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Bone Marrow Transplantation (2000) 26, 809–810  2000 Macmillan Publishers Ltd All rights reserved 0268–3369/00 $15.00 www.nature.com/bmt

Case report Long-term molecular remission induced by donor lymphocyte infusions for recurrent acute myeloblastic leukemia after allogeneic bone marrow transplantation S Imoto, T Murayama, H Gomyo, I Mizuno, T Sugimoto, T Nakagawa and T Koizumi Hematology/Oncology Division, Department of Internal Medicine, Hyogo Medical Center for Adults, Hyogo, Japan

Summary:

Case report

A case of acute myelogenous leukemia with a t(8;21) translocation relapsed 5 months after allogeneic bone marrow transplantation (allo-BMT). After chemotherapy-induced hematologic remission, the patient received donor lymphocyte infusions (DLI); 4.9 × 108/kg T cells were infused. After DLI, she achieved molecular CR for the first time after allo-BMT, which lasted for 40 months. However, she suffered from grade III acute GVHD of the skin and the liver. Hepatic GVHD was sustained and resulted in fatal outcome. The case demonstrates that DLI is a double-edged sword. Further study is necessary before DLI can be considered to be a beneficial therapy for acute leukemia. Bone Marrow Transplantation (2000) 26, 809–810. Keywords: acute leukemia; allogeneic bone marrow transplantation; relapse; donor lymphocyte infusion; graftversus-host disease; graft-versus-leukemia effect

A 21-year-old woman was diagnosed with AML M2 in August 1995. Cytogenetic analysis showed a t(8;21) with additional abnormalities, 46,X,i(X)(q10),t(8;21)(q22;q22) in 20/20 mitoses. AML1-ETO chimeric mRNA was demonstrated by RT-PCR. She entered hematological CR after combination chemotherapy (enocitabine, daunorubicin, 6mercaptopurine, prednisolone). After three courses of consolidation therapy, she was admitted to our hospital for allo-BMT from her HLA-identical brother. Bone marrow examination at our hospital revealed 3.1% myeloblasts containing Auer bodies. Cytogenetic analysis was normal, with positive RT-PCR for AML1-ETO. After conditioning with TBI (12 Gy in six fractions), CY (120 mg/kg) and VP-16 (1500 mg/m2), she underwent alloBMT on 22 March 1996. 3 × 108/kg bone marrow nucleated cells were infused without manipulation. CYA and shortcourse MTX were given for GVHD prophylaxis. Engraftment (WBC ⬎1000) was obtained on day 17. Grade I skin GVHD appeared on day 18, which resolved with 1 mg/kg prednisolone. Three months after allo-BMT, bone marrow examination showed CR with 100% of donor karyotypes (46 XY). RT-PCR of AML-ETO was positive. However, she relapsed 5 months after BMT. Myeloblasts (69.2%) were detected in her bone marrow. After withdrawal of CYA, she was treated with idarubicin + Ara-C. One month later, she obtained hematological remission. RT-PCR for AML1-ETO remained positive (Figure 1). She received DLI as consolidation therapy. Donor leukocyte

In acute leukemia, relapse after allogeneic bone marrow transplantation (allo-BMT) is the main cause of treatment failure. Therapy for post-BMT relapse of acute leukemia is difficult. While remission may be induced by chemotherapy, the duration is short in most cases. Second transplantation is associated with high therapy-related mortality.1,2 Donor lymphocyte infusion (DLI) has shown excellent graft-versus-leukemia (GVL) effects in CML in cytogenetic or chronic phase relapse after allo-BMT and is becoming established as the first choice of therapy.3–6 However, in acute leukemia, the clinical effectiveness of DLI remains to be determined.4,6–10 We report a case of AML that relapsed after allo-BMT and achieved long-term molecular CR after DLI performed as a consolidation of chemotherapy.

