Blood Res 2018; 53(2):
Published online June 25, 2018
https://doi.org/10.5045/br.2018.53.2.169
© The Korean Society of Hematology
1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
2Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
3Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Correspondence to : Jan A. Burger. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA. jaburger@mdanderson.org
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Our patient has a long history of relapsing and remitting course of FL for about 17 years. She had extramedullary relapses in the breast, axillary lymph node, and arm. She was heavily pretreated with multiple chemotherapies and biological therapies and was relatively refractory to most of the therapies currently used in the treatment of FL [1]. Our patient developed acute promyelocytic leukemia that was most likely secondary to the therapies that she received for FL. Although we expected her to achieve a remission of APL after ATRA and As2O3 therapy [2], we were surprised to observe that she also achieved a remission of FL following the ATRA and As2O3 therapy, which persisted for more than a year and stabilized her lymphoma. To our knowledge, only a small number of studies have reported on the therapeutic activity of As2O3 and ATRA in patients with FL, and none of these studies reported any responses that were as impressive as observed in our case. One phase II clinical trial of As2O3 for lymphoid malignancies showed that 0 of 3 patients with FL had a response to arsenic therapy in the frontline disease setting [3], whereas another phase II trial with 35 patients with relapsed refractory lymphoma (7 with FL) showed an overall response rate of 43%, with a median duration of response of 16 weeks [4]. There is modest efficacy of arsenic in myeloma, myelodysplastic syndrome, mantle cell lymphoma, and Burkitt's lymphoma [5,6,7]. One study reported that As2O3 can suppress mantle cell lymphoma cells by facilitating the polyubiquitination of cyclin D1 [8]. Another study [9] reported that KML001 (sodium meta-arsenite), an orally bioavailable arsenic compound, has significant anti-lymphoma activity. This agent induced G1 phase arrest via p27-induced inhibition of the kinase activities of cylin-dependent kinase (CDK)2, CDK4, and CDK6 and blocked cell signaling, including the signal transducer and activator of transcription, phosphatidylinositol-3 kinase/Akt, mitogen-activated protein kinase, and nuclear factor-κB signal pathways in KML001-treated Jurkat and Jurkat-R cells. The anti-lymphoma activity of KML001 was confirmed in a xenograft murine model. Furthermore, partial responses were observed in 1 patient with FL who was treated for 16 weeks without severe toxicities. In addition, a combination of oral As2O3 with chlorambucil and ascorbic acid was tested in patients with relapsed refractory mantle cell lymphoma (N=39). An overall response rate of 49% with a CR rate of 28% was achieved with this regimen, and only grade 1–2 toxicities were noted [7]. Similarly, ATRA therapy has also not shown any major benefit in lymphoma therapy, although in vitro evidence in 2 reports have suggested that B-cell lymphoma cell lines are sensitive to interferon gamma and ATRA [10], and mantle cell lymphoma cell can be inhibited by ATRA [11]. Precise mechanisms responsible for arsenic/ATRA combination activity in lymphoma have not been explored to date. It is therefore unclear whether this combination affects the differentiation pathway or facilitates the apoptosis or inhibits the cell proliferation in lymphoma cells. The data presented here, however, suggest that the combination of ATRA and As2O3 should be explored in preclinical studies and clinical studies in patients with relapsed refractory FL. The present case suggests that it is worthwhile to revisit the therapeutic activity of As2O3 and ATRA in lymphoid malignancies [12].
No potential conflicts of interest relevant to this article were reported.
Blood Res 2018; 53(2): 169-172
Published online June 25, 2018 https://doi.org/10.5045/br.2018.53.2.169
Copyright © The Korean Society of Hematology.
Preetesh Jain1, Sergej Konoplev2, Ohad Benjamini1, Jorge Romagura3, and Jan A. Burger1*
1Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
2Department of Hematopathology, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
3Department of Lymphoma and Myeloma, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA.
Correspondence to:Jan A. Burger. Department of Leukemia, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 428, Houston, TX 77030, USA. jaburger@mdanderson.org
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Our patient has a long history of relapsing and remitting course of FL for about 17 years. She had extramedullary relapses in the breast, axillary lymph node, and arm. She was heavily pretreated with multiple chemotherapies and biological therapies and was relatively refractory to most of the therapies currently used in the treatment of FL [1]. Our patient developed acute promyelocytic leukemia that was most likely secondary to the therapies that she received for FL. Although we expected her to achieve a remission of APL after ATRA and As2O3 therapy [2], we were surprised to observe that she also achieved a remission of FL following the ATRA and As2O3 therapy, which persisted for more than a year and stabilized her lymphoma. To our knowledge, only a small number of studies have reported on the therapeutic activity of As2O3 and ATRA in patients with FL, and none of these studies reported any responses that were as impressive as observed in our case. One phase II clinical trial of As2O3 for lymphoid malignancies showed that 0 of 3 patients with FL had a response to arsenic therapy in the frontline disease setting [3], whereas another phase II trial with 35 patients with relapsed refractory lymphoma (7 with FL) showed an overall response rate of 43%, with a median duration of response of 16 weeks [4]. There is modest efficacy of arsenic in myeloma, myelodysplastic syndrome, mantle cell lymphoma, and Burkitt's lymphoma [5,6,7]. One study reported that As2O3 can suppress mantle cell lymphoma cells by facilitating the polyubiquitination of cyclin D1 [8]. Another study [9] reported that KML001 (sodium meta-arsenite), an orally bioavailable arsenic compound, has significant anti-lymphoma activity. This agent induced G1 phase arrest via p27-induced inhibition of the kinase activities of cylin-dependent kinase (CDK)2, CDK4, and CDK6 and blocked cell signaling, including the signal transducer and activator of transcription, phosphatidylinositol-3 kinase/Akt, mitogen-activated protein kinase, and nuclear factor-κB signal pathways in KML001-treated Jurkat and Jurkat-R cells. The anti-lymphoma activity of KML001 was confirmed in a xenograft murine model. Furthermore, partial responses were observed in 1 patient with FL who was treated for 16 weeks without severe toxicities. In addition, a combination of oral As2O3 with chlorambucil and ascorbic acid was tested in patients with relapsed refractory mantle cell lymphoma (N=39). An overall response rate of 49% with a CR rate of 28% was achieved with this regimen, and only grade 1–2 toxicities were noted [7]. Similarly, ATRA therapy has also not shown any major benefit in lymphoma therapy, although in vitro evidence in 2 reports have suggested that B-cell lymphoma cell lines are sensitive to interferon gamma and ATRA [10], and mantle cell lymphoma cell can be inhibited by ATRA [11]. Precise mechanisms responsible for arsenic/ATRA combination activity in lymphoma have not been explored to date. It is therefore unclear whether this combination affects the differentiation pathway or facilitates the apoptosis or inhibits the cell proliferation in lymphoma cells. The data presented here, however, suggest that the combination of ATRA and As2O3 should be explored in preclinical studies and clinical studies in patients with relapsed refractory FL. The present case suggests that it is worthwhile to revisit the therapeutic activity of As2O3 and ATRA in lymphoid malignancies [12].
No potential conflicts of interest relevant to this article were reported.