Intramuscular PEG-Asparaginase At 1000 U/m2 Achieves Adequate Trough Activity Levels in the Majority of Patients Treated on the UKALL 2003 Childhood Acute Lymphoblastic Leukemia (ALL) Protocol

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2573-2573 ◽  
Author(s):  
Caroline YK Fong ◽  
Catriona Anne Parker ◽  
Adiba Hussain ◽  
Jizhong Liu ◽  
Monika Essink ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Antibody Detection ◽  
Activity Levels ◽  
Post Induction ◽  
Chi Squared ◽  
Drug Induction ◽  
Asparaginase Activity ◽  
Time Point

Abstract Abstract 2573 Introduction: Polyethylene glycol conjugated L-asparaginase (PEG-ASNase) is used in varying doses between 1000–2500 U/m2 in the therapy of ALL and associated with a wide variation in pharmacokinetics. UKALL 2003 used intramuscular PEG-ASNase at 1000 U/m2. Patients & Methods: Patients enrolled in the UKALL 2003 trial (ISRCTN: 07355119), were consented for trough asparaginase activity analysis during therapy. National Cancer Institute (NCI) standard risk (SR) patients with rapid early response and non-high risk (HR) cytogenetics (Lancet Oncol. 2010;11:429) received a 3 drug induction (Dexamethasone, Vincristine & PEG-ASNase). All other patients received additional Daunorubicin. PEG-ASNase was given on days 4 and 18 of induction, and at least once post induction. Trough plasma asparaginase activity was measured by the indooxine method (Anal. Biochem. 2002;309:117). The lower limit of assay detection was 34 U/L. Adequate asparaginase activity was defined as a trough level of > 100 U/L. IgG and IgM antibodies to PEG-ASNase and native asparaginase were measured by indirect ELISA. Asparaginase activity was correlated with defined risk factors, minimal residual disease (MRD) at day 28 of induction and development of anti-asparaginase antibodies using the chi-squared test. Results: Between July 2008 to July 2011, 482 patients aged 1–25 years from 27 centres were recruited. Numbers of samples assayed in induction were 335 & 371 after first and second doses respectively. Overall, 86% (n=606/706) of samples had adequate activity during induction time points. There was > 10 fold variation in activity levels (Figure 1). Three hundred and nine out of 706 samples had activity > 3 times the therapeutic threshold, while 51/100 samples with inadequate activity had no detectable drug levels (median: below detection limit, range: < 34–99 U/L). Thus, increasing the dose of PEG-ASNase in induction is unlikely to benefit patients with inadequate activity. Compared to SR patients, NCI HR patients had a higher incidence of inadequate asparaginase activity in induction (p=0.002). Inadequate asparaginase activity correlated with high MRD (≥ 10−4) in SR patients (p=0.045), especially those with good risk cytogenetics (p=0.012), and in particular the high hyperdiploid subgroup (p=0.03). Inadequate asparaginase activity during induction did not correlate with MRD in HR patients (p=0.699), possibly because these patients received in addition Daunorubicin (Table 1). Results of serial asparaginase activity (at least one time point each in induction and post induction), measured in 282 patients are summarised in Table 2. Antibodies were detected in 18 of 81 patients tested. All had anti-PEG and 7 in addition also had anti-asparaginase antibodies. While all antibody positive patients had inadequate asparaginase activity at one time point, 17 had adequate activity prior to antibody detection, suggesting immune-mediated drug inactivation at re-exposure. Antibodies were not detected in 14/15 patients who had inadequate activity at first exposure, so the mechanism here remains unclear. The reported incidence of asparaginase toxicity in this study was 6.6% (n=32/482). This included hypersensitivity (n=17/482) that was almost exclusively seen in HR patients (n=16/17), thrombosis (n=10/482) and pancreatitis (n=5/482). Conclusions: Intramuscular PEG-ASNase given fortnightly at 1000 U/m2 during induction provides adequate asparaginase activity in 86% of patients. Monitoring asparaginase activity may benefit patients who receive 3 drug induction and improve the resolution of the current prognostic classification. Disclosures: Off Label Use: PEG-asparaginase. Essink:medac: Employment. Kuehnel:medac: Employment.

