Acute lymphoblastic leukemia overview
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2] Carlos A Lopez, M.D. [3] Alberto Castro Molina, M.D.
Overview
Prognosis has improved from a 0% to 20-75% survival rate largely due to the continuous development of clinical trials and improvements in bone marrow transplantation (BMT) and stem cell transplantation (SCT) technology. The prognosis for acute lymphoblastic leukemia differs between individuals depending on a wide variety of factors such as gender, ethnicity, age, blood cell count, dissemination and genetic involvement.
Philadelphia chromosome positive acute lymphoblastic leukemia (Ph positive ALL), defined by the BCR ABL1 fusion, is the most common genetic subgroup of ALL in adults and its frequency increases with age.[1] Over the past two decades, outcomes in Ph positive ALL have improved markedly because of the integration of Bcr-abl tyrosine kinase inhibitors (TKIs), response adapted strategies guided by sensitive molecular monitoring (BCR ABL1 transcript levels), and the addition of immunotherapy such as blinatumomab.[2][3]
Natural History, Complications, and Prognosis
Natural history
If left untreated, of patients with acute lymphoblastic leukemia may progress to develop infection, bleeding, infertility, and metastasis to other organs.[4][5][6][7]
Prognosis
- The overall cure rate in children is 85%, and about 50% of adults have long-term disease-free survival.[8][9]
- Advancements in medical technology and research over the past four decades in the treatment of acute lymphocytic leukemia has improved the overall prognosis significantly from a 0% to 20-75% survival rate
- Largely due to the continuous development of clinical trials and improvements in bone marrow transplantation (BMT) and stem cell transplantation (SCT) technology.[10][11]
- It is worth noting that medical advances in recent years, both through matching the best treatment to the genetic characteristics of the blast cells and through the availability of new drugs, are not fully reflected in statistics that usually refer to five-year survival rates.
- The prognosis for acute Lymphoblastic leukemia differs between individuals depending on a wide variety of factors:
In Ph positive ALL, long term outcomes have improved substantially with modern TKI based regimens and immunotherapy, and deep molecular responses measured by BCR ABL1 transcript monitoring are strongly prognostic and increasingly guide decisions about treatment intensity and the role of allogeneic transplantation.[2][12][3]
Gender
- Females tend to fare better than males[13]
Ethnicity
- Caucasians are more likely to develop acute leukemia than African-Americans, Asians and Hispanics and tend to have a better prognosis than non-Caucasians.
Age
- Age is a significant factor in children with acute lymphoblastic leukemia and may be an important prognostic factor in adult with acute lympoblastic leukemia as well[14]
- In one study, overall the prognosis was better in patients younger than 25 years; another study found a better prognosis in patients younger than 35 years
- These findings may in part, be related to the increased incidence of the Ph1 in older acute lymphoblatic leukemia patients a subgroup associated with poor prognosis[1]
- Children between 1-10 years of age are most likely to be cured.
Blood cell count
- White blood cell count at diagnosis of less than 50,000/µl.
Dissemination
- Whether the cancer has spread to the brain or spinal cord
Genetic involvement
- Down's Syndrome tend to have a genetic involvement [15]
- Chromosomal abnormalities: Chromosomal abnormalities including aneuploidy and translocations, have been described and may correlate with prognosis
- In particular, patients with Ph1-positive t(9;22) acute lymphoblastic leukemia have a poor prognosis and represent more than 30% of adult cases[16]
- Bcr-abl-rearranged leukemias that do not demonstrate the classical Ph1 carry a poor prognosis that is similar to those that are Ph1-positive[17]
- Patients with Ph1-positive acute lymphoblastic leukemias are rarely cured with chemotherapy, although long-term survival is now being routinely reported when such patients are treated with combinations of chemotherapy and Bcr-abl tyrosine kinase inhibitors[18]
- Two other chromosomal abnormalities with poor prognosis are t(4;11), which is characterized by rearrangements of the myeloid lymphoid leukemia gene and may be rearranged despite normal cytogenetics, and t(9;22)[19]
In Ph positive ALL, the introduction of TKIs and immunotherapy has shifted many treatment strategies toward chemotherapy-reduced or chemotherapy-free regimens in selected adults, with high rates of deep molecular response and decreased dependence on allogeneic transplantation for cure in first remission at some centers.[2][20]
Cytogenetic subtypes with worse prognosis
- A translocation between chromosomes 9 and 22, known as the Philadelphia chromosome, occurs in about 20% of adult and 5% in pediatric cases of acute lymphoblastic luekemia.
