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Šio straipsnio tikslas yra parodyti, kaip ir kodėl radikalios interpretacijos metodas gali išspręsti problemas, formuluojamas įvairių skeptinių scenarijų pavidalu. Pirmiausia radikalios interpretacijos metodas neleidžia dekartiško skeptinio scenarijaus, tiek tradicinės, tiek naujesnių versijų, laikyti filosofine problema, kuri remiasi sąmoningo ir nesąmoningo melo skirtumu. Straipsnyje argumentuojama už išplėstinę natūralizuotos epistemologijos versiją, įtraukiančią ir socialinius veiksnius. Konkrečiau, hipotezių apie žinojimą ir apgaulę komunikavimui visuomet galioja bent du apribojimai. Be to, straipsnyje aiškinama nuosaikaus (percepcinio ir socialinio) eksternalizmo būtinybė dekartiškam ir hiumiškam skeptiniams scenarijams.

Twenty adults with newly diagnosed (ND) or relapsed/refractory (RR) Ph-positive acute lymphoblastic leukemia (ALL), or chronic myeloid leukemia in lymphoid blast phase (CML-LBP), were treated with mini-hyperCVD, ponatinib, and blinatumomab. Complete molecular response was achieved in 78% of ND patients, while CR/CRi was achieved in 100% of RR and CML-LBP. The 3-year overall survival rate was 76% (95% CI, 47%-90%)., (© 2024 Wiley Periodicals LLC.)

Optimal frontline use of active agents in T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is prudent to improve outcomes. We report the long-term follow-up of the phase 2 trial of HyperCVAD with nelarabine and pegylated asparaginase (Original cohort). In the latest protocol iteration venetoclax was added to the induction/consolidation regimen (Venetoclax cohort). Eligible patients were adults with untreated T-ALL/LBL or after minimal therapy and with adequate organ function. Primary endpoint of this analysis was improvement in 2-year progression free survival (PFS) and overall survival (OS) with venetoclax. From Aug 2007 to Dec 2024, 145 patients, at a median age of 35.4 years, were treated; 46 (33.8%) were in the venetoclax cohort. At median follow-up (mFU) of 62.4 months, 5-year PFS, duration of response (DOR), and OS were 63.7%, 72.0% and 66.2% respectively. In the venetoclax cohort (mFU 24.4 months) 2-year PFS (87.9% versus 64.1%, p = 0.03) and 2-year DOR (93.6% versus 69.2%, p = 0.005) were superior to the original cohort (mFU 89.4 months) and 2-year OS appeared better (87.8% versus 73.9%, p = 0.16). Febrile neutropenia was the most common serious adverse event, seen in 60% patients. The addition of venetoclax to HyperCVAD-nelarabine-pegylated asparaginase was tolerable and led to improvement in DOR and PFS., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported. In this analysis, we update our experience with the chemotherapy-free regimen of blinatumomab and ponatinib in 60 patients with newly diagnosed Philadelphia chromosome (Ph)-positive ALL. At a median follow-up of 24 months, the complete molecular response rate by reverse transcriptase-polymerase chain reaction was 83% (67% at the end of course one), and the rate of measurable residual disease negativity by next-generation clono-sequencing was 98% (45% at the end of course one). Only two patients underwent hematopoietic stem cell transplantation (HSCT). Seven patients relapsed: two with systemic disease, four with isolated CNS relapse, and one with extramedullary Ph-negative, CRLF2-positive pre-B ALL. The estimated 3-year overall survival rate was 91% and event-free survival rate was 77%. Three patients discontinued blinatumomab because of adverse events (related, n = 1; unrelated, n = 2) and nine discontinued ponatinib because of cerebrovascular ischemia, coronary artery stenosis, persistent rash, elevated liver function tests with drug-induced fatty liver, atrial thrombus, severe arterial occlusive disease of lower extremities, pleuro-pericardial effusion, and debilitation. In conclusion, the simultaneous combination of ponatinib and blinatumomab is a highly effective and relatively safe nonchemotherapy regimen. This regimen also reduces the need for intensive chemotherapy and HSCT in first remission in the majority of patients.

Background: The combination of low-intensity chemotherapy and inotuzumab ozogamicin (INO), with sequential blinatumomab, is highly effective in older adults with newly diagnosed B-cell acute lymphoblastic leukemia (ALL) and in relapsed or refractory B-cell ALL. Earlier, "dose-dense" administration of blinatumomab could lead to earlier and deeper measurable residual disease (MRD) responses and better outcomes., Patients and Methods: We performed a retrospective analysis of the safety and efficacy of a dose-dense regimen of mini-hyper-CVD (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with mini-methotrexate and cytarabine), INO, and blinatumomab in patients with B-cell ALL., Results: Twenty-one patients were treated (frontline, n = 9; MRD consolidation, n = 4; relapsed/refractory, n = 8). In the frontline cohort, all patients achieved CR/CRi and MRD negativity by flow cytometry at the end of cycle 1. Across the frontline and MRD consolidation cohorts, 10/11 patients (91%) achieved next-generation sequencing MRD negativity at a sensitivity of 10 -6 , including 6/10 evaluable patients (60%) who achieved next-generation sequencing MRD negativity after cycle 1. The CR/CRi rate in the relapsed/refractory cohort was 63%, and all responders achieved MRD negativity by flow cytometry at the end of cycle 1. The 1-year overall survival rate for the combined cohort of the frontline and MRD-positive patients was 83%. No new safety signals were observed with the dose-dense mini-hyper-CVD, INO, and blinatumomab regimen., Conclusion: Dose-dense delivery of mini-hyper-CVD, INO, and blinatumomab was safe and resulted in rapid and deep MRD negativity in patients with B-cell ALL. This regimen is now being prospectively evaluated in both the frontline and relapsed/refractory settings., Competing Interests: Disclosure N.J.S, E.J., and H.K. have received research funding and honoraria from Amgen and Pfizer Inc. The rest of the authors have no relevant conflicts to disclose., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Abstract: Preclinical studies suggest that Bcl-2 inhibition with venetoclax has antileukemic activity in acute lymphoblastic leukemia (ALL) and may synergize with conventional chemotherapy. We designed a phase 1/2 clinical trial to evaluate the safety and efficacy of low-intensity chemotherapy in combination with venetoclax in adults with relapsed or refractory ALL. Patients received the mini-hyper-CVD regimen (dose-attenuated hyperfractionated cyclophosphamide, vincristine, and dexamethasone alternating with methotrexate and cytarabine) in combination with venetoclax (200 mg or 400 mg daily) on days 1 to 14 in cycle 1 and on days 1 to 7 in consolidation cycles. Twenty-two patients were treated. The median number of prior therapies was 2 (range, 1-6). Thirteen patients (59%) had undergone prior allogeneic stem cell transplant (allo-SCT), and 7 of 18 patients (39%) with B-cell ALL had previously received both inotuzumab ozogamicin and blinatumomab. The recommended phase 2 dose of venetoclax in the combination regimen was 400 mg daily. The composite complete remission (CR) and CR with incomplete hematologic recovery (CRi) rate was 57% (CR, 43%; CRi, 14%), and 45% of responders achieved measurable residual disease negativity by multiparameter flow cytometry. Four patients proceeded to allo-SCT. The median duration of response was 6.3 months. The median overall survival was 7.1 months, and the 1-year overall survival rate was 29%. The most common grade ≥3 nonhematologic adverse events were infection in 17 patients (77%) and febrile neutropenia in 4 patients (18%). Overall, the combination of mini-hyper-CVD plus venetoclax was active in heavily pretreated relapsed/refractory ALL. Further development of venetoclax-based combinations in ALL is warranted. This trial is registered at www.clinicaltrials.gov as #NCT03808610., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

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., (© 2023 Wiley Periodicals LLC.)

