Abstract
Background: A patient with chemotherapy-resistant acute monocytic leukemia who achieved complete remission (CR) after iron chelation therapy (ICT) with deferasirox is reported for the first time. A 73-year-old Japanese man with acute monocytic leukemia who was refractory to conventional remission induction chemotherapies achieved a partial response, with some improvement of his hemoglobin level and white blood cell count after gemtuzumab ozogamicin (GO) treatment. Seven months after GO treatment, the disease relapsed and the patient developed pancytopenia. He declined further chemotherapy, and started receiving 1,200-1,800 ml of packed red blood cell transfusion per month together with ICT with deferasirox (baseline serum ferritin level was 1,412 ng/ml). Twelve months after the initiation of deferasirox, the patient's serum ferritin level decreased to below 1,000 ng/ml and deferasirox was discontinued. Four months after discontinuation of deferasirox, the blood cell count normalized and the patient became transfusion-independent. Bone marrow aspiration and biopsy revealed hematological and cytogenetic CR. Conclusion: CR was achieved after ICT with deferasirox in a patient with acute myelogenous leukemia, suggesting that deferasirox may have an antileukemic effect in the clinical setting.
- Deferasirox
- iron chelation therapy
- iron overload
- acute myelogenous leukemia
- chemotherapy-resistant
- complete remission
Iron overload is a major problem for patients receiving regular packed red blood cell (PRBC) transfusion, since it causes end organ damage such as hepatic dysfunction, heart failure, diabetes mellitus and many other diseases (1, 2). Low- or intermediate-risk myelodysplasic syndrome (MDS) patients whose life expectancy is relatively long often develop iron overload due to regular PRBC transfusion. MDS patients with transfusion dependency experience shorter survival and increased risk of progression to acute myelogenous leukemia (AML) (3, 4). Accordingly, iron chelation therapy (ICT) is recommended for MDS patients whose life expectancy is at least one year (5). On the other hand, experience with ICT in patients with AML is limited because life expectancy of transfusion-dependent AML patients is generally short. Here a case of chemotherapy-resistant acute monocytic leukemia (AMoL) who achieved complete remission (CR) after ICT with deferasirox is described.
Case Report
A 73-year-old Japanese man was referred to Kanazawa Medical University Hospital with anemia and leukocytopenia in October 2007. Peripheral blood cell count showed: hemoglobin 6.0 g/dl, white blood cell count 1.97×103/mm3 without blasts and platelet count 190×103/mm3. The bone marrow was hypercellular and contained 20% monoblasts, 32% promonocytes and 43% monocytes (Figure 1A). Bone marrow cell karyotyping revealed 48, XY, add (1) (p11), +8 of 4/20 and 46, XY of 16/20 metaphases; therefore, he was diagnosed with AMoL. After he failed to achieve CR with three courses of remission induction chemotherapies (one course of daunorubicin plus behenoyl Ara-C, two courses of mitoxantrone, behenoyl Ara-C plus etoposide), he achieved a partial response with some improvement of his hemoglobin level and white blood cell count after gemtuzumab ozogamicin (GO) treatment. In August 2008 (seven months after GO treatment), he was referred to Kanazawa Medical University Hospital again with severe anemia (hemoglobin 4.4 g/dl). His white blood cell count and platelet count were also decreased (1.65×103/mm3 without blasts and 85×103/mm3, respectively). Bone marrow aspiration was a dry tap and bone marrow biopsy revealed increased blasts with myelofibrosis (Figure 1B), indicating relapse of AMoL. The declined patient further chemotherapy, so he received 1,200-1,800 ml of PRBC transfusion per month to maintain a pretransfusional hemoglobin level of 7.0 g/dl. In September 2008, his ferritin level was 1,412 ng/mL, so ICT with 10.0 mg/kg/day deferasirox was started. The total PRBC received before deferasirox therapy was 11,400 ml. No other drugs except for lansoprazole were administered simultaneously. The deferasirox dose was reduced to 8.0 mg/kg/day in November 2008 because the patient's serum creatinine level increased. As the chelating effect was insufficient and the serum creatinine level was stable, the deferasirox dose was escalated to 16.0 mg/kg/day in May 2009. In September 2009, his serum ferritin level decreased to below 1,000 ng/ml and deferasirox was discontinued. In spite of continuous PRBC transfusion, the serum ferritin level did not increase again. While cholecystitis developed in November 2009, the symptoms disappeared immediately with intravenous antibiotic therapy with sulbactam/cefoperazone. In January 2010, the patient's blood cell count normalized (hemoglobin: 11.0 g/dl, white blood cells: 3.5×103/mm3 without blasts, platelet counts: 147×103/mm3). Bone marrow aspiration and biopsy in August 2010 revealed hematological and cytogenetic CR; the bone marrow was normocellular without leukemic monoblasts and myelofibrosis, contained 1.6% morphologically normal promonocytes and 16% mature monocytes (Figure 1C), cytogenetic abnormalities had disappeared in conventional karyotype analysis, and +8 was not detected in fluorescence in situ hybridization. To date (November 2010), normal blood cell counts have been maintained without transfusion (Figure 2).
Discussion
Several studies have demonstrated that ICT improves the survival of low- or intermediate-risk MDS patients with transfusion dependency (6-8). Moreover, ICT improved cytopenia and reduced transfusion requirements in some patients with MDS or primary myelofibrosis (9-11). The mechanism of this hematological improvement is not clear, but the following hypothesis has been made. In iron overload, excess iron which is identifiable as labile iron pool or non-transferrin-bound iron promotes the production of reactive oxygen species (ROS), which in turn causes cell and tissue damage through oxidation of lipids, proteins and nucleic acid (1, 2, 12). Thus, in patients with MDS, oxidative stress by iron overload may exacerbate ineffective hematopoiesis in bone marrow. In in vitro studies, increased ROS in red blood cells and platelets from MDS patients was ameliorated by deferoxamine or deferiprone (13). In in vivo studies, deferasirox reduced liver iron content, as well as labile plasma iron and serum ferritin levels (14), and reduced the levels of intra- and extracellular oxidative stress in MDS patients (15), suggesting that reduction of oxidative stress by ICT may be one of the mechanisms of improved hematopoiesis in MDS patients.
In the present case, the dose escalation of deferasirox to 16.0 mg/kg/day resulted in a considerable decrease of the patient's serum ferritin level to below 1,000 ng/ml, suggesting that tissue iron contents had decreased markedly. We consider that the reduction of ROS-induced toxicity to hematopoietic stem cells might be associated with the subsequent normalization of his hematopoiesis. Despite continuous PRBC transfusion after discontinuation of deferasirox, the serum ferritin levels did not increase again, suggesting that the recovering erythropoiesis utilized stored iron. Surprisingly, the patient achieved hematological and cytogenetic CR subsequently. While it is impossible to deny spontaneous remission (16-18), infections which often precede spontaneous remission had not developed except for mild cholecystitis. Furthermore, the patient had not received granulocyte colony-stimulating factor or corticosteroids. Accordingly, hematological and cytogenetic CR was considered to be induced by ICT with deferasirox, which suggested that deferasirox might have antileukemic activity in vivo. To our knowledge, this is the first case report to demonstrate the possible antileukemic effect of deferasirox in the clinical setting.
Recently, two basic studies on the antileukemic activity of deferasirox have been reported (19, 20). Ohyashiki et al. demonstrated that dephosphorylation of the mammalian target of rapamycin (mTOR) followed by up-regulation of the regulated in development and DNA damage response (REDD1)/tuberous sclerosis complex 2 (TSC2) pathway by deferasirox induced down-regulation of ribosomal S6 protein, thereby inhibiting leukemic cell proliferation (19). Messa et al. demonstrated that deferasirox inhibited the activity of NF-kappa-B, one of the most important therapeutic targets in high-risk MDS (21), in blast cells from MDS or secondary AML patients independently of its iron chelating action (20). In the present patient, the dose escalation of deferasirox to 16.0 mg/kg/day is considered to have resulted in both optimum iron chelating and antileukemic effects. The dose and pharmacokinetics of deferasirox appear to be an important factor not only for iron chelation (14, 22), but also for the antileukemic effect. Pullarkat mentioned that the major benefits of ICT are lowering of infection risk, improving the outcome of allogeneic hematopoietic stem cell transplantation and delaying leukemic transformation, which may have particular relevance for patients with higher grades of MDS (23). Prospective randomized studies that include patients with smoldering AML, high-risk MDS and minimal residual disease of acute leukemia after chemotherapy or allogeneic hematopoietic stem cell transplantation are required to confirm the antileukemic effect of deferasirox in the clinical setting.
In conclusion, CR was achieved after ICT with deferasirox in a patient with AML, suggesting that deferasirox may have an antileukemic effect in the clinical setting.
Footnotes
-
Conflict of Interest
The Authors declare no conflicts of interest.
- Received January 7, 2011.
- Revision received March 30, 2011.
- Accepted April 1, 2011.
- Copyright© 2011 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved