Clofarabine-cyclophosphamide as Salvage Therapy for Refractory and Relapsed Acute Lymphoblastic Leukemia (ALL) Adults

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.

Inclusion criteria

• Signed written informed consent according to IGH/EU/GCP and national local laws.
• Age 18-60 years.
• ALL with B-/T-precursor phenotype refractory to first line therapy.
• ALL with B-/T-precursor phenotype 1st isolated bone marrow relapse, occurring < 24 months from the achievement of first CR, after chemotherapy or hematopoietic stem-cell transplantation (HSCT) defined as follows:

• ≥ 5% leukemic blasts in the bone marrow not attributable to another cause (e.g. marrow regeneration); if there are no circulating blasts and the bone marrow contain 5-20% leukemic blasts, a repeat bone marrow performed at least a week later is necessary to confirm relapse.
• ECOG performance status 0-2 or reversible ECOG 3 score following intensive care of complications.
• Adequate hepatic and renal function, unless considered due to organ leukemic involvement:

• Serum creatinine <1.5 mg/dl; if serum creatinine >1.5 mg/dl, then the estimated glomerular filtration rate (GFR) must be > 60 mL/min/1.73 m2 as calculated by the Modification of Diet in Renal Disease equation where Predicted GFR (ml/min/1.73 m2) = 186 x (Serum Creatinine)-1.154 x (age in years)-0.023 x (0.742 if patient is female), x (1.212) if patient is black.
• Serum bilirubin ≤ 1.5 x upper limit of normal (ULN).
• Aspartate transaminase (AST)/alanine transaminase (ALT) ≤ 2.5 x ULN.
• Alkaline phosphatase ≤ 2.5 x ULN.

Exclusion criteria

• Prior exposure to Clofarabine or, in primary refractory patients only, to Cyclophosphamide during induction courses.
• Patients relapsed > 24 months from first CR. - Philadelphia chromosome-positive (Ph+) ALL.
• Diagnosis of Burkitt-type/B-ALL, or B-/T-lymphoblastic lymphoma with < 25% bone marrow involvement.
• Concurrent or isolated central nervous system (CNS) relapse.
• Pre-existing, uncontrolled pathology such as cardiac disease (congestive/ischemic, acute myocardial infarction within the past 3 months, untreatable arrythmias, NYHA classes III and IV).
• Severe neurological or psychiatric disorder that impairs the patient's ability to understand and sign the informed consent, or to cope with the intended treatment plan.
• Active uncontrolled systemic fungal, bacterial, viral, or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment).
• HIV positive serology or active hepatitis infection. - Concurrent diagnosis of active cancer requiring concurrent chemotherapy and/or radiotherapy, and/or with life expectancy < 1 year.
• Patients who are pregnant or adults of reproductive potential not employing an effective method of birth control (women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of Clofarabine-Cyclophosphamide). Post menopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drugs.