The analysis of leukemic relapse after allogeneic bone marrow transplantation]

This report presents the analysis of leukemic relapse of 52 patients who received allogeneic bone marrow transplantation between July 1984 and May 1990. Conditioning regimen consisted of TBI + CY and GVHD prophylaxis consisted of cyclosporin-A and methotrexate. The relapse ratios of chronic myelogenous leukemia (CML) (21 in chronic phase, 1 in accelerated phase, 1 in blastic crisis), acute nonlymphocytic leukemia (ANLL) (all 17 in 1st CR), acute lymphocytic leukemia (ALL) (all 12 in 1st CR) were 13%, 18%, 25%, respectively, and 3 year disease free survival (DFS) was as follows, CML 68%, ANLL 72%, ALL 49%. Regarding acute GVHD grading and chronic GVHD presence, 3 year DFS was as follows, acute GVHD 0 degree: 59%, I degree: 78%, II degree-IV degree: 53%, chronic GVHD (+): 82% GVHD (-): 77%. In our center leukemic relapse has been the major cause of death after BMT since 1984. Among 9 relapsed cases, one recurred more than 3 years after BMT, and another one got recurrent leukemia of donor origin.     

Partial chimerism after T-cell-depleted allogeneic bone marrow transplantation in leukemic HLA-matched patients: a cytogenetic documentation

We evaluated serially by cytogenetics the blood and marrow chimerism of 38 leukemic recipients of HLA-matched bone marrow transplants (BMT) who were prepared by high doses of alkylating agents and fractionated total- body irradiation (2.2 Gy X 5). Donor or host mitoses were identified by examination of sex chromosomes in 32 patients or by evaluation of the polymorphism of other chromosomes after specific banding in six patients. Twenty-four patients were recipients of untreated BMT, and 14 were recipients of T-cell-depleted BMT. In the 24 patients who received untreated BMT, all showed successful engraftment, and only three had a transient mixed chimera. In the 14 recipients of T-cell-depleted BMTs, four rejected their grafts, and seven had mixed chimeras; these mixed chimeras were more frequent in blood lymphocytes than in marrow cells and could be detected up to 26 months after BMT. This high frequency of partial chimerism after T-cell-depleted BMT by comparison with a control group suggests that the donor's T cells play an important role in the eradication of host residual hematopoiesis after allogeneic BMT.     

Interferon alpha treatment of accelerated-phase chronic myeloid leukemia in relapse after bone marrow transplantation: a case with complete cytogenetic and molecular remission

We describe here a patient with Philadelphia-positive chronic myeloid leukemia who had a hematologic and cytogenetic relapse after bone marrow transplantation. A diagnosis of accelerated phase was made when an additional malignant clone was detected. This clone was probably derived from the primitive Philadelphia clone, with duplication and rearrangement of the Philadelphia chromosome. The patient was treated with interferon alpha 2a and experienced a complete cytogenetic and molecular remission, with full reconstitution of the donor marrow.     

半相合骨髓移植术后供者源白血病复发

目的:了解半相合骨髓移植术后供者源白血病复发的特点。方法:通过HLA基因型和血型鉴定及染色体核型分析,判定半相合骨髓移植术后供者源白血病复发,并分析移植前疾病特点、复发后治疗和预后。结果:4例患者半相合骨髓移植术后7-15个月供者源复发,复发白血病均为高危急性。移植后移植物抗宿主病程度较轻,3例复发患者1-3个月内死亡。结论:复发与移植前的高危状态有关,且多为急性白血病患者;复发后治疗难度大,预后差。     

Second bone marrow transplantation after leukemia relapse in 11 patients

Since June 1977 eight patients with acute leukemia and three with chronic myelogenous leukemia (CML) have undergone cytoreductive therapy prior to a second allogeneic or syngeneic bone marrow transplantation (BMT). The median age was 24 years (range 7-49 years) and the median time to second BMT was 495 days (range 122-1887 days). Prompt hematopoietic recovery was documented in 11/11 patients and verified by cytogenetic analysis in 7/11. Early death (less than 100 days) was the result of sepsis in one, veno-occlusive disease in one and interstitial pneumonitis in two. Of seven patients who survived beyond 1 year, two patients subsequently died, one as a result of acute respiratory failure and one of leukemia relapse. Five are currently disease-free at 8+, 20+, 42+, 49+ and 72+ months after the second BMT. In this patient population which is at high risk for resistant disease and treatment-related toxicity, a second preparative therapy and BMT may offer a durable disease remission with tolerable toxicity.     

Extramedullary relapse after allogeneic bone marrow transplantation for haematological malignancy

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 1/2 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.     

