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Hematopoietic stem cell transplantation in patients with myelodysplastic syndrome
Leukemia Research 24 (2000) 653 – 663 www.elsevier.com/locate/leukres
Review
Hematopoietic stem cell transplantation in patients with myelodysplastic syndrome H. Joachim Deeg *, Frederick R. Appelbaum Fred Hutchinson Cancer Research Center and the Uni6ersity of Washington, 1100 Fair6iew A6enue North, D1 -100, P.O. Box 19024, Seattle, WA 98109 -1024, USA Received 29 March 2000; accepted 30 March 2000
Abstract Myelodysplastic syndrome (MDS) is a stem cell disorder, and hematopoietic stem cell transplantation is currently the only therapeutic modality that is potentially curative. Among patients with less advanced MDS ( B5% marrow blasts), 3-year survivals of 65–70% are achievable with HLA-identical related and HLA-matched unrelated donors. The overall probability of disease recurrence in these patients is B5%. Among patients with advanced disease ( ] 5% marrow blasts), about 35 – 45% and 25–30%, respectively, are surviving in remission after transplantation from a related or from an unrelated donor; the incidence of post-transplant relapse is 10–35%. The criteria proposed by the International Prognostic Scoring System (IPSS) derived from non-transplanted patients, also predict survival following transplantation. The development of new conditioning regimens has permitted successful hematopoietic stem cell transplants even in patients more than 60 years of age. Improved survival with transplants from unrelated volunteer donors may, in part, reflect selection of donors on the basis of high resolution (allele-level) HLA typing. Autologous stem cell transplantation may be beneficial for selected patients who have obtained a complete remission with conventional chemotherapy. Treatment-related morbidity and mortality, in particular after allogeneic transplantation, remain challenges that need to be addressed with innovative approaches. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: MDS; Hematopoietic stem cell transplantation; Cytogenetic risk group; Relapse; Organ toxicity
1. Introduction The term myelodysplastic syndrome (MDS) comprises several hematopoietic disorders characterized by ineffective hematopoiesis (single or multilineage peripheral blood cytopenia in the presence of a cellular marrow) and a tendency to develop acute leukemia [1,2]. Abbre6iations: AML, acute myelogenous leukemia; BU, busulfan; CMML, chronic myelomonocytic leukemia; CY, cyclophosphamide; EBMT, European bone marrow transplant; FAB, French– American–British; FTBI, fractionated TBI; GVHD, graft-versus-host disease; IPSS, international prognostic scoring system; MDS, myelodysplastic syndrome; RA, refractory anemia; RAEB, RA with excess blasts; RAEB-T, RAEB in transformation; RARS, RA with ring sideroblasts. * Corresponding author. Tel.: + 1-206-6675985; fax: +1-2066676124. E-mail address: [email protected] (H.J. Deeg).
Dysplastic features may be more or less pronounced, and approximately half of the patients have clonal cytogenetic abnormalities [3]. The French–American– British (FAB) classification categorizes MDS on the basis of the proportion of marrow (and peripheral blood) blasts into refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB) and RAEB in transformation (RAEB-T) [3]. An additional category, chronic myelomonocytic leukemia (CMML), has now been reclassified as a myeloproliferative disorder. While the FAB categories have proven very useful for diagnostic, prognostic and therapeutic purposes, the incorporation of cytogenetic findings and the number of cytopenias, in addition to the blast count, in a new scoring system termed International Prognostic Scoring System (IPSS) may provide further prognostic precision [4].
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The mechanisms involved in the development and evolution of MDS are poorly understood. There is overwhelming evidence, however, that MDS is a hematopoietic stem cell disorder [1]. Theoretically, hematopoietic stem cell transplantation (HSCT) should, therefore, offer definitive therapy. This is in fact borne out by observations over the past 10 – 15 years (Fig. 1). The best results have been achieved in patients with less advanced MDS ( B 5% blasts in the marrow). Originally, most transplants were carried out in younger patients with HLA-identical sibling donors. In recent years rapidly growing numbers of patients have been transplanted from unrelated volunteer donors. Also, the upper age limit for transplantation has been advanced from 60 to 65 years or older, an important development given that the median age at diagnosis of MDS is in the seventh decade. General management guidelines have been presented recently [5]. This review provides an update on results with HSCT.
2. Allogeneic transplantation
2.1. Patients with less ad6anced disease The best results with allogeneic transplants are achieved in patients with less advanced (or low grade) disease defined here as patients with RA or RARS. The European Bone Marrow Transplant (EBMT) group has reported 5-year relapse-free survivals of 46, 35, 27 and 0% for patients with RA/RARS, RAEB, RAEB-T and secondary acute myeloid leukemia, respectively [6]. Data reported to the International Bone Marrow Transplant Registry (IBMTR) on transplants carried out between 1991 and 1997 show a 3-year probability
Fig. 1. Disease-free survival by FAB classification among 241 patients transplanted from an HLA identical sibling donor. MDS/AML includes patients who developed acute myelogenous leukemia on the background of MDS.
of relapse of 10% among 204 patients with RA or RARS transplanted from an HLA-identical sibling donor, and a 3-year probability of disease-free survival of 58% [7]. The team at the Fred Hutchinson Cancer Research Center (FHCRC) originally reported relapse-free survival of approximately 60% and a probability of relapse of B 5% among patients with RA conditioned with cyclophosphamide (CY) and total body irradiation (TBI), and transplanted from an HLA-identical related donor [8]. Very similar results were obtained when a regimen of busulfan (BU), 16 mg/kg plus CY, 120 mg/kg, was studied [8]. However, while relapse rates were low, these and other reports [9,10], reveal an incidence of non-relapse mortality in the range of 30– 35%. Causes of death include infections and GVHD, and most prominently, single and multi-organ toxicity (see below). With the goal of reducing toxicity, a subsequent FHCRC study combined CY (60 mg/kg per day× 2) with TBI at doses of 800–1200 cGy using lung and liver shielding (termed total marrow irradiation [TMI]). In other studies this approach appeared to reduce regimen-related toxicity. However, in MDS, the trial was closed after enrollment of only 14 patients because four patients had recurrent disease for a relapse probability of 36%, compared to 2.3% in previous MDS trials (unpublished observations) (P=0.001). These results suggested that clonal precursors were protected by lung and liver shielding, and that CY was not sufficient as systemic therapy. A combination of BU, 16 mg/kg orally, plus CY, 60 mg/kg per day for 2 days, particularly if the BU was targeted to achieve steady-state plasma concentrations within a pre-determined range (800–900 ng/ml), had yielded encouraging results in patients with chronic myeloid leukemia (CML); the probability of posttransplant relapse was low, and toxicity was acceptable [11]. BU/CY regimens have also been used successfully by several transplant teams to transplant patients with MDS [9,10,12,13]. Thus, we tested a regimen of CY and targeted BU in patients with RA (or RARS) transplanted from an unrelated volunteer donor (see below), or from a family donor. Preliminary results have been presented recently [14]. The probability of survival in remission was greater than 60% among patients transplanted from an HLA-identical sibling. Results are illustrated in Fig. 2. The probability of post-transplant relapse remained below 5%, and the incidence of regimen-related mortality was reduced to 20–25%. As further discussed below, with this regimen even patients in their 60s were transplanted successfully [14]. As a suitably matched related donor is available for only 25–30% of patients, alternatives, in particular, transplantation from volunteer unrelated donors, have been pursued. In view of the rapidly growing number of HLA typed potential donors and the advancements in
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MDS transplanted under the auspices of the NMDP [18]. Among 510 patients, 1–62 (median 38) years of age, there were 116 with RA of whom 50% survived at 18 months. The probability was 60%, however, for patients conditioned with a BU/CY regimen. Results from this analysis also indicate that outcome was improved even further if donor and patient were more completely HLA matched [18]. Overall, these data suggest that the lack of a suitably matched related donor should not be cause to abandon plans for a transplant.
2.2. Ad6anced MDS
Fig. 2. Disease-free survival among 18 patients with refractory anemia conditioned with a regimen of targeted busulfan plus cyclophosphamide and transplanted with marrow from an HLA identical sibling donor.
