Minor Erythroid Response and Decreased WT1 Expression After Proteasome Inhibition by Bortezomib in Myelodysplastic Syndromes (GIMEMA MDS0104 Phase II Trial).
Authors: Breccia Massimo , Latagliata Roberto , Cannella Laura , Carmosino Ida , Gottardi Enrico , Cilloni Daniela , Vignetti Marco , Santopietro Michelina , Mancini Marco , Alimena Giuliana 
Published: October 2019

Abstract
Abstract 1777
Poster Board I-803

Introduction
The proteasome, a multicatalytic enzyme complex, plays an important role in the activation of nuclear factor kappa B (NF-kB), through degradation of its suppressor IkB. NF-kB can intervene in oncogenesis with its capacity to regulate the expression of genes that modulate apoptosis, cell survival as well as proliferation, inflammation, angiogenesis and tumour metastasis. Bortezomib (Velcade, formerly PS-341) is a proteasome inhibitor with documented antitumor activity in multiple myeloma and other lymphoid malignancies and has also been investigated in myeloid malignancies, such as acute leukemias (AL) and myelodysplastic syndromes (MDS), indicating some therapeutic activities. We performed a Phase II study (EudraCT number 2004-002935-23) to investigate the efficacy and safety of bortezomib in patients with MDS. Patients and methods: Ten patients were enrolled in the study: there were 6 females and 4 males, median age was 64 years (range 44-70), median duration of MDS phase was 12 months. All patients but one received prior erythropoietin therapy without efficacy. 8/10 patients required transfusional therapy at the time of enrolment (median 4 units per month).

Results
According to WHO classification, 5 patients were refractory cytopenia with multilineage dysplasia (RCMD), 1 patient was pure refractory anemia (RA), 1 patient was RCMD with ringed sideroblasts (RCMD-RS), 3 patients were refractory anemia with excess of blasts type 1 (RAEB-1). According to IPSS stratification, 5 patients were classified as low risk, 3 patients as intermediate-1 and 2 patients as intermediate-2 risk. Six patients presented cytogenetic aberrations at baseline (isolated del(5q), 2 patients; del(5q) plus t(3;12), 1 patient; del(5q) and monosomy 7, 1 patient, isolated trisomy 8, 1 patient; trisomy 8 and trisomy 11, 1 patient). WT1 gene expression was tested in all cases: 9/10 patients displayed elevated WT1 expression level in bone marrow (median 219 copies, range 20-2682) and 7/10 also in peripheral blood (median 31 copies, range 11-2247). Bortezomib was administered at the dose of 1.3 mg/mq with a 1, 4, 8, 11 day schedule, every 28 days, for a maximum of 8 cycles. Four patients discontinued therapy after 1, 3, 3 and 4 cycles respectively, due to vascular disease not related to the drug in the first two cases and to disease progression in the other two (both patients with intermediate-2 risk), whereas 6 patients performed all planned eight cycles.
As to safety, grade 3/4 neutropenia was recorded in 4 patients and grade 3/4 thrombocytopenia in 6 patients. Non-hematological side effects were recorded in 7 patients: diarrhea in 1 patient, fever in 3 patients, skin rash in 2 patients and pneumonia in 1 patient during neutropenic phase. As to response, 3 patients (50% of evaluable cases) achieved a minor erythroid response (according to IWG criteria) and 3 patients had a stable disease. We did not reveal modifications as to bone marrow blasts and cytogenetic changes with respect to pre-treatment findings. As to outcome, 7/10 patients are still alive at a median follow-up of 24 months. WT1 decrease was recorded in the 3 patients with minor erythroid response, both in bone marrow (from median 109 copies to median 14 copies at the end of treatment) and in peripheral blood (from median 70 copies to median 9 copies at the end of treatment), and in 1 patient with stable disease. In the remaining patients with stable disease, median bone marrow WT1 copies increased from 659 copies at baseline to 890 copies at the end of treatment, and to median 736 copies at baseline to 788 copies at the end of treatment in peripheral blood.

Conclusions
Present results indicate that bortezomib as single agent in MDS, seems to have some efficacy in terms of hematological improvement and to also affect the WT1 gene expression. Further studies on larger series of MDS patients are needed to confirm our observation. The combined use of this drug with other agents might potentiate its therapeutic activity.

Disclosures
No relevant conflicts of interest to declare.