Department of Medicine, Hematology/Oncology
Contributions
Type: Oral Presentation
Presentation during EHA20: From 12.06.2015 12:00 to 12.06.2015 12:15
Location: Room C1
Background
Tyrosine kinase inhibitors such as imatinib induce a high rate of complete hematologic remission (CHR) in Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL), but the overall prognosis particularly in elderly patients (pts.) remains poor, primarily due to relapse. Nilotinib is a potent ABL kinase inhibitor (TKI) approved for treatment of CML. Data on its efficacy in Ph+ ALL are limited.
Aims
The EWALL (European Working Group for Adult ALL) initiated a prospective, investigator-initiated multicenter European clinical trial to examine the efficacy and safety of nilotinib in conjunction with a chemotherapy backbone in elderly patients (above 55 years of age) with newly diagnosed Ph+ ALL.
Methods
Male or female pts. > 55 years with untreated Ph+ and/or BCR-ABL1 positive ALL were eligible if they had a WHO performance status of 0-2, adequate organ function and had signed written informed consent. The trial was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the ethics committees of all participating centres (registered under NCT01528085). After a pre-phase with dexamethasone (Dex) and cyclophosphamide (optional), nilotinib was administered at 400 mg BID and given continuously thereafter. During induction, nilotinib was combined with vincristine (VCR) and Dex, repeated weekly for 4 weeks. Consolidation cycles consisted of nilotinib 400 mg BID, methotrexate (MTX) and asparaginase for cycles 1, 3 and 5 and cytarabine for cycles 2, 4 and 6. Maintenance phase consisted of nilotinib, 6-MP, MTX and Dex/VCR. The primary end-point is the rate of pts. without an event (defined as relapse, death, SAE or study treatment discontinuation) at 12 months, secondary endpoints were the rate of CHR after induction, death during induction or in CHR, event free (and overall) survival, the rate of molecular response defined by BCR-ABL/ABL ratios < 0.1% (MMR) and < 0.001% (CMR), respectively.
Results
As of December 2015, 56 pts. (25 male, 31 female) have been enrolled. Median age is 65 years (55-85 years), twelve pts. are older than 70 years of age. To date, all pts. are evaluable for safety and 47 pts. are evaluable for efficacy. The CHR rate is 87 %, one pt. was refractory (2%), one pt. had a partial remission (2%). One pt. died during induction therapy (2%), three pts. discontinued therapy before CR evaluation. With a median follow-up of 5.5 months, 34 of the 41 pts. who achieved CR are in CCR and 3 pts. relapsed, two of whom had discontinued study treatment to undergo allogeneic SCT. 11 pts. with documented induction response have discontinued study treatment prematurely because of transfer to allogeneic SCT, as explicitly permitted by the protocol. 9 pts. of them are transplanted. 11 pts. discontinued for various other reasons. The rate of molecular remission (MMR) after induction (25 pts. evaluable) was 45.5 %, with 5 pts. having undetectable BCR-ABL1 transcripts. During consolidation, 30 of 40 pts. (80%) had a MMR, and BCR-ABL transcripts were undetectable in 10 of 40 pts. (20%). Tolerability has been acceptable. Infectious events and neutropenic fever predominated, individual SAEs included metabolic, cardiovascular, neurologic, renal and hepatic events.
Summary
Nilotinib in conjunction with chemotherapy according to the EWALL-PH-02 protocol is highly effective and well tolerated in elderly pts. with newly diagnosed Ph+ ALL. Molecular response rates are high and MRD levels in responding pts. continue to decrease with time.
Keyword(s): Acute lymphoblastic leukemia, BCR-ABL, Tyrosine kinase inhibitor
Session topic: ALL clinical trials
Type: Oral Presentation
Presentation during EHA20: From 12.06.2015 12:00 to 12.06.2015 12:15
Location: Room C1
Background
Tyrosine kinase inhibitors such as imatinib induce a high rate of complete hematologic remission (CHR) in Philadelphia positive (Ph+) acute lymphoblastic leukaemia (ALL), but the overall prognosis particularly in elderly patients (pts.) remains poor, primarily due to relapse. Nilotinib is a potent ABL kinase inhibitor (TKI) approved for treatment of CML. Data on its efficacy in Ph+ ALL are limited.
Aims
The EWALL (European Working Group for Adult ALL) initiated a prospective, investigator-initiated multicenter European clinical trial to examine the efficacy and safety of nilotinib in conjunction with a chemotherapy backbone in elderly patients (above 55 years of age) with newly diagnosed Ph+ ALL.
Methods
Male or female pts. > 55 years with untreated Ph+ and/or BCR-ABL1 positive ALL were eligible if they had a WHO performance status of 0-2, adequate organ function and had signed written informed consent. The trial was conducted in accordance with the principles of the Declaration of Helsinki and was approved by the ethics committees of all participating centres (registered under NCT01528085). After a pre-phase with dexamethasone (Dex) and cyclophosphamide (optional), nilotinib was administered at 400 mg BID and given continuously thereafter. During induction, nilotinib was combined with vincristine (VCR) and Dex, repeated weekly for 4 weeks. Consolidation cycles consisted of nilotinib 400 mg BID, methotrexate (MTX) and asparaginase for cycles 1, 3 and 5 and cytarabine for cycles 2, 4 and 6. Maintenance phase consisted of nilotinib, 6-MP, MTX and Dex/VCR. The primary end-point is the rate of pts. without an event (defined as relapse, death, SAE or study treatment discontinuation) at 12 months, secondary endpoints were the rate of CHR after induction, death during induction or in CHR, event free (and overall) survival, the rate of molecular response defined by BCR-ABL/ABL ratios < 0.1% (MMR) and < 0.001% (CMR), respectively.
Results
As of December 2015, 56 pts. (25 male, 31 female) have been enrolled. Median age is 65 years (55-85 years), twelve pts. are older than 70 years of age. To date, all pts. are evaluable for safety and 47 pts. are evaluable for efficacy. The CHR rate is 87 %, one pt. was refractory (2%), one pt. had a partial remission (2%). One pt. died during induction therapy (2%), three pts. discontinued therapy before CR evaluation. With a median follow-up of 5.5 months, 34 of the 41 pts. who achieved CR are in CCR and 3 pts. relapsed, two of whom had discontinued study treatment to undergo allogeneic SCT. 11 pts. with documented induction response have discontinued study treatment prematurely because of transfer to allogeneic SCT, as explicitly permitted by the protocol. 9 pts. of them are transplanted. 11 pts. discontinued for various other reasons. The rate of molecular remission (MMR) after induction (25 pts. evaluable) was 45.5 %, with 5 pts. having undetectable BCR-ABL1 transcripts. During consolidation, 30 of 40 pts. (80%) had a MMR, and BCR-ABL transcripts were undetectable in 10 of 40 pts. (20%). Tolerability has been acceptable. Infectious events and neutropenic fever predominated, individual SAEs included metabolic, cardiovascular, neurologic, renal and hepatic events.
Summary
Nilotinib in conjunction with chemotherapy according to the EWALL-PH-02 protocol is highly effective and well tolerated in elderly pts. with newly diagnosed Ph+ ALL. Molecular response rates are high and MRD levels in responding pts. continue to decrease with time.
Keyword(s): Acute lymphoblastic leukemia, BCR-ABL, Tyrosine kinase inhibitor
Session topic: ALL clinical trials