Midostaurin improves quality of life and mediator-related symptoms in advanced systemic mastocytosis

Background: Advanced systemic mastocytosis (advSM) is characterized by presence of the KIT D816V mutation and pathologic accumulation of neoplastic mast cells (MCs) in various tissues, leading to severe symptoms and organ damage (eg, cytopenias, liver dysfunction, portal hypertension, malabsorption, and weight loss). Treatment with midostaurin, an orally active multikinase/KIT inhibitor now approved for advSM in the United States and the European Union, resulted in a high rate of response accompanied by reduced MC infiltration of the bone marrow and lowered serum tryptase level. Objective: We aimed to determine whether midostaurin improves health-related quality of life (QOL) and MC mediator related symptoms in patients with advSM. Methods: In 116 patients with systemic mastocytosis (89 patients with advSM fulfilling the strict inclusion criteria of the D2201 study [ClinicalTrials.gov identifier NCT00782067]), QOL and symptom burden were assessed during treatment with midostaurin by using the 12-Item Short-Form Health Survey (SF-12) and the Memorial Symptom Assessment Scale patient reported questionnaires, respectively. MC mediator related symptoms were evaluated by using a specific physician-reported questionnaire Results: Over the first 6 cycles of treatment with midostaurin (ie, 6 months), patients experienced significant improvements in total SF-12 and Memorial Symptom Assessment Scale scores, as well as in subscores of each instrument. These improvements were durable during 36 months of follow-up. Similarly, we found substantial improvements (67%-100%) in all MC mediator related symptoms. Conclusion: QOL and MC mediator related symptoms significantly improve with midostaurin treatment in patients with advSM (ClinicalTrials.gov identifier, NCT00782067)

Safety and efficacy of switching to nilotinib 400 mg twice daily for patients with chronic myeloid leukemia in chronic phase with suboptimal response or failure on frontline imatinib or nilotinib 300 mg twice daily.

In a randomized, phase III trial of nilotinib versus imatinib in patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase, more patients had suboptimal response or treatment failure on front-line imatinib than on nilotinib. Patients with suboptimal response/treatment failure on imatinib 400 mg once or twice daily or nilotinib 300 mg twice daily could enter an extension study to receive nilotinib 400 mg twice daily. After a 19-month median follow up, the safety profile of nilotinib 400 mg twice daily in patients switching from imatinib (n=35) was consistent with previous reports, and few new adverse events occurred in patients escalating from nilotinib 300 mg twice daily (n=19). Of patients previously treated with imatinib or nilotinib 300 mg twice daily, respectively, 15 of 26 (58%) and 2 of 6 (33%) without complete cytogenetic response at extension study entry, and 11 of 34 (32%) and 7 of 18 (39%) without major molecular response at extension study entry, achieved these responses at any time on nilotinib 400 mg twice daily. Estimated 18-month rates of freedom from progression and overall survival after entering the extension study were lower for patients switched from imatinib (85% and 87%, respectively) versus nilotinib 300 mg twice daily (95% and 94%, respectively). Nilotinib dose escalation was generally well tolerated and improved responses in about one-third of patients with suboptimal response/treatment failure. Switch to nilotinib improved responses in some patients with suboptimal response/treatment failure on imatinib, but many did not achieve complete cytogenetic response (clinicaltrials.gov identifiers: 00718263, 00471497 - extension)

Abundant in vitro expression of the oncofetal ED-B-containing fibronectin translates into selective pharmacodelivery of 131I-L19SIP in a prostate cancer patient