HLA typing at the molecular level which has allowed for progressively better matching of patient and donor, use of volunteer donors has become increasingly attractive [15]. The EBMT group reported results in 118 patients, 0.3 – 53 (median 24) years of age, with MDS/secondary AML who were transplanted from an unrelated donor [16]. Patients transplanted within 6 months of diagnosis had a probability of relapse-free survival of 55% compared to 16% among patients transplanted more than 12 months after diagnosis. However, treatment-related mortality was high for all subcategories, about 40% for patients less than 40 years of age, and 61% among older patients. Among 24 patients with RA or RARS, the probability of relapse was 13%, and 2-year disease-free survival was 24%. IBMTR data on 48 patients with RA or RARS transplanted from an unrelated donor show a 3-year disease-free survival of 35% [11]. The authors point out that while the median interval from diagnosis to transplant was 6 months with related transplants, it was 10 months with unrelated transplants. It was not clear from this report why patients with good-risk MDS should have such a poor probability of survival. In part, this may have been related to the marked delay of transplantation after diagnosis (Table 1). Among 40 patients with RA transplanted at the FHCRC with marrow from an unrelated volunteer donor, 3-year survival was 56% [17]. Among patients who were conditioned with targeted BU and CY (as described above) and transplanted from a donor serologically matched for HLA-A and B and molecularly (allele level) matched for HLA-DRB1 and -DQB1, survival was 66%, similar to results in patients with comparable disease stage transplanted from an HLAidentical related donor (Fig. 3). This impression is confirmed by results in a larger cohort of patients with
The most obvious difference in regard to transplant outcome between patients with less advanced and more advance disease is the incidence of post-transplant relapse, reported to be in the range of 15–50% in patients with RAEB, RAEB-T and AML, compared to less than 5% among patients with RA or RARS [13,19–21]. In addition, there may be a higher incidence of non-relapse morbidity and mortality with advanced disease, conceivably because of a more prolonged disease course and duration of supportive care before transplantation. A study on 131 patients (who had not received pre-transplant induction therapy) reported to the EBMT group showed a 5-year disease-free survival of 34% for patients with RAEB and 19% for patients with RAEB-T [22]. The overall probability of relapse was 39%, 13% for RA/RARS, 44% for RAEB, and 52% for RAEB-T. Transplant-related mortality ranged from 40% in patients with RA to 60% in patients with RAEB-T. In multivariate analysis, younger age and a shorter interval from diagnosis to transplant, in addition to an absence of excess blasts, were associated with better outcome. A report from the IBMTR on 581 patients with RAEB, RAEB-T or CMML, shows 3year probabilities of relapse and disease-free survival of 35 and 40%, respectively [7]. Initial trials at the FHCRC using a conditioning regimen that combined CY and fractionated TBI showed similarly high relapse rates, and yielded a 3year survival probability of 45% [23]. In an attempt to reduce the high incidence of relapse, in a subsequent trial, CY (at a reduced dose of 50 mg/kg) and TBI (6× 200 cGy) were combined with busulfan (7 mg/kg) given over 4 days [24]; 31 patients, median age 41 years, were enrolled (25 related, six unrelated donors). The 3-year actuarial disease-free survival was 23% (similar to the rate of 30% in historical patients prepared with CY plus TBI). However, while there was a trend toward fewer relapses, there was an increase in non-relapse mortality (Fig. 4). It was of note that univariate analysis showed a higher relapse rate in HLA-matched related transplant recipients than among patients transplanted from alternative donors, suggesting a stronger
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graft-versus-MDS effect with transplants other than those from an HLA-identical sibling. In multivariable analysis, a normal pretransplant karyotype and the use of methotrexate for GVHD prophylaxis after transplantation were associated with reduced non-relapse mortality and improved survival. CY is not stem cell toxic and, while immunosuppressive, may contribute to non-relapse toxicity. Thus, a subsequent cohort of patients received busulfan (7 mg/ kg) plus TBI (6×200 cGy) but no CY. Twenty-six patients, median age 47 years, with RAEB, RAEB-T or CMML were enrolled and transplanted from a related (n = 8) or unrelated donor (n =18). With a median follow-up of 3 years, three patients relapsed (12%) and 12 patients died of transplant-related complications (cumulative incidence 46%). At the time of reporting, 11 patients were surviving disease-free for a probability of 46%, comparing favorably to the probability of 29% among 42 historical controls. Controlling for patient and disease characteristics, there appeared to be a lower
relative risk of relapse (0.08; P= 0.0008) and a lower relative risk of relapse or death (0.5; P= 0.02) in patients conditioned with BU plus TBI. An update of results is given in Fig. 5. These data underline the importance of stem cell toxic agents and indicate that CY is not required for a successful transplant in either related or unrelated transplant recipients [25]. The role of TBI in conditioning MDS patients for transplantation is still unsettled. In an analysis of 510 transplants for MDS from unrelated donors (see above; H. Castro-Malaspina, personal communication), patients in all FAB categories whose preparative regimen did not contain TBI had a higher probability of overall survival (P= 0.02) and disease-free survival (P =0.01) than patients conditioned with TBI. The difference was most striking in patients with RA. Preliminary results from ongoing FHCRC trials appear to support those findings. Crude data for outcome after transplantation from an HLA-identical sibling donor show a 3-year disease-free survival of 51% after conditioning with
Table 1 Hematopoietic cell transplantation for MDS: treatment decision by FAB disease category and IPSS risk groupsd FABa category
IPSS Criteria
Cytogenetic riske RA
Any
RARS
Low/intermediate Any High Any
RAEB
Low/intermediate Any
High
Any
RAEB-T
Any
Any
CMMLc
–––
–––
a
Donor available
Managementf
Any Any \65(70) 565(70)b Any \65 (70) 565 (70)b Any Any \65 (70) 565 (70)b Any \65 (70) 565 (70)b Any 565 (70)b Any \65 (70) 565(70)b Any \65 (70) 565 (70)b
Yes/no No Â Ì ––– Å Yes No Â Ì ––– Å Yes  No à No Ì Ã ––––Å Yes No Â Ì ––– Å Yes No Yes  No Ì ––– Å Yes No Â Ì ––– Å Yes
Observe; growth factor(s) Immunosuppressive therapy (IST)
No. of cytopenias
Low/intermediate 0/1 2/3
High
Patient age (years)
Transplantation IST Transplantation Growth factors (G-CSF plus erythropoietin)
Transplantation IST; chemotherapy; other experimental therapy Transplantation Chemotherapy; IST (?) Transplantation Chemotherapy; other experimental therapy Transplantation Observe; chemotherapy Transplantation
FAB, French–American–British; IPSS, International Prognostic Scoring System; IST, immunosuppresive therapy. Upper age limit may be higher for non-myeloablative conditioning regimens. c IPSS recommendations developed only for non-proliferative CMML. d See also NCCN practice guidelines [5]. e Cytogenetic risk: low, (normal karyotype; -y; 5q-; 20q-); high, (chromosome 7 abnormalities; ]3 clonal abnormalities); intermediate, (all other abnormalities). f Transfusion support or antibiotic prophylaxis may be required in any disease category. b
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sion with a median follow-up of 6.9 years. Five patients have relapsed (cumulative incidence 25%), five died with organ failure, and two with GVHD/infections. Shorter disease duration appeared to be associated with improved outcome. While only one patient with normal blast counts relapsed, there were four relapses among 12 patients with excess blasts. As with other disease categories, it appears preferable, therefore, to carry out a transplant earlier in the course of CMML.
2.3. Secondary MDS
Fig. 3. Disease-free survival among patients with RA conditioned with targeted busulfan plus cyclophosphamide and transplanted from an allele level HLA matched (n=21) or HLA non-identical (n = 12) unrelated donor.
Fig. 4. Probability of relapse, non-relapse mortality and disease-free survival among 33 patients with advanced MDS conditioned with a combination of busulfan, cyclophosphamide, and TBI and transplanted with marrow from a family donor [24].
BUCY compared to 42% after conditioning with BU TBI (unpublished observations). IBMTR data show a 3-year disease-free survival of 26% among 176 patients with RAEB, RAEB-T or CMML transplanted from an unrelated donor, and fail to reveal a benefit of TBI. Recently, we analyzed separately our experience in 21 patients with CMML [26]. Patients were 1 – 62 (median 47) years old and had carried their diagnoses for 2–60 (median 9) months. Twelve patients had more than 5% blasts in the marrow; 12 had normal and nine abnormal karyotypes. Patients were prepared either with BU/CY/ TBI, BU/TBI or CY/TBI or received a combination of BU (14 mg/kg) plus CY (60 mg/kg × 2), and were transplanted from a related (n =15) or unrelated (n= 6) donor. Nine patients (39%) are surviving in remis-
MDS that is presumably treatment-related (secondary) has been observed after therapy for various malignant and non-malignant disorders. Recent interest has focused on patients who develop MDS after treatment for breast cancer or following autologous HSCT. Incidence figures of 1.1–19.8% at 10 years have been reported [16,27–29]. In contrast to patients with de novo MDS, approximately half of whom have clonal cytogenetic abnormalities, an abnormal karyotype, usually of the high-risk category by IPSS criteria (monosomy 7; complex abnormalities), is found in more than 80% of patients with secondary MDS. Exposure to irradiation and chemotherapy as given for the patient’s original disease is thought to be causative and, in addition, may have resulted in tissue damage, the sequelae of which would predispose the patient to substantial morbidity and mortality while undergoing a transplant for secondary MDS. Friedberg and colleagues analyzed results in 552 patients who had received an autologous stem cell transplant for the treatment of NHL, and found 41 patients who developed MDS at a median of 47 months for an overall incidence of 7.4% [28]. The actuarial incidence at 10 years was 19.8%. Karyotypes were available in 33,
Fig. 5. Disease-free survival among 19 patients with advanced MDS who were conditioned with busulfan plus TBI and transplanted with marrow from an HLA identical sibling donor.
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al. [32], who observed 24% disease-free survival among children with secondary MDS, compared to 43% among children with de novo MDS. Clearly these results are not satisfactory. Efforts must be directed, first, at the prevention of secondary MDS, and secondly at improved tolerance of transplant conditioning. Finally, patients who are thought to be transplant candidates should be transplanted early in the disease course.
