Treatment Protocol for Newky Diagnosed Adult Ph Positive ALL

Not yet recruiting

• Conditions: Philadelphia-Positive ALL; Lymphoblastic Leukemia; Adult ALL
• Interventions: Drug: Vincristine; Drug: Dexamethasone; Drug: Imatinib; Drug: Cytarabine; Drug: Mercaptopurine; Drug: Methotrexate; Drug: Ponatinib; Procedure: allogeneic stem cell transplantation; Procedure: Total body irradiation; Drug: Cyclophosphamide; Drug: Fludarabine

• Registration Number: NCT06175702
• Lead Sponsor: PETHEMA Foundation

Brief Summary

The goal of this prospective, multicenter, open observational study is to assess the efficacy and safety of the treatment for acute lymphoblastic leukemia Ph' positive adult patients with approved combinations of chemotherapy and tyrosine kinase inhibitor (TKI).

Efficay refers to the rate of Complete Molecular Response (BCR::ABL1/ABL1 ratio 0.01%) in eah treatment arm. Safety refers to measurement of i) Adverse events (AEs) and serious adverse events (SAEs) according to standard clinical and laboratory tests (hematology and chemistry, physical examination, vital sign measurements, and diagnostic tests), ii) incidence and degree of cytopenias and iii) incidence and degree of infections.

Low-dose chemotherapy will be given together with the TKI imatinib to patients of all ages as induction to remission phase.

Consolidation treatment will continue with low-dose chemotherapy with imatinib if the patient fullfills both criteria: to show a measurable residual disease (MRD) value lower than 0,01% at 3 month of therapy, and not showing IKZF1plus genetics Those patients have any of these 2 conditions will be considered high-risk patients and will recieve consolidation treatment intensification with low-dose chemotherapy plus ponatinib as TKI and allogeneic stem cell transplantation (allo SCT). The remaining patients (standard-risk) will receive maintenance chemotherapy together with imatinib or ponatinib and will not be submitted to alloSCT.

Detailed Description

The goal of this prospective, multicenter, open observational study is to assess the efficacy and safety of the treatment for acute lymphoblastic leukemia Ph' positive adult patients with approved combinations of chemotherapy and tyrosine kinase inhibitor (TKI).

Efficay refers to the rate of Complete Molecular Response (BCR::ABL1/ABL1 ratio 0.01%) in each treatment arm. Safety refers to measurement of i) Adverse events (AEs) and serious adverse events (SAEs) according to standard clinical and laboratory tests (hematology and chemistry, physical examination, vital sign measurements, and diagnostic tests), ii) incidence and degree of cytopenias and iii) incidence and degree of infections.

Low-dose chemotherapy induction phase with vincristine (dose 1.5 mg/m2 at days 1, 8, 15 and 22), dexamethasone (dose 40 mg days 1-2, 8-9,15-16 and 22-23) will be given together with the TKI imatinib (dose 600 mg from day to consolidation start) to all patients of all ages as induction to remission phase.

Consolidation treatment will continue with low-dose chemotherapy with methotrexate (dose 1000 mg/m2 on day 1 with 24h infusion) and arabinoside of cytarabine (dose 1000 mg/m2/ days 1, 3 and 5 with 2h infusion) with imatinib (dose 600 mg per day) if the patient fullfills both criteria: i) to show a measurable residual disease (MRD) value \<0,01% at 3 month of therapy, and ii) not showing IKZF1plus genetics.

Those patients having any of these 2 conditions will be considered high-risk patients and will recieve consolidation treatment intensification with low-dose chemotherapy (same as described above) plus ponatinib (dose 30 mg per day) as TKI and allogeneic stem cell transplantation (alloSCT) followed by maintenance chemotherapy with mercaptopurine (dose 50 mg/m2 on days 1 to 28) and methotrexate (dose 20 mg/m2 on days 1, 8, 15 and 22) together with imatinib (dose 600 mg per day) or ponatinib (15 mg per day) up to 5 years. The remaining patients (standard-risk) will receive maintenance chemotherapy (as described above) together with imatinib (dose 600 mg per day) or ponatinib (15 mg per day) up to 5 years and will not be submitted to alloSCT.

