Efficacy And Safety Of Two Asparaginase Preparations In Treatment Of Adult Acute Lymphoblastic Leukemia

BackgroundAcute lymphoblastic leukemia (ALL) is a biologic heterogeneity disease originated from lymphocyte and characterized with increase of lymphoblasts in bone marrow and peripheral blood. Currently, ALL patients are treated with individualized therapy according to their disease risk stratification based on MICM (Morphology, Immunology, Cytogenetics, Molecular biology)diagnosis, which leads to great improvement in efficacy in ALL treatment. In the era of multi-drugs combined induction therapy, both adult and pediatric ALL can achieve complete (CR) rate over 90%.Moreover,75% pediatric ALL patients achieve long term disease free survival and the overall cure rate is as high as 85%. However, nearly half of adult ALL patients relapse within one to two years and only 30%～50% patients achieve long term survival, which is evidently inferior to pediatric ALL. It has been confirmed by clinical studies that asparaginase is one of the drugs that make contribution to improving in pediatric ALL’s efficacy, for which it not only enhance the CR rate, and also prolonged event free survival (EFS) time.Asparaginase hydrolyzes the amino acid asparagine to aspartic acid and ammonia, depletes circulating asparagine, hinder the synthesis of protein and nucleic acid, which selectively kills tumor cells and the tumor cells which are lymphocyte organ are more sensitive. Normal cells or tissue doesn’t need external sources of that amino acid asparagine for they have asparagine synthetase and synthesizes it by themselves. Therefore, asparaginase makes few impacts on human normal cells and tissue.Asparaginase is a noteable landmark in the progress of ALL treatment and it has been an essential and routinely used component in frontline clinical treatment for adult and pediatric ALL for its confirmed efficacy. Nowadays, asparaginase in clinical use is extracted from escherichia coli or Erwinia and it has high immunogenicity for its exogenous protein sources. This biological character may lead to formation of antibodies to asparaginase and allergic reaction, meanwhile, degrade the anti-tumor effect by lower the activity of asparaginase itself. Whereas, the half live of asparaginase is 1.24±0.17days and intravenous injection by every day or every other day is need to sustain its effective plasma concentration. Besides, patents can’t exposed to enough dosage of asparaginase not only for it hypersensitivity reaction from high immunogenicity, but also liver dysfunction, hypoproteinemia, coagulation disorders, pancreatitis, making it difficult to achieve optimal outcomes.Polyethylene glycol conjugated asparaginase (PEG-Asp) is formed by the polyethylene glycosylation of the L-Asp, resulting in a longer circulating half-life (nearly 6 days) and lower immunogenicity. It has been shown in former clinical trials that PEG-Asp has decreased incidence of allergic reactions and high titer of anti-asparaginase antibody formation in pediatric ALL, and also is equivalent to L-Asp in efficacy and other adverse events. PEG-Asp has got FDA’s approval for first-line component in pediatric ALL treatment.ObjectiveTo evaluate the efficacy and safety of L-Asp and PEG-Asp in treatment of adult ALL, in order to provide clinical evidence for choosing asparaginase preparations in adult ALL patients’ induction regimen, on the other hand, put forward strategy for preventing and handling asparaginase’s side effect, improving its safety in our clinical practice.MethodsCollected the clinical records of adult patients who were newly diagnosed as acute lymphoblastic leukemia and treated with VDLP (vincristine, daunorubicin, L-asparaginase or PEG-asparaginase, prednisone) regimen as induction therapy in NanFang Hospital, Southern Medical University, Guangzhou during January 2008 to March 2015 and retrospectively analyzed compare the efficacy and safety of L-Asp and PEG-Asp. Our study included 121 cases of ALL patients and divided them into two groups according to the asparaginase preparations given in their induction treatment. There were 75 patients in L-Asp group and 46 patients in PEG-Asp group. Clinical records included patients’ baseline data (such as sex, age), initial white blood cell (WBC) count, hemoglobin, platelet, bone marrow blast, extramedullary invasion (such as hepatosplenomegaly, lymphadenectasis and other organ or tissue leukemia invasion), immunophenotype, chromosome, molecular biology aberration, efficacy and side effect. ALL patients in our study were given a standard four-drugs of induction VDLP regimen (V:vincristine or vindesine; D:daunorubicin or idarubicin; L:L-Asp or PEG-Asp; P:prednisone). Either L-Asp or PEG-Asp was used based on the patients’ willingness. Philadelphia chromosome positive ALL (Ph+ALL) patients received tyrosine kinase inhibitors (TKIs) as long as the Philadelphia chromosome was demonstrated and bone marrow puncture was performed at 14d and the end of induction. Patients