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Ponatinib is a third-generation tyrosine kinase inhibitor (TKI), suitable for drug-resistant or intolerant chronic phase (CP), accelerated phase (AP) or blast phase (BP) chronic myeloid system Leukemia (CML) patients, Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) or T315I mutation patients
.
Today, the editor compiled 3 articles about the research progress of Pranatinib in the treatment of CML patients in the 2021 ASH annual meeting for readers' reference
.
Abstract No.
: Post-hoc analysis of the effect of baseline BCR-ABL1 levels and mutation status on the efficacy of Ponatinib in patients with chronic myeloid leukemia (CML-CP) in the chronic phase of chronic myeloid leukemia (CML-CP) in the 307OPTIC trial OPTIC (Optimizing Ponatinib Treatment in CP-CML, NCT02467270; Ongoing) is a phase II trial that evaluates the safety and effectiveness of Pranatinib in CP-CML patients who are resistant to ≥2 TKIs or have T315I mutations
.
Research methods CML-CP patients who were resistant to ≥2 TKIs or had BCR-ABL1T315I mutations were randomly assigned to prnatinib at an initial dose of 45 mg/day (group A, 45 mg→15 mg), 30 mg/day ( Group B, 30 mg→15 mg) and 15 mg/day (group C) received treatment in three groups
.
After reaching ≤1% BCR-ABL1IS in cohorts A and B, the dose was reduced to 15 mg
.
The patient may re-add to the starting dose due to no response to treatment
.
The primary endpoint is BCR-ABL1IS≤1% for 12 months; secondary endpoints include cytogenetic and molecular responses and safety results
.
In this analysis, the results were obtained by analyzing the subjects' baseline T315I mutation status and baseline disease burden
.
The BCR-ABL1 mutation was evaluated by Sanger sequencing in a central laboratory (MolecularMD, Portland, OR, USA)
.
The results of the study were 283 patients were randomized (A/B/C: n=94/94/94)
.
At baseline, 84.
1% of patients had a high disease burden (BCR-ABL1IS ≥ 10%), 23.
8% had T3151 mutations, 17.
0% had mutations other than T3151, and 57.
8% had no mutations
.
OPTIC post-mortem analysis showed that all three doses can reduce the burden of disease in drug-resistant patients
.
Regardless of the baseline BCR-ABL1IS level, the 45 mg→15 mg dose group showed the highest BCR-ABL1IS response rate of ≤1% at 36 months
.
Regardless of the status or type of gene mutation, this group of patients ≤ 1% BCR-ABL1IS has the highest response rate, which is 54%-60%
.
Regardless of the mutation status, patients treated with Pranatinib showed good survival results
.
In patients with T315I mutation, the progression-free survival (PFS) of patients was significantly better than that of other groups when the dose of 45mg→15mg was administered
.
In addition to the T315I mutation, patients with other gene mutations also achieved long-term PFS and overall survival (OS)
.
There were no significant differences between the three dose groups in terms of adverse effects during treatment (TEAE) and arterial occlusion events during treatment (TE-AOE)
.
The most common non-hematological TEAEs are hypertension (28%), headache (18%) and increased lipase (17%)
.
The most common hematological TEAEs are thrombocytopenia (40%), neutropenia (26%), and anemia (19%)
.
Overall, 6.
0% of patients experienced TE-AOE during treatment, and 4.
6% of patients experienced TE-AOE ≥ grade 3
.
Research conclusions Previous analysis confirmed that these drug-resistant patients achieved a higher remission rate when receiving Pranatinib treatment
.
Consistent with this, OPTIC post-hoc analysis showed that regardless of the T3151 mutation status at baseline, patients benefited from the three dosing regimens
.
Regardless of the baseline disease burden, according to the BCR-ABL1IS level assessment, group A showed the highest remission rate
.
Abstract No.
3603: Multi-center, prospective and retrospective observational cohort study of prnatinib in Italian CML patients: preliminary analysis of the OITI trial from an observational study of prnatinib in the treatment of CML patients in Italy (OITI ) Aims to evaluate the treatment model and results of CML patients treated in Italy since the approval of Pranatinib, including drug safety and effectiveness
.
Research method OITI is a non-interventional cohort study that included patients ≥ 18 years of age who were diagnosed with chronic, accelerated or blastic phases who had started using Pranatinib in routine clinical treatment from 26 centers in Italy
.
