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The prognosis of patients with chronic myeloid leukemia (CML) has improved significantly since the introduction of BCR-ABL1 tyrosine kinase inhibitors (TKIs)
.
Starting in the chronic phase, the use of TKIs combined with chemotherapy can induce remission, prolong patient survival, and reduce disease progression to blast-phase chronic myeloid leukemia (CML-BP)
.
However, in clinical practice, 5%-7% of patients treated with imatinib and 2%-5% of patients treated with second-generation TKIs progressed to blastic phase, and 5%-10% of patients were diagnosed with CML- BP
.
The prognosis of CML-BP patients is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only possible curative treatment, but it depends on whether patients can reach the chronic phase through salvage therapy
.
There have been previous studies on related induction chemotherapy regimens with or without TKI adjuvant therapy, but no significant effect has been obtained, so more new drug combinations are needed to improve the prognosis of CML-BP patients
.
As an oral TKI, ponatinib has been shown to be effective as a single agent in the treatment of CML-BP in previous studies (PACE study)
.
There are also previous cases that the intensive chemotherapy regimen of fludarabine + cytarabine + idarubicin + granulocyte colony-stimulating factor (FLAG-IDA) can achieve good curative effect in the treatment of CML-BP
.
Therefore, Mhairi Copland et al designed the MATCHPOINT study to determine the tolerability and optimal dose of ponatinib in combination with the FLAG-IDA regimen in patients with CML-BP
.
>>>Research Methods The MMATCHPOINT study is a multicenter Phase I/II study.
The included patients are all aged ≥16 years, diagnosed with Philadelphia chromosome (Ph)-positive or BCR-ABL1-positive CML, suitable for FLAG-IDA chemotherapy, and Patients who did not receive high-dose chemotherapy within 4 weeks of enrollment
.
During the study, patients received ponatinib 30 mg/d at the recommended dose of EffTox from day 1 of the FLAG-IDA treatment regimen to day 28
.
If the hematology recovers after the FLAG-IDA cycle, it means that ponatinib can be continuously administered for more than 28 days
.
If the patient did not experience disease remission after treatment, the dose of ponatinib was increased to 45mg/d, and if drug toxicity occurred, it was reduced to 15mg/d
.
The study was followed up at baseline and on days 1, 2, 3, 4, 5, 8, 15, 22, and 28 of each treatment cycle, or weekly if the recovery period was reached
.
The study also regularly assessed patients' hematologic, cytogenetic, and molecular responses
.
At the time of diagnosis and after induction with ponatinib + FLAG-IDA to the chronic phase, peripheral blood samples should be collected for next-generation gene sequencing
.
Adverse events were measured according to the Common Terminology Criteria for Adverse Events (4th Edition), with ongoing assessment when patients reported adverse events
.
The primary endpoint of the study was to determine the dose of ponatinib and to assess the efficacy and tolerability of ponatinib in combination with FLAG-IDA chemotherapy
.
Secondary endpoints were monitoring ponatinib toxicity, complete cytogenetic response (0% Ph-positive cells), major molecular response (BCR-ABL1 level ≤0.
1%), and complete hematologic response
.
>>>Study Results Between March 19, 2015, and April 26, 2018, a total of 17 patients were enrolled in the MATCHPOINT study, 16 of whom were eligible for the primary endpoint assessment
.
One patient completed only 4 days of the first treatment cycle due to complications caused by CML-BP, but completed the second cycle of ponatinib + FLAG-IDA treatment
.
All patients were included in the analysis of the secondary endpoint
.
The median follow-up time of the study was 41 months (range 36-48 months), and the study process is shown in Figure 1
.
Figure 1 Effective dose of ponatinib, 11 of the 16 patients (69%) reached the chronic phase after the first cycle of ponatinib + FLAG-IDA treatment; 3 patients achieved complete hematologic response, and the other patients All patients had incomplete recovery of peripheral blood counts after adequate evaluation; of the patients with major molecular remission, 5 patients (31%) achieved remission status after the first cycle of ponatinib + FLAG-IDA treatment
.
