Improved Prognosis of Children and Adolescents with Acute Lymphoblastic Leukemia (ALL) and Very-High Minimal Residual Disease (MRD) and the End of Induction therapy (EOI)? Preliminary Results of the FRALLE 2000 Protocol

Abstract MRD at EOI is a powerful prognostic indicator in childhood ALL. Cave et al (N Engl J Med 1998) and van Dongen et al (Lancet 1998) have shown that a very high EOI-MRD (≥ 10−2) is associated to a dismal prognosis (5y EFS: 15–20%). From December 2000 to July 2007 1496 children and adolescents (1–20 years, no Ph+) have been included in the ongoing FRALLE 2000 protocol. EOI-MRD at D35–42 was measured by competitive PCR of Ig/TCR markers and Gene Scan analysis and was decisional for further treatment intensification if ≥ 10−2. 1017 pts are fully evaluable (monitored data, no induction failure, evaluable EOI-MRD, outcome). MFU is 36 months. Three risk-groups have been defined. A (n=620): NCI standard risk BCP-ALL, B (n=265): NCI high risk-ALL, T (n=132): T-cell ALL. Fifty-eight pts (5.7%) have a very high EOI-MRD, 2.6% in group A, 9% in group B, 14% in group T. These pts were more likely than pts with lower MRD (< 10−2) to have a D8 poor prednisone response (PPR) (31% vs 10%, p <.001), a slow marrow response (D21M2 or M3, 24% vs 5%, p <.001) or both (22% vs 1.5%, p <.001). A very high MRD only (no high-risk cytogenetic features, no D8 PPR, no D21 M2/M3 marrow) was found in 33 out the 58 pts (57%), i.e. 3% of all pts. A group pts (n=16) with very high EOI-MRD received a 3 block-consolidation plus a double delayed intensification (DDI) while B or T group pts received a 3 block-consolidation plus DDI (24 pts) or HSCT (18 pts). 5y EFS and OS where 50±10% and 74±7% respectively for the 58 pts. A similar 5 y EFS was found for pts with BCP-ALL or T-cell ALL with very high MRD (50±12% and 48±12%, respectively). There is a trend for a better EFS for pts with very high EOI-MRD only compared to those with other associated high-risk features (60±11% vs 39±11%, p=.10). Conclusion: these results compare favourably with published results suggesting that intensification of therapy may improve the outcome of pts with bad early response to initial chemotherapy.

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Post Induction Minimal Residual Disease Levels Identifies a Group of High Risk Relapsed Childhood Acute Lymphoblastic Leukemia (rALL) with a Favorable Outcome Independent of Induction Therapy

Blood ◽

10.1182/blood.v126.23.1294.1294 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1294-1294

Author(s):

Catriona Anne Parker ◽

Marie Reeves ◽

Sharon Love ◽

Jeremy Hancock ◽

Peter M Hoogerbrugge ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

Induction Therapy ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Treatment Strategies ◽

