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Blood, Vol. 95 No. 4 (February 15), 2000:
pp. 1188-1194
CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
From the Fred Hutchinson Cancer Research Center and the University
of Washington, Seattle, WA.
We carried out bone marrow transplantation (BMT) in 50 patients with
myelodysplastic syndrome (MDS) who were 55.3 to 66.2 years of
age (median, 58.8 years). According to the criteria of the
French-American-British (FAB) classification, 13 patients had
refractory anemia (RA), 19 had RA with excess blasts (RAEB), 16 had
RAEB in transformation or acute myelogenous leukemia (RAEB-T/AML), and
2 had chronic myelomonocytic leukemia (CMML). According to the
recently established International Prognostic Scoring System (IPSS),
available for 45 patients, 2 patients were considered low risk; 14, intermediate 1 risk; 19, intermediate 2 risk; and 10, high risk.
Conditioning regimens were cyclophosphamide (CY) (120 mg/kg of body
weight) plus 12-Gy fractionated total-body irradiation (FTBI)
(n = 15), CY plus FTBI with lung and liver shielding
(n = 4), busulfan (7 mg/kg) plus FTBI (n = 4), or busulfan (16 mg/kg) plus CY (n = 27). The busulfan-plus-CY group included 16 patients in whom busulfan was targeted to plasma levels of 600 to 900 ng/mL. In these 16 patients, steady-state levels of busulfan actually
achieved were 714 to 961 ng/mL (mean ± SD, 845 ± 64 ng/mL; median,
838 ng/mL). The donors were HLA-identical siblings for 34 patients,
HLA-nonidentical family members for 4, identical twins for 4, and
unrelated volunteers for 6. All 46 patients surviving > 21 days had
engraftment, and 22 patients (44%) are surviving 9 to 80 months after
BMT. Specifically, among 13 patients with RA, 1 had relapse (cumulative
incidence [CI] at 3 years, 8%) and 8 are surviving, for a
Kaplan-Meier (KM) estimate of survival at 3 years of 59% (disease-free
survival [DSF], 53%). Among 19 patients with RAEB, 3 had relapse (CI at 3 years, 16%), and 8 are surviving disease free (KM
estimate at 3 years, 46%). Among 18 patients with RAEB-T/AML or CMML,
6 had relapse (CI at 3 years, 28%), and the KM estimate of DSF at 3 years is 33%. Relapse-free survival had an inverse correlation with
cytogenetic risk classification and with the risk score according to
the IPSS. Survival in all FAB categories was highest among patients
enrolled in a protocol in which busulfan plasma levels were targeted to
600 to 900 ng/mL. These data indicate that BMT can be carried out
successfully in patients with MDS who are older than 55 years of age.
(Blood. 2000;95:1188-1194)
Myelodysplastic syndrome (MDS) comprises a spectrum of
diagnoses that have in common single-lineage or multilineage cytopenias and a propensity to transform into acute leukemia. Approximately half
of the patients have clonal cytogenetic abnormalities that have been
classified into 3 risk groups and, along with the proportion of blasts
in the marrow and the number of cytopenias in peripheral blood, have
been incorporated into the International Prognostic Scoring System
(IPSS).1 The higher the IPSS score, the higher the risk of leukemic transformation and the shorter the life
expectancy. For patients with high-risk cytogenetic abnormalities, high
marrow blast counts, and multi-lineage cytopenias, the median life
expectancy is several months. It is important to recognize, however,
that life expectancy is determined not only by transformation of MDS into frank leukemia. In fact, 40% to 45% of patients with MDS die
from infections or hemorrhagic complications without ever developing
leukemia.2 Therefore, the mainstay of treatment, particularly in older patients, has generally been supportive care,
although the morbidity and cost of this approach are considerable.
Transplantation of marrow or peripheral blood stem cells from a healthy
donor is the only curative therapy currently available for
MDS.2 However, the median age at the time of diagnosis of
MDS is in the seventh decade of life,3 and studies have generally shown an increase in the frequency and severity of
transplantation-related complications with increasing
age.4-6 Even among younger patients, regimen-related
mortality has been reported to be as high as 30% to
35%.7-10 Furthermore, the incidence of both acute and
chronic graft-versus-host disease (GVHD) increases with
age.11,12 These considerations are particularly important
in patients with MDS who lack high-risk features and who may have a
median life expectancy of 5 to 6 years with conservative
management.1,2 Therefore, allogeneic transplantation has
been explored only cautiously in older patients.13-16
At the Fred Hutchinson Cancer Research Center (FHCRC), we have chosen
MDS as one of the diseases for which to develop transplantation regimens that can be applied successfully in patients older than 55 years. Here we describe our experience in 50 patients 55 to 66 years of
age, with MDS ranging from refractory anemia (RA) to transformation
into acute myelogenous leukemia (AML), who underwent transplantation
with marrow from an allogeneic or syngeneic donor and in whom
radiation-containing and chemotherapy-only conditioning regimens were used.
