The Pharmacogenomics add-on requires 2X 5ml blood EDTA for further DNA analyses.
Note this is an add-on study to NCT 01949129, THE ALL SCTped FORUM study. Please refer to the main study for further details.

Acute Lymphoblastic Leukemia

Blood samples (2x5ml EDTA tubes) should be collected just before the start of the conditioning regimen from every patient regardless of therapeutic arm by every centre and stored ≤-20°C Patient should be in remission (MRD negative) for this sampling, otherwise the sample should be taken using a mouth swab/saliva (not intravenously).
For second transplant patients, please provide DNA taken before first transplant or a fresh saliva samples.

Pharmacogenomics

Bu PK analysis after the first dose of IV Bu (+potential subsequent ones).
Blood sampling:
->For Bu 4 X/d: Before the first Bu dose (Time 0), then straight after the end of infusion (Time 1), then at 15 min (Time 2), 30 min (Time 3), 1 hour (Time 4) and 4 hour (Time 5) after the end of infusion
->For Bu 1 X/d: Before the first Bu dose (Time 0), then straight after the end of infusion (Time 1), then at 1 hour (Time 2), 3 hour (Time 3), 5 hour (Time 4), 7 hour (Time 5) and 11 hour (Time 6) after the end of infusion.
For centers not performing BU TDM, perform Dried Blood Sampling (DBS) analysis:
-> 0.5ml blood sample should be collected and 5µl spotted onto DBS cards in duplicate. Dry them max 5 hours and then keep in a sealed envelope and store at -80°C, as below

Busulfan plasma level measurements

Hôpital Cantonal de Genève, Département de Pédiatrie

Universitäts-Kinderspital beider Basel (UKBB), Onkologie/Hämatologie

HUG Hôpitaux Universitaire de Genève, Unité d'onco-hématologie pédiatrique

Universitäts-Kinderspital

ALL SCTped FORUM - Pharmacogenomic Study (add-on Study)

Allogeneic Stem Cell Transplant for Children and Adolescents With Acute Lymoblastic Leukemia FORUM - Pharmacogenomic Study (add-on Study)

Genotyping of candidates genes related to pharmacokinetics and pharmacodynamics of the studied agents.
Association study between the herein genetic variants and the below mentioned phenotypes (odd ratio).

defined as the first of 3 consecutive days with an absolute neutrophil count of 0.5x10^9/L or higher

Defined as the first of 3 consecutive days with platelet counts higher that 20x10^9/L without transfusion

Defined by persistent pancytopenia with no evidence of hematologic recovery of donor cells beyond 28 days after transplantation, and secondary graft failure by a rapid decrease in neutrophil count after successful engraftment

the time of transplant until all causes of death after transplant not related to relapse

the time of transplant until death, relapse or graft failure, whichever occurs first.

the time between transplantation and death due to any causes

Swiss Pediatric Oncology Group

ALL SCTped Forum

Pentostatin/Busulfan/Rituximab/Allogeneic Hematopoietic Cell Transplant (HCT).
Pre-conditioning therapy:
All participants will receive pentostatin 4 mg/m^2 on day -28. Patients may receive additional doses on days -21 & -14 depending on cell counts.
Conditioning:
Patients will receive anti-seizure prophylaxis with lorazepam 0.5 mg every 6 hours beginning day -6.
Intravenous Busulfan (1st dose) at a dose of 200mg/m^2 on day -4.
Patient will then receive pentostatin at a dose of 4 mg/m^2 by intravenous infusion over 1-2 hours on days -4, -3.
Intravenous Busulfan (2nd dose) will be administered on day (-2) to target a total AUC of 16,000 +/- 1600.
Hematopoietic progenitor cells to be infused at least 36 hours after last dose of Busulfan.
Rituximab: Patients with CD20+ expressing malignancies will be treated with rituximab at a dose of 375 mg/m^2 according to prescribing and institutional guidelines.

Pentostatin/Busulfan/Rituximab/Allogeneic Hematopoietic Cell Transplant (HCT)
Pre-conditioning therapy:
All participants receive pentostatin 4 mg/m^2 on day -28, may receive additional doses on days -21 & -14 depending on cell counts.
Conditioning:
Anti-seizure prophylaxis with lorazepam 0.5 mg every 6 hours beginning day -6
Intravenous Busulfan (1st dose) at a dose of 200mg/m^2 on day -4
Pentostatin, 4 mg/m^2 by intravenous infusion over 1-2 hours on days -4, -3
Intravenous Busulfan (2nd dose) on day (-2) to target a total AUC of 16,000 +/- 1600
Hematopoietic progenitor cells infused at least 36 hours after last dose of Busulfan
Patients with CD20+ expressing malignancies treated with rituximab at a dose of 375 mg/m^2 according to prescribing and institutional guidelines

Conditioning Followed by HCT

Sex: Female, Male

Region of Enrollment

The primary endpoint was achievement of >/= 50% donor chimerism in CD3+ peripheral blood lymphocytes by day +28 (± 7) after allogeneic hematopoietic cell transplantation (allo-HCT).

