High incidence of extramedullary relapse of AML after busulfan/cyclophosphamide conditioning and allogeneic stem cell transplantation

107

101

Summary:A total of 118 consecutive adult patients with acute leukemia (78 AML, 36 ALL, and four acute mixed lineage leukemia) underwent allogeneic hematopoietic cell transplantation (HCT) after conditioning with BuCy (n ¼ 113) or a nonmyeloablative regimen of busulfanfludarabine (n ¼ 5). After a median follow-up of 35.8 months (range, 6.4-91.0), 34 patients experienced at least one episode of leukemia relapse. Of 34 initial episodes, 14 (41%) occurred in extramedullary sites, with (n ¼ 8) or without (n ¼ 6) concomitant bone marrow involvement. The median time to relapse in the extramedullary sites was longer than that of relapse in bone marrow only (13.5 vs 6.1 months, P ¼ 0.046). Acute leukemia subtype and disease status at HCT showed an independent predictive value for overall relapse, as well as for extramedullary relapse with or without bone marrow involvement (Philadelphia chromosome positive acute leukemia vs low-risk AML, relative risk 22.68 (95% CI, 2.18-235.64); other than first CR vs first CR, relative risk 5.61 (95% CI, 1.80-17.51)), but not for bone marrow relapse. Our study suggests that there may be different pathogenetic mechanisms for bone marrow vs extramedullary relapse of acute leukemia after allogeneic HCT. The mode of relapse needs to be investigated in future reports of acute leukemia treated with allogeneic HCT. Bone Marrow Transplantation (2003) 32, 835-842. doi:10.1038/sj.bmt.1704223 Keywords: extramedullary relapse; acute leukemia; allogeneic HCT Allogeneic hematopoietic cell transplantation (HCT) is now considered part of a standard treatment modality for a significant subset of patients with acute leukemia. 1-3 The curative effect of allogeneic HCT is attributable to its ability to decrease leukemia relapse significantly when compared to conventional or high-dose chemotherapy including autologous HCT. This remarkable effect is due to the graft-versus-leukemia (GVL) effect that occurs after allogeneic HCT. Although the overall frequency of acute leukemia relapse is less after allogeneic HCT, a high proportion of extramedullary relapses 4-7 in extremely diverse sites has been reported, including the brain, [8][9][10][11] head and neck, [8][9][10]12 gastrointestinal tract, 13 breast, 14,15 liver, 9 pancreas, 16 urogenital tract, 13,17 spinal canal and paravertebral tissue, 8 bone and periosseous tissue, 13,14,18 pleura, 14 pericardium, 9 peritoneum, 19 and skin. 20 The median time from allogeneic HCT to acute leukemia relapse was longer in cases with extramedullary relapse with or without bone marrow involvement when compared to cases of bone marrow only relapse. [4][5][6] Uneven effectiveness of the GVL effect in the body of patients was suggested as one of the several possible mechanisms for the increased frequency and wide distribution of extramedullary relapse after allogeneic HCT. 4,6 However, other factors, such as nature of the leukemic blasts, status of acute leukemia at HCT, and conditioning regimen may also influence the frequency of extramedullary relapse.This study was undert...

Section: Discussionsupporting

confidence: 83%

mentioning

confidence: 99%

Bone marrow vs extramedullary relapse of acute leukemia after allogeneic hematopoietic cell transplantation: risk factors and clinical course

Choi

et al. 2003

107

101

“…Our finding is consistent with the data of Simpson et al 14 who reported a similar frequency of extramedullary relapse (45% of all relapses) with or without bone marrow involvement among 81 patients with AML. In both studies, patients received the BuCy regimen for preparation for BMT.…”

Section: Discussionsupporting

confidence: 83%

High frequency of extramedullary relapse of acute leukemia after allogeneic bone marrow transplantation

et al. 2000

Summary:We investigated the frequency and mode of relapses of acute leukemia after allogeneic BMT in a series of 50 consecutive patients. The median age of patients was 31.5 years with 26 males. Thirty-two patients had AML. Forty-three patients were in first CR. All patients received BuCy regimen with GVHD prophylaxis of cyclosporine plus methotrexate. After a median followup time of 22.4 months (range, 6.0-52.9), 14 patients (28%) relapsed. Seven patients (50%) relapsed in the bone marrow only; three (21%) relapsed in extramedullary sites only; and four (29%) relapsed in both extramedullary sites and bone marrow. Times to relapses in bone marrow only (median 6.3 months) were significantly shorter when compared to times to extramedullary relapses with or without bone marrow involvement (median 12.3 months, P = 0.048). Sites of extramedullary relapses varied widely among the patients. In conclusion, we observed a high frequency of extramedullary relapses of acute leukemia after allogeneic BMT (50%). The GVL effect observed in the extramedullary sites of the body may not be as effective as in the bone marrow in patients with acute leukemia after allogeneic BMT. Bone Marrow Transplantation (2000) 26, 147-152. Keywords: extramedullary relapse; acute leukemia; allogeneic BMT; GVL effect Twenty to 50% of patients with acute leukemia relapse with their disease after allogeneic bone marrow transplantation (BMT). Factors that predict relapse of leukemia after allogeneic BMT are status of disease at the time of BMT, T cell-depleted marrow transplantation, and absence of graftversus-host disease (GVHD). [1][2][3][4] It is now well known that relapse of acute leukemia is less frequent after allogeneic BMT than after autologous or syngeneic BMT and this is attributed to the graft-versus-leukemia (GVL) effect that occurs after allogeneic BMT. [5][6][7] In a series of 50 consecutive patients with acute leukemia who underwent allogeneic BMT in our hospital, we observed an unusually high frequency of extramedullary relapse. Overall, frequency of relapses (both medullary and extramedullary) was similar to the historically observed relapse rate of acute leukemia after allogeneic BMT. We hypothesized that the GVL effect observed after allogeneic BMT in extramedullary sites of the body may not be as potent as in the medullary site in patients with acute leukemia. In addition, the GVL effect may not be uniformly effective throughout the body in patients with acute leukemia. Patients and methods Transplantation proceduresDetailed transplantation procedures were described elsewhere. 8,9 All patients received the BuCy regimen (busulfan 4 mg/kg/day on days −7 to −4 and cyclophosphamide 60 mg/kg/day on days −3 to −2) for preparation for BMT. Regimens for prophylaxis of GVHD included cyclosporine 1.5 mg/kg intravenously every 12 h starting on day −1, then switched to an oral dose 4 times the intravenous dose when oral intake became feasible. Methotrexate 15 mg/m 2 was given intravenously on day 1, then 10 mg/m 2 was given on days 3, 6 and ...

“…This is relatively high compared to the largest reported series and also contrasts with the very low incidence of EM relapse of AML following standard-dose chemotherapy. [4][5][6]9 Bone was the most common site of EM relapse, although many different sites were affected. Previously reported cases included almost all conceivable locations.…”

Section: Discussionmentioning

confidence: 99%

“…5 Two reports, however, suggest a higher prevalence in patients with relapsed AML post alloBMT; Mortimer et al 4 noted an EM component in 20% of 95 patients and Simpson et al 6 described EM relapse in 10 of 22 patients.…”

mentioning

confidence: 99%

Extramedullary relapse after allogeneic bone marrow transplantation for haematological malignancy

Chong

Byrnes

Szer

et al. 2000

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.