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ORIGINAL ARTICLE
Year : 2019  |  Volume : 56  |  Issue : 3  |  Page : 211-215
 

A prospective, randomized study to compare the combination of imatinib and cytarabine versus imatinib alone in newly diagnosed patients with chronic phase chronic myeloid leukemia


Institute of Hematology and Transfusion Medicine (IHTM), Kolkata, West Bengal, India

Date of Web Publication19-Jul-2019

Correspondence Address:
Priyanka Samal
Institute of Hematology and Transfusion Medicine (IHTM), Kolkata, West Bengal
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijc.IJC_303_18

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 » Abstract 


INTRODUCTION: To compare the efficacy and safety of imatinib and cytarabine (ara-c) combination versus imatinib monotherapy in newly diagnosed patients with chronic phase chronic myeloid leukemia (CML-CP).
MATERIALS AND METHODS: This prospective, randomized study included adult patients (age >18 years) with newly diagnosed CML-CP. Patients received either a single oral dose of imatinib 400 mg/day in combination with a subcutaneous injection of ara-c 20 mg/m2/day (imatinib + ara-c) or a single oral dose of imatinib 400 mg/day. Primary endpoints were hematological and molecular responses at 3 months and cytogenetic responses at 6 and 12 months. Secondary endpoints included grade 3/4 hematological and nonhematological adverse events (AEs).
RESULTS: Of 30 patients included, 14 were randomized to imatinib + ara-c and 16 to imatinib alone. Complete hematologic response (CHR) at 3 months was higher with imatinib + ara-c vs. imatinib alone (100% vs. 87.5%, P = 0.48). The median time to achieve CHR was significantly (P < 0.001) lower with imatinib + ara-c (32.07 vs. 23.43 days). Molecular response at 3 months was significantly higher (P = 0.04) with imatinib + ara-c vs. imatinib alone (100% vs. 68.75%). Complete cytogenetic response was also higher with imatinib + ara-c vs. imatinib alone (42.85% vs. 25% at 6 months and 71.4% vs. 62.5% at 12 months). Neutropenia followed by thrombocytopenia and anemia were the most common AEs. Grade 3/4 hematological and nausea events were significantly (P < 0.05) higher with imatinib + ara-c. Other nonhematological events were not significantly different between the treatments. The median follow-up duration was 20 months (range: 15–23 months).
CONCLUSION: Imatinib with low-dose ara-c can be considered as a potential first-line treatment option for CML-CP.


Keywords: Chronic myeloid leukemia, chronic phase, cytarabine, imatinib mesylate


How to cite this article:
Samal P, Chakrabarti P, Nath UK. A prospective, randomized study to compare the combination of imatinib and cytarabine versus imatinib alone in newly diagnosed patients with chronic phase chronic myeloid leukemia. Indian J Cancer 2019;56:211-5

How to cite this URL:
Samal P, Chakrabarti P, Nath UK. A prospective, randomized study to compare the combination of imatinib and cytarabine versus imatinib alone in newly diagnosed patients with chronic phase chronic myeloid leukemia. Indian J Cancer [serial online] 2019 [cited 2019 Oct 14];56:211-5. Available from: http://www.indianjcancer.com/text.asp?2019/56/3/211/263029





 » Introduction Top


The annual incidence of specifically examined Chronic Myeloid Leukemia (CML) in India quoted in a recent study from the Mumbai Cancer Registry was reported as an age-adjusted rate (AAR; per 100,000) of 0.71 in males and 0.53 in females.[1] According to progression, CML is classified as chronic phase (CP; <10% blasts), accelerated phase (AP; >10%–<20% blasts), and blast crisis (BC; >20% blasts).[2]

Imatinib, a BCR-ABL protein tyrosine of kinase inhibitor (TKI),[3] has been the standard-of-care treatment for Ph+ CML [4] as monotherapy or in combination with other agents, including cytarabine (ara-c) – a preferential inhibitor of neoplastic Ph+ colony-forming units–granulocyte-macrophage. We compared imatinib plus low-dose ara-c with imatinib monotherapy in newly diagnosed Indian patients with CML-CP.


