Acute Promyelocytic Leukemia With t(15;17)(q24.1;q21.2); PML-RARA
Conditions
Brief summary
This phase III trial studies tretinoin and arsenic trioxide in treating patients with newly diagnosed acute promyelocytic leukemia. Standard treatment for acute promyelocytic leukemia involves high doses of a common class of chemotherapy drugs called anthracyclines, which are known to cause long-term side effects, especially to the heart. Tretinoin may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Arsenic trioxide may stop the growth of cancer cells by either killing the cells, by stopping them from dividing, or by stopping them from spreading. Completely removing or reducing the amount of anthracycline chemotherapy and giving tretinoin together with arsenic trioxide may be an effective treatment for acute promyelocytic leukemia and may reduce some of the long-term side effects.
Detailed description
PRIMARY OBJECTIVES: I. To eliminate exposure to conventional chemotherapy (including anthracyclines), for patients with standard risk acute promyelocytic leukemia (APL), through use of arsenic trioxide (ATO) and all-trans retinoic acid (ATRA) (tretinoin) based therapy while achieving an event free survival (EFS) that is not inferior compared to historical controls. II. To significantly reduce exposure to conventional chemotherapy, and in particular, anthracycline exposure, for patients with high risk APL, through use of ATO and ATRA based therapy while achieving an event free survival that is not inferior compared to historical controls. EXPLORATORY OBJECTIVES: I. To analyze the clinical impact of FMS-like tyrosine kinase 3 (FLT3) mutations in pediatric APL. II. To correlate clinical outcomes with the kinetics of reduction in promyelocytic leukemia (PML)/retinoic acid receptor alpha (RARalpha) transcript level by quantitative real-time (RT)-polymerase chain reaction (PCR) (RQ-PCR) in bone marrow and peripheral blood samples from diagnosis to time points during therapy. III. To monitor incidence of coagulopathy complications, utilizing standardized conventional supportive care, and correlate with a battery of coagulation testing. IV. To evaluate the neurocognitive outcomes of patients treated on this protocol using patient-completed, performance-based measures of neuropsychological functioning and parent questionnaire report. OUTLINE: INDUCTION THERAPY: Patients with standard and high risk APL receive tretinoin orally (PO) twice daily (BID) and arsenic trioxide intravenously (IV) over 2-4 hours on days 1-28. High risk APL patients also receive dexamethasone PO or IV BID on days 1-14 and idarubicin IV over 15 minutes on days 1, 3, 5, and 7. Patients achieving hematologic complete remission (hCR)/hematologic complete remission with incomplete blood count recovery (hCRi) may go on to consolidation therapy. Patients who do not achieve hCR/hCRi may continue treatment with tretinoin and arsenic trioxide for up to 70 days. CONSOLIDATION THERAPY: Patients receive tretinoin PO BID on days 1-14 and 29-42 and arsenic trioxide IV over 2-4 hours on days 1-5, 8-12, 15-19, and 22-26. Treatment repeats every 56 days for up to 3 courses in the absence of disease progression or unacceptable toxicity. Patients then receive tretinoin PO BID on days 1-14 and arsenic trioxide IV over 2-4 hours on days 1-5, 8-12, 15-19, and 22-26. MINIMAL RESIDUAL DISEASE (MRD) CONSOLIDATION THERAPY: Patients who have APL in the bone marrow after 2 courses of consolidation therapy receive MRD consolidation therapy prior to continuing onto consolidation course 3. Patients receive cytarabine IV over 1-3 hours every 12 hours on days 1-4; mitoxantrone hydrochloride IV over 15-30 minutes on days 3-6; and tretinoin PO BID on days 1-14. If there are no APL cells in the bone marrow after completion of MRD consolidation therapy, patients continue on to consolidation course 3. After completion of study treatment, patients are followed up monthly for 12 months, every 3 months for 36 months, every 6 months for 48 months, and then annually for 2 years.
