Z.S. Rohatiner, T.A. Lister, M.J. Barnett

From the Division of Haematological Oncology, St Bartholomew’s Hospital, London, United Kingdom.

Address reprint requests to Michael Barnett, BM, Department of Medical Oncology, 45 Little Britain, St Bartholomew’s Hospital, London EC1A 7BE, United Kingdom; email: Michael.Barnett{at}cancer.org.uk.

	ABSTRACT

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Purpose: To evaluate the use of reduced-intensity (RI) conditioning with allogeneic hematopoietic stem cell transplantation (HSCT) from HLA-identical family donors in patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML).

Patients and Methods: Sixteen patients (median age, 54 years; range, 37 to 66 years) underwent RI-HSCT using a conditioning regimen of fludarabine 25 mg/m² daily for 5 days and either cyclophosphamide 1 g/m² daily for 2 days (14 patients) or melphalan 140 mg/m² for 1 day (two patients). The median number of CD34⁺ cells and CD3⁺ cells infused per kilogram of recipient weight was 4.5 x 10⁶ (range, 1.8 to 7.3 x 10⁶ cells) and 2.9 x 10⁸ (range, 0.1 to 9.6 x 10⁸ cells), respectively.

Results: There was no transplant-related mortality (TRM) within 100 days of HSCT. Grade 1 to 2 acute graft-versus-host disease (GVHD) occurred in three patients, but neither grade 3 nor grade 4 disease was observed. Chronic GVHD occurred in 10 patients. One patient had cytomegalovirus (CMV) reactivation but did not develop CMV disease. With a median follow-up of 26 months (range, 15 to 45 months), 11 patients are alive (nine in continuous complete remission and one in complete remission after a second transplantation), and five have died (four from disease progression and one from bone-marrow aplasia induced by cyclosporine withdrawal). The 2-year actuarial overall and event-free survival rates were 69% (95% confidence interval [CI], 40% to 86%) and 56% (95% CI, 30% to 68%), respectively.

Conclusion: This strategy of RI-HSCT resulted in reliable engraftment with low incidence of acute GVHD and TRM. Durable remissions were observed in patients with MDS and AML consistent with a graft-versus-leukemia effect.

	INTRODUCTION

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ALLOGENEIC HEMATOPOIETIC stem cell transplantation (HSCT) is the only curative option for myelodysplastic syndrome (MDS) and is the treatment of choice for some patients with acute myeloid leukemia (AML). The efficacy of allografting is due in part to donor T cells recognizing and killing residual leukemic cells—the graft-versus-leukemia (GVL) effect.¹ Conventional allogeneic HSCT involves a conditioning regimen that is myeloablative and immunosuppressive. Significant mortality results from regimen-related toxicity (RRT) and acute graft-versus-host disease (GVHD).² Indeed, even for younger, selected adults with MDS or AML, the probability of transplant-related mortality is approximately 25% to 40%.^3,4 Conventional allogeneic transplantation has therefore been limited to those patients who are younger than 50 to 55 years of age and who have no significant dysfunction of another major organ.

It recently has been shown that engraftment of allogeneic hematopoietic stem cells can be achieved using less intensive conditioning.^5–10 These nonmyeloablative or reduced-intensity (RI) conditioning regimens are sufficiently immunosuppressive to prevent graft rejection, and they frequently lead to the presence of both donor and recipient cells within the bone marrow (ie, mixed chimerism). Residual recipient hematopoiesis may be eradicated by alloreactive T cells of donor origin by one of two maneuvers: withdrawal of the immunosuppressive agents that are given to control host-versus-graft and graft-versus-host reactions, or administration of more T cells by donor leukocyte infusions.¹¹ The risk of each maneuver is GVHD, whereas the potential benefit is eradication of residual disease through the GVL effect.

Against this background, an RI conditioning regimen of fludarabine and cyclophosphamide was investigated in patients with MDS or AML for whom conventional allogeneic transplantation was considered inappropriate.