Progression Free Survival ◽

Favorable Outcome ◽

Childhood All ◽

Post Induction

Abstract BACKGROUND: The determinants of outcome in children with rALL are the duration of first remission (CR1), site of relapse and immunophenotype. High risk (HR) relapses are defined as those occurring with a CR1 of <18 months; B-cell precursor (BCP) with bone marrow (BM) relapse within 6 months of stopping therapy and T-cell BM or combined relapses at any time. All other relapses are defined as standard risk (SR). In the UKALLR3 clinical trial for rALL, HR patients had a lower CR2 rate, higher post induction MRD and inferior survival when compared to SR patients treated in identical fashion. We investigated the effect of further intensifying induction therapy with clofarabine in HR patients. METHODS: Clofarabine was added to the UKALLR3 consolidation block of cyclophosphamide, etoposide (CCE) and used as induction therapy, with dexamethasone and PEG-Asparaginase for HR patients. The previous induction block with mitoxantrone (M) was given as consolidation and all patients were eligible for stem cell transplantation (SCT) with any donor after a third intensification block. The outcomes assessed were improvements in CR2, MRD and progression-free survival (PFS) when compared to historical controls of patients receiving idarubicin (I) or M induction in UKALLR3. A Fleming-style design, based on observed response and toxicity, was incorporated to allow an increase in the dose of cyclophosphamide from 300 mg/m2 to 440 mg/m2. RESULTS: 61, 39 at lower and 22 at the higher dose of cyclophosphamide, CCE patients were compared to 30 I and 69 M patients with HR rALL. Patients in the CCE group had a lower median age at presentation, but other prognostic variables were comparable. CR2 rates of 73%, 83%, 71% and low MRD (≤10-4) was seen in 32%, 0%, 25% of CCE, I and M groups. The higher cyclophosphamide dose was associated with improved CR rates, lower MRD but also increased toxicity levels in CCE compared to M group patients. The proportions of patients reaching transplantation were 43%, 60% and 55% of CCE, I and M patients respectively. 73/82 eligible patients received a SCT, 48 (66%) with matched and 25 (34%) with mismatched donors. The 2-year PFS with CCE, M and I regimens were 17% (11,23), 27% (19,34) and 30% (25,36) respectively (p=0.08). Outcomes of matched sibling, matched unrelated and mismatched SCT were comparable (p=0.9). Seventeen patients with a post induction MRD<10-4, had a 2-year PFS of 63% (50,75), compared to 21% (15,27) for 53 patients with MRD≥10-4 and 21% (17, 25) for the 90 patients with unknown MRD (p=0.005). All 4 patients with MRD≥10-3 prior to SCT and 8/9 not transplanted suffered a second relapse. Overall outcomes of BCP (2-year PFS 21% (15,28)) and T-cell ALL (2-year PFS 26% (16,35)) were comparable (p=0.9). PFS in BCP-ALL was 31% (24,38) and 13% (6,20) (p=0.1) for those receiving M and CCE respectively. CONCLUSIONS: We define two groups of HR rALL patients based on MRD levels attained post induction, independent of the induction regimen. Approximately a quarter of HR patients continue to have chemosensitive disease as evidenced by rapid MRD clearance (<10-4 at week 5). This group includes high-risk cytogenetics and T-cell rALL with MRD as the single discriminatory factor for outcome. These patients have a favorable outcome after SCT with any donor. In the other group (MRD≥10-4) over half of HR patients do not reach SCT primarily due to refractory disease (27%) or disease recurrence (14%). One third of patients relapse post SCT. For this group novel agents and newer treatment strategies are urgently required. Disclosures Off Label Use: Clofarabine 1st relapse childhood ALL.

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Xenografts of highly resistant leukemia recapitulate the clonal composition of the leukemogenic compartment

Blood ◽

10.1182/blood-2010-11-320309 ◽

2011 ◽

Vol 118 (7) ◽

pp. 1854-1864 ◽

Cited By ~ 55

Author(s):

Maike Schmitz ◽

Petra Breithaupt ◽

Nastassja Scheidegger ◽

Gunnar Cario ◽

Laura Bonapace ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

T Cell Receptor ◽

Disease Modeling ◽

De Novo ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Clonal Evolution ◽

Cell Receptor ◽

Very High

Abstract Clonal evolution of the leukemogenic compartment may contribute to alter the therapeutic response in acute lymphoblastic leukemia (ALL). Using xenotransplantation of primary leukemia cells, we evaluated the phenotypic and genetic composition of de novo resistant very high risk precursor B-cell ALL, a subgroup defined by the persistence of minimal residual disease despite intensive chemotherapy. Analysis of copy number alterations (CNAs) showed that the xenografted leukemia, even when reconstituted from 100 cells, remained highly related to the diagnostic sample, with minor changes in CNAs, mostly deletions, emerging in most cases in the first passage into mice. At the single-cell level, the pattern of monoallelic and biallelic deletions of the CDKN2A locus revealed distinct leukemia subpopulations, which were reproducibly tracked in xenografts. In most very high risk ALL cases, the predominant diagnostic clones were reconstituted in xenografts, as shown by multiplex polymerase chain reaction analysis of immunoglobulin and T-cell receptor loci. In other cases, the pattern in CNAs and immunoglobulin and T-cell receptor rearrangement was less concordant in xenografts, suggesting the outgrowth of subclones. These results unequivocally demonstrate the existence of clonally closely related but distinct subsets of leukemia initiating cells in ALL, which has important implications for drug development and preclinical disease modeling.