- A translocation between chromosomes 4 and 11 occurs in about 4% of cases and is most common in infants under 12 months.
- Not all translocations of chromosomes carry a poorer prognosis. Some translocations are relatively favorable. For example, hyperdiploidy (>50 chromosomes) is a good prognostic factor.
Central nervous system involvement
- As in childhood acute lymphoblastic leukemia, adult patients with acute lymphoblastic luekemia are at risk of developing central nervous system involvement during the course of their disease. This is particularly true for patients with L3 (Burkitt) morphology. Both treatment and prognosis are influenced by this complication.
Celular morphology
- Patients with L3 morphology showed improved outcomes, as evidenced in a completed cancer and Leukemia Group B study, when treated according to specific treatment algorithms.
- This study found that L3 leukemia can be cured with aggressive, rapidly cycling lymphoma-like chemotherapy regimens.
5 Year survival
- Between 2004 and 2010, the 5-year relative survival of patients with acute lymphoblastic leukemias was 70%.[21]
- When stratified by age, the 5-year relative survival of patients with acute lymphoblastic leukemias was 71.3% and 12.2% for patients <65 and ≥ 65 years of age respectively.[21]
Diagnosis
Initial evaluation of ALL includes morphologic assessment, immunophenotyping by flow cytometry, and cytogenetic and molecular testing to define risk and guide therapy. In suspected or confirmed Ph positive ALL, the BCR ABL1 fusion is commonly identified by karyotyping, FISH, and or RT-PCR, and baseline transcript quantification supports subsequent molecular monitoring of treatment response.[3][22]
Molecular monitoring of minimal residual disease in Ph positive ALL is frequently performed by quantitative PCR of BCR ABL1 transcripts, and depth of response is a key prognostic variable that can guide decisions about treatment intensification and transplantation in first remission.[3][12]
At relapse or in cases of molecular or hematologic resistance on TKIs, testing for ABL1 kinase domain mutations may inform selection of subsequent TKIs (including the use of ponatinib for T315I and other resistant mutations).[23]
Treatment
Modern treatment is risk-adapted and increasingly genotype-directed. The discussion below highlights key elements of therapy for Ph positive ALL, one of the most impactful areas of recent therapeutic progress.
Tyrosine kinase inhibitors
The addition of BCR ABL1 TKIs to chemotherapy regimens improved complete remission rates and long-term outcomes in Ph positive ALL compared with historical chemotherapy alone.[24][25] First-generation and second-generation TKIs (imatinib, dasatinib) are used in combination approaches, and third-generation ponatinib is used in selected settings including resistant disease and in frontline strategies at some centers.[26]
Chemo-reduced and chemo-free approaches with immunotherapy
Blinatumomab, a bispecific T-cell engager, has demonstrated activity in B-lineage ALL and has been incorporated into Ph positive ALL regimens to deepen molecular responses and reduce reliance on intensive chemotherapy.[27][28]
A chemotherapy-free strategy of dasatinib followed by blinatumomab produced high rates of molecular response and favorable survival outcomes in adults with newly diagnosed Ph positive ALL in a multicenter study.[2] A similar concept using ponatinib with blinatumomab has shown promising results in single-arm studies, supporting continued clinical development of chemo-reduced strategies.[20][29]
Role of allogeneic stem cell transplantation
Before the TKI era, allogeneic transplantation in first remission was often associated with superior outcomes compared with chemotherapy alone in adults with Ph positive ALL.[30] In current practice, the role of transplantation is increasingly individualized based on depth of molecular response, relapse risk, comorbidities, and treatment strategy, and some patients achieving sustained deep molecular responses may avoid transplantation in first remission.[12][29]
Maintenance and treatment discontinuation
Long-term TKI maintenance is commonly used in Ph positive ALL. In carefully selected patients with prolonged deep molecular remission, discontinuation of maintenance TKI outside of transplant has been reported, highlighting an emerging area of practice that requires close monitoring and careful patient selection.[31]
References
- ↑ 1.0 1.1 Burmeister T, Schwartz S, Bartram CR; et al. (2008). "Patients' age and BCR-ABL frequency in adult B-precursor ALL: a retrospective analysis from the GMALL study group". Blood. 112: 918–919.
