ALBERT

Description: Patient-reported outcomes among survivors of pediatric hematopoietic stem cell transplant (HSCT) are understudied. We compared symptom prevalence, health-related quality of life (HRQOL), and risk factors in adult survivors of childhood hematologic malignancies treated with HSCT to those treated with conventional therapy and noncancer controls. Survivors of childhood hematologic malignancies (HSCT N = 112 [70% allogeneic, 30% autologous]; conventionally treated N = 1106) and noncancer controls (N = 242) from the St. Jude Lifetime Cohort Study completed surveys assessing 10 symptom domains and SF-36 HRQOL summary scores. Chronic health conditions (CHCs) were validated by clinical assessment. Multivariable logistic regression reveals that compared with noncancer controls, HSCT survivors endorsed a significantly higher symptom prevalence in sensation (OR = 4.7, 95% confidence interval [CI], 2.6-8.4), motor/movement (OR = 4.3, 95% CI, 1.6-11.0), pulmonary (OR = 4.6, 95% CI, 1.8-11.8), and memory domains (OR = 4.8, 95% CI, 2.5-9.2), and poorer physical HRQOL (OR = 6.9, 95% CI, 2.8-17.0). HSCT and conventionally treated survivors had a similar prevalence of all symptom domains and HRQOL (all P 〉 .05); however, HSCT survivors had a significantly higher cumulative prevalence for specific symptoms: double vision (P = .04), very dry eyes (P 〈 .0001), and trouble seeing when wearing glasses (P 〈 .0001). Occurrence of organ-specific CHCs, instead of transplant receipt, was significantly associated with a higher prevalence of all symptom domains (all P 〈 .05) in adult survivors of childhood cancer, except for pain and anxiety domains. This study found that patient-reported outcomes were equally impaired between HSCT and conventionally treated survivors, but poorer in both groups compared with noncancer controls. Poor patient-reported outcomes in all survivors of childhood hematologic malignancies correlated with the presence of CHCs, whether treated with conventional therapy or HSCT.

Description: Background: Discontinuation of E. coli- asparaginase in patients with acute lymphoblastic leukemia (ALL) upon severe allergic reactions is unavoidable. We aimed to examine the outcomes following E.coli- asparaginase discontinuation upon severe allergic reactions in ALL. Patients and methods : In Taiwan Pediatric Oncology Group (TPOG)-2002-ALL protocol (enrolled 2002-2012), intramuscular E. coli- asparaginase (Kyowa Hakko, Japan) was given at 5000 IU/m2 per dose thrice weekly for 3 weeks during the remission induction therapy of high-risk (HR) and very-high-risk (VHR) groups. During the first 20 weeks of continuation therapy, HR patients received weekly intramuscular E. coli- asparaginase 10,000 IU/m2 per dose every week. They also received two reinduction treatments during which E.coli- asparaginase was given at 5000 IU/m2 per dose thrice weekly for 3 weeks. Patients in VHR groups received one reinduction treatment during which E. coli- asparaginase was given at 5000 IU/m2 per dose thrice weekly for 2 weeks. Patients in standard-risk (SR) group, received no E. coli- asparaginase in induction, but were randomized to receive one or two reinduction phases, during which E. coli- asparaginase was given at 5000 IU/m2 per dose thrice weekly for 2 weeks. The scheduled cumulative doses of E.coli- asparaginase in each risk group were 30,000 IU/m2 or 60,000 IU/m2 in SR, 265,000 IU/m2 in HR and 75,000 IU/m2 in VHR group. We evaluated outcome of children enrolled in TPOG-2002-ALL protocol who had E. coli- asparaginase discontinued due to severe allergic reactions (marked swelling and redness at the injection site or anaphylaxis) between 2002 and 2012, and compared outcomes between those who with Erwinase continued and those who without after the discontinuation of E. coli- asparaginase. The distributions of the Kaplan-Meier estimates of event-free survival (EFS) and overall survival (OS) were compared using log-rank test. Chi-square test was