Nancy Pennell

KIT Gene Mutations and Patterns of Protein Expression in Mucosal and Acral Melanoma

Background: Recently characterized KIT (CD117) gene mutations have revealed new pathways involved in melanoma pathogenesis. In particular, certain subtypes harbor mutations similar to those observed in gastrointestinal stromal tumors, which are sensitive to treatment with tyrosine kinase inhibitors. Objective: The purpose of this study was to characterize KIT gene mutations and patterns of protein expression in mucosal and acral melanoma. Methods: Formalin-fixed, paraffin-embedded tissues were retrieved from our archives. Histologic assessment included routine hematoxylin-eosin stains and immunohistochemical staining for KIT. Genomic DNA was used for polymerase chain reaction-based amplification of exons 11 and 13. Results: We identified 59 acral and mucosal melanoma cases, of which 78% showed variable levels of KIT expression. Sequencing of exons 11 and 13 was completed on all cases, and 4 (6.8%) mutant cases were isolated. Conclusion: We successfully optimized conditions for the detection of KIT mutations and showed that 8.6% of mucosal and 4.2% of acral melanoma cases at our institution harbor KIT mutations; all mutant cases showed strong, diffuse KIT protein expression. Our case series represents the first Canadian study to characterize KIT gene mutations and patterns of protein expression in acral and mucosal melanoma.

Management of newly diagnosed high-risk and intermediate-risk follicular lymphoma with 90Y ibritumomab tiuxetan in a phase II study

Five‐year overall survival for high‐risk Follicular Lymphoma International Prognostic Index follicular lymphoma is only approximately 50% compared with 90% for low risk. To evaluate an approach to improve upon this poor outcome, we completed an exploratory phase II trial of intensified treatment for patients with intermediate and high‐risk follicular lymphoma. Front‐line treatment with chemo‐immunotherapy consisting of rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone was followed by radio‐ immunotherapy with 90‐Yttrium ibritumomab tiuxetan consolidation, and 2 years of rituximab maintenance. The 5‐year overall survival for intermediate and high‐risk patients was 88% and 83%, respectively. Of 33 enrolled patients, 3 were off study before receiving radio‐immunotherapy. Three months post radio‐immunotherapy, 28/33 (85%) patients had achieved complete response including 6 patients who had only a partial response to chemo‐immunotherapy and converted to complete response after radio‐immunotherapy. The 5‐year progression‐free survival for intermediate and high risk was 79% and 58%, respectively. Nine of 19 patients with molecular markers patients remain in molecular and clinical complete remission with a median follow‐up of 48 months (range 3‐84 months). Post radio‐immunotherapy, hematologic toxicities were mostly grade 1 and 2. However, asymptomatic grade 3 or 4 thrombocytopenia and neutropenia occurred in 11%‐36% and 10%‐24% of patients, respectively. Myelodysplastic syndrome occurred in 1 patient 4 years post treatment. Whereas many patients had prolonged B‐cell reduction and low immunoglobulin levels post treatment, previous immunities to rubella were maintained. More aggressive upfront approaches such as this may benefit higher risk follicular lymphoma, but confirmatory trials are required. http://www.clinicaltrials.gov: NCT01446562.

Autologous stem cell transplant and combination immunotherapy of rituximab and interferon-α induces prolonged clinical and molecular remissions in patients with follicular lymphoma

ogy, 24, 2108–2112. Rutherford, S.C., Li, V., Ghione, P., Chen, Z., Martin, P. & Leonard, J.P. (2017) Bone marrow biopsies do not impact response assessment for follicular lymphoma patients treated on clinical trials. British Journal of Haematology, 179, 242– 245. Solal-Celigny, P., Roy, P., Colombat, P., White, J., Armitage, J.O., Arranz-Saez, R., Au, W.Y., Bellei, M., Brice, P., Caballero, D., Coiffier, B., Conde-Garcia, E., Doyen, C., Federico, M., Fisher, R.I., Garcia-Conde, J.F., Guglielmi, C., Hagenbeek, A., Haioun, C., LeBlanc, M., Lister, A.T., Lopez-Guillermo, A., McLaughlin, P., Milpied, N., Morel, P., Mounier, N., Proctor, S.J., Rohatiner, A., Smith, P., Soubeyran, P., Tilly, H., Vitolo, U., Zinzani, P.L., Zucca, E. & Montserrat, E. (2004) Follicular lymphoma international prognostic index. Blood, 104, 1258–1265. Wohrer, S., Jaeger, U., Kletter, K., Becherer, A., Hauswirth, A., Turetschek, K., Raderer, M. & Hoffmann, M. (2006) 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) visualizes follicular lymphoma irrespective of grading. Annals of Oncology, 17, 780–784.

PROLONGED MOLECULAR AND CLINICAL REMISSIONS IN FOLLICULAR LYMPHOMA PATIENTS TREATED WITH HDT/ASCT AND COMBINATION IMMUNOTHERAPY WITH RITUXIMAB AND INTERFERON α

underwent 1 line of therapy prior to R‐DHAP/Ox, 11 (22.9%) underwent 2 lines of therapy, and 3 (6.3%) had 3 or more lines before R‐DHAP/Ox. The median TTNT from first‐line was 14.3 months (range 10.6‐19.4). With a median follow‐up of 66 months, the 5‐year OS was 73.1% (95% CI, 61‐85%). Among the 34 patients that underwent ASCT, the 5‐year OS was 84% (95% CI, 72‐98%). Time to next treatment (TTNT) after DHAP/Ox was 30.9 months (95% CI, 18‐47%). Stem cell collection failure was reported in 6 cases (12.5%). Four cases (8.3%) of transformation to DLBCL and 3 (6.2%) secondary malignancies (2 myeloid disorders, 1 bladder carcinoma) were reported. Conclusions: In this population of high‐risk, early relapsing FL, R‐ DHAP/Ox +/− ASCT was found to be active, with aTTNT significantly longer than that experienced following first‐line therapy. This population had very similar FLIPI risk scores compared to the LymphoCare study population but appears to have experienced better survival outcomes. Late events continue to occur, and cure appears unlikely. Prospective studies of R‐DHAP/Ox +/− ASCT are warranted in this high‐risk FL population.