Phase III Clinical Study of Allogeneic Stem Cell Transplantation with Reduced Conditioning (RICT) versus Best Standard of Care in Acute Myeloid Leukemia (AML) in First Complete Remission

This study assesses if patients who are suitable for a transplant (and have a suitable bone marrow donor) will have better results if they are treated with a transplant compared to those patients that would have had a transplant but a suitable bone marrow donor was not available and instead received standard chemotherapy. The trial results will show whether future treatment of AML in patients over 50 should always include BMT whenever possible. Who is it for? You may be eligible to join this study if you are aged between 51 and 70 years of age (inclusive), diagnosed with Acute Myeloid Leukaemia (AML) of intermediate or poor prognosis, have achieved first complete remission (CR1) or complete remission with incomplete blood count recovery (CRi), have an indication for reduced intensity conditioning transplantation (RICT) but not myeloablative allogeneic hematopoietic stem cell transplantation (Allo SCT), judged to be able to tolerate further standard consolidation chemotherapy, willing to undergo a RICT if a suitable donor is found, and willing and able to comply with protocol requirements. Trial details Participants in this study will be divided into one of two groups – one group are those who will receive Reduced Intensity Conditioning Transplant (RICT) as an available suitable bone marrow donor (i.e. Matched Sibling Donor (MSD) or Matched Unrelated Donor (MLD)) has been found whilst the other group is comprised of participants will not undergo RICT as a suitable bone marrow donor was not available. Participants in the group that will undergo RICT will proceed as soon as possible to transplant as the next treatment after achieved remission. Due to medical or logistic factors, consolidation course(s) according to institutional practice may be given. Consequently, patients in the RICT group will (before conditioning) receive a total of 1-3 chemotherapy courses. If a patient in the RICT group relapses, or if a contraindication to the assigned treatment occurs, the patient will be treated at the discretion of the clinician. Centres may select any of the following conditioning regimens and are then asked to consistently use the chosen regimen. 1) Intrathecally administered methotrexate will be given to selected patients as per centre routine. As fludarabine is metabolized partly by a renal mechanism (Malspies Sem Oncol 1990), doses of fludarabine need to be modified if the calculated or assessed renal clearance is below the lower limit of the normal range. 2) Busulphan (administered orally or intravenously (IV)) and fludarabine. Fludarabine 30 mg/sqm IV infusion over 30 minutes on day –8 to day – 4 (=five days) for MSDs and on day -9 to day -5 or -4 (= five or six days) for MUDs. Busulphan may be administrated orally or intravenously. Oral busulphan will be administered as a total dose of 8 mg/kg, given as eight doses of 1 mg/kg each on day –4 (two doses), day –3 (four doses) and day –2 (two doses). Intravenous busulphan will be administered with a total dose of 6.4 mg/kg Busulphex (Registered Trademark) given as two doses of 3.2 mg/kg each, administered over 3 hours, on days -3 and -2. In-vivo T depletion with ATG, or alemtuzumab, as per local standards is permitted for MUDs. There shall be an interval of 8 hours between fludarabine and busulphan, and 48 hours between last dose of busulphan and infusion of stem cells. SUPPORTIVE MEASURES POST TRANSPLANT: Supportive measures post-transplant listed below represent basic general recommendations. In principle, centres are free to follow their local standard guidelines including blood transfusion support, antibacterial prophylaxis, herpes simplex virusand varicella zoster prophylaxis, surveillance and pre-emptive treatment of Cytomegalovirus (CMV). , fungal prophylaxis, P. carinii prophylaxis, and the use of Granulocyte colony-stimulating factor (G-CSF) in the post-transplant setting should be individualized. IMMUNOSUPRESSIVE THERAPY: Immunosuppressive therapy in the RICT setting includes the use of eithermethotrexate or mycophenolate mofetil (MMF) in addition to cyclosporine-A (CyA) in this trial. The dose of CyA should be targeted and adjusted to a serum concentration as per center preference. The first doses of CyA are given intravenously to try and ensure adequate levels at the time of transplant. If there is nausea and vomiting anytime during CyA treatment the drug should be given intravenously at the appropriate dose. Blood pressure, renal function tests (creatinine, BUN), electrolytes and magnesium need to be followed closely while receiving CyA at full dose. In principle, cyclosporine should be given IV or orally in full dose from Day –1 until day 60, then be tapered, in the absence of GvHD, and stopped at day +120. However, if Graft versus host Disease (GvHD) occurs, or if justified by chimerism data, CyA dose and duration should be individualized CyA and short course methotrexate. This immunosuppression combination includes full dose CyA and methotrexate. The dose of methotrexate is 15 mg/sqm IV day 1, 10 mg/sqm day 3 and day 6. The use of folinic acid rescue on days 4 and days 7 –10 is optional. A fourth dose (10 mg/sqm) of methotrexate Day +11 with optional use of folinic acid rescue on day +12, should be added after MUD-RICT, or otherwise if the risk of GvHD is considered high. The immunosuppression combination of CyA and MMF includes full dose CyA and MMF. The CyA dosage schedule is described above. The MMF dose, either orally or IV, is 15 mg/kg twice daily. Doses will be rounded to the nearest 250 mg (capsules are 250 mg). Most patients will receive 1000 mg twice daily. After MSD-RICT, and in the absence of GvHD, MMF will be given until day +50 post-treatment and then stopped without tapering. After MUD-RICT, MMF will be given 15mg/kg every 8 hrs to day +40, then tapered to day +96. If there is nausea and vomiting, preventing oral administration, MMF dose should be reduced accordingly, or administered intravenously. GvHD should be treated as per local routines with prednisone/prednisolone. In case of steroid-refractory GvHD, defined as progression after three days or no improvement after 7 days or incomplete response after 14 days of corticosteroid treatment, patients will be managed according to local practice or ongoing studies. Chronic GvHD will be treated according to local practice. Most centers have developed routines for chimerism assessment and immunological intervention. Therefore, only some principles are stated and centers are free to use their own routines as to the rest. For the purpose of this trial, chimerism analysis should be performed at least in PB at +1 month, at D +100 and at 1 year in PB or BM. Extra assessments may be needed in case of remaining MRD or administration of DLI. It is recommended to assess chimerism in T-cells and myeloid cells separately. Remaining or reappearing of host myeloid cells may be used as surrogate marker for MRD. Immunological intervention such as CyA taper or DLI may be considered. SURVEILLANCE AND INTERVENTION: Local or national routines for surveillance and intervention will be applied. Participants in the second study group will not undergo RICT as a suitable bone marrow donor was not available. Instead, they will receive conventional consolidation therapy according to institutional practice or within studies of post consolidation therapy. It is presumed that the participants in this group will receive a total of 3-4 chemotherapy courses. Participants in this group who relapse will be treated at the discretion of the clinician. Relapsed patients may receive any salvage treatment.