Complete Molecular Response Rates Research Articles

Clinical efficacy and safety of flumatinib versus dasatinib combined with multi-drug chemotherapy in adults with Philadelphia-positive acute lymphoblastic leukemia

Introduction: Flumatinib, a highly selective ABL kinase inhibitor, exhibits stronger inhibition of intracellular BCR-ABL tyrosine kinase activity, compared to Imatinib. However, there is limited research comparing the real-world efficacy and safety of flumatinib and dasatinib in patients with Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Objective: Investigating the differences in therapeutic efficacy and safety between flumatinib and dasatinib in combination with multi-drug chemotherapy for the treatment of newly diagnosed Ph+ ALL. Method: In this study, we assessed 43 patients with newly diagnosed Ph+ ALL (20 in the flumatinib group, 23 in the dasatinib group). Results: There were no significant differences in gender, age, fusion gene type, initial blood routine, bone marrow blast cell ratio or chromosome karyotype between the two groups. Within 1 month, there were no significant differences in the complete response (CR), major molecular response (MMR) or minimal residual disease (MRD) negativity rate between the flumatinib and dasatinib groups. Similarly, within 3 months, there were no significant differences in CR or MMR rates between the two groups. However, the rates of complete molecular response (CMR) and MRD negativity within 3 months were significantly higher in the flumatinib group, compared to the dasatinib group (P < 0.05). Additionally, the flumatinib group exhibited fewer adverse reactions compared to the dasatinib group. Conclusion: These findings suggest that flumatinib is a safe and effective tyrosine kinase inhibitor (TKI) for achieving CMR and MRD negativity in patients with Ph+ ALL, as supported by this small series of patients.

Combination of Olverembatinib and VP Regimen As First-Line Therapy for Adult Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Backgrand ： Ph+ALL is the largest genetically defined subtype in adult ALL and is considered associated with high relapse risk and inferior clinical outcomes. The combination of tyrosine kinase inhibitors (TKI) with intensive chemotherapy has achieved a major step forward in the therapy of Ph+ALL in deep response and long-term survival. The upfront use of third generation TKI ponatinib has improved the frequency of complete molecular response (CMR) and the overall survival rate to a greater extent. More interesting, the data coming from MDACC showed that combination of ponatinib in the chemotherapy in Ph+ALL maybe challenge the need for stem cell transplantation (SCT) in most patients who achieved CMR (defined BCR-ABL1 transcript &amp;lt; 0·01%) within 3 months after induction therapy. But the cardiovascular adverse event(AE) of ponatinib was more and severely frequently occurred in the former reports. Olverembatinib,a new third generation of TKI, which can also suppress the mutation of T315I and showed promising results in the Ph+CML. Herein we designed the clinical trial to invest the efficiency and safety of Olverembatinib combine with VP regimen (OVP) on Ph+ALL patients as the first-line therapy. Motheds: In this multi-centers, phase 2, single-arm trial, adult patients with previously untreated Ph+ALL were sequentially enrolled. The patients had to be aged 18 years or older, have normal cardiac function (defined by ejection fraction above 50%), and have adequate organ function (serum creatinine≦3*ULN，BUN≦3*ULN，ALT≦3*ULN，AST≦3*ULN，serum bilirubin≦3*ULN). They received three cycles of OVP regimen(for 28 days each cycle :olverembatinib 40mg qod d1-28，Vindesine 4mg d1,8,15,22,Prednisone1mg/Kg/d d1-21,0.5mg/kg/dd22-28). Twelve intrathecal injections of cytarabine alternating with methotrexate were designed as central nervous system prophylaxis in the following therapy after the diagnosis. Findings: 32 patients were screened and 29 were eligible from June 21, 2022 until 21 July,2023. 3 Patients were withdrawn from the clinical trial(1 refused therapy after induction,1 early death due to Covid infection, 1 Protocol deviation ).Among all , Male 12 and Female 17. BCR/ABL1 transcript:M-p210 (11),m-p190（18）.The Median Age was 45(19-74) years old. The Median WBC was 24.8(1.06-308.00) *10E9/L. The treatment has resulted in a 100% overall response, including 96% (24/25) CR and 4% (1/25) CRp. As of data collection,23 finished 3cycles of OVP chemotherapy and 82.6% (19/23) got CMR.AS far the rest 6 patients, 1 got CMR after 1 cycle OVP,1 got CMR after 2cycles of OVP, the other 4 patients were undergoing induction therapy. The total CMR rate was 84% (21/25) at any time. The CMR rate was 36%（9/25） ,76%（19/25）and 82.6%(19/23) at 4weeks,8weeks and 12 weeks respectively. Among all the patients finished the 3 cycles, there were 4 patients not reached the CMR and all of them were M-bcr/abl-p210 protein status. The best response was MMR for 3 patients and CR for 1patient. The CMR rate was 70% (7/10) in M-bcr/abl-p210 transcript and 100% (13/13) in that of m-bcr/abl-p190. During a median follow-up of 241 days, one patient died within one month after transplantation, while all the remaining survived without relapse. During induction therapy, 4 patients had platelets consistently above normal values and 4 patients did not experience a further decrease in hemoglobin compared to baseline. The median time for the occurrence of the lowest values of platelets, hemoglobin, and neutrophils was 6th, 12th, and 11th respectively. The most common non-Hematology AE was liver function damage. AE events greater than or equal to grade 3 included 2 cases of elevated Alanine transaminase ,3 cases γ- GT elevation and 2 cases of triglyceride elevation. Other AEs were mild and less than level 3. Discussion: Ongoing efforts exist to optimize therapeutic options in the frontline for Ph+ALL. The future lies in using less cytotoxic and more targeted agents. The first results of our ongoing trial indicate that the OVP regimen is effective in achieving early high rate of CMR in patients with newly diagnosed Ph+ALL as first-line therapy. All these results were achieved with surprisingly few toxic effects.Until now,16 patients underwent ASCT. Will the excellent outcomes be preserved with longer？ Will there be a difference in long-term outcomes between patients who underwent ASCT and those who do not?The trial is ongoing. we need more time to observe.

