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Primary myelodysplasia occurring in adults under 50 years old: a clinicopathologic study of 52 patients

Abstract

Although myelodysplastic syndromes (MDSs) are generally thought to be diseases of elderly patients, younger patients also have rarely been diagnosed with MDS. This is a report of the clinical, morphologic and cytogenetic features of 52 cases of primary MDS occurring in adults under the age of 50 years. Cases secondary to chemotherapy or radiotherapy were excluded. There were 31 males and 21 females. The median age at presentation was 39 years (range, 18 to 49 years). The interval between onset of symptoms and diagnosis was brief (median, 4 weeks; range, 1–32 weeks). Of the 49 patients for whom information about duration of symptoms was available, 13 (27%) were asymptomatic. Forty-two (81%) of the patients were classified using FAB criteria for blood and bone marrow morphology: refractory anemia (RA), 11; refractory anemia with ringed sideroblasts (RARS), four; refractory anemia with excess blasts (RAEB), 12; chronic myelomonocytic leukemia (CMML), three; refractory anemia with excess blasts in transformation (RAEB-T), 12 patients. Ten patients could not be categorized. Abnormalities involving chromosome 7 was the most frequent cytogenetic abnormality (31%). Partial chromosomal deletion and chromosome gain were also common abnormalities (22% and 9%, respectively). Translocations accounted for only 9% of the main cytogenetic abnormalities encountered in this patient population. For the 49 patients for whom information regarding AML transformation was available, 23 (47%) progressed to acute myeloid leukemia, with an overall median time to progression of 2 months (range 3 weeks to 3 years). In each category except for RARS, approximately half of the patients progressed, with a slightly less median time to progression in RAEB-T than for the other subtypes of MDS. Thirteen patients underwent bone marrow transplantation at the time of presentation of their disease.

Introduction

Myelodysplastic syndromes (MDSs) are a group of dysfunctional hematopoietic disorders that exhibit a propensity to evolve to acute leukemia over time.1,2 They are characterized by ineffective hematopoiesis and dysplastic morphology involving one or more cell lines. MDS may occur as a consequence of marrow injury caused by chemotherapeutic agents or radiation used to treat prior benign or malignant conditions.3,4,5,6,7 More commonly, MDS may occur as a primary disorder, in which no ascertainable cause for the disease can be identified. Even in the absence of leukemic evolution, most patients with MDS succumb to infection or transfusion-related complications, such as platelet alloimmunization or iron overload.

Primary MDS has a bimodal age incidence. It has been reported to be a disease of later life, with over half of the reported patients being 70 years or older. Less commonly, primary MDS occurs in the pediatric population and includes specific pediatric syndromes such as juvenile chronic myeloid leukemia and infantile monosomy 7 syndrome.8,9,10,11,12,13,14,15 Adults under 50 years old have rarely been reported to have primary MDS. The clinical and pathologic aspects of primary MDS in younger adults and their response to bone marrow transplantation have not been widely reported. One study of 37 MDS patients, 50 years old and younger, represented 6.7% of the overall study group at one hospital.16 In a report of 109 adult patients with MDS, 14 (7%) were reported to be between 28 and 50 years old.2 Other large studies of MDS have also included rare patients under the age of 50.17,18,19,20,21 One of the largest series to date is that of Sutton and associates for the Société Française de Greffe de Moelle,22 who assessed the response of 71 patients with de novo MDS to treatment by allogeneic bone marrow transplantation. In that series, 61 patients were between the age of 15 and 50 years at the time of bone marrow transplantation. Another large series of 640 primary MDS patients included 191 (30%) patients under the age of 60 years, but how many of those patients were less than 50 years old is not known.23

Numerous risk classification systems for MDS prognosis have been reported.1,19,20,24,25,26,27,28 In 1997, a large analysis designed and carried out by several investigators resulted in the International Prognosis Scoring System (IPSS) for MDS. This prognostic score includes five variables considered important in predicting the rate of AML transformation: bone marrow blast percentage, number of cytopenias, cytogenetic subgroup, age and gender. In addition, all variables (except age) were important for predicting overall survival. In that study of 816 patients, 205 (25%) patients were under the age of 60 years, but it is not known how many of those patients were also less than 50 years old.