 » Materials and Methods Top


Study population

Patients of either sex (≥18 years) with newly diagnosed CML-CP were included. The key exclusion criteria were as follows: patients with CML-CP without Ph+ on initial cytogenetic study, accelerated/BC phase, elevated serum aspartate/alanine aminotransferase, and pregnant or nursing mothers.

The study protocol was approved by the Institutional Ethics Committee, Institute of Haematology and Transfusion Medicine, Medical College, Kolkata. This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, in accordance with the International Conference on Harmonization's Good Clinical Practice guidelines, applicable regulatory requirements, and in compliance with the protocol. All patients provided informed consent prior to study participation.

Study design

This prospective, randomized study was conducted at the Institute of Haematology and Transfusion Medicine, Medical College, Kolkata, India, from January 2013 to December 2014. Patients were followed up for a median duration of 20 months (range: 15–23 months).

Study treatments

Patients were randomized to either a single oral dose of imatinib 400 mg/day in combination with a subcutaneous (s.c.) injection of ara-c 20 mg/m 2/day (imatinib + ara-c group) for 10 days every month or a single oral dose of imatinib 400 mg/day (imatinib group). Doses were modified in case of grade 3/4 hematological adverse events (AEs).

Dose reduction in the imatinib + ara-c group

In patients with platelet counts at <100 × 109/L or absolute neutrophil count (ANC) <1.5 × 109/L, ara-c was stopped and only imatinib was given with weekly blood count monitoring. Ara-c was restarted when platelet counts were >100 × 109/L or ANC >1.5 × 109/L. Similarly, patients in whom platelet counts were found at <75 × 109/L or ANC <1.25 × 109/L, ara-c was stopped with weekly blood count monitoring and restarted 2 weeks after achieving the platelet counts of >100 × 109/L or ANC >1.5 × 109/L, with 50% dose reduction (to 10 mg/m 2 with first occurrence, then 5 mg/m 2); imatinib was not stopped in these patients. But in patients with reduced platelet counts <50 × 109/L or ANC <1 × 109/L, both ara-c and imatinib were stopped with weekly blood count monitoring; imatinib was restarted when the platelet counts reached >100 × 109/L or ANC >1.5 × 109/L, while ara-C cycle was restarted 2 weeks later with 50% dose reduction (to 10 mg/m 2 with first occurrence, then 5 mg/m 2).

Dose reduction in the imatinib-alone group

In the imatinib group, the drug was stopped if platelet counts reduced to <50 × 109/L and/or ANC <1.0 × 109/L until platelets improved to ≥75 × 109/L and ANC ≥1.5 × 109/L and imatinib continued at the regular dose. In case of further reduction of platelets to <50 × 109/L or ANC <1.0 × 109/L, imatinib was stopped until platelet counts improved to ≥75 × 109/L and ANC ≥1.5 × 109/L, and imatinib was resumed at a reduced dose (200 mg daily).