2.4. The ‘older’ patient
Fig. 6. Disease-free survival in patients with ‘secondary MDS’ prepared with various conditioning regimens and transplanted from a related or unrelated donor.
and 29 of these showed monosomy 7 or complex abnormalities. Thirteen of these patients underwent allogeneic HSCT (eight from a related and five from an unrelated donor) which was T-cell depleted in eight. All patients died, at a median of 1.8 months post-transplant. Two died with relapse and 11 with transplant-related toxicity, mostly septicemia and organ toxicity. These results are in agreement with an earlier report by the EBMT group which showed a 5-year survival of 0% in patients with secondary MDS [6]. We have recently analyzed results in more than 100 patients with secondary MDS at various stages of disease evolution transplanted at the FHCRC from either a related or unrelated donor using the conditioning regimens employed for patients with de novo MDS [30]. The primary diagnoses included Hodgkin disease, non-Hodgkin lymphoma, carcinoma of the breast, aplastic anemia, multiple myeloma, polycythemia vera, and other solid tumors or hematologic or immunologic disorders. Eight patients had previously received irradiation, 38 chemotherapy, 41 a combination of both, eight had received an autologous transplant, and the remainder had received other therapy. As with de novo MDS, disease stage was the most important risk factor for outcome. Survival in remission was substantially better among patients with RA than in patients with more advanced disease (Fig. 6). The major causes of death were relapse, infections, and single or multiorgan failure. Leahy et al. presented data on 11 children with therapy-related MDS who were transplanted from a related or from an unrelated donor [31]. All but one patient were conditioned with a BU conditioning regimen. Five patients relapsed, and three patients died from non-relapse toxicity. Three patients (24%) survive disease-free. Identical results were reported by Ballen et
The median age of patients at the time of diagnosis of MDS is in the seventh decade. Physicians have generally been reluctant to consider an HSCT in patients more than 55 or even 50 years of age because of the anticipated or observed high incidence of transplant-related morbidity and mortality. We have begun to cautiously explore the feasibility of allogeneic transplants in older patients with MDS [14]. Fifty patients 55–66 (median 59) years of age, 13 with RA, 19 with RA with excess blasts (RAEB), 16 with RAEB-T/AML, and two with CMML were transplanted. By IPSS scores, available for 45 patients, two patients were scored as low, 14 as intermediate-1, 19 as intermediate-2, and 10 as high risk. Conditioning regimens consisted of CY or BU combined with fractionated TBI, or BU plus CY. The donors were HLA-identical siblings in 34, HLA-nonidentical family members in four, identical twins in four, and unrelated volunteers in six patients. Currently 22 patients (44%) are surviving at 10–81 months post-transplant. Kaplan–Meier estimates of disease-free survival at 3 years were 53, 46, and 33% among patients with RA, RAEB, and RAEB-T/AML/CMML, respectively. Relapse-free survival showed an inverse correlation with cytogenetic risk classification and with the risk scores according to the IPSS. Survival in all FAB categories was highest among patients conditioned with targeted BU and CY (68% for patients with RA). Results in 45 patients with de novo MDS are summarized in Fig. 7.
2.5. Pediatric patients There has been considerable debate as to whether MDS in childhood represents MDS as described for adults but occurring in a younger age group or whether it represents a different disease [33]. The most common variant of ‘MDS’ observed in children is CMML, which appears to be closely related to juvenile CML and the monosomy 7 syndrome of childhood. RA and other subtypes of MDS are rare in the pediatric population [34]. Irrespective of the ongoing debate, however, MDS in children can be treated effectively by HSCT. Locatelli and colleagues showed that survival without transplant was poor, with only 25% of patients surviv-
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ing at 2 years and 6% at 10 years after diagnosis. In contrast, 39% of patients who had received an allogeneic HSCT were alive at 10 years [35]. However, Creutzig et al. summarizing results of a German study, found that none of the children with more than 12% blasts in the marrow at the time of transplant survived, while five of eight patients with a lower blast count became long-term survivors [36]. Davies and colleagues reported a 3-year probability of survival of 53% [37], and Woolfrey et al. showed that six of six children with MDS transplanted from an unrelated donor were alive more than 1.5 years after transplantation [38]. It appears, therefore, that allogeneic transplantation should be pursued aggressively in children with MDS, although it may be advantageous to reduce the blast cell population by pre-transplant chemotherapy.
2.6. Post-transplant relapse As discussed above, post-transplant relapse remains a problem, particularly in patients with advanced MDS. It is currently not clear what represents optimum management. Immunotherapy in the form of lymphocyte infusions from the marrow donor (DLI) has been used very successfully, in particular in patients with CML. Reports in patients with MDS are limited [39,40]. Investigators at the FHCRC have given DLI to seven patients with MDS (five with RAEB and two with RA). Three of these (all with RAEB) achieved a complete remission, and two are alive, disease free, at more than 2 years (M. Flowers et al. unpublished observations). These observations are of interest, but firm conclusions cannot be drawn at this point. Second transplants may be possible in some patients (see below). Other approaches deserve to be investigated.
Fig. 7. Disease-free survival in 45 patients with de novo MDS more than 55 years of age and transplanted from an HLA-identical sibling or unrelated donor. Patients were conditioned either with targeted BUCY (n =15) or with other regimens (n= 30).
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2.7. Non-myeloablati6e conditioning regimens The recent development and application of nonmyeloablative transplant conditioning regimens has stirred considerable interest [41]. The basic concept of this approach is that reduction in the intensity of the regimen (irradiation, chemotherapy, or both) will reduce regimen-related toxicity. The post-transplant administration of appropriate immunosuppressive drugs (e.g. cyclosporine plus mycophenolate mofetil) will facilitate donor cell engraftment. If needed, infusions of graded doses of donor lymphocytes can be given to facilitate conversion to full donor chimerism [42]. Such an approach is certainly of interest for the treatment of a disease like MDS with a high incidence of regimen-related toxicity and generally diagnosed in older patients. This approach may also apply in patients with relapse after a conventional transplant or with secondary MDS. Data available to date are too limited to allow for firm conclusion. However, the field is developing rapidly [43].
3. Autologous transplantation Concerned about the high incidence of transplant-related morbidity and mortality after allogeneic transplantation and encouraged by the observation that some patients with MDS given intensive chemotherapy achieve a cytogenetic remission, investigators have begun to explore the feasibility of autologous transplants in MDS. Trials with combinations of topotecan or daunomycin plus cytosine arabinoside have resulted in remission (characterized by polyclonal hematopoiesis and normal karyotype) in as many as 40% of patients with RAEB or RAEB-T [44]. It should be possible, therefore, to harvest normal stem cells from those patients for transplantation. Wattel and colleagues described a prospective study of 83 patients without a suitable related donor [45]. Forty-two patients (51%) achieved a complete remission, and 24 of these eventually received an autologous transplant. At the time of publication, 12 of the 24 patients transplanted (50%) were surviving relapse-free at a median of 29 months. A joint study of European groups accrued 197 patients, 186 of whom have been observed for a minimum of 2 years [46]. Among these, 101 (54%) achieved a remission after one or two courses of induction therapy with cytosine arabinoside, etoposide and idarubicin; 90 patients also received consolidation with high dose Ara-C plus mitoxantrone. Among those 90 patients, 58 did not have an allogeneic donor, and 33 of these received an autologous transplant. For this subgroup of 33 patients (17% of the starting population), relapse-free survival at 2 years was 28%. Survival tended to be better in younger than in
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Fig. 8. Incidence of relapse after transplantation from a related or unrelated donor dependent upon pretransplant cytogenetic findings (low, intermediate or high risk cytogenetics as defined by the IPSS [4]).
older patients. While hematopoietic recovery was slow (median time to 0.5×109 neutrophils/l, 48 days; median time to 20×109 platelets/l, 95 days), transplant-related mortality was reported to be 5 10%. However, as is apparent from the numbers given above, many patients did not come to transplantation be it because of severe and prolonged myelosuppression following induction or because of the inability to collect sufficient numbers of stem cells for transplant. Therefore, with currently available treatment modalities, autologous transplantation is likely to be an option only for a small proportion of patients.
4. Relevance of IPSS score for transplant outcome The IPSS was developed in an attempt to improve our ability to assess the prognosis of patients with de novo MDS [4]. The IPSS considers the percentage of blasts in the marrow, the number of peripheral blood cytopenias, and the patient’s cytogenetic risk (low, intermediate, high). On the basis of the numeric scores assigned for those parameters, patients are classified into low (score 0), intermediate-1 (0.5 – 1.0), intermediate-2 (1.5–2.0), and high risk (] 2.5); the median survivals among non-transplanted patients reported for these four groups were 5.7, 3.5, 1.2 and 0.4 years, respectively [4]. While originally based on the survival of non-transplanted patients, recent reports suggest that IPSS scores directly impact on survival after HSCT as well [47,48]. In an analysis of results in 251 patients transplanted at the FHCRC in Seattle, the 5-year disease-free survival was 60% among low and intermediate-1 risk patients, 36% for intermediate-2, and 28% for high-risk
patients. The major cause of failure among higher risk patients was disease recurrence, and the predominant factor within the IPSS categorization appeared to be the cytogenetic risk group [47]. Updated results are summarized in Fig. 8. These results were confirmed in a more recent cohort of older patients (described above) in whom post-transplant outcome was inversely related to the pretransplant cytogenetic risk group and the IPSS score [14]. Similar results have been reported by Neville et al. who analyzed data in 60 consecutive adult patients transplanted by the Vancouver group [48]. The 7-year relapse-free survivals for patients in the good, intermediate and poor risk cytogenetic subgroups were 51, 40 and 6%, respectively. The corresponding figures for actuarial relapse were 19, 12 and 82%, respectively. There was no difference for non-relapse mortality between the three groups. Considering these results, it appears that IPSS scores and, in particular, cytogenetic risk grouping should be incorporated into the design of new protocols. For example, patients with high-risk cytogenetic abnormalities might be prepared with a more intensive conditioning regimen, whereas patients with the same proportion of blasts but a normal karyotype would receive a low-intensity (and less toxic) regimen.
5. Transplant-associated toxicity Toxicity associated with transplantation is generally related to the transplant regimen (regimen-related toxicity [RRT]) or develops on the basis of donor-host interactions (host-vs.-graft and graft-vs.-host reactions). The latter occurs theoretically only after allogeneic transplants. RRT has been observed with virtually all conditioning regimens and in all disease settings; however, the incidence, including hepatic, renal and pulmonary toxicity, has been particularly high in patients with MDS. The reasons for this are not immediately apparent. The fact that post-transplant outcome has in general been inversely related to disease duration might suggest that supportive therapy given during that time (prior to transplant) is a contributing factor. Prolonged transfusion support, which results in iron accumulation, may lead to inflammatory and structural tissue damage in the liver and other organs. Pretransplant neutropenia is associated with an increased risk of colonization and infection with various organisms, including fungal species. The persistence of organisms such as aspergillus, despite therapy, puts these patients at high risk of potentially fatal infection after transplantation. Another factor contributing to toxicity may be the aberrant cytokine profile of patients with MDS. Many patients with MDS show high levels of pro-inflammatory cytokines including TNFa, IL-1b and others
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[49,50]. High levels of TNFa, in particular, have been shown by others to be associated with increased transplant-related morbidity and mortality [51], presumably by amplifying tissue damage inflicted by the conditioning regimen and graft-host interactions. As of now, there is no indication that adverse grafthost interactions in patients with MDS are more frequent or more severe than with other disorders. There had been concern that disease-related damage to the microenvironment may interfere with sustained engraftment and hematopoietic reconstitution. However, while an occasional patient shows impaired stroma function, this is a rare problem, and in fact, MDS derived stomal layers provide excellent support for normal hematopoiesis [52]. GVHD, either acute or chronic, also does not appear to be more frequent than with other diagnoses. This deserves to be emphasized since the median patient age in several trials has been in the range of 45 – 50 years. It is beyond the scope of this paper to describe long-term effects after HSCT for MDS. Recent reviews are available [31,53], and there is no indication that any particular late effect is specifically increased after transplantation for MDS.
