Pediatric marrow transplantation for acute leukemia using unrelated donors and T-replete or -depleted grafts: a case-matched analysis

Summary:High MRD levels before transplantation in children receiving T cell-depleted unrelated grafts for relapsed ALL were associated with a 100% relapse risk. We report on two children with relapsed ALL who underwent non T cell-depleted BMT from unrelated donors. Despite a high residual tumor load pretransplant and the occurrence of only aGVHD grade I, they are still in second complete remission 2.7 and 5.2 years after transplantation, respectively. Thus, we propose that the transplant regimens influence the prognostic significance of high MRD levels pre-BMT. Bone Marrow Transplantation (2001) 28, 1087-1089. Keywords: childhood ALL; bone marrow transplantation; minimal residual disease Minimal residual disease analysis by clone-specific IgH and TCR gene rearrangements is accepted as a reliable method for monitoring submicroscopic disease in childhood ALL. Several studies revealed the highly predictive value of MRD in the early phase of front-line chemotherapy. [1][2][3] Recent emphasis is being placed on the application of MRD before transplantation, since one of the major problems after SCT is the high incidence of relapses even in patients transplanted in morphological remission. Thus, the detection of submicroscopic levels of leukemic cell burden is thought to be of additional prognostic value in outcome prediction after allo-BMT for ALL.Recently, Knechtli et al 4 showed that high MRD levels of equal or more than 10 −3 within 4 weeks before transplantation were significantly correlated with a poor outcome after transplantation. Their study was performed in children with ALL transplanted from T cell-depleted matched and mismatched unrelated grafts in first, second or subsequent remission. We report here on two children who underwent allogeneic BMT for relapsed ALL with non-T cell-depleted grafts from unrelated donors. Both chil- dren had high MRD levels of equal or more than 10 −2 using clonotypic IgH and TCR gene rearrangements as molecular markers 3 weeks before transplantation. They are still in CR after an observation time of 2.7 and 5.2 years from transplantation, respectively. These data suggest that different transplantation regimens may influence outcome after BMT in childhood ALL and, thus, the prognostic value of MRD analysis pre-BMT. PatientsWe retrospectively analyzed MRD levels 2 to 4 weeks before allogeneic non-T cell-depleted BMT in 13 children with ALL. Two of the four patients with high MRD levels of equal or more than 10 −2 pre-BMT did not relapse and are reported here. Both children were treated according to current BFM protocols (ALL-BFM 90; ALL-Rez-BFM 96 protocol). 5 They were in morphological remission before BMT. Bone marrow graft processing and supportive care were done according to standard procedures. HLA compatibility was assessed by conventional serological typing for class I and class II, and by DNA sequencing of class II antigens. Patient 1Pre-B ALL was diagnosed in a female aged 11.3 years. WBC count at diagnosis was 68 × 10 9 /l. Cytogenetic analysis revealed a normal karyoty...

Section: Discussionsupporting

confidence: 71%

Influence of transplantation regimen on prognostic significance of high-level minimal residual disease before allogeneic stem cell transplantation in children with ALL

Schneider

Hettinger

Matthes‐Martin

et al. 2001

“…9 GVHD was responsible for only 5% of deaths in our series, in contrast to studies with T-replete URD BMT in which grades III-IV acute GVHD occur in up to 45% of serologically matched recipients. 3,14,15 TCD has been reported to increase the risk of leukemic relapse, and the UK Campath study for ALL noted a relapse rate of 67%. 4 However, our relapse rate was 6% for ALL patients, and 23% for the AML/MDS patients, which is comparable to studies of T-replete URD BMT for pediatric leukemias.…”

Section: Discussionmentioning

confidence: 99%

“…However, these alternative donor transplants are associated with increased graft-versus-host disease (GVHD), graft rejection, and slow immune reconstitution. [1][2][3] T-cell depletion (TCD) may decrease the risk of GVHD, but some studies have shown an increased risk of rejection and relapse due to the loss of the graft vs. leukemia effect. 4,5 Partial (TCD) may decrease the risk of GVHD, yet allow for engraftment and retention of a graftvs-leukemia effect.…”

mentioning

confidence: 99%

Outcomes of transplantation with partial T-cell depletion of matched or mismatched unrelated or partially matched related donor bone marrow in children and adolescents with leukemias

Bunin

Aplenc

Leahey

et al. 2004

Summary:Graft-versus-host disease (GVHD) remains a major barrier to successful hematopoietic stem cell transplant for patients who lack a matched related donor. Partial T-cell depletion (TCD) of the graft may decrease the risk of severe GVHD with unrelated donors (URD) and partially matched related donors (PMRD) while retaining an antileukemic effect. We analyzed our experience using URD and PMRD for pediatric patients with leukemias from 1990 to 2001. A subgroup of 'matched' URD donor pairs was retrospectively analyzed for high-resolution class I. Partial TCD was accomplished with monoclonal antibody T10B9 or OKT3 and complement. There were 76 URD (45% matched) and 28 PMRD recipients. Event-free survival (EFS) was 38.3%, and overall survival (OS) 45.1% at 3 years. On multivariate analysis, there was no difference in survival based upon marrow source, but nonrelapse mortality was higher with the use of PMRD. Relapse occurred in 6% of ALL patients, and 22.8% of AML/MDS patients. Grades III-IV GVHD was observed in only 6.7% of patients. Partial TCD allows use of matched or mismatched URD, or PMRD with little mortality from GVHD, durable engraftment, and no increase in relapse risk. Bone Marrow Transplantation (2005) 35, 151-158.

“…18 The probability of relapse may be decreased by using T-replete transplants at the expense of more acute and chronic graft-versus-host disease (GVHD) and a higher TRM. 19 On the other hand, relapse after allograft remains problematic as the chance of response to donor lymphocyte infusion (DLI) is very low (at 18 and 5% in the two largest published series 20,21 ) and usually is not durable. The possibility of using pre-emptive DLI in those subjects at high risk of relapse has been investigated in children and it may be possible to apply these techniques to adults.…”

Section: Specific Indications For Ud Hsct In Adult Allmentioning

confidence: 99%

Alternative donor transplants for adult acute lymphoblastic leukaemia: a comparison of the three major options

Marks

Aversa

Lazarus

2006

Myeloablative sibling-matched allogeneic transplantation for adult acute lymphoblastic leukaemia provides the best outcome, but most patients lack a suitable, related histocompatible donor. We reviewed three haematopoietic stem cell donor sources used for alternative donor transplantation pointing out drawbacks of these approaches including inherent selection bias. Matched unrelated donor allografts most often are performed in Philadelphia chromosome-positive disease and in second complete remission (CR2); a nearly 30% event-free survival (EFS) can be anticipated in select patients. Transplants using haploidentical donors are most successful if undertaken in CR1 and CR2 and appear to produce EFS rates of about 25%. Limited umbilical cord blood transplant data suggest efficacy, but marked patient and treatment heterogeneity hamper conclusions. Each of these three strategies has unique potential benefits and disadvantages. The growing use of minimal residual disease detection may identify subgroups of patients unlikely to be cured by chemotherapy alone; these patients are candidates for upfront high-dose chemoradiotherapy and cellular immunotherapy. These three approaches are plagued by treatment-related mortality and relapse rates as high as 40%, but advances in technology and supportive care may make each stem cell source more feasible and efficacious.