Volume 14, Issue 2 , Pages 246-255, February 2008
Reduced-Intensity Conditioning followed by Allogeneic Hematopoietic Cell Transplantation for Adult Patients with Myelodysplastic Syndrome and Myeloproliferative Disorders
Article Outline
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is the only curative strategy for patients with myelodysplastic syndrome (MDS) and myeloproliferative disorders (MPD). We report the results of 148 patients (median age = 59 years old) with de novo MDS (n = 40), acute myelogenous leukemia (AML) after antecedent MDS/MPD (n = 49), treatment-related MDS (t-MDS) (n = 25), MPD (n = 27), and chronic myelomonocytic leukemia (CMML) (n = 7) who underwent allogeneic HCT using a conditioning regimen of low-dose total body irradiation (TBI) alone (200 cGy) on day 0 (n = 5) or with the addition of fludarabine (Flu) 30 mg/m2/day on days −4 to −2 (n = 143). Postgrafting immunosuppression consisted of cyclosporine and mycophenolate mofetil (MMF). Seventy-five patients (51%) received an allograft from a matched related donor (MRD), and 73 patients (49%) were recipients of unrelated donor (URD) grafts. There was no significant difference in the incidence of acute (gr II-IV) and chronic extensive graft-versus-host disease (aGVHD, cGVHD) between the recipients of related and unrelated donor grafts. By day +28, 75% of patients demonstrated mixed T cell chimerism. Graft rejection was seen in 15% of patients. With a median follow-up of 47 (range: 6-89) months, the 3-year relapse-free survival (RFS) and overall survival (OS) are both 27% for all patients, with a relapse incidence of 41%. The 3-year RFS for the patients with de novo MDS, AML after antecedent MDS/MPD, t-MDS, MPD, and CMML were 22%, 20%, 29%, 37%, and 43%, respectively, and the 3-year OS was 20%, 23%, 27%, 43%, and 43%, respectively. The 3-year nonrelapse mortality (NRM) was 32%. Factors associated with a lower risk of relapse were the development of extensive cGVHD and having a low risk or intermediate-1 risk International Prognostic Score for the de novo MDS patients. Nonmyeloablative HCT confers remissions in patients who otherwise were not eligible for conventional HCT but for whom relapse is the leading cause of treatment failure.
Keywords: Reduced-intensity conditioning, Nonmyeloablative transplantation, Myelodysplastic syndrome, Myeloproliferative disorders, Allogeneic
Introduction
The myelodysplastic syndromes (MDS) and myeloproliferative disorders (MPD) are clonal hematopoietic stem cell (HSC) disorders that have the potential for evolution to acute myelogenous leukemia (AML). Allogeneic hematopoietic cell transplantation (HCT) is currently the only therapy with curative potential, but most patients are of advanced age with attendant comorbidities, which has limited the number of patients who are eligible for myeloablative regimens followed by allogeneic HCT. Nonrelapse mortality (NRM) can be prohibitive, especially in the elderly, and in patients with advanced disease can be as high as 80% 1, 2, 3, 4, 5. Thus, reduced-intensity (RIC) or nonmyeloablative regimens have been increasingly offered because these treatment modalities induce engraftment with low toxicity. Nonmyeloablative HCT relies on graft-versus-tumor effects and has proved safe and efficacious in various hematologic malignancies.
This report describes the characteristics and outcomes of 148 consecutive adult patients with MDS or MPD from 14 institutions who received a nonmyeloablative conditioning regimen of low-dose total body irradiation (TBI) with or without fludarabine before HCT from HLA-matched or mismatched related or unrelated donors (URDs). The patients were not suitable candidates for conventional myeloablative conditioning because of age or comorbid conditions.
Methods
This analysis includes data from 148 patients diagnosed with MDS and MPD who underwent allogeneic HCT after nonmyeloablative conditioning on multi-institutional protocols for patients with hematologic malignancies between January 1998 and November 2004. The primary differences between protocols were the use of HLA-matched related or unrelated grafts, variations in the duration and intensity of CSP and MMF, and the addition of fludarabine to 2 Gy TBI. These changes were made over time to reduce both the risks of GVHD and graft rejection. The study protocols and written informed consents were approved by the institutional review boards (IRB) of the participating institutions. Results were analyzed as of April 30, 2007.
The 14 participating centers included Fred Hutchinson Cancer Research Center (n = 50), Stanford University Medical Center (n = 33), University of Leipzig (n = 18), Baylor University Medical Center (n = 10), Seattle Veterans Affairs Puget Sound Health Care System (n = 10), Oregon Health Sciences University (n = 6), University of Utah (n = 5), City of Hope National Medical Center (n = 4), Emory University (n = 3), Medical College of Wisconsin (n = 3), University of Colorado (n = 2), University of Torino (n = 2), University of Tuebingen (n = 1), and University of Arizona (n = 1) on prospective multicenter research protocols. The initial results of 38 of the 50 patients from the Fred Hutchinson Cancer Research Center have been described previously, and this current analysis includes an update of their results [6].