5.1. Conclusions Patients diagnosed with advanced MDS who have a suitable related or unrelated donor should be transplanted early in their disease course. Patients with less advanced disease by FAB criteria (B 5% marrow blasts) but with high-risk cytogenetic findings ( − 7; complex abnormalities) or severe multilineage cytopenias according to IPSS and transfusion dependence, should also be considered for early transplantation; even patients in their 60s can be transplanted successfully. Patients with low-risk cytogenetic features (normal karyotype; -Y; 5q-; 20q-) and without severe cytopenias may do well for extended periods of time with more conservative management. Despite progress, however, many problems remain. Relapse occurs in 20 – 30% of patients with advanced disease. Infections, especially of fungal origin, frequently in association with GVHD, result in considerable morbidity and mortality. Multiorgan toxicity, often with fatal outcome, develops in 15 – 25% of patients even when transplanted for less advanced disease. Efforts must be directed at reducing organ toxicity, at improving GVHD prophylaxis, and at containing infections. Considering the data on the impact of the IPSS score, and in particular the cytogenetic risk category, regimens designed more narrowly for certain risk groups of patients (higher intensity for high risk, lower intensity for low risk) appear desirable. To what extent non-myeloablative transplant regimens can be applied in patients with MDS remains to be determined. Proto-
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cols using targeted therapy with radioisotope conjugated anti-CD45 antibody, and modalities that block the production or effect of pro-inflammatory cytokines, present at very high levels in many patients with MDS, may be helpful in further improving outcome [54]. Autologous transplant results suggest that this approach may be useful for subgroups of patients, although it is too early to offer firm recommendations. Acknowledgements This work was supported by PHS Grants CA18029, and HL36444. HJD is also supported by a grant from the Gabrielle Rich Leukemia Fund. H.J. Deeg and F.R. Appelbaum contributed to all aspects of this series, with the drafting done by H.J. Deeg. References [1] Greenberg PL. Myelodsyplastic syndrome. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P, editors. Hematology: Basic Principles and Practice. New York: Churchill Livingstone, 2000:1106. [2] Sanz GF, Sanz MA, Vallespı` T, et al. Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 1989;74:395. [3] Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C. The French – American–British (FAB) Co-Operative Group. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189. [4] Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079. [5] Greenberg P, Bishop M, Deeg J, et al. NCCN practice guidelines for the myelodysplastic syndromes. Oncology 1998;12:53. [6] De Witte T. Stem cell transplantation in myelodysplastic syndromes (Review). Forum 1999;9:75. [7] Horowitz MM. Results of allogeneic stem cell transplantation for malignant disorders. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P, editors. Hematology: Basic Principles and Practice. New York: Churchill Livingstone, 2000:1573. [8] Anderson JE, Appelbaum FR, Schoch G, et al. Allogeneic marrow transplantation for refractory anemia: a comparison of two preparative regimens and analysis of prognostic factors. Blood 1996;87:51. [9] O’Donnell MR, Long GD, Parker PM, et al. Busulfan/cyclophosphamide as conditioning regimen for allogeneic bone marrow transplantation for myelodysplasia. J Clin Oncol 1995;13:2973. [10] Ratanatharathorn V, Karanes C, Uberti J, et al. Busulfan-based regimens and allogeneic bone marrow transplantation in patients with myelodysplastic syndromes. Blood 1993;81:2194. [11] Slattery JT, Clift RA, Buckner CD, et al. Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation. Blood 1997;89:3055. [12] Nevill TJ, Shepherd JD, Reece DE, Barnett MJ, Nantel SH, Klingemann HG, Phillips GL. Treatment of myelodysplastic syndrome with busulfan-cyclophosphamide conditioning followed by allogeneic BMT. Bone Marrow Transpl 1992;10:445.
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[13] Hsu C, Lin MT, Tang JL, Tien HF, Wang CH, Chen YC. Allogeneic stem cell transplantation for patients with high-risk myelodysplastic syndrome. J Formosan Med Assoc 1999;98:157. [14] Deeg HJ, Shulman HM, Anderson JE, et al. Allogeneic and syngeneic marrow transplantation for myelodysplastic syndrome in patients 55 to 66 years of age. Blood 2000;95:1188. [15] Petersdorf EW, Gooley TA, Anasetti C, Martin PJ, Smith AG, Mickelson EM, Woolfrey AE, Hansen JA. Optimizing outcome after unrelated marrow transplantation by comprehensive matching of HLA class I and II alleles in the donor and recipient. Blood 1998;92:3515. [16] Arnold R, De Witte T, van Biezen A, Hermans J, Jacobsen N, Runde V, Gratwohl A, Apperley JF. Unrelated bone marrow transplantation in patients with myelodysplastic syndromes and secondary acute myeloid leukemia: an EBMT survey. European Blood and Marrow Transplantation Group. Bone Marrow Transpl 1998;21:1213. [17] Bjerke J, Anasetti C, Gooley T, et al. Unrelated donor (URD) bone marrow transplantation (BMT) for refractory anemia (RA). Blood 1998;92 (Suppl 1):142a, 573 (Abstract). [18] Castro-Malaspina H, Collins JER, Gajewski J, Harris R, Ramsay N, Deeg HJ. Unrelated donor marrow transplantation for myelodysplastic syndromes (MDS). Blood 1997;90 (Suppl 1):106a, 465 (Abstract). [19] Anderson JE, Thomas ED. The Seattle experience with bone marrow transplantation (BMT) for myelodysplasia (MDS). Leuk Res 1997;21 (Suppl 1): S51(Abstract). [20] Boogaerts MA. Stem cell transplantation and intensified cytotoxic treatment for myelodysplasia (Review). Curr Opin Hematol 1998;5:465. [21] Pagliuca A, Mijovic A, Jeanes A, Perry A, Mufti GJ. Delayed platelet regeneration following allogeneic peripheral blood progenitor cell transplantation for acute leukemia. Bone Marrow Transpl 1995; 15(Supp2): S29 (Abstract). [22] Runde V, De Witte T, Arnold R et al. 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 Transpl 1998;21:255. [23] Appelbaum FR, Barrall J, Storb R, et al. Bone marrow transplantation for patients with myelodysplasia. Pretreatment variables and outcome. Ann Intern Med 1990;112:590. [24] Anderson JE, Appelbaum FR, Schoch G, et al. Allogeneic marrow transplantation for myelodysplastic syndrome with advanced disease morphology: a phase II study of busulfan, cyclophosphamide, and total-body irradiation and analysis of prognostic factors. J Clin Oncol 1996;14:220. [25] Anderson JE, Appelbaum FR, Deeg HJ, Storb R. Phase II study of busulfan (BU) and total body irradiation (TBI) as a novel preparative regimen in allogenic marrow transplantation (BMT) for advanced myelodysplastic syndrome. Leuk Res (Abstract) 1999;23:S83 – 5. [26] Zang DY, Deeg HJ, Gooley T, Anderson JE, Anasetti C, Sanders J, Myerson D, Storb R, Appelbaum F. Treatment of chronic myelomonocytic leukemia by allogeneic marrow transplantation. Br J Haematol (in press). [27] Sobecks RM, Le Beau MM, Anastasi J, Williams SF. Myelodysplasia and acute leukemia following high-dose chemotherapy and autologous bone marrow or peripheral blood stem cell transplantation. Bone Marrow Transpl 1999;23:1161. [28] Friedberg JW, Neuberg D, Stone RM, et al. Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 1999;17:3128.
