Study With a Sequential Clofarabine-cyclophosphamide Combination Schedule as Salvage Therapy for Refractory and Relapsed Acute Lymphoblastic Leukemia (ALL) Adults (LAL1610)

• The primary end-point is the rate of patients in CR after induction therapy. [ Time Frame: At day +28 from start of chemotherapy cycle 1 and after cycle 2 in pts with PR ] [ Designated as safety issue: No ]
  Disappearance of any clinical and laboratoristic sign of ALL. The patient must be transfusion-free with neutrophils >1.0 x109/L and platelets >100 x109/L. BM examination must show absence or reduction of blast cell content (< 5%, none of which obviously leukemic), with cellularity in the normal or slightly hypocellular range and with evidence of trilineage hemopoiesis. BM is examined on day 28 from start of chemotherapy cycle 1, or later as clinically indicated in ill/cytopenic patients, and after cycle 2 in patients with PR proceeding to this treatment.
  
  

• Number of participants with toxicity of grade 2 or greater (CTCAE version 4.0) events [ Time Frame: At 13 months from study entry ] [ Designated as safety issue: Yes ]
  
• Rate of ALL blast cells in apoptosis and DNA damage per patient induced by Clofarabine when used in combination with Cyclophosphamide. [ Time Frame: At 13 months from study entry ] [ Designated as safety issue: No ]
  
• Number of participants with minimal residual disease (MRD) response in remission. [ Time Frame: At week 10, 16 and 22 from start of treatment and the, every three months till study completion ] [ Designated as safety issue: No ]
  
• Disease-free survival (DFS) [ Time Frame: At one year from completion of chemotherapy ] [ Designated as safety issue: No ]
  Disease-free survival (DFS) at 1 year, defined as the time interval between the evaluation of CR and relapse of the disease or death in first CR; patients still alive, in first CR, will be censored at the time of the last follow-up. In this case, the DFS curve will be truncated at 1 year
  
  
• Overall Survival (OS). [ Time Frame: At one year from therapy completion. ] [ Designated as safety issue: No ]
  Overall Survival (OS) at 1 year; defined as the time interval between inclusion and death for any cause; patients still alive will be censored at the time of the last follow-up. In this case, the OS curve will be truncated at 1 year.
  
  
• Cumulative incidence of relapse (CIR). [ Time Frame: At one year from therapy completion. ] [ Designated as safety issue: No ]
  Cumulative incidence of relapse (CIR) at 1 year, it will be calculated from the date of achievement of the first CR, using the cumulative incidence method, considering death in CR as a competing risk. Patients still alive, without a date of relapse, will be censored at the time of the last follow-up. In this case, the CIR curve will be truncated at 1 year.
  
  
• Rate of Disease free survival (DFS) in very high risk and high risk patients [ Time Frame: At one year from therapy completion. ] [ Designated as safety issue: No ]
  DFS in two different risk groups: VHR (very high risk) includes 1st relapse within 6 months from date of 1st CR; HR (high risk) includes relapse after 6 months from date of 1st CR.
  
  
• Rate of Overall Survival (OS) in very high risk and high risk patients [ Time Frame: At one year from therapy completion. ] [ Designated as safety issue: No ]
  OS in two different risk groups: VHR (very high risk) includes 1st relapse within 6 months from date of 1st CR; HR (high risk) includes relapse after 6 months from date of 1st CR.
  
  
• Rate of Cumulative Incidence of Relapse (CIR) in very high risk and high risk patients [ Time Frame: At one year from therapy completion. ] [ Designated as safety issue: No ]
  CIR in two different risk groups: VHR (very high risk) includes 1st relapse within 6 months from date of 1st CR; HR (high risk) includes relapse after 6 months from date of 1st CR.
  
  

Drug: Clofarabine, Cyclophosphamide

The proposed treatment schedule consists of a combination of Clofarabine plus Cyclophosphamide administered over 5 consecutive days (Treatment scheme).

Clofarabine concentrate for solution for infusion should be filtered using a 0.2 micron filter and diluted to a final concentration between 0.15 mg/mL and 0.4 mg/mL with 0.9% sodium chloride injection USP or European Pharmacopeia (EP) normal saline (NS), or 5% dextrose injection (D5W) USP or EP prior to infusion.

Cyclophosphamide should be prepared for parenteral use by adding 0.9% sterile sodium chloride solution. Solutions of cyclophosphamide may be injected intravenously without further dilution or may be infused following further dilution: Dextrose Injection, USP (5% dextrose), Dextrose and Sodium Chloride Injection, USP (5% dextrose and 0.9% sterile sodium chloride), 5% Dextrose and Ringer's Injection.

The proposed treatment schedule consists of a combination of Clofarabine plus Cyclophosphamide administered over 5 consecutive days (Treatment scheme). This is an open, nonrandomized prospective phase II trial aimed to evaluating (1) activity of this combination in terms of CR rate.

• STEP 1. All eligible patients will be screened for the availability of an HLA-matched or partially mismatched compatible HSCT donor, of both family related - or unrelated type (early activation required), including cord blood and haploidentical siblings. Moreover, pre-treatment investigation will include collection and storage of patient ALL cells for specific biological studies relating to sensitivity and response to study chemotherapeutic combination.
• STEP 2. Cycle 1 will be applied to all eligible patients once all enrollment criteria are confirmed.
• STEP 3. After cycle 1, response will be evaluated.
• STEP 4. After remission induction cycle 1, only responsive patients (CR or PR, see below for definitions) could be given cycle 2, according to the opinion of the responsible physician and with a minimum intercycle interval of 4 weeks from day 1 of cycle 1. All NR patients will be declared off study and will not be given a second course with study combination. The suggested treatment following cycle 2 (or cycle 1 if cycle 2 is omitted) is HSCT.