Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter to the Editor
  • Published:

Successful treatment with anti-CC chemokine receptor 4 MoAb of relapsed adult T-cell leukemia/lymphoma after umbilical cord blood transplantation

Bone Marrow Transplantation volume 48, pages 998–999 (2013)Cite this article

Subjects

Adult T-cell leukemia/lymphoma (ATLL) is a highly aggressive hematological neoplasm of mature CD4+ T lymphocytes.1, 2 Patients with aggressive ATLL have an extremely poor prognosis because these neoplasms are resistant to conventional chemotherapy.2 Recently, Ishida et al. reported promising outcomes of treatment with a new agent, namely anti-CC chemokine receptor 4 (CCR4) MoAb (mogamulizumab), a next-generation humanized IgG1 Ab with a defucosylated Fc region. This drug markedly enhances Ab-dependent CC (ADCC) through an increased binding affinity to the Fcγ receptor on effector cells in patients with ATLL relapse.3 CCR4 is a chemokine receptor expressed on helper T cells, regulatory T cells (Tregs)4 and certain types of T-cell neoplasms such as ATLL.5 Mogamulizumab has been approved in Japan for the treatment of relapsed or refractory ATLL. Phase II development is underway for ATLL and cutaneous T-cell lymphoma in the United States, and for peripheral T-cell lymphoma in the United States and Europe. Moreover, mogamulizumab induces only ADCC activity, not complement-dependent cytotoxicity or direct effects. Although mogamulizumab is now available in Japan for patients with ATLL, allogeneic hematopoietic SCT (allo-HSCT) remains the only curative treatment because of its ability to induce an immunological reaction.6 The 3-year OS rate following allo-HSCT in ATLL patients is reportedly 30–40%.6 However, relapse remains the major cause of treatment failure in patients undergoing allo-HSCT. Although mogamulizumab can be effective for patients with ATLL that relapses after allo-HSCT, the possibility of GVHD exacerbation due to the decreased number and/or impaired function of Treg remains unknown. In addition, it is unclear whether mogamulizumab can function in the early post-transplantation period, when ADCC effector cells, such as natural killer (NK) cells, are not fully reconstituted. Here we report the case of a 66-year-old patient who was treated with mogamulizumab for ATLL relapse after allo-HSCT and has sustained CR.

In January 2012, a 66-year-old Japanese male patient presented to us with enlarged systemic lymph nodes and abnormal peripheral blood lymphocytes. Based on these findings, he was diagnosed with the acute type of ATLL according to the criteria of the Japanese Lymphoma Study Group. He underwent one cycle of the CHOP chemotherapy (CY, hydroxydaunorubicin, vincristine and prednisolone) and two cycles of CHOP–VMMV 400 mg/m2 of CY on day 1, 1 mg/m2 of vincristine on day 1, 400 mg/m2 of hydroxydaunorubicin on day 1, 35 mg/m2 of etoposide on days 1–7, 40 mg/m2 of prednisolone on days 1–3, 7 mg/m2 of mitoxantrone on day 8, 50 mg/m2 of ranimustine on day 8, 2 mg/m2 of vindesine on day 8 and 40 mg/m2 of prednisolone on days 8–10 chemotherapy. Although the size of his lymph nodes markedly decreased after this treatment, CR was not achieved. In April 2012, he received a reduced-intensity conditioning regimen comprising 4 Gy of TBI, 125 mg/m2 of fludarabine and 80 mg/m2 of melphalan, followed by umbilical cord blood transplantation (UCBT). Prophylaxis for GVHD included tacrolimus and mycophenolate mofetil. Although rapid engraftment was achieved by day 14 after UCBT, lymphadenopathy persisted. Chimerism analysis on day 19 demonstrated that his BM cells were 98.6% donor-derived. On day 21, the patient developed diarrhea and was diagnosed with grade II acute GVHD on the basis of colonic mucosal biopsy. Administration of prednisolone resulted in gradual clinical improvement in the GVHD. Immunosuppressant therapy was then tapered to induce a graft-versus-ATLL effect. However, 61 days after UCBT, ATLL cells reappeared in the peripheral blood and multiple cutaneous nodules developed all over his body. In addition, his serum lactate dehydrogenase elevated during this period. The patient was diagnosed with relapsed ATLL on the basis of skin biopsy. ATLL cells in the peripheral blood and biopsied skin specimens were positive for CCR4. On day 62, the patient was administered 100 mg/m2 etoposide, which resulted in a decrease in the number of ATLL cells; however, the cutaneous nodules continued to expand. Therefore, on day 69, i.v. mogamulizumab was initiated at 1.0 mg/kg once a week.3 Remarkably, the cutaneous nodules shrank in size immediately after the first mogamulizumab treatment cycle. Simultaneously, the systemic lymphadenopathy began to decrease and ATLL cells began to disappear from the peripheral blood. Human T-cell lymphotropic virus type 1 DNA (tax-specific primers) was eventually undetectable on day 96 after UCBT. However, after four cycles of mogamulizumab treatment, on day 91 new skin eruptions appeared on the upper extremities and spread over the entire body. Pathological examination of biopsy specimens confirmed grade II acute GVHD, but there were no signs of ATLL recurrence. Although acute GVHD was transiently exacerbated, it was confined to the skin and did not require further immunosuppressive treatment. Thereafter, the ATLL lesions continued to decrease simultaneously with the occurrence of GVHD. The patient received eight courses of mogamulizumab treatment and has been alive in CR for 6 months after UCBT.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1