Interventions
DRUGArsenic Trioxide
Given IV
DRUGCytarabine
Given IV
DRUGDexamethasone
Given PO or IV
DRUGIdarubicin
Given IV
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGMitoxantrone Hydrochloride
Given IV
OTHERQuality-of-Life Assessment
Ancillary studies
OTHERQuestionnaire Administration
Ancillary studies
DRUGTretinoin
Given PO
Sponsors
Children's Oncology Group
National Cancer Institute (NCI)
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
12 Months to 21 Years
Healthy volunteers
No
Inclusion criteria
* Patients must be newly diagnosed with a clinical diagnosis of APL (initially by morphology of bone marrow or peripheral blood) * Bone marrow is highly preferred but in cases where marrow cannot be obtained at diagnosis, peripheral blood will be accepted * If the RQ-PCR results are known at the time of study enrollment, the patient must demonstrate the PML-RARalpha transcript by RQ-PCR to be eligible * NOTE: A lumbar puncture is not required in order to be enrolled on study nor are lumbar punctures recommended at the time of diagnosis; if the diagnosis of APL is known or suspected, diagnostic lumbar punctures in patients with neurologic symptoms should be deferred until any coagulopathy is corrected; if central nervous system (CNS) disease is suspected or proven, a computed tomography (CT) or magnetic resonance imaging (MRI) should be considered to rule out the possibility of an associated chloroma; if CNS disease is documented, patients are still eligible and will receive protocol directed intrathecal treatments * Patients may receive up to a maximum of 5 days of pre-treatment with ATRA prior to administration of protocol therapy * Treatment with hydroxyurea, corticosteroids (any route) and intrathecal cytarabine prior to beginning protocol directed therapy is allowed; however, it should be noted that lumbar puncture and intrathecal therapy at initial diagnosis of APL is not recommended * All patients and/or their parents or legal guardians must sign a written informed consent * All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met
Exclusion criteria
* Patients with secondary APL are excluded; this includes all patients with APL that may have resulted from prior treatment (chemotherapy or radiation) * Patients with isolated myeloid sarcoma (myeloblastoma, chloroma, including leukemia cutis) but without evidence of APL by bone marrow or peripheral blood morphology are excluded * Patients with a pre-existing diagnosis of a prolonged QT syndrome (even if corrected QT interval \[QTc\] is normal at the time of APL diagnosis) are excluded * Patients with a baseline QTc of \> 450 msec are excluded; Bazett's formula is to be used for measurement of the corrected QT interval: the QT interval (msec) divided by the square root of the RR interval (msec) * Patients with a history or presence of significant ventricular or atrial tachyarrhythmia are excluded * Patients with right bundle branch block plus left anterior hemiblock, bifascicular block are excluded * Patients with serum creatinine \> 3.0 mg/dL and patients on active dialysis for renal dysfunction are excluded * Patients who have received treatment with any other cytotoxic chemotherapy prior to beginning protocol therapy (other than allowed in above criteria) are excluded * Female patients who are pregnant are excluded; patients should not be pregnant or plan to become pregnant while on treatment; a pregnancy test prior to enrollment is required for female patients of childbearing potential * Lactating females who plan to breastfeed their infants are excluded * Sexually active patients of reproductive potential who have not agreed to be abstinent or use 2 forms of effective contraception during treatment through 1 month off therapy are excluded
