Showing papers by "Elias Jabbour published in 2023"

Complex I inhibitor of oxidative phosphorylation in advanced solid tumors and acute myeloid leukemia: phase I trials

Abstract: Although targeting oxidative phosphorylation (OXPHOS) is a rational anticancer strategy, clinical benefit with OXPHOS inhibitors has yet to be achieved. Here we advanced IACS-010759, a highly potent and selective small-molecule complex I inhibitor, into two dose-escalation phase I trials in patients with relapsed/refractory acute myeloid leukemia (NCT02882321, n = 17) and advanced solid tumors (NCT03291938, n = 23). The primary endpoints were safety, tolerability, maximum tolerated dose and recommended phase 2 dose (RP2D) of IACS-010759. The PK, PD, and preliminary antitumor activities of IACS-010759 in patients were also evaluated as secondary endpoints in both clinical trials. IACS-010759 had a narrow therapeutic index with emergent dose-limiting toxicities, including elevated blood lactate and neurotoxicity, which obstructed efforts to maintain target exposure. Consequently no RP2D was established, only modest target inhibition and limited antitumor activity were observed at tolerated doses, and both trials were discontinued. Reverse translational studies in mice demonstrated that IACS-010759 induced behavioral and physiological changes indicative of peripheral neuropathy, which were minimized with the coadministration of a histone deacetylase 6 inhibitor. Additional studies are needed to elucidate the association between OXPHOS inhibition and neurotoxicity, and caution is warranted in the continued development of complex I inhibitors as antitumor agents.

Frontline combination of ponatinib and hyper‐CVAD in Philadelphia chromosome‐positive acute lymphoblastic leukemia: 80‐months follow‐up results

Abstract: The combination of ponatinib, a third‐generation BCR::ABL1 tyrosine kinase inhibitor, with hyper‐CVAD chemotherapy resulted in high rates of complete molecular remissions and survival, without the need for stem cell transplantation (SCT) in most patients with Philadelphia chromosome(Ph)‐positive acute lymphocytic leukemia (ALL). Confirming these results in a large cohort of patients with longer follow‐up would establish this regimen as a new standard of care. Adults with newly diagnosed Ph‐positive ALL were treated with the hyper‐CVAD regimen. Ponatinib was added as 45 mg daily × 14 during induction, then 45 mg daily continuously (first 37 patients) or 30 mg daily continuously, with dose reduction to 15 mg daily upon achievement of a complete molecular response (CMR; absence of a detectable BCR::ABL1 transcript by quantitative reverse transcription polymerase‐chain reaction at a sensitivity of 0.01%). Maintenance therapy consisted of daily ponatinib and vincristine‐prednisone monthly for 2 years, followed by daily ponatinib indefinitely. Twelve intrathecal injections of cytarabine alternating with methotrexate were given as central nervous system prophylaxis. The trial is registered on clinicaltrials.gov with the identifier NCT01424982. Eighty‐six patients were treated. Their median age was 46 years (range, 21–80). All 68 patients with active disease at the initiation of therapy achieved complete response (CR) The cumulative CMR rate was 86%. Twenty‐ patients (23%) underwent allogeneic SCT. With a median follow‐up of 80 months (range, 16–129 months), the estimated 6‐year event‐free survival rate was 65% and the overall survival rate was 75%. There was no difference in outcome by performance of allogeneic SCT in first CR. Common grade 3–5 adverse events included infection (n = 80, 93%), increased liver transaminases (n = 26, 31%) and total bilirubin (n = 13, 15%), hypertension (n = 15, 17%), pancreatitis (n = 13, 15%), hemorrhage (n = 12, 13%), and skin rash (n = 9, 10%). Two ponatinib‐related deaths from myocardial infarction (3%; at months 2.6 and 4.3, respectively; both in CR) in the first 37 patients treated led to the ponatinib dose‐modifications mentioned earlier, with no further ponatinib‐related deaths observed. The long‐term results of ponatinib and hyper‐CVAD continue to demonstrate excellent outcome results and acceptable safety data, indicating that this strategy is another standard of care approach in frontline Ph‐positive ALL.

Chronic myeloid leukemia without major molecular response after 2 years of treatment with tyrosine kinase inhibitor

Abstract: Achieving major molecular response (MMR) with BCR::ABL1 tyrosine kinase inhibitors (TKIs) is associated with lower chances of progression to advanced phase disease and higher chances of treatment‐free remission (TFR) in patients with chronic myeloid leukemia (CML). Failure to achieve this molecular milestone after 1 year has been highlighted as “suboptimal” or “warning” sign of treatment failure in CML guidelines and recommendations and implied to predict a poor long‐term outcome. In this analysis, we report the long‐term outcome of 131 patients who did not achieve MMR within the first 2 years of TKI therapy. Patients who achieved a major cytogenetic response (MCyR; roughly equivalent to BCR::ABL1 transcript levels on the International Scale [IS] <10%) had good long‐term overall survival (OS) (10‐year OS of 88%) and CML‐related overall survival (CML‐OS) (10‐year CML‐OS of 95%). The achievement of MCyR within the first 2 years of treatment predicted a better OS (HR = 0.43, p = .03). The value of MMR was even less pronounced among patients aged 60 years or older at diagnosis, in whom mortality was primarily due to comorbidities unrelated to CML (10‐year OS of 55% vs. 10‐year CML‐OS of 100%). In conclusion, achievement of MCyR within 2 years is a reasonable milestone in CML, and these patients can still have good outcomes even when MMR is not achieved.