Background: The outcome of older patients with B-cell acute lymphocytic leukaemia is inferior to that in younger patients due to the adverse disease biology and their inability to tolerate intensive therapy. We aimed to study the long-term outcomes of inotuzumab ozogamicin with or without blinatumomab in combination with low-intensity chemotherapy in these patients., Methods: For this open-label phase 2 trial, patients aged 60 years or older with newly diagnosed, Philadelphia-chromosome negative, B-cell acute lymphocytic leukaemia, and an ECOG performance status of 3 or lower were eligible. This study was conducted at the University of Texas MD Anderson Cancer Center. The induction chemotherapy consisted of mini-hyper-CVD and has been published before; inotuzumab ozogamicin was administered intravenously on day 3 of the first four cycles at a dose of 1·3-1·8 mg/m 2 in cycle 1, followed by 1·0-1·3 mg/m 2 in subsequent cycles (cycles 2-4). Maintenance therapy with dose-reduced POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) was given for 3 years. From patient 50 onwards, the study protocol was amended to fractionate inotuzumab ozogamicin to a maximum cumulative dose of 2·7 mg/m 2 (0·9 mg/m 2 during cycle 1 fractionated into 0·6 mg/m 2 on day 2 and 0·3 mg/m 2 on day 8 of cycle 1, and 0·6 mg/m 2 in cycles 2-4 fractionated into 0·3 mg/m 2 on day 2 and 0·3 mg/m 2 on day 8) followed by blinatumomab for four cycles (cycles 5-8). POMP maintenance was shortened to 12 cycles with one cycle of blinatumomab administered by continuous infusion after every three cycles of POMP. The primary endpoint was progression-free survival and was analysed on an intention-to-treat basis. This trial is registered with ClinicalTrials.gov (NCT01371630) and the present data is from the newly diagnosed, older subgroup of patients treated on the phase 2 portion of this trial; the trial is still enrolling patients., Results: Between Nov 11, 2011, and March 31, 2022, 80 patients were enrolled and treated (32 female and 48 male patients; median age 68 years [IQR 63-72]), 31 of whom were treated after the protocol amendment. With a median follow-up of 92·8 months (IQR 8·8-67·4), the 2-year progression-free survival was 58·2% (95% CI 46·7-68·2) and 5-year progression-free survival was 44·0% (31·2-54·3). At a median follow-up of 104·4 months (IQR 6·6-89·2) for the patients treated before the protocol amendment and 29·7 months (8·8-41·0) for those treated after the protocol amendment, median progression-free survival did not differ significantly between the two groups (34·7 months [95% CI 15·0-68·3] vs 56·4 months [11·3-69·7]; p=0·77). The most common grade 3-4 events were thrombocytopenia in 62 (78%) patients and febrile neutropenia in 26 (32%) patients. Six (8%) patients developed hepatic sinusoidal obstruction syndrome. There were eight (10%) deaths due to infectious complications, nine (11%) from complications related to secondary myeloid malignancy, and four (5%) from sinusoidal obstruction syndrome., Interpretation: Inotuzumab ozogamicin with or without blinatumomab added to low-intensity chemotherapy showed promising activity in terms of progression-free survival in older patients with B-cell acute lymphocytic leukaemia. Further attenuation of the chemotherapy regimen might improve tolerability while maintaining efficacy in older patients., Funding: Pfizer and Amgen., Competing Interests: Declaration of interests EJ reports research grants from AbbVie, Adaptive Biotechnologies, Amgen, Pfizer, and Takeda; and consultancy fees from AbbVie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Genentech, Incyte, Novartis, Pfizer, and Takeda. NJS reports research grants from Takeda Oncology, Astellas Pharma, Xencor, and Stemline Therapeutics; consultancy fees from Pfizer and Jazz Pharmaceuticals; and honoraria from Novartis, Amgen, Sanofi, and BeiGene. ND reports research funding from Daiichi-Sankyo, Bristol Myers Squibb, Pfizer, Gilead, Servier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen; and served in a consulting or advisory role for Daiichi-Sankyo, Bristol Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. HK reports research grants from AbbVie, Amgen, Ascentage, Bristol Myers Squibb, Daiichi-Sankyo, Immunogen, Jazz, Novartis, and Pfizer; and honoraria from AbbVie, Amgen, Aptitude Health, Ascentage, Astellas Health, Astra Zeneca, Ipsen, Pharmaceuticals, KAHR Medical, NOVA Research, Novartis, Pfizer, Precision Biosciences, and Taiho Pharmaceutical Canada. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., (© 2023. The Author(s).)

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., (© 2023 Wiley Periodicals LLC.)