- ↑ 2.0 2.1 2.2 2.3 Foà R, Bassan R, Vitale A; et al. (2020). "Dasatinib–blinatumomab for Ph-positive acute lymphoblastic leukemia in adults". N Engl J Med. 383: 1613–1623.
- ↑ 3.0 3.1 3.2 3.3 Ansuinelli M, Della Starza I, Lauretti A; et al. (2021). "Applicability of molecular monitoring in Philadelphia chromosome positive acute lymphoblastic leukemia". Hematol Oncol. 39: 680–686.
- ↑ Ma X, Urayama K, Chang J, Wiemels JL, Buffler PA (2009). "Infection and pediatric acute lymphoblastic leukemia". Blood Cells Mol. Dis. 42 (2): 117–20. doi:10.1016/j.bcmd.2008.10.006. PMC 2834409. PMID 19064328.
- ↑ Byrne J, Fears TR, Mills JL, Zeltzer LK, Sklar C, Meadows AT, Reaman GH, Robison LL (April 2004). "Fertility of long-term male survivors of acute lymphoblastic leukemia diagnosed during childhood". Pediatr Blood Cancer. 42 (4): 364–72. doi:10.1002/pbc.10449. PMID 14966835.
- ↑ Shigeta H, Tasaki N, Kitazumi S, Kitagawa Y, Kanatsuna T, Kondo M (April 1987). "[A case report of Bartter's syndrome associated with possible pseudohypoparathyroidism type II]". Nippon Naika Gakkai Zasshi (in Japanese). 76 (4): 549–52. PMID 3611913.
- ↑ Harrison's Principles of Internal Medicine, 16th Edition, Chapter 97. Malignancies of Lymphoid Cells. Clinical Features, Treatment, and Prognosis of Specific Lymphoid Malignancies.
- ↑ "National Cancer Institute".
- ↑ Barrett AJ (June 1994). "Bone marrow transplantation for acute lymphoblastic leukaemia". Baillieres Clin. Haematol. 7 (2): 377–401. PMID 7803908.
- ↑ Bishop MR, Logan BR, Gandham S, Bolwell BJ, Cahn JY, Lazarus HM, Litzow MR, Marks DI, Wiernik PH, McCarthy PL, Russell JA, Miller CB, Sierra J, Milone G, Keating A, Loberiza FR, Giralt S, Horowitz MM, Weisdorf DJ (April 2008). "Long-term outcomes of adults with acute lymphoblastic leukemia after autologous or unrelated donor bone marrow transplantation: a comparative analysis by the National Marrow Donor Program and Center for International Blood and Marrow Transplant Research". Bone Marrow Transplant. 41 (7): 635–42. doi:10.1038/sj.bmt.1705952. PMC 2587442. PMID 18084335.
- ↑ 12.0 12.1 12.2 Sasaki K, Kantarjian HM, Short NJ; et al. (2021). "Prognostic factors and outcomes in patients with Philadelphia chromosome positive acute lymphoblastic leukemia treated with tyrosine kinase inhibitors". Cancer. 127: 2648–2656.
- ↑ Pui CH, Boyett JM, Relling MV, Harrison PL, Rivera GK, Behm FG; et al. (1999). "Sex differences in prognosis for children with acute lymphoblastic leukemia". J Clin Oncol. 17 (3): 818–24. doi:10.1200/JCO.1999.17.3.818. PMID 10071272.
- ↑ Foà R (2011). "Acute lymphoblastic leukemia: age and biology". Pediatr Rep. 3 Suppl 2: e2. doi:10.4081/pr.2011.s2.e2. PMC 3206534. PMID 22053278.
