Extramedullary disease and targeted therapies for hematological malignancies—is the association real?

Abstract

During the past years targeted therapies have gained a major role in the treatment of cancer patients, including those with hematological malignancies. Extramedullary involvement is a rare manifestation of acute and chronic leukemias and of multiple myeloma. Nevertheless, with the expanding use of targeted treatments there is an impression that the incidence of extramedullary relapses is increasing. We reviewed the reports on this phenomenon in patients treated with all-trans-retinoic acid and arsenic trioxide for acute promyelocytic leukemia, thalidomide and bortezomib for multiple myeloma and imatinib for chronic myeloid leukemia. The pathogenetic mechanisms suggested are: life prolongation by these treatments allowing for disease progression arising from dormant cells; poor penetration of the drugs to sanctuary sites like the central nervous system; the requirement of some of these drugs, especially thalidomide, for the marrow microenvironment to exert their action; and finally, a possible active role for some of the drugs, like all-trans-retinoic acid. Since the use of these targeted therapies is expanding we should be aware of this association.

Extramedullary relapse of multiple myeloma associated with a shift in secretion from intact immunoglobulin to light chains

“…9 There have been numerous reports documenting increased extramedullary relapse and altered biological behavior following these therapies. 10,11 It is this environment of evolutionary pressure that is likely to engender the LEPP variant. In the context of targeted therapies, it is conceivable that LEPP represents a clonal expansion of those proliferative precursors that have not only acquired stromal independence but also lost the capacity to secrete IIG.…”

Extramedullary involvement in multiple myeloma

“…It has also been suggested that extramedullary relapse is more frequent in patients exposed to novel agents. 10 However, Varettoni et al 6 showed that previous exposure to bortezomid, thalidomide or lenalidomide was not associated to a higher risk of extramedullary relapse.…”

Imaging Features of Extramedullary, Relapsed, and Refractory Multiple Myeloma involving the Liver Across Treatment With Cyclophosphamide, Lenalidomide, Bortezomib, and Dexamethasone

“…Several reports describe the lack of sustained efficacy of thalidomide against EMD both at diagnosis and relapse. 13 However, thalidomide-based multiagent regimens have shown efficacy in EMD among patients who have experienced relapse who underwent allogeneic or ASCT. 13 Interestingly, bortezomib has proven efficacy in EMD in numerous case reports.…”

“…13 However, thalidomide-based multiagent regimens have shown efficacy in EMD among patients who have experienced relapse who underwent allogeneic or ASCT. 13 Interestingly, bortezomib has proven efficacy in EMD in numerous case reports. 13 Ali et al 14 and Moriuchi et al 15 reported four cases in which bortezomib used as a single agent or with dexamethasone failed to achieve meaningful response in EMD, suggesting the importance of combination approaches with multiple agents.…”

“…13 Interestingly, bortezomib has proven efficacy in EMD in numerous case reports. 13 Ali et al 14 and Moriuchi et al 15 reported four cases in which bortezomib used as a single agent or with dexamethasone failed to achieve meaningful response in EMD, suggesting the importance of combination approaches with multiple agents. For example, multidrug chemotherapy consisting of bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide has proven effective in patients with EMD, but the toxicity profile of this regimen can limit its utility.…”