Chemotherapy-Free Combination of Blinatumomab and Ponatinib in Adults with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Updates from a Phase II Trial

Background Blinatumomab and ponatinib demonstrated efficacy in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). A chemotherapy-free regimen combining both drugs in the frontline setting may mitigate the risk of toxicities and the need for hematopoietic stem cell transplantation (HSCT). Methods In this phase II trial, patients ≥18 years of age with newly diagnosed Ph-positive ALL were eligible. They were required to have a performance status of ≤2, total bilirubin ≤2x the upper limit of normal (ULN), and ALT/AST ≤3x the ULN. Patients with uncontrolled cardiovascular disease or clinically significant central nervous system (CNS) comorbidities (except for CNS leukemia) were excluded. Patients received up to 5 cycles of blinatumomab in combination with ponatinib, followed by ponatinib maintenance for ≥5 years. Ponatinib 30mg daily was given during Cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. Patients also received 12 doses of prophylactic intrathecal (IT) chemotherapy with alternating cytarabine and methotrexate. The primary endpoint was the CMR rate. Secondary endpoints included response rates, safety measures, event-free survival (EFS), and overall survival (OS). Results Between June 2018 and May 2023, 62 pts with newly diagnosed Ph-positive ALL were treated. Baseline characteristics are shown in Table 1. Twenty-two patients were in complete remission (CR) at the start of therapy. Among 40 patients evaluable for hematologic response, 39 (98%) achieved CR/CRi; 1 patient had early death. Among 55 patients evaluable for molecular response, 37 (67%) achieved CMR after 1 cycle, and 46 (84%) achieved CMR at any time. Forty-seven patients were evaluated for measurable residual disease (MRD) by next-generation sequencing at a sensitivity level of 10 -6, of whom 43 (91%) were found to have negative MRD. Five of these patients with undetectable MRD by NGS had low-level BCR:ABL1 transcripts detected by PCR at the same time (ranging from 0.01% to 1.23% IS). Four of them had p190 transcript and one had p210. The median follow-up was 17 months (range, 2-61 months). Six patients (10%) relapsed after a median of 21 months of remission (range, 8-24 months): two relapsed in the bone marrow (one with acquired E225V mutation), one had an extramedullary-only relapse (Ph-negative and MYC-rearranged relapse), and three had a CNS-only relapse (after 20, 22, and 23 months). Four patients died (one from intracranial hemorrhage, one from post-procedural hemorrhage, one from brain aneurysm, and one following CNS relapse with intracranial edema and septic shock). One leukemia-related death occurred on study; the estimated 2-year EFS and OS rates were 77% and 89%, respectively (Figure 1). Only one patient underwent HSCT in first CR due to persistently low-level BCR:ABL1 positivity. Among the 52 patients in ongoing remission without HSCT, the median duration of response was 16 months (range, 2-61). Most adverse events were grade 1-2 and were consistent with the known toxicity profile of the two agents. Ponatinib was discontinued in two patients due to possibly related adverse events (cerebrovascular accident and coronary artery stenosis in one patient each). Conclusions The chemotherapy-free combination of blinatumomab and ponatinib is safe and effective in newly diagnosed Ph-positive ALL, with high rates of MRD negativity. Encouraging duration of remission and OS has been observed without the need for HSCT.

Olverembatinib (HQP1351) Combined with Chemotherapy Is an Effective and Safe Treatment in Patients with Philadelphia Chromosome-Positive (Ph +) Acute Lymphoblastic Leukemia (ALL) and Chronic Myeloid Leukemia in Lymphoid Blast Phase (CML-LBP) That Failed TKI-Based Regimens

Background The prognosis of relapsed or refractory (R/R) Philadelphia Chromosome-Positive (Ph+) acute lymphoblastic leukemia (ALL) and TKI-resistant chronic myeloid leukemia in lymphoid blast phase (CML-LBP) remains poor, with lower rates of complete remission (CR) and shorter durations of response. Olverembatinib is a novel third-generation tyrosine kinase inhibitor (TKI) that has been demonstrated to effectively target a wide range of BCR::ABL1 kinase mutations, especially T315I, in patients with CML in the chronic or accelerated phase resistant to either imatinib or second-generation TKIs. However, data on olverembatinib-based regimens in R/R Ph+ ALL and CML-LBP are limited. Here, we report the efficacy and safety of olverembatinib, combined with chemotherapy, in patients with Ph+ ALL or CML-LBP that failed prior TKI-based therapies. Methods A retrospective study was conducted in adults with Ph + ALL or CML-LBP who failed imatinib- or second-generation TKI-based chemotherapy and subsequently received olverembatinib-based chemotherapy. Per NCCN 2023 guidelines: refractory disease was defined as CR not achieved at the end of induction; relapsed disease, reappearance of blasts in the blood or bone marrow (&amp;gt; 5%) or any extramedullary site after CR; molecular resistance, persistent or rising BCR::ABL1 transcript (&amp;gt; 1-log) by real-time quantitative polymerase chain reaction (RT-qPCR); and complete molecular response (CMR), BCR::ABL1 transcript &amp;lt; 0.01% by RT-qPCR. The primary endpoints of this study were CR rates in R/R patients and CMR rates in molecular-resistant patients. Results From February 2022 to May 2023, 31 patients were included in this study, including 24 (77%) with TKI-based chemotherapy-failed Ph + ALL; 7 (23%) with TKI-resistant CML-LBP; 15 (48%) with R/R disease; and 16 (52%) with molecular-resistant disease. A total of 17 (57%) patients were male, and the median (range; IQR) age was 46 (20-72; 30-64) years. Among 30 patients screened for BCR::ABL1 kinase domain mutations before administration of olverembatinib, 6 (19%) had no mutations; 15 (48%) had T315I; and 9 (29%) had other mutations, including E255K (n = 2), G250E(n = 2), D241E (n = 1), Y253H (n = 1), F317L (n = 1), F359C(n = 1), and Y253Fplus M351T (n = 1). The 15 R/R patients (11, Ph + ALL; 4, CML-BP) received olverembatinib 30 or 40 mg on alternate days combined with VP (vindesine 4 mg once per week for 4 weeks and prednisone 1 mg/kg for 3 weeks and tapered at the fourth). A total of 13 (86%) patients achieved CR after 4-week induction therapy. At a median (IQR) follow-up of 8 (4-13) months, 5 patients received allogeneic transplantation in CR, and were alive in CMR. A total of 8 patients received olverembatinib-based consolidation chemotherapy of either VP (n = 4) or hyper-CVAD (n = 4) after achieving CR. Six patients relapsed, of whom 4 died, and 1 remained in CMR. The 1-year relapse-free survival (RFS) and 1-year survival rates were 52% (95% CI, 21-83) and 68% (95% CI, 37-98), respectively. Among the 16 patients with molecular resistance to TKI-based chemotherapy (imatinib [n = 4]; dasatinib [n = 9]; flumatinib [n = 3]), 2 received olverembatinib monotherapy, 7 olverembatinib plus VP, and 7 hyper-CVAD, of whom 8 received subsequent allogeneic transplantation. At a median (IQR) follow-up of 9 (5-11) months, 1 of the patients receiving olverembatinib monotherapy progressed to hematologic relapse and was switched to CAR T-cell therapy; the other patient did not achieve CMR and underwent transplantation. Of the 14 patients receiving olverembatinib plus chemotherapy, 7 (50%) achieved CMR and 3 (21.4%) progressed to relapse, of whom 1 had hematological relapse and 2 developed central nervous system leukemia (CNSL) with bone marrow remission. A total of 7 patients received allogeneic transplantation, of whom 3 achieved and 4 did not achieve CMR before transplantation. After transplantation, all the 7 patients were in CMR except one who developed CNSL. The 1-year RFS and survival rates were 67% (95% CI, 42-91) and 93% (95% CI, 79-100), respectively. Among all patients, hematologic adverse events were readily manageable. Treatment-related nonhematologic severe adverse events were observed in 3 patients, including (each) stable angina pectoris, severe pneumonia, and fatal Klebsiella sepsis. Conclusions Olverembatinib-based chemotherapy is effective and safe in patients with R/R and molecular resistant Ph + ALL or CML-LBP.

