Treatment of relapsed acute lymphoblastic leukemia after allogeneic bone marrow transplantation with chemotherapy followed by G-CSF-primed donor leukocyte infusion: a prospective study

Abstract

Summary:Donor leukocyte infusion (DLI) alone has very limited efficacy for patients with acute lymphoblastic leukemia (ALL) who have relapsed after allogeneic bone marrow transplantation (BMT). We, therefore, prospectively tested the efficacy of cytoreductive chemotherapy (intermediate-dose cytarabine þ idarubicin þ etoposide) followed immediately by G-CSF-primed DLI (Chemo-DLI) in 10 relapsed ALL patients after allogeneic BMT. Seven achieved complete remission (CR) at a median of 25 days (19-73 days) after DLI. Of these seven CR patients, only one remains alive in CR 907 days after DLI. Two CR patients died in CR of graft-versus-host disease. The remaining four CR patients relapsed at a median of 153 days (120-991 days) after DLI. One is alive with leukemia at post-DLI day 1217. The median survival duration after DLI was 175 days (15-1217 days). In summary, although Chemo-DLI for relapsed ALL after allogeneic BMT induced a relatively high CR rate, durable remissions were rare. Although our data should be interpreted cautiously considering the small number of patients, these results suggest that poor outcome of DLI in relapsed ALL may be primarily due to intrinsic resistance to graft-versus-leukemia effect rather than to the rapid pace of the disease. For patients with acute lymphoblastic leukemia (ALL) receiving allogeneic bone marrow transplantation (BMT), relapse remains the major cause of treatment failure and is associated with a very poor prognosis. The optimal salvage treatment for patients with ALL who relapse after allogeneic BMT has not yet been established, since most therapies are of limited benefit. While reinduction chemotherapy can induce remission in about 40-60% of patients, most of these patients eventually relapse and die of uncontrolled leukemia, with a 3-year disease-free survival (DFS) rate of less than 10%. 1-4 A second BMT results in long-term event-free survival in only 10-20% of patients with relapsed ALL. 5-7 However, even these poor results may be an overestimate because only a small proportion of relapsed patients is suitable for second BMT, and hence the results may reflect the positively biased outcome of a highly selected group of patients. Only 7-20% of patients has been reported to reach the stage of a second BMT after relapse according to the performance and remission status after salvage chemotherapy. 2,8 Moreover, second BMT is associated with extremely high treatment-related mortality, ranging from 40% to 50%. [6][7][8] Another approach to the treatment of ALL patients who relapse after allogeneic BMT is donor leukocyte infusion (DLI), which may induce a graft-versus-leukemia (GVL) effect. DLI has been shown to be highly effective in patients with chronic myelogenous leukemia (CML) who relapse into the chronic phase, achieving complete and durable remission in 70-80% of these patients. 9,10 In contrast, DLI for relapsed ALL has been much less effective. Although there have been many case reports showing that patients with ALL respond to DLI, [11][12][13][14][15][16][17][18][...

Relationship between minimal residual disease measured by multiparametric flow cytometry prior to allogeneic hematopoietic stem cell transplantation and outcome in children with acute lymphoblastic leukemia

“…26 On the other hand, Bader et al reported that the administration of a low-dose of donor lymphocyte infusion in 31 children with mixed chimerism post-HSCT resulted in better outcomes. [27][28][29] In the present study, 16 patients had acute GVHD grade II-IV and no statistical differences were found in terms of event-free survival. Two of ten MRD-positive patients who are currently alive have chronic GVHD.…”

Derivation of human T lymphocytes from cord blood and peripheral blood with antiviral and antileukemic specificity from a single culture as protection against infection and relapse after stem cell transplantation

“…8 The other major cause of morbidity and mortality is relapse, occurring in more than 30% of transplant recipients with B-cell acute lymphoblastic leukemia (B-ALL), 9-12 with few appealing therapeutic options and less than 10% long-term survival. 13,14 Although donor lymphocyte infusions can be used after HSC transplantation to treat both viral infections and leukemia relapse, these are associated with potentially life-threatening GVHD, 15 have a low success rate in relapsed B-ALL, 15,16 and are unavailable for CB transplant recipients. An alternative for viral infections is the adoptive transfer of cytotoxic T lymphocytes (CTLs) directed to CMV, 17,18 EBV, 19,20 and, more recently, AdV, 21,22 which can rapidly reconstitute antiviral immunity after HSC transplantation without causing GVHD.…”

Treatment options for the management of acute leukaemia relapsing following an allogeneic transplant

“…Despite initial reports of success using DLI to treat relapsed ALL, 66 the success of this intervention has been a disappointment and remains largely anecdotal. 63,[67][68][69] This may be somewhat surprising, as in ALL there are a number of published studies [70][71][72] showing a strong association between a decrease in disease relapse in ALL patients who develop GvHD, suggesting that there is a strong GvL effect. A possible explanation for Table 1 The outcome reported in recent studies following donor leucocyte infusions for patients relapsing after an allograft 65 16 AML 16 31% (2 years) Kolb (1998) 58 43 ALL Unk B0 (2 years) Collins et al (2000) 73 44 ALL 28 13% (3 years) Choi et al (2005) 69 10 ALL 10 2/10…”