Background: Ponatinib and blinatumomab are effective therapies in patients with Philadelphia chromosome-positive (Ph-positive) acute lymphoblastic leukaemia, and their combination might be a promising treatment option. In this study, we aimed to evaluate this chemotherapy-free strategy., Methods: We did a single-centre, single-arm, phase 2 study at the University of Texas MD Anderson Cancer Center, Houston, TX, USA, in patients aged 18 years or older with newly diagnosed or relapsed or refractory Ph-positive acute lymphoblastic leukaemia or chronic myeloid leukaemia in lymphoid blast phase. Patients with an ECOG performance status of 2 or less who had a total bilirubin concentration two-times the upper limit of normal (ULN) or less (≤2·4 mg/dL), alanine aminotransferase and aspartate aminotransferase concentration no more than three-times the ULN, and serum lipase and amylase concentrations no more than three-times the ULN were eligible for inclusion. Ponatinib 30 mg orally and continuous intravenous blinatumomab 28 μg over 24 h (for 28 days each cycle) were given in combination for up to five 42-day cycles, followed by ponatinib monotherapy. Patients received 12 doses of intrathecal chemotherapy as CNS prophylaxis. The primary endpoints were complete molecular response (defined as absence of a detectable BCR-ABL1 transcript by PCR at a sensitivity of 0·01%) in patients with newly diagnosed disease and overall response in patients with relapsed or refractory disease or chronic myeloid leukaemia in lymphoid blast phase. All assessments were done according to the intention-to-treat principle. The trial completed its original target accrual and was amended on March 23, 2022, to enrol an additional 30 patients, thus increasing the sample size to 90 patients. The trial is registered with ClinicalTrials.gov, NCT03263572, and it is ongoing., Findings: Between Feb 6, 2018, to May 6, 2022, 60 (83%) of 72 patients assessed were enrolled and received ponatinib and blinatumomab (40 [67%] patients had newly diagnosed Ph-positive acute lymphoblastic leukaemia, 14 [23%] had relapsed or refractory Ph-positive acute lymphoblastic leukaemia, and six [10%] had chronic myeloid leukaemia in lymphoid blast phase). 32 (53%) patients were men and 28 (47%) were women; 51 (85%) patients were White or Hispanic; and the median age of participants was 51 years (IQR 36-68). The median duration of follow-up for the entire cohort was 16 months (IQR 11-24). Of patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia, 33 (87%) of 38 evaluable patients had a complete molecular response. 12 (92%) of 13 evaluable patients with relapsed or refractory Ph-positive acute lymphoblastic leukaemia had an overall response. 11 (79%) had a complete molecular response. Five (83%) of six patients with chronic myeloid leukaemia in lymphoid blast phase had an overall response. Two (33%) had a complete molecular response. The most common grade 3-4 adverse events that occurred in more than 5% of patients were infection (22 [37%] patients), increased amylase or lipase concentration (five [8%] patients), increased alanine aminotransferase or aspartate aminotransferase concentration (four [7%] patients), pain (four [7%] patients), and hypertension (four [7%] patients). One (2%) patient discontinued blinatumomab due to tremor. Three (5%) patients discontinued ponatinib secondary to cerebrovascular ischaemia, portal vein thrombosis, and coronary artery stenosis in one patient each. No treatment-related deaths were observed., Interpretation: The chemotherapy-free combination of ponatinib and blinatumomab resulted in high rates of complete molecular response in patients with newly diagnosed and relapsed or refractory Ph-positive acute lymphoblastic leukaemia. Patients with newly diagnosed Ph-positive acute lymphoblastic leukaemia could be spared the toxicities associated with chemotherapy and the need for allogeneic haematopoietic stem-cell transplantation in first response., Funding: Takeda Oncology and Amgen., Competing Interests: Declaration of interests EJ reports research grants from Abbvie, Adaptive Biotechnologies, Amgen, Pfizer, and Takeda; and consultancy fees from Abbvie, Adaptive Biotechnologies, Amgen, Bristol Myers Squibb, Genentech, Incyte, Novartis, Pfizer, and Takeda. NJS reports research grants from Takeda Oncology, Astellas Pharma, Xencor, and Stemline Therapeutics; consultancy fees from Pfizer and Jazz Pharmaceuticals; and honoraria from Novartis, Amgen, Sanofi, and BeiGene. ND reports research funding from Daiichi-Sankyo, Bristol-Myers Squibb, Pfizer, Gilead, Sevier, Genentech, Astellas, Daiichi-Sankyo, Abbvie, Hanmi, Trovagene, FATE therapeutics, Amgen, Novimmune, Glycomimetics, Trillium, and ImmunoGen; and served in a consulting or advisory role for Daiichi-Sankyo, Bristol-Myers Squibb, Arog, Pfizer, Novartis, Jazz, Celgene, AbbVie, Astellas, Genentech, Immunogen, Servier, Syndax, Trillium, Gilead, Amgen, Shattuck labs, and Agios. GCI reports research funding from Celgene, Kura Oncology, Syndax, and Novartis; and consultancy fees from Novartis and Kura Oncology. MK reports research funding from AbbVie, Genentech, F Hoffman La-Roche, Eli Lilly, Cellectis, Calithera, Ablynx, Stemline Therapeutics, Agios, Ascentage, AstraZeneca, Rafael Pharmaceutical, Sanofi, and Forty-Seven; consultancy fees or honoraria from AbbVie, Genentech, F Hoffman La-Roche, Stemline Therapeutics, Amgen, Forty-Seven, Kisoji, and Janssen; is on the advisory board for Stemline Therapeutics, F Hoffman La-Roche, and Janssen; and has stocks or royalties in Reata Pharmaceutical, Novartis, and Eli Lilly. HK reports research grants from AbbVie, Amgen, Ascentage, Bristol Myers Squibb, Daiichi-Sankyo, Immunogen, Jazz, Novartis, and Pfizer; and honoraria from AbbVie, Amgen, Aptitude Health, Ascentage, Astellas Health, Astra Zeneca, Ipsen, Pharmaceuticals, KAHR Medical, NOVA Research, Novartis, Pfizer, Precision Biosciences, and Taiho Pharmaceutical Canada. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Background: Blinatumomab is effective in relapsed or refractory B-cell acute lymphocytic leukaemia and results in high rates of minimal residual disease negativity. We aimed to establish whether the incorporation of blinatumomab into front-line therapy for acute lymphocytic leukaemia could improve outcomes., Methods: We conducted a single-arm, phase 2 trial at The University of Texas MD Anderson Cancer Center (Houston, TX, USA). Patients aged 14 years or older with confirmed, newly diagnosed Philadelphia chromosome (Ph)-negative B-cell acute lymphocytic leukaemia were eligible, including patients who had received up to one course of chemotherapy before enrolment. Patients received four cycles of intensive chemotherapy (hyper-CVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone] alternating with high-dose methotrexate and cytarabine), followed by four cycles of blinatumomab consolidation (up to 28 μg/day by continuous intravenous infusion for 28 days, given every 42 days). Maintenance consisted of 15 cycles of alternating blocks of three cycles of POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone) chemotherapy and one of blinatumomab. The primary endpoint was relapse-free survival evaluated in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, NCT02877303, and is still enrolling patients., Findings: Between Nov 14, 2016, and Aug 27, 2020, 38 patients with newly diagnosed B-cell acute lymphocytic leukaemia were treated (median age 37 years [IQR 29-45]; 26 [68%] male; 21 [55%] White, non-Hispanic). With a median follow-up of 37 months (IQR 28-49), estimated 3-year relapse-free survival was 73% (95% CI 56-85). No patients relapsed more than 2 years after the start of therapy. One (3%) patient developed transient grade 3 cytokine release syndrome, and four (11%) patients had a grade 3 blinatumomab-related neurological event. The most common non-haematological grade 3-4 adverse events were infections, which occurred in 14 (37%) of 38 patients during induction and in 27 (71%) of 38 patients during consolidation chemotherapy cycles. One (3%) patient discontinued therapy because of treatment-related neurotoxicity. There were two deaths-one due to infection and one due to respiratory failure-which were not considered treatment-related., Interpretation: Front-line sequential chemotherapy with blinatumomab resulted in encouraging long-term survival. Future randomised studies should evaluate the routine incorporation of blinatumomab in the treatment of patients with Ph-negative B-cell acute lymphocytic leukaemia., Funding: Amgen., Competing Interests: Declaration of interests EJ has received research funding, consulting fees, and honoraria from AbbVie, Adaptive Biotechnologies, Amgen, Ascentage, Bristol Myers Squibb, Genentech, Novartis, Pfizer, and Takeda. NS has received research funding from Astellas Pharma, Stemline Therapeutics, Xencor, and Takeda Oncology; consulting fees from Pfizer and Jazz Pharmaceuticals; and honoraria from Pfizer, Novartis, Astellas Pharma, and Amgen. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