Excellent Event Free (EFS) and Overall Survival (OS) For Children With Standard Risk Acute Lymphoblastic Leukemia (SR ALL) Despite The Absence Of a Significant Impact On Outcome With The Addition Of An Intensified Consolidation: Results Of Children’s Oncology Group (COG) AALL0331

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 837-837 ◽  
Author(s):  
Kelly W. Maloney ◽  
Meenakshi Devidas ◽  
Leonard A. Mattano ◽  
Alison M. Friedmann ◽  
Patrick Buckley ◽  
...  
Keyword(s):  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Intensive Therapy ◽  
Risk Groups ◽  
Early Response ◽  
Treatment Intensification ◽  
Post Induction ◽  
Randomized Intervention ◽  
Drug Induction

Abstract The EFS/OS for SR (age 1-9.99 yrs and initial white blood cell count <50,000/microliter) B-cell precursor (B-ALL) patients (pts) has steadily improved over time. The COG AALL0331 SR ALL trial utilized a 3 drug induction without anthracylines, with post-induction assignment into refined risk groups (SR-Low, SR-Average (Av), SR-High) based on leukemia genetics and early response. COG studies have shown that intensified post-induction therapy improved EFS/OS in NCI high risk ALL patients <10 yrs of age; however, the relative value of individual components is uncertain. AALL0331 included a 2 X 2 randomization at end-induction to standard (SC) vs. intensified consolidation (IC) and standard interim maintenance (IM) / delayed intensification (DI) vs. intensified IM/DI for SR-Av (not Low or High) pts, defined as those whose leukemic blasts did not show triple trisomies (TT) of chromosomes 4+10+17, ETV6-RUNX1, or very high risk features and had an excellent early response based on day 8 (or 15) M1 (<5% blasts) bone marrow (BM) and end-induction minimal residual disease (MRD) <0.1%. The IM/DI randomization was closed in 2008 due to superior results of escalating IV methotrexate (MTX) during IM for SR ALL pts treated on CCG 1991; all pts subsequently received escalating IV MTX during IM. AALL0331 enrolled 5311 SR B-ALL pts from 4/2005-5/2010. All patients received a 3 drug induction (dexamethasone, vincristine (VCR), PEG-asparaginase (PEG), intrathecal (IT) MTX). SR-Av pts were randomized at end-induction between SC (mercaptopurine (MP) 75 mg/m2 d 1-28, VCR 1.5 mg/m2 d 1, IT MTX d 1, 8, 15) vs. IC (cyclophosphamide 1000 mg/m2 d 1,29, cytarabine 75 mg/m2 d 1-4, 8-11, 29-32, 36-39, MP 60 mg/m2 d 1-14, 29-42, VCR 1.5 mg/m2 d 15, 22, 43, 50, PEG 2500 units/m2 d 15, 43, IT MTX d 1, 8, 15, 22). Therapy following consolidation was the same for all SR-Av pts after 2008. The 5-yr EFS/OS for all evaluable SR B-ALL pts was 89% and 96% (see Table 1). IC did not significantly improve outcome for SR Av pts, with 5-yr continuous complete remission (CCR) rates for SC vs. IC of 88% (1.6%) vs. 89.3% (1.5%) (p=0.13) and 5-yr OS rates for SC vs. IC of 95.8% (1.0%) vs. IC 95.7% (1.0%) (p=0.93). Because COG has now shown that end-induction MRD of 0.01% is a better discriminator of poor outcome than the 0.1% level used in AALL0331, we examined overall outcome and the results of the randomized intervention in two different MRD defined subsets of SR-Av pts (Table 1). The 5-yr CCR rates for pts with MRD 0.01%-<0.1% were 77% (6%) and 76% (6%) for SC and IC (p=0.31) and 89% (1.6%) vs 91.5% (1.5%) for IC (p=0.08) for MRD <0.01%.Table 1Risk Group (# pts)5 year EFS (SE)5 year CCR (SE)5 year OS (SE)All pts  (5192)89% (0.6%)96% (0.4%)SR-High (636)85% (2%)94% (1%)SR-Low (1857)95% (0.7%)99% (0.3%)SR-Av (1500)89% (1.1%)96% (0.7%)MRD <0.01% (1310)91% (1.2%)96% (0.6%)MRD >0.01-<0.1% (172)77% (4.5%)92% (3%) The outcome for the 1857 SR-Low pts (TT or ETV6-RUNX1 plus d 8 (or 15) M1 BM and d 29 MRD <0.1%) was outstanding, with 5-yr EFS/OS of 95% and 99%. SR-High pts (d 15 BM ≥5% blasts and/or d 29 MRD ≥0.1%) who were non-randomly assigned to IC and 2 intensified IM/DI phases did very well with 5-yr EFS/OS 85% and 94%. The 5-yr EFS for this group (85%) was much better than that of SR Av pts (77%) with MRD 0.01-<0.1% who received less intensive therapy, emphasizing the benefit of intensifying treatment for pts with MRD >0.01% that is now part of all COG protocols. COG AALL0331 is the largest trial of SR B-ALL pts ever conducted and establishes the value of risk directed treatment intensification. Disclosures: Matloub: Novartis: Consultancy.

