|
|||||||||
|
|
|
|
|
|
|
|
|
|
|
CORRESPONDENCE We read with great interest the report of Latagliata et
al1 on therapy-related myelodysplastic syndrome (t-MDS) and
acute myelogenous leukemia (t-AML) following treatment of acute
promyelocytic leukemia (APL). The authors observed 5 out of 77 patients
with APL, who after intensive chemotherapy including
all-trans retinoic acid (ATRA) relapsed with MDS or AML
while in molecular remission of APL. Before relapse progressive
cytopenia was observed in all 5 patients and at relapse, a phase of MDS
was verified in 4. Three of the patients presented new, cytogenetically
unrelated clones. The authors conclude that all 5 cases are induced by
idarubicin, mitoxantrone, and etoposide used as induction therapy or by
alkylating agents used before autologous stem cell transplantation in
2 patients. The chemotherapy regimen administered as frontline therapy for APL
included 3 courses of idarubicin with a total cumulative dose of
80 mg/m2 and one single course of mitoxantrone and
etoposide, all topoisomerase II inhibitors, plus cytosine-arabinoside,
plus ATRA. Maintenance treatment was methotrexate plus
6-mercaptopurine, and in some instances ATRA. This regimen is not
suspected to be extremely leukemogenic. Cases of relapsing APL were
reinduced with mitoxantrone and cytosine-arabinoside, were conditioned
with alkylating agents, and received an autologous stem cell
transplantation. Following such a procedure, the risk of t-MDS and
t-AML has been shown mainly to depend on the cumulative dose of
alkylating agents and topoisomerase II inhibitors administered as
primary therapy before transplantation.2 The 2 patients
with t-MDS or t-AML receiving autologous stem cell transplantation for
APL were apparently not heavily pretreated. Previously, close associations have been observed between therapy with
alkylating agents and development of t-MDS with deletions or loss of 5q
or 7q; and between therapy with topoisomerase II inhibitors and
development of t-AML with the recurrent balanced translocations, most
often to chromosome bands 11q23 and 21q22. Results from our studies of
49 consecutive cases of t-MDS or t-AML diagnosed in 7 closely followed
cohorts of patients receiving intensive chemotherapy3 are
shown in Table 1.
In the study by Latagliata et al1 none of the 5 relapsing patients presented any of the recurrent balanced chromosome abnormalities characteristic of t-AML following therapy with topoisomerase II inhibitors. Furthermore, the patient relapsing with monosomy 7 had not received alkylating agents. This raises doubt about the origin of the relapses of MDS or AML, at least in 4 of the 5 patients discussed, and questions the postulated extremely high risk of t-MDS and t-AML after therapy of APL. Relapse of leukemia, for instance AML, with a cytogenetically unrelated clone is a well-described phenomenon.4,5 Previously, authors have been very cautious to classify such cases as therapy-induced. Rather, a shift of karyotype with the same underlying stem cell disease has been considered. This possibility was emphasized in one of the reports on MDS following successful therapy of APL.6 A similar phenomenon with development of unrelated clones, sometimes also with loss of 5q or 7q, has been observed following therapy of CML with interferon alpha7 or imatinib mesylate8 without any previous chemotherapy. Gene-based therapy such as ATRA or imatinib mesylate may facilitate a complete shift of karyotype in myeloid malignancies with a common underlying stem cell abnormality. In the future, it is recommended that cases of MDS and AML, as described by Latagliata et al, are considered as therapy-induced, only if molecular studies have ascertained an independent origin.
Mette Klarskov Andersen and Jens Pedersen-Bjergaard
References
1.
Latagliata R, Petti MC, Fenu S, et al.
Therapy-related myelodysplastic syndrome-acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem.
Blood.
2002;99:822-824
2.
Pedersen-Bjergaard J, Andersen MK, Christiansen DH.
Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation.
Blood.
2000;95:3273-3279 3. Pedersen-Bjergaard J, Philip P, Larsen SO, et al. Therapy-related myelodysplasia and acute myeloid leukemia: cytogenetic characteristics of 115 consecutive cases and risk in seven cohorts of patients treated intensively for malignant diseases in the Copenhagen series. Leukemia. 1993;7:1975-1986[Medline] [Order article via Infotrieve]. 4. Garson OM, Hagemeijer A, Sakurai M, et al. Cytogenetic studies of 103 patients with acute myelogenous leukemia in relapse. Cancer Genet Cytogenet. 1989;40:187-202[CrossRef][Medline] [Order article via Infotrieve]. 5. Estey E, Keating MJ, Pierce S, Stass S. Change in karyotype between diagnosis and first relapse in acute myelogenous leukemia. Leukemia. 1995;9:972-976[Medline] [Order article via Infotrieve]. 6. Bseiso AW, Kantarjian H, Estey E. Myelodysplastic syndrome following successful therapy of acute promyelocytic leukemia. Leukemia. 1997;11:168-173[CrossRef][Medline] [Order article via Infotrieve]. 7. Fayad L, Kantarjian H, O'Brien S, et al. Emergence of new clonal abnormalities following interferon-alpha induced complete cytogenetic response in patients with chronic myeloid leukemia: report of three cases. Leukemia. 1997;11:767-771[CrossRef][Medline] [Order article via Infotrieve]. 8. Andersen MK, Pedersen-Bjergaard J, Kjeldsen L, Dufva IH, Brondum-Nielsen K. Clonal Ph-negative hematopoiesis in CML after therapy with imatinib mesylate is frequently characterized by trisomy 8. Leukemia. 2002;16:1390-1393[CrossRef][Medline] [Order article via Infotrieve].
Response:Independent clonal origin of therapy-related MDS-AML developing after treatment of acute promyelocytic leukemiaWe thank Drs Andersen and Pedersen-Bjergaard for their interesting comments about our recently reported article on secondary (therapy-related) myelodysplastic syndrome-acute myelogenous leukemia (sMDS-AML) developing after treatment for acute promyelocytic leukemia (APL).1 The authors outlined some presumed discrepancies between cytogenetic lesions and previous antileukemic drug exposure in our cases, as compared to those reported in the literature and observed in their own experience in postalkylating and topoisomerase II inhibitor-induced sMDS-AML. In particular, Andersen and Pedersen-Bjergaard remarked the inconsistency in our series of specific cytogenetic aberrations that should have been expected based on the previously received antileukemic agents. Based on these considerations, they raised doubts about the true nature of our MDS-AML cases and hypothesized the possible development, rather than sMDS-AML, of leukemia relapse with karyotypic shift toward a more immature phenotype, yet originating from a common stem cell with respect to the APL clone. For a number of reasons, we believe that our cases were true sMDS-AML. First, the existence of an MDS phase preceding sAML (in 4 of 5 cases), coupled with the extremely poor response to anti-AML therapy, was rather characteristic of sAML, at least from a clinical viewpoint.1 In this respect, we remark that patient 2 described in our series as alive with sMDS1(Tab2) subsequently developed sAML and died recently of resistant leukemia. As for the patient with no MDS preceding sAML, at the time of sAML development this patient showed a balanced chromosome translocation t(10;11), although not apparently involving the MLL gene, as it would be predicted for topoisomerase II inhibitor-induced leukemia. We would also like to comment that, in spite of the reported statistically significant associations between sMDS-AML karyotype lesions and previous chemotherapeutic agent type, such correlations are not absolute, as clearly shown in the table reported by Andersen and Pedersen-Bjergaard. Besides these considerations, we had the possibility to better
investigate the clonal relationships between the APL and the subsequent
AML phase in one of our patients. In fact, marrow RNA samples from both
the initial APL and subsequent AML phases (previously used for
PML/RAR
On the other hand, we agree with Andersen and Pedersen-Bjergaard's comments regarding several still unsolved issues on sMDS-AML after APL, which may be the subject of future investigation. For example, the true incidence of this severe complication is not assessed in our study and deserves to be established through tailored studies analyzing the cumulative incidence of this event taking into account all competing factors (death, APL relapse, and so forth). Finally, it remains to be clarified why sMDS-AML with alkylating agent-induced karyotypic features might occur in patients who did not receive such agents. We are prone to believe that, because anthracyclines and mitoxantrone (heavily employed in APL therapy) not only act as topoisomerase II inhibitors but are also known to intercalate the DNA strand, these drugs may result in similar DNA damage as produced by alkylating agents, thus inducing in some cases alkylating agent-type karyotypic aberrations.
Francesco Lo Coco, Roberto Latagliata, Daniela Diverio, Massimo Breccia, Patrizia Chiusolo, and Franco Mandelli
References
1.
Latagliata R, Petti MC, Fenu S, et al.
Therapy-related myelodysplastic syndrome-acute myelogenous leukemia in patients treated for acute promyelocytic leukemia: an emerging problem.
Blood.
2002;99:822-824
2.
El-Kassar N, Hetet G, Briere J, Grandchamp B.
Clonality analysis of hematopoiesis in essential thrombocythemia: advantages of studying T lymphocytes and platelets.
Blood.
1997;89:128-134   CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
Related Article in Blood Online:
This article has been cited by other articles:
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|||||||
 |
 |
 |
 |
 |
 |
 |
 |
||
| Copyright © 2002 by American Society of Hematology Online ISSN: 1528-0020 | |||||||||
testing) were still available in 2 females, 1 of
which (patient 2 in our series
X 174 DNA/BsuRI).
