To clarify the role of donor leukocyte infusion (DLI) in the treatment of leukemia relapsing after allo-BMT, data from 100 patients were collected from 46 facilities in Japan and analyzed with respect to the efficacy and adverse effects of donor leukocyte infusion. Complete remission was achieved in 11 of 12 (91%) patients with relapsed chronic myelogenous leukemia (CML) in chronic phase, three of 11 (27%) with CML in the acute phase, eight of 21 (38%) with acute myelogenous leukemia (AML), six of 23 (25%) with acute lymphoblastic leukemia (ALL) and five of 11 (45%) with myelodysplastic syndrome (MDS). The probability of remaining in CR at 3 years was 82% in CML patients in the chronic phase, but 0% in those with CML in the acute phase, 7% in those with AML, 0% with ALL and 33% with MDS. Acute GVHD (⩾2) developed in 31 of 89 (34%) patients with HLA-identical related donors and was fatal for seven (7%). Cytopenia developed in 21 of 94 (22%) with no associated fatalities. When the outcome of patients with CML in CP and MDS was analyzed, development of GVHD, cytopenia, or both, was associated with a higher GVL effect (15 of 16, 93%) than in those without adverse affects (one of 6, 17%). A leukocyte dose of 5 × 107/kg of recipient body weight appeared to be optimal as an initial dose of DLI. Given the relatively low incidence of acute GVHD and the similar GVL effect, DLI may be more beneficial to patients in Japan with recurrent leukemia than to those in Western countries. Bone Marrow Transplantation (2000) 26, 769–774.
Donor leukocyte infusion (DLI) has been established as a salvage therapy for patients with CML relapsing in the chronic phase after allogeneic BMT in Western countries.1234567 However, this adoptive immunotherapy is associated with the development of acute GVHD at a reported incidence of 59% to 90%.56789 Therefore, the beneficial effect of DLI can be offset by severe GVHD. Since the incidence and severity of GVHD after BMT is reportedly low in Japanese patients,101112 the net effect of DLI may differ from that of BMT patients in Western countries. We therefore conducted a survey on the outcome of DLI in Japanese patients with recurrent leukemia.
Materials and methods
In November 1995, centers participating in the Japanese Group for Marrow Transplant Registry were asked to report all patients treated with donor leukocyte infusion. They were asked to report additional information regarding the outcome and new patients in November 1996 and in July 1998. Thus, we collected data regarding the outcomes of 108 patients from 46 centers. Data included patient age, sex, diagnosis, stage of disease at transplantation, donor characteristics, date of transplant, conditioning regimen, method of prophylaxis for GVHD, severity of acute and chronic GVHD as well as other major complications after transplantation, time of relapse and leukocyte counts. For patients with CML, the type of relapse, namely molecular, cytogenetic or hematological in stable, accelerated or blastic phases was described.13 Treatment-related information included details of chemotherapy, prior DLI and α-interferon therapy, date and clinical as well as cytogenetic response, date and number of days of leukocyte infusions, number of leukocytes infused and the response to DLI. Outcome of the treatment was assessed according to the severity of GVHD, pancytopenia associated with DLI and response of leukemia to DLI including results of karyotyping and molecular analysis. Survival, morbidity and recurrence of leukemia after remission induction by DLI were also evaluated.
A total of 108 patients from 46 centers were retrospectively analyzed. Eight patients were excluded because six had died from the original leukemia within 14 days after infusion and two patients had received intensive chemotherapy soon after DLI. Eighty and twenty patients received donor leukocyte infusion while in relapse and while in remission following chemotherapy, respectively. Table 1 summarizes patient characteristics. Each patient had received marrow from a related donor and received DLI from the same donor. Eighty-nine patients underwent DLI from HLA-identical donors while the remaining 11 received DLI from donors with at least one HLA locus mismatch. Five of the 11 HLA-mismatched patients received purified CD34-positive marrow cells prepared using a column containing immunobeads (Isolex 50; Baxter, Deerfield, IL, USA) from donors with a two or three loci HLA mismatch and one patient who had received CD6+ T cell-depleted marrow from a donor with two mismatched HLA loci.
Definition of disease state and response criteria
Relapsed leukemia was diagnosed according to hematological signs and symptoms including cytogenetic evidence. Cytogenetic relapse in patients with CML was defined as recurrence of metaphases with the Philadelphia chromosome without hematological or clinical features of CML. Stable-phase relapse is the recurrence of CML with the characteristics of the hematological chronic phase.13 Blastic phase is defined as an increase of blasts in marrow of up to 30% or more and/or in the blood up to 20% or more. Accelerated phase is defined as an increase of blasts, eosinophils and basophils unresponsive to conventional chemotherapy that does not meet the criteria for blastic phase. The criterion for a GVL effect was complete remission after DLI without chemotherapy in patients in relapse at the time of DLI. Therapeutic effect was defined as a complete remission without fatal GVHD, and GVHD was graded clinically according to the standard criteria. Myelosuppression was defined as pancytopenia unrelated to cytotoxic chemotherapy.