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Augmented Therapy Based on PCR-MRD Levels of Children with Acute Lymphoblastic Leukemia: A Report from the Japanese Children’s Cancer and Leukemia Study Group ALL 2000 MRD Pilot Study

Blood ◽

10.1182/blood.v112.11.301.301 ◽

2008 ◽

Vol 112 (11) ◽

pp. 301-301 ◽

Cited By ~ 1

Author(s):

Toshinori Hori ◽

Kazutaka Yamaji ◽

Shohei Yokota ◽

Tomoko Okamoto ◽

Arata Watanabe ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Receptor Gene ◽

Risk Groups ◽

Pcr Primers ◽

Cell Receptor ◽

Favourable Outcome ◽

Childhood All

Abstract Many studies have shown the presence of minimal residual disease (MRD) following therapy for childhood acute lymphoblastic leukemia (ALL) to be an important prognostic marker. We have also shown a significant relationship between survival outcomes in patients enrolled in the previous ALL 911 study and molecular MRD levels 5 weeks (time point 1, TP1) and 12 weeks (TP2) following the initiation of chemotherapy (Leukaemia and Lymphoma2002; 43: 1001). The aim of this study was to evaluate if polymerase chain reaction (PCR)-based MRD assay is sufficiently dependable for tailoring therapy, and if augmented therapy can reduce MRD levels to those associated with a favourable outcome. The subjects were under 18 years of age, and had newly diagnosed precursor B or T-cell ALL. Patients below one year old and those with t(9;22) were excluded. Written informed consent was obtained from patients or their legal guardians. The ALL 941-based protocol (45thASH, San Diego, 2003) utilized PCR-based MRD assay using immunoglobulin & T-cell receptor gene rearrangements. MRD was detected by nested PCR, with screening of rearrangements using multiplex PCR primers as described previously (Leukaemia and Lymphoma2002; 43: 1001). Patients were initially stratified into 3 risk groups (in ascending order: SR, HR, and HHR) according to leukocyte count and age at time of diagnosis. The MRD+/+ patients with levels ≥ 10−3 at both TP1 and TP2 received augmented therapy 14 weeks after initiation, and the remainder continued to receive the initial risk-adapted protocols. A total of 311 patients with a median age of 5.3 years (range 1.0–16.8) were eligible for this study. There were 4 (1.3%) non-responders and no deaths in induction. Of the 307 patients stratified, 169 (55%) were SR, 107 (35%) were HR, and 31 (10%) were HHR. The 2nd stratification by MRD level at TP2 was possible for 72.3% (222/307; insufficient DNA=28; missing time-points=25; no marker=32). Out of the 222 patients stratified, 125 (56.3%) were MRD−/−, 58 (26.1%) were MRD+/−, and 38 (17.4%) were MRD+/+. At the point of analysis, the median follow-up time was 63 months (range 33–89). The overall 5-year event–free survival (EFS) rate of the 307 patients was 80.1% (SE 2.5), higher than the EFS of the ALL941 study, which was 76.2% (SE 2.1) (p=0.167). The 5-year EFS rates according to the 1st stratification were 85.5% (SE 4) for SR, 76.1% (SE 4.5) for HR, and 64.6% (SE 9.2) for HHR, while the equivalent rates for the 2nd stratification were 87.0% (SE 3.1) for MRD−/−, 75.5% (SE 7.7) for MRD+/−, and 75.3% (SE 6.4) for MRD+/+. From the 95 patients whose MRD levels were measured at 5 consecutive points from TP1 to TP5 (5, 12, 18, 24, and 30 weeks after the start of therapy), 21 subjects with MRD+/+ received an augmented chemotherapy, and MRD levels became undetectable in 9 patients at TP3, 5 patients at TP4, and 4 patients at TP5. The corresponding cumulative 5-year relapse rates of those patients were 11%, 50%, and 50%, respectively. Thus, negative MRD status at TP3, but not at TP4 or TP5, seems to be associated with a favourable outcome. Our results confirm the strong performance of MRD-based treatment interaction in a multi-institutional study without adversely affecting the outcome in childhood ALL. Moreover, present findings suggest that an augmented therapy could reduce MRD to levels associated with a favourable outcome. To improve the applicability and accuracy of MRD assay, new MRD-PCR targets and RQ-PCR-based MRD detection are needed in subsequent studies. [Acknowledgment: This study was partly supported by grants from the Children’s Cancer Association of Japan (CCAJ)].