The outcomes of patients with chronic myeloid leukemia treated with third‐line BCR::ABL1 tyrosine kinase inhibitors

Abstract: The BCR::ABL1 tyrosine kinase inhibitors (TKIs) have improved the outcomes of patients with chronic myeloid leukemia (CML). After failing second‐generation TKI (2G‐TKI), the optimal third‐line therapy in chronic phase CML (CML‐CP) is not well established. We analyzed 354 patients with CML‐CP treated with a third‐line BCR::ABL1 TKI at our institution, and in the PACE and OPTIC trials, and evaluated the outcome after alternate 2G‐TKIs or ponatinib. We performed a propensity score matching analysis to compare outcomes and multivariate analysis to identify variables associated with survival. One hundred seventy‐three (49%) patients received 2G‐TKIs and 181 (51%) ponatinib. Patients in the ponatinib group had more cardiovascular risk factors (34% versus 19%) and higher disease burden (BCR::ABL1 transcript levels >1%, 165/175 [94%] versus 75/135 [55%]; p < .001) compared with the 2G‐TKI group. Among the 173 evaluable patients treated with ponatinib, 89 (52%) achieved 2 + −log reduction of baseline transcripts (20% 2‐log reduction and 32% 3 + −log reduction). Among the 128 evaluable patients treated with 2G‐TKIs, 44 (34%) achieved 2 + −log reduction of baseline transcripts (13% 2‐log reduction and 21% 3 + −log reduction). With a median follow‐up of 46 months, the 3‐year progression‐free survival was 59% (60% before matching) with 2G‐TKI and 83% (81% before matching) with ponatinib (p < .001). The 3‐year survival was 83% (81% before matching) with 2G‐TKI and 87% (89% before matching) with ponatinib (p = .03). By multivariate analysis, third‐line therapy with ponatinib was the only independent factor associated with better survival (p = .003). In conclusion, ponatinib is an optimal treatment for patients with CML‐CP failing two prior TKIs.

Association between bariatric surgery and outcomes in chronic myeloid leukemia

Abstract: Bariatric surgery is the most effective weight loss intervention. However, it can also decrease the bioavailability of oral medications. Tyrosine kinase inhibitors, the mainstay treatment for chronic myeloid leukemia (CML), are the most successful example of an oral targeted therapy. The impact of bariatric surgery on CML outcomes is unknown.

Ultrasensitive NGS MRD assessment in Ph+ ALL: Prognostic impact and correlation with RT‐PCR for BCR::ABL1

Abstract: Reverse transcription polymerase chain reaction (RT‐PCR) for BCR::ABL1 is the most common and widely accepted method of measurable residual disease (MRD) assessment in Philadelphia chromosome‐positive acute lymphoblastic leukemia (Ph+ ALL); however, RT‐PCR may not be an optimal measure of MRD in many cases of Ph+ ALL. We evaluated the clinical impact of a highly sensitive next‐generation sequencing (NGS) MRD assay (sensitivity of 10−6) and its correlation with RT‐PCR for BCR::ABL1 in patients with Ph+ ALL. Overall, 32% of patients had a discordance between MRD assessment by RT‐PCR and NGS, and 31% of patients who achieved NGS MRD negativity were PCR+ at the same timepoint. Among eight patients with long‐term detectable BCR::ABL1 by PCR, six were PCR+/NGS−. These patients generally had stable PCR levels that persisted despite therapeutic interventions, and none subsequently relapsed; in contrast, patients who were PCR+/NGS+ had more variable PCR values that responded to therapeutic intervention. In a separate cohort of prospectively collected clinical samples, 11 of 65 patients (17%) with Ph+ ALL who achieved NGS MRD negativity had detectable BCR::ABL1 by PCR, and none of these patients relapsed. Relapse‐free survival and overall survival were similar in patients who were PCR+/NGS− and PCR−/NGS−, suggesting that PCR for BCR::ABL1 did not provide additional prognostic information in patients who achieved NGS MRD negativity. NGS‐based assessment of MRD is prognostic in Ph+ ALL and identifies patients with low‐level detectable BCR::ABL1 who are unlikely to relapse nor to benefit from therapeutic interventions.

The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades

Abstract: Progress in the research and therapy of adult acute lymphoblastic leukemia (ALL) is accelerating. This analysis summarizes the data derived from the clinical trials conducted at MD Anderson between 1985 and 2022 across ALL subtypes. In Philadelphia chromosome-positive ALL, the addition of BCR::ABL1 tyrosine kinase inhibitors (TKIs) to intensive chemotherapy since 2000, improved outcomes. More recently, a chemotherapy-free regimen with blinatumomab and ponatinib resulted in a complete molecular remission rate of 85% and an estimated 3-year survival rate of 90%, potentially reducing the role of, and need for allogeneic stem cell transplantation (SCT) in remission. In younger patients with pre-B Philadelphia chromosome-negative ALL, the integration of blinatumomab and inotuzumab into the frontline therapy has improved the estimated 3-year survival rate to 85% across all risk categories. Our future strategy is to evaluate the early integration of both immunotherapy agents, inotuzumab and blinatumomab, with low-dose chemotherapy (dose-dense mini-Hyper-CVD-inotuzumab-blinatumomab) into the frontline setting followed by CAR T cells consolidation in high-risk patients, without any further maintenance therapy. In older patients, using less intensive chemotherapy (mini-Hyper-CVD) in combination with inotuzumab and blinatumomab has improved the 5-year survival rate to 50%. Among patients ≥ 65-70 years, the mortality in complete remission (CR) is still high and is multifactorial (old age, death in CR with infections, development of myelodysplastic syndrome or acute myeloid leukemia). A chemotherapy-free regimen with inotuzumab and blinatumomab is being investigated. The assessment of measurable residual disease (MRD) by next-generation sequencing (NGS) is superior to conventional assays, with early MRD negativity by NGS being associated with the best survival. We anticipate that the future therapy in B-ALL will involve less intensive and shorter chemotherapy regimens in combination with agents targeting CD19 (blinatumomab), CD20, and CD22 (inotuzumab). The optimal timing and use of CAR T cells therapy may be in the setting of minimal disease, and future trials will assess the role of CAR T cells as a consolidation among high-risk patients to replace allogeneic SCT. In summary, the management of ALL has witnessed significant progress during the past four decades. Novel combination regimens including newer-generation BCR::ABL1 TKIs and novel antibodies are questioning the need and duration of intensive chemotherapy and allogeneic SCT.

First report of PhALLCON: A phase 3 study comparing ponatinib (pon) vs imatinib (im) in newly diagnosed patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL).

