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.