Study assessments

The efficacy endpoints were complete hematologic and molecular responses at 3 months and cytogenetic response at 6 and 12 months. Complete hematologic response (CHR) was defined as complete normalization of peripheral blood counts, leukocyte count <10 × 109/L, platelet count <450 × 109/L, absence of myelocytes, promyelocytes, or blasts in peripheral blood, and no palpable splenomegaly or disease symptoms. Molecular response was (i) major molecular response defined as ≤0.1% BCR-ABL/control gene ratio on international scale (three-log reduction in BCR-ABL transcripts) and (ii) complete molecular response defined as BCR-ABL transcript nonquantifiable and nondetectable by real-time polymerase chain reaction (RT-PCR). Cytogenetic response was evaluated by interphase fluorescence in situ hybridization (FISH) of bone marrow aspiration samples at 6 months and either FISH or conventional karyotyping of bone marrow at 12 months. Cytogenetic response was (i) complete cytogenetic response defined as undetectable Ph+ cells, (ii) partial cytogenetic response as 1%–35% Ph+ cells, (iii) minor cytogenetic response as 36%–65% Ph+ cells, (iv) minimal cytogenetic response as 66%–95% Ph+ cells, and (v) no cytogenetic response as >95% Ph+ cells. The results of relevant hematological, biochemical, cytogenetic, and molecular studies were noted. The overall response to imatinib was made based on the European LeukemiaNet (ELN) 2009 recommendations.[5] Furthermore, after study completion, ELN 2013 recommendations were available, which defined molecular responses at 3 months as follows: (i) optimal: BCR-ABL1 ≤10% and/or Ph+ ≤35%; (ii) warning: BCR-ABL1 >10% and/or Ph+ 36-95%, and (iii) failure: non-CHR and/or Ph+ >95%. While there were no changes in the measurement of hematologic and cytogenetic response criteria.[6] The safety endpoints were grade 3/4 hematologic and nonhematologic toxicities. AEs were graded using the National Cancer Institute Common Terminology Criteria for Adverse Events criteria version 3.0.[7]

Statistical analysis

Quantitative data were presented by mean and standard deviation and qualitative data by frequency and distribution. Student's t-test was used for statistical comparison of parametric data. The analysis of difference of response and P value was computed from contingency table using Fisher's exact test. P <0.05 was used as a cut-off point for all significance tests. Graphics were done using Excel and SPSS software.


 » Results Top


Patients' disposition and demographics

The study population was 100% Asian (all Indian) between the ages of 18 and 64 years with the majority being male (80%). The baseline median hemoglobin was 9.8 mg/dL (range: 7–12.8 g/dL), total leukocyte count 156.82 × 109/L (range: 87.2–363.87 × 109/L), and platelet count 366 × 109/L (range: 160–700 × 109/L). Risk stratification data on Sokal,[8] Hasford,[9] and EUTOS [10] scores are presented in [Table 1]. Initial cytogenetics showed that all patients had translocation t(9; 22) on initial karyotyping study. In addition to Philadelphia chromosome, 13.33% (4/30) of patients had one of the following chromosomal anomalies and variant translocations t(X; 4), –Y, del 7p or t(1; 7). All patients were BCR-ABL1-positive as per qualitative RT-PCR. The majority of the patients (86%; 26/30) had grade 0–1 [World Health Organization (WHO)[11]] fibrosis and none had grade 3 fibrosis. Overall, baseline characteristics were well-balanced between the groups.
Table 1: Baseline characteristics of study participants (n=30)

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Fourteen patients were randomized to the imatinib + ara-c group and 16 to the imatinib group. All 30 patients qualified for the efficacy and safety analyses [Figure 1]. Ara-c was discontinued in four patients, who did not tolerate dose reductions as defined in the protocol (from 20 to 10 mg/m 2 and further to 5 mg/m 2). In three patients, ara-c was discontinued after three cycles due to grade 3 hematologic toxicities and in one patient after five cycles due to grade 4 gastrointestinal toxicity. Dose reduction was required in 85.7% (12/14) of patients in the imatinib + ara-c arm, of which 50% dose reductions were in nine patients (64.28%) and 75% in three patients (21.42%).
Figure 1: Study participants flow

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Efficacy

Hematologic response at 3 months

The CHR was achieved in 93.33% (28/30) of patients at 3 months. Imatinib + ara-c group showed a higher CHR rate when compared with imatinib group (100% vs. 87.5%, P = 0.48) [Figure 2]. The median time to achieve CHR was significantly lower in the imatinib + ara-c group compared with imatinib group (23 vs. 32 days, P < 0.0001).
Figure 2: Hematologic and molecular responses at 3 months

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Molecular response at 3 months

At 3 months, molecular response was assessed by quantitative RT-PCR to measure BCR-ABL1 transcript levels in all the patients. An optimal response (BCR-ABL1 ≤10% as per ELN 2013 response definition [6]) was observed in 100% of patients in the imatinib + ara-c group compared with 68.75% in the imatinib group (P < 0.04) [Figure 2].