The study population included: one group was a prospective cohort, including patients who started receiving Pranatinib during the enrollment period 12 months after the start of the trial; a group was a retrospective cohort, including patients who received Pranatinib but Patients who died or failed follow-up before the start of the trial; one group was a retrospective/prospective cohort, including patients who had started treatment with Pranatinib before the start of the trial and were still on treatment or follow-up at the end of the trial
.
At the beginning of the study and during routine care visits, demographic, efficacy, and safety data were collected from the patient’s medical records
.
Starting from the first patient enrolled in the group, the duration of the study was 48 months, and the observation period ended 24 months after the last patient enrolled in the group
.
The primary endpoint is the complete cytogenetic response (CCyR) rate of CML-CP patients 6 months after starting Pranatinib
.
In the absence of cytogenetic evaluation, using molecular evaluation, patients with a molecular response (MR) of 2.
0 or better are considered to have CCyR
.
The primary and secondary endpoints were primary molecular response (MMR; MR3.
0), deep molecular response (DMR; MR4.
0 and MR4.
5), and safety
.
This article conducted a preliminary analysis of all evaluable patients with the primary endpoint (median follow-up time of 23.
7 months [1.
3-70.
8])
.
Research results The study included 119 patients (110 CML-CP, 6 CML-AP, 3 CML-BP)
.
Fifty-nine patients (49.
6%) were treated with Pranatinib in the second-line treatment, 41 patients (34.
4%) were treated in the third-line treatment, and 19 patients (16.
0%) were treated in the fourth-line treatment or later
.
The reasons for switching to Pranatinib are mostly adverse events (AE) or drug resistance
.
The starting dose of Pranatinib is 45mg (37.
0%), 30mg (41.
2%) or 15mg (21.
8%)
.
The median duration of treatment was 22.
8 months (range 1.
4-73.
6 months)
.
A total of 178 dose adjustments were made during the study, most of which were due to AEs and doctors’ decisions
.
Except for 1 patient with unavailable baseline data, at 6 months, 80/107 (74.
8%) evaluable CML-CP patients were at CCyR, 29/56 (51.
8%) reached CCyR, 50/50 (100 %) Maintain CCyR; at 6 months, 56 (52.
3%) and 13 (12.
1%) CML-CP patients achieved MMR (MR3) and DMR (MR4-MR5), respectively
.
The results of the PFS rate and OS rate of CML-CP patients are as follows
.
71 patients (59.
7%) had treatment-related adverse events (TRAE), the most common being rash, hypertension (grade 1-2) and thrombocytopenia (grade 3)
.
Two patients (1.
7%) had treatment-related arterial occlusion
.
77 patients stopped using Pranatinib, mainly due to AE (33.
3%), doctor's decision (24.
2%) and other reasons (42.
4%), such as death, disease progression and hematopoietic stem cell transplantation
.
Research conclusions This observational study shows that in standard Italian clinical practice, Pranatinib has good efficacy and safety in CML patients
.
After 6 months, 74.
8% of evaluable CP-CML patients achieved CCyR, 52.
3% and 17.
8% achieved MMR (MR3) and DMR (MR4-MR5), respectively
.
The 2-year survival rate was >88%, and there were no previously unreported safety signals
.
Early medication (84% of patients as second-line and third-line treatment) and careful dose selection seem to be the key to the safety and efficacy results observed in this real-world study
.
Abstract number: 312 Pranatinib combined with FLAG-IDA in the treatment of blast crisis of chronic myeloid leukemia: the final results of the seamless phase I/II dose exploration trial of the British Trial Acceleration Program (TAP) The prognosis of CML-BP patients is extremely poor, allogeneic Stem cell transplantation (alloSCT) is the only cure
.
More importantly, the long-term survival after transplantation depends on whether it can be restored to the chronic stage through salvage treatment
.
Therefore, new treatment options are needed to improve response and transplant results
.
In the TKI era, CML-BP has been relatively rare
.
Therefore, there are few prospective trials needed to guide clinical practice
.
This study reports the final results of a prospective trial that uses an innovative EffTox design to study the efficacy and tolerability of TKI Pranatinib combined with high-dose chemotherapy to improve the remission status and transplant outcome of CML-BP patients
.
Research method UK TAP recruited 17 patients from March 2015 to April 2018 to participate in the seamless phase I/II trial of this exploratory dose.
The trial used prnatinib combined with fludarabine, Cytarabine, granulocyte colony stimulating factor and idarubicin (PON-FLAG-IDA) rescue treatment
.