Abstract: 398868 Background: The standard of care in patients (pts) with newly diagnosed (dx) Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL) is BCR::ABL1 tyrosine kinase inhibitors (TKIs) in combination with chemotherapy (chemo) or steroids. Treated with 1st- or 2nd-generation TKIs, pts eventually progress due to emergence of resistance. Multiple studies have reported promising minimal residual disease (MRD) negativity (neg) rates and survival outcomes with pon in combination with chemo or chemo-free regimens. PhALLCON (NCT03589326), the first randomized study comparing TKIs in pts with Ph+ALL, evaluates pon vs im in combination with reduced-intensity chemo. Methods: This phase 3 open-label trial randomized adult newly dx Ph+ALL pts 2:1 to receive pon (30 mg once daily [QD]) or im (600 mg QD) with reduced-intensity chemo through end of induction (EOI; Cycles 1–3), consolidation (Cycles 4–9), and post-consolidation (Cycles 10–20). After Cycle 20, pts received single-agent pon or im until disease progression or unacceptable toxicity. The composite primary endpoint was MRD-neg ( BCR:: ABL1 ≤0.01% ) complete remission (CR) for 4 weeks at EOI. Event-free survival (EFS: any cause death, failure to achieve CR by EOI, relapse from CR) was a key secondary endpoint. Results: 245 pts were randomized to pon (n=164) or im (n=81); median age was 54 y (37% ≥60 y). At data cutoff (Aug 2022), 78 pts (pon vs im: 42% vs 12%) were on study treatment; the top 3 reasons for discontinuation were hematopoietic stem cell transplantation (31% vs 37%), adverse events (12% vs 12%), and lack of efficacy (7% vs 26%). Median follow-up was 20 mo vs 18 mo (pon vs im). The primary endpoint was met (Table) by significantly higher MRD-neg CR rate for pon vs im (34.4% vs 16.7%; p=0.0021). Survival data were not mature; however, the median EFS was reached in im and not in pon, with a trend toward improvement (HR=0.652, 95% CI 0.385–1.104). Time to treatment failure reported an improvement as well (HR=0.455). The treatment-emergent adverse event (TEAE) rates (any grade [Gr] and Gr3/4/5) were comparable between treatment arms. Arterial occlusive events (AOEs) were infrequent and similar between the arms (Table). Conclusions: Pon was superior to im in combination with reduced-intensity chemo in pts with newly dx Ph+ALL, with a significantly higher MRD-neg CR rate at the EOI. Pon was associated with deeper and more durable responses, with a trend toward improved EFS and comparable safety vs im. Clinical trial information: NCT03589326 . [Table: see text]

Sequencing antigen‐targeting antibodies and cellular therapies in adults with relapsed/refractory B‐cell acute lymphoblastic leukemia

Abstract: The recent approvals of four CD19‐or CD22‐targeted therapies for B‐cell acute lymphoblastic leukemia (B‐ALL) have transformed the treatment of relapsed/refractory (r/r) disease. Adults with r/r B‐ALL are usually eligible for all options, but there are no studies directly comparing these agents, and the treating physician must decide which to select. Each therapy has notable activity as a single agent but has limitations in particular settings, and the optimal choice varies. These therapies can be complementary and used either sequentially or concomitantly. Here, we review the current landscape of antigen‐targeted therapies for r/r B‐ALL and discuss considerations for their use.

Early mortality in acute myeloid leukemia with KMT2A rearrangement is associated with high risk of bleeding and disseminated intravascular coagulation

Abstract: Acute myeloid leukemia (AML) with rearrangement of lysine methyltransferase 2a gene (KMT2Ar) is characterized by chemotherapy resistance and high rates of relapse. However, additional causes of treatment failure or early mortality have not been well‐defined in this entity.

SOHO State of the Art Updates and Next Questions | Hyper-CVAD in 2022: Lessons Learned and New Approaches.

Abstract: Combination chemotherapy is the mainstay of treatment for acute lymphoblastic leukemia (ALL). The Hyper-CVAD regimen was developed in 1992 at MD Anderson Cancer Center and has since become a standard of care option for adult patients with ALL. Since its conception, a number of modifications have been implemented to customize the regimen for different patient populations and safely incorporate novel therapies without compromising tolerability. We aim to review the evolution of the Hyper-CVAD regimen over the past 3 decades, focusing on clinical pearls, as well as future directions.

Superior outcomes after allogeneic stem cell transplantation (SCT) among patients (Pts) ≥ 60 years (yrs) treated with cladribine (CLAD), low dose cytarabine (LDAC) plus venetoclax (Ven) for newly diagnosed acute myeloid leukemia (AML).

Abstract: 7047 Background: CLAD/LDAC/VEN alternating with AZA-VEN has shown promising outcomes in older pts with AML ( Kadia, JCO Nov 2022). Improved disease control and preserved performance status achieved with CLAD/LDAC/VEN treatment, may translate into superior post-SCT outcomes. Methods: We compared outcomes of pts ≥ 60 yrs of age treated on the phase II study of CLAD-LDAC-VEN who underwent SCT in 1st remission (CR1) to a retrospective cohort of pts ≥ 60 yrs treated with hypomethylating agent (HMA)-VEN based or intensive (INT) therapy who underwent SCT in CR1 between 2013-2022. Relapse free survival (RFS) was from response to relapse/death & overall survival (OS) from start of therapy to death. Results: 35 pts treated with CLAD-LDAC-VEN were compared to 42 pts treated with INT & 40 pts with HMA-VEN therapy for remission induction prior to SCT at our center (Table). The median age of pts in the low-intensity arms were similar (68 yrs), but lower on the INT arm (62 yrs). More pts post INT therapy received a myeloablative conditioning (MAC). At a median follow up of 17+ months (m) for CLAD-LDAC-VEN arm, 59 m for INT arm, and 30 m for HMA arm, the median RFS (NR vs. 50 m vs. 20 m respectively, p <0.01) and OS (NR vs. 58 m vs. 32 m respectively, p < 0.01) was superior for the CLAD-LDAC-VEN arm. 3-yr cumulative incidence of relapse & NRM (as competing events) were both significantly lower with CLAD-LDAC-VEN (4% and 7%) compared to INT (17% and 23%) or HMA-VEN (41% and 27%) therapy. Conclusions: Older pts with AML proceeding to SCT after CLAD-LDAC-VEN therapy had significantly improved survival, characterized by significantly lower rates of NRM and relapse compared to HMA-VEN or INT therapies. Larger studies and longer follow up is needed to confirm its benefit. [Table: see text]

Mini-hyper-CVD with venetoclax (Ven) for patients with relapsed/refractory (R/R) Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL): A phase II study.