The purpose of this study was to further examine the clinical, cytogenetic and pathologic features of primary MDS occurring in persons under 50 years old, and to compare these features to the previously published reports of patients with primary MDS. In addition, we examined the applicability of the various prognostic indices to this group of patients.

Materials and methods

The files of the Division of Pathology at the City of Hope National Medical Center (COHNMC) were searched for patients under the age of 50 years with the diagnosis of MDS, for the years 1989–1996. Follow-up was obtained to December 1999. Patients with an antecedent history of malignancy treated with alkylating agents, topoisomerase II inhibitors, or radiation were excluded from this study. Patients with a primary diagnosis of acute myelogenous leukemia (AML), but with cytogenetic and morphologic abnormalities suspicious for the AML arising in a background of MDS, were also excluded because we could not unequivocally prove a diagnosis of antecedent MDS. Clinical data, including age at presentation, gender, duration and nature of symptoms, presence of hepatosplenomegaly, lymphadenopathy or skin rashes at presentation, type of treatment, total length of follow-up, disease status at last follow-up, and cause of death (where applicable) were obtained. In addition, we recorded whether the patient's disease transformed to acute myelogenous leukemia. Evaluation of peripheral blood parameters included presenting hemoglobin, mean corpuscular volume, white blood cell count, platelet count, and percentage of blasts. Examination of bone marrow parameters included cellularity, percentage of blasts, iron status, percentage of ringed sideroblasts, and presence or absence of fibrosis. Where possible, the tissue specimens were categorized into one of the French–American–British (FAB) subtypes of myelodysplasia:1 refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), refractory anemia with excess blasts (RAEB), chronic myelomonocytic leukemia (CMML), or refractory anemia with excess blasts in transformation (RAEB-T). Other categories included hypoplastic MDS (h-MDS) and CMML in transformation (CMML-T), both of which have been defined elsewhere in the literature.1,29,30 Cases that fit into none of the above categories were designated as unclassified MDS (MDS-U). The majority of presenting diagnostic peripheral blood and bone marrow specimens were consultative material; all had been reviewed at the COHNMC. The majority of patients were also treated at COHNMC.

Where possible, cytogenetics studies on pre-treatment bone marrow or unstimulated peripheral blood were performed using standard G-banding with trypsin-Giemsa staining. Karyotypes were interpreted according to the recommendations of the ISCN.31 A karyotype was considered normal diploid if no clonal abnormalities were detected in a minimum of 20 metaphases examined. If less than 20 metaphases were examined per case, the cytogenetic study was rejected. Cytogenetic abnormalities followed the IPSS classification. ‘Favorable’ or ‘good risk’ included −Y, del(5q), del(20q) or normal karyotype. ‘Unfavorable’ or ‘poor risk’ included chromosome 7 abnormalities and complex (>3 abnormalities) karyotype. All other clonal cytogenetic aberrations were classified as ‘intermediate risk’. Presentation studies were not available for 13 cases.

Prognostic scoring systems for MDS

Each patient was classified under the FAB classification, which is one of the most widely accepted risk classification systems for MDS. In addition, prognostic scores based on four other previously published scoring systems were assigned to each patient, including the International Prognostic Scoring System for MDS,28 the Lille prognostic score,27 the modified Bournemouth score,24,25 and the Spanish prognostic score.26 The criteria for each of these four scoring systems are listed in Table 1.

Table 1 Prognostic scoring systems

Statistical analysis

Patient demographics and clinical measurements were compared between patients who transformed to AML and those who did not, using Pearson's chi-square test and Fisher's exact test. Survival curves were calculated using the method of Kaplan and Meier, with 95% confidence intervals calculated using the logit transformation on Greenwood's variance estimate.

