Frontline Treatment Of Ph Research Articles

Frontline Combination of 3 rd Generation TKI Olverembatinib and Blinatumomab for Ph+/Ph-like ALL Patients

Background The combination of dasatinib and blinatumomab represented a chemotherapy-free treatment approach, which had been employed in the management of newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL). A recent study demonstrated that combination therapy of ponatinib with blinatumomab may achieve better efficacy, with a complete molecular response (CMR) rate of 87%. However, some patients required dose reduction or even discontinuation of ponatinib for the occurrence of cardiovascular adverse events. Olverembatinib, a potent third-generation tyrosine kinase inhibitor (TKI), showed both favorable tolerability and significant efficacy in patients with TKI-resistant chronic myeloid leukemia. But its effectiveness in ALL remained unaddressed. Our recent study, a frontline combination of Olverembatinib and PDT-ALL-2016 regime in Ph+ALL, had shown a promising outcome, achieving a complete molecular response (CMR) rate of 84.6% at day 90. Herein, we explored the clinical efficacy of the frontline combination of Olverembatinib and blinatumomab for the treatment of Ph+ and ABL-class Ph-like ALL. Methods From April 2022 to May 2023, 13 patients with Ph+/Ph-like ALL treated with olverembatinib (40mg once every other day) and blinatumomab (administered for a total of 2 weeks followed by 2 weeks of break) were enrolled (Figure 1a). Two patients (15.4%, 2/13) were in Ph-like ALL group with TEL-ABL and EBF1-PDGFRB fusion gene. Five patients (38.5%, 5/13), with a median age of 58 years old, were received ≥2 cycles and eight patients (61.5%, 8/13), with a median age of 34.5 years old, were treated with 1 cycle before HSCT. Result With a median follow-up of 7 months, all patients (100%, 13/13) achieved complete remission (CR) after one cycle of treatment. Among them, nine patients (72.7%, 9/13) achieved complete molecular remission (CMR) after one cycle, and ten patients (90.1%, 10/13) after two cycles. Notably, all patients (100%, 13/13) achieved CMR within three months of olverembatinib and blinatumomab treatment (Figure 1b). The 6-month overall survival (OS) rate was 100% and the 6-month event-free survival (EFS) rate was 87.5% (Figure 1 c and d). One patient with ABL mutation EE255V died due to relapse after HSCT. The regimen was overall well tolerated. For hematologic toxicity, one patient (7.7%, 1/13) experienced grade 1 neutrophil decrease. Regarding non-hematologic toxicity, five patients (38.4%, 5/13) developed infections during treatment, including COVID-19 and herpes zoster. Five patients (38.4%, 5/13) experienced decreased levels of immunoglobulins. Ten patients (76.9%, 10/13) experienced grade 1 cytokine release syndrome (CRS). Importantly, there were no interruptions in dosing of olverembatinib during treatment while no cardiovascular adverse events were observed. Conclusion This is the first report on the combination of olverembatinib with blinatumomab for the treatment of Ph+/Ph-like ALL. Among the 13 patients enrolled, a notable rate of CR and CMR was observed, which holds promise for improved long-term survival. Additionally, the combination of olverembatinib and blinatumomab exhibited minimal adverse events, both in terms of hematologic and non-hematologic toxicities. Notably, fewer cardiovascular adverse events that required discontinuation of treatment compared to ponatinib were observed. Altogether, these findings strongly indicated that combination therapy of olverembatinib with blinatumomab has the potential to become a new standard of care in the frontline treatment of Ph+/Ph-like ALL. However, further clinical trials are needed to definitively establish the efficacy of this treatment approach and validate the potential benefits. This research was supported by the National Natural Science Foundation of China(NFSC82170163, 81970147), Clinical Study of Nanfang Hospital(LC2016ZD009/2019CR012).

