Leukemia, Lymphocytic, Acute
Conditions
Keywords
Leukemia, Lymphocytic, Acute [C04.557.337.428.511], 6-mercaptopurine, methotrexate, asparaginase
Brief summary
The present pharmacokinetic (PK)-pharmacodynamic (PD) study will explore the toxicity and antileukemic response during the initial 3 months of individualised therapy of children and young adults with acute lymphoblastic leukemia (ALL). The investigators will on an individual toxicity-titrated basis attempt to increase the dose intensity of the 6-mercaptopurine used in the two-months post-remission treatment phase of lower risk childhood ALL. This will be performed together with continuous PEG-ASP (every 2nd week) and interspersed HD-MTX (5 g/m\^2) every 3rd week. Thus, the trial will also test the feasibility of this particular drug combination.
Detailed description
In addition to the details above we will also explore * the relationship of the post-HD-MTX MRD-levels with the dose of 6MP, TPMT-activity, DNA-6TGN, E-6TGN, E-MeMP, E-MTX, and presence of ASP-antibodies, * the early development of anti-ASP antibodies during continuous PEG-ASP therapy. The study could improve the understanding of the pharmacodynamics of the 6MP/HD-MTX interaction in combination with PEG-ASP.
Interventions
DRUG6-mercaptopurine
Standard dose 25 mg/m\^2/day. Can be increased up to 75 mg/m\^2/day if the myelosuppression is acceptable (ANC\>0.5 T-count \>50)
Sponsors
Rigshospitalet, Denmark
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* B-lineage ALL * 1-17.9 years * WBC \<100, clinical remission obtained day 2 * Written consent to participation.
Exclusion criteria
* t(9;22) * Hypodiploidy * 11q23-aberrations * TPMT-deficiency * Intolerance to MTX or 6MP
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Toxicity of Treatment in Terms of Number of Participants With Serious Adverse Events or Adverse Events, Reported | 3 months ( 79 days ) | Number of participants following the protocol treatment for the full consolidation therapy with toxicity in this pilot study trying to individually titrate 6-mercaptopurine to the highest tolerable level during Consolidation. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incorporation of 6-thioguanine Nucleotides (6TGN) Into Leukocyte DNA, Development of Asparaginase Antibody Production | During the 3 months consolidation therapy | Biweekly bloodsamples during the 3 months are analyzed for 6TGN incorporation into leucocyte DNA. In addition Methylated Mercaptopurine (MeMP) and Erythrocyte-Methotrexate level is measured |
Countries
Denmark, Sweden
Participant flow
Recruitment details
38 patients were recruited in 3 different countries. Recruitment period 12/01/2007 - 12/21/2008. All recruitments were done in departments of Pediatric Hematology/oncology
Participants by arm
| Arm | Count |
|---|---|
| 6-mercaptopurine All patients received basic 6-mercaptopurine and in addition high-dose methotrexate(HDM) at 3 week intervals ((3 3-week intervals) in total) and PEG-asparaginase at 2 week intervals(5 dosis in total) . Patients received dose increments of 6-mercaptopurine 14 days after High-dose methotrexate if the myelotoxicity was acceptable | 38 |
| Total | 38 |
Baseline characteristics
| Characteristic | 6-mercaptopurine |
|---|---|
| Age, Categorical <=18 years | 38 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants |
| Age, Continuous | 7 years STANDARD_DEVIATION 3 |
| Gender Female | 21 Participants |
| Gender Male | 17 Participants |
| Region of Enrollment Denmark | 12 participants |
| Region of Enrollment Finland | 5 participants |
| Region of Enrollment Sweden | 21 participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 23 / 38 |
| serious Total, serious adverse events | 26 / 38 |
Outcome results
Primary
Toxicity of Treatment in Terms of Number of Participants With Serious Adverse Events or Adverse Events, Reported
Number of participants following the protocol treatment for the full consolidation therapy with toxicity in this pilot study trying to individually titrate 6-mercaptopurine to the highest tolerable level during Consolidation.
Time frame: 3 months ( 79 days )
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 6-mercaptopurine | Toxicity of Treatment in Terms of Number of Participants With Serious Adverse Events or Adverse Events, Reported | 26 Participants |
Secondary
Incorporation of 6-thioguanine Nucleotides (6TGN) Into Leukocyte DNA, Development of Asparaginase Antibody Production
Biweekly bloodsamples during the 3 months are analyzed for 6TGN incorporation into leucocyte DNA. In addition Methylated Mercaptopurine (MeMP) and Erythrocyte-Methotrexate level is measured
Time frame: During the 3 months consolidation therapy