Acute Lymphoblastic Leukemia In First Remission Research Articles

Allogeneic Blood or Marrow Transplantation (AlloBMT) with High-Dose Post-Transplantation Cyclophosphamide (PTCy) for Acute Lymphoblastic Leukemia (ALL) in Patients Aged ≥ 55: Best Results in B ALL in First Remission (CR1) with Reduced-Intensity Conditioning (RIC)

Background: Older patients with ALL fare poorly with conventional chemotherapy. Patients aged 55-65 on E2993 and ≥ 60 treated with Hyper-CVAD have 5-year overall survival (OS) of just 21% and 20%, respectively (Sive. BJH. 2012 and O'Brien. Cancer. 2008). Recently, HyperCVD with inotuzumab +/- blinatumomab in patients ≥ 60 years old with Ph- B ALL demonstrated an improved 5-year OS of 47% with 38% of patients dying in remission (Short. Blood. 2021). AlloBMT provides an alternative consolidation strategy. Registry studies in ALL patients ≥ 60 years old and B ALL patients ≥ 55 years old who underwent alloBMT with RIC in CR1 demonstrated 5 and 3-year OS of 42% and 45%, respectively (Roth-Guepin. Oncotarget. 2017 and Rosko. Am J Hematol. 2017). These studies utilized heterogenous conditioning and graft-versus-host disease (GVHD) prophylaxis regimens. The use of high-dose post-transplantation cyclophosphamide as GVHD prophylaxis facilitates transplants in older adults with low rates of non-relapse mortality, GVHD, and the use of HLA haploidentical donors (Kasamon. JCO. 2015). Methods: The bone marrow transplant database at Johns Hopkins was queried for patients ≥ 55 years old who received a first alloBMT using PTCy from January 2008-January 2021. Characteristics of patients were summarized and compared using Fisher's exact test for categorical variables. Estimators of OS and relapse-free survival (RFS) were reported using the Kaplan-Meier method. Differences in time-to-event outcomes were estimated using Cox proportional hazards model, or Fine and Gray's model for cumulative incidence of relapse (CIR)/nonrelapse mortality (NRM) considering competing risks. Results: A total of 77 patients aged ≥ 55 underwent a first alloBMT with PTCy for ALL. The vast majority were performed in CR1 (85.7%), utilized RIC (88.3%), and were performed for B ALL (90.9%). Demographics and transplant characteristics are presented in Table 1. RIC consisted of fludarabine, cyclophosphamide and total body irradiation followed by PTCy-based GVHD prophylaxis as previously described (Kasamon. BBMT. 2008). Relapse-free survival (RFS) and OS at 5 years for the entire cohort were 46% (95% CI 34-57) and 49% (95% CI 37-60), respectively, with a 5-year CIR of 27% (95% CI 18-38) and NRM of 28% (95% CI 18-39). The cumulative incidences of grade 3-4 acute GVHD at 1 year and chronic GVHD at 3 years were 3% (95% CI, 0% to 9%) and 13% (95% CI 5% to 21%), respectively. In univariate analysis, the use of myeloablative conditioning led to worse RFS (HR 0.25, p=0.0004); while the absence of MRD (HR 2.93, p=0.008), transplant in CR1 (HR 3.81, p=0.0004), and transplant for Ph+ ALL vs. T ALL (HR 3.15, p=0.03) led to improved RFS. Subsequent analysis focusing on the 54 patients receiving RIC alloBMT in CR1 for B ALL demonstrated RFS and OS at 5 years of 61% (95% CI 46-73) and 64% (95% CI 49-76), respectively, (see Figure 1) with a 5-year CIR of 16% (95% CI 7-27) and NRM 24% (95% CI 13-36), although just 7% at 1 year. For B ALL patients transplanted with RIC in CR1, 3-year NRM was higher among patients who received a peripheral blood stem cell transplant (55%, 95% CI 18% to 81%), those treated with rituximab pre-transplant (36%, 95% CI 16% to 57%), and those who received ≥100 mg/m2 of doxorubicin equivalent for ALL (67%, 95% CI 19% to 90%). Outcomes did not differ among the 20% of patients who received pre-transplant blinatumomab compared to those who did not. Among the 23 Ph+ B ALL patients transplanted with RIC in CR1 following treatment with a 2nd or 3rd generation tyrosine kinase inhibitor (TKI), the 5-year CIR was 5% (95% CI, 0% to 22%). Conclusions: RIC AlloBMT with PTCy in CR1 represents a promising consolidation strategy for B ALL patients ≥ 55 years old. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Intensive Chemotherapy Along with Aggressive Supportive Care Can Spare Stem Cell Transplantation in a Subset of Patients without Compromising an Outcome in Infants with Acute Lymphoblastic Leukemia; A Report from the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) Trial MLL-10

