Lymphoblastic Lymphoma
Conditions
Keywords
Lymphoblastic lymphoma
Brief summary
This is a phase II clinical trial using risk-adapted therapy. The treatment is acute lymphoblastic leukemia (ALL)-based therapy, using multi-agent regimens comprising of induction, consolidation, and continuation (maintenance) phases delivered over 24-30 months. Participants will be classified into 3 treatment stratums, based on bone marrow/peripheral blood lymphoma cells involvement at diagnosis and day 8 for T-lymphoblastic lymphoma and bone marrow/peripheral blood lymphoma cells involvement at diagnosis for B-lymphoblastic lymphoma. The Primary Objective of this study is: To improve the outcome of children with lymphoblastic lymphoma (LL) who have minimal disseminated disease (MDD) equal to or more than 1% at diagnosis by using MDD- and minimal residual disease (MRD)- based risk-adapted therapy. The Secondary Objectives of this study are: * To estimate the event-free survival and overall survival of children with lymphoblastic lymphoma who are treated with MDD- or MRD-based risk- directed therapy. * To evaluate the prognostic value of levels of MDD at diagnosis and MRD on day 8 of remission induction.
Detailed description
TREATMENT PLAN Treatment will consist of 3 main phases: remission induction, consolidation \[only for patients with any central nervous system (CNS) disease and/or testicular involvement\], and continuation. * Induction (6-7 weeks). * Consolidation for participants with CNS involvement or those with testicular disease only (10 weeks). * Reintensification - Participants with residual disease any time after induction therapy may receive 1-2 cycles of re-intensification therapy and may proceed to allogeneic stem cell transplant if suitable donor is available. * Continuation Therapy (98-120 weeks). * Intrathecal Chemotherapy (days 1 and 15; if needed also on days 8 and 22) TREATMENT SCHEME T lymphoblastic lymphoma: bone marrow/peripheral blood (BM/PB) involvement (MDD/MRD): Diagnosis: less than 1%; Day 8: +/- (Stratum 1) * Induction * Single dose of Cyclophosphamide * Steroid: prednisone * Continuation: 98 weeks T lymphoblastic lymphoma: BM/PB involvement (MDD/MRD): Diagnosis: equal to or greater than 1%; Day 8: - (Stratum 2) * Induction * Fractionated Cyclophosphamide * Steroid: prednisone * Continuation : 98 weeks T lymphoblastic lymphoma: BM/PB involvement (MDD/MRD): Diagnosis: equal to or greater than 1%; Day 8: + (Stratum 3) * Induction * Fractionated Cyclophosphamide * Steroid: prednisone and dexamethasone * Continuation: 120 weeks B lymphoblastic lymphoma: Stage I-III (Stratum 1) * Induction * Single dose of Cyclophosphamide * Steroid: prednisone * Continuation: 98 weeks B lymphoblastic lymphoma: Stage IV or testicular (Stratum 2) * Induction * Fractionated Cyclophosphamide * Steroid: prednisone * Continuation: 98 weeks Patients with CNS or testicular involvement will receive Consolidation therapy prior to continuation therapy and receive extended maintenance therapy (120 weeks). Any patient with detectable disease (MRD, bone marrow or biopsy of residual mass) at the end of induction may be considered for reintensification and/or hematopoietic stem cell transplantation (HSCT).
Interventions
DRUGPrednisone
Given orally (PO).
DRUGVincristine
Given intravenously (IV).
DRUGDaunorubicin
Given IV.
DRUGPEG-asparaginase
Given intramuscularly (IM) or IV.
Given IM or IV if allergy occurs with the first or second PEG-asparaginase dose.
DRUGDoxorubicin
Given IV.
DRUGCyclophosphamide
Given IV.
DRUGCytarabine
Given IV or IT.
DRUGThioguanine
Given PO.
DRUGClofarabine
Given IV.
DRUGMethotrexate
Given IV, IM or IT.
DRUGMercaptopurine
Given PO.
DRUGDexamethasone
Given PO or IV.
DRUGHydrocortisone
Given IT.
