Post-remission therapy for Philadelphia chromosome negative acute lymphoblastic leukemia in adults
- Richard A Larson, MD
Richard A Larson, MD
- Editor-in-Chief — Hematology
- Section Editor — Leukemia
- Professor of Medicine
- University of Chicago Pritzker School of Medicine
Over 80 percent of adult patients with newly diagnosed acute lymphoblastic leukemia (ALL) will attain a complete remission (CR) with intensive induction chemotherapy. However, without additional cytotoxic therapy, virtually all of these patients will relapse within a few weeks or months. In contrast, patients who receive post-remission therapy may expect five-year survival rates up to 60 percent in adults with standard risk disease.
Induction therapy aims to reduce the total body leukemia cell population from approximately 1012 to below the cytologically detectable level of about 109 cells. It is generally assumed, however, that a substantial burden of leukemia cells persists undetected in patients in initial clinical and morphologic CR (ie, "minimal residual disease"), leading to relapse within a few weeks or months if no further therapy were administered.
The primary aim of post-remission therapy (eg, consolidation, intensification) is to eradicate this minimal residual disease. There are three basic options for post-remission therapy (in order of increasing intensity): consolidation plus maintenance chemotherapy, autologous hematopoietic cell transplantation (HCT), or allogeneic HCT. The choice among these for an individual patient depends upon a number of factors, including:
●Expected rate of relapse with consolidation chemotherapy alone (influenced strongly by the patient and tumor characteristics)
●Expected morbidity and mortality associated with treatment options (as determined by patient characteristics such as age and comorbidities)
- Pui CH, Evans WE. Treatment of acute lymphoblastic leukemia. N Engl J Med 2006; 354:166.
- Burmeister T, Gökbuget N, Schwartz S, et al. Clinical features and prognostic implications of TCF3-PBX1 and ETV6-RUNX1 in adult acute lymphoblastic leukemia. Haematologica 2010; 95:241.
- Dhédin N, Huynh A, Maury S, et al. Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia. Blood 2015; 125:2486.
- Larson RA, Dodge RK, Bloomfield CD, Schiffer CA. Treatment of biologically determined subsets of acute lymphoblastic leukemia in adults: Cancer and Leukemia Group B studies. In: Acute Leukemias VI: Prognostic factors and treatment strategies, Buchner T, Hiddeman W, Wormann B, et al. (Eds), Springer-Verlag, Berlin 1997. p.677.
- Linker CA, Levitt LJ, O'Donnell M, et al. Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 1991; 78:2814.
- Hoelzer D, Thiel E, Löffler H, et al. Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 1988; 71:123.
- Rowe JM, Buck G, Burnett AK, et al. Induction therapy for adults with acute lymphoblastic leukemia: results of more than 1500 patients from the international ALL trial: MRC UKALL XII/ECOG E2993. Blood 2005; 106:3760.
- Hann I, Vora A, Harrison G, et al. Determinants of outcome after intensified therapy of childhood lymphoblastic leukaemia: results from Medical Research Council United Kingdom acute lymphoblastic leukaemia XI protocol. Br J Haematol 2001; 113:103.
- Ribera JM, Ortega JJ, Oriol A, et al. Prognostic value of karyotypic analysis in children and adults with high-risk acute lymphoblastic leukemia included in the PETHEMA ALL-93 trial. Haematologica 2002; 87:154.
- Schrappe M, Reiter A, Zimmermann M, et al. Long-term results of four consecutive trials in childhood ALL performed by the ALL-BFM study group from 1981 to 1995. Berlin-Frankfurt-Münster. Leukemia 2000; 14:2205.
- Visser JH, Wessels G, Hesseling PB, et al. Prognostic value of day 14 blast percentage and the absolute blast index in bone marrow of children with acute lymphoblastic leukemia. Pediatr Hematol Oncol 2001; 18:187.
- Laughton SJ, Ashton LJ, Kwan E, et al. Early responses to chemotherapy of normal and malignant hematologic cells are prognostic in children with acute lymphoblastic leukemia. J Clin Oncol 2005; 23:2264.
- Roy A, Bradburn M, Moorman AV, et al. Early response to induction is predictive of survival in childhood Philadelphia chromosome positive acute lymphoblastic leukaemia: results of the Medical Research Council ALL 97 trial. Br J Haematol 2005; 129:35.
- Beldjord K, Chevret S, Asnafi V, et al. Oncogenetics and minimal residual disease are independent outcome predictors in adult patients with acute lymphoblastic leukemia. Blood 2014; 123:3739.
- Frassoni F, Labopin M, Gluckman E, et al. Are patients with acute leukaemia, alive and well 2 years post bone marrow transplantation cured? A European survey. Acute Leukaemia Working Party of the European Group for Bone Marrow Transplantation (EBMT). Leukemia 1994; 8:924.
- Larson RA, Dodge RK, Burns CP, et al. A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 1995; 85:2025.
- Laport GF, Larson RA. Treatment of adult acute lymphoblastic leukemia. Semin Oncol 1997; 24:70.
- Ellison RR, Mick R, Cuttner J, et al. The effects of postinduction intensification treatment with cytarabine and daunorubicin in adult acute lymphocytic leukemia: a prospective randomized clinical trial by Cancer and Leukemia Group B. J Clin Oncol 1991; 9:2002.
- Cassileth PA, Andersen JW, Bennett JM, et al. Adult acute lymphocytic leukemia: the Eastern Cooperative Oncology Group experience. Leukemia 1992; 6 Suppl 2:178.