Efficacy and toxicity of pegaspargase and calaspargase pegol in childhood acute lymphoblastic leukemia/lymphoma: Results of DFCI 11-001.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 10006-10006 ◽  
Author(s):  
Lynda M. Vrooman ◽  
Traci M. Blonquist ◽  
Jeffrey G. Supko ◽  
Sarah K. Hunt ◽  
Jane E. O'Brien ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Induction Dose ◽  
Post Induction ◽  
Fda Approval ◽  
Dosing Strategies ◽  
Asparaginase Activity ◽  
To Receive

10006 Background: DFCI ALL Consortium Protocol 11-001 assessed the efficacy and toxicity of Calaspargase pegol (SC-PEG), a novel pegylated asparaginase (ASP) formulation with longer half-life, compared with standard pegaspargase (SS-PEG). Methods: Patients (pts) aged 1-21 years with newly diagnosed acute lymphoblastic leukemia (ALL) or lymphoblastic lymphoma (LL) were eligible. At study entry, pts were randomly assigned to receive either intravenous SS-PEG or SC-PEG, 2500 IU/m2/dose. Pts received 1 dose during the first treatment month. Beginning week 7, SS-PEG was administered every 2 weeks for 15 doses, SC-PEG every 3 weeks for 10 doses (30 weeks). Serum asparaginase activity (SAA) (considered therapeutic at ≥ 0.1 IU/mL) was assessed 4, 11, 18, and 25 days after the induction dose and before each post-induction dose. End-induction minimal residual disease (MRD) was assessed in ALL pts by IGH/TCR PCR. Results: Between 2012-2015, 239 eligible pts enrolled (230 ALL, 9 LL); 120 assigned to SS-PEG, 119 to SC-PEG. After dose 1, SAA remained ≥ 0.1 IU/mL in ≥ 95% of pts on both arms through day 18. Median SAA was higher (0.319 IU/mL vs 0.056 IU/mL) and more pts had therapeutic SAA (88% vs 17%, p˂0.001) with SC-PEG vs SS-PEG 25 days after dose 1. Post-induction, median nadir SAA (NSAA) were similar ( > 1.0 IU/mL) for both arms. There was no difference in rates of ASP-allergy, pancreatitis, thrombosis, hyperbilirubinemia, osteonecrosis, or infection. Of 230 evaluable pts, 99% of SS-PEG and 95% of SC-PEG pts achieved complete remission (p = 0.12). For B ALL pts, there was no difference in frequency of high end-induction MRD (10.3% SS-PEG, 9.5% SC-PEG, p = 1.0). With 4-year median follow-up, 4-year event-free survival (EFS) (90% confidence interval) for SS-PEG was 90.2% (84.3, 93.9), 87.7% (81.5, 91.9) for SC-PEG (p = 0.78); overall survival (OS) was 95.6% (91.0, 97.9) for SS-PEG, 94.8% (90.0, 97.3) for SC-PEG (p = 0.74). Conclusions: Every 3-week SC-PEG had similar EFS, OS, safety profile, and NSAA compared with every 2-week SS-PEG. The high NSAA observed for both preparations suggest dosing strategies can be further optimized. These data informed FDA approval of SC-PEG for pediatric pts. Clinical trial information: NCT01574274.

