Ponatinib and Chemotherapy in Adults with De Novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia. Final Results of Ponalfil Clinical Trial

Background and objective. The combination of HyperCVAD and ponatinib resulted in a high molecular response rate and survival in adults with Ph+ ALL, suggesting improved outcome compared with combinations of chemotherapy with first- or second-generation tyrosine kinase inhibitors (TKI) (Jabbour E, et al, Lancet Haematol. 2018;5:e618-e627). The Spanish PETHEMA group conducted the phase 2 PONALFIL trial, which incorporates ponatinib to the same chemotherapy as that of the ALL Ph08 trial that used imatinib as TKI (Ribera JM et al. Cancer 2019;125:2810-17). Final results of this trial are reported. Patients and method. PONALFIL trial (NCT02776605) combined ponatinib (30 mg/d) and induction chemotherapy (vincristine, daunorubicin, prednisone) followed by consolidation (high-dose methotrexate, high-dose ARA-C, mercaptopurine, etoposide) and allogeneic hematopoietic stem cell transplantation (alloHSCT). Ponatinib was scheduled after alloHSCT only for patients (pts) with persistence/reappearance of MRD. Response to therapy (complete morphological [CR], molecular [complete -CMR- or major -MMR-] after induction and before alloHSCT) (assessed by centralized BCR-ABL1/ABL1 ratio), disease-free survival (DFS), overall survival [OS]) and toxicity were analyzed. The following genetic studies were performed: 1. Additional gene abnormalities (Copy Number Alteration [CNA] analysis by SNP array Affymetrix 750K), 2. ABL1 mutation status at diagnosis (Sanger sequencing), 3. T315I mutation at diagnosis (allele-specific PCR). A propensity score comparison with the results of the ALL Ph08 trial was performed. Results. Median age was 49 (19-59) years (y), and 13/30 pts were female. One pt showed CNS involvement at diagnosis. ECOG score was <2 in 90% of pts. Median WBC count was 6.4 x10 9/L (0.6-359.3), Hb 90 g/L (63-145), platelets 38 x10 9/L (11-206). Immunologic phenotype was common in 26 cases, with p190 isoform in 20 pts (67%), p210 in 9 (30%) and p230 in 1 (3%). CR was attained in 30/30 pts, CMR in 14/30 (47%), MMR in 5/30 (17%) and no molecular response in 11/30 (37%). Two pts withdrew the trial during induction (thrombosis of central retina artery and severe intestinal infection, one case each). Consolidation was given to 28 pts, 2 pts withdrew the trial (physician's decision and lack of molecular response, one case each) and 26 pts received alloHSCT (20 in CMR, 6 in MMR). No relapses before HSCT were detected. One pt died by severe GVHD and two withdrew the trial (grade IV hepatic toxicity:1, protocol deviation after molecular relapse:1). One pt relapsed in BM after HSCT. Ponatinib was given after HSCT in 4/26 pts and dasatinib in 1/26 due to MRD reappearance, and 1/26 received dasatinib in CMR because of refusal to receive CNS prophylaxis, whereas 20/26 pts did not receive any TKI therapy after HSCT. Twenty-nine pts are alive (median follow-up 2.3y, range 1.3-4). 2y DFS and OS probabilities were 97% (91%-100%) and 97% (91%-100%) (Figure 1). Among 7/16 pts without CMR after consolidation and genetic material available, 4 showed IKZF1 deletion (IKZF1 plus in 2), 1 showed CDKN2A/B and PAX5 deletion and 2 did not show any CNA. Among 5/19 pts with molecular relapse, 3 showed IKZF1 deletion (1 being IKZF1 plus), and 2 pts did not show any CNA. No ABL1 mutations or T315I mutation at diagnosis were found. Propensity score with 1:1 matching identified 30 pts in each cohort (variables: age, gender, ECOG, WBC, CNS involvement, cytogenetic risk and BCR/ABL isoform). 2y DFS rates for PONALFIL and ALL Ph08 trials were 97% and 62%, (p=0.005), and 2y OS rates were 97% and 66% (p=0.001) (Figure 2). 107 adverse events (AE) were registered in 20 pts (21 severe in 11 pts), prompting to withdrawn of the trial in 3 (thrombosis of central retina artery, severe bowel infection, grade IV hepatic toxicity). The most frequent AE were hematologic (28%), gastrointestinal (14%), hepatic (11%), infections (7%), and cutaneous (5%). Cardiovascular events occurred in 2 patients (angor pectoris and thrombosis of central artery of the retina). Conclusions. The results of the PONALFIL trial show a high antileukemic efficacy with acceptable toxicity profile and compare favorably with the same chemotherapy schedule and imatinib. Supported in part by grant 2017 SGR288 (GRC) Generalitat de Catalunya and "La Caixa" Foundation. Figure 1. OS (A) and DFS (B). PONALFIL. Figure 2. OS (A) and DFS (B). PONALFIL vs. ALL Ph08. Figure 1 Figure 1. Disclosures Ribera: AMGEN: Consultancy, Research Funding, Speakers Bureau; NOVARTIS: Consultancy, Speakers Bureau; TAKEDA: Consultancy, Research Funding, Speakers Bureau; ARIAD: Consultancy, Research Funding, Speakers Bureau; SHIRE: Consultancy, Speakers Bureau; Pfizer: Consultancy, Research Funding, Speakers Bureau. Esteve: Novartis: Consultancy, Research Funding; Pfizer: Consultancy; Abbvie: Consultancy; Bristol Myers Squibb/Celgene: Consultancy; Novartis: Research Funding; Jazz: Consultancy; Astellas: Consultancy. Mercadal: Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead Sciences, Inc.: Honoraria, Speakers Bureau. Martínez-López: Roche, Novartis, Incyte, Astellas, BMS: Research Funding; Janssen, BMS, Novartis, Incyte, Roche, GSK, Pfizer: Consultancy. OffLabel Disclosure: This trial includes Ponatinib in off-label indication.