All 16 patients received 30 mg/d ponatinib, of which 4 (25%) developed dose-limiting toxicities after the first treatment cycle, including fulminant cardiomyopathy and grade 4 alanine aminotransferase elevations.
High in 1 case (6%), cerebral venous sinus thrombosis in 1 case (6%), grade 3 amylase elevation in 1 case (6%), and grade 4 alanine aminotransferase elevation in 1 case (6%)
.
The most common grade 3-4 adverse events included neutropenia (12 [71%]), thrombocytopenia (11 [65%]), anemia (7 [41%]), and febrile Neutropenia (5 patients [29%])
.
The most common non-hematologic grade 3-4 adverse events were pulmonary infection (4 [24%]), pyrexia (3 [18%]), and hypocalcemia (3 [18%])
.
A total of 11 (65%) patients reported 12 serious adverse events, of which 6 (35%) occurred during ponatinib + FLAG-IDA treatment, and 3 (18%) patients on the 29th day after study enrollment Treatment-related deaths occurred at days 71, 94, and 94, and the causes of death included cardiomyopathy, pulmonary hemorrhage, and bone marrow hypoplasia
.
Of the 16 patients who received 1 cycle of ponatinib + FLAG-IDA, 9 (56%) had drug reactions without dose-limiting toxicities, and 2 (13%) had drug reactions as well Dose-Limiting Toxicity, 2 (13%) patients experienced dose-limiting toxicity but no drug response, and 3 (19%) patients had neither drug response nor dose-limiting toxicity
.
The updated EffTox model recommends continued use of ponatinib 30 mg/d
.
The final EffTox model suggested a posterior probability of 68% (95% CI 47%-84%) for ponatinib drug efficacy and 25% (95% CI 8%-41%) for toxicity
.
With ponatinib + FLAG-IDA combined with chemotherapy, patients achieved a 97% probability of achieving a preset efficacy threshold of 45% and above, and a 91% probability of being below the 40% toxicity threshold
.
Therefore, 30 mg/d is the dose that best balances efficacy and toxicity when ponatinib is combined with FLAG-IDA chemotherapy
.
Allo-HSCT response after ponatinib induction 12 of 17 patients (71%) underwent allo-HSCT after ponatinib + FLAG-IDA combined with chemotherapy
.
Five (42%) patients underwent allo-HSCT after 1 induction cycle, with 3 (60%) having a complete cytogenetic response and 1 (20%) having a partial cytogenetic response (Ph-positive cells 35 ).
%)
.
Seven (58%) patients underwent allo-HSCT after 2 cycles of ponatinib + FLAG-IDA, of which 5 (71%) maintained intact cytogenetics since cycle 1 react
.
Three of the 12 patients (25%) had no cytogenetic response after allo-HSCT
.
Of the 5 patients (29%) who had a major molecular response after 1 cycle of ponatinib + FLAG-IDA, 1 (20%) underwent allo-HSCT directly, and 4 (80%) underwent allo-HSCT directly.
The second cycle of consolidation therapy was completed before HSCT
.
Five patients (42%) restarted ponatinib after allo-HSCT, including one patient (8%) whose dose of ponatinib was changed to 15 mg due to valganciclovir-induced cytopenias.
Take every other day
.
The remaining patients after allo-HSCT were affected by insufficient blood count recovery (3 [25%]), liver dysfunction (2 [17%]), and previous dose-limiting toxicity (serum amylase elevation in 1 [8%]).
), sepsis with multiple organ failure (1 patient [8%]) without restarting oral ponatinib
.
Two patients (17%) relapsed after allo-HSCT (5 and 7 months after HSCT, respectively), both died of CML
.
One patient (8%) relapsed 7 months after HSCT, relapsed again at 27 months, and survived 40 months after allo-HSCT
.