Leukocytes were collected from the marrow donor as buffy coat preparations that were enriched in mononuclear cells on one or more occasions within 1 to 8 weeks. One patient with CML in stable-phase relapse received eight infusions of an increasing number of cells over 8 weeks.
Probability of survival and survival curves were calculated according to the method of Kaplan and Meier. Overall survival and disease-free survival were calculated from time of the first DLI until relapse of leukemia, death or the last follow-up evaluation. The logrank test was used to analyze statistical differences between probability of survival data for each group.
GVL effect on different types of leukemia
Table 2 summarizes the effects of DLI on each type of leukemic relapse. Hematological and cytogenetic responses were complete in 11 of 12 patients (91%) with CML in chronic phase. The Ph-positive cells in the remaining patient with cytogenetic relapse were reduced from 75% to 5% after DLI at the last examination in July 1998. Five of the 12 patients received α-IFN prior to DLI without securing a remission. In contrast, only three of 11 (27%) patients with CML in acute-phase relapse achieved CR. Complete remission was induced in eight of 21 (38%) patients with AML and in six of 24 (25%) patients with ALL who had received DLI without concomitant chemotherapy. Five of the 11 (45%) patients with MDS responded to DLI. The types of MDS in five patients were RAEB (two), RAEB in T (one), eosinophilic leukemia (one) and acute leukemia evolved from RAEB in T (one). Two MDS patients who relapsed with leukemic transformation had a transient response; peripheral blasts disappeared in one and peripheral blasts were reduced from 32% to 4% in the other (Table 2). Five patients died of acute GVHD associated with DLI although they responded to DLI. Ultimately, DLI appeared to benefit 28 out of 80 patients.
Long-term survivors after DLI
Figure 1 and Table 3 show the probability of survival after DLI in each patient group. Remission was sustainable among patients with CML in chronic-phase relapse. In contrast, two of three (66%) patients with CML in the acute phase, four of eight (50%) with AML, three of six (50%) with ALL and four of five (80%) with MDS relapsed after 1, 2, 2 and 7 months of remission, respectively. One Ph-positive ALL and two AML patients treated at the time of molecular relapse maintained their CR over 12 months. Two MDS patients survived for over 36 and 12 months, respectively. A child with eosinophilic leukemia remained in remission for over 36 months after receiving DLI in early relapse. The other child relapsed after 8 months of remission and underwent a second BMT from the same donor.
Adverse effects of DLI
Table 4 shows the frequency of GVHD. Acute GVHD (⩾2) developed in 31 of 87 (34%) patients and chronic GVHD developed in 24 of 73 (33%) of those who received DLI from HLA-identical relatives. Acute GVHD developed within 4 weeks after the last DLI. Seven patients including those with ALL (three), AML (two) and CML in chronic-phase relapse (two) died 1, 2, 4, 7, 8, 12 and 14 months after the first infusion of DLI. One patient with CML in chronic-phase relapse received 7 × 107/kg of leukocytes on day 99 and developed grade IV GVHD, which initially responded to steroid therapy. However, the patient died of CMV interstitial pneumonia in June 1989. The other patient with CML in chronic-phase relapse received 13 × 107/kg of leukocytes 41 months after BMT and developed grade IV GVHD that was refractory to CYA, prednisone and antihuman thymocyte globulin. Pancytopenia developed in five patients and reversed with G-CSF. No fatalities were associated with myelosuppression. Extra medullary relapse developed in five patients after successful DLI. Two AML patients and one with ALL patient developed leukemia cutis. Another ALL patient and one with CML in blast-phase relapse developed a myeloblastoma on the skin of the hip.
Relationship between GVL effect and adverse effects
Table 5 shows the relationship between the GVL effect and adverse effects among patients with CML in chronic phase and those with MDS. A total of 23 patients received only DLI to treat leukemia relapsing after BMT. Patients with GVHD tended to have a higher response rate (nine of 11; 82%) than patients without GVHD (seven of 12; 58%). Patients tended to have a higher response rate (12 of 14; 86%) if they became cytopenic (four of nine; 44%). Patients with evidence of GVHD, myelosuppression or both, had a higher response rate (15 of 16; 93%) than did those without any such signs (one of six; 17%).
Effect of cell dose on development of GVHD and GVL effects
Table 6 shows the cell dose infused from HLA-identical related donors and incidence of GVHD and GVL effects. Only one of six (17%) patients infused with less than 5 × 107/kg of TNC developed acute GVHD, whereas three of eight (38%) patients who received 5–10 × 107/kg of TNC developed acute GVHD. The incidence of acute GVHD was 30% among patients receiving over 10 × 107/kg of cells. Figure 2 shows the distribution of the dose of cells administered to patients with fatal GVHD and those who experienced a GVL effect. Because the minimum dose of cells inducing fatal GVHD was 7 × 107/kg, 1 × 107 to 5 × 107 cells per kg of body weight appeared to be safe for DLI between an HLA-identical donor and recipient.
