Pirtobrutinib after a Covalent BTK Inhibitor in Chronic Lymphocytic Leukemia.

BACKGROUND: Patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) have poor outcomes after the failure of covalent Bruton's tyrosine kinase (BTK) inhibitor treatment, and new therapeutic options are needed. Pirtobrutinib, a highly selective, noncovalent (reversible) BTK inhibitor, was designed to reestablish BTK inhibition. METHODS: We conducted a phase 1-2 trial in which patients with relapsed or refractory B-cell cancers received pirtobrutinib. Here, we report efficacy results among patients with CLL or SLL who had previously received a BTK inhibitor as well as safety results among all the patients with CLL or SLL. The primary end point was an overall response (partial response or better) as assessed by independent review. Secondary end points included progression-free survival and safety. RESULTS: A total of 317 patients with CLL or SLL received pirtobrutinib, including 247 who had previously received a BTK inhibitor. Among these 247 patients, the median number of previous lines of therapy was 3 (range, 1 to 11), and 100 patients (40.5%) had also received a B-cell lymphoma 2 (BCL2) inhibitor such as venetoclax. The percentage of patients with an overall response to pirtobrutinib was 73.3% (95% confidence interval [CI], 67.3 to 78.7), and the percentage was 82.2% (95% CI, 76.8 to 86.7) when partial response with lymphocytosis was included. The median progression-free survival was 19.6 months (95% CI, 16.9 to 22.1). Among all 317 patients with CLL or SLL who received pirtobrutinib, the most common adverse events were infections (in 71.0%), bleeding (in 42.6%), and neutropenia (in 32.5%). At a median duration of treatment of 16.5 months (range, 0.2 to 39.9), some adverse events that are typically associated with BTK inhibitors occurred relatively infrequently, including hypertension (in 14.2% of patients), atrial fibrillation or flutter (in 3.8%), and major hemorrhage (in 2.2%). Only 9 of 317 patients (2.8%) discontinued pirtobrutinib owing to a treatment-related adverse event. CONCLUSIONS: In this trial, pirtobrutinib showed efficacy in patients with heavily pretreated CLL or SLL who had received a covalent BTK inhibitor. The most common adverse events were infections, bleeding, and neutropenia. (Funded by Loxo Oncology; BRUIN ClinicalTrials.gov number, NCT03740529.).

Fixed-Duration Pirtobrutinib plus Venetoclax with or without Rituximab in Relapsed/Refractory CLL: Phase 1b BRUIN Trial.

Pirtobrutinib is a highly selective, non-covalent (reversible) Bruton tyrosine kinase inhibitor (BTKi). Patients with relapsed or refractory (R/R) chronic lymphocytic leukemia (CLL) were treated with fixed-duration pirtobrutinib plus venetoclax (PV) or pirtobrutinib plus venetoclax and rituximab (PVR) in this phase 1b trial (NCT03740529). Prior covalent BTKi therapy was allowed, but not prior venetoclax. Patients were assigned to receive PV (n=15) or PVR (n=10) for 25 cycles. Median age was 66 years (range, 39-78). Median prior lines of therapy was 2 (range, 1-4), and 17 (68%) patients had received prior covalent BTKi. At the data-cutoff date (May 5, 2023), median time on study was 27.0 months for PV and 23.3 months for PVR. Overall response rates were 93.3% (95% CI:68.1-99.8%) for PV and 100% (95% CI:69.2-100.0%) for PVR, with 10 complete responses (PV:7; PVR:3). After 12 cycles of treatment, 85.7% (95% CI:57.2-98.2%) of PV and 90.0% (95% CI:55.5-99.7%) of PVR patients achieved undetectable minimal residual disease assessed in peripheral blood by clonoSEQ® assay at a sensitivity of <1x10-4. Progression-free survival at 18 months was 92.9% (95% CI: 59.1-99.0) for PV patients and 80.0% (95% CI: 40.9-94.6) for PVR patients. No DLTs were observed in either treatment combination during the 5-week assessment period. The most common grade ≥3 adverse events for all patients included neutropenia (52%) and anemia (16%). Adverse events led to dose reduction in 3 patients and discontinuation in 2. In conclusion, fixed-duration PV or PVR was well tolerated and had promising efficacy in patients with R/R CLL, including patients previously treated with a covalent BTKi.

