Central Nervous System Relapse In Adults With Acute Lymphoblastic Leukemia After Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Introduction Central nervous system (CNS) recurrence after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. Our goal was to investigate the post-HSCT outcome of ALL patients and identify patient groups who may benefit from post-HSCT CNS prophylaxis. Methods In this two-center retrospective study, we studied all adult (age≥18) ALL patients who underwent HSCT at MD Anderson Cancer Center or Fred Hutchinson Cancer Research Center between 1997 and 2011. We included all adult ALL patients who were transplanted in the first or second complete remission (CR) and who received any prophylactic or therapeutic CNS therapy before HSCT. We assessed the cumulative incidence of systemic and CNS relapses in a competing risks framework with a competing risk of non-relapse death. Since data from second and subsequent relapses were not available, patients whose first relapse did not include CNS involvement were censored at the time of relapse. To analyze the association between post-HSCT CNS prophylactic therapy and CNS relapse, we used a landmark analysis, including only patients who had not relapsed or died by 3 months post HSCT. Results We included 415 adult ALL patients (239 in CR1 and 176 in CR2) who were transplanted with a myeloablative total body irradiation based (MA-TBI, n=252), myeloablative non-TBI based (MA-nonTBI, n= 130), or reduced intensity conditioning regimen (RIC, n=33). Median age at HSCT was 37 years (range 18-70; 59% male). Sixty seven patients (16%) had a history of pre-HSCT CNS involvement either at diagnosis or at time of first relapse, while 339 patients (81%) had no CNS disease at any time before HSCT. Overall 175 patients (42%) received CNS prophylaxis after HSCT. CNS prophylaxis included intrathecal methotrexate, cytarabine, or both agents. Two patients received prophylactic cerebrospinal radiotherapy. The median follow-up for the 189 surviving patients was 4.2 years. Sixteen patients (3.8% of all patients, 13.2% of all relapses) developed CNS relapse (11 isolated and 5 combined with marrow relapse) at a median of 231 days (range 38-1397) after HSCT. Seven of these patients had pre-HSCT CNS disease. The 4-year cumulative incidence of relapse after HSCT among all patients was 31.7% and 28.2% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.51). The 4-year cumulative incidence of CNS relapse was 6% and 2.6% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.16) (Figure 1). When the analysis was limited to the patients without prior CNS involvement, there was still no benefit to post-HSCT CNS prophylaxis (P=0.63). Patients with a prior history of CNS involvement with leukemia had a significantly higher rate for CNS relapse, 11.6% vs. 2.7% (P=0.003) (Figure 2). The 4-year rate of CNS relapse was not impacted by intensity of the HSCT conditioning regimen and was 3%, 4%, and 6.5% for RIC, MA-TBI, and MA-nonTBI, respectively. Conclusion CNS relapse is an uncommon event following HSCT for ALL in CR1 or CR2. Furthermore, neither the intensity of the HSCT conditioning regimen nor the routine use of post-HSCT CNS prophylaxis made a significant difference in the rate of post-HSCT CNS relapse in patients who had received CNS prophylaxis prior to HSCT. Not surprisingly, patients with a pre-HSCT history of CNS involvement had a significantly higher risk of CNS relapse after HSCT. Disclosures: No relevant conflicts of interest to declare.

Central Nervous System Relapse After Stem Cell Transplantation in Adolescents and Young Adults with Acute Lymphoblastic Leukemia: A Single-Institution Experience

“…While the trend has been to omit radiotherapy in pediatric patients, recent data suggest the addition of a CB in select adult ALL populations decreases rates of CNS relapse. 10 There are currently no data to guide management decisions in AYA patients regarding the use of CNS-directed therapy in patients who may be at high risk of CNS relapse post-HCT. Our study aimed to assess disease outcomes in high-risk AYA patients undergoing allo-SCT for ALL, with a focus on CNS failure and the addition of a CB to pretransplant TBI protocols.…”

How I treat Philadelphia chromosome–positive acute lymphoblastic leukemia

“…17 Even with allo-HCT, further CNS therapy may be necessary to prevent these events particularly in patients with initial presentation with CNS involvement, although this is not our routine practice. 42 What is the role of newer, more potent TKIs?…”

ASBMT Statement on Routine Prophylaxis for Central Nervous System Recurrence of Acute Lymphoblastic Leukemia following Allogeneic Hematopoietic Cell Transplantation

“…There are no prospective, and very limited retrospective, data regarding the role of post-transplantation CNS-directed prophylactic therapy. Wide variations in clinical practice have been reported in the literature [3,17]. The Fred Hutchinson Cancer Research Center reported a retrospective analysis from 1970 to 1980 that compared 198 patients with ALL who received (n = 127) or did not receive (n = 71) CNS ITT prophylaxis in the context of total body irradiation (TBI)-based myeloablative conditioning and allogeneic bone marrow transplantation (allo-BMT) [18].…”

“…The use of TBI with conditioning (P = .96), pretransplantation cranial irradiation (P = .91), and post-transplantation ITT prophylaxis (P = .33) did not confer protection from CNS relapse post-transplantation. Finally, in the largest multicenter retrospective analysis of the role of post-transplantation ITT CNS prophylaxis, which included 452 patients age 18 years who underwent allo-HCT for ALL in the contemporary era (2000 to 2011) [17]. Owing to institutional practice variations, the authors were able to compare the incidence of CNS relapse in ALL as related to the inclusion or omission of post-transplantation prophylaxis.…”

“…The ASBMT encourages well-designed and appropriately powered studies to address this important clinical question. [19] No 433; 116 with ALL In all 116 patients with ALL without post-allo-BMT ITT prophylaxis; no isolated CNS relapses Oshima et al, 2008 [20] No 1226; 352 with ALL Increased incidence of leukoencephalopathy in patients receiving ITT prophylaxis post-allo-HCT Hamdi et al, 2014 [17] No 457 with ALL Largest multicenter study; only 8 patients experienced isolated CNS relapse, most frequently in patients with previous CNS involvement Aldoss et al, 2016 [21] No 87 with ALL Most contemporary single-center experience exclusively addressing secondary CNS prophylaxis…”