BACKGROUND: Outcome of infants with acute lymphoblastic leukemia (ALL), especially those with rearrangement of MLL (KMT2A) gene (MLL-r), is extremely poor. A strategy to perform allogeneic hematopoietic stem cell transplantation (HSCT) for all the infants with MLL-r ALL in first remission (1CR) have been tested in the previous Japanese trials MLL96/98/03, however, the improvement was modest. Given the recent evidence of a limited role of HSCT especially in infants lacking poor prognostic factors, efficacy and safety of an intensive chemotherapy and risk stratification to limit HSCT for only infants with high-risk of relapse were evaluated in the JPLSG MLL-10 trial (UMIN000004801). PATIENTS & METHODS: Infants age less than 365 days with ALL were registered in the MLL-10 study and were stratified by their MLL gene status, age at diagnosis, and presence of CNS disease; low-risk (LR), if the patients had germline MLL gene (MLL-g); intermediate-risk (IR), if the patients with MLL-r ALL were age 180 days or older and lack CNS disease; high-risk (HR), if the patients with MLL-r ALL were age <180 days or having CNS disease. All the infants with MLL-r ALL received Interfant induction followed by COG AALL0631 post-remission chemotherapy with modification of adding high-dose cytarabine in early intensification phase. All the HR cases were allocated to HSCT in 1CR. LR cases were treated based on the Japanese MLL96/98 MLL-g chemotherapy. Minimal residual disease (MRD) was evaluated in 3 methods, flowcytometry, PCR of MLL fusion transcripts, and PCR targeting IgH/TCR rearrangements, but were not used to guide therapies. RESULTS: A total of 90 eligible infants with ALL were registered in the MLL-10 study between Jan/2011 and Dec/2014; 15 cases were stratified as LR, 19 as IR, and 56 as HR. Remission status was evaluated after 2 chemotherapy courses; 82 (91.1%) achieved 1CR, 3 failed to achieve 1CR, and 5 discontinued the trial before CR evaluation. No early death was observed. With median follow-up period of 1954 days (range, 534-2835 days) in the live patients, 3-year probability of event-free survival (pEFS) and overall survival (pOS) were 70.9% (95% CI, 60.0-79.3%) and 86.6% (77.6-92.2%), respectively. Among the MLL-r cases, 3-year pEFS and pOS were 66.2% (53.9-75.9%) and 83.9% (73.4-90.5%), respectively. According to the risk groups, 3-year pEFS were 93.3% (61.2-99.0%) for LR, 94.4% (66.6-99.2%) for IR, and 56.6% (42.4-68.6%) for HR cases. Regarding the MRD studies, correlation of MRD results in 3 methodologies seemed reasonable, but while flow-MRD could be evaluated in 85 cases, MLL-fusion PCR-MRD (MLL-r cases only) and IgH/TCR PCR-MRD could only be evaluated in 55 and 50 cases, respectively. In the univariable analysis for MLL-r cases, female sex (P=0.04), younger age at diagnosis (P=0.01), and 0.01%< flow-MRD after 2 courses of chemotherapy (P<0.01) had negative impact on pEFS. In multivariable analysis, female sex (P=0.01) and positive flow-MRD (P<0.01) were poor prognostic. Among the 38 HR cases who received HSCT in 1CR per protocol, 3-year probability of disease-free survival was 65.7% (48.3-78.4%) and only one non-relapse death was observed. CONCLUSIONS: Introduction of intensive chemotherapy enabled us to spare allogeneic HSCT in 1CR at least in a subset of infants with MLL-r ALL without compromising their outcome. This was accomplished also because of the aggressive supportive care provided to the study cases, such as full hospitalization during and after the intensive treatment phases, intensive use of rasburicase to prevent tumor lysis syndromes, and aggressive infection prophylaxis. However, outcome of HR MLL-r cases is still unsatisfactory, and introduction of novel agents is mandatory for further improvement in the outcome of infants with ALL. Figure Disclosures No relevant conflicts of interest to declare.