Correspondence: Dr S Imoto, Hematology/Oncology Division, Department of Internal Medicine, Hyogo Medical Center for Adults, 13–70, Kitaoji-cho, Akashi, Hyogo, 673–8558 Japan Received 17 April 2000; accepted 25 June 2000

Figure 1 RT-PCR of AML1/ETO chimeric mRNA in bone marrow. In each photograph, the left lane is the size marker, the middle lane is AML1/ETO chimeric mRNA, and the right lane is ␤-actin mRNA, respectively.

DLI for acute leukemia relapsing after allo-BMT S Imoto et al

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apheresis was performed on a Cobe Spectra continuous flow separator (Cobe Laboratories, Lakewood, CO, USA). She received DLI three times at 7 day intervals. In total, 7.3 × 108/kg leukocytes (4.9 × 108/kg T cells) were infused. Twenty-one days after the first DLI skin eruptions appeared and rapidly spread systemically followed by hepatic dysfunction. Diagnosis of GVHD was confirmed by biopsy of skin and liver. GVHD of the skin improved after steroid pulse therapy. Hepatic GVHD was sustained and she suffered from sicca syndrome, which was controlled with prednisolone with or without CYA. On the other hand, RTPCR of AML1-ETO chimera mRNA in bone marrow became negative on day 49 of DLI for the first time after BMT and remained negative on day 969 of DLI (Figure 1). She remained in CR for 40 months. Her performance status remained at 80% until August 1999 (35 months post DLI), when she suffered from a femoral neck fracture. Thereafter, her performance status gradually deteriorated and chronic GVHD of the liver progressed. In February 2000, she died of intra-abdominal hemorrhage secondary to hepatic failure. Autopsy revealed no signs of leukemia relapse. Discussion In contrast to CML, beneficial roles of DLI for acute leukemia are still controversial. Several reports have demonstrated that DLI alone could induce CR in 0–30% of acute leukemias relapsing after allo-BMT.4,6 DLI seems to be more effective for AML than for ALL. Buzyn-Veil et al7 reported sustained molecular CR induced by DLI alone in AML1-ETO-positive AML, and they suggested that the presence of AML1-ETO is a favorable factor. However, the majority of cases relapsed again within several months. Better results have been obtained when DLI was undertaken as consolidation therapy during the chemotherapyinduced remission period, or G-CSF-mobilized PBSC were infused after high-dose chemotherapy aiming at a GVL effect and at potentiation of hematopoiesis.4,6,8,9 GVHD is the most serious problem with DLI. A close relationship between the GVL effect and GVHD in DLI has been reported.4,6–10 Collins et al6 reported that 42 of 45 completely responding patients developed acute GVHD and 36 of 41 complete responders developed chronic GVHD whereas only three patients attained CR among 23 patients without GVHD. However, severe GVHD sometimes leads to a fatal outcome. To avoid severe GVHD, reduced starting dose and dose escalation with long intervals seems to be beneficial for CML in chronic relapse.3 This method seems to be insufficient for acute leukemia, however. In most of the successful case reports of DLI for acute leukemia, infused leukocyte doses were started with 108/kg or more.4,6–10 We treated three patients with acute leukemia (two AML and one ALL) with a reduced starting dose. All the patients relapsed within 3 months, while they did not suffer from severe GVHD (data not shown). The case presented here was AML M2 with a t(8;21) translocation. AML1-ETO in RT-PCR remained positive even after allo-BMT. Hematologic relapse after allo-BMT

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was successfully treated with chemotherapy. DLI was performed as consolidation therapy. Following DLI, the patient achieved molecular CR for the first time after alloBMT, which lasted for as long as 40 months. However, she developed grade III acute GVHD of the skin and liver. Hepatic GVHD was sustained, and finally progressed to fatal hepatic failure. Our case demonstrates that DLI is a double-edged sword. Separation of GVL from severe GVHD is important for DLI to be a beneficial therapy for acute leukemia. Strategies to augment leukemia-specific immune responses are required. Further study is necessary.

Acknowledgements We thank Prof Shintaro Shiobara for encouraging us to publish our work and to Ms Kuniko Numata for her assistance in preparing the manuscript.

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