Treatment of High-Risk Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia in Adolescents and Adults According to Early Cytologic Response and Minimal Residual Disease After Consolidation Assessed by Flow Cytometry: Final Results of the PETHEMA ALL-AR-03 Trial

Ribera, Josep‐Marǐa; Oriol, Albert; Morgades, Mireia; Montesinos, Pau; Sarrà, Josep; González‐Campos, José; Brunet, Salut; Tormo, Mar; Fernández-Abellán, Pascual; Guàrdia, Ramón; Bernal, Teresa; Esteve, Jordi; Barba, Pere; Moreno, María‐José; Bermúdez, Arancha; Cladera, Antònia; Escoda, Lourdes; García‐Boyero, Raimundo; Potro, Eloy del; Bergua, Juan; Amigo, María‐Luz; Grande, Carlos; Rabuñal, María-José; Hernández‐Rivas, Jesús‐María; Feliú, Evarist

doi:10.1200/jco.2013.52.2425

Cited by 227 publications

(191 citation statements)

References 32 publications

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“…In adult ALL, MRD response has been evaluated at various time points using different techniques and threshold cutoffs. [16][17][18]20,49 Good MRD response was generally defined as an MRD level of ,10 23 to 10 24 between weeks 5 and 10 and/or MRD level of ,10 24 or not detectable between weeks 11 and 17. For logistical reasons, an earlier time point is more convenient for risk-oriented SCT decision.…”

Section: Discussionmentioning

confidence: 99%

“…18 Conversely, no superiority of SCT over chemotherapy was observed in patients with a poor early cytologic/MRD response in the Programa Español de Tratamientos en Hematología (PETHEMA) ALL-AR-03 trial, a result that could be hampered by a lower 5-year DFS after allogeneic transplant (32%) than expected in ALL in CR1. 20 We also investigated the role of SCT in patient subsets defined by newly described oncogenetic markers. In BCP-ALL patients, the presence of poor-prognosis IKZF1 gene deletions was also predictive of a positive SCT effect but was strongly related to poor early MRD response.…”

Section: Discussionmentioning

confidence: 99%

“…[13][14][15][16][17][18][19][20][21] They might thus be considered as a stratification tool, with the option to offer allogeneic SCT to patients with persistent molecular disease. 16,18,20,22 Conversely, novel genetic alterations originally described in children have also been reported to have an impact on the outcome of adult patients. In the B-cell precursor (BCP-ALL) subgroup, focal deletions of the IKZF1 gene, observed in up to 80% of Philadelphia chromosome (Ph)-positive ALL, have been associated with a poor outcome in adult patients with Ph-negative ALL.…”

Section: Introductionmentioning

confidence: 99%

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Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia

Dhédin

Huynh

Maury

et al. 2015

Blood

239

190

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Because a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome-negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10(-3) (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia

Dhédin

Huynh

Maury

et al. 2015

Blood

239

190

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“…17 Patients with standard-risk ALL were treated with pediatric-based chemotherapy, 18 whereas patients with high-risk ALL received chemotherapy with or without hematopoietic stem cell transplantation (HSCT). 17,19 Since 2002, patients with Ph-positive ALL have received chemotherapy and imatinib upfront, and these have been followed by HSCT in patients younger than 55 years. 20 Analysis of CNAs DNA samples from BM or peripheral blood with a minimal proportion of blasts of 30% (stored at 12 Spanish centers) were processed.…”