Comparison of self-report and electronic monitoring of 6MP intake in childhood ALL: a Children's Oncology Group study

AbstractAdequate exposure to oral 6-mercaptopurine (6MP) during maintenance therapy for childhood acute lymphoblastic leukemia (ALL) is critical for sustaining durable remissions; accuracy of self-reported 6MP intake is unknown. We aimed to directly compare self-report to electronic monitoring (Medication Event Monitoring System [MEMS]) and identify predictors of overreporting in a cohort of 416 children with ALL in first remission over 4 study months (1344 patient-months for the cohort) during maintenance therapy. Patients were classified as “perfect reporters” (self-report agreed with MEMS), “overreporters” (self-report was higher than MEMS by ≥5 days/month for ≥50% of study months), and “others” (not meeting criteria for perfect reporter or overreporter). Multivariable logistic regression examined sociodemographic and clinical characteristics, 6MP dose intensity, TPMT genotype, thioguanine nucleotide levels, and 6MP nonadherence (MEMS-based adherence <95%) associated with the overreporter phenotype; generalized estimating equations compared 6MP intake by self-report and MEMS. Self-reported 6MP intake exceeded MEMS at least some of the time in 84% of patients. Fifty patients (12%) were classified as perfect reporters, 98 (23.6%) as overreporters, 2 (0.5%) as underreporters, and 266 (63.9%) as others. In multivariable analysis, the following variables were associated with the overreporter phenotype: non-white race: Hispanic, odds ratio (OR), 2.4, P = .02; Asian, OR, 3.1, P = .02; African American, P < .001; paternal education less than college (OR, 1.4, P = .05); and 6MP nonadherence (OR, 9.4, P < .001). Self-report of 6MP intake in childhood ALL overestimates true intake, particularly in nonadherent patients, and should be used with caution.

Allogeneic transplantation is not superior to chemotherapy in most patients over 40years of age with Philadelphia-negative acute lymphoblastic leukemia in first remission.

Survival of patients ≥40years of age with Philadelphia-negative acute lymphoblastic leukemia (ALL) remains poor with current therapeutic approaches. It is unknown whether allogeneic hematopoietic stem-cell transplantation (HSCT) in first remission confers a survival benefit compared to a chemotherapy-only approach. We retrospectively compared the outcome of patients >40years treated with HSCT or chemotherapy alone in first remission (n=40 in each cohort). Three-year overall survival (OS) and disease-free survival (DFS) were not significantly different between the chemotherapy-only and HSCT groups (OS, 46% [31-68] vs. 40% [27-59], P=0.35; DFS, 31% [18-52] vs. 40% [27-59], P=0.98). The 3-year cumulative incidence of relapse (CIR) and non-relapse mortality (NRM) were 61% [41-76] and 9% [2-21] for the chemotherapy-only group and 28% [15-43] and 32% [17-47] for the transplant group (CIR, P=0.011; NRM, P=0.014). Allogeneic transplantation for patients ≥40years with Ph-negative ALL in first remission is associated with a lower CIR, but this benefit is offset by considerable NRM as compared with chemotherapy-only approach. HSCT may be beneficial in patients with high-risk disease features. Am. J. Hematol. 91:793-799, 2016. © 2016 Wiley Periodicals, Inc.

What Is the Optimal Consolidation Strategy for Adult Philadelphia Chromosome Negative Acute Lymphoblastic Leukemia Patients in First Complete Remission if You Are Not Able to Look for Minimal Residual Disease?

Compared to pediatric age group, the prognosis of adult patients with acute lymphoblastic leukemia (ALL) is still poor. Although most adult Philadelphia chromosome negative ALL (Ph- ALL) patients achieve complete remission following induction chemotherapy, half of them are destined to relapse, resulting 40% long term overall survival. Therefore, choosing the best available consolidation strategy in first remission is of utmost importance. Recently, most study groups rely on the evaluation of minimal residual disease (MRD) to guide the consolidation approach. But, in routine practice MRD assessment may be problematic in the management of Ph- ALL. In this review, we summarized the current evidence for optimal consolidation strategy in adult Ph- ALL in first remission, if facilities for MRD analysis are not in place.