- ↑ Mowery CT, Reyes JM, Cabal-Hierro L, Higby KJ, Karlin KL, Wang JH; et al. (2018). "Trisomy of a Down Syndrome Critical Region Globally Amplifies Transcription via HMGN1 Overexpression". Cell Rep. 25 (7): 1898–1911.e5. doi:10.1016/j.celrep.2018.10.061. PMC 6321629. PMID 30428356.
- ↑ Koo HH (2011). "Philadelphia chromosome-positive acute lymphoblastic leukemia in childhood". Korean J Pediatr. 54 (3): 106–10. doi:10.3345/kjp.2011.54.3.106. PMC 3120995. PMID 21738539.
- ↑ Nashed AL, Rao KW, Gulley ML (2003). "Clinical applications of BCR-ABL molecular testing in acute leukemia". J Mol Diagn. 5 (2): 63–72. doi:10.1016/S1525-1578(10)60454-0. PMC 1907317. PMID 12707370.
- ↑ Fielding AK (January 2010). "Current treatment of Philadelphia chromosome-positive acute lymphoblastic leukemia". Haematologica. 95 (1): 8–12. doi:10.3324/haematol.2009.015974. PMC 2805747. PMID 20065078.
- ↑ Mullighan CG (2012). "Molecular genetics of B-precursor acute lymphoblastic leukemia". J Clin Invest. 122 (10): 3407–15. doi:10.1172/JCI61203. PMC 3461902. PMID 23023711.
- ↑ 20.0 20.1 Jabbour E, Short NJ, Jain N; et al. (2023). "Ponatinib and blinatumomab for Philadelphia chromosome-positive acute lymphoblastic leukemia: a single-arm, phase 2 trial". Lancet Haematol. 10 (1): e24–e34.
- ↑ 21.0 21.1 Howlader N, Noone AM, Krapcho M, Garshell J, Miller D, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovich Z,Mariotto A, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2011, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2011/, based on November 2013 SEER data submission, posted to the SEER web site, April 2014.
- ↑ de Labarthe A, Rousselot P, Huguet-Rigal F; et al. (2007). "Imatinib combined with induction or consolidation chemotherapy in patients with de novo Philadelphia chromosome-positive acute lymphoblastic leukemia: results of the GRAAPH-2003 study". Blood. 109: 1408–1413.
- ↑ O’Hare T, Shakespeare WC, Zhu X; et al. (2009). "AP24534, a pan-BCR-ABL inhibitor for the treatment of chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance". Cancer Cell. 16: 401–412.
- ↑ Druker BJ, Sawyers CL, Kantarjian H; et al. (2001). "Activity of a specific inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome". N Engl J Med. 344: 1038–1042.
- ↑ Ottmann OG, Druker BJ, Sawyers CL; et al. (2002). "A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias". Blood. 100: 1965–1971.
- ↑ Jabbour E, Kantarjian HM, Aldoss I; et al. (2024). "Ponatinib vs imatinib in Philadelphia chromosome-positive acute lymphoblastic leukemia: a randomized clinical trial". JAMA. 331: 1814–1823.
- ↑ Topp MS, Kufer P, Gökbuget N; et al. (2011). "Targeted therapy with the T-cell-engaging antibody blinatumomab of minimal residual disease in B-lineage acute lymphoblastic leukemia patients results in high response rate and prolonged leukemia-free survival". J Clin Oncol. 29: 2493–2498.
- ↑ Topp MS, Gökbuget N, Stein AS; et al. (2015). "Safety and activity of blinatumomab for adult patients with relapsed or refractory B-precursor acute lymphoblastic leukaemia: a multicentre, single-arm, phase 2 study". Lancet Oncol. 16: 57–66.
- ↑ 29.0 29.1 Ribera J-M, García-Calduch O, Ribera J; et al. (2022). "Ponatinib, chemotherapy-free, as first-line treatment for Philadelphia chromosome-positive acute lymphoblastic leukemia". Blood Adv. 6: 5395–5402.
- ↑ Fielding AK, Rowe JM, Richards SM; et al. (2009). "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. 113: 4489–4496.
- ↑ Samra B, Kantarjian HM, Sasaki K; et al. (2021). "Discontinuation of maintenance tyrosine kinase inhibitor in Philadelphia chromosome-positive acute lymphoblastic leukemia outside of transplant". Acta Haematol. 144: 285–292.