Front-Line Treatment with Second-Generation Tyrosine Kinase Inhibitors Following By Allo-Transplantation Benefits Patients with Better Survival Inph-Positive Acute Lymphoblastic Leukemia

▪The treatment of Ph-positive acute lymphoblastic leukemia (Ph+ ALL) has entranced into tyrosine kinase inhibitors (TKIs) era. As the promising results in the treatment of chronic myeloid leukemia (CML), the second-generation TKI dasatinib has been placed as the frontline treatment of Ph+ ALL. However, who could benefit from the first line treatment of the second-generation TKIs is still unclear.Aim of this single center study is to compare the efficacy and safety of the first- and second-generation TKIs in the first-line treatment of Ph+ ALL. 77 newly diagnosed Ph+ ALL patients were enrolled and treated with TKIs combining with intensive chemotherapy, followed by allo-HSCT if donors were available. The BCR-ABL level in bone marrow was examined by RTQ-PCR and used as MRDmonitoring. 45 patients were treated with the first-generation TKI, and 32 with the second-generation TKIs. There was no significant difference in early response, including CRrate, major molecular response (MMR) and MRD negative rate between the two groups. With median follow-up of 456 (59-2327) days, a trend toward better DFS (P=0.088), but not OS (P=0.210), was seen in the patients treated with the second-generation TKIs. In subgroup analysis, both the DFS (P=0.050) and OS (P=0.048) were statistically higher in the second-generation TKIs group only if the patients received allo-HSCT.Both being treated with the second-generation TKIs and receiving allo-HSCT were multivariateanalyzedto be favorable factors for survival. There was much higher incidence of acquiring T315I mutation (4/8 vs. 1/9) after relapsed on the second-generation TKIs. In conclusion, front-line treatment of Ph+ ALL patients with the second-generation TKIs, especially dasatinib, is as effective and safe as imatinib; when allo-HSCT is incorporated as consolidation therapy following CR1, survival benefit was observed with second-generation TKIs. T315I occurred at much higher rates when patients relapsed on the second-generation TKIs and deserved further attention. DisclosuresNo relevant conflicts of interest to declare.

Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ALL)

The best strategy for incorporating imatinib in front-line treatment of Ph+ acute lymphoblastic leukemia (ALL) has not been established. We enrolled 92 patients with newly diagnosed Ph+ ALL in a prospective, multicenter study to investigate sequentially 2 treatment schedules with imatinib administered concurrent to or alternating with a uniform induction and consolidation regimen. Coadministration of imatinib and induction cycle 2 (INDII) resulted in a complete remission (CR) rate of 95% and polymerase chain reaction (PCR) negativity for BCR-ABL in 52% of patients, compared with 19% in patients in the alternating treatment cohort (P = .01). Remarkably, patients with and without a CR after induction cycle 1 (INDI) had similar hematologic and molecular responses after concurrent imatinib and INDII. In the concurrent cohort, grades III and IV cytopenias and transient hepatotoxicity necessitated interruption of induction in 87% and 53% of patients, respectively; however, duration of induction was not prolonged when compared with patients receiving chemotherapy alone. No imatinib-related severe hematologic or nonhematologic toxicities were noted with the alternating schedule. In each cohort, 77% of patients underwent allogeneic stem cell transplantation (SCT) in first CR (CR1). Both schedules of imatinib have acceptable toxicity and facilitate SCT in CR1 in the majority of patients, but concurrent administration of imatinib and chemotherapy has greater antileukemic efficacy.

Alternating Nilotinib 400 mg twice daily and Imatinib 400 mg once daily as Frontline Treatment of Ph+ Chronic Myeloid Leukemia. A Phase 2 Multicentric Study of the GIMEMA CML Working Party

Abstract 453 Background:Imatinib (IM) 400 mg daily is the standard treatment for Ph+ Chronic Myeloid Leukemia (CML) in early Chronic Phase (ECP). Nilotinib (NIL) is a 2nd generation tyrosine kinase inhibitor (TKI) with superior efficacy to IM (phase 3 ENESTnd trial). NIL has been approved for the frontline treatment of CML in many countries. The treatment with more than one TKI, according to the principles of cancer polychemotherapy, may improve the response rates and may decrease the frequency of drug-resistance. The combination of different TKIs is potentially toxic, difficult to be explored in the ECP setting. The sequential administration of IM and NIL is worth to be investigated because a significant proportion of CML patients treated with a single TKI as monotherapy develops primary or secondary resistance. Aims:To evaluate the response (either cytogenetic and molecular) and the outcome of ECP Ph+ CML patients treated with the sequential administration of NIL and IM. Methods:A phase 2 study was conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00769327). NIL was administered first because it has a more rapid therapeutic effect. Schedule: NIL 400 mg twice daily for 3 months; IM 400 mg daily for the next 3 months; then, NIL and IM turning every 3 months, for a total duration of 24 months (study core). The 3-month rotation schedule was respected, irrespectively of temporary discontinuations. The primary end-point was the Complete Cytogenetic Response (CCgR) rate at 12 months. If the conventional cytogenetic analysis resulted not evaluable, a FISH analysis was performed. If one of the 2 drugs was permanently discontinued for adverse event (AE), the patient remained in study, continuing the treatment with the other drug (except for cardiac AEs). Definitions: Major Molecular Response (MMR): BCR-ABL/ABL ratio < 0,1%IS; failure: according to 2009 ELN recommendations; event: failure, permanent discontinuation of both drug for any reason, patient refusal. All the analysis were performed according to the ITT principle. Results:123 patients have been enrolled in 38 italian hematologic Centers; median age 56 years (range 18–84); 33% low, 45% intermediate and 22% high Sokal score; median follow-up 21 months (at least 12 months observation, 24 months by November 2011). The cumulative CCgR rate by 12 months was 87%; CCgR at each milestone: 68% at 3 months, 73% at 6 months, 67% at 12 months (primary efficacy variable). The cumulative MMR rate by 12 months was 82%, while the rates of MMR at 3, 6 and 12 months were 59%, 62% and 60%, respectively. The discrepancies between cumulative response rates and response at each timepoint were mainly due to the number of patients not evaluable at each timepoint (10% of cytogenetic analysis not evaluable at 12 months) and to protocol discontinuation in stable CCgR and/or MMR. The incidence of hematologic AEs was low. Non-hematologic AEs or lab abnormalities grade > 2 observed in >5 % of patients were as follows: NIL - skin rash, pruritus, bilirubin increase, transaminase increase, lipase increase; IM - fluid retention, periorbital edema. AEs were manageable with appropriate dose adaptations. Four patients (3%) showed a prolongation of the QTcF above 450 msec (none above 500 msec). At the end of the first 12 months, 95 patients (77%) remained on study: 6 and 3 on NIL and IM monotherapy, respectively, 86 on sequential treatment with both drugs; 15% of patients permanently reduced the NIL dose to 400 mg daily and 9% of patients permanently reduced the IM dose to 300 mg daily. During the first year, 28 patients (23%) experienced an event: 10 treatment failure (8%); 2 death in CP (2%); 16 refusal, protocol violation or AE (13%). Six out of the 10 patients who failed the treatment progressed to advanced phase (3 patients: detection of a T315I mutation). Conclusions:The cumulative response rates achieved with a sequential administration of NIL and IM seem to be superior to the historical data of IM alone. The response rates at each timepoint, lower than expected, were probably due to the high number of not evaluable patients and to the number of patients not continuing the study despite a stable CCgR/MMR. However, if compared to the excellent results of 2nd generation TKI as monotherapy in ECP CML (single and randomized trials), the present analysis do not support an alternating schedule of NIL and IM as frontline treatment of ECP CML. Acknowledgments:European LeukemiaNet, COFIN, Bologna University, BolognAIL Disclosures:Castagnetti:Novartis Pharma: Honoraria; Bristol-Myers Squibb: Honoraria. Rosti:Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Novartis: Research Funding; Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Soverini:Novartis: Consultancy; ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy. Martinelli:Bristol-Myers Squibb: Consultancy; Novartis: Consultancy, Research Funding.

Evaluating the Response to Imatinib In Philadelphia-Positive Chronic Myeloid Leukemia (Ph+ CML): The Value of Major Molecular Response (MMolR) at 12 Months

AbstractAbstract 668The cytogenetic response is a confirmed early surrogate marker of the outcome of Ph+ CML patients treated with imatinib (Baccarani et al, JCO 2009;27:6041-51). Many reports and reviews highlight the value of MMolR, defined as a BCR–ABL value equal/less than 0.1% on the International Scale (Hughes et al, Blood 2006;108:20-37). The European LeukemiaNet recommendations use the BCR-ABL level for the definition of optimal response at 12 months (achievement of MMolR) and suboptimal response at 18 months (less than MMolR), but not for the definition of failure (Baccarani et al, JCO 2009; 27:6041-51). As the prognostic value of achieving a MMolR may increase with the introduction of 2nd generation tyrosine kinase inhibitors (TKIs) in the frontline treatment of Ph+ CML, we have reviewed and compared the cytogenetic and molecular data of 4 company–sponsored studies and 4 independent investigator–sponsored studies, for a total number of 2466 patients treated frontline with imatinib (Table 1). The CCgR rates at 12 months ranged between 49% and 88% (median 66%). The MMolR rates at 12 months ranged over a wider range, between 15% and 65% (median 33%). The ratio CCgR/MMolR ranged between 1.31 and 1.90 (median 1.60) in 5 out of 8 studies, while in the other 3 studies (Hammersmith, ENESTnd, and DASISION) the ratio was much higher, ranging between 2.35 and 4.00. Comparing Hammersmith, ENESTnd and DASISION studies to the other 5 studies (IRIS, TOPS, ELN, GIMEMA, and TIDEL), the CCgR rates were similar (median 64% vs. 67%, range 45–73% vs. 58–88%), while the MMolR rates were lower (median 22% vs. 40%, range 15–31% vs. 26–65%). These data cannot be used to argue that a lab, a dose of imatinib, or a study, is “better or worse” than the others, but higlight the consistency of CCgR worldwide and warns from overemphasizing the MMolR rate at 12 months for response evaluation and for treatment adaptation or modification.Molecular studies sere performed: IRIS at 3 labs (Hammersmith, Adelaide; Seattle), Hammersmith at 1 lab, TIDEL at 1 lab (Adelaide), ELN at Bologna and many other labs, TOPS at 3 labs (Naples, Adelaide and Seattle), GIMEMA at 1 lab (Bologna), ENESTnd and DASISION at 1 lab (Portland). Disclosures:Baccarani:Novartis: Consultancy, Research Funding, Speakers Bureau; Bristol Myers Squibb: Consultancy, Research Funding; Wyeth: Consultancy, Research Funding. Rosti:Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Honoraria, Speakers Bureau; Roche: Speakers Bureau. Martinelli:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Pfizer: Consultancy. Castagnetti:Novartis: Honoraria; Bristol Myers Squibb: Honoraria. Gugliotta:Novartis: Honoraria.

Autologous Stem Cell Transplantation (SCT) Following Sequential Chemotherapy and Imatinib for Adults with Newly Diagnosed Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia (Ph+ ALL) — CALGB Study 10001.

Imatinib, given sequentially or concomitantly with chemotherapy, now plays an important role in the frontline treatment of Ph+ ALL. Once in morphologic and cytogenetic remission, most patients are recommended to undergo allogeneic SCT. However, many patients lack an HLA-matched donor. No data have yet shown a benefit from autologous SCT in this disease. We hypothesized that sequential chemotherapy and imatinib would result in greater leukemia cell cytoreduction than previously achieved with chemotherapy alone, thereby allowing collection of large numbers of normal hematopoietic stem cells from the blood uncontaminated by residual Ph+ lymphoblasts. Thus, patients without matched sibling donors could undergo autologous SCT with a lower likelihood of relapse. Patients 15–59 years old with Ph+ ALL who had a CR or PR after one cycle of a 4 or 5-drug induction regimen were eligible. Imatinib 400 mg BID was then given for 4 weeks. Central nervous system prophylaxis was given with 3 weekly doses of high-dose systemic and intrathecal methotrexate, followed by another 4 weeks of imatinib. Patients with donors then received allogeneic SCT after 13.2 Gy fractionated total body irradiation (FTBI) and etoposide (60 mg/kg × 1). Those without donors received high-dose cytarabine (2 gm/m2 every 12 hours × 8), etoposide (10 mg/kg/day × 4), and G-CSF (10 mcg/kg) for stem cell mobilization and leukapheresis, followed by autologous SCT after 13.2 Gy FTBI, etoposide (60 mg/kg × 1) and cyclophosphamide (100 mg/kg × 1). Imatinib was held during the transplant period but resumed for maintenance until patients were RT-PCR negative for 12 months. To date, 35 patients have enrolled; 31 were in complete and 4 in partial morphologic remission following induction. Data are available on 16 patients who have completed their SCT so far. The median age at study entry was 41 years for the 8 allogeneic SCT patients (range, 27–54) and 47 years (range, 24–56) for the 8 autologous SCT patients. The time interval between achievement of remission and initiation of either an allogeneic SCT (109 days, range 99–132) or stem cell collection (119 days, range 98–158) was similar between the two groups. The median autologous CD34+ cell yield by leukapheresis was 67.1 × 106/kg (range, 34.8 – 309.8). Peripheral blood stem cells have been assayed from 5 patients by RT-PCR with a sensitivity of 1:105-106; 4 were negative for BCR-ABL. Median time to autologous engraftment was 29 days (range, 28–35). Two patients have relapsed at 334 and 475 days, and 6 are in continuous major molecular remission (≥3 log reduction from pretreatment level) at a median of 487 days (range, 197 – 923). Sequential chemotherapy and imatinib yields RT-PCR negative CD34+ leukapheresis products, allowing autologous SCT for patients without donors. Engraftment is not compromised. Post-transplant imatinib is tolerable. Molecular data on minimal residual disease following induction and pre- and post-autologous SCT will be presented. As patients continue to be accrued, longer follow-up will allow comparison of outcomes between patients who underwent autologous versus allogeneic SCT for Ph+ ALL in first CR.