Cytogenetic response at 6 and 12 months

Cytogenetic responses at 6 and 12 months for both the treatment arms are shown in [Figure 3]. At 12 months, a greater proportion of patients showed response (complete, partial, or minor) in the imatinib + ara-c group compared with the imatinib group. Both groups had no statistically significant response at 12 months.
Figure 3: Cytogenetic responses at 6 and 12 months

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Correlation of treatment response with number of ara-c cycles

In the imatinib + ara-c group, there was no statistically significant difference at 12 months in response between patients receiving six or more cycles of ara-c compared with patients receiving less than six cycles of ara-c. The median number of days off imatinib was 72 days in the imatinib + ara-c group compared with 37.5 days in the imatinib group. Although the difference was statistically significant, its effect on prognosis needs to be followed up.

Safety

Grade 3/4 hematological toxicity

The most frequent hematological toxicity observed in both treatment groups was grade 3/4 neutropenia followed by thrombocytopenia and anemia. Only one patient in the imatinib + ara-c group had febrile neutropenia. Overall, hematological toxicities of grade 3/4 were more common (P = 0.001) in the imatinib + ara-c group (85.7%, 12/14) compared with the imatinib group (25%, 4/16) [Table 2].
Table 2: Toxicity profile

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Grade 3/4 nonhematological toxicities

The most common nonhematological toxicities observed in both treatment arms were nausea, vomiting, abdominal pain, fatigue, muscle cramps, skin hypopigmentation, weight gain, and periorbital edema [Table 2]. Patients in the imatinib + ara-c group experienced more nausea and vomiting compared with the imatinib group, and the difference was statistically significant; other nonhematological toxicities were not significantly different.

The median duration of follow-up was 20 months ranging from 15 to 23 months. One patient in the imatinib + ara-c group died at 13 months due to progression to myeloid BC. In this patient, tyrosine kinase domain mutation study showed Y253H mutation, which conferred resistance to both imatinib and nilotinib. All the remaining patients were doing well with regular follow-ups.


 » Discussion Top


This randomized, prospective study of 30 newly diagnosed patients with CML-CP showed that the combination of imatinib and low-dose ara-c had better efficacy compared with imatinib alone. The rationale for the combination of imatinib with ara-c in this study was the results of an in vitro study suggesting possible synergistic antiproliferative effects of this combination.[12] A population of primitive quiescent stem cells has been described from peripheral blood and bone marrow in CML. These cells are Ph+, express elevated levels of CD34+, and can spontaneously exit the G0 phase of cell cycle to enter a continuously proliferating state. It has been shown that in some patients, a proportion of these Ph+ CD34+ quiescent cells were highly insensitive to imatinib mesylate; gene amplification and drug efflux could be a reasonable explanation.[13] These results have raised the critical question of cell dormancy in CML. These cells might also enter cell division, and in this scenario, mutation would confer a growth advantage to the cells leading to clinical relapse. A combination drug therapy may prevent the emergence of drug resistance in such situations and improve the outcomes.

In this study, the median age of patients was 35 years in the imatinib + ara-c group and 40 years in the imatinib group, which reflects the younger age of occurrence of CML in the Indian population when compared with the global population where CML is most frequently diagnosed among people age 65–74 years.[1] There was male preponderance in the study, with a male:female ratio of 4:1, in line with the global trend.[1] The majority of the study patients were at an intermediate risk as per Sokal [8] and Hasford [9] scores and at low risk as per the EUTOS [10] score. All the patients had translocation t(9;22) on initial karyotyping, and four patients had other chromosomal abnormalities at diagnosis. Also, BCR-ABL1 positivity was documented by qualitative RT-PCR of the patients at diagnosis. The WHO grade 1–2 myelofibrosis on bone marrow biopsy was seen in 55% of patients at diagnosis, which, however, did not affect the treatment responses.