Patients
Previous therapy
Conditioning regimens
Pharmacokinetic studies of busulfan The chemical (gas chromatography and mass spectrometry) and pharmacokinetic analyses of busulfan were previously described.29-31 To provide accurate assessments of busulfan exposure during conditioning, blood samples were collected 0, 1, 2, 4, and 6 hours after any 2 of the morning doses on days 2, 3, or 4 of busulfan administration (ie, the fifth, ninth, or 13th doses) in patients who were to receive a dose of 16 mg/kg. The busulfan plasma levels numerically represent the ratio of busulfan area under the curve over the dosage interval to the time interval between doses (6 hours). The busulfan plasma values reported are the means of the values observed in each patient on those 3 days.Donors In 44 cases, the marrow donor was a relative (an HLA-identical sibling in 36, a relative who differed for at least 1 HLA-A, HLA-B, or HLA-DR antigen in 4, and an identical twin in 4). In 6 patients without a suitably matched related donor, a search for an HLA-matched unrelated volunteer was initiated.17,32 Although our policy was to transplant marrow from unrelated donors only in patients < 56 years of age, the search in these 6 patients had been initiated when they were < 56 years old, but they had passed this anniversary by the time they had transplantation. All 50 patients were given transplants of bone marrow; this was unmanipulated in all patients but one, to whom column-enriched CD34+ cells were given.GVHD prophylaxis Prophylaxis for acute GVHD consisted of methotrexate (MTX) and cyclosporine (CSP) in 38 patients and CSP alone or combined with glucocorticoids in 8.33,34 Four patients given transplants from a syngeneic donor received no GVHD prophylaxis. MTX was given intravenously at a dose of 15 mg/m2 of body surface area on day 1 and 10 mg/m2 on days 3, 6, and 11. CSP was administered intravenously at a dose of 3 mg/kg per day in 2 divided doses, starting on the day before marrow infusion. Oral CSP (12.5 mg/kg per day) was substituted for intravenous administration when tolerated. Starting on day 50, the CSP dose was tapered by 5% weekly and discontinued on day 180 whenever possible. Doses of CSP were adjusted downward if necessary (usually because of renal or hepatic dysfunction) or occasionally upward (if evidence of GVHD developed). MTX administration was adjusted downward for severe mucositis, extravascular fluid accumulation, or impaired renal function. Methylprednisolone was started on day 7 and administered at gradually reduced doses through day 72 as previously described.34 Acute and chronic GVHD were diagnosed and graded by using established criteria.34 Acute GVHD was treated with prednisone, antithymocyte globulin, or monoclonal antibodies.35 Chronic GVHD was treated with prednisone alone or combined with CSP.Regimen-related toxicity Regimen-related toxicity was assessed by using the criteria described by Bearman et al.36 Any patient with a maximum grade of at least 2 for the bladder, renal, pulmonary, hepatic, central nervous system, mucosal, or gastrointestinal organ systems during the first 28 days after transplantation was considered to have important regimen-related toxicity.Engraftment and rejection Evidence of graft rejection was sought in patients who had relapse. When the donor and patient were of different sexes, in situ Y chromosome hybridization37 was performed on bone marrow and peripheral blood mononuclear cells (PBMC) stimulated with phytohemagglutinin. When the patient and donor were of the same sex, DNA from bone marrow and PBMC was amplified for several variable-number tandem repeat loci. The amplified fragments were examined to identify informative host and donor markers.38Relapse All patients were scheduled to have marrow samples examined morphologically and by cytogenetic and flow cytometric analyses on days 28 and 84 after transplantation and then annually or as clinically indicated. Relapse was defined as the detection of metaphases in the marrow that showed the same clonal marker or markers identified before transplantation, or the reemergence of dysplastic cells or aberrant precursors defined with use of flow cytometry.8,39Infection Blood samples were examined weekly for evidence of cytomegalovirus (CMV) either by culture or the presence of CMV antigenemia. Interstitial pneumonia was diagnosed with use of culture, histologic or histochemical analysis of bronchoalveolar lavage, open lung biopsy, or autopsy. Various strategies to prevent infectious diseases were employed during this study, including the prophylactic use of systemic antibiotics, including fluconazole, acyclovir, and ganciclovir. All CMV-seronegative patients received either screened (CMV-negative) or filtered blood products. Acyclovir was