An additional 3 patients (25%) died within 6 months after allo-HSCT due to allo-HSCT-related complications
.
Allo-HSCT was not performed in 5 (29%) patients, of whom 1 (20%) had a partial cytogenetic response to ponatinib + FLAG-IDA, and 1 (20%) had a partial cytogenetic response to ponatinib + FLAG-IDA.
FLAG-IDA has a small cytogenetic response
.
Three of the four dose-limiting toxicities included in the primary findings occurred in this group
.
In this adverse-risk cohort, the median overall survival (OS) was 2 months (range 1-3 months); all 5 patients died within 7 months of study initiation
.
Ten (59%) patients died in this study, and the median OS for all patients was 12 months (95% CI 6-not reached, Figure 2)
.
According to Kaplan-meier survival curve estimates, the 1-year OS rate was 47% (95% CI 28%-78%), the 3-year OS rate was 41% (95% CI 23%-73%), and the median disease-free survival was (DFS) has not been reached, and only 2 patients had complete cytogenetic responses
.
Median OS was not reached in patients who underwent allo-HSCT, 7 of 12 (58%) were alive after allo-HSCT, and the median follow-up was 36 months (range 31-43 months)
.
Figure 2 >>> Conclusions The MATCHPOINT study also prospectively evaluated the safety and efficacy of ponatinib combined with FLAG-IDA chemotherapy, and proposed that ponatinib 30 mg/d can produce an acceptable probability of drug toxicity and effective remission rates
.
In conclusion, the MATCHPOINT study showed that ponatinib combined with FLAG-IDA chemotherapy was tolerable and effective
.
References: Mhairi Copland, Daniel Slade, Graham McIlroy, et al.
Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial.
Lancet Haematol [Internet].
2022;9(2):e121–32.
Available from: http://dx.
doi.
org/10.
1016/S2352-3026(21)00370-7 Stamp "read" "Original", we make progress together
.
Starting in the chronic phase, the use of TKIs combined with chemotherapy can induce remission, prolong patient survival, and reduce disease progression to blast-phase chronic myeloid leukemia (CML-BP)
.
However, in clinical practice, 5%-7% of patients treated with imatinib and 2%-5% of patients treated with second-generation TKIs progressed to blastic phase, and 5%-10% of patients were diagnosed with CML- BP
.
The prognosis of CML-BP patients is poor, and allogeneic hematopoietic stem cell transplantation (allo-HSCT) is currently the only possible curative treatment, but it depends on whether patients can reach the chronic phase through salvage therapy
.
There have been previous studies on related induction chemotherapy regimens with or without TKI adjuvant therapy, but no significant effect has been obtained, so more new drug combinations are needed to improve the prognosis of CML-BP patients
.
As an oral TKI, ponatinib has been shown to be effective as a single agent in the treatment of CML-BP in previous studies (PACE study)
.
There are also previous cases that the intensive chemotherapy regimen of fludarabine + cytarabine + idarubicin + granulocyte colony-stimulating factor (FLAG-IDA) can achieve good curative effect in the treatment of CML-BP
.
Therefore, Mhairi Copland et al designed the MATCHPOINT study to determine the tolerability and optimal dose of ponatinib in combination with the FLAG-IDA regimen in patients with CML-BP
.
>>>Research Methods The MMATCHPOINT study is a multicenter Phase I/II study.
The included patients are all aged ≥16 years, diagnosed with Philadelphia chromosome (Ph)-positive or BCR-ABL1-positive CML, suitable for FLAG-IDA chemotherapy, and Patients who did not receive high-dose chemotherapy within 4 weeks of enrollment
.
During the study, patients received ponatinib 30 mg/d at the recommended dose of EffTox from day 1 of the FLAG-IDA treatment regimen to day 28
.
If the hematology recovers after the FLAG-IDA cycle, it means that ponatinib can be continuously administered for more than 28 days
.