Abstract: e19039 Background: In preclinical studies, Ven has shown promising clinical activity in patients (pts) with R/R ALL. The combination of Ven with low intensity mini-HCVD chemotherapy could improve outcomes in ALL pts. Methods: Pts ≥18 years with R/R Ph-negative B- or T-cell ALL received mini-HCVD alternating with methotrexate and cytarabine for up to 8 cycles. Ven was given at a dose of 400 mg/d on Days (D) 1-14 of Cycle (C) 1 and on D1-7 of C2-8. Rituximab (if CD20+ B-ALL) and prophylactic IT chemotherapy x8 doses were given for the first 4 cycles. Pts with T-ALL received additional 2 cycles of nelarabine and peg-asparaginase during consolidation without Ven, and 2 cycles during maintenance. Maintenance with vincristine, prednisone and Ven was given for up to 2 years. Results: Between 6/2019 and 2/2021, 23 pts were treated, with a median age of 45 years (range, 20-70). 18 (78%) pts had B-ALL and 5 (22%) T-ALL, including 1 pt with ETP ALL. Among the 23 pts, the median number of prior therapies was 2 (range, 1-6) and 13 (57%) had undergone prior allogeneic stem cell transplant (ASCT). Among the 18 B-ALL pts, 16 (89%) had received prior blinatumomab and 7 (39%) prior inotuzumab. Among 23 pts, 1 was in CR at enrollment. Overall, 12 of 22 (55%) pts responded to therapy (complete response, n=9), of whom 9 achieved best response after C1 and 3 after C2. An additional pt achieved partial response. The overall response rate among the 18 pts who had at least a bone marrow assessment after C1 was 67%. The median duration of follow-up was 26 months (range, 2-35). Among the 13 responders (including the pt in CR at start), 6 (46%) relapsed, 5 (39%) underwent ASCT (4 subsequently relapsed), and 2 (15%) died in remission. The median RFS and OS were 6.4 and 8.1 months, respectively, and the 1-year RFS and OS rates were 15% and 37%, respectively. Survival was worse in pts with adverse cytogenetics versus others (median OS, 6 vs 12 months; 1-yr OS rate, 17% vs 44%; P=0.15). In C1, the median time to platelet recovery was 27 days (range, 0-81) and neutrophil recovery was 21 days (range, 0-36); in C2+, median times to recovery were 25 days (range, 0-76) and 15 days (range, 0-26), respectively. The 30-day and 60-day mortality rates were 0% and 13%, respectively. Conclusions: The combination of low-intensity chemotherapy mini-HCVD with Ven in pts with R/R Ph-negative ALL was well-tolerated and resulted in a response rate of 67%. Further studies examining the role of Ven-based therapies in ALL are needed for newly diagnosed and R/R pts. Clinical trial information: NCT03808610 . [Table: see text]

Phase II trial of mini-hyper-CVD-inotuzumab (InO) followed by blinatumomab (blina) consolidation in patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL).

Abstract: e19037 Background: Promising results were seen with low intensity chemotherapy mini-Hyper-CVD (mini-HCVD) in combination with InO in R/R ALL. Adding blina may further improve outcomes. Methods: Pts with R/R Philadelphia-negative B-ALL were treated with mini-HCVD (Cycles 1, 3, 5, 7) and methotrexate/cytarabine (Cycles 2, 4, 6, 8) for 8 cycles. Initially, InO was given on Day (D) 3 of the first 4 cycles at the dose of 1.8-1.3 mg/m2 in Cycle (C) 1, followed by 1.3-1.0 mg/m2 in subsequent cycles. POMP maintenance was for a total of 3 yrs. Protocol was amended after pt #67 to add 4 cycles of blina after 4 cycles of mini-HCVD+InO. InO was given on D2 and 8 at the dose of 0.6 and 0.3 mg/m2 in C1, and then on D2 and 8 at the dose of 0.3 mg/m2 in subsequent cycles; blina was given at standard dose in C5-8. Maintenance was reduced to 12 cycles of POMP with 1 cycle of blina after each 3 cycles of POMP for a total of 4 cycles. Rituximab was given for CD20+ disease. All pts received 8 doses of intrathecal chemotherapy. Results: Between 2/2013 and 7/2021, 110 pts were treated. Patient characteristics are shown in the table. 79 (72%) pts were treated in Salvage (S) 1, and 31 (28%) in S2+. 21 (19%) pts had received prior ASCT. 91 (83%) pts responded (complete remission, 63%). The overall response rate was 93% in S1, 59% in S2, and 57% in S3+. The rates of MRD negativity by flow were higher in S1 vs S2+ (89% vs 67%; P=0.047). 53 (48%) pts underwent ASCT. After a median follow-up of 48 months (mo) (range, 9-115), the median OS and RFS were 17 mo (4-yr, 36%) and 13 mo (4-yr, 37%), respectively. Pts in S1 had better OS compared with S2+ (4-yr OS, 43% vs 18%; P<0.001). The 4-yr RFS was 38% in S1 and 27% in S2+ ( P=0.14). In S1, 41 pts were treated before the amendment and 38 after the amendment; their 4-yr OS was 41% and 48% ( P=0.99), and their 4-yr RFS was 39% and 36%, respectively ( P=0.95). A landmark analysis of pts who achieved remission showed no survival difference between pts who did or did not undergo ASCT, with 4-yr OS of 49% and 48% ( P=0.98), and 4-yr RFS of 46% and 37% ( P=0.68), respectively. Sinusoidal obstruction syndrome (SOS) was noted in 10 (9%) pts, and its incidence decreased from 13% with single dose of InO to 2% with lower and fractionated doses of InO ( P=0.056). Conclusions: The combination of mini-HCVD and reduced-dose InO with sequential blina improved the outcomes of pts with R/R ALL. The new treatment schedule resulted in a lower rate of SOS compared to the original schedule. Clinical trial information: NCT01371630 . [Table: see text]

The emerging use of chemotherapy-free regimens in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia.

