Haematologica 2002; 87:(04)ECR14
[Medline] [prev] [index] [next]Treatment of a secondary myelodysplastic syndrome
after allogenic bone marrow transplantation using
Mylotarg
Gerardo Hermida, Raquel Manjón, Isabel Rodríguez-Salazar, Carlos Richard MD*
Servicio De Hematología, Hospital "General Yagüe", Burgos; *Servicio de Hematología, Hospital Universitario "Marqués de Valdecilla", Facultad de Medicina, Universidad de Cantabria, Santander, Spain.
Correspondence: Gerardo Hermida, MD.Servicio de Hematología, Hospital "General Yagüe", Avenida del Cid 96, 09005 Burgos, Spain. Fax: +34.94.7281669. E-mail: ghermidaf@aehh.org
Mylotarg was used to treat a myelodysplastic syndrome after unrelated donor bone marrow transplantation for acute lymphoblastic leukemia.After the first dose the patient developed a mild VOD. A complete remission of MDS was achived.This result opens the possibility of treatment with Mylotarg in hematologic malignancies expressing CD33, other than AML.
In March 1997, an 8-year-old boy was diagnosed as having T-ALL with myeloid antigens (CD13 and CD33 positive). Cytogenetic study:92,XXYY. He was treated with PETHEMA LAL-93 protocol1 achiving complete remission. During maintenance therapy the leukemia relapsed without changes in morphology or inmunophenotype. He received protocol BFM-85/ALL-REZ2 without response and then high doses of cytarabine, achieving a second complete remission. Due to the lack of related HLA-matched donor, he underwent an allogeneic BMT from an HLA-matched unrelated female donor.
At that moment he was again in leukemic relapse (10% of blasts in bone marrow). After the BMT a third complete remission was achieved. The patient developed an extensive c-GVHD (skin, oral mucosa and liver), barely controlled with cyclosporine plus mycophenolate mophetil.
In April 2001 blood count was: Hgb: 10.1 g/dL; WBC: 1.8x109/L: platelets: 66x109/L. Biochemical parameters were: total bilirubin (TB): 6.2 mg/dL; AST: 178 UI/L; ALT: 150 UI/L; LDH: 458 UI/L; GGT: 407 UI/L; alkaline phosphatase (AP): 116 IU/L. Bone marrow aspiration showed 54% of myeloid cells with 6.5% of blastic cells (myeloperoxidase positive) and severe dysplasia. The blasts were only positive for CD33 and CD34 positive. The karyotype was: 46X, del(X)(q22), t(1;3)(q22;q21);-5,add(6)(q27), -7,+8,-10, add(11)(p15), del(12)(p13),add13(p13), +14,-15,del (22)(q11), +2mar (11% of abnormal metaphases). DNA studies showed mixed chimerism, with 5% of cells of host origin and 95% of donor origin (capillary electrophoresis; Figure 1). A diagnosis of secondary MDS, arisen in host cells, was made.
After informed consent of parents and agreement from the Spanish Agency of Drugs, we began therapy with Mylotarg (9 mg/m2 iv).Two days after, he presented VOD (painful hepatomegaly and ascitis). Biochemical parameters were: BT: 25.2 mg/dL, AST:565; ALT:371; LDH:839; GGT:395; AP: 2055 (UI/L). Treatment with furosemide and fluid restriction relieved the VOD. Three weeks later the patient was given a second dose of Mylotarg ( plus furosemide and hydric restriction) without complications.Two months later the hemogram showed a remarkable improvement: WBC: 5.6x109/L (normal differential count), Hgb: 12.3 g/dL, platelets: 96x109/L. TB level was 27.5 mg/dL, but ALT,AST,GOT, GPT and AP had returned to basal levels. Six months later the platelet count was 110x109/L. A bone marrow examination showed complete morphologic remission and the karyotype was 46,XX (100% of female metaphases). Chimerism analysis showed full hematopoiesis of donor origin (Figure 1).MDS has been reported in a few cases after allogeneic BMT. These disorders usually result from a malignant transformation of host cells.3,4 CD33 antigen is expresed both in commited normal and leukemic myeloid progenitor cells,but not on stem cells. Almost 30% of cases of ALL express CD33.5 Bone marrow mononuclear cells in MDS also express CD33.6 Treatment with Mylotarg (gemtuzumab ozogamicin), an anti-CD33 antibody linked to Calicheamicin,induces complete remissions in CD33(+) AML.7 The use of Mylotarg in hematologic malignancies other AML, is theorethically feasible if the cells express CD33.
To our knowledge this has never been demonstrated or even attempted.
The diagnosis of secondary MDS (RAEB) is supported by bone marrow morphology, complete immunophenotypic switching, karyotype (hyperdyploid at diagnosis and hypodiploid with typical abnormalities involved in secondary MDS/AML).8,9We do not exclude the possibility of a lineage switching of the leukemia. Molecular studies showed mixed chimerism, 5% of cells of host origin.
Due the poor prognosis of secondary MDS after BMT,9 we used Mylotarg. The characteristics of the case,with an initial diagnosis of T-ALL with CD33 expression and the clear positivity for the CD33 antigen in the blastic cells of the MDS, supported the hypothesis of a targeted activity of Mylotarg against this malignancy. Other treatments, such as AML-type chemoterapy, hematopoietic growth factors or palliative care were poorly satisfactory.
We did not stop the immunosuppresive treatment completely due to the high risk of impairment of severe c-GVHD. Donor lymphocyte infusions were underestimated because of the certain impairment of c-GVHD and a second UD-BMT was not taken into consideration.
Two months after the end of the treatment with Mylotarg blood counts and a bone marrow examinations confirmed the complete remission of MDS. The chimerism analysis showed 100% origin of hematopoiesis in donor cells.The patient remains in complete remission six months after the end of the treatment.
The use of Mylotarg has been associated with high liver toxicity and VOD.10 After the first dose,the patient developed a VOD but the use of furosemide and fluid restriction avoided the recurrence. The bilirubin level did not change and ALT and AST returned to "basal" levels.To our knowledge,this is the first case of complete remission induced by Mylotarg of a secondary MDS after BMT.
This result supports the possible use of Mylotarg in diseases other than AML, when the neoplastic cells express CD33 and the prognosis with standard treatments is poor. This could be applied to some ALL or MDS.
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