In case of agranulocytosis:

• treatment must be interrupted immediately and the patient must be withdrawn from the study andmonitored until resolution of the event;
• provide protective isolation; if clinically indicated, admit patient to hospital, obtain regular vital signsand administer appropriate therapy such as antibiotic therapy and granulocyte colony stimulating factor, beginning the same day that the event is identified;
• the patient will be examined the same day, if possible, collecting drug history and physical examination;
• if possible, hemocolture, viral studies (CMV, parvovirus, hepatitis A/B/C), serum ALT, BUN, creatininewill be collected.
• the patient will be monitored daily or more frequently until two successive ANCs are ≥ 1500/mm3.

Furthermore, we remind you that the study protocol requires to monitor neutrophil count weekly for the whole study period. In case of neutropenia, neutrophil count has to be monitored more frequently, even every day, in order to guarantee patients’ safety.

Neutropenia is defined as any ANC < 1500/mm3 confirmed in two consecutive measurements and reported as SAE. In case of an abnormal neutrophil count (neutrophil value < 1500/mm³), a second assessment have to be performed within 48 hours from the first one. In case of moderate neutropenia (neutrophil count 500- 1000/mm³) or agranulocytosis (neutrophil < 500/mm³), it is recommended to repeat neutrophil count on the same day or within 24 hours from the previous assessment and interrupt IMPs even before confirmation.

Management of Neutropenia

The handling and follow up of the patient will depend on the severity of the neutropenia (mild, moderate, severe/agranulocytosis) as follows.

Mild Neutropenia:

– Treatment must be interrupted and patient’s ANC must be monitored every 1-3 days, or more

frequently, until resolution of the event, defined as two consecutive ANC ≥ 1500/mm3.

– If the patient has a mild neutropenia and develops signs of infection (fever), therapy must be

interrupted immediately and ANC must be obtained and monitored every 1-2 days, or more frequently,

until resolution of the event.

– Provide protective isolation; treat the patient as per clinical need and per local protocol (antibiotic

therapy, admission to hospital if clinically indicated). If possible, hemocolture, throat swab, viral studies

(CMV, parvovirus, hepatitis A/B/C), serum ALT, BUN, creatinine will be collected.

– Therapy with DFP or DFX and continuation of trial can be restarted once all symptoms have been

resolved and when it is deemed safe by the Investigator, after having consulted the Coordinating

Investigator, in accordance with Table 4, Section 6.3 “Dose Adjustment”.

Moderate Neutropenia

– treatment must be interrupted and the patient must be withdrawn from the study and monitored until

resolution of the event

– perform early termination visit, which includes: Haematology/ biochemistry, as reported in the protocol, centralized ferritin and CHQ. Furthermore all the partially used, unused, empty DFP bottles or DFX boxes have to be collected and store them at your centre;

– provide protective isolation; if clinically indicated, admit patient to hospital, obtain regular vital signs

and treat the patient as per clinical need and per local protocol (antibiotic therapy and/or granulocyte colony stimulating factor).

– the patient will be examined the same day, if possible, collecting drug history and physical examination;

– if possible, hemocolture, viral studies (CMV, parvovirus, hepatitis A/B/C), serum ALT, BUN, creatinine will be collected.

Severe Neutropenia/Agranulocytos

– treatment must be interrupted immediately and the patient must be withdrawn from the study and

monitored until resolution of the event;

– perform early termination visit, which includes: Haematology/ biochemistry, as reported in the protocol, centralized ferritin and CHQ. Furthermore all the partially used, unused, empty DFP bottles or DFX boxes have to be collected and store them at your centre;

– provide protective isolation; if clinically indicated, admit patient to hospital, obtain regular vital signs

and administer appropriate therapy such as antibiotic therapy and granulocyte colony stimulating factor,

beginning the same day that the event is identified;

– the patient will be examined the same day, if possible, collecting drug history and physical examination;

– if possible, hemocolture, viral studies (CMV, parvovirus, hepatitis A/B/C), serum ALT, BUN, creatinine will be collected.

– the patient will be monitored daily or more frequently until two successive ANCs are ≥ 1500/mm3.

The starting dose is automatically calculated by completing the randomization form in eCRF at the moment of randomization. However, during the months following randomization, the dose can be adjusted according to the patient’s needs, within the approved range (75- 100 mg/kg/day of DFP and 20- 40 mg/kg/day of DFX).