Patients aged >49 years and <75 years old were eligible. However, patients <50 years at high risk for regimen-related toxicity using a myeloablative regimen were also allowed. Included in this study were patients with MDS, including the diagnoses of refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), chronic myelomonocytic leukemia (CMML), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and MDS transformed to AML. Patients with advanced MDS and evolution to AML were cytoreduced to <10% marrow blasts. Patients with MPD who were eligible for this study included polycythemia vera (PV) and essential thrombocythemia (ET) with persistent thrombotic or hemorrhagic complications despite conventional therapy or who had progressed to marrow fibrosis. Patients with agnogenic myeloid metaplasia (AMM) with <10% marrow blasts or <5% blasts if evolution to AML were also included. Treatment-related MDS patients had prior cytotoxic chemotherapy for previously diagnosed malignancies or autoimmune diseases.
In a subset of patients who were MRD recipients (n = 39), diagnosis was classified as “indolent” or “aggressive” for the purposes of determining rate of cyclosporine taper, which is further explained under the “Treatment and Evaluations” section of this report. Indolent disease was defined as (1) MDS with FAB diagnosis of RA or RARS; (2) CMML; (3) atypical CML in chronic phase; (4) PV or ET in proliferative phase or spent phase with or without myelofibrosis, without excess blasts (<10% marrow blasts); (5) AMM; and (6) acute leukemia with antecedent MDS or MPD induced to complete remission. Aggressive disease was defined as (1) MDS with an FAB diagnosis of RAEB or RAEB-T prior to cytoreductive therapy, (2) CMML with excess blasts or in blastic transformation prior to cytoreductive therapy, (3) atypical CML with excess blasts or in transformation prior to cytoreductive therapy, (4) PV or ET in blastic transformation prior to cytoredutive therapy, (5) AMM in blastic transformation prior to cytoreductive therapy, and (6) acute leukemia with antecedent MDS or MPD.
Exclusion criteria were creatinine clearance <50 mL/min, ejection fraction <40% (symptomatic for congestive heart failure requiring therapy, poorly controlled cardiac arrythmias, or poorly controlled hypertension were exclusion criteria), diffusing lung carbon monoxide (DLCO) <50% of predicted value, severe liver dysfunction (liver failure, cirrhosis, uncorrectable hepatic synthetic dysfunction, and symptomatic biliary disease or total bilirubin >3 mg/dL), Karnofsky performance status of <60%, active CNS involvement of disease, treatment refractory fungal infections, or active bacterial infections.
HLA Typing
Donors were HLA-matched as defined by the following criteria: (1) matched for HLA-DRB1 and DQB1 by high resolution typing; (2) serologically matched for all recognized HLA-A, -B, and –C antigens and molecularly matched for at least 5 of 6 HLA-A, -B, or -C antigens by high-resolution typing. One hundred thirty-five patients received HLA-matched grafts; 11 patients received grafts mismatched for a single class I HLA allele; 1 graft was mismatched for 2 class I HLA alleles and 1 graft was mismatched at a single class I HLA antigen. All of the mismatched grafts were among the recipients of URD grafts.
Treatment and Evaluations
One hundred forty-three patients were treated with 3 doses of fludarabine (Flu) 30 mg/m2/day from days −4 to −2 and a single fraction of 2 Gy TBI delivered at a 0.07 Gy/min from linear accelerators on day 0. Five related recipients received 2 Gy of TBI without flu. Hematopoietic cells were infused in the afternoon of day 0. One hundred forty-five patients received granulocyte-colony stimulating factor (G-CSF) mobilized allogeneic peripheral blood hematopoietic cells, whereas 4 unrelated recipients received marrow grafts. Cyclosporine (CSP) was administered orally at a dose of 6.25 mg/kg twice daily from day −3 targeting whole blood trough levels of 500-600 mg/dL. The anticipated stop date of CSP was determined by disease risk in 39 patients as previously mentioned. For the recipients of related grafts, patients in the “indolent” risk category started the CSP taper on day +100 with a target stop date by day +177, whereas patients in the “aggressive” disease risk category initiated the CSP taper on day +56 with a targeted stop day of day +81. For all other MRD recipients, CSA was either stopped by day 56 (n = 33) or day +180 (n = 3). For unrelated recipients, the CSP taper was initiated at day +100 with a target stop date of day +180. CSP was stopped earlier if progressive disease occurred. GVHD prophylaxis also included MMF 15 mg/kg by mouth twice daily, beginning on day 0 after hematopoietic cell infusion and discontinued on day +28 without a taper in related recipients. The unrelated recipients received MMF 15 mg/kg by mouth every 8-12 hours on the evening of day 0, with a taper starting day +40 with a target stop date of day +96. The MMF dosing schedule of every 8 hours was based on previously published data showing less graft rejection in unrelated recipients compared to every 12 hour dosing 7, 8.
GVHD Grading and Therapy and Supportive Care
All occurrences of acute or chronic GVHD (aGVHD, cGVHD) were graded according to established criteria 9, 10. Treatment was provided for grade II-IV aGVHD, which included CSP 5 mg/kg by mouth twice a day or 1.5 mg/kg i.v. twice a day to aim for therapeutic levels. Prednisone 2 mg/kg/day was added for grade II-IV GVHD at the discretion of the treating physician. Steroid-refractory aGVHD was treated per institutional practice. Prophylaxis against infections was implemented according to the standard practice of the individual transplant center.
