Follow-Up Study of Follicular Lymphoma (FL) Treated Using Clarithromycin: Intravenous Erythromycin Combined with Prednisolone Treatment is Effective for Refractory FL Accompanied with an Ocular Lesion

A 44-year-old man who presented lymphadenopathy was diagnosed with follicular lymphoma (FL). He was treated with rituximab, cyclophosphamide (CPM), doxorubicin, vincristine, and prednisolone (PSL), which resulted in a stable disease. The patient’s subsequent clinical course included partial remission and stable disease, each of which was treated by chemotherapy. At the third regrowth of the tumor, however, the patient was diagnosed with leukocytopenia and could not undergo further chemotherapy. Regression of his lymphadenopathy occurred following treatment with clarithromycin (CAM), which has anti-lymphoproliferative effects. CAM was continued with good outcome and then CAM was tentatively discontinued. Invasion of the lymphoma cells into the thoracic vertebrae occurred and was successfully treated by radiotherapy. Thereafter, he was successfully treated with CAM combined with PSL and CPM. At 57 years of age, he developed pancytopenia owing to therapy- related myelodysplastic syndrome; consequently, CPM was discontinued. Treatment with CAM combined with PSL was continued successfully. However, 15 months later, he complained of exophthalmos. Magnetic resonance imaging revealed a right orbital lesion. As an alternative to CAM combined with PSL, treatment with intravenous EM combined with PSL was used successfully. This case shows that treatment with intravenous EM combined with PSL may be effective in some cases of refractory FL.

We have previously reported a case of follicular lymphoma treated using CAM (6). Herein, we report this case again, in which the patient was treated using CAM combined with prednisolone (PSL) and erythromycin (EM) combined with PSL.

CASE REPORT
A 44-year-old man who presented lymphadenopathy was diagnosed with follicular lymphoma (FL). He was treated with rituximab (RX), cyclophosphamide (CPM), doxorubicin, vincristine, and PSL, which resulted in a stable disease. The patient's subsequent clinical course included partial remission and stable disease with episodes of tumor regrowth, each of which was treated by chemotherapy. At the third regrowth of the tumor, however, the patient was diagnosed with leukocytopenia and could not undergo further chemotherapy. Regression of his lymphadenopathy occurred following treatment with CAM (800 mg/day), which has anti-lymphoproliferative effects (6). 403 Case Report / Olgu Sunumu CAM was continued for 14 months with good outcome and then CAM was tentatively discontinued. Invasion of the lymphoma cells into the thoracic vertebrae occurred after 6 months and was successfully treated by radiotherapy. Thereafter, he was successfully treated with CAM (800 mg/day) combined with PSL (10 mg/day) and CPM (50 mg/day) for 4 years. At 57 years of age, he developed pancytopenia owing to therapy-related myelodysplastic syndrome (MDS); consequently, CPM was discontinued. Treatment with CAM combined with PSL was continued successfully. However, 15 months later, he complained of exophthalmos. Magnetic resonance imaging revealed a right orbital lesion ( Figure 1A). Add-on treatment with RX was ineffective. As an alternative to CAM combined with PSL (10 mg/day), treatment with intravenous EM (0.5 g three times a day) combined with PSL (30 mg/day) was used successfully ( Figure 1B). The PSL dosage was decreased gradually to 20 mg/day.

DISCUSSION
As stated above, MACs have recently been shown to exhibit antilymphoproliferative effects (1). Ishimatsu et al. reported two cases of pulmonary mucosa-associated lymphoid tissue lymphoma that were successfully treated using CAM (7). They speculated that CAM induced apoptosis of the lymphocytes by downregulation of the anti-apoptotic protein Bcl-xL. GCs are known to induce cell cycle arrest and apoptosis in lymphoid cells and are therefore an integral component in the treatment of lymphoid malignancies, particularly childhood acute lymphoblastic leukemia (8). Considering the apoptosis of lymphoid cells, CAM combined with PSL may be beneficial in the treatment of lymphoproliferative diseases. In fact, we have reported a case of diffuse large Bcell lymphoma successfully treated using CAM and PSL (3). Subsequently, we have reported a case of recurrent FL successfully treated using CAM combined with PSL and CPM (9). In the present case, the patient was treated with CAM, then CAM combined with PSL and CPM, and subsequently CAM combined with PSL. CAM combined with PSL and CPM regimen was considered to be the most effective treatment. However, this treatment induced therapy-related MDS. Thereafter, the patient was successfully treated with CAM combined with PSL.
However, a right orbital lesion appeared 15 months later. Treatment with intravenous EM (0.5g three times a day) combined with PSL (30 mg/day) was effective. The reason why the intravenous EM combined with PSL treatment was more effective than CAM combined with PSL treatment might be partly because of the difference in PSL dosage between these two treatments.
CAM after oral administration has a rapid first-pass metabolism in the liver that results in absolute bioavailability levels of ~50% (10). We administered EM intravenously in order to elevate the absolute bioavailability level of the MAC.
EM was the first macrolide to be developed. New macrolides such as CAM and azithromycin have since been developed to supersede EM. CAM is a semisynthetic macrolide antibiotic, chemically identified as 6-0methylerythromycin A (11). Only a slight structural change exists between CAM and EM. As a result, a close analogy exists between CAM and EM. In fact, EM as well as CAM has been reported to induce death of leukemic lymphoid cells (12). On the basis of these facts, the elevated absolute bioavailability of EM and/or above-mentioned slight structural change might be advantageous to intravenous EM combined with PSL treatment for providing antilymphoproliferative effects, as compared with CAM combined with PSL treatment.
More extensive research is required to validate our findings before intravenous EM combined with PSL treatment can be adopted on a wider basis.