Structural and functional features of the central retina and improvement of surgical treatment of patients with diabetic macular edema and epiretinal membrane

Purpose. Improving the efficiency of surgical treatment of patients with diabetic macular edema and epiretinal membrane. Material and methods. Clinical studies were based on the analysis of morphological and functional parameters of the central retina. Patients with diffuse diabetic macular edema (DME) and epiretinal membrane (ERM) made up group A (main) of 96 people (96 eyes). Group B (control) included 22 patients (44 eyes) without ophthalmological diseases. Depending on the chosen method of surgical treatment, patients in group A were divided into three subgroups. Results. According to the data of optical coherence tomography, it was revealed that the average index of retinal thickness as a result of edema increased by 1.35 times (p=0.011) compared with group B. When conducting microperimetry in the macular zone in patients of group A, the total light sensitivity was reduced in 1.88 times compared with group B (p=0.028). Comparative analysis of long-term results of surgical treatment of patients with DMO and ERM showed that complex simultaneous vitrectomy and administration of an angiogenesis inhibitor is preferable compared to delayed administration of drugs, which is confirmed by a decrease in the total thickness of the retina in 78.3% of cases, preservation of the total photosensitivity of the central part of the retina on average, up to 15.3±3.24 dB, visual acuity - up to 0.51±0.22, no recurrence of edema in 63.4% of patients and the development of ERM - in 100% of cases. Conclusion. If the central thickness of the retina at the preoperative stage is less than 400 microns, it is possible to use a step-by-step method (vitrectomy + intravitreal administration of an angiogenesis inhibitor after 1 month). The use of the proposed one-step operation technique is preferable when the retina thickness is more than 400 microns. Vitrectomy with peeling of the internal limiting membrane in patients with cysts in the retinal edema zone with a diameter of more than 200 µm does not lead to a positive anatomical and functional result. Key words: diabetic macular edema, angiogenesis inhibitor, vitrectomy, microperimetry, epiretinal membrane.

MRI-based 3D retinal shape determination

ObjectiveTo establish a good method to determine the retinal shape from MRI using three-dimensional (3D) ellipsoids as well as evaluate its reproducibility.Methods and analysisThe left eyes of 31 volunteers were imaged using high-resolution ocular MRI. The 3D MR-images were segmented and ellipsoids were fitted to the resulting contours. The dependency of the resulting ellipsoid parameters on the evaluated fraction of the retinal contour was assessed by fitting ellipsoids to 41 different fractions. Furthermore, the reproducibility of the complete procedure was evaluated in four subjects. Finally, a comparison with conventional two-dimensional (2D) methods was made.ResultsThe mean distance between the fitted ellipsoids and the segmented retinal contour was 0.03±0.01 mm (mean±SD) for the central retina and 0.13±0.03 mm for the peripheral retina. For the central retina, the resulting ellipsoid radii were 12.9±0.9, 13.7±1.5 and 12.2±1.2 mm along the horizontal, vertical and central axes. For the peripheral retina, these radii decreased to 11.9±0.6, 11.6±0.4 and 10.4±0.7 mm, which was accompanied by a mean 1.8 mm posterior shift of the ellipsoid centre. The reproducibility of the ellipsoid fitting was 0.3±1.2 mm for the central retina and 0.0±0.1 mm for the peripheral retina. When 2D methods were used to fit the peripheral retina, the fitted radii differed a mean 0.1±0.1 mm from the 3D method.ConclusionAn accurate and reproducible determination of the 3D retinal shape based on MRI is provided together with 2D alternatives, enabling wider use of this method in the field of ophthalmology.