Minimal Residual Disease (MRD) at the End of Induction (EOI) after a Three or Four-Drug Induction Regimen for Childhood Standard-Risk B-Cell Precursor Acute Lymphoblastic Leukemia (SR-BCP-ALL): Interim Results of the FRALLE 2000-A Protocol.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1105-1105
Author(s):  
Jean-Michel Cayuela ◽  
Kheira Beljord ◽  
Claude Preudhomme ◽  
Helene Cavé ◽  
Jean-François Eliahou ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Surrogate Marker ◽  
Added Value ◽  
Weak Positivity ◽  
Sensitivity Range ◽  
Induction Regimen ◽  
Drug Induction ◽  
Genescan Analysis ◽  
To Receive

Abstract From Dec 2000 to Dec 2003, 390 children with SR-BCP-ALL (age: 1–9, WBC&lt;50 G/L, CNS-, no MLL-R, no BCR-ABL) were included in the FRALLE 2000 -A protocol. Induction regimen is: prednisone prephase for 7 days (60 mg/m2/d) +IT MTX, dexamethasone 6 mg/m2 (D8–D28), vincristine 1.5mg/m2(D8, D15, D22, D29), L-asparaginase 6000 U/m2 (9 infusions). Good marrow responders at D21(M1 pts) are randomized to receive or not daunorubicin (DNR) 40 mg /m2 at D22 and D29. D21 M2/M3 pts are not randomized and given DNR. MRD at EOI is determined by DNA-based PCR for Ig/TCR rearrangements. Two methods are used for quantification (competitive PCR with GeneScan analysis -sensitivity: 0.5x 10-3-, RQ-PCR with clone-specific probes- sensitivity range: 10-3-10-5). EOI MRD data are evaluable for 343 pts with D21 M1 response (DNR+= 169/ DNR−= 173/ not randomized = 1) and for 20 pts M2M3 ; two pts died during induction and thus are NE. MFU of these 365pts is 22m (3–39). Median age is 4.1y(1.1–9.9), median WBC is 7.47 G/L (.9–47). MRD results are classified for analysis either in three categories (negative, weakly +ve if &lt; 10−3, highly positive if &gt; 10−3, or according to the exact level of positivity. Results: 1) 15% (51/336 pts) of the SR-BCP ALL have a detectable MRD at EOI 2) As expected, whatever the threshold, pts with D21 M2/M3 marrow are more likely to have a detectable MRD (p=.0017). But 43/316 M1 pts (14%) have a highly +ve (n=19;6%) or weakly +ve MRD (n=24 ; 8%). Surprisingly, only 1 out 20 M2M3 pts had a MRD &gt; 10−2 while it is the case for 8 out 316 M1 pts (p=NS). If only pts receiving DNR are considered (DNR+ M1 pts and all M2/M3 pts), again pts with D21 M2/M3 marrow are more likely to have a detectable MRD (p=.0015). 3) If we compare the MRD levels in the 2 arms (DNR+ve or neg) in the 315/343 M1 pts evaluable for MRD: 136 pts in each arm had no detectable MRD; 16 and 8 have a weak positivity in the DNR− and DNR+ arm respectively while 10 and 9 have a weak positivity in the DNR− and DNR+ arm respectively: p= .29). If the exact level is considered, this absence of difference remains at all levels considered. Conclusions: 15% of the SR-BCP ALL have a detectable MRD at EOI after a three or four-drug induction. D21 M2/M3 pts are more likely than M1 pts to have a detectable MRD at EOI but 14% of the D21 M1 pts have a high (&gt; 10−3) or very high MRD (&gt; 10−2) which confirms the added value of MRD detection to classical morphology. The MRD level at EOI is not different in SR-BCP-ALL after a three or four-drug induction regimen. This is of paramount importance since EOI MRD is a surrogate marker for probability of relapse.