The presence of measurable residual disease (MRD) is the strongest predictor of relapse in acute lymphoblastic leukemia (ALL). We conducted a prospective, single-arm, phase II study in adults with B-cell ALL with MRD ≥1 × 10 -4 after ≥3 months from the start of frontline therapy or one month from any salvage therapy. Blinatumomab was administered at a standard dosing of 28 micrograms daily as a continuous infusion for up to five cycles and up to four additional maintenance cycles. Thirty-seven patients with a median age of 43 years (range, 22-84 years) were treated. Twenty-seven patients (73%) were treated in first complete remission (CR) and 10 patients (27%) in second CR and beyond. Eighteen patients (49%) had Philadelphia-chromosome positive ALL and received concomitant tyrosine kinase inhibitor therapy. Twenty-three patients (62%) had a baseline MRD ≥10 -3 . A median of three cycles (range, 1-9 cycles) were administered. Overall, 27 patients (73%) achieved MRD-negative remission. With a median follow-up of 31 months (range, 5-70 months), the estimated 3-year relapse-free survival (RFS) rate was 63% (95% confidence interval [CI], 43%-77%) and overall survival (OS) rate 67% (95% CI, 46%-81%). These rates were 51% (95% CI, 27%-70%) and 61% (95% CI, 36%-78%) in patients with baseline MRD ≥1 × 10 -3 , and 83% (95% CI, 45%-95%) and 77% (95% CI, 32%-95%) in patients with baseline MRD <10 -3 respectively. The rates of adverse events were consistent with previous studies of blinatumomab. In summary, blinatumomab induced MRD negativity in most patients and resulted in high rates of RFS and OS. This study is registered at www.clinicaltrials.gov as #NCT02458014. Funding was provided by Amgen Inc., (© 2022 Wiley Periodicals LLC.)

Measurable residual disease (MRD) is highly prognostic for relapse and overall survival (OS) in acute lymphoblastic leukemia (ALL), although many patients with apparent "MRD negativity" by standard assays still relapse. We evaluated the clinical impact of a highly sensitive next-generation sequencing (NGS) MRD assay in 74 adults with ALL undergoing frontline therapy. Among remission samples that were MRD negative by multiparameter flow cytometry (MFC), 46% were MRD+ by the NGS assay. After 1 cycle of induction chemotherapy, MRD negativity by MFC at a sensitivity of 1 × 10-4 and NGS at a sensitivity of 1 × 10-6 was achieved in 66% and 23% of patients, respectively. The 5-year cumulative incidence of relapse (CIR) among patients who achieved MRD negativity by MFC at complete remission (CR) was 29%; in contrast, no patients who achieved early MRD negativity by NGS relapsed, and their 5-year OS was 90%. NGS MRD negativity at CR was associated with significantly decreased risk of relapse compared with MRD positivity (5-year CIR, 0% vs 45%, respectively; P = .04). Among patients who were MRD negative by MFC, detection of low levels of MRD by NGS identified patients who still had a significant risk of relapse (5-year CIR, 39%). Early assessment of MRD using a highly sensitive NGS assay adds clinically relevant prognostic information to standard MFC-based approaches and can identify patients with ALL undergoing frontline therapy who have a very low risk of relapse and excellent long-term survival., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Recurring genetic abnormalities have been identified in Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). Among them, IKZF1 deletion was associated with poor prognosis in patients treated with imatinib-based or dasatinib-based regimens. However, the molecular determinants for clinical outcomes in ponatinib-treated patients remain unknown. We systematically analyzed genetic alterations in adults with Ph-positive ALL uniformly treated in clinical trials with dasatinib-based regimens or a ponatinib-based regimen and investigated the molecular determinants for treatment outcomes using pretreatment specimens collected from adults with Ph-positive ALL treated with Hyper-CVAD plus dasatinib or ponatinib. DNA sequencing and SNP microarray were performed and recurrent genetic abnormalities were found in 84% of the patients, among whom IKZF1 deletion was most frequently detected (60%). IKZF1 deletion frequently co-occurred with other copy-number abnormalities (IKZF1 plus , 46%) and was significantly associated with unfavorable overall survival (OS) (false discovery rate < 0.1) and increased cumulative incidence of relapse (p = 0.01). In a multivariate analysis, dasatinib therapy, lack of achievement of 3-month complete molecular response, and the presence of IKZF1 plus status were significantly associated with poor OS. The differential impact of IKZF1 plus was largely restricted to patients given Hyper-CVAD plus ponatinib; dasatinib-based regimens had unfavorable outcomes regardless of the molecular abnormalities., (© 2022. The Author(s), under exclusive licence to Springer Nature Limited.)

Acute lymphoblastic leukemia (ALL) with t(4;11)(q21;q23)-KMT2A-AFF1 is associated with a poor prognosis. The impact of KMT2A rearrangements other than t(4;11) is uncertain, and the benefit of allogeneic stem cell transplantation (HSCT) is unclear. We reviewed adult patients with ALL treated at our institution from 1984 to 2019 and identified 50 out of 1102 (5%) with KMT2A rearrangement, including 42 (84%) with t(4;11)/KMT2A-AFF1 and 8 (16%) with other gene partners. The median age was 45 years (range, 18-78 years); median white blood cell count was 109.0 3 109/L (range, 0.5-1573.0). The complete remission (CR) rate was 88%, and the rate of measurable residual disease negativity by flow cytometry at CR was 41% (76% overall during follow-up). At the last follow-up, 14 patients were alive. The 5-year overall survival (OS) rate was 18% (95% confidence interval [CI], 9% to 35%), with no difference between t(4;11) and other KMT2A rearrangements (P 5 .87). In a 4-month landmark analysis, the 5-year OS rate was 32% (95% CI, 14% to 70%) in patients who underwent HSCT vs 11% (95% CI, 3-39) in others (P 5 .10). Our study confirms the poor prognosis of ALL with any KMT2A rearrangement and the role of HSCT in these patients., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Background: The outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper-CVAD + ofatumumab (hyper-CVAD + ofatumumab) has not been compared with the outcome of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone plus ofatumumab hyper-CVAD plus rituximab (hyper-CVAD + Rituximab) in Philadelphia chromosome-negative acute lymphoblastic leukemia (ALL) in a randomized clinical trial., Methods: The authors compared the outcomes of 69 patients treated with hyper-CVAD + ofatumumab and 95 historical-control patients treated with hyper-CVAD + Rituximab. Historical-control patients were treated with hyper-CVAD + Rituximab if they had CD20 expression ≥ 20%. Ofatumumab (day 1 of course 1, 300 mg intravenously; subsequent doses, 2000 mg intravenously) was administered on days 1 and 11 of courses 1 and 3 and on days 1 and 8 of courses 2 and 4 for a total of 8 doses. A propensity score analysis with inverse probability of treatment weighting (IPTW) was performed to adjust for baseline covariates between groups., Results: The median event-free survival with stem cell transplantation (SCT) censoring was 33 and 65 months with hyper-CVAD + Rituximab and hyper-CVAD + ofatumumab, respectively (crude P = .064; IPTW P = .054). The median overall survival with SCT censoring was 52 months and not reached, respectively (crude P = .087; IPTW P = .097)., Conclusions: Hyper-CVAD + ofatumumab was associated with better outcomes than hyper-CVAD + Rituximab among patients with newly diagnosed Philadelphia chromosome-negative ALL., (© 2021 American Cancer Society.)