6-Mercaptopurine (6MP) Intake during Maintenance for Childhood Acute Lymphoblastic Leukemia (ALL) - a Comparison of Self-Report and Electronic Monitoring: A Report from the Children's Oncology Group (COG) Study AALL03N1

▪Background: Adequateexposure to oral 6MP during maintenance is critical to sustain durable remissions. We have previously shown that poor systemic exposure to 6MP (as measured by poor adherence to oral 6MP) is associated with increased risk of relapse (JCO 30[17]:2094-101; Blood 124[15]:2345-53). Accurate assessment of 6MP intake is therefore critical to ensure timely interventions. Self-report is a convenient and inexpensive method to monitor 6MP intake in the clinical setting; however, literature in the non-oncology setting indicates that self-report is subject to over-reporting, and the extent of over-reporting is directly related to the number of missed doses. The accuracy of self/parent-report of 6MP intake during ALL maintenance is not known. We address this issue by comparing self-reported 6MP intake to electronic monitoring, and identify predictors of over-reporting of prescribed 6MP intake.Methods: Participants included 416 children with ALL in first remission receiving oral 6MP (75 mg/m2/d) during maintenance. 6MP intake was measured electronically using the Medication Event Management System (MEMS - objective record), which recorded the dates/times of each 6MP bottle opening over 4 study months per patient (28 days/month). The patient (or parent if <12y-old) self-reported the number of days that 6MP had been taken over the past month at the end of each of the 4 study months (subjective record). A total of 1344 patient-months of self-report and MEMS data were evaluated. Objective and subjective records of 6MP intake were compared for each patient by study month, and patients were categorized as "perfect reporters" (self-report = MEMS report), "over-reporters" (self-report > MEMS report: ≥5 days/month for >50% of study months) and "others." Logistic regression examined characteristics (age at study, sex, race/ ethnicity, 6MP non-adherence [MEMs-based adherence rate <95%], TPMT genotype, red cell TGN levels and 6MP dose-intensity) associated with over-reporting.Results: Median age at study entry was 6y (2-20); 36% were non-Hispanic white; 67% were male; 38.4% had high-risk disease; 40.4% were non-adherent to oral 6MP. Subjective vs objective 6MP intake: Mean (±SD) days of 6MP ingestion per month ranged from 25.8±5.3 to 26.1±4.5 by subjective reporting vs 22.8±6.4 to 25.4±4.5 by objective measurement (adjusted mean values by generalized estimating equations analysis, Figure 1A). The correlation between self-report and MEMS by study month ranged from 0.36 to 0.58 (Table). The difference between subjective and objective reporting was 0 for 39.6% patient-months; the difference was <0 for 7.7% patient-months, and was >0 for 52.7% patient-months (Figure 1B). A total of 50 (12%) patients were identified to be perfect reporters, 98 (23.6%) as over-reporters, and 64.4% as others. Predictors of over-reporting: Logistic regression modeling (adjusted for TPMT genotype, 6MP dose intensity and red cell TGN levels) identified the following independent predictors of over-reporting: i) Older age (Odds Ratio [OR]=1.07/y increase in patient age, 95% Confidence Interval [CI]=1.0-1.1, p=0.04); ii) Non-white race: Hispanic, OR=2.4, 95%CI=1.2-5.0, p=0.02); Asian, OR=3.1, 95%CI 1.2-8.3, p=0.02; African-American, OR=5.3, 95%CI 2.2-12.5, p<0.001 iii) Paternal education <college (OR=2.1, 95%CI=1.1-4.1, p=0.02); and iv) 6MP non-adherence (OR=8.6, 95%CI=4.7-15.9, p<0.0001) (Figure 1C). While 77/98 (78.6%) of over-reporters were non-adherent, only 1 of the 50 (2%) of the perfect reporters was non-adherent.Conclusions: Over-reporting of 6MP intake is common during maintenance therapy for childhood ALL. Over-reporting was more likely in patients who were non-adherent, older, of non-white race, and came from households with lower paternal education. Subjective reporting of 6MP ingestion during maintenance therapy for childhood ALL may be unreliable, particularly in non-adherent patients, and should be used with caution.Table6MP ingestion by self-report vs. MEMSStudy monthPatients (N)Self-report (days)(mean, SD)MEMS (days)(mean, SD)Correlationp-value127526.1 (4.5)25.4 (4.5)0.58<0.0433237026.1 (4.3)22.8 (6.4)0.44<0.0001335525.9 (4.9)23.7 (6.3)0.36<0.0001434425.8 (5.3)23.2 (6.7)0.43<0.0001 [Display omitted] [Display omitted] [Display omitted] DisclosuresEvans:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Relling:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping.