References

  1. Yoshida M, Seiki M, Yamaguchi K, Takatsuki K . Monoclonal integration of human T-cell leukemia provirus in all primary tumors of adult T-cell leukemia suggests causative role of human T-cell leukemia virus in the disease. Proc Natl Acad Sci USA 1984; 81: 2534–2537.

    Article  CAS  Google Scholar 

  2. Ishitsuka K, Tamura K . Treatment of adult T-cell leukemia/lymphoma: past, present, and future. Eur J Haematol 2008; 80: 185–196.

    Article  CAS  Google Scholar 

  3. Ishida T, Joh T, Uike N, Yamamoto K, Utsunomiya A, Yoshida S et al. Defucosylated anti-CCR4 monoclonal antibody (KW-0761) for relapsed adult T-cell leukemia-lymphoma: a multicenter phase II study. J Clin Oncol 2012; 30: 837–842.

    Article  CAS  Google Scholar 

  4. Baatar D, Olkhanud P, Sumitomo K, Taub D, Gress R, Biragyn A . Human peripheral blood T regulatory cells (Tregs), functionally primed CCR4+ Tregs and unprimed CCR4- Tregs, regulate effector T cells using FasL. J Immunol 2007; 178: 4891–4900.

    Article  CAS  Google Scholar 

  5. Ishida T, Utsunomiya A, Iida S, Inagaki H, Takatsuka Y, Kusumoto S et al. Clinical significance of CCR4 expression in adult T-cell leukemia/lymphoma: its close association with skin involvement and unfavorable outcome. Clin Cancer Res 2003; 9: 3625–3634.

    CAS  PubMed  Google Scholar 

  6. Fukushima T, Miyazaki Y, Honda S, Kawano F, Moriuchi Y, Masuda M et al. Allogeneic hematopoietic stem cell transplantation provides sustained long-term survival for patients with adult T-cell leukemia/lymphoma. Leukemia 2005; 19: 829–834.

    Article  CAS  Google Scholar 

  7. Ito A, Ishida T, Utsunomiya A, Sato F, Mori F, Yano H et al. Defucosylated anti-CCR4 monoclonal antibody exerts potent ADCC against primary ATLL cells mediated by autologous human immune cells in NOD/Shi-scid, IL-2R gamma(null) mice in vivo. J Immunol 2009; 183: 4782–4791.

    Article  CAS  Google Scholar 

  8. Beziat V, Nguyen S, Lapusan S, Hervier B, Dhedin N, Bories D et al. Fully functional NK cells after unrelated cord blood transplantation. Leukemia 2009; 23: 721–728.

    Article  CAS  Google Scholar 

  9. Mielke S, Rezvani K, Savani BN, Nunes R, Yong AS, Schindler J et al. Reconstitution of FOXP3+ regulatory T cells (Tregs) after CD25-depleted allotransplantation in elderly patients and association with acute graft-versus-host disease. Blood 2007; 110: 1689–1697.

    Article  CAS  Google Scholar 

  10. Kanda J, Hishizawa M, Utsunomiya A, Taniguchi S, Eto T, Moriuchi Y et al. Impact of graft-versus-host disease on outcomes after allogeneic hematopoietic cell transplantation for adult T-cell leukemia: a retrospective cohort study. Blood 2012; 119: 2141–2148.

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Hematology, Harasanshin Hospital, Fukuoka, Japan

    Y Ito, Y Chong, T Aoki & T Kamimura

  2. Department of Medicine and Biosystemic Science, Graduate School of Medical Science, Kyushu University, Fukuoka, Japan

    T Miyamoto, K Kato & K Akashi

Authors
  1. Y Ito
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Miyamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Chong
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. T Aoki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. K Kato
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. K Akashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. T Kamimura
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to T Miyamoto.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ito, Y., Miyamoto, T., Chong, Y. et al. Successful treatment with anti-CC chemokine receptor 4 MoAb of relapsed adult T-cell leukemia/lymphoma after umbilical cord blood transplantation. Bone Marrow Transplant 48, 998–999 (2013). https://doi.org/10.1038/bmt.2012.268

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/bmt.2012.268

This article is cited by

Search

Advanced search

Quick links