Background: The achievement of a 3-month complete molecular response (CMR) is a major prognostic factor for survival in patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). However, 25% of patients relapse during therapy with tyrosine kinase inhibitors (TKIs)., Methods: The authors reviewed 204 patients with Ph-positive ALL who were treated between January 2001 and December 2018 using the combination of hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus a TKI (imatinib, 44 patients [22%]; dasatinib, 88 patients [43%]; or ponatinib, 72 patients [35%]). Progression-free survival (PFS) was defined as the time from the start date of therapy to the date of relapse, death, or last follow-up. Overall survival (OS) was defined as the time from the start date of therapy to the date of death or last follow-up., Results: Overall, a 3-month CMR was observed in 57% of patients, including 32% of those who received imatinib, 52% of those who received dasatinib, and 74% of those who received ponatinib. The median follow-up was 74 months (imatinib, 180 months; dasatinib, 106 months; ponatinib, 43 months). Among 84 patients in 3-month CMR, 17 (20%) proceeded to undergo allogeneic stem cell transplantation (ASCT). The 5-year PFS and OS rates were 68% and 72%, respectively. By multivariate analysis, ponatinib therapy was the only significant favorable independent factor predicting for progression (P = .028; hazard ratio, 0.388; 95% CI, 0.166-0.904) and death (P = .042; hazard ratio, 0.379; 95% CI, 0.149-0.966). ASCT was not a prognostic factor for PFS and OS by univariate analysis., Conclusions: In patients with Ph-positive ALL, ponatinib is superior to other types of TKIs in inducing and maintaining a CMR, thus preventing disease progression. ASCT does not improve outcome once a 3-month CMR is achieved., (© 2021 American Cancer Society.)

Background: The outcome of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. The combination of inotuzumab with low-intensity mini-hyper-CVD (mini-hyper-CVD; cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m 2 × 4 doses) chemotherapy has shown encouraging results. The sequential addition of blinatumomab might improve outcome in patients with R/R ALL., Methods: We used lower intensity chemotherapy, mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, cytarabine at 0.5 g/m 2 x 4 doses) compared to conventional hyper-CVAD., Results: Ninety-six patients with a median age of 37 years (range, 18-87 years) were treated. Overall, 77 patients (80%) responded, 55 (57%) of whom achieved complete response. The overall measurable residual disease negativity rate among responders was 83%. Forty-four (46%) patients underwent later allogeneic stem cell transplantation. Veno-occlusive disease of any grade occurred in 10 (10%) patients. The rates were 13% with the original schedule and 3% with the use of lower-dose inotuzumab and sequential blinatumomab. With a median follow-up of 36 months, the median overall survival (OS) was 13.4 months, with 3-year OS rates of 33%. The 3-year OS rate for patients with CD22 expression ≥70% and without adverse cytogenetics (KMT2A rearrangements, low hypodiploidy/near triploidy) was 55%., Conclusion: The combination of inotuzumab and low-intensity mini-hyper-CVD chemotherapy with or without blinatumomab shows sustained efficacy in patients with R/R ALL., (© 2021 American Cancer Society.)

Background: The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy has dramatically improved outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). When allogeneic hematopoietic stem cell transplant (HSCT) is performed, maintenance TKI is generally given for a fixed duration. However, the optimal duration of TKI outside of HSCT remains unknown, and the common practice is to continue indefinitely. Here, we report characteristics and outcomes of 9 patients treated with chemotherapy + TKI without HSCT and later discontinued TKI., Methods: Among 188 patients with Ph-positive ALL who did not undergo HSCT, 9 of them discontinued maintenance TKI mainly due to side effects. Patients were closely monitored with serial PCR testing for the BCR-ABL1 transcript. Major molecular response (MMR) was defined as BCR-ABL1 transcript ≤0.1% on the international scale for p210 transcripts and a 3-log reduction from baseline for p190 transcripts. Deep molecular remission (DMR) was defined as the absence of quantifiable BCR-ABL1 transcripts with a sensitivity of 0.01%. Molecular relapse was defined as loss of MMR. Treatment-free remission (TFR) was defined from time of TKI discontinuation to molecular relapse, last follow-up, or death from any cause., Results: At the time of TKI discontinuation, transcript level was undetected in 6 patients, <0.01% in 2 patients, and 0.01% in another patient. Prior to discontinuation, the median duration of TKI therapy and of DMR was 70 and 47 months, respectively. No morphological relapse occurred. Three patients (33%) had molecular relapse at a median of 6 months. All 3 resumed TKI therapy, and 2 of them regained DMR after a median of 13 months. After a median follow-up of 49 months, the median TFR was not reached, and the 4-year TFR rate was 65%. The median duration of DMR in patients with and without molecular relapse was 22 and 58 months, respectively (p = 0.096)., Conclusion: TKI discontinuation outside of HSCT in Ph-positive ALL in the setting of compelling toxicity may be safe only among a highly selected group of patients with deep and prolonged DMR undergoing close and frequent monitoring. Validation of these findings in prospective clinical trials is highly needed., (© 2020 S. Karger AG, Basel.)