used to compare each parameter between groups. Results: In 700 patients from 10 hospitals retrospectively studied, 52 patients had E. coli- asparaginase treatment discontinued due to the development of severe pancreatitis in 17 patients, severe thrombosis in 2, and severe allergic reactions in 33. In Taiwan, Erwinase has been available since 2012, and could be purchased from foreign countries before. PEG-asparaginase is not available in Taiwan. In the 33 patients had E. coli- asparaginase discontinued due to severe allergic reactions, 17 continued Erwinase and 16 did not. The parameters between these two groups were similar. They were of more HR group reflecting that HR patients received more E. coli- asparaginase than other patients. The 5-year OS did not differ significantly among the 648 patients without discontinuation (81±1.6%, mean±S.E.), the 17 with allergic reactions and continued with Erwinase (88±7.8%) and the 16 with allergic reactions not treated with Erwinase (87±8.6%). The P value for the difference between the latter two groups was 0.96. In the 16 patients who did not receive Erwinase, all the 10 patients, who had received 〉= 50% scheduled dose of E.coli- asparaginase before discontinuation, survived without events. Conclusions: We suggest that patients who had received 50% or more of the scheduled doses of E. coli- asparaginase before the development of severe allergic reactions do not need to continue treatment with Erwinase. This may be helpful in those who cannot afford Erwinase or in the vast majority of the world where Erwinase is not available. It also raises a question on that how much asparaginase is enough for the treatment of childhood ALL. Disclosures No relevant conflicts of interest to declare.

Description: Backgrounds and Purposes Minimal residual disease (MRD) monitoring has been proved to be the most important prognostic predictor in childhood acute lymphoblastic leukemia (ALL). The nationwide TPOG-ALL-2013 protocol (TPOG-2013), adapted from the St. Jude Total Therapy XV Study and Total Therapy XVI Study, was launched since January 2013. This is the first MRD-directed protocol for treatment of childhood ALL in Taiwan. Here, we report the improved treatment outcomes and the impacts of adherence to MRD time points. Patients and Methods Totally, 402 patients aged between 1-18 years and diagnosed before December 31, 2018, who had MRD monitoring at the major central laboratory (Chang Gung Memorial Hospital-Linkou), were enrolled with the last follow-up on June 30, 2019. According to TPOG-2013, two MRD measurements were scheduled on days 15-19 of induction (MRD1 time point, TP1) and days 35-42, end of induction (MRD2 time point, TP2) to make the definitive risk stratification to guide subsequent therapy. The methodologies of MRD measurement included multicolor flow cytometry for leukemia-associated immunophenotypes (LAIP) (82.3% of TPOG-2013 cohort), qPCR assay for clonally rearranged antigen-receptor genes (Ig/TCR) if no LAIP (12.5%). Since January 2018, reverse transcription real-time quantitative polymerase chain reaction (RT-qPCR) was applied to patients carrying fusion transcripts (5.2%) of TCF3-PBX1, ETV6-RUNX1, BCR-ABL1, KMT2A-AFF1 (AF4) and KMT2A-MLLT3. The clinical features and outcomes of patients treated with TPOG-2013 were compared with those of 1,300 patients treated with the previous TPOG-ALL-2002 protocol (TPOG-2002), which did not integrate the MRD monitoring. Results The median follow-up time of the 402 patients of TPOG-2013 cohort was 32.5 months (range, 1.0-79.2 months). There were no significant differences in gender, age, WBC counts, and lineage at diagnosis between the patients treated with TPOG-2002 and TPOG-2013. However, based on the MRD data, the percentages of patients assigned to each risk group of TPOG-2013 was statistically differed from those of TPOG-2002 (P〈 0.0001). The 5-year event-free survival (EFS) (% ± SE) was significantly improved from 78.1 ± 1.2 of TPOG-2002 to 