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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 ◽

10.1182/blood.v122.21.837.837 ◽

2013 ◽

Vol 122 (21) ◽

pp. 837-837 ◽

Cited By ~ 9

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.

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Single Immunophenotypical Evaluation of Minimal Residual Disease before Autotransplantation of Non-Cryopreserved Bone Marrow Is Insufficient for Prediction of Outcome in High Risk Adult Acute Lymphoblastic Leukemia.

Blood ◽

10.1182/blood.v104.11.4439.4439 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4439-4439

Author(s):

Beata M. Stella-Holowiecka ◽

Krystyna Jagoda ◽

Aleksandra M. Holowiecka-Goral ◽

Tomasz Czerw ◽

Sebastian Giebel ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Conditioning Regimen ◽

Long Term Results ◽

Color Flow ◽

Childhood All ◽

Minimal Residual

Abstract For high-risk adult ALL patients alloHCT is a preferable option. However, a significant proportion of those not having a suitable donor may be successfully treated with autotransplantation (autoHCT). Based on our experience this treatment ensures low transplant related mortality below 3% and a reasonable overall survival and disease free survival of 60% and 45% respectively. The status of the disease before transplantation is an important factor for long term results. In childhood ALL most studies suggest that the level of minimal residual disease (MRD) after induction evaluated immunophenotypically or with bio-molecular methods is predictive for outcome after different treatments including chemotherapy, alloHCT and autoHCT. The results in adult ALL are more controversial. Patients selection. Among 1205 haematopoetic cell transplantations performed in our institution 224 (147 autologous, 77 allogeneic) were performed in 205 adults with ALL. For this study we selected an uniform group of 81 patients fulfilling following criteria’s: Ph (-) ALL, status CR1, evaluable MRD, strictly defined autoBMT procedure performed until the end of 2003. Methods. MRD was tested before autoBMT (median interval 10 days) using 2 ore 3-color flow-cytometry, as appropriate. The atypical immunophenotypes were evaluated using the “quadrans” analysis in all cases and since 2002 also the “empty spaces” technique. The sensitivity equals at least 0.0001. For all autoHSCT bone marrow was used as a source of stem cells. The CAV conditioning regimen consisted of cyclophosphamide 60mg/kg on d. -3, -2, cytarabine 2 g/m2 d. -3, -2, -1, etoposide 800 mg/m2 d. -3, -2. Bone marrow was not cryo-preserved after collection but stored in 40 C and re-transplanted after 72h. Results. In 41 patients; age med. 26 y (15–53), F/M=12/29, the MRD level was <0,001: the MRD (−) group. In 40 patients; age med. 29 y (16–53), F/M=18/22, the MRD was detected at the level =/> 0,001; MRD+ group. The ALL-immunophenotypes of MRD−/MRD+ groups were as follows; proB 4/7, preB 2/6, Common 18/19, B 0/1, preT 5/2, T 12/1). The interval from DGN to BMT was similar in both groups. The probability of LFS and OS at 10y calculated with median follow up time of 5y equaled; in the MRD(−) group 47% and 62% and in the MRD+ one 48% and 57% respectively (p=ns). The main reason of failure in both groups was a relapse which occurred after a median time of 277 days in the MRD(−) group and 134 days in MRD+ one (p=0.19). Conclusion and comment. Based on this observation we conclude that a single evaluation stratifying patients before autoBMT according to MRD level below or above 0.001 is not predictive for DFS and OS, because it informs only about the current amount of the disease but not about its opportunistic nature. In this respect a repeatedly confirmed MRD positivity should be more significant. Taking into consideration that the main reason of failures were relapses, this finding suggests also that in patients with chemotherapy-responsive ALL confirmed by stabile CR, the myeloablative CAV regimen is sufficiently strong to eliminate the residual disease at the level ranging 0.01–0.001. It may be speculated only that the 72h lasting incubation of bone marrow product before re-transplantation has also some kind of purging effect for leukemic blasts.

