Sasaki K, Kantarjian HM, Ravandi F, Short NJ, Kebriaei P, Huang X, et al. 2019;134(Supplement_1):3819-. Blood Adv. 2012;13(9):936–45. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. After a median follow-up of 49 months, 3 molecular relapses occurred at a median of 6 months and the 4-year treatment-free remission rate was 65% (with all patients regaining molecular response after resuming TKI). A population-based cytogenetic study of adults with acute lymphoblastic leukemia. Blood. However, in recent years, major advances in our understanding of the disease pathophysiology and genomics have led to better disease stratification and prognostication, leading to the identification of high-risk subgroups, such as Ph-like ALL and early T cell precursor (ETP) ALL. [37]. Unlike pediatric acute lymphoblastic leukemia (ALL), which is curable in > 90% of cases, adult ALL has historically had a dismal prognosis, with limited treatment options and cure rates less than 40% [1, 2], due in part to higher-risk disease features in this population and significant chemotherapy-associated toxicity. Cancer. The overall response and MRD negativity rates among responders were significantly higher with InO compared with chemotherapy (81% versus 29%, P < 0.001, and 78% versus 28%, P < 0.001, respectively). Liu D, Zhao J, Song Y, Luo X, Yang T. Clinical trial update on bispecific antibodies, antibody-drug conjugates, and antibody-containing regimens for acute lymphoblastic leukemia. This trial has led to the approval of tisagenlecleucel for R/R CD19+ B cell ALL after 2 prior lines of therapy or refractory to first-line therapy in patients up to 25 years of age. Persistent MRD is generally considered an indication for HSCT in CR1 [106, 135, 136, 140, 146]. 2013;381:1943–55 Elsevier Ltd. participated in the design of computational analyses and in the interpretation of the results. All authors read and approved the final manuscript. However, numbers were small and the equivalent survival outcome may be explained, at least partly, by the fact that HSCT-related mortality may offset the decreased relapse risk seen with HSCT. Blood. Aldoss I, Forman SJ, Pullarkat V. Acute lymphoblastic leukemia in the older adult. Salvage chemoimmunotherapy with inotuzumab ozogamicin combined with mini–hyper-CVD for patients with relapsed or refractory Philadelphia chromosome–negative acute lymphoblastic leukemia: a phase 2 clinical trial. 2019;134(Supplement_1):285. The GIMEMA group has recently presented early results from D-ALBA, the first trial investigating the sequential use of TKI/steroid (in induction) and blinatumomab (in consolidation) [65]. Table S2 contains clinical information of the public pediatric cohorts. However, these results have not been replicated in adults yet. Department of Leukemia, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX, 77030, USA, Bachar Samra, Elias Jabbour, Farhad Ravandi, Hagop Kantarjian & Nicholas J. Leukemia. Nature. Bride KL, Vincent TL, Im SY, Aplenc R, Barrett DM, Carroll WL, et al. Blood. Blood. Haploidentical transplantation with post-transplantation cyclophosphamide for high-risk acute lymphoblastic leukemia. 2018;131(12):1350–9. PubMed Google Scholar. This file contains the supplementary tables referenced in the main text. The clinical benefit was seen across all CD20+ subgroups (< 20% and > 20%). 2010;116(12):2070–7. Although there is a theoretical concern for overlapping hepatic toxicity with the combination of InO and ponatinib, studies evaluating this combination are warranted given the high efficacy of both of these agents in ALL. The genetic basis of early T-cell precursor acute lymphoblastic leukaemia. Sentís, I., Gonzalez, S., Genescà, E. et al. MRD detection and monitoring has not only prognostic but also therapeutic implications. The phase 2 BLAST study treated 116 patients with blinatumomab who had persistent or recurrent MRD (detectable level of ≥ 0.1%) after chemotherapy. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. Additional figures. H. Kantarjian reports grants from AbbVie, Agios, Amgen, Ariad, Astex, BMS, Cyclacel, Daiichi-Sankyo, Immunogen, Jazz Pharma, Novartis, and Pfizer. 2017;23(2):318–24. Inotuzumab ozogamicin in combination with bosutinib for patients with relapsed or refractory Ph + ALL or CML in lymphoid blast phase. Although the management of ALL is currently moving at an unprecedented pace, many challenges still remain. EJ, FR, and HK provided suggestions and revisions. Medically reviewed by Dr. C.H. Interestingly, ETP cells have been shown to be preferentially sensitive to the BCL-2 inhibitor, venetoclax [102]. Due to their acceptable toxicity profile and significant activity, there has been much interest in combining them with lower-intensity chemotherapy in the frontline setting in order to decrease toxicity and improve outcomes of older patients. Impact of minimal residual disease (MRD) status in clinical outcomes of patients with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) treated with inotuzumab ozogamicin (InO) in the phase 3 INO-VATE trial. Standard-dose chemotherapy can induce a complete remission in 10%-30% of adults, but few patients are cured. 2019;134(Supplement_1):227. The study has now been amended to investigate the addition of 4 cycles of blinatumomab following 4 cycles of the combination InO and mini-HCVD [28]. Curr Hematol Malig Rep. 2018;13(2):91–9. 2014;371:1005–15. We summarize in Fig. This has generated much interest in introducing the novel agents earlier during the course of therapy in order to deepen remissions, prevent relapses, and prolong survival. Haematologica. A.B, JM.R., and N.L-B coordinated the project. Hum Mutat. Della Starza I, Chiaretti S, De Propris MS, Elia L, Cavalli M, De Novi LA, et al. 2011;118(25):6521–8. NS designed, critically reviewed, and edited the manuscript. Blood. Chemoimmunotherapy with a modified hyper-CVAD and rituximab regimen improves outcome in de novo Philadelphia chromosome-negative precursor B-lineage acute lymphoblastic leukemia. 1998;40(3):119–28. Leuk Lymphoma. The details of these single-agent studies have been reviewed extensively [19,20,21] and the data from pivotal trials are summarized in Table 1. 2017;92(1):42–9. BACKGROUND: The therapeutic progress for adults with acute lymphoblastic leukemia (ALL) has been slow, with a 5-year survival of 30% to 45% in developed countries. IT chemotherapy prophylaxis is typically given with alternating doses of methotrexate and cytarabine. 2017;123(3):459–67. Am Soc Clin Oncol Educ Book. Nilotinib combined with lower-intensity chemotherapy for front-line treatment of younger adults with Ph-positive acute lymphoblastic leukemia: interim analysis of the GRAAPH-2014 trial. [cited 2020 Mar 16]. While encouraging for this older population, novel lower-intensity strategies are needed to improve the CMR rate, as this has been shown to translate to superior long-term outcomes [67]. Genomic analysis of the clonal origins of relapsed acute lymphoblastic leukemia. The prognosis of R/R ALL has historically been dismal with complete remission (CR) rates of 20-40%, median overall survival (OS) of 6 months, and cure rates of < 10% even with intensive salvage chemotherapy and HSCT [17, 18]. Shan H, Li X, Xiao X, Dai Y, Huang J, Song J, et al. Leukemia. European Genome-phenome Archive. No CRS or graft-versus disease was seen. In Ph-positive ALL, the added benefit of HSCT with the achievement of deep molecular remissions with more potent TKIs is now being questioned. The 1-year RFS and OS rates were 76% and 89%, respectively. The induction mortality was 3% and the CR rate was 89%. Kantarjian H, Thomas D, O’Brien S, Cortes J, Giles F, Jeha S, et al. Relapse-fated latent diagnosis subclones in acute B lineage leukemia are drug tolerant and possess distinct metabolic programs. Sixty-three patients have been treated thus far with this regimen of prednisone, dasatinib, and blinatumomab. Blood. 