Early Response to Therapy Is Significantly Associated with Genetic Subtype of Acute Lymphoblastic Leukemia: A Report from the Children’s Oncology Group.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 758-758
Author(s):  
Mignon L. Loh ◽  
Elizabeth Raetz ◽  
Meenakshi Devidas ◽  
Stephen B. Linda ◽  
Michael J. Borowitz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Real Time ◽  
Induction Therapy ◽  
Classification System ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Response To Therapy ◽  
Oncology Group ◽  
Genetic Features

Abstract Improved outcomes for children with acute lympboblastic leukemia (ALL) have been achieved, in part, from adaptation of risk-stratified therapy. The Children’s Oncology Group (COG) has implemented a real-time risk classification system (AALL03B1) using a combination of NCI-Rome risk criteria, blast cell genetic features, and early treatment response to determine the intensity of post-induction therapy. Between December 29, 2003 and June 1, 2007, more than 4,000 children over 1 year of age with B-precursor ALL were enrolled on AALL03B1, including 2293 (62%) with NCI Standard Risk (SR) and 1406 (38%) with NCI High Risk (HR) features who were subsequently enrolled on companion clinical trials. The most favorable genetic features used in AALL03B1 were identified in legacy COG studies and included TEL/AML1(TEL) or triple trisomies of chromosomes 4, 10, and 17 (TT). Unfavorable genetic features included the presence of BCR/ABL, MLL rearrangements, or extreme hypodiploidy (DNA index <.81 or chromosomes <44). Overall, 26% of patients were TEL+ and 24.7% had TT. These genetic subsets occurred more frequently in NCI SR vs. HR patients (30.7% and 30.9% vs. 14.5% and 11.7% respectively). Children achieving an M1 day 15 bone marrow (BM) who also had minimal residual disease (MRD) < 0.1% measured by flow cytometry on day 29 of induction therapy were deemed rapid early responders (RER), while those with either an M2/M3 day 15 marrow or MRD > 0.1% at day 29 were defined as slow early responders (SER). Among the favorable cytogenetic subsets, patterns of early response differed. The presence of TEL was significantly associated with an RER to induction therapy in both NCI SR and HR groups (p< 0.0001), while the presence of TT was not (p=0.058). For NCI SR patients, the presence of TEL was significantly associated with the achievement of an M1 bone marrow by day 8 (50.9% of TEL+ pts vs. 41.2% of TEL- pts, p< 0.0001). Patients with an M1 or M2 BM on day 29 who had MRD >1% received extended induction (EI) for two weeks followed by an additional evaluation of BM morphology and MRD at day 43 of induction. One hundred and nineteen patients received EI, with 40% having NCI SR features at diagnosis. Of the patients who received EI, 63% achieved an M1 marrow with MRD < 1% by day 43 and were eligible to continue on protocol therapy. This was more likely to occur in NCI SR patients (77% vs. 55%, p<0.013). Not surprisingly, 31% of the NCI HR patients receiving EI were BCR/ABL positive, and the presence of BCR/ABL was associated with a slower early response overall. While the presence of the BCR/ABL was associated with a greater likelihood of EI, MLL rearrangements and hypodiploidy were not. These data indicate that early response to induction therapy differs among genetic subsets of pediatric patients with newly diagnosed ALL. In addition a centralized classification system allows for robust collection of data from local and centralized reference laboratories that can be used for real time treatment assignment of ∼2000 patients/year with ALL from > 220 COG institutions.