DRUGEtoposide
Given IV.
Sponsors
National University of Singapore
St. Jude Children's Research Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
No minimum to 21 Years
Healthy volunteers
No
Inclusion criteria
1. Diagnosis of newly diagnosed lymphoblastic lymphoma (patients must have \<25% tumor cells in bone marrow by morphology) 2. Age ≤ 21 years 3. Limited prior therapy, including systemic glucocorticoids for 1 week or less, 1 dose of vincristine, emergency radiation therapy to the mediastinum, and 1 dose of IT chemotherapy. Other circumstances must be cleared by PI or co-PI. 4. Written, informed consent and assent following guidelines of the Institutional Review Board, National Cancer Institute (NCI), Food and Drug Administration (FDA), and Office of Human Research Protections (OHRP).
Exclusion criteria
1. Participants with prior therapy, other than therapy specified in 3 above. 2. Participants who are pregnant or lactating. 3. Inability or unwillingness of research participant or legal guardian/representative to give written informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Event-free Survival (EFS) | Two years post therapy. | For EFS, relapse and second malignancies are considered as failures in addition to death in complete remission. The time to EFS will be set to 0 for patients who fail to achieve complete remission. Kaplan-Meier estimates of the OS and EFS curves are computed, along with estimates of standard errors by Peto's method. Please note the unit of measurement of probabilities are percentages. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Probability of Overall Survival (OS) | Two years post therapy. | For OS, only deaths are considered failures for OS. Kaplan-Meier estimates of the OS curves are computed along with estimates of standard errors by Peto's method. Please note the unit of measurement of probabilities are percentages. |
| Minimal Disseminated Disease (MDD) | At Diagnosis | Detectable disease in bone marrow or blood: A binary measure, positive (detectable), negative (non-detectable) |
| Minimal Residual Disease (MRD) | Day 8 | Detectable disease in bone marrow or blood: A binary measure, positive (detectable), negative (non-detectable) |
Countries
United States
Participant flow
Recruitment details
23 eligible patients were recruited between 23MAY2012 and 06DEC2016
Participants by arm
| Arm | Count |
|---|---|
| Stratum 1 Minimal disseminated disease (MDD) \<1% at diagnosis in T-lymphoblastic lymphoma No bone marrow involvement microscopically at diagnosis in B-lymphoblastic lymphoma
Patients should not have:
* Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (\<5 WBC/µL of CSF with blasts) or traumatic LP (\>10 RBC/µL of CSF with blasts)
* Overt testicular involvement (evidenced by ultrasonogram). | 12 |
| Stratum 2 * MDD ≥1% and MRD negative (\<0.01%) on day 8 in T-lymphoblastic lymphoma
* Bone marrow involvement microscopically present at diagnosis in B-lymphoblastic lymphoma
* Any CNS involvement: CNS-3 status (i.e., ≥5 WBC/µL of CSF with blasts or cranial nerve palsy), CNS-2 status (\<5 WBC/µL of CSF with blasts) or traumatic LP (\>10 RBC/µL of CSF with blasts) but does not fulfill the criteria of stratum 3
* Overt testicular involvement (evidenced by ultrasonogram) but does not fulfill the criteria of stratum 3 | 7 |
| Stratum 3 Any patients with MDD ≥1% and MRD positive (≥0.01%) on day 8 in T-lymphoblastic lymphoma | 4 |
| Total | 23 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Death | 0 | 1 | 0 |
| Overall Study | Development of unacceptable toxicity during treatment | 0 | 0 | 1 |
| Overall Study | Relapse (except CNS) | 1 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 0 |
Baseline characteristics
| Characteristic | Stratum 1 | Stratum 2 | Stratum 3 | Total |
|---|---|---|---|---|
| Age, Continuous | 13.0 years | 12.3 years | 13.0 years | 12.9 years |
| Age, Customized <10 years | 5 Participants | 2 Participants | 1 Participants | 8 Participants |
| Age, Customized >=10 years | 7 Participants | 5 Participants | 3 Participants | 15 Participants |