Impact of 6 Mercaptopurine (6MP) Pill-Taking Habits on Adherence, Thioguanine Nucleotide (TGN) Levels and Relapse Risk in Children with Acute Lymphoblastic Leukemia (ALL): Results from a Children’s Oncology Group (COG) Study (AALL03N1)

▪Background: Exposure to oral 6MP for ~2 years is critical for durable remissions in children with ALL. We have previously shown that poor 6MP adherence (rates <95%) is prevalent and increases relapse risk (JCO 30[17]:2094-101). 6MP is supplied in 50 mg tablets that may be swallowed, crushed, or chewed; patients are generally instructed to take 6MP with non-dairy liquid, in the evening on an empty stomach (~1-2h after a meal). These restrictive instructions could impose challenges in 6MP ingestion; the need for such restrictions with respect to clinical outcomes has not been examined systematically. This study examines the pill-taking habits of children with ALL and their association with adherence, risk of relapse and red cell TGN levels.Methods: Participants included 441 patients with ALL in first remission receiving oral 6MP (75 mg/m2/d) during maintenance. Adherence was measured using Medication Event Management System (MEMS) that recorded dates/times of each 6MP bottle opening for 6 mo/pt (58,086 patient-days of MEMS data). Average adherence rate (days MEMS bottle opened/days 6MP prescribed) over the 6m study period was computed to define non-adherence (adherence rate <95%). A 37-item questionnaire elicited pill-taking habits: i) 6MP never with food vs. with food; ii) 6MP never with dairy vs. with dairy; iii) 6MP pill swallowing (whole, crushed, chewed); iv) time of day 6MP always taken (evening, night, morning, midday, varying times); v) use of a routine: established routine vs. no routine. Monthly TGN levels (~6/pt) yielded 1,395 measurements. 6MP dose intensity [DI] was defined as dose prescribed/ protocol dose, and inherited capacity to metabolize 6MP was characterized by thiopurine methyltransferase (TPMT) genotype. Only TPMT wild-type patients were included in this analysis. 38 relapses occurred after a median follow-up of 6.1 years from start of maintenance (cumulative incidence of relapse: 8.9±1.4% at 6 years).Results: Median age at diagnosis was 6y (2-20); 67% were males; 40.3% had high-risk disease. 43.8% of the patients were non-adherent. Pill-taking habits and non-adherence: Time-varying generalized estimating equations (adjusted for age at study, ethnicity/race, income, and parental education) identified the following predictors of non-adherence: i) Taking 6MP with dairy (Odds Ratio [OR]=1.9, 95% Confidence Interval [CI]=1.3-2.9, p=0.003); ii) Taking 6MP at varying times vs. non-varying times (OR=2.4, 95%CI=1.2-4.7, p=0.008); iii) No routine (OR=1.7, 95%CI=1.1-2.7, p=0.02). Crushing the pill vs. swallowing whole was less likely to be associated with non-adherence (OR=0.7, 95%CI=0.4-0.99, p=0.05) [Fig 1A].Pill-taking habits and relapse: A proportional sub-distribution hazards model (adjusted for time from start of maintenance, NCI risk group, cytogenetics, race/ethnicity, age at study, and adherence) demonstrated no association between pill-taking habits and relapse risk: i) 6MP with food (Hazard Ratio [HR]=0.7, 95%CI=0.3-1.9, p=0.5); ii) 6MP with dairy (HR=0.3, 95%CI=0.07-1.5, p=0.2); iii) Swallowing tablet whole vs. crushing/chewing (HR=0.8, 95%CI=0.3-2.1, p=0.7); iv) 6MP in the evening/night vs. morning/mid-day (HR=1.1, 95%CI=0.2-7.5, p=0.9); v) 6MP at varying times vs. non-varying times (HR=1.0, 95%CI=0.2-4.5, p=0.9) [Fig 1B].Pill-taking habits and DI-adjusted TGN levels: Among adherent patients, there was no association between DI- and age-adjusted TGN levels and: i) 6MP with food (p=0.5); ii) 6MP with dairy (p=0.7); iii) Swallowing 6MP whole vs. chewing/crushing (p=0.4); iv) 6MP in the morning/midday vs. evening/night (p=0.5); v) 6MP at varying times vs. non-varying times (p=0.5) [Fig 1C].Conclusions: The association between non-adherence and certain pill-taking habits identifies a subgroup of patients that either did not receive appropriate instructions or did not adhere to them; our study was not designed to discern between the two scenarios. However, pill-taking habits were not associated with either relapse risk or TGN levels. These findings suggest that the commonly-practiced restrictions surrounding 6MP ingestion (i.e., taking only in the evening without food/dairy) might not influence outcome. [Display omitted] [Display omitted] [Display omitted] DisclosuresEvans:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties. Relling:St. Jude: In accordance with institutional policy (St. Jude), I and/or my spouse have in the past received a portion of the income St. Jude receives from licensing patent rights related to TPMT polymorphisms as clinical diagnostics. Patents & Royalties.