Section: Methodsmentioning

confidence: 99%

Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols

Ribera

Morgades

Zamora

et al. 2015

Cancer

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; for the Spanish PETHEMA Group and the Spanish Society of Hematology BACKGROUND: Some copy number alterations (CNAs) have independent prognostic significance for adults with acute lymphoblastic leukemia (ALL). METHODS: This study analyzed via multiplex ligation-dependent probe amplification the frequency and prognostic impact of CNAs of 12 genetic regions in 142 adolescents and adults with de novo precursor B-cell ALL. RESULTS: The cyclindependent kinase inhibitor 2A/B (CDKN2A/B) deletion (59 of 142 or 42%) was the most frequent CNA, and it was followed by Ikaros family zinc finger 1 (IKZF1) losses (49 of 142 or 35%). IKZF1 deletions were more prevalent in Philadelphia chromosome (Ph)-positive ALL and were associated with advanced age and high white blood cell (WBC) counts. The multivariate analysis showed that advanced age and early B-cell factor 1 (EBF1) deletions were associated with chemotherapy resistance in both the whole series (hazard ratios, 0.949 and 0.135, respectively) and the Ph-negative subgroup (hazard ratios, 0.946 and 0.118, respectively). High WBC counts and focal IKZF1 deletions correlated with disease recurrence (hazard ratios, 1.005 and 1.869, respectively), whereas advanced age and CDKN2A/B losses influenced overall survival in both the whole series (hazard ratios, 1.038 and 2.545, respectively) and the Ph-negative subgroup (hazard ratios, 1.044 and 2.105, respectively). CONCLUSIONS: Deletions of EBF1, IKZF1, and CDKN2A/B have an independent adverse prognosis for adolescents and adults with B-precursor ALL, and this suggests that these CNAs should be included in the initial risk assessment of ALL. Cancer 2015;121:3809-17.

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“…[27][28][29][30] Interestingly, the achievement of MR5 significantly affected the 2-year HRFS rate of subjects that did not receive allo-HCT, but not that of subjects that received allo-HCT. It was encouraging to find that, among subjects that achieved MR5, the 2-year HRFS rate was similar between those that did not receive allo-HCT (64%) and those that received allo-HCT (78%).…”

Section: 221mentioning

confidence: 99%

Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia

Kim

Joo

Lim

et al. 2015

Blood

170

116

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Key Points• Nilotinib plus multiagent chemotherapy was feasible and showed a comparable outcome to previous results with imatinib for Ph-pos ALL.• The achievement of deep MR with nilotinib at postremission correlated well with the clinical outcomes for Ph-pos ALL.We investigated the effects of nilotinib plus multiagent chemotherapy, followed by consolidation/maintenance or allogeneic hematopoietic cell transplantation (allo-HCT) for adult patients with newly diagnosed Philadelphia-positive (Ph-pos) acute lymphoblastic leukemia (ALL). Study subjects received induction treatment that comprised concurrent vincristine, daunorubicin, prednisolone, and nilotinib. After achieving complete hematologic remission (HCR), subjects received either 5 courses of consolidation, followed by 2-year maintenance with nilotinib, or allo-HCT. Minimal residual disease (MRD) was assessed at HCR, and every 3 months thereafter. The molecular responses (MRs) were defined as MR3 for BCR-ABL1/G6PDH ratios £10 23 and MR5 for ratios <10 25. Ninety evaluable subjects, ages 17 to 71 years, were enrolled in 17 centers. The HCR rate was 91%; 57 subjects received allo-HCT. The cumulative MR5 rate was 94%; the 2-year hematologic relapse-free survival (HRFS) rate was 72% for 82 subjects that achieved HCR, and the 2-year overall survival rate was 72%. Subjects that failed to achieve MR3 or MR5 were 9.1 times (P 5 .004) or 6.3 times (P 5 .001) more prone to hematologic relapse, respectively, than those that achieved MR3 or MR5. MRD statuses just before allo-HCT and at 3 months after allo-HCT were predictive of 2-year HRFS. Adverse events occurred mainly during induction, and most were reversible with dose reduction or transient interruption of nilotinib. The combination of nilotinib with high-dose cytotoxic drugs was feasible, and it effectively achieved high cumulative complete molecular remission and HRFS rates. The MRD status at early postremission time was predictive of the HRFS. This trial was registered at www.clinicaltrials.gov as #NCT00844298. (Blood. 2015;126(6):746-756)

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Treatment of High-Risk Philadelphia Chromosome–Negative Acute Lymphoblastic Leukemia in Adolescents and Adults According to Early Cytologic Response and Minimal Residual Disease After Consolidation Assessed by Flow Cytometry: Final Results of the PETHEMA ALL-AR-03 Trial

Abstract: Prognosis for Ph-negative HR-ALL in adolescents and adults with good early response to induction and low flow-MRD levels after consolidation is quite favorable when allo-HSCT is avoided. In this study, the pattern of MRD clearance was the only prognostic factor for DFS and OS.

Cited by 227 publications

References 32 publications

Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia

Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia

Prognostic significance of copy number alterations in adolescent and adult patients with precursor B acute lymphoblastic leukemia enrolled in PETHEMA protocols

Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia

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