scholarly journals Retrospective analysis of arterial occlusive events in the PACE trial by an independent adjudication committee

2022 ◽  
Vol 15 (1) ◽  
Author(s):  
James L. Januzzi ◽  
Joseph M. Garasic ◽  
Scott E. Kasner ◽  
Vickie McDonald ◽  
Mark C. Petrie ◽  
...  
Keyword(s):  
Risk Factors ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Evaluation Trial ◽  
Peripheral Arterial ◽  
Adjusted Incidence ◽  
Adjudication Committee

Abstract Background The phase 2 PACE (Ponatinib Ph+ ALL and CML Evaluation) trial of ponatinib showed robust long-term benefit in relapsed Philadelphia chromosome-positive (Ph+) leukemia; arterial occlusive events (AOEs) occurred in ≥ 25% of patients based on investigator reporting. However, AOE rates vary depending on the definitions and reporting approach used. Methods To better understand clinically relevant AOEs with ponatinib, an independent cardiovascular adjudication committee reviewed 5-year AOE data from the PACE trial according to a charter-defined process and standardized event definitions. Results A total of 449 patients with chronic myeloid leukemia (CML) or Ph+ acute lymphoblastic leukemia (ALL) received ponatinib (median age 59 y; 47% female; 93% ≥ 2 prior tyrosine kinase inhibitors (TKIs); median follow-up, 37.3 months). The adjudicated AOE rate (17%) was lower than the non-adjudicated rate (i.e., rate before adjudication; 25%). The only adjudicated AOE in > 2% of patients was peripheral arterial occlusive disease (4%). Exposure-adjusted incidence of newly occurring adjudicated AOEs decreased over time. Patients with multiple baseline cardiovascular risk factors had higher adjudicated AOE rates than those without risk factors. Conclusions This independent adjudication study identified lower AOE rates than previously reported, suggesting earlier overestimation that may inaccurately reflect AOE risk with ponatinib. This trial was registered under ClinicalTrials.gov identifier NCT01207440 on September 23, 2010 (https://clinicaltrials.gov/ct2/show/NCT01207440).

Secondary brain tumors in children treated for acute lymphoblastic leukemia at St Jude Children's Research Hospital.

1998 ◽  
Vol 16 (12) ◽  
pp. 3761-3767 ◽  
Author(s):  
A W Walter ◽  
M L Hancock ◽  
C H Pui ◽  
M M Hudson ◽  
J S Ochs ◽  
...  
Keyword(s):  
Risk Factors ◽  
Acute Lymphoblastic Leukemia ◽  
Brain Tumors ◽  
Lymphoblastic Leukemia ◽  
Low Grade ◽  
High Grade ◽  
Research Hospital ◽  
Dose Dependent

PURPOSE To evaluate the incidence of and potential risk factors for second malignant neoplasms of the brain following treatment for childhood acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS The study population consisted of 1,612 consecutively enrolled protocol patients treated on sequential institutional protocols for newly diagnosed ALL at St Jude Children's Research Hospital (SJCRH) between 1967 and 1988. The median follow-up duration is 15.9 years (range, 5.5 to 29.9 y). RESULTS The cumulative incidence of brain tumors at 20 years is 1.39% (95% confidence interval [CI], 0.63% to 2.15%). Twenty-two brain tumors (10 high-grade gliomas, one low-grade glioma, and 11 meningiomas) were diagnosed among 21 patients after a median latency of 12.6 years (high-grade gliomas, 9.1 years; meningiomas, 19 years). Tumor type was linked to outcome, with patients who developed high-grade tumors doing poorly and those who developed low-grade tumors doing well. Risk factors for developing any secondary brain tumor included the presence of CNS leukemia at diagnosis, treatment on Total X therapy, and the use of cranial irradiation, which was dose-dependent. Age less than 6 years was associated with an increased risk of developing a high-grade glioma. CONCLUSION This single-institution study, with a high rate of long-term data capture, demonstrated that brain tumors are a rare, late complication of therapy for ALL. We report many more low-grade tumors than others probably because of exhaustive long-term follow-up evaluation. The importance of limiting cranial radiation is underscored by the dose-dependent tumorigenic effect of radiation therapy seen in this study.

Discontinuation of Maintenance Tyrosine Kinase Inhibitors in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia outside of Transplant

2020 ◽  
pp. 1-8
Author(s):  
Bachar Samra ◽  
Hagop M. Kantarjian ◽  
Koji Sasaki ◽  
Ahmad S. Alotaibi ◽  
Marina Konopleva ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Median Duration ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Cell Transplant ◽  
Tki Discontinuation

<b><i>Background:</i></b> 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. <b><i>Methods:</i></b> 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. <b><i>Results:</i></b> At the time of TKI discontinuation, transcript level was undetected in 6 patients, &#x3c;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 (<i>p</i> = 0.096). <b><i>Conclusion:</i></b> 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.

scholarly journals Atherosclerotic risk factors and complications in patients with non-functioning adrenal adenomas treated with or without adrenalectomy: a long-term follow-up study

2009 ◽  
Vol 160 (4) ◽  
pp. 647-655 ◽  
Author(s):  
Márta Sereg ◽  
Ágnes Szappanos ◽  
Judit Tőke ◽  
Kinga Karlinger ◽  
Karolina Feldman ◽  
...  
Keyword(s):  
Risk Factors ◽  
Cardiovascular Effects ◽  
Vascular Events ◽  
Unilateral Adrenalectomy ◽  
Long Term Follow Up ◽  
Peripheral Arterial ◽  
Cerebrovascular Stroke ◽  
Atherosclerotic Risk Factors