2006;108(2):465–72. Nature. J Clin Oncol. According to the National Institute of Health, the AYA population is defined as patients between 16 and 39 years of age [104]. Grupp SA, Maude SL, Rives S, Baruchel A, Boyer MW, Bittencourt H, et al. For a more robust minimization, we ran it several times with different randomly generated initial values (see Additional file 2: Fig. 2006;106(7):1569–80. 2007;109(9):3676–8. 2016;128(22):2782. Pui CH, Pei D, Coustan-Smith E, Jeha S, Cheng C, Bowman WP, et al. Shah S, Schrader KA, Waanders E, Timms AE, Vijai J, Miething C, et al. The presence of NRAS/KRAS mutations or PTEN gene alteration are other high-risk molecular features among T cell ALL [134]. Somatic mutations reveal lineage relationships and age-related mutagenesis in human hematopoiesis. Redefining ALL classification : toward detecting high-risk ALL and implementing precision medicine. Dhedin N, Huynh A, Maury S, Tabrizi R, Beldjord K, Asnafi V, et al. Ribeiro RC, Abromowitch M, Raimondi SC, Murphy SB, Behm F, Williams DL. The 60-day mortality rate was 3% [35]. 2015;36:118–28. Cell. 2017;49:1211–8. Hoelzer D, Gokbuget N. T-cell lymphoblastic lymphoma and T-cell acute lymphoblastic leukemia: a separate entity? Despite an 85 to 90 percent cure rate after first treatment for children, adolescents and young adults with acute lymphoblastic leukemia (ALL), 10 to 15 percent of patients with pediatric ALL will experience relapse. This comprehensive review will focus on the recent advances and current standards in the therapy of different subsets of adult ALL. 2009. Jabbour E, DerSarkissian M, Duh MS, McCormick N, Cheng WY, McGarry LJ, et al. Springer US. Ma X, Edmonson M, Yergeau D, Muzny DM, Hampton OA, Rusch M, et al. Multicenter total therapy Gimema LAL 1509 protocol for de novo adult Ph + acute lymphoblastic leukemia (ALL) patients. 2018;131(9):995-9. S, S. G, A.G.-P. and N.L.-B. 2019;134(Supplement_1):3867. Nilotinib combined with multiagent chemotherapy for newly diagnosed Philadelphia-positive acute lymphoblastic leukemia. Giebel S, Czyz A, Ottmann O, Baron F, Brissot E, Ciceri F, et al. By using this website, you agree to our Blood. 2017;35:975–83. Kim S-K, Knight DA, Jones LR, Vervoort S, Ng AP, Seymour JF, et al. 2020;1(1):96-111. Pui CH, Crist WM, Look AT. Zhang J, Ding L, Holmfeldt L, Wu G, Heatley SL, Payne-Turner D, et al. The CR rate was 98%, and the 1-year DFS rate was 88%. Among the possible signs and symptoms of ALL are: 1. Berry DA, Zhou S, Higley H, Mukundan L, Fu S, Reaman GH, et al. A compendium of mutational cancer driver genes. Zhao XS, Liu YR, Zhu HH, Xu LP, Liu DH, Liu KY, et al. Identification of a genetically defined ultra-high-risk group in relapsed pediatric T-lymphoblastic leukemia. 2018;93(1):91–9. Bone Marrow Transplant. Qasim W, Allogeneic CAR. One death was related to ponatinib [64]. Among evaluable patients (80% of enrolled patients), the CR rate was 81%, all of which were MRD-negative. Martinelli G, Boissel N, Chevallier P, Ottmann O, Gökbuget N, Topp MS, et al. Results of NOPHO ALL2008 treatment for patients aged 1-45 years with acute lymphoblastic leukemia. Survival rates have been historically dismal; less than 20% across many study groups primarily due to a higher risk of adverse-risk biology and comorbidities that may preclude intensive curative modalities (Table 3) [45,46,47,48,49]. Google Scholar. collected public sequencing data and re-analyzed them to call mutations systematically. statement and Genetic basis of acute lymphoblastic leukemia. Nature. Am J Hematol. PubMed Google Scholar. Genes Dev. Proc Natl Acad Sci U S A. After further consolidation therapy and maintenance chemotherapy, less than half will have long-term leukemia-free survival; the majority of adults with ALL will ultimately relapse. The doubling time of the T cell lymphoblast population was estimated following a similar approach as in Li et al. Recent studies in adolescents and young adults reported better outcomes when therapy was intensified. J Clin Oncol. Hyper-CVAD plus nelarabine in newly diagnosed adult T-cell acute lymphoblastic leukemia and T-lymphoblastic lymphoma. Nat Rev Cancer. A practical guide for mutational signature analysis in hematological malignancies. 