Lenalidomide and metronomic melphalan for CMML and higher risk MDS: A phase 2 clinical study with biomarkers of angiogenesis

Abstract

Metronomic, low dose chemotherapy may have anti-angiogenic effects and augment the effects of lenalidomide in MDS and CMML. We evaluated the clinical efficacy, tolerability and anti-angiogenic effects of melphalan 2mg and lenalidomide 10mg for 21 days/28 in CMML (n=12) and higher risk MDS (n=8) patients in a prospective phase II study. The primary endpoint was overall response and secondary endpoints included survival, progression-free survival, toxicity and biomarkers of angiogenesis. The median age was 73 years, 55% were pretreated and transfusion dependent. The overall response rate was 3(15%) of 19 evaluable patients but 25% in CMML and 33% in pCMML. Dose reductions and/or delays were common due to myelosuppression. Transient spikes in circulating endothelial cells that declined below baseline were seen in responders and patients with CMML, suggesting anti-angiogenic activity. In conclusion, lenalidomide and metronomic low dose melphalan demonstrate signals of clinical and possible anti-angiogenic activity in patients with pCMML that require future validation. This trial was registered at clinicaltrial.gov under # NCT00744536.

Effects of thalidomide on growth and VEGF-A expression in SW480 colon cancer cells

“…Therefore, the formation of new capillaries was also reduced. This may be associated with the THD-induced downregulation of VEGF (51,52). At the same time, THD was able to block the NF-κB signaling pathway, its downstream adhesion molecules and the expression of inflammatory mediators including TNF-α (53).…”

Simultaneous Manifestation of Chronic Myelomonocytic Leukemia and Multiple Myeloma during Treatment by Prednisolone and Eltrombopag for Immune-Mediated Thrombocytopenic Purpura

“…In an MDS-002 trial, the drug demonstrated transfusion independence in one quarter of MDS patients not harboring del(5q) [34]. It also shows a clinical response in CMML patients (25% of overall response), when combined with metronomic melphalan through an antiangiogenic effect [35]. We selected this drug to treat both MM and CMML.…”

Myelodysplastic Syndromes and Myelodysplastic/Myeloproliferative Neoplasms: An Update on Risk Stratification, Molecular Genetics, and Therapeutic Approaches Including Allogeneic Hematopoietic Stem Cell Transplantation

“…Although the study was small in number, a 25 and 33% response rate was identifıed in patients with myelodysplastic and myeloproliferative CMML, respectively. 160 A case study also has reported a proliferative of CMML cases with isolated del(5q) treated with lenalidomide that achieved blast clearance and cytoreduction. In RARS-T, three case reports have demonstrated clinical activity with respect to hematologic and splenomegaly improvement irrespective of cytogenetic abnormalities.…”