Real-life analysis on safety and efficacy of asciminib for ponatinib pretreated patients with chronic myeloid leukemia.

Failure of second-generation tyrosine kinase inhibitors (2GTKI) is a challenging situation in patients with chronic myeloid leukemia (CML). Asciminib, recently approved by the US Federal Drug Administration, has demonstrated in clinical trials a good efficacy and safety profile after failure of 2GTKI. However, no study has specifically addressed response rates to asciminib in ponatinib pretreated patients (PPT). Here, we present data on responses to asciminib from 52 patients in clinical practice, 20 of them (38%) with prior ponatinib exposure. We analyzed retrospectively responses and toxicities under asciminib and compared results between PPT and non-PPT patients.After a median follow-up of 30 months, 34 patients (65%) switched to asciminib due to intolerance and 18 (35%) due to resistance to prior TKIs. Forty-six patients (88%) had received at least 3 prior TKIs. Regarding responses, complete cytogenetic response was achieved or maintained in 74% and 53% for non-PPT and PPT patients, respectively. Deeper responses such as major molecular response and molecular response 4.5 were achieved in 65% and 19% in non-PPT versus 32% and 11% in PPT, respectively. Two patients (4%) harbored the T315I mutation, both PPT.In terms of toxicities, non-PPT displayed 22% grade 3-4 TEAE versus 20% in PPT. Four patients (20% of PPT) suffered from cross-intolerance with asciminib as they did under ponatinib.Our data supports asciminib as a promising alternative in resistant and intolerant non-PPT patients, as well as in intolerant PPT patients; the resistant PPT subset remains as a challenging group in need of further therapeutic options.

Different methylation signatures at diagnosis in patients with high-risk myelodysplastic syndromes and secondary acute myeloid leukemia predict azacitidine response and longer survival.

BACKGROUND: Epigenetic therapy, using hypomethylating agents (HMA), is known to be effective in the treatment of high-risk myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) patients who are not suitable for intensive chemotherapy and/or allogeneic stem cell transplantation. However, response rates to HMA are low and there is an unmet need in finding prognostic and predictive biomarkers of treatment response and overall survival. We performed global methylation analysis of 75 patients with high-risk MDS and secondary AML who were included in CETLAM SMD-09 protocol, in which patients received HMA or intensive treatment according to age, comorbidities and cytogenetic. RESULTS: Unsupervised analysis of global methylation pattern at diagnosis did not allow patients to be differentiated according to the cytological subtype, cytogenetic groups, treatment response or patient outcome. However, after a supervised analysis we found a methylation signature defined by 200 probes, which allowed differentiating between patients responding and non-responding to azacitidine (AZA) treatment and a different methylation pattern also defined by 200 probes that allowed to differentiate patients according to their survival. On studying follow-up samples, we confirmed that AZA decreases global DNA methylation, but in our cohort the degree of methylation decrease did not correlate with the type of response. The methylation signature detected at diagnosis was not useful in treated samples to distinguish patients who were going to relapse or progress. CONCLUSIONS: Our findings suggest that in a subset of specific CpGs, altered DNA methylation patterns at diagnosis may be useful as a biomarker for predicting AZA response and survival.

Application of a digital PCR method for WT1 to myeloid neoplasms in CR and deep ELN WT1 molecular response (< 10 copies).

Bone marrow WT1 mRNA levels assessed by the ELN method are useful to establish prognostic correlations in myeloid malignancies treated with chemotherapy or hematopoietic stem cell transplantation (HCT). Those patients with WT1 levels below ten copies have a good outcome. However, some of these patients relapse. To further characterize this group of cases, we applied a new and sensitive digital (ddPCR) WT1 method. A consecutive series of 49 patients with treated myeloid malignancies and with an ELN WT1 quantitation of < 10 copies were included in the study. All cases (47 AML and 2 MDS) have received intensive chemotherapy or HCT. One to four micrograms of total RNA were retrotranscribed to obtain ≥ 10,000 ABL1 copies using the ELN protocol. Only those cases with a good quality cDNA were used in the ddPCR WT1 test. The ddPCR Gene Expression WT1 Assay of Bio-Rad© was used to perform the PCR amplification, and the microdroplets were quantified in the Bio-Rad's QX200 droplet reader. Eighteen patients showed a negative WT1 ddPCR assay (0 copies/µl), whereas 31 cases were positive (results ranged from 1 to 15.2 copies/µl). Survival analysis showed statistically significant differences in terms of OS between both groups, 83 ± 8% vs. 46 ± 9% (p = 0.024). A statistically significant correlation was also found between ddPCRWT1 results and CD123+ cell number detected by flow cytometry (p = 0.024). Larger series of patients tested with the current ddPCRWT1 method will solve whether it could be used to stratify patients with myeloid malignancies achieving deep WT1 molecular response (< 10 copies).

Linfoma cutáneo de células B de la zonamarginal y sarcoidosis: presentación simultánea / Cutaneous marginal zone B-cell lymphoma and sarcoidosis: simultaneous presentation

El síndrome sarcoidosis-linfoma es la asociación en un mismo paciente de sarcoidosis y un linfoma. Describimos un paciente de 32 años que acude por tres lesiones nodulares cuya biopsia es diagnóstica de linfoma cutáneo de células B de la zona marginal. Durante el estadiaje se detectaron adenopatías mediastínicas cuya biopsia mostró granulomas no necrotizantes compatibles con sarcoidosis. Este sería el primer caso descrito que asocia linfoma cutáneo B de la zona marginal con sarcoidosis de forma simultánea (AU)

The sarcoidosis-lymphoma syndrome is the coexistence of sarcoidosis and malignant lymphoproliferative disease in the same patient. We describe a 32-year-old man who presented with three cutaneous nodular lesions. Skin biopsies revealed marginal zone cutaneous B-cell lymphoma. Radiologic Studies showed hiliar lymphadenopathy that histologically revealed non-caseating granulomas consistent with sarcoidosis. This report is the first case of simultaneous ocurrente in the same patient of primary cutaneous marginal zone B cell lymphoma and sarcoidosis (AU)