Central nervous system relapses after bone marrow transplantation for acute lymphoblastic leukemia in remission

Conflicting conclusions can be drawn from the available data concerning antileukemic efficacy and risks of intrathecal (i.t.) chemoprophylaxis to children after hematopoietic SCT (HSCT). To address this, we enrolled six transplantation centers with similar treatment and patient material. Of the 397 children included, 136 patients had received post-HSCT i.t. treatment (i.t. group) and 261 had not (non-i.t. group). The two groups were, apart from the i.t. therapy given or not given, at equal risk of post-HSCT central nervous system (CNS) relapse, which was the primary endpoint studied. Isolated CNS relapses were observed in 2 (1.5%) patients from the i.t. group and 2 (1%) from the non-i.t. group. Combined relapses, including CNS, involved 4 (3%) patients from the i.t. group and 6 (2%) from the non-i.t. group. Overall survival and the occurrence of neurological side effects did not differ significantly between the groups. There was no statistically significant difference in the incidence of isolated or mixed CNS relapses between the two groups, suggesting little or no benefit from i.t. therapy post-HSCT in children.

Section: Introductionmentioning

confidence: 99%

Use of intrathecal chemoprophylaxis in children after SCT and the risk of central nervous system relapse

Vettenranta

et al. 2010

“…43 Thus, the parallel efficacy of ABMT and conventional chemotherapy reported by the BFM group was not confirmed by us. 20 Moreover, even the data on relapse after ABMT (the patients with CNS involvement are considered at higher risk of relapse 44 ) and on TBI toxicity are reassuring in our experience. Only two local relapses were observed and no side-effects, such as major impairment of cognitive capacity or leukoencephalopathy, have been found to date in the patients who had received previous prophylactic cranial irradiation (data not shown).…”

Section: Discussionmentioning

confidence: 76%

Autologous bone marrow transplantation for childhood acute lymphoblastic leukaemia in Italy

Messina

Cesaro

Rondelli

et al. 1998

Summary:From January 1984 to December 1994, ABMT was performed on 154 children (101 males, 53 females; median age 10, range 3-21 years) with ALL and registered for BMT by the AIEOP (Italian Association of Paediatric Haemato-Oncology). All patients were in CR: 98 were in 2nd CR and 56 were in Ͼ2nd CR. Fifteen children (9.7%) died of transplant-related mortality. Ninety-five patients (61.6%) relapsed at a median of 5 (range 1-42) months after ABMT. The 8-year EFS according to pre-BMT status was 34.6% (s.e. 4.9) for 2nd CR patients and 10.6% (s.e. 5.6) for patients in Ͼ2nd CR. By univariate analysis, site of relapse (isolated extramedullary (IE) vs BM: EFS = 68.5% vs 18.2%; P Ͻ 0.0001) and TBI containing regimen (TBI vs no TBI: EFS = 48.1 vs 15.4%; P = 0.0023) were significant factors for 2nd CR patients. When the 2nd CR subset with BM involvement was analysed, TBI became insignificant (EFS = 25.4 vs 11.8%). No factors influenced EFS in patients in Ͼ2nd CR. By multivariate analysis, site of relapse was the only significant factor in 2nd CR patients (P Ͻ 0.0001). In conclusion, ABMT is an effective treatment after one early IE relapse. Few patients can be rescued after BM relapse. Keywords: childhood ALL; ABMT; BM relapse; isolated extramedullary relapse The introduction of intensive front-line therapy has improved the EFS for childhood ALL.1-3 Nevertheless, approximately 25% of children who achieve CR relapse in the BM or in extramedullary sites. After a BM relapse, in spite of aggressive second-line therapy, only 20-50% of cases survive long term at 4-6 years. relapse, most children develop BM relapse or refractory CNS leukemia. 7-11 After a testicular relapse, the reported 3-year EFS with conventional retreatment depends on the time of relapse: 20% for patients relapsing on therapy, 12,13 40% for patients relapsing during the first year after stopping therapy, 13,14 and 100% for patients who relapse later. 13Following a 2nd relapse, the likelihood of prolonged EFS is further diminished. Allogeneic BMT, from an HLAidentical sibling [15][16][17] or unrelated donor, 18 seems to be the treatment of choice following an early BM relapse. Unfortunately, only 25-30% of children has a family donor and it is not always possible to find a fully compatible or minor mismatched unrelated donor despite the increased size of bone marrow donor panels. The role of BMT after an early isolated extramedullary (IE) relapse is less clear. 19,20 In order to investigate whether ABMT could represent an alternative option for children lacking an HLA-identical donor, 21-23 we retrospectively analysed 154 ALL patients who underwent ABMT with varying remission status. Patients and methodsFrom January 1984 to December 1994, 154 ALL children in 2nd or subsequent CR underwent ABMT at 10 Italian paediatric BMT centres. The relevant data were collected by the AIEOP-BMT Registry via oriented reporting forms completed by the physician in charge at each BMT Centre. The front-line treatment was according to the AIEOP protocols of the 82, 85, 87, 88 se...