The researchers used an advanced Bayesian method, EffTox, and considered the efficacy and dose limiting toxicity (DLT) of all patients at the same time, providing a single measure of clinical utility and providing a reference for subsequent dosage recommendations
.
The main purpose is to determine the effective and tolerable dose of Pranatinib combined with chemotherapy based on the EffTox model
.
The main result is reaching the second chronic stage and reaching DLT
.
The secondary results are to explore the efficacy, safety, survival rate and transplant results
.
The results of the study were that 9 of the 17 patients completed one cycle of PON-FLAG-IDA treatment, and 8 patients completed two cycles of treatment
.
After using EffTox analysis, it was determined that the optimal dose of Pranatinib was 30 mg/day
.
Eleven patients returned to the chronic phase, and 4 patients experienced DLT, meeting the pre-specified clinical efficacy and toxicity criteria
.
After PON-FLAG-IDA rescue treatment, 8 patients got CCyR and 5 patients got MMR
.
12 patients underwent alloSCT, of which 5 patients were transplanted after 1 cycle of PON-FLAG-IDA treatment, and 7 patients were transplanted after 2 cycles
.
Among them, 3 patients died and 3 patients relapsed
.
The median OS of all patients was 12 months (95%CI: 6-NR), and the median OS of patients receiving alloSCT had not yet reached
.
Common grade 3-4 hematology AEs are neutropenia (71%), thrombocytopenia (65%), anemia (41%), and leukopenia (41%)
.
Common DLT is cardiomyopathy, cerebral venous sinus thrombosis, elevated amylase, and elevated alanine aminotransferase (ALT)
.
Treatment-related deaths occurred in 3 patients
.
Research conclusions Related trials have shown that the combined use of Pranatinib and high-dose chemotherapy has a certain degree of safety, so that CML-BP patients can recover from the blast phase to the chronic phase.
This is a new treatment strategy for this high-risk group
.
Subsequent patients receiving alloSCT treatment can achieve long-term disease-free survival
.
The EffTox method can effectively use the data of this high-risk patient group and is a model for studying new therapies for other rare cancers
.
References: [1]2021ASH.
Abstract#307.
[2]2021ASH.
Abstract#3603.
[3]2021ASH.
Abstract#312.
Stamp "read the original text", we make progress together
.
Today, the editor compiled 3 articles about the research progress of Pranatinib in the treatment of CML patients in the 2021 ASH annual meeting for readers' reference
.
Abstract No.
: Post-hoc analysis of the effect of baseline BCR-ABL1 levels and mutation status on the efficacy of Ponatinib in patients with chronic myeloid leukemia (CML-CP) in the chronic phase of chronic myeloid leukemia (CML-CP) in the 307OPTIC trial OPTIC (Optimizing Ponatinib Treatment in CP-CML, NCT02467270; Ongoing) is a phase II trial that evaluates the safety and effectiveness of Pranatinib in CP-CML patients who are resistant to ≥2 TKIs or have T315I mutations
.
Research methods CML-CP patients who were resistant to ≥2 TKIs or had BCR-ABL1T315I mutations were randomly assigned to prnatinib at an initial dose of 45 mg/day (group A, 45 mg→15 mg), 30 mg/day ( Group B, 30 mg→15 mg) and 15 mg/day (group C) received treatment in three groups
.
After reaching ≤1% BCR-ABL1IS in cohorts A and B, the dose was reduced to 15 mg
.
The patient may re-add to the starting dose due to no response to treatment
.
The primary endpoint is BCR-ABL1IS≤1% for 12 months; secondary endpoints include cytogenetic and molecular responses and safety results
.
In this analysis, the results were obtained by analyzing the subjects' baseline T315I mutation status and baseline disease burden
.
The BCR-ABL1 mutation was evaluated by Sanger sequencing in a central laboratory (MolecularMD, Portland, OR, USA)
.
The results of the study were 283 patients were randomized (A/B/C: n=94/94/94)
.
At baseline, 84.
1% of patients had a high disease burden (BCR-ABL1IS ≥ 10%), 23.
8% had T3151 mutations, 17.
0% had mutations other than T3151, and 57.
8% had no mutations
.
OPTIC post-mortem analysis showed that all three doses can reduce the burden of disease in drug-resistant patients
.