Liposomal vincristine is designed to reduce neurotoxicity and increase dose intensity delivery, and has been approved as salvage therapy in relapsed/refractory acute lymphoblastic leukemia (ALL). Our aim was to evaluate the response rate, toxicities, and outcome of adults with newly diagnosed ALL who received liposomal vincristine, rather than regular vincristine in combination with intensive chemotherapy (Hyper-CMAD). In a single-center, phase 2 study, patients ≥18 years with newly-diagnosed B-cell ALL were eligible to receive hyper-CMAD alternating with high-dose methotrexate and cytarabine. Rituximab was administered in CD20 positive ALL. Tyrosine kinase inhibitors (imatinib or dasatinib) were added in Philadelphia chromosome-positive (Ph-positive) ALL. Thirty-one patients were enrolled, median follow-up of 59 months (0.3-70). Thirteen patients (42%) had CD20 positive ALL, and 21 (68%) had Ph-positive ALL. Thirty (97%) achieved complete remission (CR). All 26 patients with abnormal karyotype achieved complete cytogenetic response (CCyR), and 27/30 (90%) achieved negative minimal residual disease status by multicolor flow cytometry. Of 20 evaluable Ph-positive ALL patients, major molecular response (MMR) was achieved in 19 patients (95%); complete molecular response (CMR) in 14 (70%). Grade 3/4 peripheral neuropathy was observed in five (16%) with all grade peripheral neuropathy in 21 (68%). With a median follow-up of 59 months, 21 (68%) patients are alive. The 5-year CR duration and survival rates were 73% and 61%, respectively. Ten (32%) patients died: one, sepsis on C1D10; four, unknown; one, post-transplant complications; four, relapse. Hyper-CMAD with liposomal vincristine is safe and demonstrated high response and survival rates in newly diagnosed ALL., (© 2020 Wiley Periodicals, Inc.)

Mutations of ABL1 are the dominant mechanism of relapse in Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL). We performed highly accurate Duplex Sequencing of exons 4-10 of ABL1 on bone marrow or peripheral blood samples from 63 adult patients with previously untreated Ph + ALL who received induction with intensive chemotherapy plus a BCR-ABL1 TKI. We identified ABL1 mutations prior to BCR-ABL1 TKI exposure in 78% of patients. However, these mutations were generally present at extremely low levels (median variant allelic frequency 0.008% [range, 0.004%-3.71%] and did not clonally expand and lead to relapse in any patient, even when the pretreatment mutation was known to confer resistance to the TKI received. In relapse samples harboring a TKI-resistant ABL1 mutation, the corresponding mutation could not be detected pretreatment, despite validated sequencing sensitivity of Duplex Sequencing down to 0.005%. In samples under the selective pressure of ongoing TKI therapy, we detected low-level, emerging resistance mutations up to 5 months prior to relapse. These findings suggest that pretreatment ABL1 mutation assessment should not guide upfront TKI selection in Ph + ALL, although serial testing while on TKI therapy may allow for early detection of clinically actionable resistant clones.

The minimal or measurable residual disease (MRD) status following induction/consolidation chemotherapy is an important prognostic endpoint in adult patients with newly diagnosed acute lymphoblastic leukemia (ALL). However, the optimal time-point (TP) of MRD assessment and its impact on outcome remains unclear. We analyzed 215 patients with newly diagnosed Philadelphia negative B-cell ALL who received intensive chemotherapy, and had available MRD assessment by multicolor flow cytometry at two separate TPs. The median time to first TP (1TP) and second TP (2TP) were 24 and 110 days, respectively. At 1TP, 148 patients (68%) were MRD negative and 67 (32%) were positive. Of the 148 patients with negative MRD at 1TP, 147 (99%) maintained it through 2TP. Patients who were MRD negative at both TPs, early MRD responders, had the 3-year event-free survival (EFS), and overall survival (OS) rates of 65% and 76%, respectively. Patients with improved MRD status from positive to negative, late MRD responders, had lower 3-year EFS and OS rates, 42% and 58%, respectively (P = .001). Multivariate analysis showed that KMT2A (MLL) rearrangement and MRD positivity at 1TP were the only factors correlated with worse OS. In conclusion, the earlier achievement of MRD negative remission is a stronger prognostic factor for survival., (© 2019 Wiley Periodicals, Inc.)

Despite the advances in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) with the introduction of tyrosine kinase inhibitors (TKIs), relapses remain challenging. We reviewed clinical data from adult patients with Ph + ALL who received frontline hyperCVAD chemotherapy with a TKI to determine their outcomes after first relapse. Patients with first morphological relapse after prior complete remission were evaluated for predictors of response and survival. For 57 of 233 (25%) patients, there was morphological relapse after a median of 15.9 months from first remission [range: 5.3-94]. The choice of salvage treatments was at the discretion of the treating physician. So, 43 (75%) patients received a TKI in combination with their salvage treatment. Second remission was achieved in 41 of 49 (84%) evaluable patients. Median relapse free survival (RFS) was 10.5 months [range, 0.2-81]. The 1-year and 2-year overall survival (OS) were 41% and 20% respectively. On multivariate analysis, only elevated LDH (units/L), the use of first-generation or no TKI at the time of first relapse and the achievement of a major molecular response (MMR) had a significant effect on OS (HR: 2.82, 95% CI:1.11-7.16, P = .029; HR = 2.39, 95% CI: 1.07,5.39, P = .034; HR = 0.39, 95% CI: 0.16-0.94, P = .03, respectively). Whereas, only achievement of MMR was significantly prognostic for RFS with a HR of 0.48 (95% CI: 0.23-0.98, P = .04). The OS and RFS were comparable between recipients and non-recipients of allogeneic hematopoietic stem cell transplantation (alloHSCT) at second remission, due to a higher non-relapse mortality (53%) seen in patients who underwent alloHSCT., (© 2019 Wiley Periodicals, Inc.)

Background: Colorectal cancer is the third leading cause of cancer death; therefore early detection by screening is beneficial. Residents at a clinic in NJ, USA were not offering other forms of colon cancer screening when patients refused colonoscopy, which lead to the creation of the quality improvement project., Methods: Residents practicing at the clinic were given an anonymous survey determining which method of colon cancer screening they used and which alternative method they offered when patients refused the original method. The residents were educated about all methods of colon cancer screening and the residents were resurveyed., Results: A total of 64% of residents offered less invasive testing when colonoscopy was refused. Six months after education, 95% of residents offered less invasive testing when colonoscopy was refused., Conclusions: Early detection and removal of polyps by colonoscopy reduce the risk of cancer development. Colonoscopy is the gold standard for colon cancer screening; however other less invasive modalities are approved. This quality improvement project lead to offering the fecal immunochemical test or fecal occult blood test once patients refused colonoscopy at the clinic, increasing the number of patients receiving colorectal cancer screening, and thus providing better medical care., Competing Interests: The authors declare that they have no conflict of interest., (Copyright 2019, Melki et al.)