- Stryckmans P, De Witte T, Marie JP, et al. Therapy of adult ALL: overview of 2 successive EORTC studies: (ALL-2 & ALL-3). The EORTC Leukemia Cooperative Study Group. Leukemia 1992; 6 Suppl 2:199.
- Thomas X, Boiron JM, Huguet F, et al. Outcome of treatment in adults with acute lymphoblastic leukemia: analysis of the LALA-94 trial. J Clin Oncol 2004; 22:4075.
- Thomas D, O'Brien S, Faderl S, et al. Anthracycline dose intensification in adult acute lymphoblastic leukemia: lack of benefit in the context of the fractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone regimen. Cancer 2010; 116:4580.
- Larson RA, Dodge RK, Linker CA, et al. A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 1998; 92:1556.
- Stock W, La M, Sanford B, et al. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? A comparison of Children's Cancer Group and Cancer and Leukemia Group B studies. Blood 2008; 112:1646.
- Kantarjian HM, O'Brien S, Smith TL, et al. Results of treatment with hyper-CVAD, a dose-intensive regimen, in adult acute lymphocytic leukemia. J Clin Oncol 2000; 18:547.
- Huguet F, Leguay T, Raffoux E, et al. Pediatric-inspired therapy in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: the GRAALL-2003 study. J Clin Oncol 2009; 27:911.
- Thiebaut A, Vernant JP, Degos L, et al. Adult acute lymphocytic leukemia study testing chemotherapy and autologous and allogeneic transplantation. A follow-up report of the French protocol LALA 87. Hematol Oncol Clin North Am 2000; 14:1353.
- Fière D, Lepage E, Sebban C, et al. Adult acute lymphoblastic leukemia: a multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Acute Lymphoblastic Leukemia. J Clin Oncol 1993; 11:1990.
- Goldstone AH, Richards SM, Lazarus HM, et al. In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 2008; 111:1827.
- Fielding AK, Goldstone AH. Allogeneic haematopoietic stem cell transplant in Philadelphia-positive acute lymphoblastic leukaemia. Bone Marrow Transplant 2008; 41:447.
- Kantarjian HM, Walters RS, Keating MJ, et al. Results of the vincristine, doxorubicin, and dexamethasone regimen in adults with standard- and high-risk acute lymphocytic leukemia. J Clin Oncol 1990; 8:994.
- Carey PJ, Proctor SJ, Taylor P, Hamilton PJ. Autologous bone marrow transplantation for high-grade lymphoid malignancy using melphalan/irradiation conditioning without marrow purging or cryopreservation. The Northern Regional Bone Marrow Transplant Group. Blood 1991; 77:1593.
- Attal M, Blaise D, Marit G, et al. Consolidation treatment of adult acute lymphoblastic leukemia: a prospective, randomized trial comparing allogeneic versus autologous bone marrow transplantation and testing the impact of recombinant interleukin-2 after autologous bone marrow transplantation. BGMT Group. Blood 1995; 86:1619.
- Powles R, Sirohi B, Treleaven J, et al. The role of posttransplantation maintenance chemotherapy in improving the outcome of autotransplantation in adult acute lymphoblastic leukemia. Blood 2002; 100:1641.
- Brenner MK, Rill DR, Moen RC, et al. Gene-marking to trace origin of relapse after autologous bone-marrow transplantation. Lancet 1993; 341:85.
- Labopin M, Gorin NC. Autologous bone marrow transplantation in 2502 patients with acute leukemia in Europe: a retrospective study. Leukemia 1992; 6 Suppl 4:95.
- Bachanova V, Verneris MR, DeFor T, et al. Prolonged survival in adults with acute lymphoblastic leukemia after reduced-intensity conditioning with cord blood or sibling donor transplantation. Blood 2009; 113:2902.
- Sebban C, Lepage E, Vernant JP, et al. Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia. J Clin Oncol 1994; 12:2580.
- Cornelissen JJ, van der Holt B, Verhoef GE, et al. Myeloablative allogeneic versus autologous stem cell transplantation in adult patients with acute lymphoblastic leukemia in first remission: a prospective sibling donor versus no-donor comparison. Blood 2009; 113:1375.
- Gupta V, Richards S, Rowe J, Acute Leukemia Stem Cell Transplantation Trialists' Collaborative Group. Allogeneic, but not autologous, hematopoietic cell transplantation improves survival only among younger adults with acute lymphoblastic leukemia in first remission: an individual patient data meta-analysis. Blood 2013; 121:339.
- Cuttner J, Mick R, Budman DR, et al. Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: a CALGB Study. Leukemia 1991; 5:425.
- Childhood ALL Collaborative Group. Duration and intensity of maintenance chemotherapy in acute lymphoblastic leukaemia: overview of 42 trials involving 12 000 randomised children. Lancet 1996; 347:1783.
- RISK STRATIFICATION
- Identifying high risk disease
- Clinical features
- Older age
- CONSOLIDATION AND INTENSIFICATION
- Standard risk disease
- - Chemotherapy
- - Chemotherapy versus allogeneic transplant
- - Chemotherapy versus autologous transplant
- - Supportive care
- High risk disease
- - Allogeneic transplantation
- - Allogeneic transplant versus chemotherapy
- - Treatment of younger adults
- MAINTENANCE THERAPY
- FOLLOW UP
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS