RELAPSED FOLLICULAR LYMPHOMA SEQUENTIALLY TREATED WITH RITUXIMAB AND 90 Y-IBRITUMOMAB TIUXETAN.

BACKGROUND
Monoclonal antibodies have dramatically changed the treatment possibilities for follicular lymphoma. (90)Y-ibritumomab tiuxetan (Zevalin) is the first radioimmunotherapy agent approved for the treatment of relapsed and resistant follicular lymphoma patients. Long-term benefit was observed especially for patients achieving CR after radioimmunotherapy.


METHODS AND RESULTS
A 65-year-old female patient with the second relapse of CD20 positive follicular lymphoma and multiple concomitant diseases was treated with four weekly doses of rituximab (375 mg/m(2)). (18)F-fluoro-deoxyglucose positron emission tomography combined with computed tomography (PET-CT) demonstrated only partial response to therapy with persistent PET scan positivity in enlarged abdominal lymph nodes. Therefore, it was decided to treat her with a 1200-MBq (32-mCi) dose of (90)Y-ibritumomab tiuxetan radioimmunotherapy. No acute complications were noted afterwards. Hematological nadirs were reached 4 weeks later, with a platelet count of 24 x 10(9)/l that normalized within the next 2 weeks. The patient had neither infection nor bleeding complications. Eight weeks after radioimmunotherapy, the PET-CT scans documented only 3 lymph nodes around the abdominal aorta, maximum size 2 x 1 cm. The PET scan analysis proved no accumulation of (18)F-fluoro-deoxy-glucose in any lymph nodes or other organs and tissues.


CONCLUSIONS
Sequential treatment with rituximab and (90)Y-ibritumomab tiuxetan may be an interesting alternative in cases of relapsed follicular or other indolent lymphomas in pretreated or older patients with other concomitant diseases.


INTRODUCTION
Follicular lymphoma (FL) is the second most frequent non-Hodgkin's lymphoma (NHL) in Europe and the USA.Despite good responsiveness to chemotherapy, most responses are incomplete and temporary, with patients relapsing from their lymphomas irrespective of which conventional regimen is administered.With standard chemotherapy, the median survival ranges from 8 to 10 years, and the prognosis of FL remained largely unchanged over the last decades of the 20 th century 1 .Recently, new treatment modalities have been developed.These include monoclonal antibodies (MAb) that have dramatically changed FL treatment possibilities.The only currently available unconjugated monoclonal antibody with proven activity in FL is rituximab -a chimeric anti-CD20 MAb.A pilot phase II study demonstrated signifi cant activity of onceweekly rituximab at a dose of 375 mg/m 2 administered for 4 weeks to previously treated FL patients 2 .The intent-to-treat response rate was 56% according to standard response criteria and the median time to progression in responding patients was 13.0 months.In spite of these promising results, it is evident that the response duration is limited.The response rate and therapeutic benefi t of the naked anti-CD20 MAb can be enhanced by using conjugated monoclonal antibodies.Radiolabeled antibodies seem to be an appealing option because lymphoma cells are generally sensitive to radiotherapy.Radioimmunotherapy (RIT) is attractive due to its so-called cross-fi re eff ect, damaging target and neighboring tumor cells including antigen-negative cells as well as those to which the antibody is unable to gain access. 90Y-ibritumomab tiuxetan was the fi rst RIT agent approved for the treatment of relapsed and resistant FL patients 3,4 .It is a murine IgG 1 kappa anti-CD20 MAb covalently bound to tiuxetan, which chelates the radioisotope 90 Y.This emits pure beta radiation over a radius of approximately 100-200 cells which allows suffi cient cross-fi re eff ect with no special isolation or protection procedures required.In a phase III randomized trial, 90 Y-ibritumomab tiuxetan was compared directly  with rituximab in the treatment of relapsed or refractory low-grade, follicular or transformed NHL 5 .The overall response (OR) and complete remission (CR) rates were signifi cantly higher with RIT (OR 83 % vs 56 %, p = 0.002; CR 30 % vs 16 %, p = 0.004) and the trend towards a longer median duration of response was observed especially for patients with follicular histology (18.5 months vs 12.1 months, p = 0.371).Long-term benefi t was observed for patients achieving CR after RIT and some responses continue for more than 3 years.The sequential rituximab immunotherapy and 90 Y-ibritumomab tiuxetan RIT may be an interesting approach to improving OR and prolonging survival in relapsed, heavily pretreated or older FL patients.Here we report the case of a 65-year-old female with FL who was successfully treated with rituximab and subsequently with 90 Y-ibritumomab tiuxetan.

CASE REPORT
The patient was diagnosed with grade II FL in 1998 (at 57 years of age), the neoplastic cells were positive for BCL-2/IgH gene rearrangement detected by polymerase chain reaction.The disease was staged as IIIB, according to the Ann Arbor staging system, with cervical, axillary, abdominal, iliac (the largest node 5x4 cm) and inguinal lymphadenopathy (the largest node 6x4 cm) causing massive lymphedema of the right leg.Bone marrow aspiration and biopsy showed no lymphoma cells.A complete blood count was in the normal range in all parameters.Other laboratory studies also displayed normal values of the main biochemical parameters including lactate dehydrogenase.Only beta-2 microglobulin was abnormally high (3.98 mg/l).The international prognostic index (IPI) was 1, follicular lymphoma IPI (FLIPI) was retrospectively counted as 2. Treatment with 6 cycles of cyclophosphamide, doxorubicine, vincristine and prednisone (CHOP) induced complete remission in January 1999.Unfortunately, the remission only lasted for 9 months and the patient relapsed in right inguinal lymph nodes (LNs) (5x3 cm), with recurrent leg lymphedema.She received 4 cycles of fl udarabine, mitoxantrone and dexamethasone (FND) and after completion of chemotherapy she underwent involved fi eld radiotherapy (40 Gy) targeted to the right inguinal region.Complete remission was confi rmed by computed tomography (CT) in May 2000.Then the patient was carefully observed but she gradually developed acute pancreatitis progressing to a chronic form, essential hypertension (WHO grade II), non-insulin dependent diabetes mellitus, chronic pyelonephritis with repeated acute urinary infection and chronic pharyngitis.
In February 2006, we diagnosed the second relapse of lymphoma in the right inguinal, pelvic and abdominal LNs (multiple LNs, maximum size 5x3 cm), the patient suff ered from B-symptoms.Histopathological analysis of extirpated inguinal LN demonstrated no evidence of lymphoma transformation, the CD20 antigen was strongly expressed.The bone marrow was still negative.In April 2006, we decided to administer four weekly doses of rituximab (375 mg/m 2 ) and dexamethasone (20 mg/m 2 ), with respect to the patient's age, concomitant diseases and her concerns about chemotherapy complications.Rituximab infusions were well tolerated and 4 weeks after the last dose, positron emission tomography (PET) combined with CT examination was carried out.The CT scans showed nine enlarged LNs (the largest LN size 4x3 cm) around the abdominal aorta that strongly accumulated 18 F-fl uorodeoxy-glucose ( 18 F-FDG), in the PET scans, the pelvic and inguinal LNs completely regressed (Fig. 1).Considering the PET-CT results, good tolerance of rituximab, no bone marrow involvement and normal blood cell count, we opted for 90 Y-ibritumomab tiuxetan therapy (June 2006).The patient was fully informed about the principles and possible adverse eff ects of radioimmunotherapy and she agreed with this treatment modality.At day 1, an intravenous infusion of rituximab (250 mg/m 2 ) was administered and one week later (day 8), the same rituximab infusion dose was followed by short i.v.application of 90 Y-ibritumomab tiuxetan in a dose of 1200 MBq (32 mCi), at the department of nuclear medicine.No acute complications were noted and the patient was discharged and followed on an outpatient basis.Hematological nadirs were reached 4 week later, with the platelet count 24x10 9 /l, white blood cell count 3.6x10 9 /l and neutrophil count 2.0x10 9 /l.The platelet count normalized within the next 2 weeks, the patient had neither infection nor bleeding complications and felt very comfortable.Eight weeks after radioimmunotherapy, another PET-CT examination was performed.The CT scans documented only 3 LNs around the abdominal aorta with the maximum size of 2x1 cm, the PET analysis proved only physiological 18 F-FDG distribution with no accumulation of the radioactive substance in any LNs (Fig. 2).The fi nal treatment result was assessed according to the standard response criteria as PET-negative unconfi rmed complete remission (CRu).Eight months after radioimmunotherapy, the patient was subjectively well, clinically in durable disease remission without any late complications or worsening of the concomitant diseases.

CONCLUSIONS
Sequential treatment with rituximab and 90 Y-ibritumomab tiuxetan may be a feasible alternative in cases of relapsed follicular or other indolent lymphomas in pretreated or older patients with other concomitant diseases.Rituximab "induction" probably reduces tumor burden and the subsequent application of 90 Y-ibritumomab tiuxetan "consolidation" can eff ectively eradicate the remaining lymphoma sites.Maintenance rituximab therapy after achieved remission could be another possible strategy for prolonging a patient's disease-or progression-free survival.

Fig. 2 .
Fig. 2. Fused positron emission tomography/computed tomography scans documenting lymph nodes around the abdominal aorta with the maximum size of 2x1 cm and physiological 18 F-fl uorodeoxy-glucose distribution -the status after 90 Y-ibritumomab tiuxetan therapy.