Abstract
Abbreviations and Acronyms:
AE (adverse event), ALL (acute lymphoblastic leukemia), alloSCT (allogeneic hematopoietic stem cell transplant), AYA (adolescent and young adult), BFM (Berlin-Frankfurt-Münster), CAR-T (chimeric antigen receptor–modified T cell), CCyR (complete cytogenetic response), CIVI (continuous intravenous infusion), CMR (complete molecular response), CNS (central nervous system), CR (complete remission), CR1 (CR after first induction), CR2 (CR after second induction), CRD (CR duration), DFS (disease-free survival), EFS (event-free survival), ETP (early thymic precursor T-cell), FCM (multiparameter flow cytometry), GMALL (German Multicenter Study Group for Adult ALL), GRAALL (Group for Research on Adult Acute Lymphoblastic Leukemia), HCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone), HCVD (hyperfractionated cyclophosphamide, vincristine, and dexamethasone), HR (hazard ratio), IT (intrathecal), IV (intravenously), MDACC (MD Anderson Cancer Center), MMR (major molecular response), MRD (minimal residual disease), ORR (overall response rate), OS (overall survival), peg (pegylated), Ph (Philadelphia chromosome), PFS (progression-free survival), POMP (6-mercaptopurine, vincristine, methotrexate, and prednisone), RFS (relapse-free survival), R/R (relapsed/refractory), TKI (tyrosine kinase inhibitor), VOD (veno-occlusive disease)- 1.Read the activity.
- 2.Complete the online CME Test and Evaluation. Participants must achieve a score of 80% on the CME Test. One retake is allowed.
Epidemiology and Etiology
American Cancer Society. Cancer Facts & Figures 2016. American Cancer Society website. www.cancer.org/research/cancerfactsstatistics/cancerfactsfigures2016. Accessed December 20, 2016.
National Comprehensive Cancer Network. Acute lymphoid leukemia (version 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed December 20, 2015.
National Cancer Institute. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed October 7, 2016.
Clinical Presentation and Laboratory Abnormalities
National Comprehensive Cancer Network. Acute lymphoid leukemia (version 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed December 20, 2015.
National Comprehensive Cancer Network. Acute lymphoid leukemia (version 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed December 20, 2015.
Diagnostic Evaluation
National Comprehensive Cancer Network. Acute lymphoid leukemia (version 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed December 20, 2015.
National Comprehensive Cancer Network. Acute lymphoid leukemia (version 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed December 20, 2015.
- Moorman A.V.
- Harrison C.J.
- Buck G.A.
- et al.
Type | Cytogenetic abnormality | Frequency in adults (%) | Genes involved |
---|---|---|---|
Hyperdiploid | NA | 2-15 | BCR-ABL1 |
Hypodiploid | NA | 5-10 | NA |
Ph-positive | t(9;22)(q34;q11) | 15-25 | BCR-ABL1 |
Others | del(11)(q22-23) | 25-30 | ATM |
t(17;19) | <5 | E2A-HLF | |
t(4;11), t(9;11) | 5-10 | MLL | |
t(7;9)(q34;q32) | <1 | TAL2 | |
del(9)(q21-22) | 6-30 | p15, p16 | |
del(13)(q14) | <5 | miR15, miR16 | |
t(1;19) | <5 | E2A-PBX1 | |
t(1;14)(p32;q11) | 10-15 | TAL1 | |
t(12;21)(p12;q22) | <1 | TEL-AML1 | |
t(10;14)(q24;q11) | 5-10 | HOX11 | |
t(5;14)(q35;q32) | 1 | HOX11L2 | |
del(6q), t(6;12) | 5 | NA | |
+8 | 10-12 | NA | |
t(8;14), t(8;22) | 5 | C-MYC | |
del(5q) | <2 | NA | |
del(7p) | 5-10 | NA |
- Moorman A.V.
- Harrison C.J.
- Buck G.A.
- et al.
Type of ALL | Cytogenetic abnormality | Protein | Genes involved | Comments |
---|---|---|---|---|
T cell | NA | NA | RAS/PTEN, FBW7, PICALM-MLLT10, NUP214-ABL1 fusion, MLL, SET-NUP214 fusion, PTPN2, NOTCH1, BCL11B, JAK1,PHF6, IL7R, EML-ABL1 | Poor outcomes with RAS/PTEN and JAK1 Favorable outcomes with FBW7 (∼20%) and/or NOTCH1 (>60%) |
B cell | Near-hypodiploid | NA | FLT3, NF1, KRAS, and NRAS | Occurs in 70% of cases |
Ph-like | NA | NUP214-ABL1, in-frame fusions of EBF1-PDGFRB IKZF1 deletions, BCR-JAK2 or STRN3-JAK2, rearrangements/mutations in CRLF2, cryptic IGH-EPOR rearrangements IGH-CRLF2 | Occurs in 15% of cases. Utilization of TKIs and/or JAK2 inhibitors and mTOR is possible | |
Hyperdiploid | NT5C2 | TP53 mutations, CREBBP, NT5C2 mutations | Occurs in 6% of cases | |
Positive BCR/ABL (Ph+) | Ikaros | IKZF1 | Outcome is poor. Occurs in approximately 80% of Ph+ cases | |
Low-hypodiploid | NA | TP53 disruptions, IKZF2, CDKN2A/B locus deletion | Occurs in 91% of cases |
Treatment
Induction Therapy
- Rytting M.E.
- Jabbour E.J.
- Jorgensen J.L.
- et al.
Consolidation Therapy
Maintenance Therapy
Central Nervous System Prophylaxis
Stem Cell Transplant
Minimal Residual Disease
- Ribera J.M.
- Oriol A.
- Morgades M.
- et al.
- Ribera J.M.