Introduction: Brugada Syndrome typically presents with sudden nocturnal arrhythmias. Diagnosis may be challenging due to variable and transient electrocardiogram patterns and nondiagnostic provocation studies. Genetic testing can establish the etiology, but results may be inconclusive with variants of uncertain significance., Case: A 24-year-old male with family history of sudden cardiac death was found unresponsive due to seizure. He was hemodynamically stable. ECG showed saddle-back ST elevations in V1 and V2. Procainamide challenge was negative. We subsequently performed genetic testing, which demonstrated AKAP9 variant., Discussion: AKAP9 is a scaffolding protein that facilitates phosphorylation of delayed-rectifier potassium channels. The AKAP9 variant alters potassium current causing disordered repolarization and ventricular reentry. It has been previously linked to other channelopathies, but its pathogenicity is fully undetermined., Conclusion: Genetic testing is a useful tool to determine the origin of channelopathy, but inconclusive results with variants of uncertain significance should be clinically correlated., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Complications of septal-occluder devices include erosion, perforation, and embolization, which are most commonly caused by oversized devices or thin rim margins. Cardiac pseudoaneurysm is a rare phenomenon that forms as a result of device erosion into the myocardium. Although this is often an incidental finding, they are at risk for rupture. ( Level of Difficulty: Intermediate. )., (© 2019 The Authors.)

Background: The aim of the study was to compare the efficacy and safety of bivalirudin versus unfractionated heparin (UFH) in patients with acute myocardial infarction who undergo percutaneous coronary intervention (PCI). Earlier trials comparing bivalirudin and UFH during PCI demonstrated that bivalirudin caused less bleeding with more stent thrombosis. Since then, adjunct antiplatelet strategies have evolved. Improved upstream platelet inhibition with potent P2Y12 inhibitors decreased the need for routine glycoprotein IIb/IIIa inhibitor (GPI), resulting in similar outcomes among UFH and bivalirudin. Therefore, the role of bivalirudin in modern PCI practices is questionable., Methods: We utilized Cochrane Review Manager (RevMan) 5.3 to perform a meta-analysis of seven randomized controlled trials (RCTs) with 22,844 patients to compare bivalirudin to UFH in patients with acute myocardial infarction requiring revascularization., Results: There was no difference between bivalirudin and UFH regarding major adverse cardiac events (MACE), risk ratio (RR) 0.99, 95% confidence interval (CI) 0.87 - 1.12; P = 0.83) or cardiovascular mortality (RR 0.87, 95% CI 0.71 - 1.07; P = 0.18). Bivalirudin increased acute stent thrombosis (RR 2.77, 95% CI 1.49 - 5.13; P = 0.001), which was only significant among ST-elevation myocardial infarction (STEMI) only trials. Bivalirudin caused less major bleeding (RR 0.66, 95% CI 0.49 - 0.90; P = 0.007), which was negated when GPI was used provisionally (RR 0.93, 95% CI 0.64 - 1.33; P = 0.67)., Conclusions: Among patients with acute myocardial infarction who underwent PCI, bivalirudin and UFH demonstrated similar MACE and cardiovascular mortality. Bivalirudin increased acute stent thrombosis, which was more remarkable among STEMI. Bivalirudin decreased major bleeding, but this benefit was negated when GPI was used provisionally., Competing Interests: None to declare., (Copyright 2019, Patel et al.)

The purpose of this analysis was to evaluate the cardioprotective benefit of β blockers in preventing anthracycline-induced cardiotoxicity (AIC) in breast cancer patients. Anthracyclines are the cornerstone treatment for breast cancer. Yet, their use has declined in the last decade due to associated AIC. Although β blockers may protect left ventricular (LV) function, previous trials were underpowered with equivocal results. The authors systematically searched online databases through August 2018 for studies evaluating effectiveness of β blockers in preventing AIC in breast cancer patients. We analyzed 9 studies including 771 patients. Data on converting-enzyme inhibitors, trastuzumab, or other malignancies were excluded. The primary outcome was comparison of postchemotherapy LV ejection fraction (LVEF) between β blocker and placebo. Secondary outcomes were changes in global longitudinal strain, LV end-diastolic diameter (LVEDD), and diastolic function parameters, as assessed by 2D echocardiogram and MRI. The mean pre-chemotherapy LVEF was >60% in all studies. Our pooled analysis demonstrated significantly higher LVEF postchemotherapy in the β blocker group in comparison to placebo: mean difference -3.84 with 95% confidence interval [-(6.19 to 1.48) p = 0.001]. The absolute change in EF also favored β blockers: mean difference -3.66 with 95% confidence interval [-(6.20 to 1.12) p = 0.005]. Diastolic function, global longitudinal strain, and LVEDD were also preserved by β blockers, but only LVEDD reached statistical significance. In conclusion, this study suggests that β blockers during anthracycline chemotherapy may prevent cardiotoxicity by preserving LV function., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The outcome of older patients with newly diagnosed, Philadelphia chromosome (Ph)-negative acute lymphoblastic leukemia (ALL) is poor. The combination of targeted therapy with low-intensity chemotherapy is safe and effective. The objective of the current analysis was to compare the outcome of patients who received a combination of inotuzumab ozogamicin plus low-intensity chemotherapy (mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone [mini-HCVD]) with or without blinatumomab versus the outcome of those who received the standard, intensive, hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (HCVAD) regimen., Methods: The authors analyzed 135 older patients with newly diagnosed, Ph-negative ALL who were treated prospectively with standard HCVAD (n = 77) or with the combination of inotuzumab ozogamicin plus mini-HCVD with or without blinatumomab (n = 58). A propensity score analysis was conducted using 1:1 matching using the nearest neighbor matching method., Results: Propensity score matching identified 38 patients in each cohort. The antibody plus low-intensity chemotherapy combination induced higher response rates (98% vs 88%), with lower rates of early death (0% vs 8%) and lower rates of death in complete remission (5% vs 17%). With propensity score matching, the 3-year event-free survival rates for patients who received HCVAD and those who received the combination of inotuzumab ozogamicin plus mini-HCVD with or without blinatumomab were 34% and 64%, respectively (P = .003), and the 3-year overall survival rates were 34% and 63%, respectively (P = .004). By multivariate analysis, age (P = .019; hazard ratio, 1.045) and the combination of inotuzumab plus mini-HCVD with or without blinatumomab (P = .020; hazard ratio, 0.550) were identified as independent prognostic factors for survival., Conclusions: The combination of inotuzumab ozogamicin plus mini-HCVD with or without blinatumomab is safe and effective in older patients with newly diagnosed, Ph-negative ALL and confers a better outcome compared with standard HCVAD chemotherapy., (© 2019 American Cancer Society.)