| Race/Ethnicity, Customized Black | 2 Participants | 2 Participants | 1 Participants | 5 Participants |
| Race/Ethnicity, Customized Multiple Race (NOS) | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Non Spanish speaking, Non Hispanic | 12 Participants | 6 Participants | 4 Participants | 22 Participants |
| Race/Ethnicity, Customized NOS Spanish,Hispanic,Latino | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized White | 10 Participants | 4 Participants | 3 Participants | 17 Participants |
| Sex: Female, Male Female | 5 Participants | 3 Participants | 1 Participants | 9 Participants |
| Sex: Female, Male Male | 7 Participants | 4 Participants | 3 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 2 / 12 | 2 / 7 | 0 / 4 | 4 / 23 |
| other Total, other adverse events | 12 / 12 | 7 / 7 | 4 / 4 | 23 / 23 |
| serious Total, serious adverse events | 0 / 12 | 1 / 7 | 0 / 4 | 1 / 23 |
Outcome results
Primary
Probability of Event-free Survival (EFS)
For EFS, relapse and second malignancies are considered as failures in addition to death in complete remission. The time to EFS will be set to 0 for patients who fail to achieve complete remission. Kaplan-Meier estimates of the OS and EFS curves are computed, along with estimates of standard errors by Peto's method. Please note the unit of measurement of probabilities are percentages.
Time frame: Two years post therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum 1 | Probability of Event-free Survival (EFS) | 91.7 percentage of event-free patients |
| Stratum 2 | Probability of Event-free Survival (EFS) | 71.4 percentage of event-free patients |
| Stratum 3 | Probability of Event-free Survival (EFS) | 100 percentage of event-free patients |
| All Enrollments | Probability of Event-free Survival (EFS) | 86.96 percentage of event-free patients |
Secondary
Minimal Disseminated Disease (MDD)
Detectable disease in bone marrow or blood: A binary measure, positive (detectable), negative (non-detectable)
Time frame: At Diagnosis
Population: Fourteen patients had MDD data at diagnosis.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stratum 1 | Minimal Disseminated Disease (MDD) | Negative | 4 participants |
| Stratum 1 | Minimal Disseminated Disease (MDD) | Positive | 1 participants |
| Stratum 2 | Minimal Disseminated Disease (MDD) | Negative | 2 participants |
| Stratum 2 | Minimal Disseminated Disease (MDD) | Positive | 3 participants |
| Stratum 3 | Minimal Disseminated Disease (MDD) | Negative | 0 participants |
| Stratum 3 | Minimal Disseminated Disease (MDD) | Positive | 4 participants |
Secondary
Minimal Residual Disease (MRD)
Detectable disease in bone marrow or blood: A binary measure, positive (detectable), negative (non-detectable)
Time frame: Day 8
Population: Seventeen participants had MRD data at day 8
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Stratum 1 | Minimal Residual Disease (MRD) | Negative | 8 participants |
| Stratum 1 | Minimal Residual Disease (MRD) | Positive | 0 participants |
| Stratum 2 | Minimal Residual Disease (MRD) | Negative | 4 participants |
| Stratum 2 | Minimal Residual Disease (MRD) | Positive | 1 participants |
| Stratum 3 | Minimal Residual Disease (MRD) | Negative | 0 participants |
| Stratum 3 | Minimal Residual Disease (MRD) | Positive | 4 participants |
Secondary
Probability of Overall Survival (OS)
For OS, only deaths are considered failures for OS. Kaplan-Meier estimates of the OS curves are computed along with estimates of standard errors by Peto's method. Please note the unit of measurement of probabilities are percentages.
Time frame: Two years post therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Stratum 1 | Probability of Overall Survival (OS) | 91.7 percentage of patients alive |
| Stratum 2 | Probability of Overall Survival (OS) | 71.4 percentage of patients alive |
| Stratum 3 | Probability of Overall Survival (OS) | 100 percentage of patients alive |
| All Enrollments | Probability of Overall Survival (OS) | 86.96 percentage of patients alive |