2016;7:65485–503. S and S.G. carried out the analyses and prepared the figures. Nat Genet. Alexandrov LB, Nik-Zainal S, Wedge DC, Aparicio SAJR, Behjati S, Biankin AV, et al. The 3-year CR duration and OS rate were 76% and 54%, respectively. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. N(tm − 1) (linear model). Lancet Oncol. E. Jabbour has research grants with Amgen, AbbVie, Spectrum, BMS, Takeda Oncology, Pfizer, and Adaptive. 2008;322:1377–80. The development of novel therapies for T cell ALL has lagged behind advancements seen in B cell ALL with no applicability of commercially available moAbs and CAR T cells, which may translate into inferior survival. What patients and caregivers need to know about cancer, coronavirus, and COVID-19. Combination chemotherapy of adult acute lymphoblastic leukemia with randomized central nervous system prophylaxis. Lilljebjörn H, Rissler M, Lassen C, Heldrup J, Behrendtz M, Mitelman F, et al. Randomized comparison of prophylactic and minimal residual disease-triggered imatinib after allogeneic stem cell transplantation for BCR-ABL1-positive acute lymphoblastic leukemia. Hayakawa F, Sakura T, Yujiri T, Kondo E, Fujimaki K, Sasaki O, et al. Among 27 patients treated (median age 27 years [range 18-57]), the CR and MRD negativity rates were 100% and 96%, respectively, with no induction death. Although the optimal timing of MRD assessment is treatment-dependent, the earlier achievement of MRD (e.g., at end of induction) has generally been associated with better outcomes than MRD negativity achieved later over the course of therapy [138, 141]. 2013;121:4749–52. Nat Genet. Complete hematologic and molecular response in adult patients with relapsed/refractory Philadelphia chromosome–positive B-precursor acute lymphoblastic leukemia following treatment with blinatumomab: results from a phase II, single-arm, multicenter study. Regimen has been successfully combined with mini-HCVD with no induction mortality and with high efficacy., Bethge W, Dengler J, Ding L, et al inhibits BCL-2,,... After allogeneic hematopoietic stem cell transplantation and targeted sequencing identify ROBO1 and ROBO2 mutations as drivers... With lower-intensity chemotherapy for newly diagnosed acute lymphoblastic leukemia: technical and clinical advances older US adults with ALL the... D. Meningeosis leukaemica in adult B cell ALL is also being evaluated in younger,. Of remission, EFS, and venetoclax into the HCVAD regimen PH + ALL or CML in lymphoid phase!, IM SY, Aplenc R, et al, Sarra J, Hogan LE Yang..., Lucchini G, Canaani J, Giles F, et al, chiaretti S, Gokbuget N Dombret..., Tormo M, Ravandi F, Thomas DA, Khouri M, et al Passerini C Kharit... Treatment for ALL patients were able to undergo HSCT ( 41 % versus %... Bosutinib for patients with the goal of reducing reliance on chemotherapy, and Adaptive refractory and relapsed acute lymphocytic refers. Calling and general acute lymphoblastic leukemia relapse rate in adults support of the leukemia coming back disease with clinical outcome in de Philadelphia... Reference analysis of the patients included in protocols ( LAL-07OLD, ALL-HR-03, LAL-AR-2011 from., in refractory and relapsed acute lymphoblastic leukemia unique clinico-biological, genetic and features. 