Abstract: Before the development of tyrosine kinase inhibitors (TKIs), the outcome of patients with a diagnosis of Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia was dismal. Combinations of TKIs and chemotherapy improved survival rates, but allogeneic stem cell transplant was still relied on to avoid relapse in most cases. More recently, the chemotherapy-free combination of blinatumomab plus newer-generation TKIs has shown favorable results and may eliminate the need for allogeneic stem cell transplant. This review discusses the evolution of the treatment of Ph-positive acute lymphoblastic leukemia with chemotherapy-free regimens in the current era.

Abstract CT101: Phase I study of the T-cell receptor-like antibody Hu8F4 in patients with advanced hematologic malignancies

Abstract: Background: Despite recent advances in the treatment of AML, most approaches are rarely curative and most patients (pts) succumb to relapsed disease. The effectiveness of stem cell transplant and associated graft vs. leukemia effect implies an important role for immune-based therapy in producing long lasting remissions. Traditional approaches using immunotherapy have failed to establish a suitable surface target or treatment paradigm that is effective in myeloid malignancies. Hu8F4 is a humanized T-cell receptor-like monoclonal antibody that binds to the conformational epitope of PR1 bound to HLA-A2, which is highly, differentially expressed on the surface of AML compared to normal progenitors. Methods: We conducted a first in human, phase I dose escalation trial of Hu8F4 in pts with myeloid malignances. Pts with R/R AML, MDS, CMML, and myeloid blast phase of CML with adequate organ function and PS ≤ 2 were eligible. Pts were treated on 7 escalating dose levels, ranging from 0.01 mg/kg to 10 mg/kg IV on D1 & 15. Initial dose levels required 1 pt per dose (0.01, 0.03, 0.1, 0.3, 1), followed by 3 pts per dose (3, 10). Results: 10 pts with R/R AML have been enrolled, with a median age of 65 years (range, 23-77), including 6 females (60%). Pts had received a median of 4 (1-4) prior therapies; 5 pts (50%) had a PS of 2. At enrollment, the median WBC was 1.9 (0.1 - 18.4), median BM blasts were 32% (8 - 76); 9 (90%) pts had complex karyotype and 3 (30%) had a TP53 mutation. All pts had > 98% surface expression of PR1 on the myeloid blasts. Hu8F4 Cmax ranged up to 160,000 ng/mL with t1/2 of 48 hours and clearance of 2.61 hr*ng/mL at the highest dose. Weak anti-drug antibodies were observed after week 4 in 2 of 3 pts treated at 3 mg/kg. With a median follow up of 3.5 months (1.1 - 9.9), pts have received a median of 1 (1-4) cycle of therapy. Two pts had decline in BM blasts and 4 had stable disease. Routine peripheral blood testing revealed sharp decline in peripheral blasts immediately after infusion of Hu8F4 on D1 and 15 with associated elevation in serum LDH in some pts and a rise in normal granulocytes, consistent with on-tumor effects. The pharmacokinetic parameters and transient blast reduction indicated a possible sink effect mediated by high levels of circulating blasts. SAEs documented on study were mostly disease-related and included infections, cytopenias, hemoptysis, pneumonia, and GI bleeding. Treatment related AEs were temporally related to the infusion included hypotension (Grade 2: N=2), rigors (Grade 2: N=2; Grade 1: N=1). All infusion reactions were observed at dose levels of 3 and 10 mg/kg, but were transient, and managed with steroids and antihistamines. All pts proceeded with their next dose without further issues. No cytokine release syndrome or neurologic toxicity was observed. Correlative studies support antibody dependent cellular cytotoxicity and phagocytosis as important mechanisms of anit-AML activity. Conclusion: Hu8F4 was well tolerated with no dose-limiting toxicities observed at the maximum planned dose. On-target peripheral blast reduction temporally related to infusion suggests biological activity. Real-time pharmacokinetic data on study indicate a possible sink effect that may be overcome by a more frequent dosing strategy. Citation Format: Tapan M. Kadia, Hagop Kantarjian, Gheath Alatrash, Anna Sergeeva, Hong He, Lisa St. John, Priya Koppikar, Celine Kerros, Abhishek Maiti, Courtney Dinardo, Elias Jabbour, Serge Vesrstovsek, Naveen Pemmaraju, Nitin Jain, Ghayas Issa, Guillermo Montalban-Bravo, Aditi Shastri, Daniel Couriel, Rhona Pinsoy, Sapna Parshottam, Richard Champlin, Jorge Cortes, Jeffrey Molldrem. Phase I study of the T-cell receptor-like antibody Hu8F4 in patients with advanced hematologic malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT101.

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.

Abstract: 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]

Epigenomic mapping in B-cell acute lymphoblastic leukemia identifies transcriptional regulators and noncoding variants promoting distinct chromatin architectures

Abstract: B-cell lineage acute lymphoblastic leukemia (B-ALL) is comprised of diverse molecular subtypes and while transcriptional and DNA methylation profiling of B-ALL subtypes has been extensively examined, the accompanying chromatin landscape is not well characterized for many subtypes. We therefore mapped chromatin accessibility using ATAC-seq for 10 B-ALL molecular subtypes in primary ALL cells from 154 patients. Comparisons with B-cell progenitors identified candidate B-ALL cell-of-origin and AP-1-associated cis-regulatory rewiring in B-ALL. Cis-regulatory rewiring promoted B-ALL-specific gene regulatory networks impacting oncogenic signaling pathways that perturb normal B-cell development. We also identified that over 20% of B-ALL accessible chromatin sites exhibit strong subtype enrichment, with transcription factor (TF) footprint profiling identifying candidate TFs that maintain subtype-specific chromatin architectures. Over 9000 inherited genetic variants were further uncovered that contribute to variability in chromatin accessibility among individual patient samples. Overall, our data suggest that distinct chromatin architectures are driven by diverse TFs and inherited genetic variants which promote unique gene regulatory networks that contribute to transcriptional differences among B-ALL subtypes. HIGHLIGHTS Pro-B progenitor cells as the most common cell-of-origin for B-ALL AP-1 TF-associated cis-regulatory rewiring in B-ALL Subtype-specific accessible chromatin signatures representing 20% of all B-ALL sites Role for distinct TFs in promoting subtype-specific chromatin architectures Thousands of inherited genetic variants identified impacting chromatin state

Functional investigation of inherited noncoding genetic variation impacting the pharmacogenomics of childhood acute lymphoblastic leukemia treatment

Abstract: Although acute lymphoblastic leukemia (ALL) is the most common childhood cancer, there is limited understanding of the contribution of inherited genetic variation on inter-individual differences in chemotherapy response. Defining genetic factors impacting therapy failure can help better predict response and identify drug resistance mechanisms. We therefore mapped inherited noncoding variants associated with chemotherapeutic drug resistance and/or treatment outcome to ALL cis-regulatory elements and investigated their gene regulatory potential and genomic connectivity using massively parallel reporter assays and promoter capture Hi-C, respectively. We identified 53 variants with reproducible allele-specific effects on transcription and high-confidence gene targets. Subsequent functional interrogation of the top variant (rs1247117) determined that it disrupted a PU.1 consensus motif and PU.1 binding affinity. Importantly, deletion of the genomic interval containing rs1247117 sensitized ALL cells to vincristine. Together, these data demonstrate that noncoding regulatory variation associated with diverse pharmacological traits harbor significant effects on allele-specific transcriptional activity and impact sensitivity to chemotherapeutic agents in ALL.

Sudden lymphoid blast crisis after tyrosine kinase inhibitor discontinuation in chronic phase chronic myeloid leukemia: cautionary tales for appropriate molecular monitoring

Abstract: myeloid leukemia (

Outcomes of adult patients with relapsed/refractory CRLF2 rearranged B‐cell acute lymphoblastic leukemia

Abstract: To the Editor: Philadelphia chromosome-like (Ph-like) B-cell acute lymphoblastic leukemia (B-ALL) is characterized by a gene expression profile that is similar to Philadelphia chromosome-positive (Ph+) B-ALL but without the presence of BCR::ABL1 translocation. Among adult patients with Ph-like ALL, those with CRLF2 overexpression tend to have worse outcomes after treatment with conventional chemotherapy. As patients with CRLF2-rearranged B-ALL have activation of the JAK/STAT pathway, ruxolitinib has been investigated in combination with conventional chemotherapy with limited clinical activity. Given the dismal prognosis of patients with CRLF2-rearranged B-ALL, the outcomes of these patients are important to study, especially in the context of novel B-cell targeting therapies such as inotuzumab ozogamicin, blinatumomab, and chimeric antigen receptor T (CAR T) cell therapy. We retrospectively analyzed the treatment outcomes of patients with relapsed and/or refractory (R/R) CRLF2-rearranged B-ALL treated at our institution [MD Anderson Cancer Center (MDACC), Houston, TX]. CRLF2 expression was assessed by flow cytometry and/or fluorescence in-situ hybridization (FISH) and/or gene expression profile. We previously reported 100% concordance between flow cytometry for CRLF2 expression and FISH for CRLF2 rearrangement in patients with B-ALL. We assessed prior treatment details, disease characteristics including cytogenetics and JAK2 mutation status, salvage therapy received at our institution, response, and survival outcomes. The timepoint of study entry of patients in this retrospective analysis was the time of first therapy received at our institution with relapsed and/or refractory disease. For patients who had received their frontline therapy at our institution, we assessed outcomes from the first salvage regimen for the first relapse or primary refractory disease. For patients who presented to our institution with R/R disease after prior therapy at an outside hospital, study entry was at the time of first therapy received at MDACC. Relapse-free survival (RFS) was calculated from response to salvage therapy to subsequent relapse or death; overall survival (OS) was calculated from study entry to death. Kaplan Meier method was used for survival analysis and GraphPad Prism version 9.3.1 for Windows, GraphPad Software, San Diego, California United States, was used for statistical analysis. From November 2001 to March 2021, 69 patients with R/R CRLF2-rearranged B-ALL who received treatment at our center were identified. A total of 41 patients were identified on the basis of CRLF2 overexpression by CRLF2 flow cytometry of which 26 patients had a concomitant CRLF2 FISH performed, and all had CRLF2 rearrangement (18 IGH, 6 P2RY8, and 2 with unknown partner gene). The remaining 28 patients were identified by gene expression profile (St. Jude Children's Research Hospital). Seventy-one percent of patients were male and 70% of all patients identified as Hispanic. The median age at presentation was 36 years (range, 18–72 years) and the median number of prior lines of therapy was 1 (range, 1–5). Baseline patient characteristics are described in Table S1. Fifty-one patients (74%) had received only chemotherapy prior to study entry; the remaining 18 patients (26%) received targeted therapy (inotuzumab ozogamicin, blinatumomab, and/or CAR T cell therapy) prior to study entry. Nine patients (9/69, 13%) had a prior allogeneic stem cell transplantation (allo-SCT). The median time to study entry from initial diagnosis of B-ALL was 15 months (range, 0.5–280 months). Of the 61 patients who were assessed for JAK2 mutation, 24 (39%) had a mutation. Patients were divided into two cohorts based on their first salvage therapy at MDACC: (1) targeted therapy cohort (T; patients who received inotuzumab ozogamicin and/or blinatumomab, and/or CAR T cell therapy, n = 28) with or without a chemotherapy backbone; (2) conventional chemotherapy cohort (C; n = 41). Treatment regimens for both cohorts are detailed in Table S2. The median age in the T and C cohorts was 39 years and 35 years, respectively. The two groups were well balanced for age, prior lines of therapy and prior allo-SCT; however, more patients in the C cohort had JAK2 mutation than in the T cohort (50% vs. 22% in the C and T cohorts, respectively) and a higher proportion of patients in the T cohort had received prior targeted therapy (32% vs. 21% in the T and C cohorts, respectively). The complete remission/complete remission with incomplete count recovery (CR/CRi) rate was 43% for the whole group [15 of 28 patients (54%) in the T cohort and 15 of 41 patients (37%) in the C cohort, p = .21]. Twelve of 15 (80%) responding patients in the T cohort and 12 of 14 (85%) responding patients in the C cohort evaluated for measurable residual disease (MRD) status were MRD negative. The median number of cycles to respond for the entire cohort was 1 (range, 1–3). At a median follow-up of 46 months for the whole cohort from study entry, the median OS was 9.2 months; the median OS among the responding patients was 24.4 months, as detailed in Figure S1. The median OS for the targeted therapy group was 11.8 versus 5.8 months for the conventional chemotherapy group (p log rank = 0.11) (Figure 1). We further analyzed the survival outcomes based on the JAK2 mutation status. Overall, the median OS was shorter in patients with JAK2 mutations (JAK2) versus JAK2 Received: 21 December 2022 Revised: 20 February 2023 Accepted: 2 March 2023