Study Timeline

• Status Verified: 2023-11
• Study First Submitted: 2023-11-17
• Study First Submitted QC: 2023-12-15
• Last Update Submitted: 2023-12-15
• Study First Posted: 2023-12-19
• Last Update Posted: 2023-12-19
• Study Start: 2023-12-25
• Primary Completion: 2028-12-25
• Study Completion: 2030-12-25

Recruitment & Eligibility

• Status: NOT_YET_RECRUITING
• Sex: All
• Target Recruitment: 150

Inclusion Criteria

1. Patients with de novo avute lymphoblastic leukeima (ALL) Philadelphia chromosome-positive (BCR::ABL1) aged ≥18 years.
2. CML blast crisis will be included. These patients will always receive transplantation, regardless of the molecular response or the genetic risk, following the recommendations of the SEHH CML group (Chronic Myleoid Leukemia Group from the Spanish Society of Hematology).
3. Performance status 0-2; patients with performance status>2 attributable to ALL can be included.
4. Patients without functional alteration of organs; liver function: total bilirubin, GOT, GPT, GGT and alkaline phosphatase less than 3 times the upper limit of the normal range of the laboratory; renal function: serum creatinine <2 mg/dl or creatinine clearance > 30 ml/min (except altered renal function attributable to ALL); normal heart function: EF ventricular > 50%; absence of severe chronic respiratory disease. In case that the alterations are secondary to the disease, it is at the discretion of the physician to determine if the patient can be included in the study.

Exclusion Criteria

1. Any other subtype of ALL.
2. Patients with chronic liver disease.
3. Patients with chronic respiratory failure.
4. Renal failure not due to ALL.
5. Lipase and amylase>1.5× ULN.
6. Patients with positive HIV serology.
7. Serious neurological alterations not due to ALL.
8. Serious general condition condition (grades 3 or 4 on the WHO scale) not attributable to ALL.
9. Pregnant or breastfeeding women.
10. Impaired cardiac function (defined by an ejection fraction less than 50%), any clinically significant active or uncontrolled cardiovascular condition, uncontrolled hypertension, arrhythmias, ischemic cardiovascular or neurological events, deep vein thrombosis, pulmonary thromboembolism, history of acute pancreatitis in the year before diagnosis of ALL or history of chronic pancreatitis and triglycerides >450 mg/dL.