If the patient did not experience disease remission after treatment, the dose of ponatinib was increased to 45mg/d, and if drug toxicity occurred, it was reduced to 15mg/d
.
The study was followed up at baseline and on days 1, 2, 3, 4, 5, 8, 15, 22, and 28 of each treatment cycle, or weekly if the recovery period was reached
.
The study also regularly assessed patients' hematologic, cytogenetic, and molecular responses
.
At the time of diagnosis and after induction with ponatinib + FLAG-IDA to the chronic phase, peripheral blood samples should be collected for next-generation gene sequencing
.
Adverse events were measured according to the Common Terminology Criteria for Adverse Events (4th Edition), with ongoing assessment when patients reported adverse events
.
The primary endpoint of the study was to determine the dose of ponatinib and to assess the efficacy and tolerability of ponatinib in combination with FLAG-IDA chemotherapy
.
Secondary endpoints were monitoring ponatinib toxicity, complete cytogenetic response (0% Ph-positive cells), major molecular response (BCR-ABL1 level ≤0.
1%), and complete hematologic response
.
>>>Study Results Between March 19, 2015, and April 26, 2018, a total of 17 patients were enrolled in the MATCHPOINT study, 16 of whom were eligible for the primary endpoint assessment
.
One patient completed only 4 days of the first treatment cycle due to complications caused by CML-BP, but completed the second cycle of ponatinib + FLAG-IDA treatment
.
All patients were included in the analysis of the secondary endpoint
.
The median follow-up time of the study was 41 months (range 36-48 months), and the study process is shown in Figure 1
.
Figure 1 Effective dose of ponatinib, 11 of the 16 patients (69%) reached the chronic phase after the first cycle of ponatinib + FLAG-IDA treatment; 3 patients achieved complete hematologic response, and the other patients All patients had incomplete recovery of peripheral blood counts after adequate evaluation; of the patients with major molecular remission, 5 patients (31%) achieved remission status after the first cycle of ponatinib + FLAG-IDA treatment
.
All 16 patients received 30 mg/d ponatinib, of which 4 (25%) developed dose-limiting toxicities after the first treatment cycle, including fulminant cardiomyopathy and grade 4 alanine aminotransferase elevations.
High in 1 case (6%), cerebral venous sinus thrombosis in 1 case (6%), grade 3 amylase elevation in 1 case (6%), and grade 4 alanine aminotransferase elevation in 1 case (6%)
.
The most common grade 3-4 adverse events included neutropenia (12 [71%]), thrombocytopenia (11 [65%]), anemia (7 [41%]), and febrile Neutropenia (5 patients [29%])
.
The most common non-hematologic grade 3-4 adverse events were pulmonary infection (4 [24%]), pyrexia (3 [18%]), and hypocalcemia (3 [18%])
.
A total of 11 (65%) patients reported 12 serious adverse events, of which 6 (35%) occurred during ponatinib + FLAG-IDA treatment, and 3 (18%) patients on the 29th day after study enrollment Treatment-related deaths occurred at days 71, 94, and 94, and the causes of death included cardiomyopathy, pulmonary hemorrhage, and bone marrow hypoplasia
.
Of the 16 patients who received 1 cycle of ponatinib + FLAG-IDA, 9 (56%) had drug reactions without dose-limiting toxicities, and 2 (13%) had drug reactions as well Dose-Limiting Toxicity, 2 (13%) patients experienced dose-limiting toxicity but no drug response, and 3 (19%) patients had neither drug response nor dose-limiting toxicity
.
The updated EffTox model recommends continued use of ponatinib 30 mg/d
.
The final EffTox model suggested a posterior probability of 68% (95% CI 47%-84%) for ponatinib drug efficacy and 25% (95% CI 8%-41%) for toxicity
.
With ponatinib + FLAG-IDA combined with chemotherapy, patients achieved a 97% probability of achieving a preset efficacy threshold of 45% and above, and a 91% probability of being below the 40% toxicity threshold
.