The rates of CHR were almost similar in both treatment groups. Cytogenetic responses at 6 and 12 months were also similar with slightly higher complete cytogenetic response rates in the combination group, which was not statistically significant. There was a statistically significant difference in molecular response at 3 months, with higher optimal molecular response rates in the imatinib + ara-c group. This molecular response was measured as per updated ELN 2013 recommendations, though ELN 2009 was mentioned in the study plan. The results are similar to the study by Hurtado-Monroy et al. in patients with CML-CP receiving imatinib 400 mg orally everyday (n = 81) or s.c. imatinib + ara-C 10 mg/m 2/day for 10 days each month (n = 31). In both the groups, CHR was achieved in > 90% of patients. However, imatinib + ara-c achieved in a shorter median time with a higher complete cytogenetic response rate compared with imatinib (48.5% vs. 34%).[14] A French Group [15] showed a CHR rate of 100% at 6 months and complete cytogenetic response in 83% patients at 12 months with the combination.

Grade 3/4 hematological toxicities were significantly higher with the combination therapy (85.7% vs. 25%) with a median follow-up of 20 months. However, nonhematological toxicity was not significantly higher except for nausea/vomiting. In the CML French Group study,[15] grade 3/4 hematologic and nonhematologic toxicities were observed in 53% and 23% of patients, respectively, in the imatinib + ara-c group, but with a longer follow-up of 4 years.

In this study, most (85.7%) of the patients in the imatinib + ara-c arm required dose reduction, of which 64.28% patients required 50% dose reduction and 21.42% patients required 75% dose reduction; nonhematological AEs were the reason for dose reduction. The ara-c treatment was discontinued in four patients: in three patients after third cycle due to grade 3 hematologic toxicities and in one patient after five cycles due to grade 4 gastrointestinal toxicity.

The follow-up period in this study was short and a longer follow-up is necessary to assess whether earlier molecular response achieved with the combination therapy actually translates into better progression free and overall survival. Imatinib was the first TKI available for the treatment of CML followed by the second- and third-generation TKIs.[16] The use of TKIs has been limited in developing countries like India because of high cost and safety issues including vascular toxicities. Hence, combining the drugs with distinct mechanisms of action, that is, imatinib and low-dose ara-c, could be a cost-effective option to achieve higher rates of sustained cytogenetic and molecular remission without cardiac toxicities.

Since the rate of achievement of optimal molecular response at 3 months, a major determinant in achieving a deep and sustained molecular response, was significantly higher with imatinib + ara-c combination, it may prove to be noninferior to the prohibitively expensive second- and third-generation TKIs.

In conclusion, imatinib and ara-c combination showed higher hematologic, molecular, and cytogenetic response compared with imatinib monotherapy in newly diagnosed patients with CML-CP. Imatinib along with low-dose ara-c can be considered as a potential first-line treatment option. However, long-term studies are required to evaluate the efficacy and safety of this combination.

Acknowledgements

The authors thank Mr. Shreekant Sharma, Dr. Venugopal Madhusudhana (Lambda Therapeutic Research Ltd.), Drs. Mujtaba Khan and Nisarg Joshi (Intas Pharmaceuticals Ltd.) for support in developing the concept, additional editorial support and follow up with the journal.