	PATIENTS AND METHODS

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Between April 1999 and October 2001, 16 consecutive patients underwent RI allogeneic HSCT for MDS or AML at St Bartholomew’s Hospital (London, United Kingdom). The hospital ethics committee approved the protocol. Informed consent was obtained from patients and donors. Eligibility criteria were affliction with AML (in complete remission) or MDS, availability of a suitable HLA-identical family donor, and patient inability or unwillingness to undergo a conventional allograft.

Patient Characteristics
The clinical characteristics of patients are shown in Table 1. The median patient age was 54 years (range, 37 to 66 years).

Eleven of 16 patients were 50 years of age or older, which is beyond the upper limit for conventional allogeneic HSCT at St Bartholomew’s Hospital. The following were indications for RI allografting in the patients younger than 50 years: Patient 2 was dependent on opiates and had hepatitis C infection and prior fungal pneumonia; patient 7 had poorly controlled epilepsy and intolerance of chemotherapy; patient 9 had severe sepsis during chemotherapy; patient 10 had recent fungal pneumonia; and patient 15 had received multiple lines of therapy, including high-dose cyclophosphamide and total-body irradiation.

Donor Characteristics
Patients received allografts from HLA-identical family donors: 15 siblings and one daughter. One donor chose to donate bone marrow harvested under general anesthesia. The other donors gave peripheral blood by leukapheresis after administration of 10 µg/kg of granulocyte colony-stimulating factor (filgrastim; Neupogen Amgen, Thousand Oaks, CA) subcutaneously for 5 days with collection on days 5 and 6. The median donor age was 53 years (range, 31 to 74 years).

Conditioning Regimen
The conditioning regimen comprised fludarabine 25 mg/m² given intravenously on each of 5 days (day -6 to day -2) and cyclophosphamide 1 g/m² given intravenously on each of 2 days (day -3 and -2).

Two patients (patients 1 and 15), both among the first to be treated, received melphalan 140 mg/m², given intravenously on 1 day (day -1), instead of cyclophosphamide. This was the choice of the attending physician.

Content of the Graft
The median number of CD34⁺ cells and CD3⁺ cells infused per kilogram of recipient weight was 4.5 x 10⁶ (range, 1.8 to 7.3 x 10⁶ cells) and 2.9 x 10⁸ (range, 0.1 to 9.6 x 10⁸ cells), respectively. Five transplantations involved a major ABO blood group mismatch between recipient and donor. In all but one of the transplants, either the recipient or donor or both were positive for cytomegalovirus (CMV), as determined by serologic testing.

GVHD Prophylaxis
Cyclosporine was given intravenously at 5 mg/kg/d from 24 hours before allograft until 2 days postallograft, when the dose was reduced to 3 mg/kg/d. Subsequently, the dose was adjusted to keep the level at 150 to 300 ng/mL. Once the patient was able to eat, cyclosporine was given by mouth. Methotrexate was given intravenously at 5 mg/m² on the days +1, +3, and +6 after allograft infusion. The dose was adjusted depending on the presence of mucositis and effusions, as well as impaired renal and liver function.

Strategy for Immunosuppression
After allografting, cyclosporine was continued as immunosuppressive therapy, according to donor/recipient chimerism results (measured in blood samples taken every 1 to 2 weeks starting 1 month postallograft); if the donor cells reached 100% or continued to increase, the cyclosporine was maintained at therapeutic dose until 2 months postallograft (early in the study) or 3 to 4 months postallograft (later in the study) when, in the absence of GVHD, cyclosporine was tapered off over 4 weeks. If the proportion of donor cells decreased or stopped increasing, the cyclosporine was withdrawn sooner, either abruptly or over 2 to 4 weeks, according to circumstances.

