Posology : מינונים

4.2    Posology and method of administration

BESPONSA should be administered under the supervision of a physician experienced in the use of cancer therapy and in an environment where full resuscitation facilities are immediately available.
When considering the use of BESPONSA as a treatment for relapsed or refractory B cell ALL, baseline CD22 positivity of > 0% using a validated and sensitive assay is required prior to initiating treatment (see section 5.1).

For patients with circulating lymphoblasts, cytoreduction with a combination of hydroxyurea, steroids, and/or vincristine to a peripheral blast count ≤ 10,000/mm3 is recommended prior to the first dose.

Pre-medication with a corticosteroid, antipyretic, and antihistamine is recommended prior to dosing (see section 4.4).

For patients with a high tumour burden, pre-medication to reduce uric acid levels and hydration is recommended prior to dosing (see section 4.4).
Patients should be observed during, and for at least 1 hour after the end of infusion for symptoms of infusion -related reactions (see section 4.4).

Posology

BESPONSA should be administered in 3- to 4-week cycles.
For patients proceeding to haematopoietic stem cell transplant (HSCT), the recommended duration of treatment is 2 cycles. A third cycle may be considered for those patients who do not achieve a complete remission (CR) or complete remission with incomplete haematological recovery (CRi) and minimal residual disease (MRD) negativity after 2 cycles (see section 4.4). For patients not proceeding to HSCT, additional cycles of treatment, up to a maximum of 6 cycles, may be administered. Patients who do not achieve a CR/CRi within 3 cycles should discontinue treatment.

Table 1 shows the recommended dosing regimens.

For the first cycle, the recommended total dose of BESPONSA for all patients is 1.8 mg/m2 per cycle, given as 3 divided doses on Days 1 (0.8 mg/m2), 8 (0.5 mg/m2), and 15 (0.5 mg/m2). Cycle 1 is 3 weeks in duration but may be extended to 4 weeks if the patient achieves a CR or CRi, and/or to allow recovery from toxicity.

For subsequent cycles, the recommended total dose of BESPONSA is 1.5 mg/m2 per cycle given as 3 divided doses on Days 1 (0.5 mg/m2), 8 (0.5 mg/m2), and 15 (0.5 mg/m2) for patients who achieve a CR/Cri, or 1.8 mg/m2 per cycle given as 3 divided doses on Days 1 (0.8 mg/m2), 8 (0.5 mg/m2), and 15 (0.5 mg/m2) for patients who do not achieve a CR/CRi. Subsequent cycles are 4 weeks in duration.

Table 1.     Dosing regimen for Cycle 1 and subsequent cycles depending on response to treatment

Day 1                  Day 8a                  Day 15a
Dosing regimen for Cycle 1
All patients:
Dose (mg/m2)                             0.8                 0.5                                 0.5 Cycle length                                              21 daysb
Dosing regimen for subsequent cycles depending on response to treatment Patients who have achieved a CRc or CRid:
Dose (mg/m2)                             0.5                 0.5                                0.5 Cycle length                                              28 dayse c       d
Patients who have not achieved a CR or CRi :
Dose (mg/m2)                             0.8                 0.5                                0.5 Cycle length                                              28 dayse
Abbreviations: ANC=absolute neutrophil counts; CR=complete remission; CRi=complete remission with incomplete haematological recovery.
a
+/- 2 days (maintain minimum of 6 days between doses).
b
For patients who achieve a CR/CRi, and/or to allow for recovery from toxicity, the cycle length may be extended up to 28 days (i.e., 7-day treatment-free interval starting on Day 21).


Table 1.      Dosing regimen for Cycle 1 and subsequent cycles depending on response to treatment

Day 1                   Day 8a                 Day 15a c
CR is defined as < 5% blasts in the bone marrow and the absence of peripheral blood leukaemic blasts, full recovery of peripheral blood counts (platelets ≥ 100 × 109/L and ANC ≥ 1 × 109/L) and resolution of any extramedullary disease.
d
CRi is defined as < 5% blasts in the bone marrow and the absence of peripheral blood leukaemic blasts, incomplete recovery of peripheral blood counts (platelets < 100 × 109/L and/or ANC < 1 × 109/L) and resolution of any extramedullary disease.
e
7-day treatment-free interval starting on Day 21.

Dose modifications

Dose modification of BESPONSA may be required based on individual safety and tolerability (see section 4.4). Management of some adverse drug reactions may require dosing interruptions and/or dose reductions, or permanent discontinuation of BESPONSA (see sections 4.4 and 4.8). If the dose is reduced due to BESPONSA-related toxicity, the dose should not be re-escalated.

Table 2 and Table 3 show the dose modification guidelines for haematological and non-haematological toxicities, respectively. BESPONSA doses within a treatment cycle (i.e., Days 8 and/or 15) do not need to be interrupted due to neutropenia or thrombocytopenia, but dosing interruptions within a cycle are recommended for non-haematological toxicities.