Regardless of the baseline BCR-ABL1IS level, the 45 mg→15 mg dose group showed the highest BCR-ABL1IS response rate of ≤1% at 36 months
.
Regardless of the status or type of gene mutation, this group of patients ≤ 1% BCR-ABL1IS has the highest response rate, which is 54%-60%
.
Regardless of the mutation status, patients treated with Pranatinib showed good survival results
.
In patients with T315I mutation, the progression-free survival (PFS) of patients was significantly better than that of other groups when the dose of 45mg→15mg was administered
.
In addition to the T315I mutation, patients with other gene mutations also achieved long-term PFS and overall survival (OS)
.
There were no significant differences between the three dose groups in terms of adverse effects during treatment (TEAE) and arterial occlusion events during treatment (TE-AOE)
.
The most common non-hematological TEAEs are hypertension (28%), headache (18%) and increased lipase (17%)
.
The most common hematological TEAEs are thrombocytopenia (40%), neutropenia (26%), and anemia (19%)
.
Overall, 6.
0% of patients experienced TE-AOE during treatment, and 4.
6% of patients experienced TE-AOE ≥ grade 3
.
Research conclusions Previous analysis confirmed that these drug-resistant patients achieved a higher remission rate when receiving Pranatinib treatment
.
Consistent with this, OPTIC post-hoc analysis showed that regardless of the T3151 mutation status at baseline, patients benefited from the three dosing regimens
.
Regardless of the baseline disease burden, according to the BCR-ABL1IS level assessment, group A showed the highest remission rate
.
Abstract No.
3603: Multi-center, prospective and retrospective observational cohort study of prnatinib in Italian CML patients: preliminary analysis of the OITI trial from an observational study of prnatinib in the treatment of CML patients in Italy (OITI ) Aims to evaluate the treatment model and results of CML patients treated in Italy since the approval of Pranatinib, including drug safety and effectiveness
.
Research method OITI is a non-interventional cohort study that included patients ≥ 18 years of age who were diagnosed with chronic, accelerated or blastic phases who had started using Pranatinib in routine clinical treatment from 26 centers in Italy
.
The study population included: one group was a prospective cohort, including patients who started receiving Pranatinib during the enrollment period 12 months after the start of the trial; a group was a retrospective cohort, including patients who received Pranatinib but Patients who died or failed follow-up before the start of the trial; one group was a retrospective/prospective cohort, including patients who had started treatment with Pranatinib before the start of the trial and were still on treatment or follow-up at the end of the trial
.
At the beginning of the study and during routine care visits, demographic, efficacy, and safety data were collected from the patient’s medical records
.
Starting from the first patient enrolled in the group, the duration of the study was 48 months, and the observation period ended 24 months after the last patient enrolled in the group
.
The primary endpoint is the complete cytogenetic response (CCyR) rate of CML-CP patients 6 months after starting Pranatinib
.
In the absence of cytogenetic evaluation, using molecular evaluation, patients with a molecular response (MR) of 2.
0 or better are considered to have CCyR
.
The primary and secondary endpoints were primary molecular response (MMR; MR3.
0), deep molecular response (DMR; MR4.
0 and MR4.
5), and safety
.
This article conducted a preliminary analysis of all evaluable patients with the primary endpoint (median follow-up time of 23.
7 months [1.
3-70.
8])
.
Research results The study included 119 patients (110 CML-CP, 6 CML-AP, 3 CML-BP)
.
Fifty-nine patients (49.
6%) were treated with Pranatinib in the second-line treatment, 41 patients (34.
4%) were treated in the third-line treatment, and 19 patients (16.
0%) were treated in the fourth-line treatment or later
.
The reasons for switching to Pranatinib are mostly adverse events (AE) or drug resistance
.
The starting dose of Pranatinib is 45mg (37.
0%), 30mg (41.
2%) or 15mg (21.
8%)
.
The median duration of treatment was 22.
8 months (range 1.
4-73.
6 months)
.
A total of 178 dose adjustments were made during the study, most of which were due to AEs and doctors’ decisions
.
Except for 1 patient with unavailable baseline data, at 6 months, 80/107 (74.
8%) evaluable CML-CP patients were at CCyR, 29/56 (51.
8%) reached CCyR, 50/50 (100 %) Maintain CCyR; at 6 months, 56 (52.
3%) and 13 (12.
1%) CML-CP patients achieved MMR (MR3) and DMR (MR4-MR5), respectively
.
The results of the PFS rate and OS rate of CML-CP patients are as follows
.