Effect of long-term hyperglycemia on cornea and retina morphology in rats with streptozotocin-induced diabetes mellitus

Цель исследования - изучение динамики морфологических изменений роговицы и заднего отдела глаза крыс при длительной гипергликемии. Методика. Исследование выполнено на 36 самцах крыс Wistar. Сахарный диабет индуцировали внутрибрюшинной инъекцией стрептозотоцина (65 мг/кг), после чего ежедневно вводили подкожно малые дозы инсулина (2 ЕД/кг). На 50-е, 58-е и 66-е сут эксперимента производили энуклеацию глаз у глубоко наркотизированных животных. Гистологические срезы фрагментов глаз окрашивали гематоксилин-эозином, проводили морфометрию параметров роговицы и сетчатки. Результаты. Средняя концентрация глюкозы и кетоновых тел крови в группе сахарного диабета составила 29,8 ммоль/л и 0,889 ммоль/л, в контрольной группе - 6,2 ммоль/л и 0,847 ммоль/л соответственно. Анализ гистологических срезов глаз выявил признаки отека роговицы, хориоидеи и наружных слоев центральных отделов сетчатки до появления других качественных и количественных морфологических изменений. Заключение. Оценка толщины роговицы, хориоидеи и наружных слоев центральных отделов сетчатки может служить предиктором развития диабетической ретинопатии. The aim was to study morphological changes in the cornea and the posterior part of rat eye during prolonged hyperglycemia. Methods. The study was performed on 36 Wistar male rats. Diabetes mellitus was induced by an injection of streptozotocin (65 mg/kg, i.p.) followed by daily injections of low doses of insulin (2 U/kg, s.c.). Eyes were enucleated from deeply anesthetized rats on days 50, 58, and 66 of the experiment. Histologic sections were stained with hematoxylin-eosin, and morphometry of the cornea and the retina was performed. Results. Mean blood concentrations of glucose and ketone bodies were 29.8 mmol/L and 0.889 mmol/L, respectively, in the diabetic group and 6.2 mmol/L and 0.847 mmol/L, respectively, in the control group. The histological analysis revealed signs of edema in the cornea, choroid and outer layers of the central retina, which preceded other morphological changes. Conclusion. Evaluating thickness of the cornea, choroid and outer layers of the central retina may serve for prediction of diabetic retinopathy.

Sildenafil-evoked photoreceptor oxidative stress in vivo is unrelated to impaired visual performance in mice

Purpose The phosphodiesterase inhibitor sildenafil is a promising treatment for neurodegenerative disease, but it can cause oxidative stress in photoreceptors ex vivo and degrade visual performance in humans. Here, we test the hypotheses that in wildtype mice sildenafil causes i) wide-spread photoreceptor oxidative stress in vivo that is linked with ii) impaired vision. Methods In dark or light-adapted C57BL/6 mice ± sildenafil treatment, the presence of oxidative stress was evaluated in retina laminae in vivo by QUEnch-assiSTed (QUEST) magnetic resonance imaging, in the subretinal space in vivo by QUEST optical coherence tomography, and in freshly excised retina by a dichlorofluorescein assay. Visual performance indices were also evaluated by QUEST optokinetic tracking. Results In light-adapted mice, 1 hr post-sildenafil administration, oxidative stress was most evident in the superior peripheral outer retina on both in vivo and ex vivo examinations; little evidence was noted for central retina oxidative stress in vivo and ex vivo. In dark-adapted mice 1 hr after sildenafil, no evidence for outer retina oxidative stress was found in vivo. Evidence for sildenafil-induced central retina rod cGMP accumulation was suggested as a panretinally thinner, dark-like subretinal space thickness in light-adapted mice at 1 hr but not 5 hr post-sildenafil. Cone-based visual performance was impaired by 5 hr post-sildenafil and not corrected with anti-oxidants; vision was normal at 1 hr and 24 hr post-sildenafil. Conclusions The sildenafil-induced spatiotemporal pattern of oxidative stress in photoreceptors dominated by rods was unrelated to impairment of cone-based visual performance in wildtype mice.

Vitelliform changes in the central retina occurring in adults

Introduction. Vitelliform lesions of the central retinal area in adult patients represent a heterogeneous group of diseases. This article describes different variants of vitelliform changes in adults, based on the published literature data. Materials and methods. We have analyzed and described different variants of vitelliform changes in adults, based on literature data, examples from own clinical practice using multimodal approach are included. Discussion. Vitelliform lesions of the central retinal area are can debut at various ages, occurring in mono- or multifocal way, have various stages of degradation of vitelliform material, masquerading as other lesions of the macular area and of the posterior pole. Many of these diseases appear due to mutations in determined genes, though, a fairly large proportion of cases is considered to be sporadic. Nowadays, characteristic signs of different diseases with the vitelliform material are described. But differential diagnosis with other similar diseases (some age-related macular degeneration forms and those of central serous chorioretinopathy) is fairly difficult and requires a multimodal ophthalmologic approach, and in some cases genetic studies. Conclusions. Vitelliform lesions of the central retinal area, occurring in adult patients are a group of diseases that are difficult to diagnose and masquerade themselves as other diseases of the central retina, which requires certain doctors knowledge and ability to carry out a multimodal imaging and prescribe the appropriate treatment if needed.