Adaptation of Augmented Berlin-Frankfurt-Munster (ABFM) Therapy in Adolescents and Young Adults with Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4342-4342
Author(s):  
Michael Rytting ◽  
Deborah Thomas ◽  
Hagop Kantarjian ◽  
Jorge Cortes ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Young Adults ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Infectious Complications ◽  
Mri Findings ◽  
Color Flow ◽  
Treatment Delays ◽  
Early Evaluation ◽  
Drug Induction

Abstract Comparisons of survival of adolescents up to age 21 years of age treated on either pediatric or adult ALL protocols so far show improved survival for patients (pts) treated with pediatric therapies. ABFM therapy has been shown to be effective therapy for teen-aged pts up to age 21, and is the standard therapy arm of the current Children’s Oncology Group high-risk ALL trial. We have initiated a trial of ABFM based therapy for pts up to the age of 30 with lymphoblastic leukemia. Pts receive four drug induction with prednisone 60 mg/m2 daily for 28 days, daunorubicin 25 mg/m2 weekly for four doses, vincristine 2 mg weekly for four doses, and a single dose of intravenous pegylated asparaginase (PEG-asp) in week one of therapy. Intrathecal (IT) cytarabine is given on day one, and IT methotrexate is given on days 8 and 29. IT therapy is intensified depending on the presence of spinal fluid blasts. Induction is extended by two weeks for patients who do not acheive a bone marrow morphologic remission (MR) by day 29. Pts that are in MR by day 15 are rapid early responders; they receive one phase of delayed intensification. Pts who are not in MR by day 15 but enter MR by day 29 or 42 are slow early responders; they receive two delayed intensifications. Upon completion of induction, pts continue with intensive phases of chemotherapy for approximately 6 months. They then start 24 months of maintenance therapy. 13 patients with newly diagnosed ALL have been enrolled with a planned enrollment of 80. The median age is 20 (range 14–28). 10(77%) have pre-B ALL and 3(23%) have T-ALL. 12(92%) are rapid early responders. All pts are in MR by day 29. Minimal residual disease (MRD) status is evaluated at day 29 and day 84 by four-color flow cytometry. 8(62%)pts are MRD negative by day 29. All pts so far are MRD negative by day 84. One pt has relapsed. There are no treatment related deaths. Treatment delays for bone marrow suppression are common. There has been 1 allergic reaction to PEG-asp and 2 cases of clinical pancreatitis. 2 pts have had stroke-like symptoms with MRI findings compatible with treatment toxicity; complete clinical resolution has occurred in both. 4 pts have had grade (Gr) 3–4 hyperglycemia. 2 pts have had Gr 3–4 hyperbilirubinemia. 2 patients have been non-compliant. One pt has had Gr 4 sepsis. Other infectious complications are not common. Early evaluation indicates that ABFM therapy is effective in inducing rapid MR in young adults with ALL. The regimen appears tolerable, but morbidity is frequent. Gr 3–4 toxicity occurs more often than recently reported for similar therapy in adults with ALL (Douer D, et al. Blood, 1 Apr2007, 2744050).

Flow Cytometric Minimal Residual Disease Levels After First Inducton Can Define T-Acute Lymphoblastic Leukemia Patients with High Risk of Relapse

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4817-4817 ◽  
Author(s):  
Veselka Nikolova ◽  
Velizar Shivarov ◽  
Ricardo Morilla
Keyword(s):  
Bone Marrow ◽  
T Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Treatment Options ◽  
Phenotypic Expression ◽  
Time Points ◽  
Group 2 ◽  
Time Point ◽  
Group 1