71 patients (59.
7%) had treatment-related adverse events (TRAE), the most common being rash, hypertension (grade 1-2) and thrombocytopenia (grade 3)
.
Two patients (1.
7%) had treatment-related arterial occlusion
.
77 patients stopped using Pranatinib, mainly due to AE (33.
3%), doctor's decision (24.
2%) and other reasons (42.
4%), such as death, disease progression and hematopoietic stem cell transplantation
.
Research conclusions This observational study shows that in standard Italian clinical practice, Pranatinib has good efficacy and safety in CML patients
.
After 6 months, 74.
8% of evaluable CP-CML patients achieved CCyR, 52.
3% and 17.
8% achieved MMR (MR3) and DMR (MR4-MR5), respectively
.
The 2-year survival rate was >88%, and there were no previously unreported safety signals
.
Early medication (84% of patients as second-line and third-line treatment) and careful dose selection seem to be the key to the safety and efficacy results observed in this real-world study
.
Abstract number: 312 Pranatinib combined with FLAG-IDA in the treatment of blast crisis of chronic myeloid leukemia: the final results of the seamless phase I/II dose exploration trial of the British Trial Acceleration Program (TAP) The prognosis of CML-BP patients is extremely poor, allogeneic Stem cell transplantation (alloSCT) is the only cure
.
More importantly, the long-term survival after transplantation depends on whether it can be restored to the chronic stage through salvage treatment
.
Therefore, new treatment options are needed to improve response and transplant results
.
In the TKI era, CML-BP has been relatively rare
.
Therefore, there are few prospective trials needed to guide clinical practice
.
This study reports the final results of a prospective trial that uses an innovative EffTox design to study the efficacy and tolerability of TKI Pranatinib combined with high-dose chemotherapy to improve the remission status and transplant outcome of CML-BP patients
.
Research method UK TAP recruited 17 patients from March 2015 to April 2018 to participate in the seamless phase I/II trial of this exploratory dose.
The trial used prnatinib combined with fludarabine, Cytarabine, granulocyte colony stimulating factor and idarubicin (PON-FLAG-IDA) rescue treatment
.
The researchers used an advanced Bayesian method, EffTox, and considered the efficacy and dose limiting toxicity (DLT) of all patients at the same time, providing a single measure of clinical utility and providing a reference for subsequent dosage recommendations
.
The main purpose is to determine the effective and tolerable dose of Pranatinib combined with chemotherapy based on the EffTox model
.
The main result is reaching the second chronic stage and reaching DLT
.
The secondary results are to explore the efficacy, safety, survival rate and transplant results
.
The results of the study were that 9 of the 17 patients completed one cycle of PON-FLAG-IDA treatment, and 8 patients completed two cycles of treatment
.
After using EffTox analysis, it was determined that the optimal dose of Pranatinib was 30 mg/day
.
Eleven patients returned to the chronic phase, and 4 patients experienced DLT, meeting the pre-specified clinical efficacy and toxicity criteria
.
After PON-FLAG-IDA rescue treatment, 8 patients got CCyR and 5 patients got MMR
.
12 patients underwent alloSCT, of which 5 patients were transplanted after 1 cycle of PON-FLAG-IDA treatment, and 7 patients were transplanted after 2 cycles
.
Among them, 3 patients died and 3 patients relapsed
.
The median OS of all patients was 12 months (95%CI: 6-NR), and the median OS of patients receiving alloSCT had not yet reached
.
Common grade 3-4 hematology AEs are neutropenia (71%), thrombocytopenia (65%), anemia (41%), and leukopenia (41%)
.
Common DLT is cardiomyopathy, cerebral venous sinus thrombosis, elevated amylase, and elevated alanine aminotransferase (ALT)
.
Treatment-related deaths occurred in 3 patients
.
Research conclusions Related trials have shown that the combined use of Pranatinib and high-dose chemotherapy has a certain degree of safety, so that CML-BP patients can recover from the blast phase to the chronic phase.
This is a new treatment strategy for this high-risk group
.
Subsequent patients receiving alloSCT treatment can achieve long-term disease-free survival
.
The EffTox method can effectively use the data of this high-risk patient group and is a model for studying new therapies for other rare cancers
.
References: [1]2021ASH.
Abstract#307.
[2]2021ASH.
Abstract#3603.
[3]2021ASH.
Abstract#312.
Stamp "read the original text", we make progress together