Financial support and sponsorship

The manuscript development support was provided by Intas Pharmaceuticals Ltd.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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Dikshit RP, Nagrani R, Yeole B, et al. Changing trends of chronic myeloid leukemia in greater Mumbai, India over a period of 30 years. Indian J Med Paediatr Oncol 2011;32:96-100.  Back to cited text no. 1
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American Cancer Society. How Is Chronic Myeloid Leukemia Staged? Available from: https://www.cancer.org/cancer/chronic-myeloid-leukemia/detection-diagnosis-staging/staging.html. [Last accessed on 2018 Mar 13].  Back to cited text no. 2
    
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Deininger MW, Goldman JM, Lydon N, Melo JV. The tyrosine kinase inhibitor CGP57148B selectively inhibits the growth of BCR-ABL-positive cells. Blood 1997;9:3691-8.  Back to cited text no. 3
    
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Baccarani M, Rosti G, Castagnetti F, Haznedaroglu I, Porkka K, Abruzzese E, et al. Comparison of imatinib 400 mg and 800 mg daily in the front-line treatment of high-risk, Philadelphia-positive chronic myeloid leukemia: A European LeukemiaNet Study. Blood 2009;19:4497-504.  Back to cited text no. 4
    
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Baccarani M, Cortes J, Pane F, Niederwieser D, Saglio G, Apperley J, et al. Chronic myeloid leukemia: An update of concepts and management recommendations of European LeukemiaNet. J Clin Oncol 2009;35:6041-51.  Back to cited text no. 5
    
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Baccarani M, Deininger MW, Rosti G, Hochhaus A, Soverini S, Apperley JF, et al. European LeukemiaNet recommendations for the management of chronic myeloid leukemia: 2013. Blood 2013;6:872-84.  Back to cited text no. 6
    
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Cancer Therapy Evaluation Program, Common Terminology Criteria for Adverse Events, Version 3.0, DCTD, NCI, NIH, DHHS March 31, 2003 (http://ctep.cancer.gov), Published Date: August 9, 2006.  Back to cited text no. 7
    
8.
Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, et al. Prognostic discrimination in “good-risk” chronic granulocytic leukemia. Blood 1984;4:789-99.  Back to cited text no. 8
    
9.
Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, et al. A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa Writing Committee for the Collaborative CML Prognostic Factors Project Group. J Natl Cancer Inst 1998;11:850-9.  Back to cited text no. 9
    
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Hasford J, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, et al. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood 2011;3:686-92.  Back to cited text no. 10
    
11.
Thiele J, Kvasnicka HM, Facchetti F, Franco V, van der Walt J, Orazi A. European consensus on grading bone marrow fibrosis and assessment of cellularity. Haematologica 2005;8:1128-32.  Back to cited text no. 11
    
12.
Sokal JE, Leong SS, Gomez GA. Preferential inhibition by cytarabine of CFU-GM from patients with chronic granulocytic leukemia. Cancer 1987;1:197-202.  Back to cited text no. 12
    
13.
Graham SM, Jorgensen HG, Allan E, Pearson C, Alcorn MJ, Richmond L, et al. Primitive, quiescent, Philadelphia-positive stem cells from patients with chronic myeloid leukemia are insensitive to STI571 in vitro. Blood 2002;1:319-25.  Back to cited text no. 13
    
14.
Hurtado-Monroy R, Vargas-Viveros P, Candelaria M, Cervera E, Cruz J, Gutierrez O, et al. Imatinib compared with imatinib/cytarabine for the first-line treatment of early philadelphia chromosome–positive chronic myeloid leukemia: Results of a randomized clinical trial of the Mexican Collaborative Leukemia Group. Clin Leuk 2008;2:128-32.  Back to cited text no. 14
    
15.
Gardembas M, Rousselot P, Tulliez M, Vigier M, Buzyn A, Rigal-Huguet F, et al. Results of a prospective phase 2 study combining imatinib mesylate and cytarabine for the treatment of Philadelphia-positive patients with chronic myelogenous leukemia in chronic phase. Blood 2003;13:4298-305.  Back to cited text no. 15
    
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Giles FJ. New directions in the treatment of imatinib failure and/or resistance. Semin Hematol 2009;2(Suppl. 3):S27-33.  Back to cited text no. 16
    


    Figures

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    Tables

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