Abstract Abstract 4817 T-cell acute lymphoblastic leukemia (T-ALL) patients have increased risk for treatment resistance and early relapse. The precise bone marrow evaluation for the presence of minimal residual disease (MRD) is essential for guiding treatment options. This requires techniques more sensitive than the level of sensitivity of light microscopic technique such as multicolour flow cytometry (FCM). Immunophenotypic alterations called leukemia associated immunophenotypic patterns (LAIP) (i.e.aberrant myeloid markers) and ectopic phenotypic expression (i.e. appearance of immature phenotypes such as TdT, CD1a and CD3 outside their normal site in the thymus) are of benefit to track the residual leukemic cells in T-ALL. A retrospective data analysis of MRD was done comprising T-ALL patients diagnosed and followed-up at the Institute of Cancer Research/Royal Marsden Hospital by means of 3-colour flow cytometry (3C FCM).The aim was to answer a question whether the 3C FCM can reliably split patients into two groups (positive, MRD+ and negative, MRD-) and predict a subsequent relapse and to define a right time point for performing MRD tests. Eight patients were enrolled in the study following the inclusion criteria: (i) complete remission after 1st induction phase of chemotherapy, (ii) presence of LAIP or an ectopic phenotypic expression, and (iii) monitored at defined time points after initial treatment. MRD was measured during the first year of treatment as follows: at the end of phase 1 induction (day 29–35, MRD1), before the start of consolidation (3 months, MRD2), after consolidation (MRD3), during the maintenance therapy (12 months, MRD4). Immunophenotyping was performed on lysed-washed bone marrow samples using CD45 gating strategy and originally defined blast gates at diagnosis. The phenotypes to be followed-up included: TdT+/CytCD3+, CD34+/CYTCD3+, TdT+/CD2+, CD8+/CD10+, CD2+/CD10+, CD7+/CD10+, CD7+/CD33+, CD7+CD34+. Patients were divided into 2 groups in relation to subsequent relapse. Group 1 included 6 patients without relapse. Patient characteristics of the group were: male:female 5:1, mean age 17.7 years, overall survival (OS) 59 months, relapse free survival (RFS) 85 months. Group 2, relapsed patients, included 2 men, mean age 56 years, OS 13 months, RFS 8.5 months. According to the EGIL classification system the 2 men in Group 2 were with an early T-precursor phenotype, whilst Group 1 was heterogenous but cortical-T-ALL predominated. Cytogenetics/FISH and RQ-PCR studies were performed at diagnosis and showed normal karyotype in only one of the Group 2 patients. MRD results showed a difference between the two groups as regards MRD1 and MRD2 time points. Group 1 patients had negative or low MRD levels (below 0.18%) in their MRD1 bone marrow - MRD-, n=4 and MRD+,n=2 (0.18% and 0.12% respectively, sensitivity 0.04%). Those of them who were tested at MRD2 and MRD3 were negative. Both patients in Group 2 showed higher levels of MRD positivity at MRD1 (1% of total bone marrow cells), the first one of them also being positive at MRD2 and the second one becoming MRD+ at MRD4 time point. Although turning to MRD- at MRD3 time point both Group 2 patients relapsed 2.5 and 4.5 months, respectively, after the end of consolidation treatment. Additionally, Group 1 patients had a significantly longer RFS than Group 2 (median 58 months RFS vs. 8.5 months; P <0.001). Conclusions: Reliable detection of MRD in T-ALL is possible by 3C FCM using a combination of TdT and a T cell marker (cytCD3 or mCD3) as such a combination is normally found exclusively in the thymus. The higher MRD-positive levels in Group 2 reflect the more resistant disease in this group and higher probability of early relapse and shortened overall survival. Early T-cell precursor phenotype in these patients appeared to be a subtype at very high risk for treatment failure irrespective of the lack or the presence of genetic lesions. Based on MRD positivity above 0.18% at time points MRD1 or both MRD1 and MRD2 these patients need reassessment of treatment options and more intensive therapy has to be considered for relapse prevention. Finally, the results of our retrospective study suggest the usefulness of implementation of MRD testing by FCM for taking clinical decisions in the prospective clinical trials for novel therapies for T-ALL. Acknowledgments: The study was supported by the Union for International Cancer Control, Geneva, Switzerland (Grant ICRETT-080–2011) Disclosures: No relevant conflicts of interest to declare.