“…5,6 There is not enough data available to allow calculations of how many patients should receive i.t. prophylaxis in different diseases to prevent one CNS relapse in case i.t.…”

Section: Discussionmentioning

confidence: 99%

“…prophylaxis given after the transplantation was found to prevent CNS relapses in acute lymphoblastic leukaemia (ALL) but not in acute nonlymphoblastic leukaemia, 4 whereas in two other studies no effect on the CNS relapse rate in patients with acute leukaemia was seen. 5,6 Although the evidence for the usefulness of i.t. prophylaxis given either immediately before the transplantation or post-transplant has been very limited, such prophylaxis has been used since the 1970s.…”

mentioning

confidence: 99%

Use of intrathecal prophylaxis in allogeneic haematopoietic stem cell transplantation for malignant blood diseases: a survey of the European Group for Blood and Marrow Transplantation (EBMT)

Ruutu

Corradini

Gratwohl

et al. 2004

Summary:A survey was carried out among EBMT centres to describe the current practice concerning intrathecal (i.t.) prophylaxis in allogeneic stem cell transplantation for malignant diseases in patients with no central nervous system (CNS) manifestations of the disease at any time. A total of 90 centres reported their practice: 42 centres (47%) never used pre-transplant i.t. prophylaxis as part of the conditioning, whereas 48 centres (53%) gave i.t. prophylaxis to selected groups. The main indications were acute lymphoblastic leukaemia (ALL), acute myeloid leukaemia (AML), and lymphoma (53, 33, and 23% of all centres, respectively). Prophylaxis was usually given to all patients with ALL, but often restricted to high-risk patients in AML and lymphoma. Of the 90 centres, 29 (32%) gave prophylactic i.t. treatment after the transplantation, mainly for the same indications as pre-transplant. This survey illustrates the heterogeneity in the current practice of i.t. prophylaxis in allogeneic transplantation for malignant blood disorders in Europe. The documentation in the literature to support the use of i.t. prophylaxis as part of transplantation for malignant diseases in patients without preceding CNS involvement is sparse. Based on the rarity of isolated CNS relapse after allogeneic stem cell transplantation, EBMT does not recommend routine i.t. prophylaxis to patients without prior CNS involvement. In conventional allogeneic stem cell transplantation for malignant diseases, a central aim is to eradicate the malignant cells with the conditioning as completely as possible. As many drugs given intravenously or orally do not reach the central nervous system (CNS) in optimal concentrations, it might be logical to give intrathecal (i.t.) treatment as part of some conditioning regimens. Of the main components of the two most widely used conditioning regimens, total body irradiation (TBI) treats CNS effectively. After intravenous administration of cyclophosphamide, the alkylating activity is much lower in the cerebrospinal fluid than in the plasma, 1,2 whereas busulphan concentrations after oral administration are similar in the plasma and cerebrospinal fluid. Reports in the literature of CNS relapses after allogeneic transplantation and of the effect of i.t. prophylaxis on the CNS relapse rate are rare. We have not found any studies about the efficacy of i.t. prophylaxis pre-transplant as part of the conditioning. In one study, i.t. prophylaxis given after the transplantation was found to prevent CNS relapses in acute lymphoblastic leukaemia (ALL) but not in acute nonlymphoblastic leukaemia, 4 whereas in two other studies no effect on the CNS relapse rate in patients with acute leukaemia was seen. 5,6 Although the evidence for the usefulness of i.t. prophylaxis given either immediately before the transplantation or post-transplant has been very limited, such prophylaxis has been used since the 1970s. 4 The practice has varied from centre to centre. In order to try to standardize allogeneic transplantation procedures, we ca...