To evaluate patient characteristics for prediction of time from diagnosis to transformation to AML, variables thought to be relevant were analyzed using Cox proportional-hazards regression, after checking for validity of the proportionality assumption. The demographics age and gender, and the clinical measurements bone marrow cellularity, bone marrow blasts, white blood cell count, hemoglobin, hematocrit, mean corpuscular volume, and platelet count were considered as predictor variables. Receipt of bone marrow transplant was included as a time-dependent covariable. The risk ratio was calculated for each significant variable, along with the 95% confidence limits.

To determine variables that were independent predictors, variables significant at P < 0.20 were entered into a stepwise Cox regression to produce a multivariate model. Among the candidate variables were statistics that themselves were produced from published risk models (FAB, IPSS, Lille, Modified Bournemouth and Spanish). Since the risk models were likely to be highly collinear, only the most significant one was allowed to enter the stepwise model. The same techniques were repeated with the outcome disease-free survival, measured as time to relapse or death, with censoring at the date of last contact. For this endpoint, transformation to AML and receipt of bone marrow transplant were included as time-dependent covariates.

Results

Clinical findings

One hundred and eight patients between the ages of 18 and 50 years with a diagnosis of MDS were reviewed. Fifty-five (51%) of these patients had primary MDS – in other words, no previous history of malignancy for which alkylating agents, topoisomerase II inhibitors, or radiation therapy had been administered. Fifty-three (49%) of the 108 patients were found to have a treatment-related MDS, having received chemotherapy or radiation for Hodgkin's disease, AML unassociated with MDS, acute lymphoblastic leukemia, multiple myeloma, non-Hodgkin's lymphoma, or carcinoma; by definition, they were excluded from this evaluation. Follow-up was available for 52 of the 55 patients with primary MDS.

Table 2 outlines pertinent clinical and hematomorphologic data for the 52 patients. There were 31 males and 21 females. Race was distributed as follows: 33 Caucasians, 10 Latinos, seven Asian-Americans, one African-American, and one mixed Asian-Caucasian. The median age at presentation was 38.5 years (range, 18 to 49 years).

Table 2 Demographics and laboratory measurements

The median bone marrow cellularity was normal or higher than expected for age for all MDS categories, except h-MDS. The median hemoglobin value for all subcategories of MDS, except CMML, was less than normal. As expected, the median WBC and platelet counts were also low except for the two categories related to CMML. Moderate or marked fibrosis was seen in eight of 34 (24%) of the trephines stained for reticulin. An iron stain was performed on 35 marrow samples; 15 (43%) had increased amounts of iron and 11 (31%) had low to absent iron stores. The four cases of RARS had increased amount of iron, with numerous (>30%) ringed sideroblasts (by definition).

The most common presenting complaints were fatigue, weakness, headaches and recurrent infections. Six patients had recurrent upper respiratory tract infections, unresponsive to antibiotics. Of the 49 patients for whom information about duration of symptoms was available, 13 (27%) had no acute symptoms. Seven of these 13 patients were diagnosed at the time of routine physical examination or prenatal screening. Another three patients had an autoimmune disease antedating the diagnosis of MDS: immune thrombocytopenic purpura (3.5 years), systemic lupus erythematosus (5 years), or Wegener's granulomatosis (17 years). The other three patients had a single cytopenia (anemia or neutropenia) for a variable length of time (5–22 years) before acquiring a diagnosis of MDS. None of these patients had a family history of autoimmune diseases or hematologic disorders.

Physical findings were relatively uncommon. Of the 49 patients for whom this information was available, only 12 patients (24%) had findings, including nine noted to have splenomegaly (18%), five with hepatomegaly (10%), three with lymphadenopathy (6%) and three with skin rashes (6%).

For the 49 patients for whom information about AML transformation was available, 23 underwent leukemic transformation. Slightly more than half of the patients had a bone marrow transplant. The median follow-up time for the 52 patients was 16.4 months (range, 1–112). At the time of last follow-up, 20 of the 52 patients were alive, with a median follow-up time of 50.5 months (range, 1–94.2).