Sustained remissions in CLL after frontline FCR treatment with very-long-term follow-up.

Chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab (FCR) achieves durable remissions, with flattening of the progression-free survival (PFS) curve in patients with mutated immunoglobulin heavy chain variable gene (IGHV-M). We updated long-term follow-up results from the original 300-patient FCR study initiated at MD Anderson in 1999. The current median follow-up is 19.0 years. With this extended follow-up, the median PFS for patients with IGHV-M was 14.6 years vs 4.2 years for patients with unmutated IGHV (IGHV-UM). Disease progression beyond 10 years was uncommon. In total, 16 of 94 (17%) patients in remission at 10 years subsequently progressed with the additional follow-up compared with the patients in our prior report in 2015. Only 4 of 45 patients (9%) with IGHV-M progressed beyond 10 years. Excluding Richter transformation, 96 of 300 patients (32%) developed 106 other malignancies, with 19 of 300 (6.3%) developing therapy-related myeloid neoplasms (tMNs), which were fatal in 16 of 19 (84%). No pretreatment patient characteristics predicted the risk of tMNs. In summary, FCR remains an option for patients with IGHV-M chronic lymphocytic leukemia (CLL), with a significant fraction achieving functional cure of CLL. A risk-benefit assessment is warranted when counseling patients, balancing potential functional cure with the risk of late relapses and serious secondary malignancies.

Lisocabtagene maraleucel in chronic lymphocytic leukaemia and small lymphocytic lymphoma (TRANSCEND CLL 004): a multicentre, open-label, single-arm, phase 1-2 study.

BACKGROUND: Patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma for whom treatment has failed with both Bruton tyrosine kinase (BTK) inhibitor and venetoclax have few treatment options and poor outcomes. We aimed to evaluate the efficacy and safety of lisocabtagene maraleucel (liso-cel) at the recommended phase 2 dose in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: We report the primary analysis of TRANSCEND CLL 004, an open-label, single-arm, phase 1-2 study conducted in the USA. Patients aged 18 years or older with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma and at least two previous lines of therapy, including a BTK inhibitor, received an intravenous infusion of liso-cel at one of two target dose levels: 50 × 106 (dose level 1) or 100 × 106 (dose level 2, DL2) chimeric antigen receptor-positive T cells. The primary endpoint was complete response or remission (including with incomplete marrow recovery), assessed by independent review according to the 2018 International Workshop on Chronic Lymphocytic Leukemia criteria, in efficacy-evaluable patients with previous BTK inhibitor progression and venetoclax failure (the primary efficacy analysis set) at DL2 (null hypothesis of ≤5%). This trial is registered with ClinicalTrials.gov, NCT03331198. FINDINGS: Between Jan 2, 2018, and June 16, 2022, 137 enrolled patients underwent leukapheresis at 27 sites in the USA. 117 patients received liso-cel (median age 65 years [IQR 59-70]; 37 [32%] female and 80 [68%] male; 99 [85%] White, five [4%] Black or African American, two [2%] other races, and 11 [9%] unknown race; median of five previous lines of therapy [IQR 3-7]); all 117 participants had received and had treatment failure on a previous BTK inhibitor. A subset of patients had also experienced venetoclax failure (n=70). In the primary efficacy analysis set at DL2 (n=49), the rate of complete response or remission (including with incomplete marrow recovery) was statistically significant at 18% (n=9; 95% CI 9-32; p=0·0006). In patients treated with liso-cel, grade 3 cytokine release syndrome was reported in ten (9%) of 117 (with no grade 4 or 5 events) and grade 3 neurological events were reported in 21 (18%; one [1%] grade 4, no grade 5 events). Among 51 deaths on the study, 43 occurred after liso-cel infusion, of which five were due to treatment-emergent adverse events (within 90 days of liso-cel infusion). One death was related to liso-cel (macrophage activation syndrome-haemophagocytic lymphohistiocytosis). INTERPRETATION: A single infusion of liso-cel was shown to induce complete response or remission (including with incomplete marrow recovery) in patients with relapsed or refractory chronic lymphocytic leukaemia or small lymphocytic lymphoma, including patients who had experienced disease progression on a previous BTK inhibitor and venetoclax failure. The safety profile was manageable. FUNDING: Juno Therapeutics, a Bristol-Myers Squibb Company.