Supportive Care
Patients received irradiated and CMV-compatible blood products. Oral ciprofloxacin 750 mg and colistin 1.5 MU twice daily were used as prophylaxis against bacterial infection. Intravenous antibiotics were administered according to the hospital protocol and depending on the results of microbiologic investigation. Fungal prophylaxis consisted of amphotericin lozenges and oral fluconazole 400 mg daily (or itraconazole 200 mg twice daily) continued until day 75 following the transplant. Patients with CMV-positive immunoglobulin G serology or a CMV-positive donor were given intravenous acyclovir 5 mg/kg tid until discharge. At discharge, this was converted to oral acyclovir 200 mg qid. Other patients were given oral acyclovir 200 mg qid for a year after the transplant. Polymerase chain reaction testing for CMV was performed weekly on plasma, and if positive results were confirmed, pre-emptive therapy with ganciclovir or foscarnet was given. Pneumocystis carinii prophylaxis comprised oral cotrimoxazole 960 mg three times per week starting at discharge from the hospital and continued until at least 6 months posttransplant.

Evaluations and Definitions
RRT¹³ and GVHD^14,15 were graded according to standard criteria. The degree of donor/recipient chimerism on whole peripheral blood or bone marrow samples was determined using an analysis of short tandem repeats.¹⁶ Neutrophil recovery was defined by a neutrophil count of 0.5 x 10⁹/L or more for 3 consecutive days. Platelet recovery was defined by an unsupported platelet count of 20 x 10⁹/L or more for 3 consecutive days.

Statistical Analysis
Event-free survival (EFS) was defined as survival with no evidence of persistent or recurrent disease by morphology. The actuarial probabilities of overall survival, EFS, and chronic GVHD were plotted using the methodology of Kaplan and Meier.¹⁷ The analysis was carried out when the minimum follow-up of patients was 15 months.

	RESULTS

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Hematologic Recovery
The median time to neutrophil recovery was 17 days (range, 12 to 28 days). The median duration of severe neutropenia (neutrophils < 0.5 x 10⁹/L) was 14 days (range, 11 to 23 days). One patient (patient 7) was severely neutropenic because of the underlying MDS from before admission and was not included in the latter calculation. The neutrophil count was more than 0.5 x 10⁹/L from day 15 onward in this patient. The median time to platelet recovery of 20 x 10⁹/L and 50 x 10⁹/L was 14 days (range, 0 to 29 days) and 18 days (range, 12 to 36 days), respectively. One patient (patient 10) never achieved a platelet count of more than 50 x 10⁹/L, because of persistent MDS. The median number of adult platelet pools administered during admission was five (range, 0 to 10 platelet pools). The median number of red cell units transfused during admission was six (range, 2 to 15 red cell units).

The median day 28 and day 100 donor chimerism was 92% (range, 42% to 100%) and 87% (range, 7% to 100%), respectively. All patients except one achieved 100% donor chimerism. The median time to 100% donor chimerism was 61 days (range, 28 to 218 days). Both patients who received conditioning with fludarabine and melphalan reached 100% donor chimerism by day 28.

RRT
The median grade of RRT was 0 (range, grade 0 to 2). The following toxicities were seen in patients receiving fludarabine and cyclophosphamide: 11 patients had grade 0 toxicity in all systems; one patient had grade 1 gastrointestinal toxicity; one patient had grade 1 mucositis; and one patient had grade 2 hepatic toxicity. Grade 2 mucositis occurred in one of the two patients who received conditioning with fludarabine and melphalan.

Infectious Complications
Twelve of 16 (75%) patients required intravenous antibiotics during the admission for neutropenic fever or cellulitis. One patient (patient 11) died of systemic Aspergillus infection after 5 months with persistent bone marrow aplasia induced by cyclosporine withdrawal. One patient (patient 10) developed CMV reactivation while receiving high-dose corticosteroids for grade 2 acute GVHD; he was treated with foscarnet and did not develop CMV disease.

GVHD
Three patients developed acute GVHD: one grade 1 and two grade 2. No patients developed grade 3 or 4 acute GVHD. One of the grade 2 patient cases involved the skin only, and the other involved the gut only (Table 2). Ten patients developed chronic GVHD (Fig 1), which was extensive in all but one patient. The 1-year actuarial probability of chronic GVHD was 66% (95% confidence interval [CI], 40% to 90%). The median donor chimerism was 100% at onset of GVHD (acute or chronic) with a range of 97% to 100%. Six of 10 patients with chronic GVHD continue to receive immunosuppressive therapy.