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Event-free Survival (EFS) in Standard Risk Acute Promyelocytic Leukemia (APL) Patients | Up to 24 months | EFS is defined as the time from on study to failure to achieve hematological complete response (CR) prior to start of consolidation, persistence of molecular positive disease after minimal residual disease (MRD) positive consolidation course, relapse (molecular, morphologic or extramedullary), or death. The Kaplan-Meier method will be used to estimate 2-year EFS along with 90% log-minus-log transformed confidence limits. |
| EFS in High Risk APL Patients | Up to 24 months | EFS is defined as the time from on study to failure to achieve hematological CR prior to start of consolidation, persistence of molecular positive disease after MRD positive consolidation course, relapse (molecular, morphologic or extramedullary), or death. The Kaplan-Meier method will be used to estimate 2-year EFS along with 90% log-minus-log transformed confidence limits. |
Countries
Australia, Canada, New Zealand, Puerto Rico, Saudi Arabia, United States
Contacts
PRINCIPAL_INVESTIGATORMatthew A Kutny
Children's Oncology Group
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard Risk WBC \<10,000 cells/µL | 101 |
| High Risk WBC ≥10,000 cells/µL | 57 |
| Total | 158 |
Baseline characteristics
| Characteristic | Standard Risk | High Risk | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 85 Participants | 53 Participants | 138 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 16 Participants | 4 Participants | 20 Participants |
| Age, Continuous | 13.9 Years STANDARD_DEVIATION 4.5 | 12.3 Years STANDARD_DEVIATION 4.7 | 13.4 Years STANDARD_DEVIATION 4.6 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 32 Participants | 14 Participants | 46 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 56 Participants | 37 Participants | 93 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 13 Participants | 6 Participants | 19 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 13 Participants | 26 Participants |
| Race (NIH/OMB) More than one race | 3 Participants | 0 Participants | 3 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 18 Participants | 7 Participants | 25 Participants |
| Race (NIH/OMB) White | 60 Participants | 34 Participants | 94 Participants |
| Region of Enrollment Australia | 5 participants | 1 participants | 6 participants |
| Region of Enrollment Canada | 6 participants | 2 participants | 8 participants |
| Region of Enrollment United States | 90 participants | 54 participants | 144 participants |
| Sex: Female, Male Female | 48 Participants | 25 Participants | 73 Participants |
| Sex: Female, Male Male | 53 Participants | 32 Participants | 85 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 1 / 101 | 0 / 57 |
| other Total, other adverse events | 89 / 101 | 50 / 57 |
| serious Total, serious adverse events | 3 / 101 | 2 / 57 |
Outcome results
Primary
EFS in High Risk APL Patients
EFS is defined as the time from on study to failure to achieve hematological CR prior to start of consolidation, persistence of molecular positive disease after MRD positive consolidation course, relapse (molecular, morphologic or extramedullary), or death. The Kaplan-Meier method will be used to estimate 2-year EFS along with 90% log-minus-log transformed confidence limits.
Time frame: Up to 24 months
Population: Patients ineligible, did not start treatment, or RQPCR positive not confirmed are excluded from analyses of EFS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Risk | EFS in High Risk APL Patients | 96.1 percentage of participants |
Primary
Event-free Survival (EFS) in Standard Risk Acute Promyelocytic Leukemia (APL) Patients
EFS is defined as the time from on study to failure to achieve hematological complete response (CR) prior to start of consolidation, persistence of molecular positive disease after minimal residual disease (MRD) positive consolidation course, relapse (molecular, morphologic or extramedullary), or death. The Kaplan-Meier method will be used to estimate 2-year EFS along with 90% log-minus-log transformed confidence limits.