Purpose: The extradomain B of fibronectin (ED-B) is a promising vascular target for selective pharmacodelivery in cancer patients. We analyzed a large series of prostatectomies from patients with prostate cancer, hyperplastic prostate disease, and normal prostates to study extent and tumor-selectivity of ED-B expression. Methods: Using immunohistology, 68 adenocarcinomas of the prostate or prostate cancer-inflicted lymph nodes, 4 samples of benign prostatic hyperplasia, and 6 normal prostate glands were studied for ED-B expressing newly formed blood vessels. Further, we treated an advanced prostate cancer patient with the anti-ED-B antibody 131I-L19SIP to study in vivo target accessibility. Results: ED-B-positive blood vessels were found significantly more frequent in prostate cancers as compared with peritumoral prostate tissues or normal prostate glands, independent of tumor differentiation. The ED-B-positive blood vessels' density was 97 (±23), 65 (±9), and 59 (±9)/mm2 in G3, G2, and G1 prostate cancers, respectively, and 7 (±5)/mm2 in normal prostate glands. In high-grade (G3) prostate cancers, also the peritumoral tissue showed a higher density of ED-B vessels than normal prostate glands. Similar results were obtained when ED-B-positive vessel density was expressed as a fraction of CD34-positive vessel density. Finally, selective uptake of ED-B-binding 131I-L19SIP to tumor lesions was found in an advanced prostate cancer patient by whole-body planar scintigraphy. Conclusions: ED-B-positive blood vessels were found to a large extent in prostate cancer tissues, but only rarely in normal prostates or benign prostatic hyperplasia. Whole-body planar scintigraphy in a prostate cancer patient confirmed selective uptake of 131I-L19SIP in the prostate cancer tissues, qualifying ED-B as a promising target for selective pharmacodelivery of anticancer agents in prostate cancer. © 2013 Springer-Verlag Berlin Heidelberg

Radioimmunotherapy with radretumab in patients with relapsed hematologic malignancies

We present here a systematic analysis of lymphoma and MM patients recruited into 2 clinical trials or treated with radretumab according to compassionate use, describing the biodistribution, dosimetry, safety, and clinical activity of radretumab. Methods: Uptake in lymphoma lesions, safety, and clinical activity of radretumab radioimmunotherapy (R-RIT) were evaluated in 18 relapsed lymphoma or multiple myeloma patients. Results: In 14 of 18 patients, selective tumor uptake was found; 11 of 15 lymphoma patients, including 9 of 11 with Hodgkin lymphoma (HL), were eligible for R-RIT (a priori criteria-based target-tobone marrow ratio > 10:1 for EudraCT no. 2005-000545 or > 4:1 for EudraCT no. 2007-007241-12 at dosimetric imaging). Two HL and 1 diffuse large B cell lymphoma patient achieved complete response; 1 HL patient had partial response. Both multiple myeloma patients receiving R-RIT experienced stabilization of disease. Therefore, the overall objective response rate was 40%. Uncomplicated grade 3-4 thrombocytopenia or leukocytopenia was observed in 5 R-RIT patients, lasting 4-129 d. Conclusion: R-RIT showed a favorable benefit and risk profile in advanced relapsed lymphoma patients and induced complete response in 2 heavily pretreated, relapsed HL patients and in 1 diffuse large B cell lymphoma patient. These results warrant further exploration of R-RIT in larger phase II clinical trials. Copyright © 2012 by the Society of Nuclear Medicine, Inc

Expression of the oncofetal ED-B-containing fibronectin isoform in hematologic tumors enables ED-B-targeted 131I-L19SIPradioimmunotherapy in Hodgkin lymphoma patients

Current treatment of hematologic malignancies involves rather unspecific chemotherapy, frequently resulting in severe adverse events. Thus, modern clinical research focuses on compounds able to discriminate malignant from normal tissues. Being expressed in newly formed blood vessels of solid cancers but not in normal mature tissues, the extradomain B of fibronectin (ED-BFN) is a promising target for selective cancer therapies. Using immunohistology with a new epitope retrieval technique for paraffin-embedded tissues, ED-B FN expression was found in biopsies from more than 200 Hodgkin and non-Hodgkin lymphoma patients of nearly all entities, and in patients with myeloproliferative diseases. ED-B FN expression was nearly absent in normal lymph nodes (n = 10) and bone marrow biopsies (n = 9). The extent of vascular ED-B FN expression in lymphoma tissues was positively correlated with grade of malignancy. ED-B FN expression was enhanced in lymph nodes with severe lymphadenopa-thy and in some hyperplastic tonsils. The in vivo accessibility of ED-B FN was confirmed in 3 lymphoma patients, in whom the lymphoma lesions were visualized on scintigra-phy with 131I-labeled L19 small immunopro-tein ( 131I-L19SIP). In 2 relapsed Hodgkin lymphoma patients, 131I-L19SIP radioimmu-notherapy induced a sustained partial response, qualifying ED-B FN as a promising target for antibody-based lymphoma therapies. copyright 2007 by The American Society of Hematology