[29] Wilson CS, Traweek ST, Slovak ML, Niland JC, Forman SJ, Brynes RK. Myelodysplastic syndrome occurring after autologous bone marrow transplantation for lymphoma. Am. J. Clin. Pathol 1997;108:369. [30] Witherspoon RP, Deeg HJ. Allogeneic bone marrow transplantation for secondary leukemia or myelodysplasia. Haematologica 1999;84:1085. [31] Leahey AM, Friedman DL, Bunin NJ. Bone marrow transplantation in pediatric patients with therapy-related myelodysplasia and leukemia. Bone Marrow Transpl 1999;23:21. [32] Ballen KK, Gilliland DG, Guinan EC, et al. Bone marrow transplantation for therapy-related myelodysplasia: comparison with primary myelodysplasia. Bone Marrow Transpl 1997;20:737. [33] Hasle H, Arico M, Basso G, et al. Myelodysplastic syndrome, juvenile myelomonocytic leukemia, and acute myeloid leukemia associated with complete or partial monosomy 7. Leukemia 1999;13:376. [34] Barnard DR, Kalousek DK, Wiersma SR, et al. Morphologic, immunologic, and cytogenetic classification of acute myeloid leukemia and myelodysplastic syndrome in childhood: a report from the Childrens Cancer Group. Leukemia 1996;10:5. [35] Locatelli F, Niemeyer C, Angelucci E. Eurpoean Working Group on Myelodysplastic Syndrome in Childhood. Allogeneic bone marrow transplantation for chronic myelomonocytic leukemia in childhood: a report from the European Working Group on Myelodysplastic Syndrome in Childhood. J Clin Oncol 1997;15:566. [36] Creutzig U, Bender-Gotze C, Ritter J, Zimmermann M, Stollmann-Gibbels B, Korholz D, Niemeyer C. The role of intensive AML-specific therapy in treatment of children with RAEB and RAEB-t. Leukemia 1998;12:652. [37] Davies SM, Wagner JE, DeFor T, et al. Unrelated donor bone marrow transplantation for children and adolescents with aplastic anaemia or myelodysplasia. Br J Haematol 1997;96:749. [38] Woolfrey AE, Gooley TA, Sievers EL, et al. Bone marrow transplantation for children less than 2 years of age with acute myelogenous leukemia or myelodysplastic syndrome. Blood 1998;92:3546. [39] Castagna L, El Weshi A, Bourhis JH, Ribrag V, Naccache P, Vantelon JM, Brault P, Pico JL. Successful donor lymphocyte infusion (DLI) in a patient with myelodysplastic syndrome (MDS) after failure of T-cell-depleted bone marrow transplantation (TD-BMT) (Letter). Br J Haematol 1998;103:284. [40] Bader P, Klingebiel T, Schaudt A, et al. Prevention of relapse in pediatric patients with acute leukemias and MDS after allogeneic SCT by early immunotherapy initiated on the basis of increasing mixed chimerism: a single center experience of 12 children. Leukemia 1999;13:2079. [41] Carella AM, Champlin R, Slavin S, McSweeney P, Storb R. Mini-allografts: ongoing trials in humans (Editorial). Bone Marrow Transpl 2000;25:345. [42] McSweeney PA, Storb R. Mixed chimerism: preclinical studies and clinical applications (Review). Biol Blood Marrow Transpl 1999;5:192. [43] Storb R, McSweeney PA, Sandmaier BM. Allogeneic hematopoietic stem cell transplantation: from the nuclear age into the 21st century. Transpl Proc (in press). [44] Beran M, Estey E, Kantarjian H. Emerging role of topoisomerase I inhibitors in the therapy of high risk MDS and CMML. Leuk Res 1999;23 (Suppl 1):S70, 183, Fifth International Symposium on Myelodysplastic Syndromes, Prague, Czech Republic, 21 – 24 April (Abstract). [45] Wattel E, Solary E, Leleu X, et al. A prospective study of autologous bone marrow or peripheral blood stem cell transplantation after intensive chemotherapy in myelodysplastic syndromes. Leukemia 1999;13:524.
H.J. Deeg, F.R. Appelbaum / Leukemia Research 24 (2000) 653–663 [46] De Witte T, van Biezen A, Hermans J, et al. Autologous bone marrow transplantation for patients with myelodysplastic syndrome (MDS) or acute myeloid leukemia following MDS. Chronic and Acute Leukemia Working Parties of the European Group for Blood and Marrow Transplantation. Blood 1997;90:3853. [47] Appelbaum FR, Anderson J. Allogeneic bone marrow transplantation for myelodysplastic syndrome: outcomes analysis according to IPSS score. Leukemia 1998;12(suppl 1):S25–9. [48] Nevill TJ, Fung HC, Shepherd JD, et al. Cytogenetic abnormalities in primary myelodysplastic syndrome are highly predictive of outcome after allogeneic bone marrow transplantation. Blood 1998;92:1910. [49] Gersuk GM, Beckham C, Loken MR, et al. A role for tumor necrosis factor-, Fas and Fas-ligand in marrow failure associated with myelodysplastic syndrome. Br J Haematol 1998;103:176. [50] Shetty V, Mundle S, Alvi S, et al. Measurement of apoptosis, proliferation and three cytokines in 46 patients with myelodysplastic syndromes. Leuk Res 1996;20:891.
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[51] Holler E, Kolb HJ, Mittermuller J, et al. Modulation of acute graft-versus-host-disease after allogeneic bone marrow transplantation by tumor necrosis factor alpha (TNF alpha) release in the course of pretransplant conditioning: role of conditioning regimens and prophylactic application of a monoclonal antibody neutralizing human TNF alpha (MAK 195F). Blood 1995;86:890. [52] Deeg HJ, Beckham C, Loken MR, Bryant E, Lesnikova M, Shulman HM, Gooley T. Negative regulators of hemopoiesis and stroma function in patients with MDS. Leuk Lymphoma 2000;37:405. [53] Deeg HJ. Delayed complications after hematopoietic cell transplantation. In: Thomas ED, Blume KG, Forman SJ, editors. Hematopoietic Cell Transplantation, 2nd Edition. Boston: Blackwell Science, 1999. p. 776. [54] Matthews DC, Appelbaum FR, Eary JF, et al. Phase I study of 131 I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome. Blood 1999;94:1237.
Review
Hematopoietic stem cell transplantation in patients with myelodysplastic syndrome H. Joachim Deeg *, Frederick R. Appelbaum Fred Hutchinson Cancer Research Center and the Uni6ersity of Washington, 1100 Fair6iew A6enue North, D1 -100, P.O. Box 19024, Seattle, WA 98109 -1024, USA Received 29 March 2000; accepted 30 March 2000
Abstract Myelodysplastic syndrome (MDS) is a stem cell disorder, and hematopoietic stem cell transplantation is currently the only therapeutic modality that is potentially curative. Among patients with less advanced MDS ( B5% marrow blasts), 3-year survivals of 65–70% are achievable with HLA-identical related and HLA-matched unrelated donors. The overall probability of disease recurrence in these patients is B5%. Among patients with advanced disease ( ] 5% marrow blasts), about 35 – 45% and 25–30%, respectively, are surviving in remission after transplantation from a related or from an unrelated donor; the incidence of post-transplant relapse is 10–35%. The criteria proposed by the International Prognostic Scoring System (IPSS) derived from non-transplanted patients, also predict survival following transplantation. The development of new conditioning regimens has permitted successful hematopoietic stem cell transplants even in patients more than 60 years of age. Improved survival with transplants from unrelated volunteer donors may, in part, reflect selection of donors on the basis of high resolution (allele-level) HLA typing. Autologous stem cell transplantation may be beneficial for selected patients who have obtained a complete remission with conventional chemotherapy. Treatment-related morbidity and mortality, in particular after allogeneic transplantation, remain challenges that need to be addressed with innovative approaches. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: MDS; Hematopoietic stem cell transplantation; Cytogenetic risk group; Relapse; Organ toxicity
1. Introduction The term myelodysplastic syndrome (MDS) comprises several hematopoietic disorders characterized by ineffective hematopoiesis (single or multilineage peripheral blood cytopenia in the presence of a cellular marrow) and a tendency to develop acute leukemia [1,2]. Abbre6iations: AML, acute myelogenous leukemia; BU, busulfan; CMML, chronic myelomonocytic leukemia; CY, cyclophosphamide; EBMT, European bone marrow transplant; FAB, French– American–British; FTBI, fractionated TBI; GVHD, graft-versus-host disease; IPSS, international prognostic scoring system; MDS, myelodysplastic syndrome; RA, refractory anemia; RAEB, RA with excess blasts; RAEB-T, RAEB in transformation; RARS, RA with ring sideroblasts. * Corresponding author. Tel.: + 1-206-6675985; fax: +1-2066676124. E-mail address: [email protected] (H.J. Deeg).
Dysplastic features may be more or less pronounced, and approximately half of the patients have clonal cytogenetic abnormalities [3]. The French–American– British (FAB) classification categorizes MDS on the basis of the proportion of marrow (and peripheral blood) blasts into refractory anemia (RA), RA with ringed sideroblasts (RARS), RA with excess blasts (RAEB) and RAEB in transformation (RAEB-T) [3]. An additional category, chronic myelomonocytic leukemia (CMML), has now been reclassified as a myeloproliferative disorder. While the FAB categories have proven very useful for diagnostic, prognostic and therapeutic purposes, the incorporation of cytogenetic findings and the number of cytopenias, in addition to the blast count, in a new scoring system termed International Prognostic Scoring System (IPSS) may provide further prognostic precision [4].
0145-2126/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 1 4 5 - 2 1 2 6 ( 0 0 ) 0 0 0 4 9 - 7
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The mechanisms involved in the development and evolution of MDS are poorly understood. There is overwhelming evidence, however, that MDS is a hematopoietic stem cell disorder [1]. Theoretically, hematopoietic stem cell transplantation (HSCT) should, therefore, offer definitive therapy. This is in fact borne out by observations over the past 10 – 15 years (Fig. 1). The best results have been achieved in patients with less advanced MDS ( B 5% blasts in the marrow). Originally, most transplants were carried out in younger patients with HLA-identical sibling donors. In recent years rapidly growing numbers of patients have been transplanted from unrelated volunteer donors. Also, the upper age limit for transplantation has been advanced from 60 to 65 years or older, an important development given that the median age at diagnosis of MDS is in the seventh decade. General management guidelines have been presented recently [5]. This review provides an update on results with HSCT.