given for prophylaxis throughout the study period to all patients who were seropositive for herpes simplex virus. Ganciclovir was given to all CMV-seropositive recipients at engraftment or at the first documentation of antigenemia.40Causes of death Deaths that occurred after posttransplantation relapse were categorized as due to relapse irrespective of the proximate cause; deaths in the absence of relapse were categorized as nonrelapse mortality. Infection was considered the cause of death when a bacterial, viral, or fungal infection other than interstitial pneumonia was the proximate cause of death in patients who had not had relapse. Infections were further categorized according to whether or not they were associated with GVHD and with organ failure. Multiorgan failure was considered the cause of death if decompensation occurred in at least 2 organ systems (eg, liver and kidneys or liver and lungs) and could not be attributed to GVHD or infection alone.Statistical analysis Overall survival and relapse-free survival estimates were obtained by using the method of Kaplan and Meier.41 Relapse and nonrelapse mortality were summarized by using cumulative incidence estimates.42 For the endpoint of relapse, death without relapse was regarded as a competing risk, and relapse was considered a competing risk for the endpoint of nonrelapse mortality. No formal statistical comparisons are made between groups; rather, the data are presented in a descriptive fashion. The data analyzed were current through November 11, 1998.
Engraftment Four patients died before day 21 after transplantation on days 2, 13, 14 and 16, respectivelyand were considered unevaluable for
engraftment. The remaining 46 patients all had sustained engraftment. A
neutrophil count of 0.5 × 109/L was reached at 12 to 29 days (median, 20 days), and a platelet count of
20 × 109/L at 7 to 87 days (median, 19.5 days).
GVHD Among 46 patients with engraftment, 43 survived beyond 28 days and were evaluated for the development of acute GVHD. Thirty-three (77%) had grades II-IV and 7 (16%) had grades III-IV GVHD (Table 2). Chronic GVHD occurred in 20 of 32 patients at risk (62%).
Relapse Ten patients relapsed at 23 days to 38 months after transplantation (Table 2), for a cumulative incidence of 19% at 3 years (Figure 1). Seven of these recurrences were observed in the 42 patients with primary MDS (17%), and 3 were among the 8 patients with secondary MDS (38%) (P = NS).
Overall survival The overall probability of survival is shown in Figure 1. Currently, 22 patients (44%) are surviving 0.7 to 7.1 years (median, 2.2 years) after transplantation, for a Kaplan-Meier estimate of survival of 46% (relapse-free survival, 42%). Among 4 patients given a transplant from an HLA-nonidentical related donor, none are surviving. Survival was comparable for the other subgroups of patients: 2 of 4 patients (57.6-65 years of age) given marrow from a syngeneic donor are surviving 3.2 and 3.3 years, respectively, after transplantation, 3 of 6 patients (55.5-56.4 years of age) given marrow from an unrelated donor are surviving 1 to 3 years after transplantation, and 17 of 36 patients (55.3-66.2 years of age) given transplants from an HLA-identical sibling are surviving 0.7 to 7.1 years after transplantation. As illustrated in Figure 2, the survival probability appeared to be higher in patients with de novo (primary) MDS than in those in whom MDS developed after therapy for another disease (secondary MDS). At the time of last contact, the Karnofsky performance scores of the surviving patients were 100 in 11 patients, 90 to 95 in 6 patients, and < 90 in 5 patients.
Survival according to disease variables Results are summarized in Table 3. The probabilities of relapse-free survival at 3 years in patients with RA, RAEB, RAEB-T/AML, and CMML were 0.53, 0.46, 0.38, and 0.0, respectively. In addition to FAB classification as a prognostic risk factor, recent studies have examined the impact of the type of cytogenetic abnormalities, and a scoring system (the IPSS) has been developed that considers the effect of proportion of blasts in the marrow, the number of cytopenias, and cytogenetic abnormalities on disease course in patients who have not undergone transplantation.1 The current study in older patients undergoing transplantation suggests that those risk factors are also relevant for the posttransplantation outcome: patients with low-risk or intermediate-risk cytogenetic findings did better than those with a high-risk karyotype, and patients with a score that was low according to the IPSS fared better than those with a higher score. Specifically, patients with high-risk cytogenetic abnormalities and those with high-risk disease according to the IPSS tended to do worse than the remaining patients.
