Medical and Biological Sciences XXVI/2 - Collegium Medicum ...

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50 Beata Kuryło-Rafińska et. al. Table II. Comparison of ex vivo drug resistance profile between first and subsequent relapse of childhood acute myeloid leukemia Tabela II. Porównanie profile oporności ex vivo na cytostatyki u pacjentów z pierwszą i kolejnymi wznowami ostrej białaczki mieloblastycznej DRUG Lek FIRST RELAPSE Pierwsza wznowa SUBSEQUENT RELAPSE Kolejna wznowa N Median Minimum Maximum N Median Minimum Maximum Prednisolone 17 95.10 3.40 250.00 7 112.36 36.07 147.50 1.2 0.924 Dexamethasone 12 6.00 0.03 6.00 6 6.00 6.00 6.00 1.0 0.303 Vincristine 17 4.27 0.13 20.00 7 2.59 0.57 10.47 0.6 0.775 Idarubicin 17 0.39 0.03 2.00 9 0.26 0.12 2.00 0.7 0.725 Daunorubicin 17 0.55 0.03 2.00 7 0.55 0.24 1.59 1.0 0.727 Doxorubicin 13 5.00 0.34 8.00 6 1.06 0.64 8.00 0.2 0.472 Epirubicin 8 0.87 0.28 2.00 4 0.79 0.48 0.92 0.9 0.732 Mitoxantrone 12 0.55 0.01 1.00 6 0.61 0.10 1.00 1.1 0.772 Etoposide 18 20.14 0.30 50.00 6 22.03 15.75 50.00 1.1 0.662 L-asparaginase 15 1.40 0.01 10.00 7 1.49 0.20 10.00 1.2 0.800 Cytarabine 16 0.81 0.22 10.00 8 0.64 0.14 10.00 0.8 0.478 Fludarabine 13 1.46 0.06 20.00 6 1.19 0.17 20.00 0.8 0.929 Cladribine 17 10.00 0.00 40.00 8 0.09 0.00 40.00 0.1 0.438 Treosulfan 9 0.60 0.00 1.00 6 0.58 0.00 2.11 1.0 0.903 Thiotepa 9 1.59 0.03 12.11 5 1.96 0.59 4.00 1.2 0.947 Melfalan 8 5.27 0.91 34.45 3 6.65 1.35 15.06 1.3 0.838 4-HOO-cyclophosphamide 10 2.74 0.38 17.41 6 1.29 0.39 3.13 0.5 0.193 4-HOO-ifosfamide 3 16.82 8.17 96.90 3 9.72 1.19 32.05 0.6 0.513 Bortezomib 3 1044.27 261.82 2000.00 2 1199.43 398.85 2000.00 1.1 0.767 Busulfan 3 64.65 33.53 1200.00 2 488.06 24.12 952.00 7.5 0.564 6-Thiguanine 10 21.25 1.56 50.00 5 6.25 4.42 18.95 0.3 0.141 6-Mercaptopurine 9 308.72 141.01 500.00 4 63.55 31.25 81.39 0.2 0.105 RR p Median and range of LC50, as the value of in vitro resistance is provided given in IU/ml for L-asparaginase, nM for bortezomib, µM for clofarabine and in µg/ml for the remaining drugs; n – number of patients; RR – relative resistance = median LC50 (subsequent relapse) / median LC50 (first relapse); n, number of patients; p-value, Mann-Whitney U-test. (1.7-fold), fludarabine (3.7-fold) and busulfan (4.3- fold). For other four drugs, a trend for higher resistance at relapse was observed: for daunorubicin, mitoxantrone, L-asparaginase and cladribine. DISCUSSION In this study we have shown that drug resistance of myeloblasts in relapsed patients is higher than that of de novo ones. Still, relapse remains a significant problem for all children with AML. In the study of Dutch-German group, no significant differences in drug resistance were reported in a large cohort of childhood AML samples taken at diagnosis between patients remaining in continuous complete remission versus refractory/relapsed patients [10]. In general, relapsed AML has a dismal prognosis mainly related to the time-interval between initial diagnosis and relapse, and possibly cellular drug resistance can play a key role in therapy failure of relapsed childhood AML. It is important, as relapsed patients had myeloblasts more resistant to basic drugs used in the therapy of childhood acute myeloid leukemia, such as: cytarabine, idarubicin, daunorubicin, mitoxantrone and etoposide. Relapsed leukemic blasts were also more resistant to drugs commonly used in the therapy of relapsed AML: fludarabine, cytarabine and idarubicin. High ex vivo drug resistance in childhood acute myeloid leukemia might partially explain worse clinical results of therapy, when compared to acute lymphoblastic