2. Allogeneic transplantation
2.1. Patients with less ad6anced disease The best results with allogeneic transplants are achieved in patients with less advanced (or low grade) disease defined here as patients with RA or RARS. The European Bone Marrow Transplant (EBMT) group has reported 5-year relapse-free survivals of 46, 35, 27 and 0% for patients with RA/RARS, RAEB, RAEB-T and secondary acute myeloid leukemia, respectively [6]. Data reported to the International Bone Marrow Transplant Registry (IBMTR) on transplants carried out between 1991 and 1997 show a 3-year probability
Fig. 1. Disease-free survival by FAB classification among 241 patients transplanted from an HLA identical sibling donor. MDS/AML includes patients who developed acute myelogenous leukemia on the background of MDS.
of relapse of 10% among 204 patients with RA or RARS transplanted from an HLA-identical sibling donor, and a 3-year probability of disease-free survival of 58% [7]. The team at the Fred Hutchinson Cancer Research Center (FHCRC) originally reported relapse-free survival of approximately 60% and a probability of relapse of B 5% among patients with RA conditioned with cyclophosphamide (CY) and total body irradiation (TBI), and transplanted from an HLA-identical related donor [8]. Very similar results were obtained when a regimen of busulfan (BU), 16 mg/kg plus CY, 120 mg/kg, was studied [8]. However, while relapse rates were low, these and other reports [9,10], reveal an incidence of non-relapse mortality in the range of 30– 35%. Causes of death include infections and GVHD, and most prominently, single and multi-organ toxicity (see below). With the goal of reducing toxicity, a subsequent FHCRC study combined CY (60 mg/kg per day× 2) with TBI at doses of 800–1200 cGy using lung and liver shielding (termed total marrow irradiation [TMI]). In other studies this approach appeared to reduce regimen-related toxicity. However, in MDS, the trial was closed after enrollment of only 14 patients because four patients had recurrent disease for a relapse probability of 36%, compared to 2.3% in previous MDS trials (unpublished observations) (P=0.001). These results suggested that clonal precursors were protected by lung and liver shielding, and that CY was not sufficient as systemic therapy. A combination of BU, 16 mg/kg orally, plus CY, 60 mg/kg per day for 2 days, particularly if the BU was targeted to achieve steady-state plasma concentrations within a pre-determined range (800–900 ng/ml), had yielded encouraging results in patients with chronic myeloid leukemia (CML); the probability of posttransplant relapse was low, and toxicity was acceptable [11]. BU/CY regimens have also been used successfully by several transplant teams to transplant patients with MDS [9,10,12,13]. Thus, we tested a regimen of CY and targeted BU in patients with RA (or RARS) transplanted from an unrelated volunteer donor (see below), or from a family donor. Preliminary results have been presented recently [14]. The probability of survival in remission was greater than 60% among patients transplanted from an HLA-identical sibling. Results are illustrated in Fig. 2. The probability of post-transplant relapse remained below 5%, and the incidence of regimen-related mortality was reduced to 20–25%. As further discussed below, with this regimen even patients in their 60s were transplanted successfully [14]. As a suitably matched related donor is available for only 25–30% of patients, alternatives, in particular, transplantation from volunteer unrelated donors, have been pursued. In view of the rapidly growing number of HLA typed potential donors and the advancements in
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MDS transplanted under the auspices of the NMDP [18]. Among 510 patients, 1–62 (median 38) years of age, there were 116 with RA of whom 50% survived at 18 months. The probability was 60%, however, for patients conditioned with a BU/CY regimen. Results from this analysis also indicate that outcome was improved even further if donor and patient were more completely HLA matched [18]. Overall, these data suggest that the lack of a suitably matched related donor should not be cause to abandon plans for a transplant.
2.2. Ad6anced MDS
Fig. 2. Disease-free survival among 18 patients with refractory anemia conditioned with a regimen of targeted busulfan plus cyclophosphamide and transplanted with marrow from an HLA identical sibling donor.
HLA typing at the molecular level which has allowed for progressively better matching of patient and donor, use of volunteer donors has become increasingly attractive [15]. The EBMT group reported results in 118 patients, 0.3 – 53 (median 24) years of age, with MDS/secondary AML who were transplanted from an unrelated donor [16]. Patients transplanted within 6 months of diagnosis had a probability of relapse-free survival of 55% compared to 16% among patients transplanted more than 12 months after diagnosis. However, treatment-related mortality was high for all subcategories, about 40% for patients less than 40 years of age, and 61% among older patients. Among 24 patients with RA or RARS, the probability of relapse was 13%, and 2-year disease-free survival was 24%. IBMTR data on 48 patients with RA or RARS transplanted from an unrelated donor show a 3-year disease-free survival of 35% [11]. The authors point out that while the median interval from diagnosis to transplant was 6 months with related transplants, it was 10 months with unrelated transplants. It was not clear from this report why patients with good-risk MDS should have such a poor probability of survival. In part, this may have been related to the marked delay of transplantation after diagnosis (Table 1). Among 40 patients with RA transplanted at the FHCRC with marrow from an unrelated volunteer donor, 3-year survival was 56% [17]. Among patients who were conditioned with targeted BU and CY (as described above) and transplanted from a donor serologically matched for HLA-A and B and molecularly (allele level) matched for HLA-DRB1 and -DQB1, survival was 66%, similar to results in patients with comparable disease stage transplanted from an HLAidentical related donor (Fig. 3). This impression is confirmed by results in a larger cohort of patients with
The most obvious difference in regard to transplant outcome between patients with less advanced and more advance disease is the incidence of post-transplant relapse, reported to be in the range of 15–50% in patients with RAEB, RAEB-T and AML, compared to less than 5% among patients with RA or RARS [13,19–21]. In addition, there may be a higher incidence of non-relapse morbidity and mortality with advanced disease, conceivably because of a more prolonged disease course and duration of supportive care before transplantation. A study on 131 patients (who had not received pre-transplant induction therapy) reported to the EBMT group showed a 5-year disease-free survival of 34% for patients with RAEB and 19% for patients with RAEB-T [22]. The overall probability of relapse was 39%, 13% for RA/RARS, 44% for RAEB, and 52% for RAEB-T. Transplant-related mortality ranged from 40% in patients with RA to 60% in patients with RAEB-T. In multivariate analysis, younger age and a shorter interval from diagnosis to transplant, in addition to an absence of excess blasts, were associated with better outcome. A report from the IBMTR on 581 patients with RAEB, RAEB-T or CMML, shows 3year probabilities of relapse and disease-free survival of 35 and 40%, respectively [7]. Initial trials at the FHCRC using a conditioning regimen that combined CY and fractionated TBI showed similarly high relapse rates, and yielded a 3year survival probability of 45% [23]. In an attempt to reduce the high incidence of relapse, in a subsequent trial, CY (at a reduced dose of 50 mg/kg) and TBI (6× 200 cGy) were combined with busulfan (7 mg/kg) given over 4 days [24]; 31 patients, median age 41 years, were enrolled (25 related, six unrelated donors). The 3-year actuarial disease-free survival was 23% (similar to the rate of 30% in historical patients prepared with CY plus TBI). However, while there was a trend toward fewer relapses, there was an increase in non-relapse mortality (Fig. 4). It was of note that univariate analysis showed a higher relapse rate in HLA-matched related transplant recipients than among patients transplanted from alternative donors, suggesting a stronger
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graft-versus-MDS effect with transplants other than those from an HLA-identical sibling. In multivariable analysis, a normal pretransplant karyotype and the use of methotrexate for GVHD prophylaxis after transplantation were associated with reduced non-relapse mortality and improved survival. CY is not stem cell toxic and, while immunosuppressive, may contribute to non-relapse toxicity. Thus, a subsequent cohort of patients received busulfan (7 mg/ kg) plus TBI (6×200 cGy) but no CY. Twenty-six patients, median age 47 years, with RAEB, RAEB-T or CMML were enrolled and transplanted from a related (n = 8) or unrelated donor (n =18). With a median follow-up of 3 years, three patients relapsed (12%) and 12 patients died of transplant-related complications (cumulative incidence 46%). At the time of reporting, 11 patients were surviving disease-free for a probability of 46%, comparing favorably to the probability of 29% among 42 historical controls. Controlling for patient and disease characteristics, there appeared to be a lower
relative risk of relapse (0.08; P= 0.0008) and a lower relative risk of relapse or death (0.5; P= 0.02) in patients conditioned with BU plus TBI. An update of results is given in Fig. 5. These data underline the importance of stem cell toxic agents and indicate that CY is not required for a successful transplant in either related or unrelated transplant recipients [25]. The role of TBI in conditioning MDS patients for transplantation is still unsettled. In an analysis of 510 transplants for MDS from unrelated donors (see above; H. Castro-Malaspina, personal communication), patients in all FAB categories whose preparative regimen did not contain TBI had a higher probability of overall survival (P= 0.02) and disease-free survival (P =0.01) than patients conditioned with TBI. The difference was most striking in patients with RA. Preliminary results from ongoing FHCRC trials appear to support those findings. Crude data for outcome after transplantation from an HLA-identical sibling donor show a 3-year disease-free survival of 51% after conditioning with
Table 1 Hematopoietic cell transplantation for MDS: treatment decision by FAB disease category and IPSS risk groupsd FABa category
IPSS Criteria
Cytogenetic riske RA
Any
RARS
Low/intermediate Any High Any
RAEB
Low/intermediate Any
High
Any
RAEB-T
Any
Any
CMMLc
–––
–––
a
Donor available
Managementf
Any Any \65(70) 565(70)b Any \65 (70) 565 (70)b Any Any \65 (70) 565 (70)b Any \65 (70) 565 (70)b Any 565 (70)b Any \65 (70) 565(70)b Any \65 (70) 565 (70)b
Yes/no No Â Ì ––– Å Yes No Â Ì ––– Å Yes  No à No Ì Ã ––––Å Yes No Â Ì ––– Å Yes No Yes  No Ì ––– Å Yes No Â Ì ––– Å Yes
Observe; growth factor(s) Immunosuppressive therapy (IST)
No. of cytopenias
Low/intermediate 0/1 2/3
High
Patient age (years)
Transplantation IST Transplantation Growth factors (G-CSF plus erythropoietin)
Transplantation IST; chemotherapy; other experimental therapy Transplantation Chemotherapy; IST (?) Transplantation Chemotherapy; other experimental therapy Transplantation Observe; chemotherapy Transplantation
FAB, French–American–British; IPSS, International Prognostic Scoring System; IST, immunosuppresive therapy. Upper age limit may be higher for non-myeloablative conditioning regimens. c IPSS recommendations developed only for non-proliferative CMML. d See also NCCN practice guidelines [5]. e Cytogenetic risk: low, (normal karyotype; -y; 5q-; 20q-); high, (chromosome 7 abnormalities; ]3 clonal abnormalities); intermediate, (all other abnormalities). f Transfusion support or antibiotic prophylaxis may be required in any disease category. b
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sion with a median follow-up of 6.9 years. Five patients have relapsed (cumulative incidence 25%), five died with organ failure, and two with GVHD/infections. Shorter disease duration appeared to be associated with improved outcome. While only one patient with normal blast counts relapsed, there were four relapses among 12 patients with excess blasts. As with other disease categories, it appears preferable, therefore, to carry out a transplant earlier in the course of CMML.