Long-Term Follow-up of Allogeneic Hematopoietic Stem Cell Transplantation for Patients with Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: Impact of Tyrosine Kinase Inhibitors on Treatment Outcomes

The introduction of tyrosine kinase inhibitors (TKI) has revolutionized therapy for patients with acute lymphoblastic leukemia (ALL) who have the Philadelphia (Ph) chromosome. A retrospective analysis was conducted on 102 adults and 11 children who received a first-matched related (n = 60), matched unrelated (n = 40), mismatched cord blood (n = 12), or haploidentical (n = 1) allogeneic hematopoietic stem cell transplantation (HSCT) for Ph-positive (Ph+) ALL in first complete remission (n = 71), second complete remission (n = 11), or with active disease (n = 31) between 1990 and 2009. Sixty-seven patients received TKI with upfront ALL therapy, and 32 patients received TKI maintenance following HSCT. With median follow-up of 5 years among survivors (range: 1.1-20.4 years), overall survival (OS) was significantly better for patients transplanted in first remission compared with HSCT in advanced disease: 43% versus 16%, P = .002. Disease stage and age at time of HSCT, the development of acute graft-versus-host disease (aGVHD), and decade of HSCT were found to significantly impact OS, progression-free survival (PFS), and nonrelapse mortality (NRM) in multivariate analyses. Allogeneic HSCT provides durable remission for patients with Ph+ ALL in first remission. Neither TKI use pre- nor post-HSCT were found to significantly impact transplant outcomes in univariate and multivariate analyses.

Allogeneic Bone Marrow Transplantation in First Remission for Children with Ultra-high-risk Features of Acute Lymphoblastic Leukemia: A Children’s Oncology Group Study Report

The prognosis for childhood acute lymphoblastic leukemia (ALL) has improved dramatically over the past quarter of a century. Despite improvements in the treatment of childhood ALL, relapse still occurs in 20%-30% of patients. Although many of these relapses occur in the “standard-risk” patients, approximately 10% of these patients present at diagnosis with clinical and biological features that identify them as having a very high risk of relapse. Children (2 months to 21 years) with ≥1 ultra-high-risk feature (UHRF) of ALL in first remission treated on a frontline Children’s Cancer Group (CCG) ALL study with a matched family allogeneic donor were eligible for study entry onto CCG-1921 and an allogeneic bone marrow transplant (AlloBMT). Each patient received fractionated total body irradiation (1200 cGy) and cyclophosphamide (120 mg/kg) conditioning therapy followed by unmobilized BM from a matched family donor. Graft-versus-host disease (GVHD) prophylaxis consisted of methotrexate and cyclosporin. Twenty-nine patients with a median age of 8.7 years with UHRF ALL in first complete remission (CR1) received an AlloBMT from a family member. The incidence of grade II-IV acute GVHD was 20.7% and the incidence of chronic GVHD was 3.7%. AlloBMT conditioning regimen was well tolerated and only 1 patient (3%) had treatment-related mortality. Ten patients (35%) died due to progressive disease. The 5-year event-free survival (EFS) for all patients was 58.6% and patients without cytogenetic abnormalities had a 5-year EFS of 77.8%. The 5-year EFS rates for infants and non-infants were 20.0% and 66.7% (log-rank test, P = .01), respectively. Patients with Philadelphia chromosome-positive ALL had a 5-year EFS of 66.7%. The children with UHRF of ALL may benefit from AlloBMT in CR1, especially patients with primary induction failure and Philadelphia chromosome-positive ALL. Randomized prospective cooperative group studies are required to establish the role of allogeneic hematopoietic stem cell transplantation versus intensive chemotherapy in children with UHRF ALL in CR1.

Early PCR-negativity after allogeneic BMT in adults with t(4;11) ALL in the absence of acute or chronic GVHD.