Olverembatinib Combined with Venetoclax and Reduced-Intensity Chemotherapy for Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Early Results from a Phase II Study

Background The combination of olverembatinib (HQP1351), a novel third-generation tyrosine kinase inhibitors (TKIs), with venetoclax generated high response rates in patients with relapsed/refractory Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). However, the efficacy and safety of these two agents-based regimens as frontline treatment remains unknown. Methods This is a single-arm phase II study (NCT05594784) that enrolled patients (pts) ≥ 14 years (yrs) of age with newly diagnosed Ph + ALL. Pts were required to have an ECOG performance score ≤ 2 and adequate organ function. Pts with accelerated phase or blastic phase of chronic myeloid leukemia were excluded. Pts were treated with a combination of venetoclax (100 mg d1, 200 mg d2, 400 mg d3-28), olverembatinib 40 mg once every continuously other day, vincristine 1.4 mg/m 2 (maximum dose 2 mg) on day 1, 8, 15, 22, and prednisone 60 mg/m 2 on day 1-14; 40 mg/m 2 on day 15-28 in cycle 1. In cycle 2-3, oral treatment with venetoclax 400 mg × 7 days, olverembatinib once every other day continuously and prednisone 60 mg/m 2 × 7 days was administrated in the form of outpatient treatment (Figure 1A). Cycles were repeated every 28 days. Olverembatinib 40 mg once every other day was given during cycle 1 and was reduced to 30 mg once every other day for pts achieving a complete molecular response (CMR). Routine triple intrathecal injection (methotrexate 10 mg, cytarabine 50 mg, and dexamethasone 10 mg) was performed to prevent central nervous system involvement. The selection of subsequent treatment was determined based on the patient's molecular response at 3 months and the availability of donor. The primary end point of this study was the CMR rate at 3 months. CMR was defined as undetectable BCR:ABL1 transcripts by using RT-PCR method with sensitivity of 0.001%. Major molecular response (MMR) was defined as more than 3-log reduction of BCR:ABL1 transcripts. Results From August 2022 to April 2023, a total of 31 pts were enrolled. All pts completed 3 cycles of treatment and could be assessed for the primary end point. Th data cutoff date was 25 th July 2023 with a median follow-up time of 5.8 months. The median age was 40 years (range, 20-66 years) and males accounted for 58.1%. Twenty-three pts (74.2%) expressed the p190 transcript and 8 pts (25.8%) expressed the p210 transcript. The median expression level of BCR:ABL1 was 96.33% (range, 70.79%-175.39%). All patients achieved CR at the end of cycle 1 and no tumor lysis syndrome or treatment-related deaths occurred. Molecular response at the end of cycle 1 was CMR in 17 patients (54.8%), MMR in 8 (25.8%), and less than MMR in 6 (19.4%). Molecular response at 3 months was CMR in 19 patients (61.3%), MMR in 10 (32.3%), and less than MMR in 2 (6.5%) (Figure 1B). Of the 10 pts with MMR at 3 months, 8 pts had BCR:ABL1 transcript levels fluctuating between 0.001% and 0.01%. No patients developed relapses or deaths at the last follow-up. The regimen was well-tolerated and safe. Most side effects were grade 1-2. The demand for transfusion and the incidence of infections significantly decreased compared to our historic data treating with intensive chemotherapy plus TKIs. No patient discontinued olverembatinib or venetoclax due to toxicity. Conclusion The combination of olverembatinib and venetoclax with reduced-intensity chemotherapy is a safe and effective regimen in patients with newly diagnosed Ph + ALL. The regimen results in high rates of CMR in the absence of intensive chemotherapy or immunotherapy.

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).

Blinatumomab with Tyrosine Kinase Inhibitor for Ph-Positive B-Acute Lymphoblastic Leukemia (B-ALL): Multicenter Retrospective Review

Background: Ph-positive B-ALL has long been considered an adverse cytogenetic abnormality in ALL, and it is generally recommended to proceed with a stem cell transplant (SCT) in first remission. Historically, the addition of Tyrosine Kinase Inhibitors (TKI) to the stander chemotherapy backbone improved long-term survival, with better results noted in the second-generation than in first-generation TKIs. Recent reports on a non-chemotherapy-based approach with the combination of immunotherapy (Blinatumomab) and TKI showed encouraging results and potentially eliminated the need for consolidative SCT (Foà NEJM 2020, Jabbour Lancet Haematol 2023). In this retrospective analysis, we reviewed all Ph-positive B-ALL treated with blinatumomab and TKI at two major academic centers. Methods: A retrospective review of adolescents and adults (14 years or older) with Ph-positive B-ALL patients who received blinatumomab with TKI at two major institutions (KFSHRC &amp; KFMC) between 7/2018 and 7/2023. Patients who received up to 3 cycles of chemotherapy before being transitioned to therapy with blinatumomab and TKI were considered as frontline if there was no history of relapsed disease. Relapse/refractory patients with Ph-positive B-ALL treated with blinatumomab and TKI were also included in the R/R cohort, excluding patients with prior single-agent exposure to blinatumomab or ponatinib. Patients with a history of CNS disease were included. Chronic myeloid leukemia in a lymphoid blast phase (LBP-CML) treated with blinatumomab and TKI were also included. Patients were assessed for toxicity as well as for efficacy. Results: We identified 17 patients, with a median age of 40 yrs (range, 15-78): 9 pts (53%) were frontline Ph-positive B-ALL, 5 (29%) pts were relapsed/refractory Ph-positive B-ALL, and 3 (18%) were LBP-CML patients. Pt characteristics and outcomes by cohort are outlined in Table. All patients in all the cohorts achieved complete remission and were included in the RFS analysis [ Figure]. Of 7 evaluable pts in the frontline cohort, all patients achieved complete molecular response (CMR) using PCR for BCR::ABL (CMR=100%). No relapse was documented, with a median follow-up of 6.9 months. In the relapse/refractory cohort, all patients achieved complete molecular response (CMR) using PCR for BCR::ABL (CMR=100%). No relapse was documented, with a median follow-up of 6.7 months. In 3 patients with LBP-CML, two patients achieved complete molecular response (CMR) using PCR for BCR::ABL, and one patient achieved MMR (0.036%). No relapse was documented, with a median follow-up of 19.7 months. Only four patients proceeded to SCT, two with LBP-CML and two with newly diagnosed Ph-positive B-ALL. All patients proceeded with SCT in CMR except one with LBP-CML with positive PCR for BCR::ABL at 0.03%, although with undetectable MRD by flow cytometry (&amp;lt;0.01%). Patients were treated with dasatinib (4 patients) and ponatinib (13 patients). The median number of blinatumomab cycles was 4 (1-5). One death occurred at seven months in a patient treated with dasatinib and blinatumomab. The patient presented to the emergency department with pleural effusion and cardiac tamponade and died during her ICU stay with infectious complication. The death is likely contributed to by dasatinib. Conclusion: Although with short follow-up, combining TKI with blinatumomab seems to have a high complete molecular response rate in patients with newly diagnosed and relapsed/refractory Ph-positive B-ALL. Similar to prior reports, patients with newly diagnosed Ph-positive B-ALL perhaps they could be spared the toxicities associated with chemotherapy and the need for allogeneic hematopoietic stem-cell transplantation in the first remission using this approach. Further evaluation of this novel strategy is warranted.