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Not complete molecular response or high-risk genetics (IKZF1plus)	Dexamethasone	Patients in Complete Remission and without Complete Molecular Response at the end of Induction therapy or showing the IKZF1plus genotype, will receive consolidation treatment with ponatinib and chemotherapy followed by allogeneic stem cell transplantation and maintenance therapy.
Not complete molecular response or high-risk genetics (IKZF1plus)	Total body irradiation	Patients in Complete Remission and without Complete Molecular Response at the end of Induction therapy or showing the IKZF1plus genotype, will receive consolidation treatment with ponatinib and chemotherapy followed by allogeneic stem cell transplantation and maintenance therapy.
Not complete molecular response or high-risk genetics (IKZF1plus)	allogeneic stem cell transplantation	Patients in Complete Remission and without Complete Molecular Response at the end of Induction therapy or showing the IKZF1plus genotype, will receive consolidation treatment with ponatinib and chemotherapy followed by allogeneic stem cell transplantation and maintenance therapy.
Complete molecular response and low risk genetics	Imatinib	Patients in Complete Remission and Complete Molecular Response at end Induction therapy will receive consolidation with imatinib (or dasatinib if intolerance) and chemotherapy, unless they show the IKZF1plus genotype, which will imply switch to the not complete molecular response or high-risk genetics (IKZ1plus) group.
Complete molecular response and low risk genetics	Vincristine	Patients in Complete Remission and Complete Molecular Response at end Induction therapy will receive consolidation with imatinib (or dasatinib if intolerance) and chemotherapy, unless they show the IKZF1plus genotype, which will imply switch to the not complete molecular response or high-risk genetics (IKZ1plus) group.
Complete molecular response and low risk genetics	Dexamethasone	Patients in Complete Remission and Complete Molecular Response at end Induction therapy will receive consolidation with imatinib (or dasatinib if intolerance) and chemotherapy, unless they show the IKZF1plus genotype, which will imply switch to the not complete molecular response or high-risk genetics (IKZ1plus) group.
Complete molecular response and low risk genetics	Cytarabine	Patients in Complete Remission and Complete Molecular Response at end Induction therapy will receive consolidation with imatinib (or dasatinib if intolerance) and chemotherapy, unless they show the IKZF1plus genotype, which will imply switch to the not complete molecular response or high-risk genetics (IKZ1plus) group.
Complete molecular response and low risk genetics	Methotrexate	Patients in Complete Remission and Complete Molecular Response at end Induction therapy will receive consolidation with imatinib (or dasatinib if intolerance) and chemotherapy, unless they show the IKZF1plus genotype, which will imply switch to the not complete molecular response or high-risk genetics (IKZ1plus) group.
Complete molecular response and low risk genetics	Mercaptopurine	Patients in Complete Remission and Complete Molecular Response at end Induction therapy will receive consolidation with imatinib (or dasatinib if intolerance) and chemotherapy, unless they show the IKZF1plus genotype, which will imply switch to the not complete molecular response or high-risk genetics (IKZ1plus) group.
Not complete molecular response or high-risk genetics (IKZF1plus)	Vincristine	Patients in Complete Remission and without Complete Molecular Response at the end of Induction therapy or showing the IKZF1plus genotype, will receive consolidation treatment with ponatinib and chemotherapy followed by allogeneic stem cell transplantation and maintenance therapy.
Not complete molecular response or high-risk genetics (IKZF1plus)	Ponatinib	Patients in Complete Remission and without Complete Molecular Response at the end of Induction therapy or showing the IKZF1plus genotype, will receive consolidation treatment with ponatinib and chemotherapy followed by allogeneic stem cell transplantation and maintenance therapy.
Not complete molecular response or high-risk genetics (IKZF1plus)	Imatinib	Patients in Complete Remission and without Complete Molecular Response at the end of Induction therapy or showing the IKZF1plus genotype, will receive consolidation treatment with ponatinib and chemotherapy followed by allogeneic stem cell transplantation and maintenance therapy.
Not complete molecular response or high-risk genetics (IKZF1plus)	Cytarabine	Patients in Complete Remission and without Complete Molecular Response at the end of Induction therapy or showing the IKZF1plus genotype, will receive consolidation treatment with ponatinib and chemotherapy followed by allogeneic stem cell transplantation and maintenance therapy.
Not complete molecular response or high-risk genetics (IKZF1plus)	Mercaptopurine	Patients in Complete Remission and without Complete Molecular Response at the end of Induction therapy or showing the IKZF1plus genotype, will receive consolidation treatment with ponatinib and chemotherapy followed by allogeneic stem cell transplantation and maintenance therapy.
Not complete molecular response or high-risk genetics (IKZF1plus)	Methotrexate	Patients in Complete Remission and without Complete Molecular Response at the end of Induction therapy or showing the IKZF1plus genotype, will receive consolidation treatment with ponatinib and chemotherapy followed by allogeneic stem cell transplantation and maintenance therapy.
Not complete molecular response or high-risk genetics (IKZF1plus)	Cyclophosphamide	Patients in Complete Remission and without Complete Molecular Response at the end of Induction therapy or showing the IKZF1plus genotype, will receive consolidation treatment with ponatinib and chemotherapy followed by allogeneic stem cell transplantation and maintenance therapy.
Not complete molecular response or high-risk genetics (IKZF1plus)	Fludarabine	Patients in Complete Remission and without Complete Molecular Response at the end of Induction therapy or showing the IKZF1plus genotype, will receive consolidation treatment with ponatinib and chemotherapy followed by allogeneic stem cell transplantation and maintenance therapy.

Primary Outcome Measures

Name	Time	Method
Overall survival	5 Years	Improvement of OS compared to that observed in the previous protocols (PETHEMA LALPh08 and LALOPh07).

Secondary Outcome Measures

Name	Time	Method
Change the complete molecular response (CMR) rate with Ponatinib	5 Years	Change the CMR rate at the end of consolidation with the administration of ponatinib to those patients who do not achieve CMR at the end of induction or have high-risk genetics (IKZF1plus).
Limit the number of alloTPH compared to that observed in the previous protocols (PETHEMA LALPh08 and LALOPh07).	5 Years	Limit the number of alloTPH to any of the following: * Lack of CMR at the end of consolidation.; * High-risk genetics (IKZF1plus).
Maintenance	5 Years	To assess the number of non-transplanted participants who receive maintenance treatment.
Treatment with TKI after HSCT	5 Years	To assess the number of transplanted patients who receive TKI maintenance treatment preemptively (upon of MRD\>0.01%).
Assess the frequency and degree of Adverse Events	5 Years	Assess the frequency of cytopenias and degree. Assess the frequency of infections and degree. Assess the frequency of vascuar events and degree. Assess the frequency of hepatic events and degree. Assess the frequency of pancreatic events and degree.