Outcomes with reduced intensity therapy in a low-risk subset of children with National Cancer Institute (NCI) standard-risk (SR) B-lymphoblastic leukemia (B-ALL): A report from Children’s Oncology Group (COG) AALL0932.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 10509-10509
Author(s):  
Reuven J. Schore ◽  
Anne J. Angiolillo ◽  
John A Kairalla ◽  
Meenakshi Devidas ◽  
Karen R. Rabin ◽  
...  
Keyword(s):  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Alkylating Agents ◽  
Disease Free Survival ◽  
Low Risk ◽  
Free Survival ◽  
Leucovorin Rescue ◽  
Drug Induction ◽  
Pre Treatment ◽  
Post Hoc

10509 Background: Post-hoc analysis of COG P9904 identified a low risk (LR) group of SR B-ALL patients aged 1-9.99 years with WBC < 50,000/µL, no CNS3, and either ETV6/RUNX1 or double trisomies (DT) of chromosomes 4 and 10 with day 8 peripheral blood (PB) and day 29 marrow (BM) minimal residual disease (MRD) < 0.01% who had a 5-year event-free survival (EFS) of 97±2% and overall survival (OS) 98.8±0.8%. Outstanding results were also obtained for LR patients on COG AALL0331 using CCG-based ALL therapy. AALL0932 tested prospectively whether LR B-ALL patients could attain a 5-year EFS ≥95% with these regimens. Methods: Following a 3-drug induction, eligible AALL0932 LR patients had NCI SR B-ALL (no testicular leukemia, unfavorable genetics or Down syndrome) with DT or ETV6/RUNX1 fusion, CNS1, no steroid pre-treatment, with Day 8 PB and Day 29 BM MRD < 0.01%. Between 2010-16, 603 LR patients were randomized to P9904-based regimen LR-M (n = 301) or CCG 1991/COG AALL0331-based regimen LR-C (n = 302). LR-M included 6 24-hour infusions of 1 gm/m2 of methotrexate (MTX) with leucovorin rescue, but no anthracyclines or alkylating agents. Maintenance followed with daily 6-mercaptopurine (6-MP) and weekly oral MTX, and every 16 week 7-day pulses of dexamethasone (DEX) with vincristine (VCR) on days 1 and 8. Boys and girls were treated for 2.5 years from diagnosis. LR-C had no 24-hour MTX infusions, but included 2 Interim Maintenance (IM) phases with VCR and escalating IV MTX without leucovorin rescue given every 10 days for 5 doses, flanking an 8-week Delayed Intensification (DI) phase that included DEX, VCR, pegasparagase, doxorubicin (75 mg/m2), cyclophosphamide (1 gm/m2) and 8 doses of low-dose cytarabine (75 mg/m2/dose). LR-C Maintenance included daily 6-MP and weekly oral MTX with 5-day pulses of DEX and 1 dose of VCR given every 12 weeks. Girls received 2 years and boys 3 years of therapy from the start of IM I. Results: Both regimens achieved outstanding outcomes: 5-yr disease-free survival (±SE) 98.8%±0.8% for LR-M and 98.5%±0.9% for LR-C (p = 0.67). Both had 5-yr OS 100%. Therapies were well tolerated with higher rates of mucositis (12.9 vs 6.3%; p = 0.008) and allergic reactions (2.3% vs 0%; p = 0.02) on LR-C. Conclusions: AALL0932 demonstrated that application of stringent risk criteria can identify a favorable B-ALL subgroup almost certain to be cured with either LR-M or LR-C, allowing physicians and families to select the optimal treatment approach in the future. Clinical trial information: NCT01190930.

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