Follow-up
Patients were examined by a healthcare provider in the outpatient department during the period of neutropenia per institutional guidelines. Bone marrow aspirates were performed for histology, cytogenetic analysis, and chimerism on day +28, +56, +84, and +180, and then annually. Percentages of donor-host chimerism were evaluated by fluorescein in situ hybridization (FISH) for X and Y chromosomes if patients and donors were sex mismatched or by polymerase chain reaction-based amplification of variable number of tandem repeat sequences unique to donors and hosts if patients and donors were sex matched. Mixed chimerism was defined as between 5% and 95% peripheral blood donor T cells, and full chimerism was defined as >95% donor T cells. After day +56 and if patients were clinically stable, routine evaluation including a history and physical exam, complete blood counts, and serum chemistry panel were performed at 3, 4, 6, 9, 12, and 18 months, then at 2 years and yearly thereafter.
Treatment of Persistent, Progressive, or Relapsed Diseases and Prevention of Graft Rejection
Patients with progressive disease or persistent disease were eligible for donor lymphocyte infusion (DLI) as therapeutic intervention. Declining chimerism was also considered an indication for DLI administration. Patients with any grade (II-IV) aGVHD or extensive cGVHD were not eligible for DLI. Other eligibility criteria to receive DLI included completion of immunosuppression taper for 1-2 weeks before DLI administration and presence of at least mixed hematopoietic chimerism as defined by >5% donor peripheral blood T cells. Patients who had developed GVHD (except grade 1 aGVHD or limited cGVHD) must have successfully completed GVHD therapy for 8 weeks before DLI was given. If a patient had progressive disease, consideration was given toward early discontinuation of immunosuppression as a first line intervention.
Statistical Methods
Survival curves were estimated according to the Kaplan-Meier method. Overall survival (OS) was defined as time from transplantation to death of any cause. Relapse-free survival (RFS) was defined as time from transplantation to relapse, progression, or death of nonrelapse causes. Cumulative incidence estimates were calculated for aGVHD, cGVHD, relapse/progression, and NRM. Deaths were treated as competing events in analyses of graft rejection, GVHD, and disease progression. Univariate and multivariate analyses of risk factors for all outcomes were performed using Cox regression. The relationship between rejection and aGVHD and cGVHD with subsequent outcomes was assessed by treating these factors as time-dependent covariates.
Results
Patient Characteristics
Characteristics for all patients and for each disease subtype are listed in Table 1, Table 2. The median age for all patients was 59 (range: 26-73) years. The 5 disease subtypes were AML after antecedent MDS/MPD (n = 49), de novo MDS (n = 40), treatment-related MDS (n = 25), MPD (n = 27), and CMML (n = 7). The patients with de novo MDS were divided into 2 subsets for the purposes of analysis: low/intermediate-1 and intermediate-2/high. Seventy-five patients were recipients of HLA-matched related donor (MRD) grafts (51%) and 73 patients (49%) received grafts from URD. Regarding hematopoietic cell source, 144 patients received G-CSF mobilized peripheral blood hematopoietic cells and 4 patients received bone marrow. The median CD34+ cell dose was 6.9 × 106/kg (range: 1.0-34) and median CD3+ cell dose was 2.7 × 108/kg (range 0.17-26). Median follow-up after HCT for alive patients was 47 (range: 6-89) months.
Table 1. Patient Characteristics
| All patients (n = 148) | AML after Antecedent MDS/MPD (n = 49) | De Novo MDS (n = 40) | t-MDS (n = 25) | MPD (n = 27) | CMML (n = 7) | |
|---|---|---|---|---|---|---|
| Patient age, median (range) | ||||||
| 59 (26-73) | 62 (26-72) | 60 (42-72) | 56 (46-73) | 58 (27-73) | 58 (39-62) | |
| Time from diagnosis to HCT in months, median (range) | ||||||
| 11 (2-223) | 9 (2-142) | 11 (3-165) | 6 (3-223) | 14 (3-157) | 10 (3-32) | |
| Patient age, n (%) | ||||||
 <60 years old | 78 (53%) | 19 (39%) | 20 (50%) | 18 (72%) | 17 (63%) | 4 (57%) |
| ≥60 years old | 70 (47%) | 30 (61%) | 20 (50%) | 7 (28%) | 10 (37%) | 3 (43%) |
| Donor relation, n (%) | ||||||
| MRD | 75 (51%) | 24 (49%) | 23 (58%) | 12 (48%) | 11 (41%) | 5 (71%) |
| URD | 73 (49%) | 25 (51%) | 17 (43%) | 13 (52%) | 16 (59%) | 2 (29%) |
| Patient sex, n (%) | ||||||