Cytomegalovirus infection after autologous bone marrow transplantation with comparison to infection after allogeneic bone marrow transplantation

Cytomegalovirus (CMV) infection was detected in 65 of 143 (45%) autologous bone marrow transplant (BMT) patients. CMV pneumonitis occurred in only 2% of the patients and CMV retinitis occurred in none. Infection occurred in half of the 40 initially seronegative patients and 47% of the 94 initially seropositive patients. Among initially seropositive patients, platelet recovery was slower in infected patients than in those not infected (97 v 35 days median, P = .003), and neutrophil recovery was slightly delayed in infected patients (31 days v 24 days, P = .02). Although the incidence of CMV infection was comparable in autologous and allogeneic BMT patients, CMV pneumonitis was less frequent in autologous BMT patients (2% v 12%, P less than .001). The risk for CMV pneumonitis in autologous BMT patients was comparable with that in allogeneic BMT patients without graft-v-host disease (GVHD) (2% v 6%), but significantly lower than the risk in allogeneic BMT patients with GVHD (2% v 23%, P less than .001).     

Hematologic and cytogenetic remission of 5q-refractory anemia after syngeneic bone marrow transplantation

Refractory macrocytic anemia with hypolobulated megakaryocytic nuclei and partial deletion of the long arm of chromosome 5 has been termed the 5q- syndrome. Although long survival has been reported in a few cases of 5q- refractory anemia, accumulating evidence suggests that this syndrome is a preleukemic state with risk of transformation to acute nonlymphocytic leukemia as well as complications of bone marrow failure. This report describes the first apparently successful therapy for this disorder in a young man who originally presented with a clinical picture consistent with pure red cell aplasia and normal marrow chromosomes but with hypolobulated megakaryocytic nuclei. He was treated with vitamins, androgens, and sequential trials of immunosuppressive therapy, all without response. Two years after diagnosis, repeated marrow cytogenetic studies showed a 5q- abnormality in 70 percent and later in 100 percent of marrow metaphases. Because of transfusion-induced hemosiderosis and the availability of a cytogenetically normal monozygotic twin, bone marrow transplantation was undertaken. In light of the clonal (and suspected preleukemic) nature of the 5q- syndrome, the patient's marrow was ablated with a busulfan plus cyclophosphamide regimen used for patients with nonlymphocytic leukemia. Sustained engraftment of cytogenetically normal marrow ensued. Two years after transplantation, and following six months of regular phlebotomy, the patient was hematologically normal with a normal serum ferritin level.     

Prediction and prevention of relapse of acute lymphoblastic leukaemia after bone marrow transplantation

Results of bone marrow transplantation (BMT) in 63 adults and children with ALL transplanted in the 5-year period 1979-83 were analysed. Twenty-one patients (33%) relapsed, 25% of the group died in relapse and 19% died from complications of BMT. The actuarial disease-free survival at 6 years was 38%. Relapse after BMT could be predicted by standard prognostic diagnostic features such as age, sex, cell type and presenting blast cell count. Patients transplanted in first remission selected for their poor prognosis had a lower relapse risk than a similar group of poor prognosis patients transplanted in second or subsequent remission (P less than 0.05). Relapse following second and subsequent remission BMT was predicted by a score based on standard prognostic features or by the pace of the disease: patients with an interval of less than 2 years between diagnosis and first relapse having a 15% actuarial disease-free survival, compared with 81% for patients with an interval greater than 2 years (P less than 0.001). These results emphasize that ALL is a heterogeneous disease and establishes the importance of determining relapse risk when selecting BMT and other treatment schedules for ALL patients.     

Isolated extramedullary relapse of acute lymphoblastic leukaemia after allogeneic bone marrow transplantation

Isolated extramedullary relapse of acute lymphoblastic leukaemia (ALL) with sparing of the marrow after allogeneic bone marrow transplantation (BMT) is a rare occurrence, and the mechanisms underlying the selective involvement of extramedullary sites remain undefined. These might be due to relapse in sanctuary sites where the leukaemic cells are resistant to chemotherapy, or a stronger putative graft-versus-leukaemia (GVL) effect in the marrow as compared with peripheral tissues. We report two ALL patients with repeated episodes of extramedullary relapse after BMT in whom both mechanisms might be operating. In the first patient, the marrow was in morphologic and molecular remission before isolated leukaemic relapse in the central nervous system (CNS) occurred. Subsequent secondary infiltration of leukaemic cells into the marrow was only evident molecularly but not morphologically, implying that the relapse had arisen in a sanctuary CNS site. In the second patient, a first relapse in the marrow, which was induced into morphologic and molecular remission by chemotherapy and donor lymphocyte infusion, was followed by extramedullary relapses without any subsequent involvement of the marrow. This suggested that factors, likely to be due to a GVL effect, were stronger in the marrow than in peripheral tissues.     

