Correspondence. Successful unrelated allogeneic stem cell trans- plantation after treatment of lymphoid blast crisis CML with imatinib and imatinib-contai-.
Bone Marrow Transplantation (2003) 32, 541–542 & 2003 Nature Publishing Group All rights reserved 0268-3369/03 $25.00
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Correspondence
In patients with lymphoid blast crisis in chronic myeloid leukemia (CML), the overall rate of response is approximately 50%, but remissions are short lived with a median survival of 9 months.1–5 Here, we report a 16-year-old male patient diagnosed with BCR-ABL-positive lymphoid blast crisis, who was successfully treated with imatinib mesylate for remission induction followed by a myeloablative conditioning regimen combined with imatinib mesylate and allogeneic SCT. A 16-year-old male (177 cm, 73 kg) was diagnosed with BCR-ABL-positive CML in chronic phase. He was treated with 6.5 106 IU interferon-a per day subcutaneously for 20 months. His disease progressed, with thrombocytopenia, headache, muscle pain and nausea at the end of this period, and lymphoid blast crisis as assessed by bone marrow cytology and immunophenotyping of bone marrow cells was diagnosed. Analysis of cerebrospinal fluid showed 22/ml leukemic cells. For treatment of central nervous system (CNS) involvement, methotrexate (12 mg), cytarabine (30 mg) and prednisolone (10 mg) intrathecally were given three times at weekly intervals. The patient was enrolled in a multicenter clinical study of imatinib mesylate (STI571, Novartis protocol 0115) in CML lymphoid blast crisis. Treatment with imatinib mesylate as monotherapy was initiated with 600 mg p.o. per day. Only mild nausea and emesis occurred necessitating a reduction to 400 mg p.o. per day for 4 days. The patient’s condition improved steadily, and no further imatinib mesylate-related toxicity occurred. After 3 weeks, bone marrow investigation revealed complete hematologic remission of CML. Molecular remission was not achieved immediately prior to SCT, but BCR-ABL expression was as low as 5 10 5 (4.0 log decrease). Imatinib mesylate treatment was continued for two more weeks, when the preparation for allogeneic SCT was initiated. During irradiation therapy consisting of craniospinal boost (3 2 Gy, days d–10 to d 8) and total body irradiation (6 2 Gy, d 7 to d 5) treatment with imatinib mesylate was continued to enhance antileukemic efficacy until the start of the administration of cyclophosphamide (60 mg/kg, i.v., d 3 to d 2) and etoposide (40 mg/kg, i.v., d 4). For prophylaxis of graft rejection, antithymocyte globulin was given (rabbit, Pasteur Merieux, Lyon, France, 10 mg/kg per day, d 3 to d 1). On day 0, a total of 9.6 106/kg CD34+ highly purified hematopoietic
Equivalent to dilution of K562 cells
Bone Marrow Transplantation (2003) 32, 541–542. doi:10.1038/sj.bmt.1704167
stem cells and an add-back of 10 106 CD3+ T cells from an HLA-matched unrelated donor were transfused. Graftversus-host disease (GvHD) prophylaxis consisted of cyclosporin A (3 mg/kg/day in two divided doses, i.v.) starting on d 1. G-CSF treatment was started on d+5 (5 mg/kg, i.v.). Hematologic recovery was rapid with more than 1000 leukocytes/ml on d+13. No GVHD occurred. Complete molecular remission was maintained as confirmed by negative sequential RQ-RT PCRs for BCR-ABL tested at 4-weeks-intervals in bone marrow and peripheral blood during the whole post transplant course (Figure 1). The limit of sensitivity for detecting BCR/ABL-positive cells is 1 10 5 K562 cells on a background of normal mononuclear cells.6 Although the patient developed a complete lymphopoietic donor chimerism, mixed hematopoietic chimerism increased to 50%, necessitating administration of four donor lymphocyte transfusions with twice 25, once 50 and
BCR-ABL kinetic in bone marrow
10 0 10 10
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50 100 150 200 250 300 350 400 Days since transplant
Figure 1 BCR-ABL kinetics in bone marow.
Chimerism in peripheral blood Chimerism in bone marrow Lymphopoietic Chimerism
Donor lymphocyte infusion
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Successful unrelated allogeneic stem cell transplantation after treatment of lymphoid blast crisis CML with imatinib and imatinib-containing conditioning regimen in a 16-year-old male
30 20 10 0 0
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Days since transplant Figure 2 Analysis of chimerism.
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SCT and imatinib in lymphoid blast crisis CML M Koch et al
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once 100 cells 103/kg on d+110, +130, +315 and +393. Temporarily mixed hematopoietic chimerism decreased to 25%, while an increase in host lymphopoietic chimerism to 20% was established. As shown in Figure 2, mixed hematopoietic chimerism again increased to 50% on day +386. Quantitative evaluation of hematopoietic chimerism was performed using PCR-based amplification of short tandem repeats (STR) as reported previously.7 The patient is currently 400 days post transplant with no evidence of disease. CD3+ lymphocytes were counted at 61%, mixed hematopoietic chimerism remained at 50% and the BCR-ABL PCR assay in blood and bone marrow revealed negative results. Treatment of blastic transformation prior to allogeneic SCT has generally consisted of chemotherapy given for acute leukemia. This is toxic and associated with significant infectious complications which may make later allogeneic SCT difficult. Treatment of lymphoid blast crisis with vincristine and steroids induces complete remission in twothirds of patients and allogeneic SCT in second chronic phase leads to 40% survival.8 There are very few reports in adult patients using imatinib mesylate before or after allogeneic SCT.2,9,10 Sawyers et al 9 reported a survival of four out of 10 adult patients in myeloid blast crisis of CML who discontinued imatinib mesylate to undergo bone marrow transplantation. Imatinib mesylate had a significant antileukemic effect in this pediatric patient with lymphoid blast crisis CML with a favorable toxicity profile. After 3 weeks of imatinib mesylate treatment, complete hematological remission was achieved with a parallel 4.0 log decrease of the kinetics of BCR-ABL expression. In this patient with lymphoid blast crisis of CML, molecular remission could not be achieved by imatinib mesylate treatment alone, but in combination with myeloablative radiochemotherapy and allogeneic SCT imatinib, mesylate induced sustained molecular remission, which has now lasted for more than 400 days post transplant. The xBCR-ABL level reached extremely low levels (1 10 4 to 1 10 5) immediately prior to SCT, which may be a good prognostic factor for long-term remission. Imatinib mesylate treatment sensitizes BCR-ABL-positive human leukemia cells to apoptosis due to irradiation.11 The specific inhibition of BCR-ABL tyrosine kinase by imatinib mesylate results in the downregulation of antiapoptotic XIAP, cIAP1, and Bcl-xL levels.12 As illustrated in this case, imatinib mesylate in combination with total body irradiation may be very effective for treatment of CML lymphoid blast crisis. Whether imatinib mesylate should be the standard treatment for blastic transformation before allogeneic SCT will need further study.
Acknowledgements We thank Professor Meinolf Suttorp, Children´s hospital, Dresden University, for helpful suggestions and advice.
Bone Marrow Transplantation
M Koch1 P Lang1 P Bader1 H Kreyenberg1 M Schumm1 H Scheel-Walter1 A Hochhaus2 D Niethammer1 J Greil1
1
Universita¨ts-Kinderklinik Tu¨bingen, Tu¨bingen, Germany; and 2 III. Medizinische Klinik, Klinikum Mannheim, Universita¨t Heidelberg, Mannheim, Germany
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