received commutative courses of the Hyper CVAD-A/B regimen for consolidation chemotherapy after induction. Bone marrow puncture, lumber puncture and central nervous system leukemia (CNSL) prophylaxis were given during every consolidation therapy. Patients who had human-leukocyte-antigen-matched donors went through an allogeneic bone marrow transplant (allo-BMT) after commutative courses of the Hyper CVAD-A/B regimen. The overall median age at their diagnosis was 25 years old and it was 27.5 years old in PEG-Asp group while 23 years old in L-Asp group. Among all patients, there were 76 male patients and 45 female patients, for there were 30 male patients and 16 female patients in PEG-Asp group while 46 male patients and 29 female patients in L-Asp group. The dosage of asparaginase preparations in the VDLP regimen our patients received were as follow: ①L-Asp 6000U/m2 for seven times (Qianhong Biochemical pharmaceutical co., LTD, Changzhou) ②PEG-Asp 2500IU/m2 for one time (Hengrui pharmaceutical co., LTD,Jiangsu). Compare the baseline data of patients and relevant imformation about their disease such as hemogram, ratio of primitive and uvenile lymphocyte in bone marrow, leukemia extramedullary invasion, morphology, immunology, cytogenetics, molecular biology abnormality. Moreover, the CR rate, time to achieve CR, incidence of CNSL and long-term survival time were needed to evaluate the efficacy of two asparaginase preparations. Meanwhile, we also compared the side effect of the asparaginase preparations, such as allergic reaction, liver dysfunction, renal function damage, and pancreatic lesion, the change of coagulation function (PT:prothrombin time; APTT:activated partial thromboplastin time; Fbg:fibrinogen), the beginning and duration time of coagulation dysfunction and myelosuppression and incidence of bleeding event, grade Ⅳ～Ⅴ infections and infection-related death.Results1. Patients’ baseline data and relevant information about ALL(1)Baseline data:Patients in neither PEG-Asp group or L-Asp had similar age and constituent ratio of sex, there was no significant difference between two groups (P>0.05).(2)Relevant information about ALL:There were no significant differences between two groups in terms of hemogram, ratio of primitive and uvenile lymphocyte in bone marrow, leukemia extramedullary invasion, immunology, cytogenetics, molecular biology abnormality (P>0.05).2. Efficacy(1) CR rate:As two patients in the PEG-Asp group died during induction, there were 119 patients to evaluate complete remission rate between two groups. Totally, 111 patients achieved CR after the induction regimen and the overall CR rate was 93.28%(111/119).41 patients achieved CR in PEG-Asp group while 70 patients achieved complete remission in L-Asp group and the complete remission rate were 93.18%(41/44)and 93.33%(70/75) respectively. No significant difference was shown between two groups (P>0.05).(2) Time to achieve CR:The patients in PEG-Asp group achieved complete remission at a median time of 30(13～94)days and patients in L-Asp group made it at a median time of 28(13-89)days. There was no statistical difference between two groups (P>0.05).(3) CNSL:During the consolidation phase, central nervous system leukemia occurred in 5 of the 44 patients (11.36%) in the PEG-Asp group and 22of the 75 patients (29.33%) in the L-Asp group. The incidence of central nervous system leukemia in the L-Asp group was significantly higher than that in the PEG-Asp group (P=0.024).(4) Long-term survival:As one patient in the PEG-Asp group died of severe pulmonary infection after achieving CR, there were forty-three patients to follow up in PEG-Asp group. At a median follow-up of 15.23 months, the median RFS was 10.20 (0.50～47.17) months for the PEG-Asp group and 7.27 (0～73.33) months for the L-Asp group. In addition, the median OS for the PEG-Asp group was 14.07 (1.76 -48.97) months and that for the L-Asp group was 16.50 (1.93-74.37) months. We observed no significant difference in RFS and OS between the two groups (P>0.05).3. The side effect between two groups:(1) Allergic reaction:During the induction, allergic reaction occurred in 1 of the 46 patients in the PEG-Asp group and also 1 of the 75 patients in the L-Asp group after asparaginase preparations were given. The allergy rate were 2.17%(1/46, PEG-Asp) and 1.33%(1/75, L-Asp group), respectively. There was no statistical difference between two groups (P>0.05).(2) Liver dysfunction, renal function damage, and pancreatic lesion:After asparaginase preparations were given, Ⅲ～Ⅳgrade of liver dysfunction occurred in 11 of the 46 patients in the PEG-Asp group and also 9 of the 75 patients in the L-Asp group, the rate of Ⅲ～Ⅳgrade of liver dysfunction were 23.91%(11/46,PEG-Asp) and 12.00%(9/75,L-Asp group), respectively. In the aspect of renal function damage, no patients experienced renal function damage in both group. Furthermore, there were totally 6 patients had pancreatic lesion, for which 3 patients in the PEG-Asp group and 3 patients in the L-Asp group, respectively. There were no statistical differences between two groups in terms of liver dysfunction, renal function damage, and pancreatic lesion (P>0.05).