| Male | 98 (66%) | 32 (65%) | 28 (70%) | 14 (56%) | 20 (74%) | 4 (57%) |
| Female | 50 (34%) | 17 (35%) | 12 (30%) | 11 (44%) | 7 (26%) | 3 (43%) |
| Donor sex, n (%) | ||||||
| Male | 75 (51%) | 22 (45%) | 20 (50%) | 12 (48%) | 18 (67%) | 3 (43%) |
| Female | 73 (49%) | 27 (55%) | 20 (50%) | 13 (52%) | 9 (33%) | 4 (57%) |
| Prior autologous HCT, n (%) | ||||||
| No | 130 (88%) | 49 | 39 (98%) | 9 (36%) | 26 (96%) | 7 |
| Yes | 18 (12%) | 0 | 1 (3%) | 16 (64%) | 1 (4%) | 0 |
| Prior myelosuppresive chemotherapy, n (%) (unknown for 3 patients) | ||||||
| No | 61 (42%) | 7 (15%) | 28 (72%) | 2 (8%) | 22 (85%) | 2 (29%) |
| Yes | 84 (58%) | 41 (85%) | 11 (28%) | 23 (92%) | 4 (15%) | 5 (71%) |
| In CR at transplant, n (%) (unknown for 17 patients) | ||||||
| No | 90 (69%) | 14 (33%) | 30 (86%) | 17 (71%) | 23 (96%) | 6 |
| Yes | 41 (31%) | 28 (67%) | 5 (14%) | 7 (29%) | 1 (4%) | 0 |
| IPSS group, n (%) (unknown for 1 de novo MDS patient) | ||||||
| Low | — | — | 22 (56%) | — | — | — |
| High | — | — | 17 (44%) | — | — | — |
Table 2. Diagnoses and Subtypes
| De novo myelodysplastic syndrome | 40 |
| IPSS | |
| Low | 7 |
| Intermediate-1 | 15 |
| Intermediate-2 | 12 |
| High | 5 |
| Unknown | 1 |
| FAB | |
| Refractory anemia | 18 |
| Refractory anemia with ringed sideroblasts | 3 |
| Refractory anemia with excess blasts | 16 |
| Unknown | 3 |
| Myeloproliferative disorder | 27 |
| Idiopathic myelofibrosis | 12 |
| Chronic myelogenous leukemia | 3 |
| Essential thrombocythemia | 4 |
| Polycythemia vera | 1 |
| Undifferentiated | 7 |
| Chronic myelomonocytic leukemia | 7 |
| Treatment-related MDS | 25 |
| Prior autologous HCT | 18 |
| Prior myeloablative HCT | 1 |
| Prior conventional chemotherapy | 6 |
Chimerism, Engraftment and Rejection
One hundred forty-two patients survived to day +28 and 129 patients were assessed for T cell chimerism at that time. Of these evaluable patients, only 5 (4%) failed to achieve ≥5% donor T cell chimerism. Four of these 5 patients relapsed (at days 27, 35, 113, and 174) and the other died of nonrelapse causes on day +41. Of these 5 patients, 1 patient had received TBI only as the conditioning regimen with the other 4 receiving both TBI plus flu. Twenty-three (16%) patients rejected their grafts with a median time to rejection of 72 days. Rejection was an adverse risk factor for both OS (hazard ratio [HR] = 2.40, 95% confidence interval [CI] 1.5-3.9, P = .001) and RFS (HR = 2.86, 95% CI 1.6-5.1, P = .002). There was no difference in rejection incidences between the unrelated (16%) and the related (15%) recipients. CD3+ cell dose, CD34+ cell dose, and prior HCT also did not impact incidence of rejection. Younger age, prior myeloablative chemotherapy, and transplant in remission were associated with lower risk of rejection in univariate analysis; however, none of these factors had significant associations in multivariate analysis.
Five patients received DLI, 3 for progressive disease and 2 for declining T cell chimerism at a median of 219 (range: 154-762) days following HCT. The median CD3+ cell dose infused was 26 × 107/kg (range: 1 × 107/kg – 1 × 108/kg). Three of the DLI products were collected at steady state (unmobilized) and the other 2 products were G-CSF mobilized. Two patients subsequently died from progressive disease: 1 died from sepsis and 1 succumbed to hepatic GVHD. One of the patients is alive and in remission from refractory anemia at 6 years after HCT after receiving DLI for declining chimerism.
Acute and Chronic GVHD
The incidences of aGVHD and cGVHD by donor source are listed in Table 3. Fifty-seven patients (39%) developed grade II-IV aGVHD. Median time to the diagnosis of aGVHD was 41 days. There was no difference in incidences of aGVHD or cGVHD by donor source (MRD versus URD). aGVHD was the cause of death in 24 (16%) patients (11 with unrelated and 13 with related donors). Seventy-one patients developed cGVHD, which was extensive in 55 patients, with a cumulative incidence at 2 years of 37%. The median time to extensive cGVHD was 141 days. Patients with extensive cGVHD experienced significantly less relapse (HR = 0.42, 95% CI 0.2-1.0, P = .04). We separately analyzed the subset of 39 MRD recipients in which CSA taper varied according to the “indolent” (n = 10) versus “aggressive” (n = 29) disease risk category and found no significant differences in incidence of aGVHD, cGVHD, or relapse; however, the small sample size limits our ability to conclude that differences do not exist.