- Oriol A.
- Morgades M.
- et al.
Frontline Therapy
Treatment of Adult and AYA Patients
- Rytting M.E.
- Jabbour E.J.
- Jorgensen J.L.
- et al.
Treatment of Elderly Patients
- Goekbuget N.
- Beck J.
- Bruggemann M.
- et al.
Treatment of Mature B-Cell and Burkitt ALL
Treatment of Precursor B-Cell ALL
Rituximab
Ofatumumab
Treatment of Ph-Positive ALL
National Comprehensive Cancer Network. Acute lymphoid leukemia (version 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed December 20, 2015.
- Dombret H.
- Gabert J.
- Boiron J.M.
- et al.
Outcome of treatment in adults with Philadelphia chromosome-positive acute lymphoblastic leukemia—results of the prospective multicenter LALA-94 trial.
- Chalandon Y.
- Thomas X.
- Hayette S.
- et al.
Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia.
- Chalandon Y.
- Thomas X.
- Hayette S.
- et al.
Randomized study of reduced-intensity chemotherapy combined with imatinib in adults with Ph-positive acute lymphoblastic leukemia.
- Ottmann O.G.
- Pfeifer H.
- Cayuela J.-M.
- et al.
Treatment of T-Cell ALL
National Comprehensive Cancer Network. Acute lymphoid leukemia (version 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed December 20, 2015.
National Comprehensive Cancer Network. Acute lymphoid leukemia (version 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed December 20, 2015.
National Comprehensive Cancer Network. Acute lymphoid leukemia (version 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed December 20, 2015.
National Comprehensive Cancer Network. Acute lymphoid leukemia (version 2.2015). http://www.nccn.org/professionals/physician_gls/pdf/all.pdf. Accessed December 20, 2015.
Salvage Treatment
Blinatumomab
Minimal Residual Disease
Relapsed and Refractory Disease
Topp MS, Stein A, Gökbuget N, et al. Blinatumomab improved overall survival in patients with relapsed or refractory Philadelphia negative B-cell precursor acute lymphoblastic leukemia in a randomized, open-label phase 3 study (TOWER) [abstract S149]. European Hematology Association Learning Center website. http://learningcenter.ehaweb.org/eha/2016/21st/135182/max.topp.blinatumomab.improved.overall.survival.in.patients.with.relapsed.or.html?f=m3s168109e968. Accessed September 21, 2016.
- Martinelli G.
- Dombret H.
- Chevallier P.
- et al.
Topp MS, Stein A, Gökbuget N, et al. Blinatumomab improved overall survival in patients with relapsed or refractory Philadelphia negative B-cell precursor acute lymphoblastic leukemia in a randomized, open-label phase 3 study (TOWER) [abstract S149]. European Hematology Association Learning Center website. http://learningcenter.ehaweb.org/eha/2016/21st/135182/max.topp.blinatumomab.improved.overall.survival.in.patients.with.relapsed.or.html?f=m3s168109e968. Accessed September 21, 2016.
- Martinelli G.
- Dombret H.
- Chevallier P.
- et al.
Parameters | Ph-negative | Ph-positive | ||
---|---|---|---|---|
Pivotal phase 2 (N=36) | Confirmatory phase 2 (N=189) | Phase 3 (TOWER trial) (N=405) | Pivotal phase 2 (ALCANTRA trial) (N=45) | |
CR/CRh | 25 (69) | 81 (43) | NR | 16 (36) |
RFS (mo), median | 7.6 | 5.9 | NR | 6.7 |
OS (mo), median | 9.8 | 6.1 | 7.7 | 7.1 |
Salvage 1 | 11 | 35 | 91 | NR |
Salvage ≥2 | 10 | 151 | 66 | NR |
Topp MS, Stein A, Gökbuget N, et al. Blinatumomab improved overall survival in patients with relapsed or refractory Philadelphia negative B-cell precursor acute lymphoblastic leukemia in a randomized, open-label phase 3 study (TOWER) [abstract S149]. European Hematology Association Learning Center website. http://learningcenter.ehaweb.org/eha/2016/21st/135182/max.topp.blinatumomab.improved.overall.survival.in.patients.with.relapsed.or.html?f=m3s168109e968. Accessed September 21, 2016.
- Martinelli G.
- Dombret H.
- Chevallier P.
- et al.
Inotuzumab Ozogamicin
Parameters | Single dose | Weekly dose | CR 39 patients (35.8%) CRi 49 patients (45%) | INO + mini-HCVD | |
---|---|---|---|---|---|
INO dose/schedule | 1.8 mg/m2 on day 1 every 3-4 wk | 0.8 mg/m2 on day 1, 0.5 mg/m2 on days 8 and 15 | 0.8 mg/m2 on day 1, 0.5 mg/m2 on days 8 and 15 | 1.8 mg/m2 in cycle 1 followed by 1.3 mg/m2 for remaining courses on day 3 of first 4 courses | |
Results | INO | SC | |||
ORR | 57% | 66% | 81% | 33% | 77% |
CR | 18% | 31% | 35.8% | 53% | |
CRp | 10%/29% | 34% | 45% | 19% | |
OS (mo) | 5 | 7.4 | 7.7 | 6.7 | 11 |
Chimeric Antigen Receptor–Modified T Cells
- Park J.H.
- Riviere I.
- Wang X.
- et al.
Treatment Approach
Adolescents and Young Adults
Elderly Patients
Mature B-Cell ALL
Pre–B-Cell ALL
T-Cell ALL
Ph-Positive ALL
Stem Cell Transplant
Conclusion
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Footnotes
Potential Competing Interests: Drs Elias J Jabbour and Hagop M Kantarjian have research grants from Pfizer, Amgen, Ariel, and Bristol-Myers Squibb.
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