Cutaneous Leukemic Infiltrates Successfully Treated With Biomodulatory Therapy in a Rare Case of Therapy-Related High Risk MDS/AML

Abstract

Cutaneous manifestations in hematologic malignancies, especially in leukemia, are not common and may be very variable. Here we report a very unusual case of a patient (female, 70 years old) who was admitted to the hospital in 2016 because of skin lesions on the face, the trunk of the body and the extremities. She had a history of breast cancer in the year 2004 (pT1b, pN0, cM0, L0, V0, R0) which had been resected and treated with adjuvant radiation and chemotherapy (cyclophosphamide, methotrexate, 5-fluorouracile) as well as psoriasis treated with methotrexate and cyclosporine. Because of mild cytopenia a bone marrow aspirate/biopsy was performed showing myelodysplastic syndrome (MDS) with multilineage dysplasia. Cytogenetic review revealed a complex aberrant karyotype denoting adverse outcome. Simultaneously, a skin biopsy could confirm leukemic skin infiltration. Consequently, a therapy with azacitidine was started. After the first cycle the patient developed severe pancytopenia with a percentage of 13% peripheral blasts (previously 0–2%) as well as fever without evidence for infection which was interpreted as progressive disease. Therefore, the therapeutic regimen was changed to a biomodulatory therapy consisting of low-dose azacitidine 75 mg/day (given sc d1-7 of 28), pioglitazone 45 mg/day per os, and all-trans-retinoic acid (ATRA) 45 mg/m2/day per os. After cycle 1 of this combined biomodulatory therapy the patient showed hematologic recovery; besides a mild anemia (hemoglobin 11.1 g/dl) she developed a normal blood count. Moreover, the cutaneous leukemic infiltrates which had been unaffected by the azacitidine ameliorated tremendously after 2 cycles resulting in a complete remission of the skin lesions after cycle 6. In conclusion, we report a very unusual case with cutaneous infiltrates being the first clinical manifestation of hematologic disease, preceding the development of acute myeloid leukemia. While azacitidine alone was ineffective, a combined biomodulatory approach resulted in a complete remission of the cutaneous manifestation.

Anakoinosis: Correcting Aberrant Homeostasis of Cancer Tissue—Going Beyond Apoptosis Induction

“…Therefore, genetically different acute myelocytic leukemias constitute a unique phenotype, rapidly displaced normal hematopoiesis in the bone marrow. Accordingly, unique pro-anakoinotic therapy approaches may differentiate blasts from genetically different acute myelocytic leukemias into granulocyte-like cells (32, 34,[38][39][40][41][42].…”

“…At the same time available biological and clinical response data indicate the administered drugs' activity profile can define them as master modifiers of tumor tissue (9). In addition to this clinical data, there is increasing biological data indicating master modifiers' mechanisms of action (22,32,41,42,(54)(55)(56).…”

“…A possible "off-target" effect seems to be the induction of tumor cell death and continuous complete remission following anakoinosis inducing therapies. For example, while controlling refractory AML with pioglitazone, all-trans retinoic acid and azacitidine, differentiation induction, and gain of function of blast-derived granulocytes may not be the only mechanisms explaining continuous complete remission, even molecular remission in single patients (41,42).…”

“…Induction of complete remission in p53 mutated acute myelocytic leukemia (AML) with pioglitazone, all-trans retinoic acid and azacitidine demonstrates that undruggable targets may be by-passed by activating alternative druggable pathways (42,71). In refractory AML and advanced multiple myeloma patients responses in the form of long-term disease stabilization can be achieved with metronomic scheduling of master modifiers, even in case of complex karyotypes (42,111).…”

Editorial: Tumor Systems Biology: How to Therapeutically Redirect Dysregulated Homeostasis in Tumor Systems (i.e., Anakoinosis)

“…Although, the added transcriptional modulators show no monoactivity in AML, their pro-anakoinotic activity “normalizes” AML-associated homeostatic disbalances in a therapeutically meaningful way ( Heudobler et al ). As already mentioned, outcome of biomodulatory therapies is strongly context-dependent and ranges in AML between continuous complete remission and stabilization of disease with peripheral blasts without need of transfusion [ Kattner et al ; ( 1 , 4 , 5 )].…”