Combination Lenalidomide and Azacitidine: A Novel Salvage Therapy in Patients Who Relapse After Allogeneic Stem-Cell Transplantation for Acute Myeloid Leukemia

Craddock, Charles; Slade, Daniel; Santo, Carmela De; Wheat, Rachel; Ferguson, Paul; Hodgkinson, Andrea; Brock, Kristian; Cavenagh, Jamie; Ingram, Wendy; Dennis, Mike; Malladi, Ram; Siddique, Shamyla; Mussai, Francis; Yap, Christina

doi:10.1200/jco.18.00889

Cited by 57 publications

(57 citation statements)

References 30 publications

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“…Normal monocytes seem important both in immunoregulation and possibly also for carcinogenesis/leukemogegesis [1,17]. The aim of the present study was therefore to investigate whether monocyte functions are altered by IMiDs, a class of pharmacological agents that have cereblon as a common intracellular molecular target [2] and are considered for the treatment of various cancers, especially hematological malignancies [1,27,28]. Our main conclusion based on the present study is that IMiDs can alter both monocyte metabolism as well as cytokine release, and despite their common molecular target these pharmacological effects differ among IMiDs.…”

Section: Discussionmentioning

confidence: 99%

Immunomodulatory Drugs Alter the Metabolism and the Extracellular Release of Soluble Mediators by Normal Monocytes

et al. 2020

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Immunomodulatory drugs (IMiDs) are used in the treatment of hematological malignancies, especially multiple myeloma. IMiDs have direct anticancer effects but also indirect effects via cancer-supporting stromal cells. Monocytes are a stromal cell subset whose metabolism is modulated by the microenvironment, and they communicate with neighboring cells through extracellular release of soluble mediators. Toll-like receptor 4 (TLR4) is then a common regulator of monocyte metabolism and mediator release. Our aim was to investigate IMiD effects on these two monocyte functions. We compared effects of thalidomide, lenalidomide, and pomalidomide on in vitro cultured normal monocytes. Cells were cultured in medium alone or activated by lipopolysaccharide (LPS), a TLR4 agonist. Metabolism was analyzed by the Seahorse XF 96 cell analyzer. Mediator release was measured as culture supernatant levels. TLR4 was a regulator of both monocyte metabolism and mediator release. All three IMiDs altered monocyte metabolism especially when cells were cultured with LPS; this effect was strongest for lenalidomide that increased glycolysis. Monocytes showed a broad soluble mediator release profile. IMiDs decreased TLR4-induced mediator release; this effect was stronger for pomalidomide than for lenalidomide and especially thalidomide. To conclude, IMiDs can alter the metabolism and cell–cell communication of normal monocytes, and despite their common molecular target these effects differ among various IMiDs.

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Section: Discussionmentioning

confidence: 99%

Immunomodulatory Drugs Alter the Metabolism and the Extracellular Release of Soluble Mediators by Normal Monocytes

et al. 2020

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“…Another option might be to integrate lenalidomide as maintenance therapy after SCT, but previous experiences raised serious concerns about an increased risk of acute GvHD (44,45). However, interesting results of the combination of lenalidomide and azacytidine have been recently published (46).…”

Section: Discussionmentioning

confidence: 99%

Allogeneic stem cell transplantation using HLA-matched donors for acute myeloid leukemia with deletion 5q or monosomy 5: a study from the Acute Leukemia Working Party of the EBMT