Table 2.      Dose modifications for haematological toxicities at the start of a treatment cycle (Day 1)

Haematological toxicity                Toxicity and dose modification(s) Levels prior to BESPONSA treatment:
ANC was ≥ 1 × 109/L                  If ANC decreases, interrupt the next cycle of treatment until recovery of ANC to ≥ 1 × 109/L.
Platelet count was                 If platelet count decreases, interrupt the next cycle of ≥ 50 × 109/La                      treatment until platelet count recovers to ≥ 50 × 109/La.
ANC was < 1 × 109/L and/or         If ANC and/or platelet count decreases, interrupt the next platelet count was                 cycle of treatment until at least one of the following occurs: < 50 × 109/La                      - ANC and platelet count recover to at least baseline levels for the prior cycle, or
- ANC recovers to ≥ 1 × 109/L and platelet count recovers to ≥ 50 × 109/La, or
- Stable or improved disease (based on most recent bone marrow assessment) and the ANC and platelet count decrease is considered to be due to the underlying disease
(not considered to be BESPONSA-related toxicity).
Abbreviation: ANC=absolute neutrophil count.
a
Platelet count used for dosing must be independent of blood transfusion.

Table 3.      Dose modifications for non-haematological toxicities at any time during treatment 
Non-haematological toxicity              Dose modification(s)
VOD/SOS or other severe liver            Permanently discontinue treatment (see section 4.4).
toxicity

Table 3.    Dose modifications for non-haematological toxicities at any time during treatment 
Non-haematological toxicity           Dose modification(s)
Total bilirubin > 1.5 × ULN and       Interrupt the dosing until recovery of total bilirubin to AST/ALT > 2.5 × ULN                   ≤ 1.5 × ULN and AST/ALT to ≤ 2.5 × ULN prior to each dose unless due to Gilbert’s disease or haemolysis. Permanently discontinue treatment if total bilirubin does not recover to
≤ 1.5 × ULN or AST/ALT does not recover to ≤ 2.5 × ULN
(see section 4.4).
Infusion- related reaction            Interrupt the infusion and institute appropriate medical management. Depending on the severity of the infusion- related reaction, consider discontinuation of the infusion or administration of steroids and antihistamines. For severe or life-threatening infusion reactions, permanently discontinue treatment (see section 4.4).
Grade ≥ 2a non-haematological         Interrupt treatment until recovery to Grade 1 or pre-treatment toxicity (BESPONSA-related)           grade levels prior to each dose.
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; ULN=upper limit of normal; VOD/SOS=venoocclusive disease/sinusoidal obstruction syndrome.
a
Severity grade according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 3.0.

Table 4 shows the dose modification guidelines depending on the duration of dosing interruptions due to toxicity.

Table 4.    Dose modifications depending on duration of dosing interruption due to toxicity 
Duration of dosing                  Dose modification(s) interruption due to toxicity
< 7 days (within a cycle)           Interrupt the next dose (maintain a minimum of 6 days between doses).
≥ 7 days                            Omit the next dose within the cycle.
≥ 14 days                           Once adequate recovery is achieved, decrease the total dose by 25% for the subsequent cycle. If further dose modification is required, then reduce the number of doses to 2 per cycle for subsequent cycles. If a 25% decrease in the total dose followed by a decrease to 2 doses per cycle is not tolerated, then permanently discontinue treatment.
> 28 days                           Consider permanent discontinuation of BESPONSA.

Special populations

Elderly
No adjustment to the starting dose is required based on age (see section 5.2).

Hepatic impairment

No adjustment to the starting dose is required in patients with hepatic impairment defined by total bilirubin ≤ 1.5 × upper limit of normal (ULN) and aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ≤ 2.5 × ULN (see section 5.2). There is limited safety information available in patients with total bilirubin > 1.5 × ULN and AST/ALT > 2.5 × ULN prior to dosing. Interrupt dosing until recovery of total bilirubin to ≤ 1.5 × ULN and AST/ALT to ≤ 2.5 × ULN prior to each dose unless due to Gilbert’s syndrome or haemolysis. Permanently discontinue treatment if total 
bilirubin does not recover to ≤ 1.5 × ULN or AST/ALT does not recover to ≤ 2.5 × ULN (see Table 3 and section 4.4).

Renal impairment

No adjustment to the starting dose is required in patients with mild, moderate, or severe renal impairment (creatinine clearance [CLcr] 60-89 mL/min, 30-59 mL/min, or 15-29 mL/min, respectively) (see section 5.2). The safety and efficacy of BESPONSA have not been studied in patients with end-stage renal disease.

Paediatric population

The safety and efficacy of BESPONSA in children aged 0 to <18 years have not been established. No data are available. Currently available data are described in sections 4.8, 5.1 and 5.2 but no recommendation on a posology can be made.


Method of administration
BESPONSA is for intravenous use. The infusion must be administered over 1 hour.

BESPONSA should not be administered as an intravenous push or bolus.

BESPONSA must be reconstituted and diluted before administration. For instructions on reconstitution and dilution of BESPONSA before administration, see section 6.6.