Skip to main content
Erschienen in: Current Treatment Options in Oncology 1/2019

01.01.2019 | Leukemia (PH Wiernik, Section Editor)

Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

verfasst von: Iman Abou Dalle, MD, Elias Jabbour, MD, Nicholas J. Short, MD, Farhad Ravandi, MD

Erschienen in: Current Treatment Options in Oncology | Ausgabe 1/2019

Einloggen, um Zugang zu erhalten

Opinion statement

With the introduction of tyrosine kinase inhibitors (TKIs) in the management of Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL), the prognosis of patients has improved dramatically. Currently, the standard of care in the frontline setting for fit patients is TKI in combination with chemotherapy. Age-adjusted chemotherapy or corticosteroids alone have been used with TKIs in elderly patients with comorbidities with modest long-term benefit. The primary goal of treatment is the achievement of early deep molecular remission as the achievement of complete molecular remission (CMR) at 3 months has been demonstrated to be predictive of higher long-term survival. The probability of attaining this goal by a more potent TKIs like dasatinib or ponatinib is higher, thus we recommend the use of second- or third-generation TKIs over imatinib. Clinicians should be aware of possible fatal cardiovascular events mainly related to ponatinib. Allogeneic hematopoietic stem cell transplantation (alloHSCT) should still be considered in first remission, especially for younger patients treated with imatinib combination therapy. A subset of patients achieving CMR at 3 months may be able to continue consolidation and maintenance with chemotherapy and TKI without the need for alloHSCT. Because of higher risk of relapses in the central nervous system, intrathecal chemoprophylaxis is mandatory for all patients. New strategies incorporating novel agents, such as antibody-drug conjugates, bispecific monoclonal antibodies, potent TKIs, and CAR T cells are under investigation.
Literatur
1.
Zurück zum Zitat Moorman AV, Harrison CJ, Buck GAN, Richards SM, Secker-Walker LM, Martineau M, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007;109(8):3189–97. https://doi.org/10.1182/blood-2006-10-051912.CrossRefPubMed Moorman AV, Harrison CJ, Buck GAN, Richards SM, Secker-Walker LM, Martineau M, et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. Blood. 2007;109(8):3189–97. https://​doi.​org/​10.​1182/​blood-2006-10-051912.CrossRefPubMed
4.
Zurück zum Zitat Kantarjian H, Thomas D, O’Brien S, Cortes J, Giles F, Jeha S, et al. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004;101(12):2788–801. https://doi.org/10.1002/cncr.20668.CrossRefPubMed Kantarjian H, Thomas D, O’Brien S, Cortes J, Giles F, Jeha S, et al. Long-term follow-up results of hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone (Hyper-CVAD), a dose-intensive regimen, in adult acute lymphocytic leukemia. Cancer. 2004;101(12):2788–801. https://​doi.​org/​10.​1002/​cncr.​20668.CrossRefPubMed
5.
Zurück zum Zitat Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2(5):561–6.CrossRefPubMed Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, et al. Effects of a selective inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive cells. Nat Med. 1996;2(5):561–6.CrossRefPubMed
9.
Zurück zum Zitat Bassan R, Rossi G, Pogliani EM, Di Bona E, Angelucci E, Cavattoni I, et al. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol. 2010;28(22):3644–52. https://doi.org/10.1200/jco.2010.28.1287.CrossRefPubMed Bassan R, Rossi G, Pogliani EM, Di Bona E, Angelucci E, Cavattoni I, et al. Chemotherapy-phased imatinib pulses improve long-term outcome of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: Northern Italy Leukemia Group protocol 09/00. J Clin Oncol. 2010;28(22):3644–52. https://​doi.​org/​10.​1200/​jco.​2010.​28.​1287.CrossRefPubMed
10.
14.
18.
Zurück zum Zitat Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007;110(7):2309–15. https://doi.org/10.1182/blood-2007-02-073528.CrossRefPubMed Ottmann O, Dombret H, Martinelli G, Simonsson B, Guilhot F, Larson RA, et al. Dasatinib induces rapid hematologic and cytogenetic responses in adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia with resistance or intolerance to imatinib: interim results of a phase 2 study. Blood. 2007;110(7):2309–15. https://​doi.​org/​10.​1182/​blood-2007-02-073528.CrossRefPubMed
20.