Table 3. Patient Outcomes
| All Patients (n = 148) | AML after Antecedent MDS/MPD (n = 49) | De Novo MDS (n = 40) | t-MDS (n = 25) | MPD (n = 27) | CMML (n = 7) | |
|---|---|---|---|---|---|---|
| Primary endpoints | ||||||
| Overall survival at 3 years | 27% | 20% | 23% | 27% | 43% | 43% |
| Relapse-free survival at 3 years | 27% | 22% | 20% | 29% | 37% | 43% |
| Relapse at 3 years | 41% | 49% | 40% | 40% | 26% | 57% |
| NRM at 200 days | 21% | 20% | 23% | 16% | 30% | 0% |
| NRM at 3 years | 32% | 29% | 40% | 31% | 37% | 0% |
| GVHD endpoints | MRD | URD | P-value |
|---|---|---|---|
| Acute grade II-IV | 36% | 40% | .31 |
| Acute grade III-IV | 11% | 10% | .99 |
| Extensive chronic | 43% | 32% | .31 |
Survival and Causes of Death
With a median follow-up of 47 months, 37 of 148 (25%) patients are alive. The median OS and RFS were 180 days and 296 days, respectively. Table 3 and Figure 1, Figure 2, Figure 3 demonstrate patient outcomes by disease subgroup. For the 40 patients with de novo MDS, no significant differences were seen in RFS or NRM (P = .07 and .68, respectively) between the low/intermediate-1 group and the intermediate-2/high groups, but the latter group had a significantly higher incidence of relapse/progression (HR = 2.92, 95% CI 1.0-8.6, P = .04; see Figure 4, Figure 5). Relapse was the leading cause of death (55%). The median time to relapse was 113 days. Prior autologous HCT did not affect NRM even though these patients were heavily pretreated. Patients with chemotherapy-induced remissions before HCT did not have superior survival or progression incidences compared to patients who did not receive pre-HCT chemotherapy. In univariate analysis, factors significantly associated with relapse/progression were the occurrence of clinical extensive cGVHD (see above) and, among patients with de novo MDS, an IPSS risk score of intermediate-2 or higher (HR = 2.92, 95% CI 1.0-8.6, P = .04; see Table 4). In multivariate analysis, being in CR at the time of transplantation was associated with decreased relapse risk (HR = 0.47, 95% CI 0.2-1.0, P = .05); no other factors were significantly associated with any outcome.
Figure 1
Relapse-free survival (years) by disease subgroup.
Figure 2
Overall Survival (years) by disease subgroup.
Figure 3
Relapse incidence (years) by disease subgroup.
Figure 4
Relapse-free survival (years) by IPSS grouping. There was no significant difference in relapse-free survival (RR = 1.38, P = .37).
Figure 5
Relapse/progression incidence (years) by IPSS grouping. The patients in the intermediate-2/high-risk group had a significantly higher risk of relapse/progression (RR = 2.92, P = .04).
Table 4. Univariate Analysis of Risk Factors
| OS (111 events) | RFS (114 events) | Relapse/prog (64 events) | NRM (50 events) | |||||
|---|---|---|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | HR (95% CI) | P | |
| Disease group | ||||||||
| AML (n = 49) | 1.0 | 1.0 | 1.0 | 1.0 | ||||
| MDS (n = 40) | 0.86 (0.5-1.4) | 0.86 (0.5-1.4) | 0.64 (0.3-1.2) | 1.27 (0.6-2.6) | ||||
| t-MDS (n = 25) | 0.83 (0.5-1.4) | 0.82 (0.5-1.4) | 0.70 (0.3-1.5) | 1.01 (0.4-2.4) | ||||
| MPD (n = 27) | 0.61 (0.3-1.1) | .53 | 0.63 (0.4-1.1) | .60 | 0.41 (0.2-1.0) | .14 | 0.98 (0.4-2.2) | .20 |
| CMML (n = 7) | 0.74 (0.3-1.9) | 0.84 (0.4-2.0) | 1.28 (0.5-3.1) | 0.0 (undefined) | ||||
| Patient age | ||||||||
| <60 yo (n = 78) | 1.0 | 1.0 | 1.0 | 1.0 | ||||
| ≥60 yo (n = 70) | 0.71 (0.5-1.0) | .07 | 0.73 (0.5-1.1) | .10 | 0.74 (0.5-1.2) | .24 | 0.72 (0.4-1.3) | .25 |
| Donor relation | ||||||||
| MRD (n = 75) | 1.0 | 1.0 | 1.0 | 1.0 | ||||
| URD (n = 73) | 1.32 (0.9-1.9) | .15 | 1.25 (0.9-1.8) | .23 | 1.07 (0.7-1.8) | .78 | 1.53 (0.8-2.7) | .14 |
| Patient sex | ||||||||
| Male (n = 98) | 1.0 | 1.0 | 1.0 | 1.0 | ||||
| Female (n = 50) | 0.79 (0.5-1.2) | .24 | 0.79 (0.5-1.2) | .24 | 0.82 (0.5-1.4) | .47 | 0.75 (0.4-1.4) | .34 |
| Donor sex | ||||||||
| Male (n = 75) | 1.0 | 1.0 | 1.0 | 1.0 | ||||
| Female (n = 73) | 0.93 (0.6-1.3) | .69 | 0.86 (0.6-1.2) | .41 | 0.82 (0.5-1.3) | .44 | 0.90 (0.5-1.6) | .72 |
| Prior autologous HCT | ||||||||
| No (n = 130) | 1.0 | 1.0 | 1.0 | 1.0 | ||||
| Yes (n = 18) | 0.94 (0.5-1.7) | .83 | 0.88 (0.5-1.6) | .67 | 0.85 (0.4-1.9) | .67 | 0.93 (0.4-2.2) | .87 |
| Prior myelosuppressive chemotherapy (unknown for 3 patients) | ||||||||
| No (n = 61) | 1.0 | 1.0 | 1.0 | 1.0 | ||||
| Yes (n = 84) | 1.20 (0.8-1.8) | .34 | 1.13 (0.8-1.6) | .54 | 1.47 (0.9-2.5) | .14 | 0.81 (0.5-1.4) | .46 |
| In CR at transplant (unknown for 17 patients) | ||||||||
| No (n = 90) | 1.0 | 1.0 | 1.0 | 1.0 | ||||
| Yes (n = 41) | 1.04 (0.7-1.6) | .86 | 0.95 (0.6-1.4) | .80 | 0.93 (0.5-1.6) | .79 | 0.97 (0.5-1.9) | .93 |
| Chronic GVHD (clinical extensive, as time-dependent covariate) | ||||||||
| No (n = 93) | 1.0 | 1.0 | 1.0 | 1.0 | ||||
| Yes (n = 5) | 0.73 (0.5-1.2) | .19 | 0.68 (0.4-1.2) | .16 | 0.42 (0.2-1.0) | .04 | 1.02 (0.5-2.1) | .96 |
| IPSS risk (among de novo MDS only, unknown for 1 patient) | ||||||||
| Low (n = 22) | 1.0 | 1.0 | 1.0 | 1.0 | ||||