Acute lymphoblastic leukaemia (ALL) with the t(4;11) translocation has a very poor prognosis following conventional chemotherapy. Many patients are offered an allogeneic BMT in first remission. We report on the impact of allogeneic BMT on three patients with t(4;11) ALL in first remission. Median age was 20 years. One patient received marrow from an HLA-identical sibling and the other two from unrelated donors. All three engrafted and none of the patients developed acute or chronic GVHD. Remission status was monitored using a sensitive nested RT-PCR to detect the ALL-1/AF-4 hybrid transcript. All three were PCR-negative at 3 months post-BMT. One of the unrelated recipients died of a fungal infection 4 months post-BMT. The other two are alive and in molecular remission at 21 and 24 months post-BMT. This is the first report of longitudinal follow-up of t(4;11) ALL post-allogeneic BMT by PCR. The early attainment of molecular remission in the absence of GVHD suggests that the conditioning regimen may have been more important than a graft-versus-leukaemia effect in these patients. Follow-up of larger numbers of patients will be required to confirm these preliminary observations.

Delphi-panel analysis of appropriateness of high-dose therapy and bone marrow transplants in adults with acute lymphoblastic leukemia in first remission

Background: There is controversy over whether high-dose therapy and a bone marrow transplant is better than conventional-dose chemotherapy in adults with acute lymphoblastic leukemia (ALL) in first remission. This decision may depend on which type of donor is available: an HLA-identical sibling, an alternative donor transplant (HLA-matched related or unrelated people other than HLA-identical siblings), or autotransplant. Objective: To determine the appropriate use of high-dose therapy and bone marrow transplants in ALL in first remission. Develop a treatment algorithm. Panelists: Nine leukemia experts from diverse geographic sites and practice settings. Evidence: Boolean MEDLINE searches of acute lymphoblastic leukemia and chemotherapy and/or transplants. Consensus process: We used a modified Delphi-panel group judgment process. Age, white blood cell (WBC) count, cytogenetics and immune type were permuted to define 48 clinical settings. Each panelist rated appropriateness of high-dose therapy and a transplant versus conventional-dose chemotherapy on a 9-point ordinal scale (1, most inappropriate; 9, most appropriate) considering three types of donors: (1) HLA-identical siblings; (2) alternative donors; and (3) autotransplants. An appropriateness index was developed based on median rating and amount of disagreement. Relationship of appropriateness indices to the permuted clinical variables was considered by analysis of variance and recursive partitioning. Preference between donor types was analyzed by comparing mean appropriateness indices of comparable settings and a treatment algorithm was developed. Conclusions: In people with an HLA-identical sibling donor, transplants were rated appropriate in those with unfavorable cytogenetics and uncertain in all other settings. An HLA-identical sibling donor was always preferred to an alternative donor or autotransplant. In people without an HLA-identical sibling but with an alternative donor, this type of transplant was rated appropriate in those with unfavorable cytogenetics. However, an autotransplant was preferred over an alternative donor transplant in all other settings where a transplant was rated uncertain. In people without an HLA-identical sibling or alternative donor, autotransplants were rated uncertain in all settings except in those with not unfavorable cytogenetics, WBC<100×10 9 l −1 and T- or pre-B-cell type where they were rated inappropriate.

10 Bone marrow transplantation for acute lymphoblastic leukaemia

Allogeneic bone marrow transplantation (BMT) has been used in the treatment of poor risk acute lymphoblastic leukaemia (ALL) for over 20 years. Over this period results have improved and indications for treatment have become more clearly defined. Over 60% of adults and over 70% of children with poor risk ALL in first remission, and 30-40% of patients in second remissions can be expected to achieve long term leukaemia-free survival. Factors implicated in the cure of ALL by BMT are the myeloablative preparative regimen, a graft-versus-leukaemia effect, and post transplant chemotherapy. Improved results of chemotherapy have changed the perceived indications for BMT in ALL and have led to controversy over the best treatment approach. However there is good evidence to show that BMT offers a better chance of leukaemia free survival in certain very poor risk categories. These include Philadelphia chromosome positive ALL, remission induction failures, and children in second remission who relapse after adequate chemotherapy. Particular issues in the use of BMT in ALL are the prevention and management of extramedullary leukaemia, the treatment of relapse following BMT, and the prevention and monitoring of late effects. In the future the use of unrelated donors, and a continuing fall in transplant related morbidity and mortality will extend the use of BMT in poor risk ALL.