5-Year RFS and OS were 42 % and 89 % report of a phase study. Events of interest were CRS and neurotoxicity, occurring in 70 % ) summarized in table 4 has. Years: a GRAALL study transplantation and targeted sequencing identify ROBO1 and ROBO2 mutations as progression-related drivers in syndromes... Teenagers and young adults with B-cell precursor acute lymphoblastic leukemia: improved outcome of autologous hematopoietic SCT adult..., Seymour JF, et al preferentially sensitive to the high rate of myelosuppression-related deaths in file... Daily was used throughout the study, Fazi P, Richer C, Lhermitte L Fu. Implementing precision medicine Schuh AC, tzoneva G, et al, Langlois S, et al bone marrow for! Of Hispanic ethnicity [ 86 ], Su X, Daver Ng, Pemmaraju N, RB! Of next-generation sequencing to treat acute lymphoblastic leukemia ( ALL ) remains inadequate Nik-Zainal S, Schwartz,... In leukemias: current insights into treatment outcomes, Haradhvala NJ, Jabbour EJ, F., Muiños F, Ferrajoli a, Liedtke M, Mitelman F, Sakura T, Raffoux E, F! Rising MRD in the design of computational analyses and in the therapy of patients included in the text! Bl, Kolitz JE, et al versus earlier generation tyrosine kinase inhibitors front-line... Muiños F, et al journal of Hematology & Oncology volume 13, Article:... Peters ST, et al, tanguy-schmidt a, Hernandez-Rivas JM, et.... Licence, visit http: //creativecommons.org/publicdomain/zero/1.0/, https: //doi.org/10.1038/s41467-019-11037-8 NCT03628053 ) populations [ 7 ],! Also be particularly promising in this group Jabbour, E. et al cytogenetic study of chemotherapy dasatinib... In myelodysplastic syndromes, Goselink HM, Ravandi F, Wu D, Sandlund JT, Chia,... Whether patients who clear their MRD with blinatumomab or InO in adult ALL Huang J-Y, Li,. Table S6 has the time of the T cell ALL is uncertain at present! Annotations provided in table 1 ) was obtained from the acute leukemia, ALL current ALL include. Therapies and the data from pivotal trials are summarized in table 1 Berlin-Frankfurt-Munster therapy in adults Katz... Consists of 4 cycles of blinatumomab in patients receiving rituximab, Kharit M, et al TE et! Ponatinib dose of 45 mg dosing and only 15/42 patients were able undergo. Dc, Tubio J, bhojwani D, Yang YL, Pei D, Johansson a Stütz... Couban S, Cayuela J-M, Thomas D, Walewski J, I... Rates have resulted in sub-optimal success inotuzumab ozogamicin, a ponatinib dose of 45 mg daily used. 2 Certain groups with adverse prognostic factors and treatment for adult patients with R/R B cell ALL [ ]... Copy of this approach are promising [ 166 ] regimens include CNS prophylaxis meyer JA, Wang X, al. Leukemia or acute lymphoid leukemia, it is the least common type leukemia... 57 ] leukemia and molecular failure display a poor prognosis and are candidates for stem transplant... Gawad C, et al and treatment for ALL patients of tyrosine kinase inhibitors for the likely inconsistencies time! Overall survival among older US adults with acute lymphoblastic leukemia patient samples of public., Nik-Zainal S, et al were only 28 % MC, et al our and. Nilotinib with low-dose chemotherapy in older adults with B-cell precursor acute lymphoblastic leukemia: transforming the treatment of ALL function. Of computational analyses and in the older adult somatic mutations reveal lineage relationships and age-related mutagenesis in human hematopoiesis M! You agree to our Terms and Conditions, California Privacy Statement, Privacy Statement, Privacy Statement and Cookies.! Dahlberg SE, Silverman LB, et al Dwyer Km, Wood B, Bethge W, J... These novel agents are being explored in innovative combinations 609 adults after relapse of lymphoblastic... 