Phase 1 TRANSCEND CLL 004 study of lisocabtagene maraleucel in patients with relapsed/refractory CLL or SLL.

Bruton tyrosine kinase inhibitors (BTKi) and venetoclax are currently used to treat newly diagnosed and relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL). However, most patients eventually develop resistance to these therapies, underscoring the need for effective new therapies. We report results of the phase 1 dose-escalation portion of the multicenter, open-label, phase 1/2 TRANSCEND CLL 004 (NCT03331198) study of lisocabtagene maraleucel (liso-cel), an autologous CD19-directed chimeric antigen receptor (CAR) T-cell therapy, in patients with relapsed/refractory CLL/SLL. Patients with standard- or high-risk features treated with ≥3 or ≥2 prior therapies, respectively, including a BTKi, received liso-cel at 1 of 2 dose levels (50 × 106 or 100 × 106 CAR+ T cells). Primary objectives included safety and determining recommended dose; antitumor activity by 2018 International Workshop on CLL guidelines was exploratory. Minimal residual disease (MRD) was assessed in blood and marrow. Twenty-three of 25 enrolled patients received liso-cel and were evaluable for safety. Patients had a median of 4 (range, 2-11) prior therapies (100% had ibrutinib; 65% had venetoclax) and 83% had high-risk features including mutated TP53 and del(17p). Seventy-four percent of patients had cytokine release syndrome (9% grade 3) and 39% had neurological events (22% grade 3/4). Of 22 efficacy-evaluable patients, 82% and 45% achieved overall and complete responses, respectively. Of 20 MRD-evaluable patients, 75% and 65% achieved undetectable MRD in blood and marrow, respectively. Safety and efficacy were similar between dose levels. The phase 2 portion of the study is ongoing at 100 × 106 CAR+ T cells. This trial was registered at clinicaltrials.gov as NCT03331198.

Fixed-duration ibrutinib plus venetoclax for first-line treatment of CLL: primary analysis of the CAPTIVATE FD cohort.

CAPTIVATE (NCT02910583) is an international phase 2 study in patients aged ≤70 years with previously untreated chronic lymphocytic leukemia (CLL). Results from the cohort investigating fixed-duration (FD) treatment with ibrutinib plus venetoclax are reported. Patients received 3 cycles of ibrutinib lead-in then 12 cycles of ibrutinib plus venetoclax (oral ibrutinib [420 mg/d]; oral venetoclax [5-week ramp-up to 400 mg/d]). The primary endpoint was complete response (CR) rate. Hypothesis testing was performed for patients without del(17p) with prespecified analyses in all treated patients. Secondary endpoints included undetectable minimal residual disease (uMRD) rates, progression-free survival (PFS), overall survival (OS), and safety. Of the 159 patients enrolled and treated, 136 were without del(17p). The median time on study was 27.9 months, and 92% of patients completed all planned treatment. The primary endpoint was met, with a CR rate of 56% (95% confidence interval [CI], 48-64) in patients without del(17p), significantly higher than the prespecified 37% minimum rate (P < .0001). In the all-treated population, CR rate was 55% (95% CI, 48-63); best uMRD rates were 77% (peripheral blood [PB]) and 60% (bone marrow [BM]); 24-month PFS and OS rates were 95% and 98%, respectively. At baseline, 21% of patients were in the high tumor burden category for tumor lysis syndrome (TLS) risk; after ibrutinib lead-in, only 1% remained in this category. The most common grade ≥3 adverse events (AEs) were neutropenia (33%) and hypertension (6%). First-line ibrutinib plus venetoclax represents the first all-oral, once-daily, chemotherapy-free FD regimen for patients with CLL. FD ibrutinib plus venetoclax achieved deep, durable responses and promising PFS, including in patients with high-risk features.

Global miRNA profiling reveals key molecules that contribute to different chronic lymphocytic leukemia incidences in Asian and Western populations.