Anti-CD19 CAR T-cell consolidation therapy combined with CD19+ feeding T cells and TKI for Ph+ acute lymphoblastic leukemia.

We conducted a single-arm, open-label, single-center phase 1 study to assess the safety and efficacy of multicycle-sequential anti-CD19 chimeric antigen receptor (CAR) T-cell therapy in combination with autologous CD19+ feeding T cells (FTCs) and tyrosine kinase inhibitor (TKI) as consolidation therapy in patients under the age of 65 years with de novo Ph-positive CD19+ B-cell acute lymphoblastic leukemia. Participants were given induction chemotherapy as well as systemic chemotherapy with TKI. Afterward, they received a single cycle of CD19 CAR T-cell infusion and another 3 cycles of CD19 CAR T-cell and CD19+ FTC infusions, followed by TKI as consolidation therapy. CD19+ FTCs were given at 3 different doses. The phase 1 results of the first 15 patients, including 2 withdrawals, are presented. The most common adverse events were cytopenia (13/13) and hypogammaglobinemia (12/13). There was no incidence of cytokine release syndrome above grade 2 or immune effector cell-associated neurotoxicity syndrome or grade 4 nonhematological toxicities. All 13 patients achieved complete remission, including 12 patients with a complete molecular response (CMR) at the data cutoff. The relapse-free survival was 84%, and the overall survival was 83% with a median follow-up of 27months. The total number of CD19-expressing cells decreased with an increasing CMR rate. CD19 CAR T cells survived for up to 40months, whereas CD19+ FTCs vanished in 8 patients 3months after the last infusion. These findings could form the basis for the development of an allo-HSCT-free consolidation paradigm. This trial was registered at www.clinicaltrials.gov as #NCT03984968.

Response-adapted therapy (tx) with nivolumab plus brentuximab vedotin (nivo + BV) without autologous hematopoietic cell transplantation (auto-HCT) in children, adolescents, and young adults (CAYA) with low-risk relapsed/refractory (R/R) classic Hodgkin lymphoma (cHL): CheckMate 744.

7515 Background: Outcomes are poor for patients (pts) with cHL who develop R/R disease after first-line (1L) chemotherapy ± radiotherapy (RT). Salvage tx that attain high event-free survival (EFS) rates and minimize late toxicity by omitting high-dose chemotherapy (HDCT)/auto-HCT are needed. CheckMate 744 (NCT02927769) is the first multicenter phase 2 study evaluating a risk-stratified, response-adapted salvage tx with nivo + BV in CAYA with R/R cHL. In the standard-risk cohort, complete molecular response (CMR) rate before consolidation with HDCT/auto-HCT was 94% (Harker-Murray et al. Blood 2022). With highly active salvage tx, pts in low-risk cohort could achieve high EFS without HDCT/auto-HCT; we report data from this cohort. Methods: Pts were aged 5–30 y and had ≤ 3 cycles (C) of 1L anthracycline-based systemic tx. Risk stratification was described in Harker-Murray et al. Pts received 4C of nivo + BV induction. Pts with CMR received additional 2C nivo + BV before involved-site radiation therapy (ISRT) consolidation (dose, 30–30.6 Gy). Pts with suboptimal response received 2C BV + bendamustine intensification; pts with CMR proceeded to ISRT consolidation. Primary endpoints: CMR rate (Lugano 2014) any time before ISRT and 3-y EFS rate, both per blinded independent central review (BICR). For CMR and overall response rate (ORR), a 90% confidence interval (CI) was used per statistical plan. Results: Among 28 pts treated with nivo + BV, median (range) age was 17 (6–27) y; 64% of pts were aged &lt; 18 y. Most (64%) pts had stage II disease at relapse; 82% had relapse ≥ 12 mo after 1L tx, 2 pts had prior RT. Median (range) follow-up was 31.9 (2.2–55.3) mo. CMR, ORR, 3-y EFS and PFS rates are shown in Table. Median duration of response was not reached; 87% of pts had sustained response at 36 mo’ follow-up. Efficacy outcomes were comparable in the pediatric population (CMR per BICR before ISRT, 88.9%; 3-y EFS rate, 78.3%). During induction, 22 (78.6%) pts had treatment-related adverse events (TRAEs; grade 3/4, 25.0% pts; hematologic, &lt; 10% pts; immune-mediated, 21.4%). Serious AEs leading to discontinuation included rash, pyrexia, and acute kidney injury (1 pt each). Conclusions: The findings demonstrate that most CAYA with low-risk R/R cHL can be salvaged with chemoimmunotherapy with a favorable toxicity profile, and do not require HDCT/auto-HCT. Clinical trial information: NCT02927769 . [Table: see text]

Subgroup analysis from a phase II trial of ponatinib and blinatumomab in relapsed/refractory (R/R) Philadelphia chromosome-positive acute lymphoblastic leukemia or chronic myeloid leukemia in lymphoid blast phase.

e19038 Background: The chemotherapy-free combination of ponatinib and blinatumomab improved outcomes in patients (pts) with newly diagnosed Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This regimen may also induce deeper responses and prolong remissions in patients (pts) with R/R Ph+ ALL and chronic myeloid leukemia in lymphoid blast phase (CML-LBP). Methods: In this phase II trial, pts with R/R Ph+ ALL or CML-LBP received up to 5 cycles of blinatumomab. Pts received ponatinib 30mg daily in Cycle 1, with dose reduction to 15mg daily once in complete molecular response (CMR). After completion of blinatumomab, ponatinib was continued for at least 5 years. 12 doses of prophylactic intrathecal chemotherapy were administered in all pts. Results: 21 pts were treated (14 R/R, 7 CML-LBP) between 2/2018 and 7/2022. The median age of the R/R Ph+ ALL and CML-LBP cohorts were 38 years (range, 24-61) and 67 years (range, 29-82), respectively. BCR:ABL1 transcripts were p190 in 93% of the R/R cohort. 43% of pts in the R/R Ph+ ALL cohort were in Salvage 2+. Among the CML-LBP pts, 4 were de novo and 3 were transformed from previously treated CML (1 of whom had received prior therapy for LBP). Among the 14 pts with R/R Ph+ ALL, the rate of CR/CRi was 92% (12 of 13 evaluable pts), with CR in 11 (85%) pts. MMR was achieved in 86% and CMR in 79%. Six of 7 (86%) pts with CML-LBP achieved CR/CRi. Rates of MMR and CMR were 57% and 43%, respectively. The median follow-up is 24 months (range, 19-57) in the R/R cohort, and 27 months (range, 7-46) in the CML-LBP cohort. Among the 14 pts in the R/R cohort, 1 did not respond, 6 proceeded to ASCT (1 of whom relapsed and died), 4 did not undergo ASCT and relapsed after a median of 6.4 months (range, 2.7-8.1), 1 died in CR, and 2 are in ongoing response without ASCT after a median CR duration of 34 months (range, 17-51). Of the 5 relapses, 2 were hematologic only, 2 were in the CNS with MRD positivity in the bone marrow, and 1 was CNS only. The estimated 2-year EFS and OS for the R/R cohort were 50% and 64%, respectively. Among the 6 responders in the CML-LBP cohort, 3 relapsed and 3 are in ongoing response without ASCT after a median CR duration of 34 months (range, 3-43). The 2-year EFS and OS for the CML-LBP cohort are 38% and 50%, respectively. Grade 3 adverse events were febrile neutropenia, cytokine release syndrome, elevation of lipase and alkaline phosphatase in 1 pt each. There were no Grade 4-5 events. 1 pt discontinued ponatinib due to grade 3 portal vein thrombosis. 1 pt discontinued blinatumomab due to persistent grade 2 tremor. Conclusions: The combination of ponatinib and blinatumomab is an effective and well-tolerated chemotherapy-free regimen for pts with R/R Ph+ ALL. The rate of deep molecular response was relatively low in CML-LBP, suggesting that chemotherapy might still be needed in these pts. Clinical trial information: NCT03263572 .