The present survey of DLI among Japanese patients with leukemia relapsing after allogeneic BMT demonstrated that the GVL effect of DLI in Japanese patients was similar to that in Western patients.567 The benefit of DLI was most evident among patients with CML in chronic phase and in those with MDS. DLI induced remission in only a few patients with AML, ALL and CML in the acute phase, as reported by others. Remissions were sustainable in CML patients, whereas those in MDS, AML and ALL were transient, except in the cases of three patients with acute leukemia who received DLI during molecular relapse.
Slavin et al14 reported that durable remissions can be induced even in ALL patients with molecular and cytogenetic relapse by sequentially administering donor leukocytes and r-IL2. Ogawa et al15 described success in treating a patient with AML in molecular relapse by monitoring the molecular level of WT1 mRNA and giving DLI early. Another report described one patient with Ph-positive ALL in molecular relapse who maintained remission for over 1 year after DLI.16 Thus, DLI may produce a durable GVL effect even in patients with acute leukemia if used during the early stage of relapse.
After DLI from an HLA-identical related donor, 31 of 87 (34%) patients developed acute GVHD (⩾2) and seven died of this complication. The incidence and severity of acute GVHD, however, were lower than those reported from Western countries: acute GVHD (⩾2) complicated 46% of a North America BMT Group,7 41% of an EBMT Group6 and 54% of cumulative international patients.5 The number of cells infused in the present study appeared to be similar to that of published reports. This may reflect a difference in genetic diversity between Japan and Western countries. A large-scale study of Japanese BMT patients revealed a less diverse genetic background among HLA-compatible pairs than in Western countries.101112 The high frequency of finding an HLA-matched unrelated donor in the Japan marrow donor program1112 and the higher risk of developing transfusion-associated GVHD due to the similarity of HLA haplotypes between blood donor and recipient in Japan is compatible with this hypothesis.17
One of the aims of this study was to find an optimal starting cell dose for DLI. The results show that 5 × 107 leukocytes per kg of body weight can be safely administered as an initial dose of DLI for patients with CML in chronic-phase relapse and in those with MDS. This dose is higher than those described in reports from Western countries. Mackinnon et al,18 recommended a T cell dose of 1 × 107/kg as an initial dose based on their finding that 12.5% (one of eight) of patients developed acute GVHD with this dose whereas 73% (eight of 11) patients developed acute GVHD when given 5 × 107/kg T cells or more. In our survey, 17% (one of six) of patients developed acute GVHD when infused with less than 5 × 107/kg leukocytes, 36% (three of eight) patients developed acute GVHD after DLI with between 5 × 107 and 1 × 108/kg which included 50–60% T cells. The incidence of acute GVHD did not exceed 30% even when doses of TNC over 1 × 108/kg were infused. Since the incidence of severe GVHD was low, a relatively high dose of donor leukocytes appeared to be tolerated well by Japanese patients. Considering the relatively low incidence of severe GVHD and the similar GVL response, DLI may be more beneficial to Japanese, than to Western patients.
Institutes participating in this survey were: Sapporo Hokuyu Hospital; The Institute of Medical Science, the University of Tokyo; Nihon University School of Medicine; The Jikei University School of Medicine; School of Medicine, Keio University; Tokyo Medical College Hospital, Tokyo Metropolitan Komagome Hospital; Tokyo Metropolitan Huchu Hospital; Yokohama City University Hospital; Kanagawa Children’s Medical Center; Kanagawa Cancer Center; Tohkai University Hospital; Chiba University School of Medicine; Ibaraki Children’s Hospital; Jichi Medical Hospital; Juntendo University, School of Medicine; Saiseikai Maebashi Hospital; Niigata University Medical Hospital; Japanese Red Cross Nagoya First Hospital; Nagoya Daini Red Cross Hospital; Meitetsu Hospital; Nagoya University Hospital; Aichi Medical School Hospital; Nagoya City Hospital; Fujita Health University Hospital; Hamamatsu Medical Center; Kanazawa University School of Medicine; Kanazawa Medical University; Toyama Prefectural Central Hospital; Fukui Medical School; Center for Adult Disease, Osaka; Hyogo Medical Center for Adults; Kinki University School of Medicine; Osaka University School of Medicine; Osaka Medical Center and Research Institute for Maternal and Child Health; Kyoto University Hospital; Okayama University School of Medicine, Tokushima University Hospital; Kyushu University Hospital; National Kyushu Cancer Center.
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This work was supported in part by a grant-in-aid for Cancer Research 7–3 from the Ministry of Health and Welfare.
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Shiobara, S., Nakao, S., Ueda, M. et al. Donor leukocyte infusion for Japanese patients with relapsed leukemia after allogeneic bone marrow transplantation: lower incidence of acute graft-versus-host disease and improved outcome. Bone Marrow Transplant 26, 769–774 (2000) doi:10.1038/sj.bmt.1702596
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