Azacytidine plus olaparib for relapsed acute myeloid leukaemia, ineligible for intensive chemotherapy, diagnosed with a synchronous malignancy

Abstract

Patients with relapsed/refractory acute myeloid leukaemia (AML), ineligible for intensive chemotherapy and allogeneic stem cell transplantation, have a dismal prognosis. For such cases, hypomethylating agents are a viable alternative, but with limited success. Combination chemotherapy using a hypomethylating agent plus another drug would potentially bring forward new alternatives. In the present manuscript, we present the cell and molecular background for a clinical scenario of a 44‐year‐old patient, diagnosed with high‐grade serous ovarian carcinoma, diagnosed, and treated with a synchronous AML. Once the ovarian carcinoma relapsed, maintenance treatment with olaparib was initiated. Concomitantly, the bone marrow aspirate showed 30% myeloid blasts, consistent with a relapse of the underlying haematological disease. Azacytidine 75 mg/m2 treatment was started for seven days. The patient was administered two regimens of azacytidine monotherapy, additional to the olaparib‐based maintenance therapy. After the second treatment, the patient presented with leucocytosis and 94% myeloid blasts on the bone marrow smear. Later, the patient unfortunately died. Following this clinical scenario, we reproduced in vitro the combination chemotherapy of azacytidine plus olaparib, to accurately assess the basic mechanisms of leukaemia progression, and resistance to treatment. Combination chemotherapy with drugs that theoretically target both malignancies might potentially be of use. Still, further research, both pre‐clinical and clinical, is needed to accurately assess such cases.

Targeting PARP proteins in acute leukemia: DNA damage response inhibition and therapeutic strategies

“…However, we have to take into account the evidence that in solid tumors treatment with PARPi is associated with a significantly higher risk of therapy-related MDS and AML [ 168 ] (0.73%; 95% confidence interval [CI]: 0·50–1·07) compared with placebo treatment (0.47%; 95% CI: 0·26–0·85; p = 0.026), with a median latency between first PARPi exposure and disease development of 17.8 months (8.4–29.2) [ 169 ]. Accordingly, treatment of relapsed disease in a high-grade serous ovarian carcinoma patient affected by a synchronous AML with olaparib-based maintenance therapy and the antileukemic agent azacitidine resulted in a dramatic expansion of malignant myeloid cells after two cycles, which was fatal to the patient [ 170 ]. Recent data also suggest that mutations of the DDR genes TP53 , PPM1D and CHEK2 , that are involved in clonal hematopoiesis, occur with increased frequency in cancer patients that were exposed to treatment, and in particular to platinum or topoisomerase II inhibitors or radiation therapy [ 171 ], indicating that DDR gene alterations improve the competitive fitness of the cells under these conditions.…”