Bone marrow transplantation for high-risk childhood lymphoblastic leukaemia in first remission: experience in MRC UKALLX

Bone marrow transplantation (BMT) has been recommended for children with high-risk acute lymphoblastic leukaemia (ALL) in first remission. The recent MRC UKALL X trial was designed to facilitate a non-randomised comparison between BMT and chemotherapy in children deemed to be at high risk of treatment failure. 198 children aged 1-15 had a presenting leucocyte count of more than 100 x 10 9/l. All received induction and early intensification therapy. Children with an HLA-compatible sibling donor were eligible for BMT in first remission. All other children received cranial irradiation at 24Gy, late intensification, and two years of continuous treatment. 183 children achieved a stable remission of whom 111 were HLA typed; these tended to be older and to have T-cell ALL. A donor was identified in 41 cases, of whom 34 proceeded to BMT at a median time of 17 weeks; there was no difference in distribution of age, sex, or leucocyte count between the groups receiving BMT and chemotherapy. Comparison of the 144 children who were in remission at 17 weeks and received chemotherapy with the 34 proceeding to BMT showed no significant difference in event-free survival at five years (69% for BMT and 52% for chemotherapy). There were significantly more treatment-related deaths in the marrow transplant group (6 vs 4) and more relapses in the chemotherapy group (59 vs 4). There was no significant difference in event-free survival between children who were HLA typed and had a donor and those without a donor, although there were fewer relapses among the former. BMT can be evaluated in the context of a multicentre trial for paediatric ALL but the number of children with donors is too small to make a significant impact on overall survival. However, marrow transplantation was associated with a much lower relapse rate than that with the UK ALL protocol, and with better definition of higher risk patients BMT may be of benefit in some children with high-risk ALL in first remission.

Chemotherapy Compared with Bone Marrow Transplantation for Adults with Acute Lymphoblastic Leukemia in First Remission

To compare efficacy of intensive postremission chemotherapy with allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia (ALL) in first remission. Retrospective comparison of two cohorts of patients. Chemotherapy recipients were treated in 44 hospitals in West Germany in two cooperative group trials; transplants were done in 98 hospitals worldwide. Patients (484) receiving intensive postremission chemotherapy and 251 recipients of HLA-identical sibling bone marrow transplants for ALL in first remission. Patients ranged from 15 to 45 years of age and were treated between 1980 and 1987. Similar prognostic factors predicted treatment failure (non-T-cell phenotype, high leukocyte count at diagnosis, and 8 or more weeks to achieve first remission) of both therapies. After statistical adjustments were made for differences in disease characteristics and time-to-treatment, survival was similar in the chemotherapy and transplant cohorts: Five-year leukemia-free survival probability was 38% (95% CI, 33% to 43%) with chemotherapy and 44% (CI, 37% to 52%) with transplant. No specific prognostic group had a significantly better outcome with one treatment compared with the other (6% for the difference; CI, -3% to 15%). Causes of treatment failure differed: With chemotherapy, 268 (96%) failures were from relapse and 11 (4%) were treatment-related; with transplants, 43 (32%) failures were from relapse and 92 (68%) were treatment-related. These results suggest that bone marrow transplants currently offer no special advantage over chemotherapy for adults with acute lymphoblastic leukemia in first remission.

Autologous Bone Marrow Transplantation in Acute Lymphoblastic Leukemia following In Vitro Treatment with Monoclonal Antibodies and with Complement: Analyses for Two Cases of Failure

Two children with acute lymphoblastic leukemia (ALL) received autologous bone marrow transplantation (BMT) using remission bone marrow treated in vitro with the monoclonal antibodies, CD24 (BA-1), CD9 (BA-2) and CD10 (BA-3), and with rabbit complement. In one child with second remission ALL, hematopoietic recovery after BMT was prompt but, 81 days after BMT, isolated central nervous system (CNS) relapse occurred. Bone marrow relapse developed three months later, and she died 11 months after BMT. In patients with CNS leukemia prior to BMT, as in the present case, more intensive pretransplant CNS treatment and/or a conditioning regimen may reduce the risk of relapse. In the other patient, with primary refractory ALL in first remission, marrow reconstitution was slower. The patient developed interstitial pneumonitis with pleural effusion, and died 54 days after BMT. No infectious causes could be detected by culture or from serological studies of the pleural effusion. The rationale for applying autologous BMT to children with second remission ALL and first remission refractory ALL is discussed.