Extramedullary relapse after favorable molecular response to donor leukocyte infusions for recurring acute leukemia

Relapse of pediatric acute lymphoblastic leukemia (ALL) remains the main cause of treatment failure after allogeneic stem cell transplantation (alloSCT). A high level of minimal residual disease (MRD) before alloSCT has been shown to predict these relapses. Patients at risk might benefit from a preemptive alloimmune intervention. In this first prospective, MRD-guided intervention study, 48 patients were stratified according to pre-SCT MRD level. Eighteen children with MRD level X1 Â 10 À4 were eligible for intervention, consisting of early cyclosporine A tapering followed by consecutive, incremental donor lymphocyte infusions (n ¼ 1-4). The intervention was associated with graft versus host disease Xgrade II in only 23% of patients. Event-free survival in the intervention group was 19%. However, in contrast with the usual early recurrence of leukemia, relapses were delayed up to 3 years after SCT. In addition, several relapses presented at unusual extramedullary sites suggesting that the immune intervention may have altered the pattern of leukemia recurrence. In 8 out of 11 evaluable patients, relapse was preceded by MRD recurrence (median 9 weeks, range 0-30). We conclude that in children with high-risk ALL, immunotherapy-based regimens after SCT are feasible and may need to be further intensified to achieve total eradication of residual leukemic cells.

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“…50,51 These interventions may be combined with adjuvant therapy and/or supportive chemotherapy to prevent relapses in immuneprivileged sites. 52 …”

Section: Discussionmentioning

confidence: 99%

Preemptive alloimmune intervention in high-risk pediatric acute lymphoblastic leukemia patients guided by minimal residual disease level before stem cell transplantation

et al. 2010

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“…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][19] analyses of larger patient groups in multicenter registry studies have shown that DLI alone has limited efficacy in ALL, with one of 12 patients in the European registry study 20 and two of 15 in the North American registry study 21 reported to achieve CR with DLI alone. In the Japanese registry study, DLI alone induced CR in six of 24 patients, but only one patient maintained CR for 1 year.…”

Section: Discussionmentioning

confidence: 99%

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

Choi

Lee

Kim

et al. 2005

Bone Marrow Transplant

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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][...

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“…Three patients have been reported with EM relapse while in sustained marrow remission following DLI for myeloid leukaemia relapsing post alloBMT, two of whom had significant GVHD. 15,17 Zomas et al 18 reported a patient with plasmacytomata which persisted despite DLI inducing marrow remission. Against the concept of site-dependent graftversus-tumour effects, however, are reports of EM relapse of acute leukaemia responding to DLI.…”

Section: Discussionmentioning

confidence: 99%

Extramedullary relapse after allogeneic bone marrow transplantation for haematological malignancy

Chong

Byrnes

Szer

et al. 2000

Bone Marrow Transplant

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Summary:We describe the risk factors for and the natural history and response to treatment of extramedullary (EM) relapse in 183 patients who underwent allogeneic bone marrow transplantation (alloBMT) for a variety of haematological malignancies at our institution over a 7. year period. Fifty-one patients relapsed; 15 had EM relapse either alone or in association with marrow involvement. A retrospective analysis found that the presence of chronic GVHD and a longer interval between transplant and relapse were independently associated with an increased risk of EM compared to marrow-only relapse. EM relapse was also associated with a longer post-relapse survival. Patients with EM relapse appeared to respond to cytotoxic therapy but not to DLI. EM relapse after alloBMT may be more common than previously thought and have a better prognosis than marrow-only relapse. While patients developing chronic GVHD after alloBMT have a lower overall relapse risk than those who do not, they may be more prone to delayed relapse at EM sites. Bone Marrow Transplantation (2000) 26, 1011-1015. Keywords: allogeneic bone marrow transplantation; extramedullary relapse; graft-versus-host disease; donor lymphocyte infusion Allogeneic bone marrow transplantation (alloBMT) is potentially curative therapy for haematological malignancies including acute leukaemia, myelodysplastic syndrome (MDS), and chronic myeloid leukaemia (CML). 1-3 However, 30-50% of patients transplanted for acute myeloid leukaemia (AML) beyond first remission eventually relapse -usually within 12 months. 4 The post-transplant relapse rate for advanced acute lymphoblastic leukaemia (ALL) is higher, and accelerated phase CML carries a relapse risk of up to 60%. 2,3 Disease relapse is usually in the bone marrow, but some patients develop extramedullary (EM) relapse either alone, or in association with marrow relapse. EM relapse after alloBMT has been thought to be rare and the prognosis relatively poor. A survey conducted by the European Group Little is known about predisposing factors, natural history and response to treatment of EM as compared to marrow relapse. We addressed these issues in a retrospective analysis of a cohort of patients with relapsed haematological malignancy following alloBMT. In this analysis, hepatosplenomegaly and lymphadenopathy were not considered manifestations of extramedullary disease. Leptomeningeal disease was not considered extramedullary unless positive cerebrospinal fluid cytology was accompanied by a structural lesion on radiological imaging.

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Extramedullary relapse after favorable molecular response to donor leukocyte infusions for recurring acute leukemia

Cited by 34 publications

References 30 publications

Preemptive alloimmune intervention in high-risk pediatric acute lymphoblastic leukemia patients guided by minimal residual disease level before stem cell transplantation

Preemptive alloimmune intervention in high-risk pediatric acute lymphoblastic leukemia patients guided by minimal residual disease level before stem cell transplantation

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

Extramedullary relapse after allogeneic bone marrow transplantation for haematological malignancy

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