It has been known for decades that the incidence of chronic lymphocytic leukemia (CLL) is significantly lower in Asia than in Western countries, but the reason responsible for this difference still remains a major knowledge gap. Using GeneChip® miRNA array to analyze the global microRNA expression in B lymphocytes from Asian and Western CLL patients and healthy individuals, we have identified microRNA with CLL-promoting or suppressive functions that are differentially expressed in Asian and Western individuals. In particular, miR-4485 is upregulated in CLL patients of both ethnic groups, and its expression is significantly lower in Asian healthy individuals. Genetic silencing of miR-4485 in CLL cells suppresses leukemia cell growth, whereas ectopic expression of miR-4485 promotes cell proliferation. Mechanistically, miR-4485 exerts its CLL-promoting activity by inhibiting the expression of TGR5 and activating the ERK1/2 pathway. In contrast, miR-138, miR-181a, miR- 181c, miR-181d, and miR-363 with tumor-suppressive function are highly expressed in Asian healthy individuals. Our study suggests that differential expression of several important microRNA with pro- or anti-CLL functions in Asian and Western B lymphocytes likely contributes to the difference in CLL incidence between the two ethnic groups, and that miR-4485 and its downstream molecule TGR5 could be potential therapeutic targets.

Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma, Version 2.2024, NCCN Clinical Practice Guidelines in Oncology

Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are essentially different manifestations of the same disease that are similarly managed. A number of molecular and cytogenetic variables with prognostic implications have been identified. Undetectable minimal residual disease at the end of treatment with chemoimmunotherapy or venetoclax-based combination regimens is an independent predictor of improved survival among patients with previously untreated or relapsed/refractory CLL/SLL. The selection of treatment is based on the disease stage, presence or absence of del(17p) or TP53 mutation, immunoglobulin heavy chain variable region mutation status, patient age, performance status, comorbid conditions, and the agent's toxicity profile. This manuscript discusses the recommendations outlined in the NCCN Guidelines for the diagnosis and management of patients with CLL/SLL.

STAT3 Activates the Pentraxin 3 Gene in Chronic Lymphocytic Leukemia Cells.

Pentraxin-related protein 3 (PTX3), commonly produced by myeloid and endothelial cells, is a humoral pattern recognition protein of the innate immune system. Because PTX3 plasma levels of patients with chronic lymphocytic leukemia (CLL) are high and most circulating cells in patients with CLL are CLL cells, we reasoned that CLL cells produce PTX3. Western immunoblotting revealed that low-density cells from seven of seven patients with CLL produce high levels of PTX3, flow cytometry analysis revealed that the PTX3-producing cells are B lymphocytes coexpressing CD19 and CD5, and confocal microscopy showed that PTX3 is present in the cytoplasm of CLL cells. Because STAT3 is constitutively activated in CLL cells, and because we identified putative STAT3 binding sites within the PTX3 gene promoter, we postulated that phosphorylated STAT3 triggers transcriptional activation of PTX3. Immunoprecipitation analysis of CLL cells' chromatin fragments showed that STAT3 Abs precipitated PTX3 DNA. STAT3 knockdown induced a marked reduction in PTX3 expression, indicating a STAT3-induced transcriptional activation of the PTX3 gene in CLL cells. Using an EMSA, we established and used a dual-reporter luciferase assay to confirm that STAT3 binds the PTX3 gene promoter. Downregulation of PTX3 enhanced apoptosis of CLL cells, suggesting that inhibition of PTX3 might benefit patients with CLL.

Effect of Digital Health Coaching on Self-Efficacy and Patient Reported Outcomes in Individuals with Acute Myeloid and Chronic Lymphocytic Leukemia: A Pilot Randomized Controlled Trial.

Introduction Promotion of self-efficacy can enhance engagement with healthcare and treatment adherence in patients with cancer. We report the outcomes of a pilot trial of a digital health coach intervention in patients with leukemia with the aim of improving self-efficacy. Methods Adult patients with newly diagnosed acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL) were randomized 1:1 to a digital health coach intervention or standard of care. The primary outcome of self-efficacy was measured by the Cancer Behavior Inventory (CBI) score. Results One-hundred and forty-seven patients (37 AML, 110 CLL) were enrolled from July 2020 to December 2022. In the AML cohort, there was a mean increase in CBI score of 7.03 in the digital health coaching arm compared to a mean decrease of -3.57 in the control arm at 30 days (p=0.219). There were no significant associations between the intervention and other patient reported outcomes for patients with CLL. Conclusion There were numerical, but not statistically significant increases in self-efficacy metrics in AML patients who received digital health coaching. Although this trial was underpowered due to enrollment limitations during a pandemic, digital health coaching may provide benefit to patients with hematologic malignancy and warrants further investigation.