Evaluation of remission state in chronic myeloid leukemia patients after bone marrow transplantation using cytogenetic and molecular genetic approaches

The remission state of 13 Philadelphia positive chronic myeloid leukemia patients was studied after bone marrow transplantation (BMT) by cytogenetic and Southern blot analysis of the breakpoint cluster region (BCR) gene. Eight of 13 patients showed neither clinical nor genetic evidence of residual disease. In two patients hematological relapse was confirmed by cytogenetic and molecular analysis. Evidence for residual leukemic cells in otherwise complete remission was obtained genetically in three patients. One of the latter cases revealed BCR rearrangement despite negative cytogenetic findings, while in another patient cytogenetic relapse was observed without demonstrable rearrangement within the major BCR. Our results may indicate that cytogenetic and molecular genetic methods complement rather than replace each other for the detection of residual CML cells after BMT.     

Donor lymphocyte infusion induced molecular remission in relapse of acute myeloid leukaemia after allogeneic bone marrow transplantation.

Donor lymphocyte infusion (DLI) has been used successfully to induce remissions in relapse of acute myeloid leukaemia (AML) after bone marrow transplantation (BMT), but molecular eradication of leukaemia has rarely been documented. A patient with AML-M4Eo relapsed after HLA-identical sibling BMT in first complete remission (CR). Cytogenetic and molecular genetic investigations confirmed inv(16) and CBFbeta/MYH11 fusion characteristic of M4Eo. A second remission was obtained with chemotherapy. Full donor chimerism was demonstrated by fluorescence in situ hybridisation. However, molecular evidence of minimal residual disease still persisted, and donor lymphocyte infusion (DLI) was administered. This resulted in molecular eradication, and the patient remained in clinical and molecular remission 16 months from DLI. Our observations showed that, for AML relapse after BMT, molecular leukaemia eradication could be achieved by DLI so that, in cases where genetic markers are available, molecular monitoring should be performed to assess the efficacy of treatment.     

Molecular analysis of relapse in chronic myeloid leukemia after allogeneic bone marrow transplantation

Four patients with Philadelphia (Ph') positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone.     

Leukemic relapse 5 1/2 years after allogeneic bone marrow transplantation.

A 13-yr-old male with acute myelogenous leukemia was treated with various chemotherapy regimens for 3 1/2 yr and then underwent an allogeneic bone marrow transplantation. The donor marrow was successfully engrafted, and the patient remained in remission free of all chemotherapy. Then, 5 1/2 yr later, he developed an extramedullary relapse with a chloroma of his maxillary sinus. This case illustrates the need for prolonged followup of transplant recipients and suggest that statements proposing cure as a result of this procedure may be premature.     

Long-term follow-up after bone marrow transplantation for chronic myelogenous leukemia: factors associated with relapse

Data on 281 patients with chronic myelogenous leukemia who received bone marrow transplants were analysed. The median follow-up time was 40 months; 170 patients were in first chronic phase, 14 were in second chronic phase, 73 were in accelerated phase and 24 were in blastic crisis. The overall actuarial survival was 50% at 5 years. In multivariate analyses, the probability of relapse correlated with the phase of the disease, the method of total body irradiation, the T cell depletion of the marrow and the occurrence of a chronic graft-versus-host disease (GVHD). The probability of survival was better for patients with grade 0-1 GVHD than for patients with grade 2-4 GVHD. In contrast, the probability of disease-free survival was significantly better for patients who received a non-T cell-depleted marrow than for recipients of T cell-depleted marrow. Interval between diagnosis and transplant, splenectomy before transplant, patient age and donor recipient sex match were not significantly associated with outcome. Bone marrow transplantation in first chronic phase with an HLA identical non-T cell depleted marrow offers the better chance of prolonged leukemia-free survival.     

Donor leucocyte transfusions for relapse in myelodysplastic syndrome after allogeneic bone marrow transplantation

A 31-year-old man with refractory anaemia of excess blasts, which had karyotypic abnormalities, received an allogeneic bone marrow transplant (BMT). At time of relapse, 3 months after BMT, he was treated with donor leucocyte transfusions (DLT). Grade III acute GVHD (graft-versus-host disease) occurred 35 d after DLT which was fully reversed with cyclosporin and prednisolone. His condition was complicated by a herpes zoster infection. 2 months after DLT, neutrophil and platelet count were increased and karyotypic abnormalities disappeared. This observation demonstrates that DLT is an effective treatment for relapse of myelodysplastic syndrome (MDS) after BMT.