Differential ex vivo drug resistance profile in first and subsequent relapsed childhood acute myeloid leukemia... 51 Table III. Comparison of ex vivo drug resistance profile between relapsed and de novo childhood acute myeloid leukemia Tabela III. Porównanie profile oporności ex vivo na cytostatyki u pacjentów z ostrą białaczką mieloblastyczną i jej wznowami DRUG Lek INITIAL AML AML de novo RELAPSED AML Wznowa AML n Median Min Max n Median Min Max Prednisolone 38 94.65 0.40 250.00 24 100.65 3.40 250.00 1.1 0.295 Dexamethasone 18 6.00 0.01 8.00 18 6.00 0.03 6.00 1.0 0.664 Vincristine 38 2.73 0.02 16.09 24 4.08 0.13 20.00 1.5 0.435 Idarubicin 40 0.22 0.01 2.00 26 0.38 0.03 2.00 1.8 0.041 Daunorubicin 37 0.27 0.01 2.00 24 0.55 0.03 2.00 2.0 0.052 Doxorubicin 33 1.69 0.24 8.00 19 1.41 0.34 8.00 0.8 0.870 Epirubicin 17 0.90 0.13 2.00 12 0.80 0.28 2.00 0.9 0.790 Mitoxantrone 34 0.23 0.00 13.28 18 0.61 0.01 1.00 2.6 0.077 Etoposide 36 3.44 0.05 50.00 24 20.14 0.30 50.00 5.9 0.007 L-asparaginase 33 0.68 0.03 10.00 22 1.35 0.01 10.00 2.0 0.058 Cytarabine 40 0.47 0.01 12.19 24 0.78 0.14 10.00 1.7 0.050 Fludarabine 35 0.40 0.02 15.54 19 1.46 0.06 20.00 3.7 0.022 Cladribine 32 0.04 0.00 40.00 25 0.75 0.00 40.00 21.2 0.072 Treosulfan 31 0.32 0.00 1.00 15 0.60 0.00 2.11 1.9 0.572 Thiotepa 31 1.88 0.12 100.00 14 1.94 0.03 12.11 1.0 0.787 Melfalan 25 4.65 0.10 40.00 11 6.57 0.91 34.45 1.4 0.973 4-HOO-cyclophosphamide 30 1.68 0.24 9.35 16 2.16 0.38 17.41 1.3 0.890 4-HOO-ifosfamide 13 1.98 0.35 34.74 6 13.27 1.19 96.90 6.7 0.136 Bortezomib 16 353.74 191.50 1096.83 5 1044.27 261.82 2000.00 3.0 0.137 Busulfan 14 15.19 1.17 42.30 5 64.65 24.12 1200.00 4.3 0.004 6-Thiguanine 17 14.63 1.36 50.00 15 14.79 1.56 50.00 1.0 0.533 6-Mercaptopurine 18 106.15 15.63 500.00 13 229.25 31.25 500.00 2.2 0.118 RR P Median and range of LC50, as the value of in vitro resistance is provided given in IU/ml for L-asparaginase, nM for bortezomib, µM for clofarabine and in µg/ml for the remaining drugs; n – number of patients; RR – relative resistance = median LC50 (initial AML) / median LC50 (relapsed AML); n, number of patients; p-value, Mann-Whitney U-test. leukemia. It is commonly assumed that relapsed patients are more drug resistant than those diagnosed de novo, and it was shown in this analysis for relapsed AML samples. No conclusive results were obtained for stem cell transplant teams, as relapsed patients were highly resistant to busulfan, which is a key compound used in conditioning of AML patients before hematopoietic stem cell transplantation. On the other hand, no significant differences were found between de novo and relapsed patients for cyclophosphamide and treosulfan. In current therapeutic regimens, based on reduced intensity conditioning, these drugs play an important role. Unlike ALL, the role of individual in vitro tumor response testing in childhood AML has not been established yet. Several groups reported possible prognostic value of in vitro drug sensitivity in pediatric AML, showing a good correlation between in vitro drug resistance and short-term clinical outcome after chemotherapy [7,11-14]. These findings were related mainly to cytarabine [7] and cyclophosphamide [14]. Part of these studies included both children and adults. Newer, large studies showed no correlation between in vitro drug resistance to individual drugs and long-term clinical outcome in childhood AML [15-17]. So far, no data exist to support the prognostic value of any in vitro drug resistance profile in childhood AML, while this relationship has been confirmed in adult AML [18]. In our previous preliminary report of our group, we showed the possible prognostic value of a combined fludarabine, treosulfan and mitoxantrone resistance profile in children with AML [8]. Recently,
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