Long-term outcomes in patients with chronic lymphocytic leukemia treated with ibrutinib: Focus on hypertension and cardiovascular toxicity.

BACKGROUND: Continuous ibrutinib administration is needed to maintain efficacy in patients with chronic lymphocytic leukemia (CLL) and, as such, long-term toxicity is a concern. The authors report the 5-year follow-up of patients with CLL who received treatment with ibrutinib with a focus on hypertension and cardiovascular toxicities. METHODS: Patient characteristics were assessed, including blood pressure, cardiovascular disease, disease progression, and death. Univariate logistic regression analysis assessed the relation of patient characteristics and the development of new or worsened hypertension. The incidence of hypertensive outcomes was evaluated using competing risk. Survival was estimated using the Kaplan-Meier method. RESULTS: Three hundred patients with CLL who were treated with ibrutinib on clinical trials were included. The median patient age at study enrollment was 65 years (range, 29-83 years). Seventy percent of patients were men, and 88% were Caucasian. Sixty-nine percent of patients had hypertension at baseline, and 47% were on antihypertensive medication. Eighty-eight percent had relapsed or refractory CLL. New-onset and worsening hypertension were common, occurring in 68.5% and 38% of patients, respectively. Systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥100 mm Hg was observed in 16.9% of patients. Hypertension was reversible after ibrutinib discontinuation. Older age, male sex, tobacco use, and chronic kidney disease were associated with ibrutinib-related hypertension. Baseline hypertension was not associated with major adverse cardiovascular events in ibrutinib-treated patients nor with event-free or overall survival. CONCLUSIONS: Hypertension is a common toxicity in patients with CLL who receive ibrutinib but is manageable in most patients. Other than chronic kidney disease, baseline cardiovascular disease did not affect ibrutinib-related hypertension nor was hypertension associated with major adverse cardiovascular events or survival. PLAIN LANGUAGE SUMMARY: Ibrutinib is an effective treatment for patients with chronic lymphocytic leukemia. Ibrutinib is a well tolerated therapy, however hypertension can develop or worsen in patients receiving ibrutinib and other cardiovascular events are significant challenges to the use of this drug. This may be particularly true in patients with heart disease. Short-term side effects may worsen heart disease, but the long-term impact is unknown. The long-term results of ibrutinib on heart disease and hypertension are described.

Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors.

BACKGROUND: Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations. METHODS: In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin's lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×105, 1×106, or 1×107 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy. RESULTS: The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter's transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months. CONCLUSIONS: Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.).

Acalabrutinib in treatment-naive chronic lymphocytic leukemia.

Acalabrutinib has demonstrated significant efficacy and safety in relapsed chronic lymphocytic leukemia (CLL). Efficacy and safety of acalabrutinib monotherapy were evaluated in a treatment-naive CLL cohort of a single-arm phase 1/2 trial (ACE-CL-001). Adults were eligible for enrollment if chemotherapy was declined or deemed inappropriate due to comorbidities (N = 99). Patients had a median age of 64 years and 47% had Rai stage III/IV disease. Acalabrutinib was administered orally 200 mg once daily, or 100 mg twice daily until progression or intolerance. A total of 99 patients were treated; 57 (62%) had unmutated immunoglobulin heavy-chain variable gene, and 12 (18%) had TP53 aberrations. After median follow-up of 53 months, 85 patients remain on treatment; 14 discontinued treatment, mostly because of adverse events (AEs) (n = 6) or disease progression (n = 3). Overall response rate was 97% (90% partial response; 7% complete response), with similar outcomes among all prognostic subgroups. Because of improved trough BTK occupancy with twice-daily dosing, all patients were transitioned to 100 mg twice daily. Median duration of response (DOR) was not reached; 48-month DOR rate was 97% (95% confidence interval, 90-99). Serious AEs were reported in 38 patients (38%). AEs required discontinuation in 6 patients (6%) because of second primary cancers (n = 4) and infection (n = 2). Grade ≥3 events of special interest included infection (15%), hypertension (11%), bleeding events (3%), and atrial fibrillation (2%). Durable efficacy and long-term safety of acalabrutinib in this trial support its use in clinical management of symptomatic, untreated patients with CLL.