2.3. Secondary MDS
Fig. 3. Disease-free survival among patients with RA conditioned with targeted busulfan plus cyclophosphamide and transplanted from an allele level HLA matched (n=21) or HLA non-identical (n = 12) unrelated donor.
Fig. 4. Probability of relapse, non-relapse mortality and disease-free survival among 33 patients with advanced MDS conditioned with a combination of busulfan, cyclophosphamide, and TBI and transplanted with marrow from a family donor [24].
BUCY compared to 42% after conditioning with BU TBI (unpublished observations). IBMTR data show a 3-year disease-free survival of 26% among 176 patients with RAEB, RAEB-T or CMML transplanted from an unrelated donor, and fail to reveal a benefit of TBI. Recently, we analyzed separately our experience in 21 patients with CMML [26]. Patients were 1 – 62 (median 47) years old and had carried their diagnoses for 2–60 (median 9) months. Twelve patients had more than 5% blasts in the marrow; 12 had normal and nine abnormal karyotypes. Patients were prepared either with BU/CY/ TBI, BU/TBI or CY/TBI or received a combination of BU (14 mg/kg) plus CY (60 mg/kg × 2), and were transplanted from a related (n =15) or unrelated (n= 6) donor. Nine patients (39%) are surviving in remis-
MDS that is presumably treatment-related (secondary) has been observed after therapy for various malignant and non-malignant disorders. Recent interest has focused on patients who develop MDS after treatment for breast cancer or following autologous HSCT. Incidence figures of 1.1–19.8% at 10 years have been reported [16,27–29]. In contrast to patients with de novo MDS, approximately half of whom have clonal cytogenetic abnormalities, an abnormal karyotype, usually of the high-risk category by IPSS criteria (monosomy 7; complex abnormalities), is found in more than 80% of patients with secondary MDS. Exposure to irradiation and chemotherapy as given for the patient’s original disease is thought to be causative and, in addition, may have resulted in tissue damage, the sequelae of which would predispose the patient to substantial morbidity and mortality while undergoing a transplant for secondary MDS. Friedberg and colleagues analyzed results in 552 patients who had received an autologous stem cell transplant for the treatment of NHL, and found 41 patients who developed MDS at a median of 47 months for an overall incidence of 7.4% [28]. The actuarial incidence at 10 years was 19.8%. Karyotypes were available in 33,
Fig. 5. Disease-free survival among 19 patients with advanced MDS who were conditioned with busulfan plus TBI and transplanted with marrow from an HLA identical sibling donor.
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al. [32], who observed 24% disease-free survival among children with secondary MDS, compared to 43% among children with de novo MDS. Clearly these results are not satisfactory. Efforts must be directed, first, at the prevention of secondary MDS, and secondly at improved tolerance of transplant conditioning. Finally, patients who are thought to be transplant candidates should be transplanted early in the disease course.
2.4. The ‘older’ patient
Fig. 6. Disease-free survival in patients with ‘secondary MDS’ prepared with various conditioning regimens and transplanted from a related or unrelated donor.
and 29 of these showed monosomy 7 or complex abnormalities. Thirteen of these patients underwent allogeneic HSCT (eight from a related and five from an unrelated donor) which was T-cell depleted in eight. All patients died, at a median of 1.8 months post-transplant. Two died with relapse and 11 with transplant-related toxicity, mostly septicemia and organ toxicity. These results are in agreement with an earlier report by the EBMT group which showed a 5-year survival of 0% in patients with secondary MDS [6]. We have recently analyzed results in more than 100 patients with secondary MDS at various stages of disease evolution transplanted at the FHCRC from either a related or unrelated donor using the conditioning regimens employed for patients with de novo MDS [30]. The primary diagnoses included Hodgkin disease, non-Hodgkin lymphoma, carcinoma of the breast, aplastic anemia, multiple myeloma, polycythemia vera, and other solid tumors or hematologic or immunologic disorders. Eight patients had previously received irradiation, 38 chemotherapy, 41 a combination of both, eight had received an autologous transplant, and the remainder had received other therapy. As with de novo MDS, disease stage was the most important risk factor for outcome. Survival in remission was substantially better among patients with RA than in patients with more advanced disease (Fig. 6). The major causes of death were relapse, infections, and single or multiorgan failure. Leahy et al. presented data on 11 children with therapy-related MDS who were transplanted from a related or from an unrelated donor [31]. All but one patient were conditioned with a BU conditioning regimen. Five patients relapsed, and three patients died from non-relapse toxicity. Three patients (24%) survive disease-free. Identical results were reported by Ballen et
The median age of patients at the time of diagnosis of MDS is in the seventh decade. Physicians have generally been reluctant to consider an HSCT in patients more than 55 or even 50 years of age because of the anticipated or observed high incidence of transplant-related morbidity and mortality. We have begun to cautiously explore the feasibility of allogeneic transplants in older patients with MDS [14]. Fifty patients 55–66 (median 59) years of age, 13 with RA, 19 with RA with excess blasts (RAEB), 16 with RAEB-T/AML, and two with CMML were transplanted. By IPSS scores, available for 45 patients, two patients were scored as low, 14 as intermediate-1, 19 as intermediate-2, and 10 as high risk. Conditioning regimens consisted of CY or BU combined with fractionated TBI, or BU plus CY. The donors were HLA-identical siblings in 34, HLA-nonidentical family members in four, identical twins in four, and unrelated volunteers in six patients. Currently 22 patients (44%) are surviving at 10–81 months post-transplant. Kaplan–Meier estimates of disease-free survival at 3 years were 53, 46, and 33% among patients with RA, RAEB, and RAEB-T/AML/CMML, respectively. Relapse-free survival showed an inverse correlation with cytogenetic risk classification and with the risk scores according to the IPSS. Survival in all FAB categories was highest among patients conditioned with targeted BU and CY (68% for patients with RA). Results in 45 patients with de novo MDS are summarized in Fig. 7.
2.5. Pediatric patients There has been considerable debate as to whether MDS in childhood represents MDS as described for adults but occurring in a younger age group or whether it represents a different disease [33]. The most common variant of ‘MDS’ observed in children is CMML, which appears to be closely related to juvenile CML and the monosomy 7 syndrome of childhood. RA and other subtypes of MDS are rare in the pediatric population [34]. Irrespective of the ongoing debate, however, MDS in children can be treated effectively by HSCT. Locatelli and colleagues showed that survival without transplant was poor, with only 25% of patients surviv-
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ing at 2 years and 6% at 10 years after diagnosis. In contrast, 39% of patients who had received an allogeneic HSCT were alive at 10 years [35]. However, Creutzig et al. summarizing results of a German study, found that none of the children with more than 12% blasts in the marrow at the time of transplant survived, while five of eight patients with a lower blast count became long-term survivors [36]. Davies and colleagues reported a 3-year probability of survival of 53% [37], and Woolfrey et al. showed that six of six children with MDS transplanted from an unrelated donor were alive more than 1.5 years after transplantation [38]. It appears, therefore, that allogeneic transplantation should be pursued aggressively in children with MDS, although it may be advantageous to reduce the blast cell population by pre-transplant chemotherapy.
2.6. Post-transplant relapse As discussed above, post-transplant relapse remains a problem, particularly in patients with advanced MDS. It is currently not clear what represents optimum management. Immunotherapy in the form of lymphocyte infusions from the marrow donor (DLI) has been used very successfully, in particular in patients with CML. Reports in patients with MDS are limited [39,40]. Investigators at the FHCRC have given DLI to seven patients with MDS (five with RAEB and two with RA). Three of these (all with RAEB) achieved a complete remission, and two are alive, disease free, at more than 2 years (M. Flowers et al. unpublished observations). These observations are of interest, but firm conclusions cannot be drawn at this point. Second transplants may be possible in some patients (see below). Other approaches deserve to be investigated.
Fig. 7. Disease-free survival in 45 patients with de novo MDS more than 55 years of age and transplanted from an HLA-identical sibling or unrelated donor. Patients were conditioned either with targeted BUCY (n =15) or with other regimens (n= 30).
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2.7. Non-myeloablati6e conditioning regimens The recent development and application of nonmyeloablative transplant conditioning regimens has stirred considerable interest [41]. The basic concept of this approach is that reduction in the intensity of the regimen (irradiation, chemotherapy, or both) will reduce regimen-related toxicity. The post-transplant administration of appropriate immunosuppressive drugs (e.g. cyclosporine plus mycophenolate mofetil) will facilitate donor cell engraftment. If needed, infusions of graded doses of donor lymphocytes can be given to facilitate conversion to full donor chimerism [42]. Such an approach is certainly of interest for the treatment of a disease like MDS with a high incidence of regimen-related toxicity and generally diagnosed in older patients. This approach may also apply in patients with relapse after a conventional transplant or with secondary MDS. Data available to date are too limited to allow for firm conclusion. However, the field is developing rapidly [43].