Incidence of Greater Than or Equal to 50% Donor Chimerism

Hematologic engraftment: defined as time to achieve an absolute neutrophil count (ANC) >/= 500/µl for 3 consecutive days or a platelet count of >/= 20,000//µl without the need for platelet support.

Cumulative Incidence of Hematopoietic Cell Engraftment

Median Percentage of Donor Cells in Study Population (Chimerism).

Rate of T-cell (CD3+) and Myeloid (CD33+) Chimerism by Day +28

Rate of T-cell (CD3+) and Myeloid (CD33+) Chimerism by Day +100

The cumulative incidence of NRM after allo-HCT.

Non-relapse Mortality Rate (NRM)

Infections: Incidence of infections (opportunistic and non-opportunistic) following conditioning.

Incidence of Infections

The median time from allo-HCT to the initiation of tacrolimus (TAC) taper.
The median time to onset of acute GVHD (aGVHD). Clinical manifestations of acute GVHD include a classic maculopapular rash; persistent nausea and/or emesis; abdominal cramps with diarrhea; and a rising serum bilirubin concentration.

Time to Incidence of Graft Versus Host Disease (GVHD)

By day +100, the cumulative incidence of GVHD, acute of grades 2-4, and 3-4.
At 2 years, the cumulative incidence of chronic GVHD of any severity according to National Institutes of Health (NIH) consensus criteria. Diagnosis of chronic GVHD requires the presence of at least one diagnostic clinical sign of chronic GVHD or the presence of at least one distinctive manifestation confirmed by pertinent biopsy or other relevant tests in the same or another organ. Furthermore, other possible diagnoses for clinical symptoms must be excluded. No time limit is set for the diagnosis of chronic GVHD.
At 2 years, the cumulative incidence of moderate/severe chronic GVHD.

Incidence of Graft Versus Host Disease (GVHD)

PFS at 2 years post-transplant. PFS, defined as time from day of hematopoietic cell infusion to disease relapse. Relapsed disease: Disease was in complete remission post-transplant but returned (e.g., >5% blast in bone marrow or any peripheral blasts).

Percentage of Participants With Progression Free Survival (PFS)

OS at 2 years post-transplant. OS, defined as time from day of hematopoietic cell infusion to death from any cause.

Percentage of Participants With Overall Survival (OS)

Pentostatin/Busulfan/Rituximab/Allogeneic Hematopoietic Cell Transplant (HCT)
Pre-conditioning therapy:
All participants receive pentostatin 4 mg/m^2 on day -28, may receive additional doses on days -21 & -14 depending on cell counts.
Conditioning:
Anti-seizure prophylaxis with lorazepam 0.5 mg every 6 hours beginning day -6
Intravenous Busulfan (1st dose) at a dose of 200mg/m^2 on day -4
Pentostatin, 4 mg/m^2 by intravenous infusion over 1-2 hours on days -4, -3
Intravenous Busulfan (2nd dose) on day (-2) to target a total area under curve (AUC) of 16,000 +/- 1600
Hematopoietic progenitor cells infused at least 36 hours after last dose of Busulfan
Patients with CD20+ expressing malignancies treated with rituximab at a dose of 375 mg/m^2 according to prescribing and institutional guidelines

Overall Study

Marcie Riches, MD

Hematologic Malignancies

Pre-conditioning therapy:
All participants will receive pentostatin 4 mg/m^2 on day -28. Patients may receive additional doses on days -21 & -14 depending on cell counts.
Participant will receive pentostatin at a dose of 4 mg/m^2 by intravenous infusion over 1-2 hours on days -4, -3.

Pentostatin

Pre-conditioning therapy:
Intravenous Busulfan (1st dose) at a dose of 200mg/m^2 on day -4.
Intravenous Busulfan (2nd dose) will be administered on day (-2) to target a total AUC of 16,000 +/- 1600.

Busulfan

Pre-conditioning therapy:
Patients with CD20+ expressing malignancies will be treated with rituximab at a dose of 375 mg/m^2 according to prescribing and institutional guidelines.

Rituximab

Hematopoietic progenitor cells to be infused at least 36 hours after last dose of Busulfan.

Allogeneic Hematopoietic Cell Transplant

H. Lee Moffitt Cancer Center & Research Institute

Phase II Trial of Pentostatin and Targeted Busulfan

Phase II Trial of Pentostatin and Targeted Busulfan as a Novel Reduced Intensity Regimen for Allogeneic Hematopoietic Stem Cell Transplantation Using Laboratory-Guided (CD4-guided) Immunosuppression.

hepatic veno-occlusive disease/癲癇性発作

ALL SCTped FORUM - Pharmacogenomic Study (add-on Study)

Phase II Trial of Pentostatin and Targeted Busulfan

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