Cytogenetics

Cytogenetic data from the time of diagnosis were available for review in 41 of the 52 patients (Table 3). Three of the patients had insufficient material for analysis. In eight patients, there was either no growth of material or no sample. Thirty-two (78% of evaluable patients) had clonal abnormalities; abnormalities involving chromosome 7 were the most frequently observed abnormality (31%). Trisomy 8 and partial chromosomal deletion were also common abnormalities (9% and 22% of cases). Only four patients had translocations only; these all involved chromosomes 3 and 5. None of the patients had del(5q) as their sole abnormality; however, three patients had del(5q) as part of complex abnormalities.

Table 3 Summary of cytogenetic data by FAB classification

Prognostic scoring system scores

We were able to assign traditional FAB subtypes on the basis of blood and bone marrow findings to 42 (81%) of the 52 patients (Table 4). RA and RARS were diagnosed in 11 and four patients, respectively. RAEB and RAEB-T accounted for 12 patients each. Two of the patients with RAEB-T were upgraded solely on the basis of the presence of Auer rods in the blasts. The blast counts were 7.5% and 12%, respectively, in the bone marrow aspirate samples. Three patients presented with CMML. The presenting marrows of the remaining 10 patients were classified as follows: h-MDS, four; CMML-T, four; MDS-U, two. One of the patients classified as MDS-U fit the criteria for refractory cytopenia with trilineage dysplasia, a new MDS category proposed by the Reclassification Project of the World Health Organization.32 The other MDS-U patient had incomplete information or insufficient material for full peripheral blood and bone marrow evaluation.

Table 4 Frequencies and univariate statistics discarding unknown MDS by FAB score

For the 41 patients for whom peripheral blood counts, bone marrow blast counts and cytogenetic data were available, an IPSS prognostic score was assigned (Table 4). Sixteen (39%) of the patients fell into the low or int-1 risk groups, whereas 25 (61%) patients fell into the int-2 or high risk groups. For the 11 patients for whom no IPSS score was assigned, cytogenetic study was rejected in three cases (see criteria above), cytogenetic study was not carried out in six cases, and two patients had incomplete peripheral blood count and cytogenetic information.

The distributions of patients with a modified Bournemouth prognostic score, Lille score and Spanish score are also listed in Table 4. Fifty-one patients each had sufficient data for assignment of both a modified Bournemouth prognostic score and a Spanish prognostic score; 42 patients had sufficient data to receive a Lille score.

Transformation to AML

For statistical purposes, two patients with MDS-U were eliminated from analysis. Forty-nine patients had clinical information regarding AML transformation. Of these, 23 (47%) patients developed AML. Twenty-two of the 23 (96%) patients progressed to AML before initiation of induction chemotherapy or conditioning chemotherapy for BMT, with a median time of AML development of 2 months (range, 0.5–36 months). The other patient who developed AML received hydroxurea at the time of diagnosis of CMML-T; his AML progression occurred within 1 month. For purposes of statistical analysis, the FAB groups RA, RARS, and h-MDS were combined into a single group (‘low risk’), RAEB and CMML were combined into another group (‘intermediate risk’), and RAEB-T and CMML-T were combined into the final group (‘high risk’). Four of 19 patients (21%) in the ‘low risk’ FAB diagnosis category transformed to AML. In contrast, nine of 16 (56%) patients with RAEB or CMML, and 10 of 15 (67%) patients with RAEB-T or CMML-T transformed to AML. As shown in Table 5, by univariate Cox regression, the significant predictors of time to transformation were age at diagnosis (P = 0.05), percentage of bone marrow blasts (P = 0.0001), hematocrit (P = 0.02), and FAB diagnosis grouping (P = 0.001). Time to AML transformation was also statistically significantly associated with IPSS and Lille scores (P = 0.01 and P = 0.01, respectively). The modified Bournemouth prognostic score and a Spanish prognostic score were not associated with AML transformation (P > 0.25). By stepwise Cox regression, only the FAB classification significantly predicted time to AML transformation (P = 0.001, Table 6). Disease-free survival (DFS) is shown in Figure 1. Two-year and 5-year survival rates for the group of 52 patients were 46% (95% confidence interval (CI) 34–62%) and 33% (95% CI 22–50%), respectively. Disease-free survival is also shown separated by FAB grouping in Figure 2, with RA/RARS/h-MDS showing significantly better disease-free survival by Mantle–Haenszel log-rank analysis than the other two groupings (P = 0.004). Table 7 shows the univariate Cox regression results for disease-free survival. Because most of the patients were referred from other institutions over a long period of time, their treatment varied greatly. The survival statistics do not account for the variation in type or timing of therapy. Age at diagnosis was predictive of disease-free survival (P = 0.002). The relative risk of death or relapse, respectively, increased by nearly two-fold with each successive decade. Disease-free survival was also statistically associated with the percentage of bone marrow blasts (P = 0.001), increased WBC (P = 0.0008), and FAB diagnosis grouping (P = 0.007). The other prognostic scoring systems were not statistically significantly predictive of disease-free survival. In addition, AML transformation (as a time-dependent variable) was statistically significantly associated with disease-free survival (P = 0.0009), with AML transformation having a greater than three-fold risk of relapse compared to those patients whose disease did not undergo transformation. Bone marrow transplantation was also statistically significantly associated with relapse as a time-dependent variable (P = 0.03).