Safety and efficacy of obecabtagene autoleucel (obe-cel, AUTO1), a fast-off rate CD19 CAR, in relapsed/refractory adult B-cell acute lymphoblastic leukemia (r/r B-ALL): Top line results of the pivotal FELIX study.

Abstract: 7000 Background: Obe-cel is an autologous CD19CAR with a fast off-rate CD19 binding domain designed to reduce CAR-T immunotoxicity and improve persistence. Its clinical activity has been tested in r/r paediatric and adult B-ALL trials (CARPALL, Ghorashian S et al., Nat Med 2019; ALLCAR19, Roddie C et al., JCO 2021) and more recently in adults with r/r B-cell malignancies (NCT02935257). Here, we present data from adult r/r B-ALL patients treated with obe-cel in the pivotal FELIX study (NCT04404660). Methods: FELIX is an open-label, multi-centre, global, single-arm Phase Ib/II study enrolling r/r B-ALL patients with morphological disease (≥5% BM blasts), measurable residual disease (MRD) (≥0.1% to < 5% BM blasts), or isolated extramedullary disease (Cohorts A, B and C). CAR-T products were generated using an automated closed process from fresh leukapheresate. Patients underwent bridging therapy as necessary and lymphodepletion with fludarabine (4x30mg/m2) and cyclophosphamide (2x500mg/m2). Patients received a target dose of 410E+6 CAR T cells as a split dose on Day 1 and Day 10. The dosing schedule is based on the % BM blasts performed locally prior to the pre-conditioning. Primary endpoint was overall remission rate (ORR) defined as proportion of patients achieving CR/CRi by central assessment. Results: As of 9th September 2022, a pre-specified interim analysis was conducted based on the first 50 patients infused in Cohort A who have been followed for 3 months or discontinued before month 3. The median age was 50 years (range 20-81), 22% had Ph+ B-ALL. The median number of prior lines of treatment was 2 (range 1-5), 42% underwent prior transplant. At screening, patients had a median of 55% BM blasts (range 6-96%) and 26% had EMD. The geometric mean of peak CAR expansion was 126147.6 copies/ug genomic DNA. Persistence was ongoing in majority of responders at last follow-up. Based on central assessment, the CR/CRi was 70% [95% CI: 55%, 82%] (p-value < 0.0001). As of 9th September 2022, a total of 92 patients received obe-cel and were evaluable for safety. 63% developed any grade CRS (3% Grade ≥3) at a median of 9 days post-infusion and a median duration of 5 days. Any grade ICANS was observed in 23% (8% Grade ≥3) at a median of 15 days post-infusion and of median duration 8 days. Other common Grade≥3 adverse events regardless of causality were febrile neutropenia (25%) and anaemia (20%). Conclusions: The pre-specified interim analysis of the FELIX study demonstrated that obe-cel for adult r/r B-ALL is safe with low rates of Grade >3 CRS and/or ICANS, even in patients with high burden disease. Obe-cel is effective with high CR/CRi rates and ongoing CAR T persistence in the majority of responders. The trial has completed dosing of all patients in Cohort A. Additional data and longer follow up will be reported at the conference. Clinical trial information: NCT04404660 .

Evolving trends and outcomes in older patients with acute myeloid leukemia including allogeneic stem cell transplantation.

Abstract: Outcomes in older patients with acute myeloid leukemia (AML) have historically been poor. Given advances in low-intensity therapy (LIT) and stem cell transplantation (SCT), we performed a retrospective single-center study to evaluate the contemporary outcomes of this population. We reviewed all patients ≥60 years with newly diagnosed AML between 2012 and 2021 and analyzed treatment and SCT-related trends and outcomes. We identified 1073 patients with a median age of 71 years. Adverse clinical and cytomolecular findings were frequent within this cohort. In total, 16% of patients were treated with intensive chemotherapy, 51% with LIT alone, and 32% with LIT plus venetoclax. The composite complete remission rate with LIT plus venetoclax was 72%, which was higher than with LIT alone (48%, p < .0001) and comparable to intensive chemotherapy (74%, p = .6). The median overall survival (OS) with intensive chemotherapy, LIT, and LIT plus venetoclax was 20.1, 8.9, and 12.1 months, respectively. 18% of patients received SCT. SCT rates were 37%, 10%, and 22% in patients treated with intensive chemotherapy, LIT, and LIT plus venetoclax, respectively. The 2-year OS, relapse-free survival (RFS), cumulative incidence (CI) of relapse, and CI of treatment-related mortality with frontline SCT (n = 139) were 59%, 52%, 27%, and 22%, respectively. By landmark analysis, patients undergoing frontline SCT had superior OS (median 39.6 vs. 21.4 months, p < .0001) and RFS (30.9 vs. 12.1 months, p < .0001) compared with responding patients who did not. Outcomes in older patients with AML are improving with more effective LIT. Measures should be pursued to increase access to SCT in older patients.