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Outcome of Patients with T-Cell Lymphoblastic Leukemia or Lymphoma: The GRAALL Experience.

Blood ◽

10.1182/blood.v110.11.2818.2818 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2818-2818

Author(s):

Stéphane Leprètre ◽

Martine Escoffre-Barbe ◽

Patrice Chevallier ◽

Thibaut Leguay ◽

Laurence Legros ◽

...

Keyword(s):

T Cell ◽

High Risk ◽

Lymphoblastic Leukemia ◽

Early Response ◽

Cell Phenotype ◽

High Dose ◽

Cns Involvement ◽

Childhood All ◽

High Risk Disease ◽

Mediastinal Disease

Abstract In 2003, the GRAALL intergroup initiated two twin protocols for adult patients with acute lymphoblastic leukemia (ALL; ≥ 20% marrow blasts) or lymphoblastic lymphoma (LL; < 20% marrow blasts), namely the GRAALL-2003 and LL-2003 trials. Treatment strategy was inspired by childhood ALL trials, including corticosteroid prephase, 5-drug induction, high dose-intensity consolidation, late intensification, CNS prophylaxis with IT injections and cranial irradiation, and 2-year maintenance. An original induction reinforcement with sequential cyclophosphamide (HyperC) was offered to ALL patients with poor early response (cortico- and/or chemo-resistance) and to all LL patients. A total of 108 patients with T-cell phenotype have been treated (76 ALL and 32 LL; median age, 30 years; M/F sex ratio, 86/22; CNS+, 9; median follow-up, 2 years). Baseline characteristics were not different among ALL and LL subgroups, except for marrow blast percentage and mediastinal enlargement (47% vs 78% for ALL vs LL; P=.005), which correlated negatively, as well as for blood counts (WBC, 27 vs 8.7 × 109/L; platelets, 60 vs 328 × 109/L; Hb, 116 vs 134 g/L for ALL vs LL; P<.001). Bulky mediastinal disease was present in 57% LL vs 22% ALL patients (P=.002). Two patients (1 ALL, 1 LL) died early while the 106 remaining (98%) reached CR. With respect to mediastinal involvement, need for a salvage course with idarubicine and high-dose cytarabine to reach CR was more frequent in LL than in ALL patients (10 LL vs 2 ALL, P<.001). Allogeneic stem cell transplantation (SCT) was offered to patients with high-risk disease, defined here as CNS involvement, poor early response, or need for salvage. Among the 55 CR patients with high-risk disease (41 ALL, 14 LL), 26 received allogeneic SCT in first CR (20 ALL, 6 LL). Overall, 23/106 CR patients relapsed (18 ALL, 5 LL) while 8 died in first CR (7 ALL, 1 LL; 4 after SCT). At 2 years, estimated DFS and overall survival were 66% (64% vs 75% for ALL vs LL, P=.59) and 75% (74% vs 78% for ALL vs LL, P=.75), respectively. The only factors which influenced outcome in this risk-adapted strategy were need for salvage (higher relapse incidence) and CNS involvement (shorter survival). As compared to historical experiences, we report here a notable gain in outcome when treating patients with T-cell lymphoblastic disease, including lymphoma, with a pediatric-inspired ALL strategy. The efficacy of this approach leads to comparable outcome for both diseases. The systematic use of HyperC induction in LL patients was well tolerated, but the need for salvage therapy was more frequent in these patients possibly due to difficulty in early mediastinal response evaluation. The presence of CNS disease at diagnosis remains an unfavorable feature. The role of HyperC during induction and the place of allogeneic SCT in first CR deserve further evaluation in this new context.

