Thrombocytopenia After Gemtuzumab Is Reversible by Intravenous Immunoglobulin

CORRESPONDENCE

Thrombocytopenia after gemtuzumab is reversible by intravenous immunoglobulin

Leukemia (2005) 19, 1077–1078. doi:10.1038/sj.leu.2403757 tion of acute myeloid leukemia with dysmegakaryopoiesis. Published online 7 April 2005 Gemtuzumab treatment led to good disease control, as shown by the recovery of absolute neutrophil count and a morpholo- TO THE EDITOR gical remission marrow with decrease in blast population and active and mature granulopoiesis. Remarkably, the platelet count remained extremely low and the marrow showed Gemtuzumab ozogamicin (Mylotarg) is a humanized anti-CD33 increased megakaryocytes, mostly of normal morphology. The monoclonal antibody conjugated to a potent antitumor anti- clinicopathologic picture led us to suspect a possible immune biotic calicheamicin.1 Since its approval by Food Drug cause of thrombocytopenia. This proposition is supported by the Administration (FDA) in 2000, it has been increasing used to swift response and the complete recovery of platelet counts after treat elderly patients who have refractory or relapsed acute IVIG treatment. myeloblastic leukemia (AML) with an overall complete The cause of persistent thrombocytopenia in AML patients remission rate of 30%.2 In a phase II clinical trial on safety who otherwise showed complete bone marrow remission and efficacy, gemtuzumab is shown to cause prolonged after gemtuzumab treatment has not been elucidated. thrombocytopenia in 13% patients who have otherwise Myelotoxicity of gemtuzumab is often linked to its antiproli- achieved complete hematological remission, and some of these ferative and cytotoxic effects on normal CD33 hematopoietic patients died of fatal intracranial hemorrhage.2 The causes of progenitors. However, only a small minority of megakaryo- thrombocytopenia have not been fully elucidated. We reported cytes expresses CD33, suggesting that other mechanisms a patient whose clinicopathologic picture might shed light on might account for the phenomenon of prolonged thrombo- the mechanism of thrombocytopenia after treatment with cytopenia. Although gemtuzumab has not been shown to gemtuzumab.3 induce antiplatelet antibodies, the platelet recovery after Mr RC was a 72-year-old retired architect with good past health who was admitted to Queen Mary Hospital, Hong Kong on Nov 8, 2004, because of symptomatic anemia. At presentation, his peripheral blood film showed leucoerythro- blastic blood picture with hemoglobin 5.8 g/dl, total white cell 1.5 Â 109/l, absolute neutrophil 0, and platelet 16 Â 109/l. Bone marrow aspirate showed AML with multi-lineage dysplasia, with prominent dyserythropoiesis and dysmegakaryopoiesis (Figure 1). Two doses of gemtuzumab (9 mg/m2/dose) were given 2 weeks apart as salvage therapy. At 30 days after the first dose of gemtuzumab, the absolute neutrophil count increased precipitously back to normal level. No colony- stimulating factors or buffy coat has been given throughout the course. A bone marrow aspirate performed 5 weeks after the first dose of gemtuzumab showed good morphological remission with plentiful megakaryocytes of normal morphology and blast count was not increased. However, the patient remained thrombocytopenic despite repeated platelet transfusions. These observations suggested a peripheral cause of thrombocytopenia and led us to treat him with intravenous immunoglobulin (IVIG, 0.5 g/kg/day) for five days as a salvage therapy. At 3 days after commencement of IVIG therapy, the platelet count rose precipitously to above 100 Â 109/l without transfusion, and within a week the platelet count has remained above 300 Â 109/l. Results from this patient demonstrated a possible immune Figure 1 Effects of gemtuzumab on a patient with AML. (a) cause of thrombocytopenia after treatment of gemtuzumab. The Photomicrograph showing bone marrow aspirate at presentation with initial thrombocytopenia at presentation is part of the manifesta- predominance of blast cells, dyserythropoiesis and dysmegakaryopoiesis. The insert showed megakaryocytes with prominent dysplastic features characterized by nuclear hypolobulation and separated nuclei. (b) Photomicrograph showing bone marrow aspirate five Correspondence: Dr AYH Leung, Division of Hematology and Bone weeks after the first dose of gemtuzumab. Noted that granulopoiesis Marrow Transplantation, Department of Medicine, University of Hong has reached full maturation. The insert showed megakaryocytes of Kong, Hong Kong; Fax: þ 852 29741165; normal morphology. (c) Profile of platelet counts upon treatment with E-mail: [email protected] gemtuzumab. Small arrows: time of platelet transfusion. Asterisks: time Received 20 January 2005; accepted 1 March 2005; Published online of bone marrow biopsies as shown in (a) and (b). The horizon bars in 7 April 2005 (a) and (b) represent 20 mm. Correspondence 1078 IVIG in this patient may suggest a yet uncharacterized References immune-mediated process. IVIG is widely used in patients with autoimmune thrombocytopenic purpura by blockade 1 Voutsadakis IA. Gemtuzumab Ozogamicin (CMA-676, Mylotarg) of the Fc receptors in macrophages, thereby reducing for the treatment of CD33+ acute myeloid leukemia. Anti-Cancer clearance of antibody-coated platelets. Whether a similar Drugs 2002; 13: 685–692. mechanism might operate in this patient is presently 2 Sievers EL, Larson RA, Stadtmauer EA, Estey E, Lowenberg B, Dombret 4 H et al., Mylotarg Study Group. Efficacy and safety of Gemtuzumab unclear. This report might therefore provide ground of research Ozogamicin in patients with CD33-positive acute myeloid leukemia in into the cause of thrombocytopenia after gemtuzumab first relapse. J Clin Oncol 2001; 19: 3244–3254. treatment. 3 Larson RA, Boogaerts M, Estey E, Karanes C, Stadtmauer EA, Sievers EL et al., Mylotarg Study Group. Antibody-targeted chemotherapy of older patients with acute myeloid leukemia in first relapse using Mylotarg (gemtuzumab ozogamicin). Leukemia 2002; 16: AYH Leung1 1Division of Hematology and Bone Marrow 1627–1636. R Liang1 Transplantation, Department of Medicine, 4 Hansen RJ, Balthasar JP. Mechanisms of IVIG action in immune University of Hong Kong, Hong Kong thrombocytopenic purpura. Clin Lab 2004; 50: 133–140.