Background: The combination of chemotherapy and ponatinib in Philadelphia chromosome-positive acute lymphoblastic leukaemia has the potential to be a new standard of care for the disease; however, long-term efficacy and safety data are needed. Our aim was to evaluate the long-term efficacy and safety of this regimen in patients with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia in this ongoing phase 2 trial., Methods: In our single-centre, phase 2, single-arm trial in the USA, adult patients with previously untreated Philadelphia chromosome-positive acute lymphoblastic leukaemia were sequentially enrolled. Eligible patients had newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukaemia, were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 2 or less, a left ventricular ejection fraction above 50%, and adequate hepatic and renal function (serum bilirubin ≤3·0 mg/dL and serum creatinine ≤3·0 mg/dL, unless higher levels were believed to be due to leukaemia at the discretion of the investigator). Patients received eight cycles of 21 days, alternating between two drug combinations: hyper-fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (hyper-CVAD) and high-dose methotrexate and cytarabine. Ponatinib was given orally at 45 mg per day for the first 14 days of cycle 1 then continuously at 45 mg per day for the subsequent cycles. After 37 patients were treated, the protocol was amended to reduce the dose of ponatinib to 30 mg per day at cycle 2, with further reduction to 15 mg once a complete molecular response (defined as absence of quantifiable BCR-ABL1 transcripts) was achieved. Patients in complete remission received maintenance with ponatinib daily (30 mg or 15 mg) indefinitely, and with vincristine (2 mg intravenously on day 1) and prednisone (200 mg orally on days 1-5) monthly for 2 years. The primary endpoint was 3-year event-free survival in the intention-to-treat population. The trial is registered at ClinicalTrials.gov, number NCT01424982, and is ongoing and still enrolling patients., Findings: 76 patients with a median age of 47 years (IQR 39-61) were enrolled and treated between Nov 19, 2011, and April 4, 2018. The 3-year event-free survival was 70% (95% CI 56-80). The most common grade 3 or 4 adverse events were infection (n=65, 86%), increased transaminases (n=24, 32%), increased bilirubin (n=13, 17%), pancreatitis (n=13, 17%), hypertension (n=12, 16%), bleeding (n=10, 13%), and skin rash (n=9, 12%). Six patients died while still on study treatment. Three patients (4%) died from infection and one (1%) from haemorrhage. Two patients died from myocardial infarction related to early ponatinib use; neither death occurred after protocol revision., Interpretation: The combination of chemotherapy with ponatinib is effective in achieving long-term remission in patients with newly diagnosed Philadelphia chromosome-positive  acute lymphoblastic leukaemia. This regimen could represent a new standard of care for this population. A randomised, phase 3 study to evaluate the efficacy of this combination compared with chemotherapy plus earlier-generation tyrosine-kinase inhibitors is warranted., Funding: Takeda Oncology., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The outcomes of patients with relapsed or refractory (R-R) acute lymphoblastic leukemia (ALL) are poor. Inotuzumab ozogamicin and blinatumomab have single-agent activity in R-R ALL. Their addition to low-intensity chemotherapy may further improve the outcomes of patients with ALL in their first relapse., Methods: The chemotherapy was lower in intensity than conventional hyperfractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone and was called mini-hyperfractionated cyclophosphamide, vincristine, and dexamethasone (or mini-HCVD). Inotuzumab was given on day 3 of each of the first 4 cycles at 1.8 to 1.3 mg/m 2 for cycle 1, and this was followed by 1.3 to 1.0 mg/m 2 for subsequent cycles. From patient 39 onward, the inotuzumab dose was reduced and fractionated into weekly doses (0.6 and 0.3 mg/m 2 during cycle 1 and 0.3 and 0.3 mg/m 2 during subsequent cycles), and blinatumomab was administered for up to 4 cycles after inotuzumab therapy., Results: Forty-eight patients with Philadelphia chromosome-negative ALL with a median age of 39 years were treated during their first relapse. Overall, 44 patients (92%) responded, with 35 of them (73%) achieving a complete response. The overall minimal residual disease negativity rate among the responders was 93%. Twenty-four patients (50%) underwent allogeneic stem cell transplantation (ASCT). Veno-occlusive disease of any grade occurred in 5 patients (10%). With a median follow-up of 31 months, the median progression-free survival (PFS) and the median overall survival (OS) were 11 and 25 months, respectively. The 2-year PFS and OS rates were 42% and 54%, respectively. Of the 24 patients (50%) who underwent ASCT, 14 patients were alive at the last follow-up (13 [54%] in remission). Of the remaining 20 responding patients who did not undergo subsequent ASCT, 6 (30%) remained in remission at the last follow-up. According to propensity score matching, the combination of mini-HCVD and inotuzumab with or without blinatumomab conferred better outcomes than intensive salvage chemotherapy or inotuzumab alone., Conclusions: The combination of inotuzumab and low-intensity mini-HCVD chemotherapy with or without blinatumomab shows encouraging results in patients with ALL in first salvage., (© 2018 American Cancer Society.)

Importance: The outcome of patients with relapsed or refractory (R/R) acute lymphoblastic leukemia (ALL) is poor. Inotuzumab ozogamicin, a CD22 monoclonal antibody bound to calicheamicin, has single-agent activity in R/R ALL., Objective: To evaluate the efficacy and safety of inotuzumab ozogamicin plus low-intensity chemotherapy in patients with R/R ALL., Design, Setting, and Participants: A single-arm, phase 2 study of adults with R/R B-cell ALL conducted at The University of Texas MD Anderson Cancer Center, Houston., Interventions: The chemotherapy used was lower intensity than hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [trade name, Adriamycin; Pfizer], and dexamethasone) and is referred to as mini-hyper-CVD (mini-HCVD: cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrexate at 75% dose reduction, and cytarabine at 0.5 g/m2 × 4 doses). Inotuzumab was given on day 3 of the first 4 courses at 1.8 to 1.3 mg/m2 for cycle 1 followed by 1.3 to 1.0 mg/m2 for subsequent cycles., Main Outcomes and Measures: The primary end points were the overall response rate and overall survival (OS). Secondary end points included safety, relapse-free survival (RFS), the rate of allogeneic stem cell transplantation (ASCT), and the minimal residual disease (MRD) negativity rate., Results: Fifty-nine patients (30 women and 29 men) with a median age of 35 years (range, 18-87 years) were treated. Overall, 46 patients (78%) responded, 35 of them (59%) achieving complete response. The overall MRD negativity rate among responders was 82%. Twenty-six patients (44%) received ASCT. Grade 3 to 4 toxic effects included prolonged thrombocytopenia (81%; n = 48), infections (73%; n = 43), and hyperbilirubinemia (14%; n = 8). Veno-occlusive disease (VOD) occurred in 9 patients (15%). With a median follow-up of 24 months, the median RFS and OS were 8 and 11 months, respectively. The 1-year RFS and OS rates were 40% and 46%, respectively. The 1-year OS rates for patients treated in salvage 1, salvage 2, and salvage 3 or beyond were 57%, 26%, and 39%, respectively (P = .03)., Conclusions and Relevance: The combination of inotuzumab with low-intensity mini-HCVD chemotherapy shows encouraging results in R/R ALL. The risk of VOD should be considered carefully in patients with previous liver damage and among transplant candidates., Trial Registration: clinicaltrials.gov Identifier: NCT01371630.