ObjectiveDespite the increased prevalences of hypertension, type 2 diabetes mellitus (T2DM), hyperlipidemy, and obesity in patients with non-functioning adrenal adenomas (NFAAs), there is a paucity of data on long-term atherosclerotic morbidity as well as the long-term cardiovascular effects of adrenalectomy in these patients.Design, patients, and methodsThis retrospective study includes the results of baseline and follow-up investigations of 125 patients (29 males and 96 females; mean age 60.1 years) with NFAAs referred for endocrine evaluation between 1990 and 2001. Of the 125 patients, 47 underwent unilateral adrenalectomy, while 78 patients were followed conservatively. These patients were reinvestigated after a mean follow-up time of 9.1 (5–16) years in 2006, with special emphasis on laboratory and other atherosclerotic risk factors (ARF), vascular events, and interventions.ResultsThe prevalences of hypertension, impaired glucose tolerance or T2DM, hyperlipidemy, and obesity were 82, 43, 58, and 50%, and 89, 58, 82, and 50% at baseline and follow-up, respectively. None of the investigated ARF prevalences were different between patients treated and not treated with adrenalectomy, and between patients with and without subclinical Cushing's syndrome. The prevalences of angina pectoris, acute myocardial infarction, coronary, and peripheral arterial interventions or cerebrovascular stroke did not differ significantly between patients treated and not treated with adrenalectomy.ConclusionOur study confirms previous investigations reporting markedly increased prevalences of various ARF in patients with NFAAs. Adrenalectomy performed in these patients failed to decrease the prevalence of ARF and atherosclerotic morbidity.

scholarly journals Combined Inhibition of Bcl2 and Bcr-Abl1 Exercises Anti-Leukemia Activity but Does Not Eradicate the Primitive Leukemic Cells

2021 ◽  
Vol 10 (23) ◽  
pp. 5606
Author(s):  
Michele Massimino ◽  
Paolo Vigneri ◽  
Stefania Stella ◽  
Elena Tirrò ◽  
Maria Stella Pennisi ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Leukemic Cells ◽  
Proliferation And Apoptosis ◽  
Apoptosis Assay ◽  
Clonogenic Potential ◽  
Apoptotic Activity ◽  
Cells Death

Background: The management of Philadelphia Chromosome-positive (Ph+) hematological malignancies is strictly correlated to the use of BCR-ABL1 tyrosine kinase inhibitors (TKIs). However, these drugs do not induce leukemic stem cells death and their persistence may generate a disease relapse. Published reports indicated that Venetoclax, a selective BCL2 inhibitor, could be effective in Ph+ diseases, as BCL2 anti-apoptotic activity is modulated by BCR-ABL1 kinase. We, therefore, investigated if BCL2 inhibition, alone or combined with Nilotinib, a BCR-ABL1 inhibitor, affects the primitive and committed Ph+ cells survival. Methods: We used Ph+ cells isolated from leukemic patients at diagnosis. To estimate the therapeutic efficacy of BCL2 and BCR-ABL1 inhibition we employed long-term culture, proliferation and apoptosis assay. Immunoblot was used to evaluate the ability of treatment to interfere with the down-stream targets of BCR-ABL1. Results: Blocking BCL2, we observed reduced proliferation and clonogenic potential of CML CD34-positive cells and this cytotoxicity was improved by combination with BCR-ABL1 inhibitor. However, BCL2 inhibition, alone or in combination regiment with BCR-ABL1 inhibitor, did not reduce the self-renewal of primitive leukemic cells, while strongly induced cell death on primary Ph+ Acute Lymphoblastic Leukemia (ALL). Conclusion: Our results suggest that primitive CML leukemic cells are not dependent on BCL2 for their persistence and support that committed CML and Ph + ALL cells are dependent by BCL2 and BCR-ABL1 cooperation for their survival. The antileukemic activity of BCL2 and BCR-ABL1 dual targeting may be a useful therapeutic strategy for Ph+ ALL patients.

Treatment of Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia in Adults: A Broader Range of Options, Improved Outcomes, and More Therapeutic Dilemmas

2015 ◽  
pp. e352-e359 ◽  
Author(s):  
Adele K. Fielding
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Hematopoietic Stem ◽  
Improved Outcomes ◽  
Therapeutic Choice ◽  
Major Progress ◽  
Philadelphia Chromosome Positive

The article addresses selected key areas of flux in the management of Philadelphia chromosome–positive acute lymphoblastic leukemia. There is no doubt that tyrosine kinase inhibitors (TKIs) have made a major contribution to higher rates of complete remission and that more patients are now surviving long term. Many patients tolerate TKIs well, and remission can be achieved with minimal toxicity. Because remissions can include a proportion of patients who become BCR-ABL1 transcript negative, the question of whether allogeneic hematopoietic stem cell transplantation can be avoided requires discussion. Despite the major progress that has been made and the relative profusion of therapeutic choice compared with 10 years ago, evidence is still lacking for many of the major possible interventions, and how to combine them is unclear. Because of the rarity of the condition and the enticing possibility of increasing traction to therapy, clinical trials and international cooperation remain paramount.

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