(3) Coagulation dysfunction: ①Before the usage of asparaginase, there were no significant differences between two groups in terms of coagulation index (PT, APTT and Fbg) (P>0.05). After the asparaginase preparations were given, the PTmax, APTTmax, Fbgmin were 16.1(10.5±49.0)s,49.5(26.5±100.7)s,1.08 (0.15±2.4) g/L in PEG-Asp group while 14.6(10.2±24.0)s,45.6(30.6±79.9)s、1.05(0.25± 2.19)g/L in L-Asp group, respectively. The difference in PTmax between PEG-Asp group (16.1s) and L-Asp group (14.6s) was statistically different (P=0.009). There were no statistical differences between two groups in terms of APTTmax and Fbgmin (P>0.05).② Patients in the PEG-Asp group had a longer duration of coagulation dysfunction (9.80±5.51 d vs.6.80±4.21 d, P=0.037) than those in L-Asp group. ③ Clinical bleeding events were occurred in 4 patients in PEG-Asp group and 3 patients in L-Asp group, no significant difference was observed in bleeding events between the two groups(8.70% vs.4.00%, P>0.05).(4) Myelosuppression: ① Patients in both PEG-Asp and L-Asp group experienced myelosuppression phase after induction and the grade of myelosuppression was similar between two groups. No difference was observed in terms of granulocytopenia, anemia and thrombocytopenia (P>0.05).②Duration time of myelosuppression:Although the grade of myelosuppression between the two groups was similar for those patients who achieved CR(41 patients in PEG-Asp and 70 patients in L-Asp group), the duration of agranulocytosis was significantly longer for the patients treated with PEG-Asp than for those in the L-Asp group (19.26±9.41 d vs.11.89±8.53 d, P<0.01). Besides, no difference was observed in terms of duration of hemoglobin below 60g/L and platelet below 20×109/L (P>0.05).(5) Infection:Among patients who achieved CR,11 patients in PEG-Asp group and only 4 patients in L-Asp group suffered from grade Ⅳ-Ⅴ infection. The incidence of Ⅳ-Ⅴ infection were 26.83% for PEG-Asp group and 5.71% for L-Asp group and it suggested that patients who received PEG-Asp had a higher incidence of Ⅳ-Ⅴ grade infection than those who received L-Asp (P=0.002). As a patient in the PEG-Asp group died of severe pulmonary infection after achieving CR, the rate of infection related death were 2.44% for PEG-Asp group and 0% for L-Asp group. No significant difference was observed in aspect of infection related death (P>0.05).Conclusion1.Adult de novo ALL patients treated with neither PEG-Asp or L-Asp as part of VDLP regimen can achieve over 90% complete remission rate, suggesting that PEG-Asp is equivalent to L-Asp in adult ALL patients’induction efficacy.2. The median times taken to achieve CR were 30 days in the PEG-Asp group and 28 days in the L-Asp group, demonstrating that the time to achieve CR is similar between two groups.3.During the consolidation phase, the incidence of CNSL in L-Asp group was significantly higher than that in the PEG-Asp group, suggesting that PEG-Asp had a potential role in preventing CNSL among adult ALL patients. However, more clinical evidences are required to further confirm it.4. There were no statistical differences in RFS and OS between patients treated with PEG-Asp and those treated with L-Asp.5. The rate of allergic reaction was similar in the two groups and the difference was no statistically significant.6. Both PEG-Asp and L-Asp can lead to liver dysfunction, and pancreatic lesion. The occurrences of liver dysfunction and pancreatic lesion were similar between PEG-Asp and L-Asp. Besides, the clinical manifestations were mild and patients can tolerate them under supportive treatment.7. PEG-Asp and L-Asp can lead to similar grade of coagulation dysfunction, however, patients treated with PEG-Asp have a longer duration of coagulation dysfunction than those treated with L-Asp. But this doesn’t result in higher incidence of bleeding events under supportive care.8. Although PEG-Asp or L-Asp as part of VDLP regimen can lead to similar grade of myelosuppression, the duration of agranulocytosis was significantly longer for the patients treated with PEG-Asp than those treated with L-Asp. Furthermore, the patients who receive PEG-Asp had a higher incidence of IV-V grade infection than those who received L-Asp. However, it doesn’t increase the incidence of infection-related death.PEG-Asp is equivalent to L-Asp in CR rate, time to achieve CR and long-term efficacy in treatment of adult de novo ALL, but it may decrease rate of CNSL in consolidation phase compared to L-Asp, which needs more clinical evidences to confirm. Appling PEG-Asp also refers to prolonged time of coagulation dysfunction and agranulocytosis and higher severe infection rate, but doesn’t increase rates of bleeding event and infection-related mortality. In addition, PEG-Asp is more convenient to use and it can be the front-line chemotherapeutic for adult ALL treatment.