85.4 ± 2.5 of TPOG-2013 (P〈 0.0001). Further, the cumulative incidences (% ± SE) of isolated CNS relapse and any CNS relapse significantly decreased from 4.0 ± 0.5 to 0.3 ± 0.3 (P= 0.001) and from 5.8 ± 0.7 to 1.2 ± 0.9 (P= 0.001), respectively. The issue of non-adherence to MRD monitoring emerged since the implementation of MRD-directed TPOG-2013. For further analysis, 321 (80%) patients with exact adherence (EA) to both TPs were assigned as MRD EA group; 80 (20%) patients who were non-adherence (NA) to either one of TPs as MRD NA group; and one patient died between the two TPs was excluded for the comparative outcome analysis. The rate of non-adherence decreased significantly from 26.5% in 2013 to 2.4% in 2018. The major causes of non-adherence for both TPs were delaying MRD monitoring due to neutropenic fever and documented infections. In MRD EA group, 12.5% of patients were upgraded to higher-risk treatment groups based on their MRD results. The MRD NA group had older age (≥ 10 years), lower standard-risk and lower incidence of ETV6-RUNX1 compared with MRD EA group. There were significant differences in outcomes between MRD EA and MRD NA groups: the 5-year EFS were 89.4 ± 2.4 and 71.9 ± 7.4, respectively (P= 0.0005), overall survival (OS) were 90.9 ± 2.1 and 75.6 ± 5.8, respectively (P= 0.0003), and the cumulative incidence of isolated CNS relapse were 0 and 1.4 ± 1.3, respectively (P= 0.048) (Figure 1). In multivariate analysis, older age (≥ 10 years), higher WBC count (≥ 50 × 109/L) at diagnosis and MRD non-adherence were independent predictors for inferior EFS. In addition to these three factors, a higher-risk classification also predicted an inferior OS (Figure 2). Conclusions Contemporary MRD-directed therapy has improved the treatment outcomes of childhood ALL in Taiwan. The adherence to MRD time points remains a significantly prognostic predictor in the era of MRD-guided treatment. Disclosures No relevant conflicts of interest to declare.

Description: Background and Objectives Enumeration of hematopoietic progenitor cells (HPC) using an automated hematology analyzer provides rapid, inexpensive, and less technically dependent prediction of peripheral blood stem cell (PBSC) mobilization. This study aimed to incorporate HPC enumeration along with other predictors for optimizing a successful harvest. Materials and Methods Between 2007 and 2012, 189 consecutive patients who proceeded to PBSC harvesting with a preharvest HPC ≥ 20 x 106 /L were recruited. A failed PBSC mobilization was defined as 〈 2 x 106 CD34+ cells/kg. Variables predicting a successful harvest identified by multivariate logistic regression and correlation analysis were subjected to classification and regression tree (CART) analysis. Results A total of 154 (81.5%) patients successfully achieved mobilization of CD34+ cells (median 8.18 x 106 CD34+ cells/kg). Five independent host predictors including age ≥ 60, a diagnosis of solid tumor, prior chemotherapy cycles ≥ 5, prior radiotherapy, and mobilization with G-CSF alone or high-dose cyclophosphamide, as well as laboratory markers including HPC and mononuclear cell (MNC) counts, were used for CART analysis. The number of host predictors with a cutoff at two, HPC cutoff at 28 x 106/L and MNC cutoff at 3.5 x 109 /L were best discriminative for successful prediction. In the decision tree algorithm, patients predicted as good mobilizers (0 to 2 risk factors) had a higher success rate (150/169, 88.8%) than that (4/20, 20.0%) of those predicted as poor mobilizers (3-5 risk factors). Moreover, patients predicted as good mobilizers and further with a HPC enumeration ≥ 28 x 106/L had a high probability of achieving successful mobilization (138/148, 93.2%). Conclusion Our CART algorithm incorporating host predictors, HPC enumeration and MNC count may improve prediction and thus increase the success of PBSC mobilization. Further prospective validation is necessary. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.