3. Autologous transplantation Concerned about the high incidence of transplant-related morbidity and mortality after allogeneic transplantation and encouraged by the observation that some patients with MDS given intensive chemotherapy achieve a cytogenetic remission, investigators have begun to explore the feasibility of autologous transplants in MDS. Trials with combinations of topotecan or daunomycin plus cytosine arabinoside have resulted in remission (characterized by polyclonal hematopoiesis and normal karyotype) in as many as 40% of patients with RAEB or RAEB-T [44]. It should be possible, therefore, to harvest normal stem cells from those patients for transplantation. Wattel and colleagues described a prospective study of 83 patients without a suitable related donor [45]. Forty-two patients (51%) achieved a complete remission, and 24 of these eventually received an autologous transplant. At the time of publication, 12 of the 24 patients transplanted (50%) were surviving relapse-free at a median of 29 months. A joint study of European groups accrued 197 patients, 186 of whom have been observed for a minimum of 2 years [46]. Among these, 101 (54%) achieved a remission after one or two courses of induction therapy with cytosine arabinoside, etoposide and idarubicin; 90 patients also received consolidation with high dose Ara-C plus mitoxantrone. Among those 90 patients, 58 did not have an allogeneic donor, and 33 of these received an autologous transplant. For this subgroup of 33 patients (17% of the starting population), relapse-free survival at 2 years was 28%. Survival tended to be better in younger than in
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Fig. 8. Incidence of relapse after transplantation from a related or unrelated donor dependent upon pretransplant cytogenetic findings (low, intermediate or high risk cytogenetics as defined by the IPSS [4]).
older patients. While hematopoietic recovery was slow (median time to 0.5×109 neutrophils/l, 48 days; median time to 20×109 platelets/l, 95 days), transplant-related mortality was reported to be 5 10%. However, as is apparent from the numbers given above, many patients did not come to transplantation be it because of severe and prolonged myelosuppression following induction or because of the inability to collect sufficient numbers of stem cells for transplant. Therefore, with currently available treatment modalities, autologous transplantation is likely to be an option only for a small proportion of patients.
4. Relevance of IPSS score for transplant outcome The IPSS was developed in an attempt to improve our ability to assess the prognosis of patients with de novo MDS [4]. The IPSS considers the percentage of blasts in the marrow, the number of peripheral blood cytopenias, and the patient’s cytogenetic risk (low, intermediate, high). On the basis of the numeric scores assigned for those parameters, patients are classified into low (score 0), intermediate-1 (0.5 – 1.0), intermediate-2 (1.5–2.0), and high risk (] 2.5); the median survivals among non-transplanted patients reported for these four groups were 5.7, 3.5, 1.2 and 0.4 years, respectively [4]. While originally based on the survival of non-transplanted patients, recent reports suggest that IPSS scores directly impact on survival after HSCT as well [47,48]. In an analysis of results in 251 patients transplanted at the FHCRC in Seattle, the 5-year disease-free survival was 60% among low and intermediate-1 risk patients, 36% for intermediate-2, and 28% for high-risk
patients. The major cause of failure among higher risk patients was disease recurrence, and the predominant factor within the IPSS categorization appeared to be the cytogenetic risk group [47]. Updated results are summarized in Fig. 8. These results were confirmed in a more recent cohort of older patients (described above) in whom post-transplant outcome was inversely related to the pretransplant cytogenetic risk group and the IPSS score [14]. Similar results have been reported by Neville et al. who analyzed data in 60 consecutive adult patients transplanted by the Vancouver group [48]. The 7-year relapse-free survivals for patients in the good, intermediate and poor risk cytogenetic subgroups were 51, 40 and 6%, respectively. The corresponding figures for actuarial relapse were 19, 12 and 82%, respectively. There was no difference for non-relapse mortality between the three groups. Considering these results, it appears that IPSS scores and, in particular, cytogenetic risk grouping should be incorporated into the design of new protocols. For example, patients with high-risk cytogenetic abnormalities might be prepared with a more intensive conditioning regimen, whereas patients with the same proportion of blasts but a normal karyotype would receive a low-intensity (and less toxic) regimen.
5. Transplant-associated toxicity Toxicity associated with transplantation is generally related to the transplant regimen (regimen-related toxicity [RRT]) or develops on the basis of donor-host interactions (host-vs.-graft and graft-vs.-host reactions). The latter occurs theoretically only after allogeneic transplants. RRT has been observed with virtually all conditioning regimens and in all disease settings; however, the incidence, including hepatic, renal and pulmonary toxicity, has been particularly high in patients with MDS. The reasons for this are not immediately apparent. The fact that post-transplant outcome has in general been inversely related to disease duration might suggest that supportive therapy given during that time (prior to transplant) is a contributing factor. Prolonged transfusion support, which results in iron accumulation, may lead to inflammatory and structural tissue damage in the liver and other organs. Pretransplant neutropenia is associated with an increased risk of colonization and infection with various organisms, including fungal species. The persistence of organisms such as aspergillus, despite therapy, puts these patients at high risk of potentially fatal infection after transplantation. Another factor contributing to toxicity may be the aberrant cytokine profile of patients with MDS. Many patients with MDS show high levels of pro-inflammatory cytokines including TNFa, IL-1b and others
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[49,50]. High levels of TNFa, in particular, have been shown by others to be associated with increased transplant-related morbidity and mortality [51], presumably by amplifying tissue damage inflicted by the conditioning regimen and graft-host interactions. As of now, there is no indication that adverse grafthost interactions in patients with MDS are more frequent or more severe than with other disorders. There had been concern that disease-related damage to the microenvironment may interfere with sustained engraftment and hematopoietic reconstitution. However, while an occasional patient shows impaired stroma function, this is a rare problem, and in fact, MDS derived stomal layers provide excellent support for normal hematopoiesis [52]. GVHD, either acute or chronic, also does not appear to be more frequent than with other diagnoses. This deserves to be emphasized since the median patient age in several trials has been in the range of 45 – 50 years. It is beyond the scope of this paper to describe long-term effects after HSCT for MDS. Recent reviews are available [31,53], and there is no indication that any particular late effect is specifically increased after transplantation for MDS.
5.1. Conclusions Patients diagnosed with advanced MDS who have a suitable related or unrelated donor should be transplanted early in their disease course. Patients with less advanced disease by FAB criteria (B 5% marrow blasts) but with high-risk cytogenetic findings ( − 7; complex abnormalities) or severe multilineage cytopenias according to IPSS and transfusion dependence, should also be considered for early transplantation; even patients in their 60s can be transplanted successfully. Patients with low-risk cytogenetic features (normal karyotype; -Y; 5q-; 20q-) and without severe cytopenias may do well for extended periods of time with more conservative management. Despite progress, however, many problems remain. Relapse occurs in 20 – 30% of patients with advanced disease. Infections, especially of fungal origin, frequently in association with GVHD, result in considerable morbidity and mortality. Multiorgan toxicity, often with fatal outcome, develops in 15 – 25% of patients even when transplanted for less advanced disease. Efforts must be directed at reducing organ toxicity, at improving GVHD prophylaxis, and at containing infections. Considering the data on the impact of the IPSS score, and in particular the cytogenetic risk category, regimens designed more narrowly for certain risk groups of patients (higher intensity for high risk, lower intensity for low risk) appear desirable. To what extent non-myeloablative transplant regimens can be applied in patients with MDS remains to be determined. Proto-
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cols using targeted therapy with radioisotope conjugated anti-CD45 antibody, and modalities that block the production or effect of pro-inflammatory cytokines, present at very high levels in many patients with MDS, may be helpful in further improving outcome [54]. Autologous transplant results suggest that this approach may be useful for subgroups of patients, although it is too early to offer firm recommendations. Acknowledgements This work was supported by PHS Grants CA18029, and HL36444. HJD is also supported by a grant from the Gabrielle Rich Leukemia Fund. H.J. Deeg and F.R. Appelbaum contributed to all aspects of this series, with the drafting done by H.J. Deeg. References [1] Greenberg PL. Myelodsyplastic syndrome. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P, editors. Hematology: Basic Principles and Practice. New York: Churchill Livingstone, 2000:1106. [2] Sanz GF, Sanz MA, Vallespı` T, et al. Two regression models and a scoring system for predicting survival and planning treatment in myelodysplastic syndromes: a multivariate analysis of prognostic factors in 370 patients. Blood 1989;74:395. [3] Bennett JM, Catovsky D, Daniel MT, Flandrin G, Galton DAG, Gralnick HR, Sultan C. The French – American–British (FAB) Co-Operative Group. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189. [4] Greenberg P, Cox C, LeBeau MM, et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997;89:2079. [5] Greenberg P, Bishop M, Deeg J, et al. NCCN practice guidelines for the myelodysplastic syndromes. Oncology 1998;12:53. [6] De Witte T. Stem cell transplantation in myelodysplastic syndromes (Review). Forum 1999;9:75. [7] Horowitz MM. Results of allogeneic stem cell transplantation for malignant disorders. In: Hoffman R, Benz EJ, Shattil SJ, Furie B, Cohen HJ, Silberstein LE, McGlave P, editors. Hematology: Basic Principles and Practice. New York: Churchill Livingstone, 2000:1573. [8] Anderson JE, Appelbaum FR, Schoch G, et al. Allogeneic marrow transplantation for refractory anemia: a comparison of two preparative regimens and analysis of prognostic factors. Blood 1996;87:51. [9] O’Donnell MR, Long GD, Parker PM, et al. Busulfan/cyclophosphamide as conditioning regimen for allogeneic bone marrow transplantation for myelodysplasia. J Clin Oncol 1995;13:2973. [10] Ratanatharathorn V, Karanes C, Uberti J, et al. Busulfan-based regimens and allogeneic bone marrow transplantation in patients with myelodysplastic syndromes. Blood 1993;81:2194. [11] Slattery JT, Clift RA, Buckner CD, et al. Marrow transplantation for chronic myeloid leukemia: the influence of plasma busulfan levels on the outcome of transplantation. Blood 1997;89:3055. [12] Nevill TJ, Shepherd JD, Reece DE, Barnett MJ, Nantel SH, Klingemann HG, Phillips GL. Treatment of myelodysplastic syndrome with busulfan-cyclophosphamide conditioning followed by allogeneic BMT. Bone Marrow Transpl 1992;10:445.
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