DISCUSSION
Thrombocytopenia is a frequent event in oncological patients. According to Common terminology criteria for adverse events (CTCAE) v5.0, it is defined as a decrease in number of platelets in a blood specimen, and 4 severity categories are recognized: grade 1 for counts ranging between the upper normal level and 75 × 10^9/L, grade 2 between 75 and 50 × 10^9/L, grade 3 between 50 and 25 × 10^9/L and grade 4 under 25 × 10^9/L. [7]
Its incidence is estimated to range from 10% to 68%, according to different studies. [8] About 21% of patients with hematologic malignancies and up to 6% of patients with solid tumors present thrombocytopenia before chemotherapy. The most frequently associated histotypes are acute leukemia (37.3%) and multiple myeloma (24.4%); among solid tumors, melanoma (21.4%), ovarian (14.7%) and lung (14.3%) cancer. After three months of chemotherapy, the reported incidence rates increase to 28.2% and 12.8% for hematological and solid neoplasms, respectively. [9]
Chemotherapy has a well-known impact on platelet and other blood cell counts, through an acute damage and apoptosis of hematopoietic cells. [10] Acute thrombocytopenia generally occurs within 10 days from the infusion and is of short duration due to the bone marrow replication reserve. [11] A long term bone marrow injury may occur when chemotherapy inhibits the self-renewal potential of hematopoietic stem cells, causing their senescence. [12, 13] Moreover, chemotherapy drugs may interfere with the hematopoietic microenvironment, resulting in bone marrow loss and adipogenic differentiation of stem cells. [14]
Gemcitabine is associated with the highest risk of thrombocytopenia, followed by platinum-based regimens; on the opposite, anthracyclines and taxanes have lower rates. [9, 15, 16] High dose ifosfamide has a well-known hematological toxicity, with a grade 3-4 thrombocytopenia occurrence rate of almost 30% in some studies [17] A recent study has also showed that a low platelet count was significantly associated with ifosfamide and etoposide chemotherapy in Ewing sarcoma patients. [18]
While most cases are asymptomatic, a decrease in platelet count may lead to minor and major bleeding, especially when platelet counts drop to grade 2 and lower. A study by Elting and colleagues demonstrated how bleeding episodes complicated 9% of chemotherapy cycles in patients with a history of previous bleeding and who had baseline platelet count lower than 75000/mm3, bone marrow metastases or poor performance status. [19]
No clear guidelines on management of patients with bone marrow infiltration are available: most data are obtained by case reports or small retrospective studies of patients treated with different cytotoxics according to histology, with a great heterogeneity on outcomes. A French retrospective study showed the efficacy and feasibility of weekly, low dose paclitaxel in 26 patients with breast cancer BMI. [20] Similarly, analogous cases of breast cancer BMI have been successfully treated with continuous infusion doxorubicin [21] or weekly nab-paclitaxel [22]. On the other hand, a patient with neuroblastoma did not derive any benefit from combination therapy of standard dose topotecan and cyclophosphamide [23].
Among mesenchymal tumors, Ewing sarcoma and pediatric rhabdomyosarcoma BMI is not uncommon [24-25]; more rarely, bone marrow infiltration from other histologic subtypes like angiosarcoma [26], epithelioid sarcoma [27] and follicular dendritic cell sarcoma [28] has been reported. Given the aggressiveness of such sarcoma subtypes, most cases were treated with high dose, multidrug regimens with poor responses and severe hematological toxicity, often fatal. [29] Of note, one patient with alveolar rhabdomyosarcoma treated with schedule-adapted VDC/IE had an optimal response with 15-months PFS [30] Chemotherapy, acting on the very first cause of thrombocytopenia, surely has a leading role in the treatment of bone marrow infiltration. All the reported successful cases have in common the administration of low dose, continuous infusion or weekly fractionated chemotherapy regimens, with the aim of reducing the negative impact on hematopoietic bone marrow cells.
To our knowledge, this is the first described case of management of bone marrow infiltration from Ewing sarcoma presenting with severe thrombocytopenia successfully managed with low-dose continuous infusion ifosfamide, providing almost 7 months of progression-free survival.
Such results are highly clinically significant, considering the poor prognosis of relapsed Ewing sarcoma, and might be of help when decision-making is required in this setting.