Evolution Of

Theories of MDS evolution in the context of the pathophysiology of AA

A fundamental question in the evolution of clonal disease in AA is whether its pathophysiology is intrinsic to the natural history of AA, and now only observed, as patients survive longer, due to effective therapies. Alternatively, clonal evolution may be secondary to the treatment of AA, as a complication of IS therapy, or more recently, due to chronic growth factor administration. Theoretically, inhibition of immune surveillance could lead to the uncontrolled outgrowth of abnormal clones. However, MDS has occurred in AA treated with androgens only,104 105 arguing against the theory that the clonal evolution to MDS is a consequence of immunosuppression. In addition, patients with primary MDS have been treated with IS agents and no acceleration of the disease has been observed.36 106 107 While prolonged G-CSF treatment was linked by Japanese investigators to the evolution of monosomy 7,105,108-110 there was no increased risk observed in a randomized study of ATG and CsA with and without G-CSF111 or in the analysis of the European Group for Blood and Marrow Transplantation (EBMT)

data.112 In a National Institutes of Health (NIH) study,34 many of the AA patients who developed cytogenetic abnormalities received hematopoietic growth factors, mainly as support or as salvage therapy after unsuccessful immunosuppression, and refractory disease itself may be the underlying risk factor for clonal evolution.

Diagnosis of evolution, its frequency, and timing

The relationship between AA, a disease dominated by an immune pathophysiology similar to other organ-specific autoimmune diseases, and MDS, usually viewed as a pre-malignant process, remains unclear in many clinical and pathophysiologic aspects. Aberrant differentiation of hematopoietic precursor cells, increased numbers of myeloblasts, and marrow hypercellularity are all characteristic of MDS, but persistent bone marrow hypocellu-larity in AA may preclude reliable morphologic analysis. Clinical similarities between MDS and AA are most obvious in the hypocellular form of dysplasia, and clinical distinction is often not possible.

The development of MDS in the setting of diagnosed AA has been described in several studies, but these vary significantly in their design, and especially in case definition,12'109'113-118 exemplifying diverse views with respect to the criteria required for the diagnosis of both MDS and AA. In historical studies of AA, patients with abnormal cytogenetics and hypoplastic marrows at presentation were often included,119-122 and in some institutions, abnormal cytogenetic studies are compatible with a primary diagnosis of AA.104,122-124

Most commonly, abnormal cytogenetics was felt to exclude a diagnosis of AA, regardless of marrow morphology; in a series from the NIH involving 122 patients treated with intensive immunosuppression consisting of ATG and CsA, all patients showed a normal karyotype at presentation, and 14 subsequently developed karyotypic abnormalities, with a risk of about 21% at 10 years. Only two patients were diagnosed as having a late MDS by marrow morphology alone, with normal chromosomes.119 In an early study from Seattle, an abnormal karyotype was reported in 7 of 183 AA patients, but only 3 of these developed after immunosuppression.104 The differences in the diagnostic criteria are also obvious, such as in a recent analysis by the EBMT AA Working Party, in which karyotypic abnormalities occurred in 23 of 170 patients, but in 4 cases chromosomal changes were present at first diagnosis119 and would be classified as MDS at other institutions. Similarly, in a recent British series of 13 patients with AA and abnormal cytogenet-ics, only 2 presented with normal karyotype and later developed an abnormality.123 In a study of 159 children with AA from Japan, the authors identified 6 patients with the diagnosis of "AA with cytogenetic abnormalities."122 In another cohort compiled of 100 patients from the GITMO (Gruppo Italiano Trapianto di Midollo Osseo) and EBMT study involving anti lym phocyte globulin (ALG), CsA, prednisone, and G-CSF, during a median follow-up of 1424 days, 11 patients developed cytogenetic abnormalities.125 In the interval of 11 years, 8% of patients enrolled in the randomized ATG +/- CsA study developed MDS or AML.126

The evolution of an abnormal karyotype has also been reported in children. In a series of 114 pediatric patients from Europe, 7 developed chromosomal abnormalities but the aberrant clone was retrospectively found in 2 at presentation,127 decreasing the true evolution rate in this study to 5/114. Among 40 Japanese pediatric patients treated with G-CSF and CsA, 11 showed clonal evolution, mainly to monosomy 7.109 Recently, the same group reported on the development of MDS or AML in 5 of 41 children treated with immunosuppression for their hepatitis-associated AA.128

After clonal evolution, marrow morphology was characterized by a predominance of hypercellularity (41%) and patchy biopsy cellularity (27%), while continued hypocellularity was found in 1/3 of the patients. Frank dysplasia, including changes in megakaryocyte morphology, was found in 15 of 29 patients, and a left shift in myeloid differentiation was observed in 12. However, in 9 of 29 patients, there were no morphologic changes suggestive of MDS.34 While the entity of AA with cytogenetic abnormalities may exist, the new appearance of a karyotypically abnormal clone in the course of AA warrants the change of current diagnosis of AA to MDS. In a recent NIH analysis, patients with AA were followed with periodic cytogenetic analyses of marrows, and evolution of abnormal karyotypes was identified in 29 patients (a total of 189 patients were analyzed), allowing for the estimation of the evolution rate of 14% in 5 years and 20% in 10 years, respectively.34 While the detection of a new cytoge-netic abnormality is a stringent diagnostic sign, it may not reflect the total rate of MDS evolution in AA. In primary MDS, the proportion of patients with a normal karyotype is 40-60%, and by analogy, it is possible that also in post-AA, MDS can evolve without overt chromosomal damage.

Risk factors

As various types of MDS and clonal abnormalities may have different underlying pathophysiologies, it may be difficult to identify specific risk factors for progression to clonal disease. For example, mono-somy 7 appears to evolve in primary refractory patients or those with incomplete responses to immunosuppression, while trisomy 8 was observed in patients whose counts improved adequately.34 A similar clinical observation was made for the 13q- abnormality.129 In another study, a similar distribution of clonal evolution between responders and nonrespon-ders and monosomy 7 was observed in both groups of patients.127

Chromosomal abnormalities

The most commonly found cytogenetic abnormalities following AA were aberrations of chromosome 7 and trisomy 8. For example, in a study from Seattle, monosomy 7 was found in three and trisomy 8 in two of seven patients with karyotypic abnormalities104 and, in a Dutch series, in three of five AA patients who evolved to MDS.114 In a recent report from Japan, a series of 9 patients with 13q- following otherwise typical AA was reported129; in the NIH experience, 13q— was also reported in several of the 29 patients who developed an abnormal karyotype after AA.34 In agreement with the Japanese report, both patients showed stable counts and a good response to immunosuppression. In a study of children in Japan, monosomy 7 occurred at the highest frequency,130 and in children reported from Germany and Austria, monosomy 7 was present in two of seven patients, while trisomy 8 was encountered once.127 In a long-term update of the NIH ATG/CsA trial, aberrations of chromosome 7 were present in 10 and trisomy 8 in 2 out of 13 patients.81 All other abnormalities appear to occur more randomly, and given the overall low number of patients reported, it is difficult to establish individual frequencies.

There are no predictive factors to identify patients at risk for the clonal evolution of myelodysplasia. In retrospect, blood counts of patients at the time of the cytogenetic evolution to trisomy 8 were significantly higher than those of patients with monosomy 7. Additionally, even after evolution to trisomy 8, sustained improved blood counts were often dependent upon continued CsA administration. Patients with monosomy 7 and those with complex karyotypes usually (but not always) had a poor response to immuno-suppression and persistent pancytopenia.34

Although the appearance of a cytogenetic abnormality in a patient with AA is strong evidence of clonal evolution to MDS, in some studies a high proportion of apparently transient chromosomal changes would diminish the diagnostic and prognostic implications of new cytogenetic findings. Conversion to a normal karyotype is not a frequent event, and may also be a function of the frequency of marrow examinations. In our previously published study,34 such an event was observed in only 2 of 29 patients, but since publication of this report another patient reverted (unpublished observation). It is likely that abnormal clones may be recruited and contribute to blood production for limited periods of time.


MDS, evolving from AA, and primary MDS differ in the distribution of specific cytogenetic abnormalities. In primary MDS, aberration of chromosome 5 is generally cited as the most frequent abnormality, present in 10-37% of all patients,131-136 but this chromosome is only rarely affected in AA patients. 20q— and — Y also are more often abnormal in primary MDS in compari son to AA.131,133 Conversely, monosomy 7, most prominent in the late evolution of MDS from AA, occurs in a minority of primary MDS (6.5-11%).12'131'134-138 Trisomy 8 appears to have a comparable incidence among cytogenetic abnormalities evolving from AA and in primary MDS (6-20%131-138).

Clearly, the diagnosis of MDS in the course of AA has prognostic significance. Most obvious modifiers include the presence of blasts, a hypercellular bone marrow, certain types of defects, and recurrence or persistence of profound cytopenia, all constituting unfavorable prognostic markers. For example, in one report, AA patients who developed secondary chromosomal abnormalities had a mortality rate of about 27% with a mean follow-up after evolution of 29 months (from the initial diagnosis, the total observation interval was 70 months). All but two deaths were related to AML.34 Response to immunosuppression in patients with aplasia and abnormal karyotypes may be as high as 50%,122 and certain karyotypic abnormalities (trisomy 8, 13q—) may favorably respond to immunosuppression. While the low numbers of patients reported preclude generalization, no individual abnormality predicted unresponsiveness. However, certain types of chromosomal defects are less likely to benefit from immunosuppression, including monosomy 7, complex karyotypes or 5q— syndrome. A stem cell transplantation may be the only therapeutic option for patients affected.

0 0

Post a comment