| High (n = 17) | 1.05 (0.5-2.1) | .89 | 1.38 (0.7-2.8) | .37 | 2.92 (1.0-8.6) | .04 | 0.69 (0.2-2.0) | .47 |
Regimen-Related Toxicities and Infections
The NRM for all patients at 200 days and 3 years was 21% and 32%, respectively. Donor source, prior autologous HCT, prior myelosuppressive chemotherapy, patient age, IPSS risk, or presence of aGVHD or cGVHD did not impact the incidence of NRM.
There were 156 documented episodes of blood-borne infections among 64 patients. Ninety-six (62%) of these episodes were bacterial, of which 48% were because of coagulase negative Staphylococcus species. Fifty-five (35%) episodes were viral, of which most (87%) were because of CMV reactivation. Four patients experienced documented CMV pulmonary disease, 5 patients had BK virus in their urine, and 1 patient developed an acute hepatitis C infection. Fungemia was documented in 5 patients.
Discussion
The development of nonmyeloablative or RIC regimens has broadened the eligibility of allogeneic HCT to patients who otherwise might not be offered this potentially curative modality. This study details the results of the largest published series of MDS and MPD patients who were given a nonmyeloablative or RIC regimen before receiving unmanipulated allogeneic hematopoietic cells. All patients were considered at high risk to undergo myeloablative conditioning because of age, comorbid medical conditions, or failed autologous or allogeneic HCT.
Overall, the conditioning regimen of flu and low-dose TBI was well tolerated, with a 100-day and 200-day mortality of 11% and 21%, respectively. Receipt of a prior myeloablative HCT was not a risk factor for increased NRM in this heavily pretreated subset, which confirms the low toxicity of the regimen. Donor type, specifically grafts from unrelated donors, also did not an adversely affect NRM as has been observed with myeloablative regimens. With longer follow-up, however, the NRM increased to 32% at 3 years. The median age of our patients was 59 years old, and older recipient age is a known negative prognostic factor for NRM and OS 1, 2, 11, 12.
In our series, relapse represented the leading cause of death. This could be partly explained by the fact that over half of the patients had treatment-related MDS (t-MDS), CMML, and transformed AML, malignancies inherently associated with poor prognoses. Of the de novo MDS patients, approximately 43% had intermediate-2 or high risk IPSS scores. Type of donor (related versus unrelated) did not significantly impact relapse incidence. However, RIC regimens rely primarily on the graft-versus-tumor effect to confer remissions with the intensity of the conditioning regimen also being an important factor in controlling disease kinetics in this patient population. Our immunuosuppressive conditioning regimen offered minimal cytoreduction and was mainly immunosuppressive, which also could have contributed to relapse.
Two published retrospective series, 1 from the European Bone Marrow Transplant group and the other from the Dana Farber Cancer Institute, retrospectively compared the outcomes of patients with hematologic malignancies including MDS who received either a myeloablative or a RIC regimen 13, 14. Both reports showed significantly decreased relapse rates in the myeloablative group but at the expensive of higher NRM. Thus, survival outcomes were comparable between the 2 types or regimens. These observations of lower NRM but higher relapse among RIC recipients reinforces that some degree of cytoreduction in the conditioning regimen is necessary to control disease prior to the establishment of the graft-versus-tumor effect.
The incidence of aGVHD and cGVHD in this trial was comparable to other published studies using RIC with this patient population. Type of donor did not impact the rates of either aGVHD or cGVHD in our study. The incidence of cGVHD varies widely in the literature after RIC transplantation, which could be accounted for by variable lengths of follow-up and different sample sizes 15, 16, 17, 18, 19, 20, 21, 22. In this report, the occurrence of cGVHD but not aGVHD was associated with a lower risk of relapse/progression. This finding is in accordance with other reports and confirms the crucial role of the GVL effect. In a prospective series of 37 patients with AML and MDS, a Spanish group reported a significantly lower risk of disease progression in patients who developed aGVHD or cGVHD compared to those who did not (13% versus 58%) after receiving an RIC regimen of flu and busulfan [20]. In a large retrospective series of 221 patients with hematologic malignancies from the Fred Hutchinson Cancer Research Center, an association with cGVHD and a reduced relapsed incidence was also observed with the beneficial effects most notable in the MDS and AML patients [23]. In contrast, a recent report from M.D. Anderson on 112 patients with AML and MDS who received flu and melphalan as a preparative regimen reported no effect of cGVHD on progression or survival with aGVHD negatively impacting survival [24].
