The CD33 antigen is highly expressed on acute promyelocytic leukemia (APL) cells, so the monoclonal anti-CD33 antibody, gemtuzumab ozogamicin, is currently used as a treatment option for relapsed APL after all-trans retinoic acid (ATRA)-containing regimens.1 Previous data indicated that a positive reaction on the reverse transcription-polymerase chain reaction (RT-PCR) test for the mRNA of PML-RARα after consolidation treatment could be highly predictive of hematological relapse.2 It has been proposed that salvage therapy should be started when the mRNA of PML-RARα converts to positive rather than delaying treatment until morphological relapse.3 The effect of gemtuzumab ozogamicin treatment for patients with APL who have relapsed at the molecular level has been demonstrated.4 Here, we present a 45-year-old female with APL admitted to the Department of Hematology, Hamanomachi Hospital. She achieved a complete remission with ATRA plus chemotherapy, being consolidated with three courses of intermediate-dose cytarabine combined with anthracyclines, as described previously.5 She was administered intermittent ATRA orally for 12 months as maintenance therapy.6 Bone marrow samples were collected at 3-month intervals for the identification of relapse. The determination of gene expression by RT-PCR of PML-RARα mRNA was performed at the Center for Molecular Biology and Cytogenetics Gene Analysis Section, SRL Inc. A negative result of RT-PCR was defined as the absence, on ethidium bromide-stained electrophoresis gel, of the specific PML/RARα amplification band detected at diagnosis, in the presence of RNA integrity, as evaluated by minigel visualization, and successful amplification of the internal control.4 A positive result of RT-PCR was defined as the reappearance on the gel of the same amplification band detected at diagnosis. Molecular remission was defined as a normal bone marrow cellularity with less than 5% leukemic cells and negative results for RT-PCR of PML-RARα mRNA. After 12 months from the last consolidation, the patient maintained hematological remission, while mRNA of PML-RARα was detected in a bone marrow sample. Then, she received arsenic trioxide (ATO) at a dose of 0.15 mg/kg/day for 30 consecutive days as a salvage therapy. However, mRNA of PML-RARα was still detected in a bone marrow sample. There was no evidence of disease at the morphologic analysis, so molecular relapse was diagnosed as the conversion from a negative to positive test of RT-PCR for PML/RARα detected in two successive bone marrow samples, as described previously.7 After obtaining informed consent, she received gemtuzumab ozogamicin at a dose of 9 mg/m2 to achieve molecular remission. Low molecular weight heparin and ursodeoxycholic acid were administered to prevent veno-occlusive disease. The next day, the elevation of transaminase (AST/ALT=141/138 IU/l) was shown, becoming normalized for 1 week. Thrombocytopenia lower than 30 × 109/l occurred 4 days after gemtuzumab ozogamicin, which recovered to over 100 × 109/l 10 days after gemtuzumab ozogamicin administration. Neutropenia (below 0.5 × 109/l) occurred 7 days after gemtuzumab ozogamicin and remained for 11 days. Bone marrow findings at 14 days after gemtuzumab ozogamicin administration showed granulocytic aplasia, while erythropoiesis and megakaryopoiesis had almost recovered. Her condition was complicated with febrile neutropenia, leading to administration of G-CSF (filgrastim) at a dose of 100 μg/m2/day combined with antibiotics from 14 to 18 days after gemtuzumab ozogamicin. The CD34+ hematopoietic cells in the peripheral blood showed 22/μl at 21 days after gemtuzumab ozogamicin administration. Twelve hours after administration of filgrastim at 400 μg/m2/day, peripheral blood CD34+ hematopoietic cells (1.93 × 106 cells/kg) were harvested using the COBE Spectra cell separator for 2 consecutive days. Neither the bone marrow nor the harvested sample showed the presence of PML-RARα mRNA using RT-PCR. After 98 days following gemtuzumab ozogamicin administration, she maintained hematological remission in the absence of PML-RARα mRNA. Then, she received a conditioning regimen consisting of high-dose cytarabine, high-dose etoposide and busulfan combined with G-CSF.5 She received autologous SCT, of which the interval from gemtuzumab ozogamicin administration was 112 days. Granulocyte engraftment (the first day of three consecutive measurements of a neutrophil count over 500/μl) occurred on day 17 after transplantation. The platelet count rose to over 20 000/μl on day 14 after transplantation. She has maintained hematological remission in the absence of PML-RARα mRNA in the bone marrow for 15 months after transplantation.