Description: Introduction The nationwide TPOG-ALL-2002 protocol for treating children with acute lymphoblastic leukemia (ALL) was activated in January 2002 in Taiwan. To eliminate cranial radiation (CrRT)-related sequelae and minimize the adverse prognostic impact of traumatic lumbar puncture with blasts (TLP), we conducted a prospective study beginning in 1999 to modify CNS-directed therapy with delayed first triple intrathecal therapy (TIT) and omission of CrRT for all risk groups of newly diagnosed ALL. This approach improved CNS control at the single-institution study (J Clin Oncol, 2014) and has been used in whole TPOG since January 2009. Patients with non-CNS-1 status (i.e., CNS-2, CNS-3 and TLP) have higher risk of CNS relapse and need intensive CNS therapy. On behalf of TPOG members, we reported the outcomes of these non-CNS-1 patients in the two eras (2002-2008 and 2009-2012) with or without the modified CNS therapy. Methods From 2002 to 2012, all newly diagnosed ALL children in Taiwan were enrolled in TPOG-ALL-2002 protocol (Leukemia, 2010). B-precursor ALLs were stratified into standard risk (SR), high risk (HR) and very high risk (VHR) groups, according to age, WBC count, cytogenetics and molecular analysis at diagnosis. T-cell ALL was designated as VHR. Since 2009, patients had been treated with TIT alone without CrRT. The first TIT was performed until the disappearance of blasts from peripheral blood (PB), no later than 10 days. SR patient with detectable PB blasts on day 8 was upgraded to HR group. SR with CNS-1 received 14 doses of TIT, and those with CNS-2, or TLP got 2 additional TITs during induction and 3 additional TITs during maintenance therapy. Totally, SR with CNS-2 or TLP received 19 doses of TIT. And SR patients with CNS-3 or cranial nerve palsy at diagnosis were classified as HR. For HR with CNS-1, 17 doses of TIT were given. If HR groups with CNS-2, CNS-3, or TLP, they will receive total 25 doses of TIT including 2 additional ones during induction and 6 additional ones during maintenance therapy. Before 2009, only SR and HR with refractory CNS leukemia (failure to clear CSF blasts after 3 consecutive TITs) and those with CNS relapse will receive CNS radiation. For VHR group before 2009, CrRT of 18 Gy was given to all patients at the end of remission induction. Instead, TIT was given for age 〈 2 years. After 2009, CrRT was totally omitted. VHR with CNS-1 received 19 doses of TIT. For VHR patients with CNS-2, CNS-3 or TLP at diagnosis, TIT was administered once/week until achieving CSF remission and then once 4 weeks during maintenance therapy. Results Since January 2009, all patients received TIT alone, irrespective of risk groups. The two cohorts, totally 1,366 patients, 909 treated with CrRT (2002-2008) and 457 without CrRT (2009-2012) were balanced in presenting features and distribution of CNS status. There were no significant differences between two eras in the event-free survival (EFS), overall survival (OS), incidences of isolated CNS relapse and any CNS relapse (Pediatr Blood Cancer, accepted June 2016). The number of patients with CNS-2, CNS-3 and TLP were 35, 26 and 19 before 2009; and 18, 10 and 9 after 2009, respectively. Patients with younger age (〈 1 year), higher WBC counts (〉 100 X 109/L), HR/VHR or MLL rearrangement had significantly more non-CNS-1 status in the era of 2002-2008. And the significant factors prone to be non-CNS-1 were male, T-lineage and HR/VHR with the first TIT delaying. There were no significant differences between the two eras in the 5-year EFS and OS. Though the incidence of 5-year any CNS relapse was not significantly different, fewer relapses were observed in the era of 2002-2008 (Table 1). Before 2009, eleven CNS relapses experienced between 1 month and 3.1 years (median, 10 months) after remission. Two relapses after 2009 occurred on 1 month and 7 months, respectively. Conclusions Delayed first TIT until the clearance of circulating blasts and total omission of CrRT did not compromise the survivals and CNS control of childhood ALL patients with CNS-2, CNS-3 and traumatic lumbar puncture with blasts. Moreover, this approach prevents the adverse sequelae caused by CrRT. Furthermore, a skillful TIT is mandatory to improve results. Disclosures No relevant conflicts of interest to declare.