Rapid response to IFN-α in a patient with relapsed follicular lymphoma after cord blood transplantation

Allogeneic hematopoietic SCT (HSCT) has emerged as a promising treatment modality for selected patients with relapsed or refractory follicular lymphoma. However, substantial treatment-related mortality after myeloablative conditioning and an increased risk of late disease progression after reduced-intensity conditioning are major concerns.1 Bloor et al.2 reported that 13 of 17 patients with relapsed or refractory follicular lymphoma after HSCT responded to donor lymphocyte infusion (DLI). Their results supported the existence of a clinically significant graft-vs-tumor effect in follicular lymphoma. However, DLI cannot be performed in patients who relapse after umbilical cord blood transplantation (UCBT) with a few exceptions, and no alternative strategies have yet been established. We report a patient with relapsed follicular lymphoma after UCBT who was treated successfully with IFN-alpha (IFN-α) without DLI or re-transplantation.

The patient was a 60-year-old man with an 18-year history of treatment for follicular lymphoma. Although each lymph node was <2 cm in diameter, leukemic changes, non-infectious fever and pancytopenia had been induced by massive BM infiltration of lymphoma cells with reticulin fibrosis. Chemotherapy was ineffective, resulting in the need for frequent blood transfusions. He therefore underwent one-HLA-A-mismatched UCBT with a conditioning regimen consisting of fludarabine, melphalan, and TBI. Cyclosporine and short-term MTX were administered for GVHD prophylaxis. Examination of BM aspirated on day 28 showed complete donor chimerism. There were no symptoms of chronic GVHD, and cyclosporine was stopped on day 172. Several opportunistic infections including HHV-6 reactivation, Aspergillus antigenemia, relapsed chickenpox and Pneumocystis pneumonia developed, but resolved with appropriate antimicrobial therapy.

Fifteen months after cord blood transplantation (CBT), the patient noticed swelling of the cervical and inguinal lymph nodes. A whole-body computed tomography (CT) scan showed several lymph nodes up to 1.5 cm in diameter throughout the body, and mild splenomegaly. Relapse was confirmed by the presence of 24% lymphoma cells in the BM, with abnormal IgH-Bcl2 fusion gene shown by fluorescence in situ hybridization (FISH) analysis. Prednisone, etoposide, procarbazine and CY (PEP-C) was selected as a salvage regimen, taken orally two or three times per week.3 The lymph nodes were no longer palpable after 4 weeks. CD4-cells in the peripheral blood decreased from 896 to 280 cells/mm3, and hemorrhagic cystitis developed. PEP-C therapy was immediately suspended, but the hemorrhagic cystitis took 7 weeks to resolve. Then analysis of aspirated BM cells revealed the remaining 8% abnormal IgH-Bcl2 cells.

IFN therapy was planned to induce a GVL effect. Written consent was received from the patient, and six MIU of natural IFN-α (mixture of IFN-α species) was subcutaneously injected five times per week for the first 2 weeks, followed by three times per week, without interruption. Transient fever and general malaise developed after a few days. Two weeks after the start of IFN therapy, FISH analysis of aspirated BM using IgH/Bcl2 probes showed a reduction in lymphoma cells from 8 to 0%. Flow cytometric analysis of BM lymphocytes showed abnormal λ-chain restriction (upper left quadrant, κ/λ ratio=2.97) before initiation of IFN-α, and lack of restriction (lower left, κ/λ ratio=1.57) after 2 weeks (Figure 1). CD4+CD25+lymphocytes in the BM decreased from 2.0 (upper right) to 1.3% (lower right). Serum transaminase levels had increased to more than twice the upper limit of normal, but no other symptoms suggestive of GVHD were noted. BM was examined by FISH analysis using X-/Y-chromosome probes or IgH/Bcl2 probes at 4, 12 and 24 weeks, and showed undetectable lymphoma cells or recipient blood cells. The para-aortic lymph nodes detected by CT were reduced in size. The patient continued IFN-α therapy and remained in CR and able to work after 9 months, with no serious opportunistic infections.

Figure 1
figure1

Flow cytometric analysis of BM cells before (upper) and 2 weeks after (lower) initiation of IFN-α therapy. The gated lymphocytes were analyzed using anti-κ/anti-λ (left) or anti-CD4/anti-CD25 antibodies (right). Abnormal λ-chain restriction before initiation of IFN-α (upper left quadrant) had disappeared after 2 weeks (lower left). CD4+CD25+lymphocytes in the BM decreased from 2.0 (upper right) to 1.3% (lower right).

Several phase II trials conducted during the 1980s reported response rates for IFN-α of up to 55% in patients with non-Hodgkin lymphoma.4, 5 However, the efficiency of IFN-α as a single agent has seldom been shown in phase III trials, although a number of groups have analyzed its synergistic effects with other chemotherapeutic agents. Rohatiner et al.6 performed a meta-analysis of these randomized trials of patients with follicular lymphoma, and concluded that IFN-α was associated with a significant survival advantage when high-dose or high-dose-intensity of IFN-α was combined with aggressive regimens containing anthracycline. However, further exploration of the use of IFN-α for non-Hodgkin lymphoma was halted by the development of the new drug, rituximab.

IFN-α was reported to have the potential to induce GVL when administered with DLI in patients who relapsed after allogeneic transplantation. Grigg et al.7 reported that, of 18 post-HSCT patients who received DLI and IFN-α, 14 developed significant GVHD, which resolved after cessation of IFN-α alone in four patients.

However, because of the difficulty in harvesting a sufficient number of lymphocytes for DLI from CBT donors, we chose IFN-α monotherapy in the current patient, with favorable results. This case showed two surprising features of IFN-α therapy. The first was its rapid effect; a previously reported phase II trial of IFN-α therapy suggested that it took 2–4 months to suppress follicular lymphoma in non-HSCT patients.4, 5 However, IFN-α alone induced remission in our patient in just 2 weeks. It is possible that this rapid response was caused by a GVL effect. The second observation was the decrease in regulatory T cells (Tregs). Tatsugami et al.8 recently investigated the changes in numbers of Tregs in patients with metastatic renal carcinoma after IFN-α monotherapy. CD4+ and FoxP3+Tregs were significantly decreased for 2 weeks after the initiation of IFN-α, but recovered as treatment proceeded. In our case, the number of CD4+CD25+lymphocytes in the BM decreased from 2.0 to 1.3% in the first 2 weeks. Although we did not analyze FoxP3+cells, the downregulation of Tregs was possibly associated with the GVL effect.

Further studies involving a larger number of cases are required to adequately assess the efficacy and safety of IFN-α in patients who relapse after CBT. IFN-α could be effective in patients with CML, myeloma and in some patients with AML. To conduct clinical trials, it would be necessary to establish an appropriate endpoint. The short-term efficiency of IFN-α could be evaluated over a period of around 2 weeks, as this was found to be adequate to detect a response in this study.

In conclusion, IFN-α therapy may be a suitable first-choice treatment for relapsed malignancy after CBT.

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Arima, N., Yoshinaga, N., Maruyama, W. et al. Rapid response to IFN-α in a patient with relapsed follicular lymphoma after cord blood transplantation. Bone Marrow Transplant 46, 448–449 (2011) doi:10.1038/bmt.2010.104

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