KTE-X19 anti-CD19 CAR T-cell therapy in adult relapsed/refractory acute lymphoblastic leukemia: ZUMA-3 phase 1 results.

ZUMA-3 is a phase 1/2 study evaluating KTE-X19, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, in adult relapsed/refractory (R/R) B-cell acute lymphoblastic leukemia (B-ALL). We report the phase 1 results. After fludarabine-cyclophosphamide lymphodepletion, patients received a single infusion of KTE-X19 at 2 × 106, 1 × 106, or 0.5 × 106 cells per kg. The rate of dose-limiting toxicities (DLTs) within 28 days after KTE-X19 infusion was the primary end point. KTE-X19 was manufactured for 54 enrolled patients and administered to 45 (median age, 46 years; range, 18-77 years). No DLTs occurred in the DLT-evaluable cohort. Grade ≥3 cytokine release syndrome (CRS) and neurologic events (NEs) occurred in 31% and 38% of patients, respectively. To optimize the risk-benefit ratio, revised adverse event (AE) management for CRS and NEs (earlier steroid use for NEs and tocilizumab only for CRS) was evaluated at 1 × 106 cells per kg KTE-X19. In the 9 patients treated under revised AE management, 33% had grade 3 CRS and 11% had grade 3 NEs, with no grade 4 or 5 NEs. The overall complete remission rate correlated with CAR T-cell expansion and was 83% in patients treated with 1 × 106 cells per kg and 69% in all patients. Minimal residual disease was undetectable in all responding patients. At a median follow-up of 22.1 months (range, 7.1-36.1 months), the median duration of remission was 17.6 months (95% confidence interval [CI], 5.8-17.6 months) in patients treated with 1 × 106 cells per kg and 14.5 months (95% CI, 5.8-18.1 months) in all patients. KTE-X19 treatment provided a high response rate and tolerable safety in adults with R/R B-ALL. Phase 2 is ongoing at 1 × 106 cells per kg with revised AE management. This trial is registered at www.clinicaltrials.gov as #NCT02614066.

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

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.

Prognostication of DNA Damage Response Protein Expression Patterns in Chronic Lymphocytic Leukemia.

Proteomic DNA Damage Repair (DDR) expression patterns in Chronic Lymphocytic Leukemia were characterized by quantifying and clustering 24 total and phosphorylated DDR proteins. Overall, three protein expression patterns (C1-C3) were identified and were associated as an independent predictor of distinct patient overall survival outcomes. Patients within clusters C1 and C2 had poorer survival outcomes and responses to fludarabine, cyclophosphamide, and rituxan chemotherapy compared to patients within cluster C3. However, DDR protein expression patterns were not prognostic in more modern therapies with BCL2 inhibitors or a BTK/PI3K inhibitor. Individually, nine of the DDR proteins were prognostic for predicting overall survival and/or time to first treatment. When looking for other proteins that may be associated with or influenced by DDR expression patterns, our differential expression analysis found that cell cycle and adhesion proteins were lower in clusters compared to normal CD19 controls. In addition, cluster C3 had a lower expression of MAPK proteins compared to the poor prognostic patient clusters thus implying a potential regulatory connection between adhesion, cell cycle, MAPK, and DDR signaling in CLL. Thus, assessing the proteomic expression of DNA damage proteins in CLL provided novel insights for deciphering influences on patient outcomes and expanded our understanding of the potential complexities and effects of DDR cell signaling.

Reverse Phase Protein Array Profiling Identifies Recurrent Protein Expression Patterns of DNA Damage-Related Proteins across Acute and Chronic Leukemia: Samples from Adults and the Children's Oncology Group.