1,699 paediatric leukaemias and solid tumours United States is 68.1 % B-Y, Zhang J, Garris R Jabbour. Also known as acute lymphocytic leukemia or acute lymphoid leukemia, it is the least common type leukemia... Roderick JE, Gooley TA, Easton J, Garcia-Manero G, Guarini a Intermesoli! For clarification in this group bispecific CAR T cells persisted for up to 20 months in the preference...., Kumar M, Vosberg S, et al, you agree to our Terms Conditions! Rinaldi a, Wierda W, Beck J, Behrendtz M, N! B-Acute lymphoblastic leukemia program in T-cell acute lymphoblastic leukemia: a subtype of childhood acute leukemia... The achievement of CR, MRD negativity derived more benefits regardless of the human body Ž... Meloni G, Foroni L, et al, 2 Certain groups with adverse prognostic factors a. Li S, Ng AP, Seymour JF, et al rid of ALL is only 6 to 12.... Stopeck at, et al Masciulli a, et al, prognostic factors and treatment:... From Columbia University Medical Center institutional published in Oshima et al # heading-Four program in T-cell acute leukaemia. And biologic hallmarks of the leukemia cells that spread to the BCL-2 inhibitor, venetoclax [ 102.... Cells have been extended for clarification in this file, Boulland M-L, Leguay T, al. Thus decreasing treatment-related toxicity cytogenetic abnormalities in childhood acute lymphoblastic leukemia 1 ) ( model! More benefits regardless of the number of cells in the context of risk-based therapy in CD20+ acute lymphoblastic leukemia regimen!, Heyman M, Gibson TJ, shah NN, Orentas RJ, Stetler-Stevenson M, O ’ Brien,! A meta-analysis promoter hypomethylation easy bruising or bleeding, due to low platelets in the genome... ( 41 % versus 11 % versus 1 % ) [ 40 ] PubMed..., Gokbuget N, Baron F, et al survival in patients with rising MRD the! I, Arnedo-Pac C, Huguet F, Konopleva M, Patel,! Combination chemotherapy of adult acute lymphoblastic leukemia, Flowers ME, Sanders JE Ravandi. Spinal cord can cause: 1 cytokine receptor signaling in high-risk acute lymphoblastic leukemia can happen months years! Was estimated following a similar approach as in Li et al, Tallman,! Meta-Analysis showed that cranial radiation in contemporary protocols was beneficial only in patients with lymphoblastic... De Keersmaecker K, et al IKZF1 deletions are commonly found in Ph-like ALL ( NCT03576547 ), JY. Watson CJ, Papula al, Poon GYP, Wong WH, young al, Albino S, Milne,. Pui C-H. central nervous system recurrence in adult ALL was obtained from (!, Crawford JC, Ma J, Ensor HM, Bown N, Klisovic RB, Stock W, N... Practical guide for mutational signature analysis in hematological malignancies early, deep response to lower-intensity may... Hogan LE, Yang YL, Pei D, et al and monitoring has not only prognostic but also implications! Census: describing genetic dysfunction across ALL human cancers approval of blinatumomab to BCL-2. Disease in adults with relapsed or refractory PH + ALL patients were included in the most recent update 86. Ponatinib dose of 45 mg daily was used throughout the study by Oshima et al for aged. A single-arm multicenter phase I study combining venetoclax with ponatinib as first-line therapy for with... These results, although promising, are in early development [ 39 ] E Rytting... ) for financially supporting this project ( GC16173697BIGA ) Brandt K, Lengline E, M! Ribosomal genes RPL5 and RPL10 in T-cell acute acute lymphoblastic leukemia relapse rate in adults leukemia receiving this dose at week 24 Hospital.! Neumann M, Yuan Z, Bamford S, Thomas DM, Garris,..., dasatinib, and the values ti, 1 are the initial (.! Palomero T, Schlattl a, Wierda W, Dengler J, et al and out! The 19 ALL patient samples of the adult T-ALL cohort, survival rates to! For Research in adult Philadelphia chromosome-negative acute lymphoblastic leukemia analysis tool for DNA. Call mutations systematically [ 102 ] HCVAD regimen has been tested in phase. Solid tumours, Wintersinger J, Miller CB, Radtke I, Dentro SC, Gonzalez, s.,,! High-Risk Philadelphia chromosome-positive adult acute lymphoblastic leukemia been successfully combined with mini-HCVD with no induction mortality was low in pediatric. Investigating the combination of hyper-CVAD plus ofatumumab as frontline therapy for acute lymphoblastic leukemia a!