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Phase II Trial of the Anti-CD19 Bispecific T Cell–Engager Blinatumomab Shows Hematologic and Molecular Remissions in Patients With Relapsed or Refractory B-Precursor Acute Lymphoblastic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2014.56.3247 ◽

2014 ◽

Vol 32 (36) ◽

pp. 4134-4140 ◽

Cited By ~ 364

Author(s):

Max S. Topp ◽

Nicola Gökbuget ◽

Gerhard Zugmaier ◽

Petra Klappers ◽

Matthias Stelljes ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

Phase Ii ◽

Phase Ii Trial ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Clinical Activity ◽

Hematopoietic Stem ◽

Dismal Prognosis ◽

Bispecific T Cell Engager

Purpose Patients with relapsed or refractory acute lymphoblastic leukemia (ALL) have a dismal prognosis. CD19 is homogenously expressed in B-precursor ALL and can be targeted by the investigational bispecific T cell–engager antibody blinatumomab. A phase II trial was performed to determine clinical activity in this patient cohort. Patients and Methods Thirty-six patients with relapsed or refractory B-precursor ALL were treated with blinatumomab in cycles of 4-week continuous infusion followed by a 2-week treatment-free interval in a single-arm study with a dose-finding stage and an extension stage. The primary end point was complete remission (CR) or CR with partial hematologic recovery (CRh). Major secondary end points included minimal residual disease (MRD) response, rate of allogeneic hematopoietic stem-cell transplantation (HSCT) realization, relapse-free survival (RFS), overall survival (OS), and incidence of adverse events (AEs). Results Median age was 32 years (range, 18 to 77 years). Twenty-five patients (69%) achieved a CR or CRh, with 88% of the responders achieving an MRD response. Median OS was 9.8 months (95% CI, 8.5 to 14.9), and median RFS was 7.6 months (95% CI, 4.5 to 9.5). Thirteen responders (52%) underwent HSCT after achieving a CR or CRh. The most frequent AE during treatment was pyrexia (grade 1 or 2, 75%; grade 3, 6%). In six patients with nervous system or psychiatric disorder AEs and in two patients with cytokine release syndrome, treatment had to be interrupted or discontinued. These medical events were resolved clinically. Conclusion The data support further investigation of blinatumomab for the treatment of adult patients with relapsed or refractory ALL in a larger confirmatory study.

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Nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia: association with high-risk clinical features

Blood ◽

10.1182/blood.v74.1.409.bloodjournal741409 ◽

1989 ◽

Vol 74 (1) ◽

pp. 409-415 ◽

Cited By ~ 1

Author(s):

SB Murphy ◽

SC Raimondi ◽

GK Rivera ◽

M Crone ◽

RK Dodge ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

T Cell ◽

High Risk ◽

Clinical Features ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Cell Phenotype ◽

