Local Field Radiotherapy Induced Therapy Related Myeloid Neoplasms and Bone Marrow Suppression

Introduction:

Different cytotoxic agents have been implicated in development of therapy related myeloid neoplasm (t-MN). These include alkylating agents, topoisomerase II inhibitors, antimetabolites, and ionizing field radiation given to large field including active bone marrow (BM) (Swerdlow, 2016).

This report highlight the impact of local field radiotherapy on BM through discussing few patients diagnosed in our center who showed profound BM hypocellularity or developed t-MN following exposure to local field radiotherapy without chemotherapy.

Local field Radiotherapy as a causative agent for t-MN:

A result of retrospective study performed in our center through (2012-2018), a total of 20 patients of t-MN out of 232 total AML patients (8.6%) were detected. Two patients out of 20 (10%) in our cohort had developed t-MN following exposure to local field radiotherapy.

Patient (1): 50-year old Asian male diagnosed as Vocal cord tumor, received local field radiotherapy for 2 months with no chemotherapy. 15.8 months later, he presented to with two days history of gum bleeding associated with pancytopenia (WBCx10^3/µl:2.3, Hb g/dl:6.7, Platelets x10^3/µl:100). Peripheral blood smear showed infiltration with many leukaemic promyelocytes and diagnosed as Acute promyelocytic leukemia (APL). The diagnosis was confirmed by BM examination and detection of PML RARA classic rearrangement fusion indicating PML/RARA, t(15;17) in 88.5% cells. Reticulin stain shows increased reticulin fibrosis (1-2/ 3). The patient was stratified as intermediate risk and started on ATRA followed by PETHEMA protocol with complete remission.

Patient (2): A 62-year old Egyptian lady with background of hepatitis C and previous stroke, diagnosed as Endometrioid Endometrial Cancer FIGO grade I. The patient received Brachytherapy 21 Gy dose to vaginal vault, in 3 fractions (7 Gy each) without complications. 22 months later, she developed progressive neutropenia and diagnosed as high grade myelodysplastic syndrome (MDS-EB-2) with complex karyotype and P53 somatic mutation, managed by palliative therapy.

Discussion:

Generally laryngeal cancers radiotherapy is directed to confined area and secondary cancers are more common in the area of close proximity to radiation field.

Brachytherapy is a limited source of radiation placed into a cylinder and inserted within the prostate or the vagina for treatment of cancer prostate or endometrial carcinoma respectively.

Compared to external radiotherapy (RT), the limited field radiotherapy (including external beam RT and brachytherapy), the doses received by BM is very low and hence the risk of secondary leukaemia is expected to be significantly lower.

Although local field RT appears to be associated with a small increase in the incidence of solid cancers, only a few studies have evaluated the risk of developing myeloid malignancies after limited field radiotherapy.

Numerous cases of (t-APL) have been reported in the literature mostly following TOPO isomerase II inhibitors. However, up to our knowledge no previous reports of t-MN with recurrent genetic translocations (including t-APL) following local field radiotherapy.

Local field radiotherapy induced bone marrow suppression:

Two male patients with previous history of cancer prostate and limited field radiotherapy.

BM examination for both patients revealed profound hypocellularity (<5-5%) with suppressed trilineage hematopoiesis.

Patient (3):

A 66 year-old male diagnosed as cancer prostate, subjected to radical prostatectomy, followed by salvage radiotherapy. Two months later, the patient was referred for persistent cytopenia (WBC 2.9 x10^3/uL, Hemoglobin 12.8 gm/dL and platelets (92 x10^3/uL).

Follow-up revealed persistent thrombocytopenia. No follow-up BM was performed.

Patient (4):

A 73-year old male patient with previous history of marginal zone lymphoma and cancer prostate treated by brachytherapy. He underwent BM examination for lymphoma staging.

Discussion:

For patients who have received adjuvant, salvage or radical RT, a significant portion of the pelvic BM receives a substantial dose of RT. To our knowledge, there are no significant published data assessing the impact of limited field radiotherapy on BM particularly radiation induced BM suppression.

Larger studies are required in order to accurately assess the actual effect of local field radiotherapy on hematopoiesis and its genetic profiling.