Low-intensity chemotherapy (mini-HCVD) and ponatinib followed by blinatumomab (blina) and ponatinib for the treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL): A phase II study.

e19028 Background: The combination of mini-HCVD and ponatinib followed by blina and ponatinib may improve outcomes compared with HCVAD/ponatinib in patients (pts) with Ph+ ALL while reducing toxicity and the need for ASCT. Methods: Pts with newly diagnosed (ND) or relapsed/refractory (R/R) Ph+ ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Mini-HCVD alternating with methotrexate (MTX)/cytarabine were given on Cycles(C) 1-4, followed by blina/ponatinib on C5-8. Pts received ponatinib 30mg daily in C1, with dose reduction to 15mg daily once in complete molecular response (CMR). Rituximab was given for CD20+ disease. Maintenance was with ponatinib and vincristine/prednisone for 15 cycles alternating with blina/ponatinib every 3 cycles, followed by ponatinib for at least 5 years. All pts received 12 intrathecal chemotherapy injections. Results: 17 pts (11 ND, 3 R/R, 3 CML-LBP) were treated between 11/2019 and 7/2022 (Table). BCR:ABL1 transcripts were p190 in 7 (64%) pts in the ND cohort. In the ND cohort, 4 (36%) pts had BCR:ABL1 in myeloid cells by FISH and 1 (9%) had a small population of myeloid blasts, suggesting a myeloid component. None of the pts with CML-LBP had received prior therapy. All evaluable pts achieved CR. Among evaluable pts in the ND, R/R, and CML-LBP cohorts, CMR was achieved in 6/8 (75%), 2/2 (100%), and 2/3 (67%) pts, respectively. 2 of the 5 ND pts who had evidence of myeloid involvement did not achieve CMR (1 had negative MRD by NGS). With a median follow-up of 28 months (range, 6-37), the 2-year continuous remission duration and OS rates were 93% and 82% in the entire cohort, and 90% and 82% in the ND cohort, respectively. In the ND cohort, 1 (9%) pt had isolated CNS relapse, 3 (27%) pts died (2 in CR due to COVID-19 and 1 of ASCT complications), and 7 (64%) pts are in remission without ASCT. No pts relapsed in the R/R cohort, 1 pt underwent ASCT, 1 pt died in CR from MTX-associated disseminated necrotizing leukoencephalopathy, and 1 pt is in remission without ASCT. None of the CML-LBP relapsed; 1 pt underwent ASCT in CR. Ponatinib dose was reduced in 2 pts prior to obtaining CMR (1 pancreatitis, 1 cardiomyopathy). One pt switched from ponatinib to dasatinib due to pulmonary embolism in C2. No pts required dose modification of blina. The 60-day mortality rate was 0%. Conclusions: In Ph+ ALL, the sequential combination of mini-HCVD/ponatinib followed by blina/ponatinib resulted in high rates of CMR, encouraging survival, and had an acceptable safety profile. Clinical trial information: NCT03147612 . [Table: see text]

Ponatinib vs. Imatinib as Frontline Treatment for Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Matching Adjusted Indirect Comparison.

Efficacy of ponatinib-based treatment for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) has not been compared to imatinib-based treatments in head-to-head clinical trials. We evaluated its efficacy versus imatinib-based regimens using a matching adjusted indirect comparison. Two ponatinib studies were used: the phase 2 MDACC study of ponatinib+hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) in adult patients and the phase 2 GIMEMA LAL1811 study of ponatinib+steroids in patients>60years/unfit for intensive chemotherapy and stem cell transplant. Studies on imatinib as first-line treatment in adults with Ph+ALL were identified using a systematic literature search. Population adjustment was based on the prognostic factors and effect modifiers identified by clinical experts. Hazard ratios (HRs) were calculated for overall survival (OS) and odds ratios (ORs) for complete molecular response (CMR). The systematic literature search identified two studies (GRAAPH-2005 and NCT00038610) reporting the efficacy of first-line imatinib+hyper-CVAD and one study reporting the efficacy of first-line imatinib monotherapy induction+imatinib-based consolidation (CSI57ADE10). Ponatinib+hyper-CVAD prolonged OS and gave a higher CMR rate than imatinib+hyper-CVAD. The adjusted HR [95% confidence interval (CI)] for OS was 0.35 (0.17-0.74) for MDACC vs. GRAAPH-2005 and 0.35 (0.18-0.70) for MDACC vs. NCT00038610; the adjusted OR (95% CI) for CMR was 12.11 (3.77-38.87) for MDACC vs. GRAAPH-2005 and 5.65 (2.02-15.76) for MDACC vs. NCT00038610. Ponatinib+steroids prolonged OS and gave a higher CMR rate than imatinib monotherapy induction+imatinib-containing consolidation. The adjusted HR (95% CI) for OS was 0.24 (0.09-0.64) and the adjusted OR (95% CI) for CMR was 6.20 (1.60-24.00) for GIMEMA LAL1811 vs. CSI57ADE10. In adults with newly diagnosed Ph+ALL, first-line treatment with ponatinib was associated with better outcomes than first-line treatment with imatinib.

Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukaemia: a US, single-centre, single-arm, phase 2 trial

Ponatinib and blinatumomab are effective therapies in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia, and their combination might be a promising treatment option. In this study, we aimed to evaluate this chemotherapy-free strategy. We did a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center, Houston, TX, USA, in patients aged 18 years or older with newly diagnosed or relapsed or refractory Ph-positive acute lymphoblastic leukaemia or chronic myeloid leukaemia in lymphoid blast phase. Patients with an ECOG performance status of 2 or less who had a total bilirubin concentration two-times the upper limit of normal (ULN) or less (≤2·4 mg/dL), alanine aminotransferase and aspartate aminotransferase concentration no more than three-times the ULN, and serum lipase and amylase concentrations no more than three-times the ULN were eligible for inclusion. Ponatinib 30 mg orally and continuous intravenous blinatumomab 28 μg over 24 h (for 28 days each cycle) were given in combination for up to five 42-day cycles, followed by ponatinib monotherapy. Patients received 12 doses of intrathecal chemotherapy as CNS prophylaxis. The primary endpoints were complete molecular response (defined as absence of a detectable BCR-ABL1 transcript by PCR at a sensitivity of 0·01%) in patients with newly diagnosed disease and overall response in patients with relapsed or refractory disease or chronic myeloid leukaemia in lymphoid blast phase. All assessments were done according to the intention-to-treat principle. The trial completed its original target accrual and was amended on March 23, 2022, to enrol an additional 30 patients, thus increasing the sample size to 90 patients. The trial is registered with ClinicalTrials.gov, NCT03263572, and it is ongoing. Between Feb 6, 2018, to May 6, 2022, 60 (83%) of 72 patients assessed were enrolled and received ponatinib and blinatumomab (40 [67%] patients had newly diagnosed Ph-positive acute lymphoblastic leukaemia, 14 [23%] had relapsed or refractory Ph-positive acute lymphoblastic leukaemia, and six [10%] had chronic myeloid leukaemia in lymphoid blast phase). 32 (53%) patients were men and 28 (47%) were women; 51 (85%) patients were White or Hispanic; and the median age of participants was 51 years (IQR 36-68). The median duration of follow-up for the entire cohort was 16 months (IQR 11-24). Of patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia, 33 (87%) of 38 evaluable patients had a complete molecular response. 12 (92%) of 13 evaluable patients with relapsed or refractory Ph-positive acute lymphoblastic leukaemia had an overall response. 11 (79%) had a complete molecular response. Five (83%) of six patients with chronic myeloid leukaemia in lymphoid blast phase had an overall response. Two (33%) had a complete molecular response. The most common grade 3-4 adverse events that occurred in more than 5% of patients were infection (22 [37%] patients), increased amylase or lipase concentration (five [8%] patients), increased alanine aminotransferase or aspartate aminotransferase concentration (four [7%] patients), pain (four [7%] patients), and hypertension (four [7%] patients). One (2%) patient discontinued blinatumomab due to tremor. Three (5%) patients discontinued ponatinib secondary to cerebrovascular ischaemia, portal vein thrombosis, and coronary artery stenosis in one patient each. No treatment-related deaths were observed. The chemotherapy-free combination of ponatinib and blinatumomab resulted in high rates of complete molecular response in patients with newly diagnosed and relapsed or refractory Ph-positive acute lymphoblastic leukaemia. Patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia could be spared the toxicities associated with chemotherapy and the need for allogeneic haematopoietic stem-cell transplantation in first response. Takeda Oncology and Amgen.

A Phase II Study of the Sequential Combination of Low-Intensity Chemotherapy (mini-hyper-CVD) and Ponatinib Followed By Blinatumomab and Ponatinib in Patients with Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Background Hyper-CVAD plus ponatinib is highly effective in Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The sequential combination of low-intensity chemotherapy and ponatinib followed by blinatumomab and ponatinib may lead to deeper and more durable responses, while minimizing toxicity of intensive chemotherapy and sparing the need for allogenic stem cell transplantation (ASCT). Methods In this phase II study, adults with either newly diagnosed (ND) Ph+ ALL, relapsed/refractory (R/R) Ph+ ALL, or chronic myeloid leukemia in lymphoid blast phase (CML-LBP) were eligible. Patients (pts) in the ND cohort could have received up to two cycles of therapy prior to enrollment. Pts received mini-hyper-CVD alternating with methotrexate and cytarabine on cycles 1-4, followed by blinatumomab and ponatinib on cycles 5-8. Ponatinib 30mg daily was given in cycle 1, and the dose was reduced to 15mg daily once a complete molecular response (CMR) was achieved. Pts with CD20+ disease received rituximab on cycles 1-4. Pts received 12 total administrations of prophylactic intrathecal chemotherapy with alternating cytarabine and methotrexate. Following consolidation, pts received maintenance therapy with 15 cycles of ponatinib plus vincristine/prednisone (maintenance cycles 1-3, 5-7, 9-11, and 13-15) alternating with ponatinib plus blinatumomab (maintenance cycles 4, 8, and 12) followed by ponatinib monotherapy daily for at least 5 years. The primary endpoint for pts with ND Ph+ ALL was the CMR rate. The primary endpoint for pts with R/R Ph+ ALL or CML-LBP was the CR/CRi rate. Secondary endpoints included complete remission duration (CRD), overall survival (OS), and safety. Results Between November 2019 and December 2021, 16 pts were treated (11 ND, 3 R/R, 2 CML-LBP). Baseline characteristics are shown in Table 1. The median age of the ND cohort was 35 (range, 25-59). BCR::ABL1 transcripts were p190 in 7 (64%) pts in the ND cohort. All pts in the R/R and CML-LBP cohorts were p210. Five pts (31%) in the ND cohort had evidence of a myeloid component to their disease (BCR::ABL1 in the myeloid compartment by FISH analysis in 4 pts and a small population of myeloid blasts in 1 pt). One of the R/R pts was in salvage 1, and 2 pts were in salvage 2; none of the R/R pts had previously received ponatinib. Neither of the 2 pts with CML-LBP had received any prior therapy, including a TKI. Nine pts (6 ND, 2 R/R and 1 CML-LBP) were in CR at the time of enrollment, and 4 pts (3 ND and 1 R/R) were in CMR. All pts who were evaluable for morphological response achieved CR. Among 8 evaluable ND pts, 6 achieved CMR. Two of 3 evaluable R/R pts and 1 of 2 evaluable CML-LBP pts achieved CMR. Among the 9 pts who achieved CMR, all but one achieved CMR during the chemotherapy plus ponatinib cycles. Out of the 5 ND pts who had evidence of myeloid involvement at presentation, 2 did not achieve CMR (both p190). All 6 pts who underwent Clonoseq MRD assessment achieved MRD negativity at 10-6 by this assay. With a median follow-up of 23 months (range, 6-31), the 2-year CRD and OS rates are 90% and 78%, respectively, across all cohorts (Figure 1), and are 89% and 82%, respectively in the ND cohort. Among the 11 ND pts, 1 pt (9%) relapsed, 2 pts (18%) died in CR (both due to COVID-19), and 8 pts (73%) are in continuous remission without ASCT. The 1 ND pt who relapsed developed CNS-only relapse during maintenance in the setting of non-compliance with ponatinib. Among the 3 R/R pts, no pts relapsed, 1 pt underwent ASCT, 1 pt died in CR from methotrexate-associated disseminated necrotizing leukoencephalopathy (autopsy-proven), and 1 pt is alive in continuous remission without ASCT. Among the 2 CML-LBP pts, neither relapsed, 1 pt underwent ASCT in first remission, and both are alive. Treatment was overall well-tolerated. The ponatinib dose was reduced in 2 pts prior to obtaining CMR due to toxicity (1 pancreatitis, 1 cardiomyopathy). One pt discontinued ponatinib and switched to dasatinib due to pulmonary embolism that occurred in cycle 2. No pts required dose-reduction or discontinuation of blinatumomab. The 30- and 60-day mortality rates were 0%. Conclusion Sequential combination of low-intensity chemotherapy and ponatinib followed by blinatumomab and ponatinib is highly effective and well tolerated in Ph+ ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Frontline Combination of Hyper-CVAD with Ponatinib for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia-6-Year Follow-up Results