View larger version (6K): [in this window] [in a new window]   Fig 1. Actuarial probability of chronic graft-versus-host disease (GVHD) after reduced-intensity conditioning with allogeneic hematopoietic stem cell transplantation (RI-HSCT; n = 16).

Two patients (patients 6 and 11) developed pancytopenia caused by marrow aplasia 6 and 8 weeks after withdrawal of cyclosporine. In both patients, the cyclosporine had been withdrawn because of low donor chimerism, with only 30% of cells being of donor origin (on days 80 and 73 after transplant, respectively). The aplasia coincided with an increase in the percentage of donor cells, and both patients subsequently developed GVHD (clinically acute). In one patient, hematologic recovery occurred; the other patient died as a result of aspergillosis during prolonged aplasia.

Other Complications
One patient (patient 7) who had received a major ABO mismatched allograft developed pure red cell aplasia. She was treated with corticosteroids and immunoglobulin infusions without response and developed recurrent AML 8 months after transplantation.

One patient (patient 9) developed pericardial and pleural effusions 40 days after transplantation. The etiology was unclear, and the effusions (which contained neutrophils and lymphocytes but no malignant cells) resolved spontaneously.

Survival
Eleven patients are alive, nine of whom are in continuous remission, with a median follow-up of 26 months (range, 15 to 45 months; Table 2). The 2-year actuarial overall survival and EFS rates were 69% (95% CI, 40% to 86%) and 56% (95% CI, 30% to 68%), respectively (Fig 2). The three patients (patients 14, 15, and 16) with therapy-related MDS or AML remain in remission of the first malignancy.

View larger version (7K): [in this window] [in a new window]   Fig 2. Actuarial probability of overall survival (OS) and event-free survival (EFS) after reduced-intensity conditioning with allogeneic hematopoietic stem cell transplantation (RI-HSCT; n = 16).

Donor leukocyte infusions were not administered to patients with persistent or recurrent disease for the following reasons: two patients (patients 2 and 10) were in poor condition with overwhelming disease; two patients (patients 12 and 14) had low residual donor chimerism, were believed to be at high risk for marrow aplasia, and underwent a second transplantation; one patient (patient 11) developed marrow aplasia on withdrawal of cyclosporine; one patient (patient 7) had an unsuccessful attempt to reinduce remission; and one patient (patient 8) had persistent disease despite the onset of grade 2 acute GVHD and was considered unlikely to benefit. The 11 surviving patients enjoy robust health, with World Health Organization performance scores of either 0 or 1 (Table 2).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION REFERENCES

 
In this study, the use of an RI conditioning regimen allowed allografting to be carried out in patients with MDS and AML for whom conventional allogeneic HSCT was considered inappropriate. Toxicity within the first few months of the transplantation was minimal. Beyond this time, the main complication was chronic GVHD, the incidence of which was high. However, the small patient number precludes meaningful comparison with patients observed after standard allografting.^18,19 The 2-year EFS of approximately 50% is similar to what would be expected for a younger group of patients in the same situation undergoing conventional allogeneic HSCT.^20,21 Moreover, durable remissions were achieved in patients with poor-prognosis disease (as defined by karyotype), who are at high risk of recurrence after allografting.^22,23

It seems improbable that the conditioning regimen employed—fludarabine (25 mg/m² daily for 5 days) and cyclophosphamide (1 g/m² daily for 2 days)—brought about the impressive disease control reported here. The more likely explanation is that the GVL effect was responsible. Support for this comes from two observations. First, in accord with results from a similar study that demonstrated a correlation between GVHD and disease-free survival,²⁴ no patient with chronic GVHD developed recurrent disease. Second, persistent karyotypic abnormalities were eradicated in two patients with the onset of GVHD after withdrawal of cyclosporine.

Conventionally, acute GVHD has been defined as that which occurs within 100 days of transplantation. The low incidence as well as absence of severe forms of acute GVHD in this study is gratifying. However, GVHD that clinically resembled the classic acute form was observed beyond day 100. This difference in the onset of the GVHD may be due to delayed attainment of full donor chimerism; it is unusual for GVHD to occur unless 100% of the T cells are of donor origin.⁷ Conventional conditioning regimens lead rapidly to full donor chimerism, whereas the majority of patients reported here did not reach this state until at least 2 months had elapsed. Thus, the clinical entity of GVHD was delayed rather than avoided and, interestingly, was quite often hyrbrid (ie, having features of both acute and chronic GVHD). In the context of RI-HSCT, perhaps it would be more appropriate to define the forms of GVHD according to the time of attainment of full donor chimerism.