Zurück zum Zitat Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: results from a phase 3 study. Am J Hematol. 2010;85(3):164–70. https://doi.org/10.1002/ajh.21615.CrossRefPubMed Lilly MB, Ottmann OG, Shah NP, Larson RA, Reiffers JJ, Ehninger G, et al. Dasatinib 140 mg once daily versus 70 mg twice daily in patients with Ph-positive acute lymphoblastic leukemia who failed imatinib: results from a phase 3 study. Am J Hematol. 2010;85(3):164–70. https://​doi.​org/​10.​1002/​ajh.​21615.CrossRefPubMed
21.
Zurück zum Zitat • Ravandi F, O’Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, et al. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015;121(23):4158–64. https://doi.org/10.1002/cncr.29646 Long term study evaluating the use of hyperCVAD chemotherapy in combination with dasatinib in the frontline treatment of Ph+ ALL.CrossRefPubMed • Ravandi F, O’Brien SM, Cortes JE, Thomas DM, Garris R, Faderl S, et al. Long-term follow-up of a phase 2 study of chemotherapy plus dasatinib for the initial treatment of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Cancer. 2015;121(23):4158–64. https://​doi.​org/​10.​1002/​cncr.​29646 Long term study evaluating the use of hyperCVAD chemotherapy in combination with dasatinib in the frontline treatment of Ph+ ALL.CrossRefPubMed
24.
Zurück zum Zitat Chiaretti S, Vitale A, Elia L, Fedullo AL, Albino S, Piciocchi A, et al. Multicenter total therapy Gimema LAL 1509 Protocol for De Novo Adult Ph+ Acute Lymphoblastic Leukemia (ALL) Patients. Updated results and refined genetic-based prognostic stratification. Blood. 2015;126(23):81. Chiaretti S, Vitale A, Elia L, Fedullo AL, Albino S, Piciocchi A, et al. Multicenter total therapy Gimema LAL 1509 Protocol for De Novo Adult Ph+ Acute Lymphoblastic Leukemia (ALL) Patients. Updated results and refined genetic-based prognostic stratification. Blood. 2015;126(23):81.
28.
Zurück zum Zitat Ottmann OG, Pfeifer H, Cayuela J-M, Spiekermann K, Beck J, Jung WE, et al. Nilotinib (Tasigna®) and chemotherapy for first-line treatment in elderly patients with <em>De Novo</em> Philadelphia chromosome/BCR-ABL1 positive acute lymphoblastic leukemia (ALL): a trial of the European Working Group for Adult ALL (EWALL-PH-02). Blood. 2014;124(21):798. Ottmann OG, Pfeifer H, Cayuela J-M, Spiekermann K, Beck J, Jung WE, et al. Nilotinib (Tasigna®) and chemotherapy for first-line treatment in elderly patients with <em>De Novo</em> Philadelphia chromosome/BCR-ABL1 positive acute lymphoblastic leukemia (ALL): a trial of the European Working Group for Adult ALL (EWALL-PH-02). Blood. 2014;124(21):798.
29.
Zurück zum Zitat Chalandon Y, Rousselot P, Cayuela JM, Thomas X, Clappier E, Havelange V et al. Nilotinib combined with lower-intensity chemotherapy for front-line treatment of younger adults with Ph-positive acute lymphoblastic leukemia (ALL): interim analysis of the GRAAPH-2014 trial. EHA meeting. 2018. Chalandon Y, Rousselot P, Cayuela JM, Thomas X, Clappier E, Havelange V et al. Nilotinib combined with lower-intensity chemotherapy for front-line treatment of younger adults with Ph-positive acute lymphoblastic leukemia (ALL): interim analysis of the GRAAPH-2014 trial. EHA meeting. 2018.
30.
Zurück zum Zitat Soverini S, De Benedittis C, Papayannidis C, Paolini S, Venturi C, Iacobucci I, et al. Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: the main changes are in the type of mutations, but not in the frequency of mutation involvement. Cancer. 2014;120(7):1002–9. https://doi.org/10.1002/cncr.28522.CrossRefPubMed Soverini S, De Benedittis C, Papayannidis C, Paolini S, Venturi C, Iacobucci I, et al. Drug resistance and BCR-ABL kinase domain mutations in Philadelphia chromosome-positive acute lymphoblastic leukemia from the imatinib to the second-generation tyrosine kinase inhibitor era: the main changes are in the type of mutations, but not in the frequency of mutation involvement. Cancer. 2014;120(7):1002–9. https://​doi.​org/​10.​1002/​cncr.​28522.CrossRefPubMed
31.
Zurück zum Zitat Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, Binckebanck A, et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2007;110(2):727–34. https://doi.org/10.1182/blood-2006-11-052373.CrossRefPubMed Pfeifer H, Wassmann B, Pavlova A, Wunderle L, Oldenburg J, Binckebanck A, et al. Kinase domain mutations of BCR-ABL frequently precede imatinib-based therapy and give rise to relapse in patients with de novo Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood. 2007;110(2):727–34. https://​doi.​org/​10.​1182/​blood-2006-11-052373.CrossRefPubMed