HCT at the time of leukemic progression portends a poor prognosis, but the optimal timing of HCT for early MDS remains unclear. Over half of the patients in our series (58%) received myelosuppressive chemotherapy prior to HCT. Compared to patients who did not receive myelosuppressive chemotherapy, no advantage was seen in terms of survival, relapse, or NRM. However, our results might be affected by selection bias as this was a retrospective analysis. Previously published transplant series have demonstrated advantages for patients who entered transplant with low disease burdens as increased numbers of blasts in the blood or bone marrow have been described as 1 of the most important risk factors for relapse 12, 25, 26. However, the value of cytoreduction in this setting remains controversial, and most prior reports have shown no benefit.
Direct comparison of the 5 subgroups in this report is difficult because of the relatively small sample sizes of each group. CMML typically contains features of both MDS and MPD and carries a median survival of only 6-24 months, depending on prognostic features [27]. Of the 7 patients with CMML, 5 patients have expired from relapse. Three reports utilizing primarily myeloablative regimens for CMML patients report DFS ranging from 18%-41%, with relapse incidences ranging from 23%-63%. Transplantation early in the disease course and having few or no comorbidities predicted for a better outcome 28, 29, 30.
The prognosis for patients with t-MDS is poor with a median survival of 4 months and the efficacy of HCT for this specific population is difficult to assess as most of the data reported is combined with primary MDS patients [31]. In our series, the 25 patients with t-MDS had a PFS and OS of 29% and 27%, which is similar to the outcomes of the 40 patients with primary MDS. The relapse rate of 40% was identical between both groups. The RFS of 29% is comparable to the the few published reports of myeloablative allogeneic HCT specifically for t-MDS with RFS ranging from 8%-30%. Our NRM of 31% at 3 years, however, appeared significantly less, as these previously mentioned myeloablative reports detailed NRM rates ranging from 42%-58% 1, 5, 32.
As seen with MDS patients, allogeneic HCT also remains the only curative treatment for MPD patients. The prognosis varies widely among idiopathic myelofibrosis, PV, and essential thrombocythemia and allogeneic HCT has historically been offered later in the course of the disease. Previously published series detailing the feasibility of myeloablative HCT for MPD patients demonstrate long-term disease-free survival (DFS) with actual reversal of myelofibrosis in the marrow. Overall survival (OS) figures have ranged from 38%-47% at 5 years, but NRM has been reported as high as 48% 3, 4, 33, 34. Our series contained 27 patients with MPD, among whom 12 had myelofibrosis. For all 27 patients, the 3-year RFS and OS were 37% and 43%, respectively, with an actuarial relapse rate and NRM of 26% and 37%, respectively. These statistics are comparable to previously published myeloablative series, and it appears NRM was not significantly improved with the conditioning regimen chosen. Relapse represented the leading cause of death.
In summary, our regimen of low-dose TBI and fludarabine was well tolerated considering our older patient population, and certain subsets of patients have benefited with long-term RFS. Relapse, however, was the major cause of treatment failure, and this particular regimen may not have conferred enough cytoreduction for adequate disease control. Novel regimens that have incorporated radioimmunoconjugates show promising results [35]. Allogeneic HCT remains the only curative modality for MDS and MPD, with nonmyeloablative or RIC regimens clearly benefiting this older population by reducing upfront toxicity. However, further investigation is warranted to determine the optimal regimen with adequate dose intensity and low toxicity.
Acknowledgments
This work was supported in part by grants: PO1-CA 49605, HL36444, CA78902, CA92058, CA18029, and CA15704 from the National Institutes of Health, Department of Health and Human Services (DHHS), Bethesda, MD. The authors wish to thank the data coordinators Luci Fetzko, Debbie Bassuk, and John Sedgwick, and the study nurses Kathryn Tierney, Mary Hinds, and Michelle Bouvier for their invaluable help in making the study possible. The authors also wish to thank the physicians, nurses, and support personnel for their care of patients involved in this study.