Survival according to conditioning regimen The development of transplantation conditioning regimens for patients with MDS has been driven by concerns about disease recurrence and regimen-related toxicity, particularly in older patients.7,8,26,28 Previous observations in patients with chronic myelogenous leukemia (CML) given transplants from a sibling donor suggested that "optimization" of busulfan dosage to achieve a certain plasma level (targeted busulfan) would reduce toxicity (due to excessive levels) and disease recurrence (due to low levels).29,43 Therefore, the MDS protocol was changed so that patients 55 years of age at transplantation would be
conditioned with targeted busulfan. Thus, the 16 patients in this study
who most recently underwent transplantation were given oral busulfan
with the aim of achieving busulfan plasma levels of 600 to 900 ng/mL.
As illustrated in Figure 3, patients in
this group had the best survival (A) and the lowest nonrelapse mortality (B) of all patients in this study, and the incidence of
relapse did not appear to be increased (C). For the "best case" scenario, that is, among 6 patients in cytogenetic-risk group 1 who
were conditioned with busulfan (targeted) and CY, 5 are surviving, compared with only 1 among 6 patients in cytogenetic-risk group 3 who were conditioned with other regimens.
Causes of death As shown in Table 4, 8 patients died with relapse and 20 died from other causes, for overall and nonrelapse mortality rates at 2 years of 55% and 39%, respectively. When the 42 patients with primary MDS were considered separately, the 2-year overall mortality and nonrelapse mortality rates were 51% and 37%, respectively. The most frequent cause of death was multiorgan failure, either alone or combined with infection, which accounted for half of all deaths in patients who did not relapse. GVHD was expected to be a problem in this older patient population and, indeed, was the primary cause of death in 5 patients. All but one of the deaths associated with infections were due to fungal (Aspergillus or Candida) organisms. Other causes of death included hemorrhage in one patient and late development of a colon carcinoma in another patient.
Because studies in younger patients have shown that MDS can be cured by hemopoietic stem-cell transplantation,8,9,21,26,28 we investigated whether this treatment can also be applied successfully to older patients. Our results indicate that transplantation in patients 55 to 66 years of age is feasible and offers an excellent outlook for certain subgroups of patients. As previously observed in younger patients, advanced disease stage and high-cytogenetic-risk category were associated with higher relapse probability and lower survival. Outcome was better for primary than for secondary MDS, and patients given transplants from an HLA-matched donor fared better than did recipients of an HLA-nonidentical transplant. However, because of the small numbers of patients in each of these subgroups, differences did not reach statistical significance. The Kaplan-Meier estimates for relapse-free survival at 3 years for patients with primary RA, RAEB, and RAEB-T/AML were 57%, 52%, and 45%, respectively. For patients with low-risk, intermediate-risk, and high-risk cytogenetic features, the probabilities of survival were 49%, 83%, and 30%, respectively. If the IPSS criteria are used, survival estimates at 3 years were 100%, 54%, 44%, and 30% for low-risk, intermediate-1 risk, intermediate-2 risk, and high-risk groups, respectively. The IPSS was based on data from patients who did not undergo transplantation. However, recent reports suggest that the variables considered in this scoring system also affect posttransplantation outcome.21,44 The results of our study are consistent with such an assessment, although it is not a priori clear why multiple cytopenias, which are corrected by transplantation, should affect posttransplantation outcome. It is possible that problems due to pretransplantation transfusion support or infections acquired because of neutropenia affect the posttransplantation course.
We thank Helen Crawford and Bonnie Larson for typing the manuscript and Elizabeth Soll and Deborah Monroe for assistance with data collection.
Submitted May 17, 1999; accepted October 8, 1999.
Supported in part by National Institutes of Health grants HL36444, CA15704 and CA18029; H.J.D. is also supported by a grant from the G. Rich Foundation. J.E.A. was supported by an American Cancer Society Career Development Award.
Reprints: H. Joachim Deeg, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, D1-100, PO Box 19024, Seattle, WA 98109-1024; e-mail: jdeeg{at}fhcrc.org.
The publication costs of this article were defrayed in part by page charge payment. Therefore, and solely to indicate this fact, this article is hereby marked "advertisement" in accordance with 18 U.S.C. section 1734.
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Abstract
Introduction
y, 5q