Therefore, 30 mg/d is the dose that best balances efficacy and toxicity when ponatinib is combined with FLAG-IDA chemotherapy
.
Allo-HSCT response after ponatinib induction 12 of 17 patients (71%) underwent allo-HSCT after ponatinib + FLAG-IDA combined with chemotherapy
.
Five (42%) patients underwent allo-HSCT after 1 induction cycle, with 3 (60%) having a complete cytogenetic response and 1 (20%) having a partial cytogenetic response (Ph-positive cells 35 ).
%)
.
Seven (58%) patients underwent allo-HSCT after 2 cycles of ponatinib + FLAG-IDA, of which 5 (71%) maintained intact cytogenetics since cycle 1 react
.
Three of the 12 patients (25%) had no cytogenetic response after allo-HSCT
.
Of the 5 patients (29%) who had a major molecular response after 1 cycle of ponatinib + FLAG-IDA, 1 (20%) underwent allo-HSCT directly, and 4 (80%) underwent allo-HSCT directly.
The second cycle of consolidation therapy was completed before HSCT
.
Five patients (42%) restarted ponatinib after allo-HSCT, including one patient (8%) whose dose of ponatinib was changed to 15 mg due to valganciclovir-induced cytopenias.
Take every other day
.
The remaining patients after allo-HSCT were affected by insufficient blood count recovery (3 [25%]), liver dysfunction (2 [17%]), and previous dose-limiting toxicity (serum amylase elevation in 1 [8%]).
), sepsis with multiple organ failure (1 patient [8%]) without restarting oral ponatinib
.
Two patients (17%) relapsed after allo-HSCT (5 and 7 months after HSCT, respectively), both died of CML
.
One patient (8%) relapsed 7 months after HSCT, relapsed again at 27 months, and survived 40 months after allo-HSCT
.
An additional 3 patients (25%) died within 6 months after allo-HSCT due to allo-HSCT-related complications
.
Allo-HSCT was not performed in 5 (29%) patients, of whom 1 (20%) had a partial cytogenetic response to ponatinib + FLAG-IDA, and 1 (20%) had a partial cytogenetic response to ponatinib + FLAG-IDA.
FLAG-IDA has a small cytogenetic response
.
Three of the four dose-limiting toxicities included in the primary findings occurred in this group
.
In this adverse-risk cohort, the median overall survival (OS) was 2 months (range 1-3 months); all 5 patients died within 7 months of study initiation
.
Ten (59%) patients died in this study, and the median OS for all patients was 12 months (95% CI 6-not reached, Figure 2)
.
According to Kaplan-meier survival curve estimates, the 1-year OS rate was 47% (95% CI 28%-78%), the 3-year OS rate was 41% (95% CI 23%-73%), and the median disease-free survival was (DFS) has not been reached, and only 2 patients had complete cytogenetic responses
.
Median OS was not reached in patients who underwent allo-HSCT, 7 of 12 (58%) were alive after allo-HSCT, and the median follow-up was 36 months (range 31-43 months)
.
Figure 2 >>> Conclusions The MATCHPOINT study also prospectively evaluated the safety and efficacy of ponatinib combined with FLAG-IDA chemotherapy, and proposed that ponatinib 30 mg/d can produce an acceptable probability of drug toxicity and effective remission rates
.
In conclusion, the MATCHPOINT study showed that ponatinib combined with FLAG-IDA chemotherapy was tolerable and effective
.
References: Mhairi Copland, Daniel Slade, Graham McIlroy, et al.
Ponatinib with fludarabine, cytarabine, idarubicin, and granulocyte colony-stimulating factor chemotherapy for patients with blast-phase chronic myeloid leukaemia (MATCHPOINT): a single-arm, multicentre, phase 1/2 trial.
Lancet Haematol [Internet].
2022;9(2):e121–32.
Available from: http://dx.
doi.
org/10.
1016/S2352-3026(21)00370-7 Stamp "read" "Original", we make progress together
