Treatment of High Risk Adult Acute Lymphoblastic Leukemia

Study Overview
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Brief Summary
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Current therapeutic protocols for adult ALL consider MRD together with the baseline risk factors (age, WBC count, immunophenotype, cytogenetics) and speed in response to therapy for treatment decisions. On the other hand, the systematic use of allogeneic SCT for all adult patients (pts) with Ph- HR-ALL is still a matter of debate. The aim of the prospective study ALL-AR-03 from the Spanish PETHEMA Group was to evaluate the response to a differentiated therapy (chemotherapy or allogeneic SCT) according to early bone marrow blast clearance and MRD levels (assessed by cytofluorometry at the end of induction and consolidation therapy) in HR Ph- adult ALL patients.

Detailed Description
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HR ALL included one or more of the following baseline parameters: age 30-60 yr, WBC count >25x109/L and 11q23 or MLL rearrangements. Induction therapy included vincristine, prednisone and daunorubicin for 4 weeks. In pts with slow cytologic response to therapy (≥10% blasts in bone marrow assessed on d14) intensified induction with high dose ARA-C and mitoxantrone was administered. Early consolidation therapy included 3 cycles with rotating cytotoxic drugs including high-dose methotrexate, high-dose ARA-C and high-dose asparaginase. Pts. with slow cytologic response on d14 or MRD level >0.05% after consolidation were assigned to allogeneic SCT (related or unrelated) and those with standard cytologic response on d14 and MRD level <0.05% after consolidation received 3 additional cycles of delayed consolidation (identical to those of early consolidation) followed by maintenance therapy up to 2yr in CR.

Official Title
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Treatment of High Risk Adult Acute Lymphoblastic Leukemia

Conditions
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Acute Lymphoblastic Leukemia

Intervention / Treatment
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* Drug: Vincristine
* Drug: Daunorubicin
* Drug: Prednisone
* Drug: Mitoxantrone
* Drug: Cytosine Arabinoside
* Drug: Dexamethasone
* Drug: Methotrexate (MTX)
* Drug: Cytarabine
* Drug: ASP
* Drug: Mercaptopurine
* Drug: Teniposide
* Drug: Hydrocortisone


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: High risk ALL adult patients (age> 15 years)no treated previously High-risk ALL: One or more of the following: Age 30-60 yr. WBC count >25x109/L 11q23 or ALL1/AF4 Very high-risk ALL: HR ALL and one or the following: Slow cytologic response (>10% blasts in BM on d14 of induction therapy). MRD>0.05% (by flow cytometry) at the end of consolidation Exclusion Criteria: L3 ALL or B mature(sIg +) or t(8;14), t(2;8), t(8;22). ALL Ph (BCR/ABL) positive. Bifenotipics ALL as EGIL criteria. Indifferentiated ALL. Patients with cardiac pathology Patients with chronic liver disease in activity fase Pulmonary disease Renal insufficiency not due to ALL Neurological disorders not due to ALL PS (grades 3 and 4) not due to ALL.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Intervention/Treatment |
| --- |
|Drug: Vincristine|Vincristine (VCR): 1.5 mg/m2 (max 2 mg) IV d 1, 8, 15, 22 in induction VCR 2 mg, IV, d 1,8 in consolidation (cycle 1, 2)|
|Drug: Daunorubicin|Daunorubicin (DNR): 60 mg/m2 IV d 1, 8, 15, 22|
|Drug: Prednisone|Prednisone (PDN): 60 mg/m2/d IV or PO, d 1-28|
|Drug: Mitoxantrone|Mitoxantrone:12 mg/m2, IV d 15-17 in induction 12 mg/m2, IV,d 5 in cycle 2 consolidation|
|Drug: Cytosine Arabinoside|ARA-C 2,000 mg/m2/12h IV, d18,19 (4 doses) in induction|
|Drug: Dexamethasone|Dexamethasone 20 mg/m2,IV, d 1-5,10 mg/m2,IV, d 6 and 5 mg/m2,IV, d 7 in Consolidation (3 cycles)|
|Drug: Methotrexate (MTX)|Methotrexate (MTX)3 g/m2,IV, d1 (24h)in consolidation, cycles 1 and 2 MTX (15 mg/m2/wk, IM)in maintenance MTX 15 mg, IT|
|Drug: Cytarabine|Cytarabine 2g/m2/12h, IV d5 in cycle 1 consolidation Cytarabine 2g/m2/12h, IV d 1,2 in cycle 3 consolidation Cytarabine 30 mg, intrathecal|
|Drug: ASP|ASP 25,000 IU/m2, IV, d5 in consolidation (cycle 1, 2, 3)|
|Drug: Mercaptopurine|Mercaptopurine 100 mg/m2, PO, d 1-5 in consolidation|
|Drug: Teniposide|Teniposide 150 mg/m2, IV d 3,4 in consolidation cycle 3|
|Drug: Hydrocortisone|Hydrocortisone 20 mg, IT d 1, 28, 49, 77, 105, 175, 203, 231, 259,287, 311 intrathecal|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To evaluate the response to a differentiated therapy (chemotherapy or allogeneic SCT) according to early bone marrow blast clearance and MRD levels in HR Ph- adult ALL patients. |  | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Acute Lymphoblastic Leukemia, High-Risk (HR), Philadelphia Chromosome-Negative