Time frame: Up to 24 months
Population: Patients ineligible, did not start treatment, or RQPCR positive not confirmed are excluded from analyses of EFS
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Risk | Event-free Survival (EFS) in Standard Risk Acute Promyelocytic Leukemia (APL) Patients | 97.9 percentage of participants |
Other Pre-specified
Change in Adaptive Functioning, Defined by Declines on the Adaptive Behavior Assessment System-II General Adaptive Behavior Composite Score
One sample t-test on the change of score will be used to examine if there is significant decline in neurocognitive function from end of induction to 2 years off therapy. Linear mixed models using scores from all time-points as outcome will also be used to estimate the change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time frame: End of treatment to 4 years post-treatment
Other Pre-specified
Change in CogState Scores, Defined as a Decline of 5 Units in Mean Scores Apparent at 2 Years Off Therapy
Actual CogState scores for each domain at each time point will be summarized and examined by descriptive statistics and scatter plots. Change in score for a domain from end of induction will be calculated and summarized by descriptive statistics. The mean change of score from end of induction to a later time-point will be estimated with its 95% confidence interval. Linear mixed models using scores from all time-points as outcome will also be used to estimate the change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time frame: End of induction up to 2 years post-treatment
Other Pre-specified
Change in Intellectual Functioning, Defined by Declines on the Wechsler-derived Estimated Intelligence Quotient and Processing Speed Scores
One sample t-test on the change of score will be used to examine if there is significant decline in neurocognitive function from end of induction to 2 years off therapy. Linear mixed models using scores from all time-points as outcome will also be used to estimate the change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time frame: End of treatment to 4 years post-treatment
Other Pre-specified
Change in Memory Functioning, Defined by Declines on the Children's Memory Scale Faces and Stories Memory Scores
One sample t-test on the change of score will be used to examine if there is significant decline in neurocognitive function from end of induction to 2 years off therapy. Linear mixed models using scores from all time-points as outcome will also be used to estimate the change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time frame: End of treatment to 4 years post-treatment
Other Pre-specified
Change in Parent-reported Executive Functioning Over Time, Defined as a Decline of 5 Units in Mean Scores Apparent at 2 Years Off Therapy
Measured by the Behavioral Regulation, Working Memory and Metacognition Indices of the Behavior Rating Inventory of Executive Function. Change in score for a domain from end of induction will be calculated and summarized by descriptive statistics. The mean change of score from end of induction to a later time-point will be estimated with its 95% confidence interval. Linear mixed models using scores from all time-points as outcome will be used to estimate change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time frame: End of induction up to 2 years post-treatment
Other Pre-specified
Change in Parent-reported Psychosocial Functioning Over Time
Psychosocial functioning over time as defined by declines on the Behavior Assessment System for Children-Second Edition (BASC-2) Anxiety, Depression, and Social Skills scores, and the Pediatric Quality of Life Inventory (PedsQL) Total and Physical Health scores.
Time frame: End of treatment to 4 years off-therapy
Other Pre-specified
Change in Parent-reported Quality of Life (QOL) Over Time
QOL over time as defined as declines on the BASC-2 Anxiety, Depression, and Social Skills scores, and the PedsQL Total and Physical Health scores.
Time frame: End of treatment to 4 years
Other Pre-specified
Change in Verbal Learning Functioning, Defined by Declines on the California Verbal Learning Test Total Score
One sample t-test on the change of score will be used to examine if there is significant decline in neurocognitive function from end of induction to 2 years off therapy. Linear mixed models using scores from all time-points as outcome will also be used to estimate the change in scores between time-points with adjustment for within-patient correlation of the score by random effects for individual patients.
Time frame: End of treatment to 4 years post-treatment
Other Pre-specified
Disease Free Survival (DFS)
For patients in remission at the end of induction, the log-rank test will be used to test for differences in DFS for those with end of induction real-time quantitative polymerase chain reaction (RQ-PCR) of \< 1 normalized copy number (NCN) compared with those with end of Induction RQ-PCR \>= 1 NCN.
Time frame: Up to 70 days
Other Pre-specified
Incidence of Serious Early Coagulopathy Events, Defined as Grade 3 or Higher Hemorrhage or Thrombosis
Will calculate the International Society of Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) score and compare the sensitivity and specificity of ISTH with that of thrombomodulin using McNemar's test for paired data. To improve the predictive ability of the ISTH DIC score, will use a stepwise combination of biomarkers. Receiver operating characteristic (ROC) curve will be used to assess the accuracy in prediction of bleeding events during induction and the areas under the ROC curve will be compared.
Time frame: Up to 29 days of induction therapy
Other Pre-specified
Induction Death Rate for Patients With FLT3 Mutations and Wild Type FLT3
A Fisher's exact test will be used to compare the induction death rate for patients with FLT3 mutations to patients with wild type FLT3.
Time frame: Up to 70 days