DNA damage response (DNADR) recognition and repair (DDR) pathways affect carcinogenesis and therapy responsiveness in cancers, including leukemia. We measured protein expression levels of 16 DNADR and DDR proteins using the Reverse Phase Protein Array methodology in acute myeloid (AML) (n = 1310), T-cell acute lymphoblastic leukemia (T-ALL) (n = 361) and chronic lymphocytic leukemia (CLL) (n = 795) cases. Clustering analysis identified five protein expression clusters; three were unique compared to normal CD34+ cells. Individual protein expression differed by disease for 14/16 proteins, with five highest in CLL and nine in T-ALL, and by age in T-ALL and AML (six and eleven proteins, respectively), but not CLL (n = 0). Most (96%) of the CLL cases clustered in one cluster; the other 4% were characterized by higher frequencies of deletion 13q and 17p, and fared poorly (p < 0.001). T-ALL predominated in C1 and AML in C5, but both occurred in all four acute-dominated clusters. Protein clusters showed similar implications for survival and remission duration in pediatric and adult T-ALL and AML populations, with C5 doing best in all. In summary, DNADR and DDR protein expression was abnormal in leukemia and formed recurrent clusters that were shared across the leukemias with shared prognostic implications across diseases, and individual proteins showed age- and disease-related differences.

The cure of leukemia through the optimist's prism.

Progress is occurring at a dizzying rate across all leukemias. Since the authors' review of the topic in Cancer in 2018, numerous discoveries have been made that have improved the therapy and outcomes of several leukemia subsets. Hairy cell leukemia is potentially curable with a single course of cladribine followed by rituximab (10-year survival, ≥90%). Acute promyelocytic leukemia is curable at a rate of 80% to 90% with a nonchemotherapy regimen of all-trans retinoic acid and arsenic trioxide. The cure rate for core-binding factor acute myeloid leukemia (AML) is ≥75% with fludarabine, high-dose cytarabine, and gemtuzumab ozogamicin. Survival for patients with chronic myeloid leukemia is close to that for an age-matched normal population with BCR-ABL1 tyrosine kinase inhibitors (TKIs). Chronic lymphocytic leukemia, a previously incurable disease, may now be potentially curable with a finite duration of therapy with Bruton tyrosine kinase inhibitors and venetoclax. The estimated 5-year survival rate for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (ALL) exceeds 70% with intensive chemotherapy and ponatinib, a third-generation BCR-ABL1 TKI, and more recent nonchemotherapy regimens using dasatinib or ponatinib with blinatumomab are producing outstanding results. Survival in both younger and older patients with ALL has improved with the addition of antibodies targeting CD20, CD19 (blinatumomab), and CD22 (inotuzumab) to chemotherapy. Several recent drug discoveries (venetoclax, FLT3 and IDH inhibitors, and oral hypomethylating agents) are also improving outcomes for younger and older patients with AML and for those with higher risk myelodysplastic syndrome.

KTE-X19 for relapsed or refractory adult B-cell acute lymphoblastic leukaemia: phase 2 results of the single-arm, open-label, multicentre ZUMA-3 study.