The low incidence of acute GVHD probably has an explanation in addition to a delay in its occurrence. A correlation between tissue damage and GVHD has been observed in animal models of transplantation²⁵ and in humans.²⁶ This is thought to be due to the release of proinflammatory cytokines that stimulate donor T cells to produce a response against recipient cells. The fludarabine plus cyclophosphamide regimen was associated with minimal tissue damage as assessed by RRT. Even if this were not the case, after RI-HSCT the so-called cytokine storm may have subsided by the time full donor chimerism was achieved.

The two episodes of marrow aplasia (patients 6 and 11), both of which occurred after cyclosporine withdrawal in response to low donor chimerism, are instructive. Subsequent chimerism analysis indicated that donor hematopoiesis was replacing residual recipient hematopoiesis but with some delay in production of differentiated cells (ie, a period of crossover or critical switch²⁷ occurred). For such patients, the administration of T-cell–depleted CD34⁺ donor cells may shorten the duration of severe cytopenia.

When patients are selected for RI-HSCT, factors related to both patient and disease must be considered. The former include age and general condition. In this study, for example, which used grafts replete with T cells, the main toxicity (but probably also associated efficacy¹) was chronic GVHD, the likelihood of which increases with age.^28,29 The patient must, therefore, be able to tolerate GVHD as well as the prolonged immunosuppressive therapy required to treat it. Accordingly, although RI-HSCT is more widely applicable than conventional allografting, judicious patient selection is still required. In the light of these considerations, an upper age limit of approximately 65 years would seem reasonable.

The disease status at transplantation is important when, as in this study, the conditioning regimen has minimal antileukemic activity and the GVL effect is being relied on to eradicate the disease. Donor leukocyte infusions are successful in only a minority of patients with recurrent AML after conventional allogeneic HSCT.³⁰ Thus, the chance of RI-HSCT resulting in durable remission for those with persistent morphologic evidence of AML is remote. For the same reason, the procedure is unlikely to benefit patients with MDS who have an excess of blasts at transplantation.

These results and those from other pilot studies^24,31 justify the evaluation of RI-HSCT as consolidation of first remission in larger numbers of patients with standard- or poor-risk AML. Indeed, this is a component of the new Medical Research Council trial (AML 15). The encouraging outcomes in the three patients with therapy-related MDS/AML described here and the high transplant-related mortality with standard allografting³² also support additional study of RI-HSCT in these diseases. Similarly, although the role of this treatment for primary MDS may prove more difficult to define, collaborative trials are indicated.^24,33

Despite earlier pessimism regarding the role of RI-HSCT in the management of patients with MDS and AML,³⁴ evidence is accumulating that this treatment is relatively safe and effective, and thus warrants further study.

	ACKNOWLEDGMENTS

 
We thank the nursing and medical staff of the Bodley Scott Unit and Paget Ward, as well as the technical staff of the Stem Cell Laboratory, at St Bartholomew’s Hospital. We also thank the physicians who referred patients and Janet Matthews, who collected and prepared the data.

	NOTES

 
Supported by Cancer Research UK.

Presented in part at the American Society of Hematology annual meeting, Philadelphia, PA, December 2002.

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Submitted February 12, 2003; accepted May 28, 2003.

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				C. Crawley, R. Szydlo, M. Lalancette, A. Bacigalupo, A. Lange, M. Brune, G. Juliusson, A. Nagler, A. Gratwohl, J. Passweg, et al. Outcomes of reduced-intensity transplantation for chronic myeloid leukemia: an analysis of prognostic factors from the Chronic Leukemia Working Party of the EBMT Blood, November 1, 2005; 106(9): 2969 - 2976. [Abstract] [Full Text] [PDF]

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