Background: The combination of cytotoxic chemotherapy with a BCR::ABL1 tyrosine kinase inhibitor (TKI) has historically been standard of care for patients (pts) with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is 3rd generation TKI with more potent BCR::ABL1 inhibition than earlier-generation TKIs. Ponatinib also suppresses T315I clones, which are responsible for most relapses with other TKIs. Here we present the 6-year follow-up results of hyper-CVAD plus ponatinib for patients with newly diagnosed Ph+ ALL. Methods: This was a phase 2, single-arm study to evaluate the efficacy and safety of hyper-CVAD with ponatinib in adults with newly diagnosed Ph+ ALL. Pts age 18 years or older with previously untreated Ph+ ALL were eligible; pts who had received 1 to 2 courses of prior chemotherapy, with or without a TKI, were also eligible. Pts were required to have an ECOG performance status of 2 or less, bilirubin <3mg/dl, creatinine <3mg/dl, and normal cardiac function. Pts received hyper-CVAD alternating with high-dose methotrexate and cytarabine for 8 cycles. Initially, ponatinib was given at a dose of 45 mg daily. Due to 2 deaths due to cardiovascular events related to ponatinib, beginning with pt #37, the protocol was amended. After the amendment, ponatinib was administered at a dose of 45 mg for 14 days in cycle 1, then 30mg daily once patients achieved CR and 15mg daily once a complete molecular response (CMR) was achieved. Maintenance therapy was given for 2 years, vincristine, prednisone and ponatinib. Pts received 12 doses of intrathecal chemotherapy with alternating doses of cytarabine and methotrexate. Results: 86 pts were treated. Pts characteristics are summarized in Table 1. The median age was 46 years (range 21-80). Sixty-six pts (77%) had received no prior ALL-directed therapy, and 20 pts (23%) had received 1-2 courses of therapy prior to enrollment. Among these 20 pts, 18 were in CR and 2 had persistent disease at the time of enrollment. Sixty three pts (73%) had a p190 transcript, and 21 (24%) had a p210 transcript. Among 68 pts with active disease at enrollment, all pts achieved CR. Among 54 pts evaluable for cytogenetic response, all pts achieved complete cytogenetic response, including 50 pts (93%) after 1 cycle. Among 85 pts evaluable for molecular response, 83 pts (98%) achieved at least a major molecular response and 73 pts (86%) achieved a CMR. No pts died in the first 4 weeks of therapy. After a median follow up of 75 months (range, 16-123+ months), the 5-year overall survival (OS) and relapse-free survival rates were 75% and 68%, respectively (Figure 1). Twenty pts (23%) underwent stem cell transplantation (SCT) in first remission (5 of whom relapsed post SCT and 1 of whom died from post-SCT complications), 10 pts (12%) died in CR, 13 pts (19%) relapsed without SCT, and 43 pts (50%) are in ongoing remission without SCT. Of the relapsed pts, 5 were on ponatinib at the time of relapse, 2 of whom acquired an E255K kinase domain mutation at relapse; and 5 were on imatinib or dasatinib at the time of relapse, 3 of whom acquired a T315I kinase domain mutation. Among the 10 deaths in CR, 2 were treatment-related (both due to myocardial infarction before the amendment to implement lower doses of ponatinib). In a 8-month landmark analysis, the 5-year OS for pts without ASCT and with ASCT were 87% and 70%, respectively (p =0.09). Among the pts who are in ongoing remission without ASCT, 3 received subsequent therapy for MRD-positive disease. The most common grade ≥3 AE was infections and/or febrile neutropenia, seen in 82 pts (95%). Other grade ≥3 AEs including elevated transaminases in 25 pts (29%), increased amylase and/or lipase in 15 (17%), hyperbilirubinemia in 13 pts (15%), and clinical pancreatitis in 13 pts (15%). Five pts (6%) had a grade ≥3 venous thrombotic event, and 5 pts (6%) had a grade ≥3 arterial cardiovascular event. Two patients died from ponatinib-related cardiovascular complications, both from MI during cycle 2. Conclusion: The combination of hyper-CVAD and ponatinib results deep and durable remissions in pts with newly diagnosed Ph+ ALL. The overall CMR rate was 86% and the 5-year OS was 75%, which compares favorably with regimens using first- or second-generation TKIs in this population. The combination was safe; the use of lower doses of ponatinib maintained efficacy and mitigated the risk of ponatinib-related toxicity. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

A phase II trial of a chemotherapy-free combination of ponatinib and blinatumomab in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL).

7009 Background: Ponatinib and blinatumomab are highly active in Ph+ ALL. A chemotherapy-free combination of these agents may lead to durable remissions and reduce the need for stem cell transplant (SCT) in first remission. Methods: In this phase II study, adults with newly diagnosed (ND) Ph+ ALL, relapsed/refractory (R/R) Ph+ ALL, or CML in lymphoid blast phase (CML-LBP) received up to 5 cycles of blinatumomab. Ponatinib 30mg daily was given during cycle 1 and decreased to 15mg daily once a complete molecular response (CMR) was achieved. After completion of blinatumomab, ponatinib was continued for at least 5 years. All patients (pts) received 12 doses of prophylactic IT chemotherapy. Results: Between 2/2018 and 1/2022, 55 pts were treated (35 ND, 14 R/R and 6 CML-LBP). Baseline characteristics and responses are shown in Table. Among 23 pts with ND Ph+ ALL evaluable for response, 22 (96%) achieved CR/CRi; 1 pt had early death due to myelosuppression from prior chemotherapy. Among 13 evaluable pts with R/R Ph+ ALL, 12 (92%) achieved CR/CRi. The CMR rates for the ND, R/R and CML-LBP cohorts were 64%, 71%, and 17% after cycle 1 and were 85%, 79%, and 33% overall, respectively. In the ND cohort, 4/17 evaluable pts (24%) achieved CMR in the peripheral blood within 1 week, and 9/15 (60%) within 2 weeks. The median follow-up is 11 months (range, 1-46+ months). Among the 35 pts in the ND cohort, 33 pts (94%) are alive and in continuous remission. Only 1 pt in the ND underwent SCT in first remission (due to persistent MRD positivity), and no relapses have been observed. The 2-year EFS and OS rates in the ND cohort are 93%. Among the 13 responding pts in the R/R cohort, 6 (46%) underwent SCT. The 2-year EFS and OS rates for the R/R cohort are 42% and 61%, and for the CML-LBP cohort are 33% and 60%, respectively. Most side effects were grade 1-2 and were consistent with the known toxicity profile of the two agents individually. Two pts discontinued ponatinib due to toxicity (1 due to stroke and 1 due to DVT). One pt discontinued blinatumomab due to recurrent neurotoxicity. Conclusions: The chemotherapy-free combination of ponatinib and blinatumomab was safe and effective in Ph+ ALL and CML-LBP. Longer follow-up continues to demonstrate durable remissions, particularly in ND Ph+ ALL, even without SCT in first remission. Clinical trial information: NCT03263572. [Table: see text]