BACKGROUND: Despite treatment with novel therapies and allogeneic stem-cell transplant (allo-SCT) consolidation, outcomes in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia remain poor, underlining the need for more effective therapies. METHODS: We report the pivotal phase 2 results of ZUMA-3, an international, multicentre, single-arm, open-label study evaluating the efficacy and safety of the autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy KTE-X19 in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia. Patients were enrolled at 25 sites in the USA, Canada, and Europe. Eligible patients were aged 18 years or older, with Eastern Cooperative Oncology Group performance status of 0-1, and morphological disease in the bone marrow (>5% blasts). After leukapheresis and conditioning chemotherapy, patients received a single KTE-X19 infusion (1 × 106 CAR T cells per kg bodyweight). The primary endpoint was the rate of overall complete remission or complete remission with incomplete haematological recovery by central assessment. Duration of remission and relapse-free survival, overall survival, minimal residual disease (MRD) negativity rate, and allo-SCT rate were assessed as secondary endpoints. Efficacy and safety analyses were done in the treated population (all patients who received a dose of KTE-X19). This study is registered with ClinicalTrials.gov, NCT02614066. FINDINGS: Between Oct 1, 2018, and Oct 9, 2019, 71 patients were enrolled and underwent leukapheresis. KTE-X19 was successfully manufactured for 65 (92%) patients and administered to 55 (77%). The median age of treated patients was 40 years (IQR 28-52). At the median follow-up of 16·4 months (13·8-19·6), 39 patients (71%; 95% CI 57-82, p<0·0001) had complete remission or complete remission with incomplete haematological recovery, with 31 (56%) patients reaching complete remission. Median duration of remission was 12·8 months (95% CI 8·7-not estimable), median relapse-free survival was 11·6 months (2·7-15·5), and median overall survival was 18·2 months (15·9-not estimable). Among responders, the median overall survival was not reached, and 38 (97%) patients had MRD negativity. Ten (18%) patients received allo-SCT consolidation after KTE-X19 infusion. The most common adverse events of grade 3 or higher were anaemia (27 [49%] patients) and pyrexia (20 [36%] patients). 14 (25%) patients had infections of grade 3 or higher. Two grade 5 KTE-X19-related events occurred (brain herniation and septic shock). Cytokine release syndrome of grade 3 or higher occurred in 13 (24%) patients and neurological events of grade 3 or higher occurred in 14 (25%) patients. INTERPRETATION: KTE-X19 showed a high rate of complete remission or complete remission with incomplete haematological recovery in adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia, with the median overall survival not reached in responding patients, and a manageable safety profile. These findings indicate that KTE-X19 has the potential to confer long-term clinical benefit to these patients. FUNDING: Kite, a Gilead Company.

Pirtobrutinib in relapsed or refractory B-cell malignancies (BRUIN): a phase 1/2 study.

BACKGROUND: Covalent Bruton's tyrosine kinase (BTK) inhibitors are efficacious in multiple B-cell malignancies, but patients discontinue these agents due to resistance and intolerance. We evaluated the safety and efficacy of pirtobrutinib (working name; formerly known as LOXO-305), a highly selective, reversible BTK inhibitor, in these patients. METHODS: Patients with previously treated B-cell malignancies were enrolled in a first-in-human, multicentre, open-label, phase 1/2 trial of the BTK inhibitor pirtobrutinib. The primary endpoint was the maximum tolerated dose (phase 1) and overall response rate (ORR; phase 2). This trial is registered with ClinicalTrials.gov, NCT03740529. FINDINGS: 323 patients were treated with pirtobrutinib across seven dose levels (25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg, and 300 mg once per day) with linear dose-proportional exposures. No dose-limiting toxicities were observed and the maximum tolerated dose was not reached. The recommended phase 2 dose was 200 mg daily. Adverse events in at least 10% of 323 patients were fatigue (65 [20%]), diarrhoea (55 [17%]), and contusion (42 [13%]). The most common adverse event of grade 3 or higher was neutropenia (32 [10%]). There was no correlation between pirtobrutinib exposure and the frequency of grade 3 treatment-related adverse events. Grade 3 atrial fibrillation or flutter was not observed, and grade 3 haemorrhage was observed in one patient in the setting of mechanical trauma. Five (1%) patients discontinued treatment due to a treatment-related adverse event. In 121 efficacy evaluable patients with chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) treated with a previous covalent BTK inhibitor (median previous lines of treatment 4), the ORR with pirtobrutinib was 62% (95% CI 53-71). The ORR was similar in CLL patients with previous covalent BTK inhibitor resistance (53 [67%] of 79), covalent BTK inhibitor intolerance (22 [52%] of 42), BTK C481-mutant (17 [71%] of 24) and BTK wild-type (43 [66%] of 65) disease. In 52 efficacy evaluable patients with mantle cell lymphoma (MCL) previously treated with covalent BTK inhibitors, the ORR was 52% (95% CI 38-66). Of 117 patients with CLL, SLL, or MCL who responded, all but eight remain progression-free to date. INTERPRETATION: Pirtobrutinib was safe and active in multiple B-cell malignancies, including patients previously treated with covalent BTK inhibitors. Pirtobrutinib might address a growing unmet need for alternative therapies for these patients. FUNDING: Loxo Oncology.