t(11;14) does not predict long-term survival in myeloma

Leukemia (2005) 19, 1078–1079. doi:10.1038/sj.leu.2403744 Vysis (Downers, Grove, IL, USA). A patient was considered to Published online 7 April 2005 have t(11;14) if the percent of clonal plasma cells exceeded 10% of signals with a abnormal pattern (fusions) indicative of a TO THE EDITOR t(11;14). All of the cases were also tested for chromosome 13q status using the probes LSI CEP8 and D13S319 as described previously.8 The translocation t(11;14) involving immunoglobulin heavy- Of the 20 cases, t(11;14) was detected in only one patient chain gene switch region and cylin D1 is the most common IgH with 94% clonal plasma cells involved. This patient who had translocation (15–20%) in multiple myeloma (MM).1,2 MM PFS of 20 months after autologous stem cell transplant and is patients with t(11;14) are considered in some studies to have a alive B3 years post-transplant and 10.5 years after initial better prognosis when treated with either conventional che- diagnosis. Chromosome 13q deletions were found in three cases motherapy or autologous stem cell transplant.3,4 In contrast, (15%), with a median of 43% clonal plasma cells involved. All patients with chromosome 13q deletions (40–50%) have a poor three patients are alive. prognosis.5–7 These results would predict that long-term Since only one (5%) of the long-term MM survivors harbored survivors of MM would more frequently harbor a t(11;14) but t(11;14), this study argues against a major role of t(11;14) in not a 13q deletions. To address this, we used cytoplasmic Ig- prolonging the survival of these MM patients. Hence, despite its enhanced fluorescence in situ hybridization (cIg-FISH) to association with a better prognosis, our results suggest that evaluate clonal plasma cells for t(11;14) and 13q status from t(11;14) should not be used as a predictor for long-term survivors 20 long-term survivor MM cases. in MM. As anticipated, 13q deletions were infrequent in this All of these patients met the diagnostic criteria for MM before group of MM. May 1995 and have survived greater than or equal to 8 years from diagnosis at the time of analysis. The 11 male and nine H Chang1,2 1Department of Laboratory Hematology, Princess female had a median age of 52 years (range 39–62 years), with a XY Qi1,2 Margaret Hospital/University Health Network, median bone marrow plasmacytosis of 30% (range, 10–80%) at 3 Toronto, ON, Canada; AK Stewart 2 diagnosis. None of these cases had smoldering myeloma or Department of Laboratory Medicine and MGUS using standard definitions. In all, 11 had IgG, six IgA, Pathobiology, University of Toronto, Toronto, ON, Canada; and two free light chains and one nonsecretory. Of the 20 patients, 3Department of Medical Oncology and 17 received autologous stem cell transplantation. The median Hematology, Princess Margaret Hospital/ duration between diagnosis to transplant was 24 months (range University Health Network, University 5–149 months), and the median progression-free survival (PFS) of Toronto, Toronto, ON, Canada after transplant was 32 months (range, 1–62 months). One patient died 3 years after transplant and 10 years after diagnosis. The other 19 patients remain alive. We used cIg-FISH with a fusion strategy for detection of References t(11;14). The IgH probe labeled with SpectrumGreen and the cyclin D1 probe labeled with SpectrumRed were obtained from 1 Bergsagel PL, Kuehl WM. Chromosome translocations in multiple myeloma. Oncogene 2001; 20: 5611–5622. 2 Avet-Loiseau H, Li JY, Facon T, Brigaudeau C, Morineau N, Correspondence: Dr H Chang, Department of Laboratory Hematology, Maloisel F et al. High incidence of translocations t(11;14)(q13;q32) Princess Margaret Hospital, University Health Network, 610 Uni- and t(4;14)(p16;q32) in patients with plasma cell malignancies. versity Avenue, 4-320, Toronto, ON, Canada M5G 2M9; Cancer Res 1998; 58: 5640–5645. Fax: þ 1 416 946 4616; E-mail: [email protected] 3 Fonseca R, Blood EA, Oken MM, Kyle RA, Dewald GW, Bailey RJ Received 2 February 2005; accepted 25 February 2005; Published et al. Myeloma and t(11;14)(q13;q32): evidence for a biologically online 7 April 2005 defined unique subsets of patients. Blood 2002; 99: 3735–3741.

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