Results of salvage therapy with mini-hyper-CVD and inotuzumab ozogamicin with or without blinatumomab in pre-B acute lymphoblastic leukemia

Abstract: Abstract Background Historically, adults with relapsed-refractory acute lymphoblastic leukemia (ALL) experienced poor outcomes with intensive chemotherapy. This mature analysis explores the benefit of the addition of sequential blinatumomab to low-intensity mini-Hyper-CVD chemotherapy with inotuzumab ozogamicin in this setting. Methods Mini-Hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 83% dose reduction) was combined with inotuzumab during the first 4 courses. From Patient #68 and onwards, inotuzumab was given in reduced and fractionated doses, and blinatumomab was added sequentially for 4 courses. Maintenance therapy with prednisone, vincristine, 6-mercaptopurine and methotrexate was given for 12 courses, and blinatumomab for 4 additional courses. Results Among 110 patients (median age, 37 years) treated, 91 (83%) responded (complete response, 69 patients, 63%). Measurable residual disease negativity was documented in 75 patients (82% of responders). Fifty-three patients (48%) received allogeneic stem cell transplantation (SCT). Hepatic sinusoidal obstruction syndrome occurred in 9/67 patients (13%) on the original inotuzumab schedule and in 1/43 (2%) on the modified schedule. With a median follow-up of 48 months, the median overall survival (OS) was 17 months, and the 3 year OS was 40%. The 3 year OS was 34% with mini-Hyper-CVD plus inotuzumab and 52% with additional blinatumomab ( P = 0.16). By landmark analysis at 4 months, the 3 year OS was 54%, similar between patients who did or did not receive allogeneic SCT. Conclusion Low-intensity mini-Hyper-CVD plus inotuzumab with or without blinatumomab showed efficacy in patients with relapsed-refractory ALL, with better survival after the addition of blinatumomab. Trial registration The trial was registered on clinicaltrials.gov with the identifier NCT01371630.

A phase 2 study of the combination of decitabine (DAC), venetoclax (VEN), and ponatinib in patients (Pts) with chronic myeloid leukemia (CML) in accelerated phase (AP)/myeloid blast phase (MBP) or Philadelphia-chromosome positive (Ph+) acute myeloid leukemia (AML).

Abstract: e19044 Background: CML-AP/MBP and Ph+ AML are therapeutic challenges. Based on published pre-clinical data of synergism (Leonard et.al., Sci Transl Med 2016), we hypothesized that combining ponatinib with DAC and VEN might lead to high rates of response and facilitate allogeneic stem cell transplantation (SCT). Methods: The study (NCT04188405) enrolled pts ≥ 18 years of age with CML-AP, CML-MBP or Ph+ AML with ECOG PS ≤ 3 and adequate liver/renal function. Pts with significant uncontrolled cardiovascular comorbidities were excluded. Therapy was with DAC (20 mg/m2/day) x 5 days, VEN (400 mg equivalent dose/day) x 21 days, and ponatinib (45mg/day) x 21 days in cycle 1 and then continuously in cycles 2-24. Each cycle was for 28 days. Ponatinib was reduced to 30mg/day for pts in CR/CRi and to 15 mg/day for pts in CMR. Intrathecal prophylaxis with 4 doses of cytarabine was recommended. The primary objective was to determine the overall response rate (ORR) with the regimen. Results: From Jul 2020 to Jan 2023, 15 pts were treated, 4 with CML-AP, 10 with CML-MBP and 1 with Ph+ AML (Table). 11 pts (73%) had prior TKI exposure, including 4 pts with prior ponatinib. 5 of 13 tested pts (38%) had an ABL1 kinase domain mutation (T315I, Q252H, L384M in 1 pt each and E255K in 2 pts). The median number of cycles received was 3 (range, 1-7). 11 pts (73%) responded; 6 pts (40%) with CR/CRi and 5 (33%) with MLFS. Best response was achieved after cycle 1 in 9 of 11 (82%) responders. All 4 pts with CML-AP responded, and 9 of 11 pts (82%) with prior TKI exposure responded. Four pts underwent subsequent SCT. At a median follow-up of 9.8 months, the median overall survival (OS) was 11.0 months, and the estimated 10-month OS was 63%. The median relapse-free survival was 5.7 months. Among the 11 responders, 5 relapsed (one after SCT), and 6 are in ongoing response (3 after SCT). One pt had a related grade 3 mucositis. No grade 4-5 related non-hematological adverse events were observed. Of the 10 pts who received > 1 cycle of therapy, 5 pts had delay (>1 week) in initiation of subsequent cycles due to cytopenias. The 60-day mortality rate was 0%. Two pts died on study, one from leukemia and one from infection while in MLFS. Conclusions: A triplet combination of DAC, VEN and ponatinib was well-tolerated and resulted in an ORR of 73% in this poor-risk population of pts with advanced Ph+ leukemias. Clinical trial information: NCT04188405 . [Table: see text]

Low-Dose Dasatinib (50 mg Daily) Frontline Therapy in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia: 5-Year Follow-Up Results.

Abstract: Dasatinib is a BCR::ABL1 tyrosine kinase inhibitor approved as frontline therapy at a 100 mg daily for chronic myeloid leukemia in chronic phase (CML-CP). The use of a lower dose of dasatinib (50 mg daily) has demonstrated better tolerance and improved outcomes compared with the standard dose. Here, we report the updated results in a large cohort with a 5-year follow-up.Patients with newly diagnosed CML-CP were eligible. Entry and response-outcome criteria were standard. Dasatinib was given as 50 mg orally daily.Eighty-three patients were included. At 3 months, 78 (96%) patients achieved BCR::ABL1 transcripts (IS) ≤10%, and at 12 months, 65 (81%) patients achieved BCR::ABL1 transcript (IS) ≤0.1%. The cumulative incidence of complete cytogenetic, major molecular, and deep molecular responses at 5 years were 98%, 95%, and 82%, respectively. Rates of failures due to resistance (n = 4; 5%) and toxicity (n = 4; 5%) were low. The 5-year overall survival was 96% and event-free survival 90%. No transformations to accelerated or blastic phase were observed. Grade 3 to 4 pleural effusions developed in 2% of patients.Dasatinib 50 mg daily is an effective and safe treatment for newly diagnosed CML-CP.