Table 5 Univariate Cox regressions with outcome: months from diagnosis to transformation
Table 6 Stepwise Cox regressions to determine predictors of time from diagnosis to transformation to AML: final model after controlling for variables listed in the univariate analyses (n = 49)
Figure 1
figure1

Disease-free survival.

Figure 2
figure2

Disease-free survival separated by FAB categories.

Table 7 Univariate Cox regressions with outcome: disease-free survival in months

By stepwise Cox regression (Table 8), WBC, transplantation and age were significant independent predictors of disease-free survival (P = 0.001). Time to AML transformation was not significantly associated with disease-free survival after adjusting for WBC, transplantation, or age.

Table 8 Stepwise Cox regression to determine predictors of disease-free survival: final model after controlling for variables listed in the univariate analyses (n = 50)

Discussion

This study was designed to focus on primary or de novo MDS, although we did see an equivalent number of treatment-related MDS patients during the same time period. None of our patients had rare forms of MDS, including HIV-related MDS or ‘hyperfibrotic’ MDS.33,34,35,36,37 Unlike a previous study of primary MDS in adults less than 50 years old, we found no patients with a familial form of MDS and no patients with a known occupational exposure to toxins.16

Fifty-eight percent of our patients were between 18 and 40 years old, a higher percentage than found in the study by Fenaux and associates.16 This relatively increased percentage of young patients most likely represents the increased awareness of diagnosing this entity in younger patients, perhaps because of improved therapeutic options compared to 10 years ago.16

Patients with MDS have been reported to have impaired immunity in several forms, including an increased susceptibility to infection and autoimmune disease, as well as an increased incidence of non-hematopoietic malignancies.38 In this study, six patients presented with recurrent upper respiratory tract infections. One patient had antecedent systemic lupus erythematosus, and another had antecedent idiopathic thrombocytopenic purpura. None of the patients in this study had an associated solid tumor. The low proportion of immunodeficiency-associated problems in this study most likely relates to the lower age of our population compared to the typical elderly MDS population, whose age may contribute to their weakened immune states.

Over half of the patients in this study had advanced disease (RAEB, RAEB-T, and CMML-T). This is similar to a previous study of primary MDS in adults 50 years or younger,16 but is in contrast to the demographics in studies of MDS in older patients, which indicate that RAEB and in RAEB-T represent only 30–35% of all MDS types.39 However, because the current study population, as well as those in the Fenaux study, are derived from patients referred to centers that focus on bone marrow transplants, there may be a selection bias favoring referral of patients with more clinically aggressive disease by hematologists in the community. Four patients had well-documented cases of RARS, a subtype not described in other studies with young MDS patients.2,18,39