Imatinib Given Concurrently with Induction Chemotherapy Is Superior to Imatinib Subsequent to Induction and Consolidation in Newly Diagnosed Philadelphia-Positive Acute Lymphoblastic Leukemia (PH+ALL).

Background and study design: Despite intensive chemotherapy (ChThx), preferably followed by allogeneic SCT, the prognosis of adult patients with Ph+ALL is poor. Adding Imatinib to first-line treatment may improve efficacy and outcome and reduce the occurrence of Imatinib-resistance. However, it has not yet been established how Imatinib is best incorporated in front-line treatment of Ph+ALL. In a prospective, multicenter study of the GMALL, we compared the safety, anti-leukemic efficacy and MRD response of two strategies in which Imatinib was incorporated either intercurrently between (cohort 1) or simultaneously with (cohort 2) induction and consolidation cycles. Cohort 1 patients had to have a CR after induction therapy, with persistance of minimal residual disease (MRD) by RT-PCR; in contrast, patients in cohort 2 received Imatinib simultaneously with the 2nd phase of induction irrespective of remission status, with continuation of Imatinib for up to 8 weeks after the first consolidation cycle. Results: Cohort 1 encompasses 48 pts. (median age 47 y, range: 24–72), 46 of whom were in CR and 2 in PR upon starting Imatinib at 400 mg/d (n=36) or 600 mg (n=12). Imatinib was initiated 18 (5–52) days after completion of induction and given for a median of 28 (13–176) days. No patient relapsed during post-induction Imatinib, three pts. relapsed prior to SCT and one death occurred in CR after consolidation therapy due to septicaemia. Hematologic and non-hematologic toxicities were limited to WHO grades I/II. Cohort 2 encompasses 46 pts. (median age 39 y, range: 19–62) enrolled to date; 58% (19/33) had achieved a CR prior to initiation of Imatinib after induction phase I, a PR or non-response was documented in 18% and 24%, respectively. After completion of induction phase II concurrent with Imatinib, 96% (23/24 evaluable) had achieved a CR, one pt. (4%) failed and died. Comparison of median bcr/abl transcripts prior to and after induction II showed no significant decrease in cohort I (ChThx alone) in contrast to a 1.4 log reduction in cohort 2 (ChThx+Imatinib). Comparison of bcr/abl transcripts prior to consolidation I with pre-induction II levels showed a 3.9 log reduction in cohort 2 versus a 1.5 log reduction in cohort 1. Moreover, the frequency with which bcr/abl transcripts became undetectable by RT-PCR prior to consolidation I increased from 10% in cohort 1 to 50% in cohort 2. The duration of grade III/IV thrombocytopenia and neutropenia in cohort 2 was 12 (3–57) days and 16 (3–47) days, respectively, with cytopenias and/or infectious complications entailing Imatinib dose reductions in 40% and interruption of Imatinib in 77% of pts. The most frequent grade III/IV non-hematologic toxicity was hepatic (43% of evaluable pts.). There were no treatment related deaths. Summary: Imatinib given concurrently with and subsequent to induction and consolidation is highly effective first-line treatment for adult Ph+ALL, with a CR rate exceeding 90% and 50% MRD negativity. This strategy is more effective than alternating chemotherapy and Imatinib cycles, but is accompanied by substantial hematologic and non-hematologic toxicity. The overall impact on long-term survival in this very high risk group or patients remains to be determined, particularly in light of subsequent allogeneic SCT in a large proportion of patients.