References
- Haematopoietic stem cell transplantation for patients with myelo-dysplastic syndromes and secondary acute myeloid leukaemias: a report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol. 2000;110:620–630
- Bone marrow transplantation from HLA-identical siblings as treatment for myelodysplasia. Blood. 2002;100:1997–2004
- Allogeneic hematopoietic stem cell transplantation for myelofibrosis. Blood. 2003;102:3912–3918
- Allogeneic stem cell transplantation for agnogenic myeloid metaplasia: a European Group for Blood and Marrow Transplantation, Societe Francaise de Greffe de Moelle, Gruppo Italiano per il Trapianto del Midollo Osseo, and Fred Hutchinson Cancer Research Center Collaborative Study. Blood. 1999;93:2831–2838
- Hematopoietic stem-cell transplantation for treatment-related leukemia or myelodysplasia. J Clin Oncol. 2001;19:2134–2141
- Myeloablative vs nonmyeloablative allogeneic transplantation for patients with myelodysplastic syndrome or acute myelogenous leukemia with multilineage dysplasia: a retrospective analysis. Leukemia. 2006;20:128–135
- Pharmacodynamics of mycophenolate mofetil after nonmyeloablative conditioning and unrelated donor hematopoietic cell transplantation. Blood. 2005;106:4381–4388
- Unrelated donor granulocyte colony-stimulating factor-mobilized peripheral blood mononuclear cell transplantation after nonmyeloablative conditioning: the effect of postgrafting mycophenolate mofetil dosing. Biol Blood Marrow Transplant. 2006;12:454–465
- Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18:295–304
- . Graft-vs-host-disease. In: Blume KG, Forman SJ, Applebaum FR editor. Hematopoietic cell transplantation. 3rd ed.. Oxford, UK: Blackwell Publishing Ltd; 2004;p. 635–664
- Reduced-intensity allogeneic hematopoietic stem cell transplantation for myelodysplastic syndrome and acute myeloid leukemia with multilineage dysplasia using fludarabine, busulphan, and alemtuzumab (FBC) conditioning. Blood. 2004;104:1616–1623
- Bone marrow transplantation from HLA-identical siblings as first-line treatment in patients with myelodysplastic syndromes: early transplantation is associated with improved outcome. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Bone Marrow Transplant. 1998;21:255–261
- Retrospective comparison of reduced-intensity conditioning and conventional high-dose conditioning for allogeneic hematopoietic stem cell transplantation using HLA-identical sibling donors in myelodysplastic syndromes. Blood. 2006;108:836–846
- Comparative outcome of nonmyeloablative and myeloablative allogeneic hematopoietic cell transplantation for patients older than 50 years of age. Blood. 2005;105:1810–1814
- Reduced-intensity conditioning for allogeneic hematopoietic stem cell transplantation from HLA-identical siblings in adults with myelodysplastic syndromes: a comparison with standard myeloablative conditioning: a study of the EBMT-Chronic Leukemia Working Party. Blood. 2003;102:184a
- Allogeneic stem cell transplantation after a fludarabine/busulfan-based reduced-intensity conditioning in patients with myelodysplastic syndrome or secondary acute myeloid leukemia. Ann Hematol. 2003;82:336–342
- Durable remissions of myelodysplastic syndrome and acute myeloid leukemia after reduced-intensity allografting. J Clin Oncol. 2003;21:3060–3065
- Reduced-intensity conditioning for unrelated donor hematopoietic stem cell transplantation as treatment for myeloid malignancies in patients older than 55 years. Blood. 2003;102:3052–3059
- Reduced-intensity transplantation for patients with myelodysplastic syndrome achieves durable remission with less graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9:753–759
- Evidence for a graft-versus-leukemia effect after allogeneic peripheral blood stem cell transplantation with reduced-intensity conditioning in acute myelogenous leukemia and myelodysplastic syndromes. Blood. 2002;100:2243–2245
- Once-daily intravenous busulfan and fludarabine: clinical and pharmacokinetic results of a myeloablative, reduced-toxicity conditioning regimen for allogeneic stem cell transplantation in AML and MDS. Blood. 2004;104:857–864
- HLA-matched unrelated donor hematopoietic cell transplantation after nonmyeloablative conditioning for patients with hematologic malignancies. Blood. 2003;102:2021–2030
- Graft-versus-tumor effects after allogeneic hematopoietic cell transplantation with nonmyeloablative conditioning. J Clin Oncol. 2005;23:1993–2003
- Allogeneic hematopoietic stem cell transplantation for the treatment of high-risk acute myelogenous leukemia and myelodysplastic syndrome using reduced-intensity conditioning with fludarabine and melphalan. Biol Blood Marrow Transplant. 2007;13:454–462
- Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy. Blood. 1997;89:2578–2585
- Factors influencing outcome in de novo myelodysplastic syndromes treated by allogeneic bone marrow transplantation: a long-term study of 71 patients Societe Francaise de Greffe de Moelle. Blood. 1996;88:358–365
- Prognostic factors and scoring systems in chronic myelomonocytic leukemia: a retrospective analysis of 213 patients. Blood. 2002;99:840–849
- Allogeneic hematopoietic cell transplantation for chronic myelomonocytic leukemia. Biol Blood Marrow Transplant. 2005;11:713–720
- Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT). Br J Haematol. 2002;118:67–73
- Allogeneic stem cell transplantation and donor lymphocyte infusions for chronic myelomonocytic leukemia. Bone Marrow Transplant. 2006;37:1003–1008
- . Prognosis and therapy of secondary myelodysplastic syndromes. Haematologica. 1998;83:543–549
- Bone marrow transplantation for therapy-related myelodysplasia: comparison with primary myelodysplasia. Bone Marrow Transplant. 1997;20:737–743
- Outcome of allogeneic stem cell transplantation in patients with myelofibrosis. Bone Marrow Transplant. 2004;34:807–813
- Stem cell transplantation for myelofibrosis: a report from two Canadian centers. Bone Marrow Transplant. 2003;32:35–40
- 131 I-Anti-CD45 antibody plus fludarabine, low-dose total body irradiation and peripheral blood stem cell infusion for elderly patient with advanced acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (MDS). Blood. 2005;106:119a
PII: S1083-8791(07)00575-7
doi:10.1016/j.bbmt.2007.11.012
© 2008 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.
Volume 14, Issue 2 , Pages 246-255, February 2008