Ten of the 52 patients (19%) in this study had abnormalities that did not conform to any of the five traditional categories of the FAB classification of MDS. Four of the patients had the well-recognized MDS variant of hypoplastic MDS, defined as having a cellularity of less than 25–30%.29,30 The difficulties in distinguishing this MDS variant from aplastic anemia include scant amounts of marrow for analysis and somewhat similar morphologies. In this study, three of the four patients with h-MDS were initially diagnosed with aplastic anemia, but the presence of a chromosomal abnormality (eg −Y, +8, inv(17)) and clinical behavior favored MDS. The other patient was diagnosed only after extended treatment for aplastic anemia did not succeed; this patient later developed an abnormal del(6q) clone, which may have been therapy-related. Many studies show no prognostic value to hypocellularity, although two of the h-MDS patients in this study had poor clinical outcomes. Another four patients with non-conventional MDS presented with CMML with >20% blasts. On the basis of increased monocytes and increased numbers of blasts, they were diagnosed as CMML-T, a category used by many investigators.40

Seventy-eight percent of our study population had cytogenetic abnormalities, similar to the number reported in the Fenaux series,39 and a slightly higher incidence than the 30–50% described in other de novo MDS studies.28,41 In this study, over 40% of the cytogenetic abnormalities were due to complete or partial chromosomal loss, which is similar to previous reports that cite approximately half of the chromosomal abnormalities to be due to chromosomal loss.42 The high percentage of monosomy 7 is more similar to cases of de novo MDS in adults >50 years old than to younger adults in the study of Fenaux et al.16 Chromosomal gain consisted exclusively of cases of trisomy 8, which is the most common chromosomal gain in de novo or acquired MDS. Interestingly, all four translocations involved t(3;5); these have been presented elsewhere.43,44 In addition, the percentage of patients (35.7%) in poor cytogenetic risk groups was far greater in our study compared to the IPSS study,28 but similar to another large study of primary MDS, which found 51% of patients to have clonal karyotypic abnormalities.23

For the 49 patients for whom information regarding leukemic transformation was available, 23 (47%) progressed to acute myeloid leukemia, with an overall median time to progression of 2 months (range, 1–36 months). In each category except for RARS, approximately half of the patients progressed, with a slightly less median time to progression in RAEB-T than for the other subtypes of MDS. The percentage of AML transformation is greater than seen in other studies of young adult MDS, and is also greater than in pediatric patients with the specific MDS subtype of juvenile chronic myelogenous leukemia. Similar to other studies, none of the patients in this series transformed to acute lymphoblastic leukemia.45,46

The recently published IPSS for MDS has been shown to be an improved method for evaluating prognosis of patients with MDS. The percentage of our patients who fell into the int-2 or high risk IPSS groups (61%) was significantly greater than the percentage of patients <60 years in the equivalent groups in the IPSS study (28%), and also significantly greater than all patients (29%) in the IPSS study, which again may represent selection bias for referral of high-risk patients to a tertiary bone marrow transplantation center. The IPSS and Lille prognostic systems were found to have statistically significant predictive value for time to AML transformation, but the other scoring systems did not have statistical significance for our patient population. Other studies of the predictive value of prognostic systems for MDS have also found differences in the applicability of prognostic systems for individual cases.23,47

In summary, the clinical, pathologic and cytogenetic features of primary MDS in younger adults appear to be different than those in elderly patients, suggesting that this may represent a biologically different disease. The high proportion of primary MDS transforming to AML in patients <50 years also represents an area for study of transforming events affecting hematopoietic stem cells. While the IPSS score appears somewhat predictive of transformation, more young patients need to be assessed to determine whether this system will be of prognostic utility in this patient population.

The overall poor outcome for patients with primary MDS, particularly those with increased blast percentage, indicates a need for innovative treatment strategies, as well as techniques to protect stem cells from injury by known injurious agents such as radiation, alkylators and epipodophylotoxins. Further molecular and biologic investigation may uncover unique alterations that result in the clinical aggressiveness of this set of diseases.

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Correspondence to KL Chang.

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Chang, K., O'Donnell, M., Slovak, M. et al. Primary myelodysplasia occurring in adults under 50 years old: a clinicopathologic study of 52 patients. Leukemia 16, 623–631 (2002). https://doi.org/10.1038/sj.leu.2402391

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Keywords

  • myelodysplastic syndromes
  • bone marrow transplantation
  • younger adults

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