34.
Zurück zum Zitat •• Jabbour E, Kantarjian H, Ravandi F, Thomas D, Huang X, Faderl S, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015;16(15):1547–55. https://doi.org/10.1016/s1470-2045(15)00207-7 Initial results of a phase 2 trial investigating the combination of hyperCVAD chemotherapy in combination with ponatinib in the frontline therapy of Ph+ ALL. This study reported early and deep molecular responses with a 3 year overall survival approching 80%.CrossRefPubMedPubMedCentral •• Jabbour E, Kantarjian H, Ravandi F, Thomas D, Huang X, Faderl S, et al. Combination of hyper-CVAD with ponatinib as first-line therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukaemia: a single-centre, phase 2 study. Lancet Oncol. 2015;16(15):1547–55. https://​doi.​org/​10.​1016/​s1470-2045(15)00207-7 Initial results of a phase 2 trial investigating the combination of hyperCVAD chemotherapy in combination with ponatinib in the frontline therapy of Ph+ ALL. This study reported early and deep molecular responses with a 3 year overall survival approching 80%.CrossRefPubMedPubMedCentral
37.
Zurück zum Zitat •• Martinelli G, Piciocchi A, Papayannidis C, Paolini S, Robustelli V, Soverini S, et al. First report of the Gimema LAL1811 Phase II Prospective Study of the Combination of Steroids with ponatinib as frontline therapy of elderly or unfit patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2017;130(Suppl 1):99 Initial results of a phase 2 trial by the GIMEMA investigators evaluating the use of ponatinib with corticosteroids in elderly or unfit patients. This study will allow a chemotherapy-free approach for elderly patients who are unfit for intensive chemotherapy. •• Martinelli G, Piciocchi A, Papayannidis C, Paolini S, Robustelli V, Soverini S, et al. First report of the Gimema LAL1811 Phase II Prospective Study of the Combination of Steroids with ponatinib as frontline therapy of elderly or unfit patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2017;130(Suppl 1):99 Initial results of a phase 2 trial by the GIMEMA investigators evaluating the use of ponatinib with corticosteroids in elderly or unfit patients. This study will allow a chemotherapy-free approach for elderly patients who are unfit for intensive chemotherapy.
38.
Zurück zum Zitat • Sasaki K, Jabbour EJ, Ravandi F, Short NJ, Thomas DA, Garcia-Manero G, et al. Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a propensity score analysis. Cancer. 2016;122(23):3650–6. https://doi.org/10.1002/cncr.30231 This study indicates the superiority of hyperCVAD plus ponatinib over dasatinib in the frontline setting using a propensity score analysis.CrossRefPubMed • Sasaki K, Jabbour EJ, Ravandi F, Short NJ, Thomas DA, Garcia-Manero G, et al. Hyper-CVAD plus ponatinib versus hyper-CVAD plus dasatinib as frontline therapy for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia: a propensity score analysis. Cancer. 2016;122(23):3650–6. https://​doi.​org/​10.​1002/​cncr.​30231 This study indicates the superiority of hyperCVAD plus ponatinib over dasatinib in the frontline setting using a propensity score analysis.CrossRefPubMed
40.
Zurück zum Zitat Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009;113(19):4489–96. https://doi.org/10.1182/blood-2009-01-199380.CrossRefPubMedPubMedCentral Fielding AK, Rowe JM, Richards SM, Buck G, Moorman AV, Durrant IJ, et al. Prospective outcome data on 267 unselected adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia confirms superiority of allogeneic transplantation over chemotherapy in the pre-imatinib era: results from the International ALL Trial MRC UKALLXII/ECOG2993. Blood. 2009;113(19):4489–96. https://​doi.​org/​10.​1182/​blood-2009-01-199380.CrossRefPubMedPubMedCentral
41.
