Temozolomide induced bone marrow Suppression–A single institution outcome analysis and review of the literature
Authors: Taxiarchis V. Kourelis, Jan C. Buckner, Naseema Gangat, Mrinal M. Patnaik
Journal: American Journal of Hematology (2015)

Temozolomide (TMZ) is an oral alkylating agent used mostly in the treatment of patients with malignant gliomas 1. It is generally well tolerated, and Grade 3 or 4 hematologic toxicity is seen in approximately 5–10% of patients 1. TMZ induced cytopenias are reversible on discontinuation of the drug but prolonged TMZ induced bone marrow suppression (TMZ-BMS) has also been identified as a potential adverse event of the drug. Whereas patients experiencing Grade 3–4 but transient cytopenias tend to recover fully, TMZ-BMS is associated with significant morbidity and mortality, mainly related to complications of bone marrow failure. Existing, larger case series lack detailed clinical information, do not include a consistent definition of BMS nor do they describe BMS duration or long term outcomes of patients 2-4. Furthermore, publication bias is possible since the more severe cases are likely to be reported. Here, we describe a cohort of patients evaluated at our institution, with TMZ-BMS and systematically review their outcomes along with those from published cases. We identified cases of TMZ-BMS seen at the Mayo Clinic in Minnesota, from 2003–2014. We also performed a literature search to identify published cases of TMZ-BMS. We excluded case series that did not have detailed clinical information. One case was excluded as it involved an accidental overdosage of TMZ 5. Similar to aplastic anemia, BMS was defined, as depression of at least two of three hematopoietic cell lines below normal range. To qualify as prolonged TMZ-BMS, BMS should have persisted for more than 28 days after the last TMZ dose. The 28 day cutoff was chosen, because most TMZ regimens consist of 28 day cycles and the hematologic toxicity from prior cycles is expected to have resolved after this period. BMS severity was classified similar to the classification scheme used for aplastic anemia: severe, if bone marrow cellularity was <25% or at least two of the following were satisfied: (a) absolute reticulocyte count <40,000/ml (b) absolute neutrophil count (ANC) <500/ml; or (c) platelet count <20,000/ml; very severe BMS was defined as ANC< 200/ml. All other cases were considered moderate BMS. The date of TMZ-BMS diagnosis was defined as they day of cell count nadir. We believe that this definition is a surrogate of severe bone marrow suppression and captures a population of patients very distinct from those with Grade 3 or more hematologic toxicity reported so far; not only in terms of clinical management, complications, and outcomes but also in terms of their underlying pathophysiology. TMZ for central nervous system malignancies was administered according to the Stupp protocol 6. In non-CNS cases, TMZ was administered orally at a dose of 200 mg/m2, days 1–5, every 28 days. Of 2356 successive Mayo Clinic patients treated with TMZ from 2003–2014, 15 (0.6%) developed BMS. An additional 15 reported cases (Supporting Information) were identified from the literature. The patients' baseline characteristics are shown in the table. Reported cases had more severe TMZ-BMS with lower mean hemoglobin, white blood cells, and platelets compared to Mayo Clinic patients (Table 1). When considering Mayo Clinic cases, patients with TMZ-BMS were more likely to be female compared to those without TMZ-BMS (80% vs. 41%, P < 0.0001). In the entire group of 30 patients, 17 (57%) developed very severe, 9 (30%) severe, and 4 (13%) had moderate BMS. The median follow-up of patients from diagnosis of BMS to recovery of ANC, hemoglobin and platelets was 64, 70, and 70 days, respectively. Median recovery time for ANC, hemoglobin and platelets were 70 days, 118 days and not reached, respectively (P = 0.002) (Supporting Information Fig. 1). At last follow-up, recovery of ANC, hemoglobin and platelets to normal levels was noted in 18 (60%), 7 (23%), and 6 (20%) patients, respectively. When considering patients who did not recover their counts, median levels of ANC, hemoglobin and platelets at last follow-up were 2570/ml (with growth factor support), 9.2 g/dL and 38,000/ml (1 remains on eltrombopag). When considering patients that were alive at last follow-up, none had received any chemotherapy after TMZ. The median follow-up of patients from diagnosis of BMS for overall survival (OS) was 210 days. At last follow-up, 17 (57%) patients had died; causes of death were as follows: 7 died as a result of BMS, 5 because of progressive malignancy, 1 as a result of complications related to allogeneic stem cell transplant and for the remaining 4 the cause of death was unknown. Median OS for the whole cohort was not reached (Supporting Information Fig. 2a). Ninety day mortality for the whole cohort was 23%. Median OS for Mayo Clinic patients not reached vs. 210 days for reported cases, P = 0.03, (Supporting Information Fig. 2b), which is likely a reflection of more severe baseline TMZ-BMS in published cases. Ninety day mortality for Mayo Clinic patients was also better compared to that of published cases (7% vs. 44%, respectively, P = 0.03; Supporting Information Fig. 2b). Twenty-two patients (73%) developed neutropenic fever (10 fulfilled criteria for sepsis), and 4 developed significant bleeding (requiring transfusion support); 15 patients (52%) required G-CSF support (median duration of 36 days; range, 5–660 days). Three patients required erythropoietin for 66 and 69 days (unknown duration in one patient). One patient received eltrombopag and had multilineage response and remains on the drug, 120 days after BMS diagnosis. Two patients received rituximab and antithymocyte globulin, respectively, with no response. Two patients underwent allogeneic stem cell transplantation (Supporting Information). Sixteen patients (53%) were independent of transfusions at last follow-up and no data were available for two patients. This is the first and largest study to report the detailed, long term clinical outcome of a well-defined population of patients with severe, prolonged TMZ-BMS. We demonstrate that TMZ-BMS is uncommon and usually tends to occur after the first cycle of therapy. Platelets and hemoglobin remain suppressed for longer. Half of the patients became transfusion independent but approximately a quarter required prolonged growth factor support. The use of immunosuppressive agents was attempted in two cases with no benefit. In refractory cases, allogeneic stem cell transplantation can be potentially curative. The authors would like to thank Dr. Ewa Wysokinska for help with translating the case report published in Polish. Taxiarchis V. Kourelis,1* Jan C. Buckner,2 Naseema Gangat,1 Mrinal M. Patnaik1 1Division of Hematology, Mayo Clinic, Rochester, Minnesota 2Department of Medical Oncology, Mayo Clinic, Rochester, Minnesota Additional Supporting Information may be found in the online version of this article. Supporting Information Supporting Information Supporting Information Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.