Term Survival ◽

Childhood All ◽

Chromosome 9P

To assess the frequency and significance of nonrandom abnormalities of chromosome 9p in childhood acute lymphoblastic leukemia (ALL), we analyzed our experience with 398 consecutive cases with completely banded karyotypes. Forty cases (10%) with abnormalities of 9p were identified: 26 with deletions, nine with unbalanced translocations resulting in the loss of 9p material, and five with apparently balanced reciprocal translocations. As compared with children with ALL lacking 9p abnormalities, these 40 cases were significantly older, had higher initial circulating WBC counts, more “lymphomatous” disease characteristics (including presence of a mediastinal mass in 15%. T- cell phenotype in 26%, splenomegaly greater than 8 cm in 25%), an increased failure rate in the first 2 to 3 years after diagnosis, and a higher incidence of extramedullary relapse. Conversely, lymphomatous ALL cases were twice as likely (19% v 8%) to have an abnormality of chromosome 9p than ALL cases lacking lymphomatous features (P = .01). The finding of an abnormal chromosome 9p, however, was not specific for lymphomatous ALL or T-cell lineage, because most cases were neither lymphomatous nor T-cell, and the overall Kaplan-Meier distribution of treatment failures for abnormal 9p cases was not statistically significantly different from control ALL cases receiving the same treatment who lacked abnormalities of 9p (P = .06, by log-rank test). We conclude that nonrandom abnormalities of chromosome 9p, especially a breakpoint in 9p21–22, occur with increased frequency in childhood ALL in association with some high-risk clinical features. Despite this association, the chromosome anomaly is nonspecific in its syndrome delineation and confers no major adverse consequence on long-term survival of childhood ALL treated with modern therapy. However, due to an apparently increased hazard of involvement of the CNS (eight of 17 failures), it may be inadvisable to lessen the intensity of CNS preventive therapy for this group of patients.

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Minimal residual disease at end of induction and consolidation remain important prognostic indicators for newly diagnosed children and young adults with very high-risk (VHR) B-lymphoblastic leukemia (B-ALL): Children’s Oncology Group AALL1131.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.10004 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 10004-10004

Author(s):

Wanda L. Salzer ◽

Michael James Burke ◽

Meenakshi Devidas ◽

Yunfeng Dai ◽

Nyla A. Heerema ◽

...

Keyword(s):

Young Adults ◽

High Risk ◽

Minimal Residual Disease ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Newly Diagnosed ◽

Post Induction ◽

Children And Young Adults ◽

Very High ◽

Minimal Residual

10004 Background: Children and young adults with very high risk (VHR) B-acute lymphoblastic leukemia (B-ALL) [13-30 years of age with any features or 1-30 years of age with adverse prognostic features including KMT2A rearrangements, iAMP21, hypodiploidy (<44 chromosomes/DNA index < 0.81), central nervous system disease, end of induction (EOI) minimal residual disease (MRD) >0.01%, or induction failure] collectively have a predicted 4-year disease free survival (DFS) of approximately 70%. Whether patients with VHR B-ALL who are MRD positive at EOI and become MRD negative at the end of consolidation (EOC) will have improved survival versus patients remaining MRD positive at EOC is unknown. Methods: Patients with newly diagnosed NCI high risk B-ALL enrolled on AALL1131 or NCI standard risk B-ALL enrolled on AALL0932 and classified as VHR at EOI were treated on the VHR stratum of AALL1131 which sought to improve DFS with intensive post-Induction therapy using fractionated cyclophosphamide (CPM), etoposide (ETOP) and clofarabine (CLOF).Patients were randomly assigned post-Induction to Control Arm (CA) with modified augmented BFM CPM + fractionated cytarabine + mercaptopurine, Experimental Arm 1 (Exp1) with CPM + ETOP, or Experimental Arm 2 (Exp2) with CLOF + CPM + ETOP during Part 2 of Consolidation and Delayed Intensification. Doses of vincristine and pegaspargase were identical on all arms. Exp2 was permanently closed September 2014 due to excessive toxicities, and these patients are excluded from this report. MRD was measured by 6-color flow cytometry at EOI and for those who consented at the EOC. Results: 4-yr DFS for all patients (n=823) with VHR B-ALL was 76.8 ± 2.0%. As we reported previously, 4-year DFS was not significantly different between CA and Exp 1 (85.5 ± 6.8% versus 72.3 ± 6.3%; p=0.76; Burke, Haematologica 2019). 4-yr DFS for patients who were EOI MRD <0.01%, (n=325) versus >0.01 (n=498) was 83.3% ± 2.6% vs 72.0% ± 2.8%, p=0.0013. 4-Year DFS of Patients EOI MRD > 0.01%. Conclusions: MRD is a powerful prognostic indicator in VHR B-ALL with inferior outcomes in patients who are EOI MRD positive. Among patients who were EOI MRD positive treated on Exp1, outcomes were similar for EOC MRD negative and EOC MRD positive, though numbers were small. In contrast, patients who were EOI MRD positive treated on CA that were EOC MRD negative had significantly improved DFS compared to those that were EOC MRD positive. The CA remains the standard of care for COG ALL trials. With this therapy, patients with VHR B-ALL that are EOI MRD positive and EOC MRD negative have significantly improved DFS compared to those that remain MRD positive at EOC. Clinical trial information: NCT02883049. [Table: see text]

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Immunogenicity of Childhood T-ALL.

Blood ◽

10.1182/blood.v108.11.1840.1840 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1840-1840

Author(s):

Renate Panzer-Grümayer ◽

Andrea Inthal ◽

Gerd Krapf ◽

Thomas Felzmann ◽

Helmut Gadner ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Recombinant Expression ◽

Lymphoblastic Leukemia ◽

Intracellular Localization ◽

T Cell Response ◽

Expression Cloning ◽

Expression Library ◽

Childhood All ◽

Dismal Prognosis

Abstract Background: Acute lymphoblastic leukemia (ALL) with a T cell immunophenotype accounts for about 15% of childhood ALL. While contemporary treatment protocols have improved the relapse free survival for children with T-ALL, it has for a long time been considered a malignancy with a dismal prognosis. In fact, this type of leukemia is still at a higher risk for treatment failure and early relapses than B cell precursor ALLs. Further intensification of conventional treatment or stem cell transplantation may increase the cure rate for only some subtypes of ALL but is also associated with considerable treatment-related mortality and morbidity. Thus, new treatment strategies that are less toxic and, at the same time, more effective for patients with a resistant disease, are needed. The aim of the study was to evaluate whether a specific immune reaction is triggered in children with T-ALL and to identify the respective targets. We chose SEREX (serological identification of leukemia derived antigens by recombinant expression cloning) to screen a T-ALL expression library with plasma from 18 children with T-ALL. Results: Thirteen antigens with homology to known genes that are involved in critical cellular processes were detected. Some of them have already been implicated in the induction of an immune response in a variety of cancer types. From four of these genes novel isoforms were identified and further analyzed. mRNA expression of three isoforms (HECTD1Δ, CX-ORF-15Δ and hCAP-EΔ) was restricted to more than 70% of T-ALLs (n=22) and specific antibodies against these isoforms were detected in up to 30% of patients (n=16) with the highest frequency for HECTD1Δ. The alternative splicing leads to the deletion of one glutamic acid located in a putative PEST domain thereby decreasing the PEST score suggesting a higher stability of the protein. Interestingly, the HECTD1 protein was present at high abundance in T-ALLs while is was not detectable in normal hematopoietic tissues. Since the leukemia-associated antigens detected in this study have an intracellular localization, a feature that is shared by the majority of SEREX defined antigens, the generation of immune effector responses most likely requires antigen presentation. To test this assumption, dendritic cells were loaded with HECTD1Δ protein and used for T cell stimulation. A specific T cell response was induced in vitro in all three donors, including a former T-ALL patient. Conclusion: Leukemia-associated antigens, identified by SEREX, appear to be capable of inducing both a humoral and cellular immune response in children with T-ALL. Thus, these data support further studies to establish new approaches for immunotherapy.

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