Poiré¹,

Labopin²,

Polge³

et al. 2019

Haematologica

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Deletion 5q or monosomy 5 (-5/5q-) in acute myeloid leukemia is a common high-risk feature referred to allogeneic stem cell transplantation. However, -5/5q-is frequently associated with other high-risk cytogenetic aberrations such as complex karyotype, monosomal karyotype, monosomy 7 (-7), or 17p abnormalities (abn (17p)), the significance of which is unknown. In order to address this question, we studied adult patients with acute myeloid leukemia harboring -5/5q-having their first allogeneic transplantation between 2000 and 2015. Five hundred and one patients with -5/5q-have been analyzed. Three hundred thirty-eight patients (67%) were in first remission and 142 (28%) had an active disease at time of allogeneic transplantation. The 2-year probabilities of overall survival and leukemia-free survival were 27% and 20%, respectively. The 2-year probability of treatment-related mortality was 20%.We identified 4 different cytogenetic groups according to additional abnormalities with prognostic impact: -5/5q-without complex karyotype, monosomal karyotype or abn(17p), -5/5q-within a complex karyotype, -5/5q-within a monosomal karyotype and the combination of -5/5q-with abn(17p). In multivariate analysis, factors associated with worse overall survival and leukemia-free survival across the 4 groups were active disease, age, monosomal karyotype and abn(17p). The presence of -5/5q-without monosomal karyotype or abn (17p) was associated with a significantly better survival rate while -5/5q-in conjunction with monosomal karyotype or abn(17p) translated into a worse outcome. The patients harboring the combination of -5/5q-with abn(17p) showed very limited benefit from allogeneic transplantation.

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“…Among the treatments prescribed for the acute type of the disease, the median survival rate for interferon alpha (IFN-α)/zidovudine (ZDV) and the hyper-CVAD regimens was 5months, while using lenalidomide/ZDV regimen had a lower survival time. However, in AML in a salvage therapy after stem-cell treatment, had very promising outcome [24]. The laboratory data indicated that serum calcium, LDH, ALT, AST, direct bilirubin, urea, and creatinine levels, and atypical cell count were related to the patients' survival.…”

Section: Discussionmentioning

confidence: 99%

Combination therapy and survival time in Adult T cell Leukemia/Lymphoma (ATLL)

Borojerdi

Rahimi

Ghezeldasht

et al. 2019

Preprint

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Background: The urgent need for the treatment of ATLL has highlighted in 18th-International Conference on Human Retrovirology-HTLV-1 (Tokyo, 2017). Therefore, in this study the median survival times (MST) of routine therapies for ATLL were evaluated in context of laboratory tests . Methods: In a perspective-retrospective cohort study, the efficiencies of therapy regimens, including interferon-alfa and zidovudine (IFN/ZDV), cyclophosphamide, vincristine, doxorubicin, dexamethasone (hyper-CVAD), lenalidomide/ZDV, cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) were evaluated in 67 acute ATLL patients. The demographic, clinical, MST, and routine and molecular laboratory data were then collected and analyzed . Results: The MST for acute and lymphoma subjects was 5 and 11 months, respectively, including 5 months (95% CI 3.378 6.622) for IFN/ZDV, 5 months (95% CI 2.067.94) for CVAD, 3months (95% CI 0.009.86) for lenalidomide/ZDV and 11 months (95%CI 8.45913.54) for CHOP regimen. Importantly, patients who received IFN/ZDV and hyper-CVAD therapy, had a better OS (HR, 0.663; 95%CI, 0.540 to 0.814; P=0.0001), compared with the lenalidomide /ZDV alone. The MST for subjects with hypercalcemia was 5 months, and for patients with normal calcium level was 9 months (p=0.017). Conclusions: High expressions of BIM and CERB were more frequent in lymphomatous type, and considering these factors, platelet counts and HTLV-1-proviral load (PVL) might be predictive factors for differentiating acute and chronic types. Low MST was observed in acute and lymphomatous ATLL, even in the combinational chemo-therapeutic regimens. Therefore, it seems that ATLL treatment should be personalized according to the virus-host interactions on survival signaling pathways, the platelet count and calcium level.

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Combination Lenalidomide and Azacitidine: A Novel Salvage Therapy in Patients Who Relapse After Allogeneic Stem-Cell Transplantation for Acute Myeloid Leukemia

Cited by 57 publications

References 30 publications

Immunomodulatory Drugs Alter the Metabolism and the Extracellular Release of Soluble Mediators by Normal Monocytes

Immunomodulatory Drugs Alter the Metabolism and the Extracellular Release of Soluble Mediators by Normal Monocytes

Allogeneic stem cell transplantation using HLA-matched donors for acute myeloid leukemia with deletion 5q or monosomy 5: a study from the Acute Leukemia Working Party of the EBMT

Combination therapy and survival time in Adult T cell Leukemia/Lymphoma (ATLL)

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