Updated Results of a Phase II Study of Ponatinib and Blinatumomab for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Updated Results of a Phase II Study of Ponatinib and Blinatumomab for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Safety and Efficacy of Acalabrutinib Plus Venetoclax and Rituximab in Patients with Treatment-Naïve (TN) Mantle Cell Lymphoma (MCL)

Safety and Efficacy of Acalabrutinib Plus Venetoclax and Rituximab in Patients with Treatment-Naïve (TN) Mantle Cell Lymphoma (MCL)

Trial in Progress: A Phase II Trial of Belinostat As Consolidation Therapy with Zidovudine for Adult T-Cell Leukemia-Lymphoma (ATLL)

Background: Adult T-cell leukemia-lymphoma (ATLL), a lymphoid malignancy associated with human T-cell leukemia virus type 1 (HTLV-1), is endemic in regions such as southwestern Japan, the Caribbean basin, and parts of South America, and central Africa where HTLV-1 is prevalent. Generally, ATLL cannot be cured with chemotherapy alone, and has dismal long-term outcomes. Previous clinical trials have only yielded modest results.Zidovudine (ZDV) is a synthetic nucleoside analog that inhibits reverse transcriptase and DNA polymerase resulting in inhibition of DNA replication and cell proliferation. Studies have demonstrated ZDV plus interferon (IFNα) therapy, as induction, followed by maintenance therapy, can be an efficacious first line treatment in leukemic forms of ATLL. A meta-analysis showed ZDV/IFNα therapy compared better to conventional chemotherapy for acute and chronic leukemic type ATLL in terms of overall survival. NCCN guidelines include ZDV/IFNα as a first-line therapy option for ATLL. While ZDV-IFNα can be effective in some ATLL patients, as with chemotherapy, molecular response rates are suboptimal, and patients usually relapse and succumb to their disease. Therefore, new therapeutic approaches and strategies are urgently needed to treat ATLL.Belinostat, a pan-HDAC inhibitor, obtained accelerated approval in 2015 for treatment of relapsed/refractory PTCL based on efficacy and duration of response. We hypothesize that belinostat will exert anti-neoplastic effects in ATLL cells through a variety of molecular mechanisms including activation of silenced key cellular genes and suppression of HBZ (only HTLV-1 protein consistently expressed in all ATLL tumors) and through HDAC inhibition, belinostat will reactivate HTLV-1 provirus in ATLL cells and infected T-cell reservoirs, thus eliciting an immune response against virus infected cells.Here, we describe a trial designed to evaluate safety and response of belinostat in combination with ZDV as consolidation therapy for treatment of ATLL. Correlative studies include measuring HTLV-1 reactivation in peripheral blood T-cells, assessing cytotoxic T-cell response in vivo, and investigating molecular effects of belinostat in ATLL cells in vivo.Study Design: This phase 2, single arm, open-label trial will evaluate the combination of belinostat and ZDV as consolidation therapy followed by standard ZDV-based maintenance therapy with optional IFNα-2b or pegylated interferon-alfa-2b (PEG-IFN-α-2b). The study will include up to 20 adult participants with histologically or cytologically documented ATLL, HTLV-1 infection, who have achieved and maintained at least a partial hematologic response to prior ZDV/IFNα therapy or chemotherapy. Residual ATLL in peripheral blood is required prior to enrollment. Patients must have measurable, clinically evaluable or molecular disease, with adequate end organ and bone marrow function (unless due to lymphomatous infiltration) and KPS ≥50% or ECOG performance status ≤3.The active study period includes a treatment period of up to 8 cycles (21 days each = ~6-months). Additional assessments will occur at the end of Cycle 8, Month 9, Month 12 and an end-of-treatment visit (≤ 30-days after the last dose of study treatment). Patients who achieve/maintain CR and complete 1 year of therapy will undergo follow-up assessments every 3 months for 1 year, and survival assessment every 6 months up to Year 5.ZDV will be administered in the outpatient setting as 300mg tablets orally, three times daily, starting at least 24-hours prior to the first dose of belinostat. Belinostat will be administered as 1,000 mg/m 2 IV infusion over 30 minutes on Days 1-5, every 21 days, on cycles 1- 8, followed by continuation of ZDV (+/- IFN-α) as maintenance therapy up to the end of Month 12. ZDV may be administered for a minimum 12 months from the beginning of the study.Primary objectives are to evaluate safety and determine complete molecular response rate after addition of belinostat as consolidation therapy for ATLL during ZDV-based maintenance treatment. Secondary outcomes will include evaluation of clinical response rates, investigation of whether belinostat disrupts HTLV-1 latency load in vivo, investigation of whether belinostat provokes immune or cytotoxic T-cell response in vivo and determine the impact of belinostat/ZDV (+/- IFNα) on HTLV-1 proviral load (measure of HTLV-1 infected reservoirs), in vivo. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Dasatinib and dexamethasone followed by hematopoietic cell transplantation for adults with Ph-positive ALL

AbstractPost-remission strategies after dasatinib-corticosteroid induction in adult Philadelphia chromosome (Ph)–positive acute lymphoblastic leukemia (ALL) are not well studied. We evaluated dasatinib and dexamethasone induction then protocol-defined post-remission therapies, including hematopoietic cell transplantation (HCT). Adults (N = 65) with Ph-positive ALL received dasatinib-dexamethasone induction, methotrexate-based central nervous system (CNS) prophylaxis, reduced-intensity conditioning (RIC) allogeneic HCT, autologous HCT, or chemotherapy alone, and dasatinib-based maintenance. Key end points were disease-free survival (DFS) and overall survival (OS). The median age was 60 years (range, 22-87 years). The complete remission rate was 98.5%. With a median follow-up of 59 months, 5-year DFS and OS were 37% (median, 30 months) and 48% (median, 56 months), respectively. For patients receiving RIC allogeneic HCT, autologous HCT, or chemotherapy, 5-year DFS were 49%, 29%, and 34%, and 5-year OS were 62%, 57%, and 46%, respectively. Complete molecular response rate after CNS prophylaxis was 40%. Relative to the p190 isoform, p210 had shorter DFS (median 10 vs 34 months, P = .002) and OS (median 16 months vs not reached, P = .05). Relapse occurred in 25% of allogeneic HCT, 57% of autologous HCT, and 36% of chemotherapy patients. T315I mutation was detected in 6 of 8 marrow relapses. Dasatinib CNS concentrations were low. Dasatinib-dexamethasone followed by RIC allogeneic HCT, autologous HCT, or chemotherapy was feasible and efficacious, especially with RIC allogeneic HCT. Future studies should address the major causes of failure: T315I mutation, the p210 BCR-ABL1 isoform, and CNS relapse. This study was registered at www.clinicaltrials.gov as #NCT01256398.