Zurück zum Zitat •• Giebel S, Labopin M, Potter M, Poire X, Sengeloev H, Socie G, et al. Comparable results of autologous and allogeneic haematopoietic stem cell transplantation for adults with Philadelphia-positive acute lymphoblastic leukaemia in first complete molecular remission: an analysis by the Acute Leukemia Working Party of the EBMT. Eur J Cancer. 2018;96:73–81. https://doi.org/10.1016/j.ejca.2018.03.018 This is a retrospective analysis comparing autologous and allogeneic HSCT in patients with first complete molecular remission in the era of TKIs. Overall survival was comparable between the two groups.CrossRefPubMed •• Giebel S, Labopin M, Potter M, Poire X, Sengeloev H, Socie G, et al. Comparable results of autologous and allogeneic haematopoietic stem cell transplantation for adults with Philadelphia-positive acute lymphoblastic leukaemia in first complete molecular remission: an analysis by the Acute Leukemia Working Party of the EBMT. Eur J Cancer. 2018;96:73–81. https://​doi.​org/​10.​1016/​j.​ejca.​2018.​03.​018 This is a retrospective analysis comparing autologous and allogeneic HSCT in patients with first complete molecular remission in the era of TKIs. Overall survival was comparable between the two groups.CrossRefPubMed
42.
Zurück zum Zitat •• Short NJ, Jabbour E, Sasaki K, Patel K, O’Brien SM, Cortes JE, et al. Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2016;128(4):504–7. https://doi.org/10.1182/blood-2016-03-707562 Retrospective analysis identifying the achievment of complete molecular remission at 3 months as the only factor predictive of survival with a 4-year overall survival of 66%, without the need for alloHSCT.CrossRefPubMedPubMedCentral •• Short NJ, Jabbour E, Sasaki K, Patel K, O’Brien SM, Cortes JE, et al. Impact of complete molecular response on survival in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2016;128(4):504–7. https://​doi.​org/​10.​1182/​blood-2016-03-707562 Retrospective analysis identifying the achievment of complete molecular remission at 3 months as the only factor predictive of survival with a 4-year overall survival of 66%, without the need for alloHSCT.CrossRefPubMedPubMedCentral
44.
Zurück zum Zitat Topp MS, Gokbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, et al. 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. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(36):4134–40. https://doi.org/10.1200/jco.2014.56.3247.CrossRef Topp MS, Gokbuget N, Zugmaier G, Klappers P, Stelljes M, Neumann S, et al. 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. J Clin Oncol Off J Am Soc Clin Oncol. 2014;32(36):4134–40. https://​doi.​org/​10.​1200/​jco.​2014.​56.​3247.CrossRef
47.
Zurück zum Zitat •• Martinelli G, Boissel N, Chevallier P, Ottmann O, Gokbuget N, Topp MS, et al. 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. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(16):1795–802. https://doi.org/10.1200/jco.2016.69.3531 Phase 2 trial evaluating blinatumomab in the setting of relapsed/refractory Ph+ ALL with overall response rate of 36%. Blinatumomab was used as a bridge to alloHSCT with acceptable overall survival.CrossRef •• Martinelli G, Boissel N, Chevallier P, Ottmann O, Gokbuget N, Topp MS, et al. 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. J Clin Oncol Off J Am Soc Clin Oncol. 2017;35(16):1795–802. https://​doi.​org/​10.​1200/​jco.​2016.​69.​3531 Phase 2 trial evaluating blinatumomab in the setting of relapsed/refractory Ph+ ALL with overall response rate of 36%. Blinatumomab was used as a bridge to alloHSCT with acceptable overall survival.CrossRef
55.
Zurück zum Zitat Jain N, Cortes JE, Ravandi F, Konopleva M, Alvarado Y, Kadia T, et al. Inotuzumab ozogamicin in combination with bosutinib for patients with relapsed or refractory Ph+ ALL or CML in lymphoid blast phase. Blood. 2017;130(Suppl 1):143. Jain N, Cortes JE, Ravandi F, Konopleva M, Alvarado Y, Kadia T, et al. Inotuzumab ozogamicin in combination with bosutinib for patients with relapsed or refractory Ph+ ALL or CML in lymphoid blast phase. Blood. 2017;130(Suppl 1):143.
Metadaten
Titel
Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia
verfasst von
Iman Abou Dalle, MD
Elias Jabbour, MD
Nicholas J. Short, MD
Farhad Ravandi, MD
Publikationsdatum
01.01.2019
Verlag
Springer US
Erschienen in
Current Treatment Options in Oncology / Ausgabe 1/2019
Print ISSN: 1527-2729
Elektronische ISSN: 1534-6277
DOI
https://doi.org/10.1007/s11864-019-0603-z

Weitere Artikel der Ausgabe 1/2019

Current Treatment Options in Oncology 1/2019 Zur Ausgabe

Leukemia (PH Wiernik, Section Editor)

Blastic Plasmacytoid Dendritic Cell Neoplasm

Upper Gastrointestinal Cancers (L Rajdev, Section Editor)

Systemic Therapy for Advanced Hepatocellular Carcinoma in an Evolving Landscape

Update Onkologie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.