This is the first reported case whereby peripheral blood CD34+ hematopoietic cells were harvested during hematological recovery after the administration of gemtuzumab ozogamicin. In this case, although gemtuzumab ozogamicin was administered in the state of hematological remission, the myelosuppression was prominent. Then, in the early periods of granulopoietic recovery, the CD34+ hematopoietic cells were clearly mobilized in the peripheral blood. As a result, in association with G-CSF, CD34+ hematopoietic cells could be harvested, and hematological reconstitution was established after autologous transplantation. It is true that ATO might be the first choice for relapsed APL because of its high efficacy and safety.8 However, on the assumption that a patient is refractory or contraindicated for ATO, it is reasonable to take into consideration gemtuzumab ozogamicin or allogeneic transplantation. A curative effect of autologous SCT for relapsed APL has been demonstrated if it is performed during the second remission at the molecular level.9 So, we suggest that achieving molecular remission using gemtuzumab ozogamicin might facilitate a cure via autologous SCT in such a clinical setting. It is important to note that gemtuzumab ozogamicin could lead to sinusoidal obstruction at a higher rate if SCT is performed.10 We waited to perform the transplantation procedure carefully after gemtuzumab ozogamicin treatment, on the grounds of the high risk of developing veno-occlusive disease if transplantation is conducted within 3.5 months of gemtuzumab ozogamicin treatment.10 However, we should point out the fact that relapse may occur when more than 3 months have passed following gemtuzumab ozogamicin treatment, as reported.4
Petti MC, Pinazzi MB, Diverio D, Romano A, Petrucci MT, De Santis S et al. Prolonged molecular remission in advanced acute promyelocytic leukaemia after treatment with gemtuzumab ozogamicin (Mylotarg CMA-676). Br J Haematol 2001; 115: 63–65.
Jurcic JG, Nimer SD, Scheinberg DA, DeBlasio T, Warrell Jr RP, Miller Jr WH . Prognostic significance of minimal residual disease detection and PML/RAR-alpha isoform type: long-term follow-up in acute promyelocytic leukemia. Blood 2001; 98: 2651–2656.
Lo-Coco F, Breccia M, Diverio D . The importance of molecular monitoring in acute promyelocytic leukaemia. Best Pract Res Clin Haematol 2003; 16: 503–520.
Lo-Coco F, Cimino G, Breccia M, Noguera NI, Diverio D, Finolezzi E et al. Gemtuzumab ozogamicin (Mylotarg) as a single agent for molecularly relapsed acute promyelocytic leukemia. Blood 2004; 104: 1995–1999.
Gondo H, Harada M, Miyamoto T, Takenaka K, Tanimoto K, Mizuno S et al. Autologous peripheral blood stem cell transplantation for acute myelogenous leukemia. Bone Marrow Transplant 1997; 20: 821–826.
Fenaux P, Chastang C, Chevret S, Sanz M, Dombret H, Archimbaud E et al. A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999; 94: 1192–1200.
Lo Coco F, Diverio D, Avvisati G, Petti MC, Meloni G, Pogliani EM et al. Therapy of molecular relapse in acute promyelocytic leukemia. Blood 1999; 94: 2225–2229.
Sanz MA, Fenaux P, Lo Coco F, European APL Group of Experts. Arsenic trioxide in the treatment of acute promyelocytic leukemia. A review of current evidence. Haematologica 2005; 90: 1231–1235.
de Botton S, Fawaz A, Chevret S, Dombret H, Thomas X, Sanz M et al. Autologous and allogeneic stem-cell transplantation as salvage treatment of acute promyelocytic leukemia initially treated with all-trans-retinoic acid: a retrospective analysis of the European acute promyelocytic leukemia group. J Clin Oncol 2005; 23: 120–126.
Wadleigh M, Richardson PG, Zahrieh D, Lee SJ, Cutler C, Ho V et al. Prior gemtuzumab ozogamicin exposure significantly increases the risk of veno-occlusive disease in patients who undergo myeloablative allogeneic stem cell transplantation. Blood 2003; 102: 1578–1582.