Haematologica 2002; 87:(12)ECR38
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Combination of imatinib and established antileukemic treatment modalities for otherwise refractory BCR-ABL positive lymphoblastic leukemia.
Stefan Fruehauf, Julian Topaly, Eike C. Buss, Moritz Schad,* Martin Goerner, W. Jens Zeller,* Anthony D. Ho
Department of Internal Medicine V, University of Heidelberg, Heidelberg, Germany; *German Cancer Research Center, Heidelberg, Germany.
Correspondence: Dr. Stefan Fruehauf, M.D., Department of Internal Medicine V, University of Heidelberg, Hospitalstraße 3, D-69115 Heidelberg. Phone: international + 49.6221.562781. Fax: international +49.6221.565722.
E-mail:stefan_fruehauf@med.uni-heidelberg.de

Imatinib is a potent drug used for treatment of BCR-ABL-positive leukemias. However, not all patients achieve a complete response and particularly in patients with lymphoblastic leukemias, relapses occur rapidly. Combinations of imatinib and a series of cytotoxic agents act synergistically in vitro. In this report on a patient with BCR-ABL-positive lymphoblastic leukemia refractory to standard chemotherapy and only partially responding to imatinib monotherapy we show that administration of imatinib + synergistic high-dose chemotherapy and imatinib + synergistic irradiation-based conditioning was tolerable and achieve a state of minimal leukemic cell burden so that a potentially curative allogeneic transplantation could be performed.
Patients with BCR-ABL-positive acute lymphoblastic leukemia (ALL) have a dismal prognosis. Even imatinib (formerly STI571) which inhibits the BCR-ABL tyrosine kinase that causes leukemia can only induce short-lasting remissions.¹ The value of stem cell transplantation as consolidation treatment in blast crisis patients or patients with BCR-ABL-positive leukemia transplanted in remission is the subject of ongoing trials.² Detection of residual leukemic cells after high-dose chemotherapy is a strong predictor for clinical relapse in BCR-ABL-positive disease.³ Strategies to improve the conditioning therapy may help to increase the remission rates. Several preclinical studies suggest that combinations of imatinib and different chemotherapeutic agents or irradiation would display synergistic activity in BCR-ABL-positive leukemia cells.^4-7 For example, we observed strong synergisms for imatinib+irradiation, +cytarabine, +mitoxantrone, +mafosfamide and additive activity for imatinib+fludarabine.⁸
Therefore, we treated a 19-year old patient with refractory BCR-ABL-positive ALL with imatinib-based combination therapy. Until then the leukemia (initial white blood cell count [WBC] 159x10⁹/L, 89% blasts, Figure 1A) was refractory to conventional induction therapy² comprising dexamethasone, vincristine, daunorubicine, cyclophosphamide, cytarabine and 6-mercaptopurine, with 46% blasts detectable in the peripheral blood (PB, WBC 2.7x10⁹/L) after completion of the second induction cycle (day 48 of therapy).
The patient never became aplastic during induction therapy. Subsequently, imatinib monotherapy was started at a dose of 600 mg/day. Within the first week of imatinib treatment a partial response was noted with a minimal WBC of 0.68/nL that did not drop further in the second week of treatment. A major population of 20% leukemic cells was detected in the bone marrow (BM) after two weeks of imatinib. Therefore, we combined imatinib (600 mg/day, days 1-5) with MitoFLAG-chemotherapy⁹ containing the synergistic compounds mitoxantrone (7 mg/m²/day, days 1,3,5) and cytarabine (2x1000 mg/m²/day, days 1-5). The regimen further comprises fludarabine (2x15 mg/m²/day, days 1-5) and G-CSF (5 µg/kg/day, day 0 until neutrophil count >0.5x10⁹/L).
The patient became severely aplastic for the first time and on day 17 after start of MitoFLAG no leukemic cells were detectable by flow cytometry in PB (WBC 0.05x10⁹/L, 800 cells measured). However, in the recovery phase 2% (day 38) and 15% (day 34) leukemic cells were found in the PB and BM, respectively. Subsequently, a conditioning therapy comprising total body irradiation (total dose 12 Gy, days 1-3)/cyclophosphamide (60 mg/kg/day, days 4-5) was administered concurrently with imatinib (600 mg/day, days 1-5) because both, irradiation and the active cyclophosphamide metabolite mafosfamide, were previously found to be strongly synergistic with imatinib. Ref. 5 Again, the leukemic population in the PB dropped below the detection limit during conditioning therapy and on day 7, immediately before transplantation 6% leukemic cells were noted in the BM. Following PB progenitor cell transplantation from an HLA-identical sibling donor the hematologic recovery was uneventful with WBC >1.0x10⁹/L on day 16 and thrombocytes >50x10⁹/L on day 21 after transplantation. The patient suffered from severe mucositis during aplasia. In a follow-up examination 2 months after transplant a leukemic cell population was for the first time not detectable any more in BM by flow cytometry (Figure 1B). A nested RT-PCR for BCR-ABL was also negative. The patient continues to be in complete remission more than four months after allogeneic transplantation.
This is noteworthy, because in a previous study none of seven patients with chemotherapy-refractory BCR-ABL-positive ALL remained disease-free more than 4.5 months after allogeneic transplantation. Ref. 10
This case shows that combination therapy with imatinib and synergistically active chemotherapeutic drugs or irradiation can be safely administered and can induce a leukemic cell depletion that was not possible by either high-dose induction chemotherapy or imatinib alone. Although the combined modality treatment was not curative by itself it helped to achieve a state of minimal residual disease which allowed potentially curative allogeneic stem cell transplantation. This treatment approach should be systematically explored in refractory or relapsing high-risk BCR-ABL-positive leukemias.

References

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