Chronic myelogenous leukemia natural history
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Overview
If left untreated, majority of patients with chronic myelogenous leukemia may progress from a chronic phase where differentiation is reasonably well-maintained to blast or acute phase (BP) where differentiation is lost. The progression to BP occurs at a median of 3–5 years from diagnosis in untreated patients. some complications of chronic myelogenous leukemia include fatigue, excess bleeding, enlarged spleen, and infection. Prognosis is generally poor, and the 5-year survival rate of patients with chronic myelogenous leukemia is approximately 59.9%. Targeted therapy with small molecule tyrosine kinase inhibitors (TKIs) dramatically alter the natural history of the disease, improving 10-year overall survival from 20 to 80–90%.
Natural History
- If left untreated, majority of patients with chronic myelogenous leukemia may progress from a chronic phase where the disease is relatively asymptomatic and histollogically the differentiation is reasonably well-maintained to blast or acute phase (BP) where differentiation is lost completely which concomitantly results in complications and appearance of various symptoms.
- The progression to BP occurs at a median of 3–5 years from diagnosis in untreated patients. Without treatment, the patient will develop symptoms of anemia, excess bleeding, enlarged spleen, and infection which may eventually lead to death.[1][2][3][4][5]
Complications
- Chronic myelogenous leukemia may lead to the following complications:[1][6][7][8][9]
- Fatigue
- Night Sweats
- Bone pain
- Infections
- Blood related complication:
- Recurrent bleeding due to thrombocytopenia
- Enlarged spleen
- Weight loss
- Myeloid sarcoma
- Skin changes
- Leukemia cutis
- Leukemic cells enter the skin. The sores or patches can be any size and are usually pink or tan in color.
- Sores usually appear on the extremities
- Sweet's syndrome (acute febrile neutrophilic dermatosis)
- Fever
- Painful sores that may appear anywhere on the body
Prognosis
- Prognosis is generally good.
- Between 2004 and 2010, the 5-year relative survival of patients with CML was 59.9%.
- When associated with old age, the 5-year survival rate of patients with chronic myelogenous leukemia was 80.2% and 37.1% for patients <65 and ≥ 65 years of age, respectively.[4]
- The prognosis and treatment options depend on the following:[1]
- The patient’s age
- Elderly people have a less favorable prognosis
- The phase of CML
- Accelerated or blast phase at the time of diagnosis is a less favorable prognostic factor
- The amount of blasts in the blood or bone marrow
- A high number of blasts in the blood or bone marrow at diagnosis is a less favorable prognostic factor
- The size of the spleen at diagnosis
- Splenomegaly at diagnosis is a less favorable prognostic factor
- Thrombocytopenia or thrombocytosis at diagnosis is a less favorable prognostic factor
- Eosinophils and basophils
- A higher number of eosinophils and basophils in the blood samples indicates a less favorable prognosis
- Patients with Philadelphia chromosome (Ph+) at diagnosis have a more favorable prognosis than those who do not have the Philadelphia chromosome (Ph-)
- Presence of anemia at diagnosis is a less favorable prognostic factor
- Bone marrow involvement
- A large number of leukemia cells in the bone marrow at the time of diagnosis is a less favorable prognostic factor
- Performance status
- People with a low performance status at the time of diagnosis have a less favorable prognosis
- Serum lactate dehydrogenase blood level
- High serum lactate dehydrogenase (LDH) in the blood is a less favorable prognostic factor
- Response to treatment
- The treatment is effective if a person has a major cytogenetic response after treatment, which means that less than 30% of a person’s blood cells have the Philadelphia chromosome. A major cytogenetic response occurs in about 50–70% of people considered to have good-risk disease (favorable prognostic factors) and in 20% of people considered to have poor-risk disease (unfavorable prognostic factors).
- The patient’s general health
- Regarding phases, survival is clearly dependent on the phase of disease with an adverse outcome for those who are in an accelerated or blast phase of CML.
- In CML-BP, the survival time is short, only a few patients survive more than 6 months[10]
- Apart from the phase of disease, a number of individual clinical and pathologic variables have been identified as prognostic factors.[11]
- Independent prognostic
variables include:
- Splenomegaly
- Basophilia[12]
- Therefore, a number of attempts have been made to establish scoring systems that predict the risk regarding progression and/or survival in patients with CML.
- These scoring systems include:
| Hasford Score | |||||
|---|---|---|---|---|---|
| 1 | 0.6666 | X | Age | 0 When age is less than 50 yrs, 1 when age is above 50 years | |
| 2 | + | 0.0420 | X | Spleen size | cm below costal margin |
| 3 | + | 0.0584 | X | Blast % | % of blasts in peripheral blood smear |
| 4 | + | 0.0413 | X | Eosinophils | % eosinophils in peripheral blood smear |
| 5 | + | 0.2039 | X | Basophils | 0 when basophils are < 3 % and 1 when basophils are higher |
| 6 | + | 1.0956 | X | Platelets | 0 when platelets are less than 1500 x 106 per L and 1 when above than this value. |
| Add together and multiply with 1000 to obtain the score | |||||
| Risk Group | Scoring result | Median Survival | Overall Survival at 5 years |
|---|---|---|---|
| Low risk | <780 | 96 Months | 73% |
| Intermediate risk | 780-1480 | 65 Months | 55% |
| High risk | >1480 | 45 Months | 37% |
- It must be emphasized that stem cell transplant is still the only available curative approach for patients with CML, but is also associated with a considerable risk of therapy-related mortality.
- To estimate the probability of a successful allogeneic stem cell transplant in individual patients with CML, another scoring-system.
- The “Gratwohl Score”.[16]
- This score includes a number of variables known to be reflective of a higher risk to die from stem cell transplant and related complications.
- Most important ‘risk-indicators’ in this regard appear to be:
- Age
- Type
- Sex of donor
- Time from disease onset
Rest is described in the following tables:
| Feature | Score | ||
|---|---|---|---|
| A | Donor type | HLA identical sibling
Unrelated donor |
0
1 |
| B | Disease phase | Chronic phase
Accelerated phase Blast phase |
0
1 2 |
| C | Age | <20
20-40 >40 |
0
1 2 |
| D | Donor/Recipient | Other
Female donor to male recipient |
0
1 |
| E | Time from diagnosis
to transplantation |
<12 months
>12 months |
0
1 |
| Risk score | Luikemia free survival | Survival | Transplant related mortality | Relapse Incidence |
|---|---|---|---|---|
| 0 | 62 | 76 | 21 | 26 |
| 1 | 61 | 73 | 21 | 23 |
| 2 | 44 | 59 | 35 | 32 |
| 3 | 34 | 49 | 47 | 31 |
| 4 | 28 | 38 | 53 | 28 |
| 5 | 37 | 39 | 45 | 41 |
| 6 | 15 | 19 | 81 | 32 |
| 7 | - | - | - | - |
- An important aspect is that most of the above mentioned scoring systems have been developed and used for CML patients treated with IFNα, i.e. before imatinib has become available.
- Thus, it remains open whether all these risk scores can be translated (one-to-one) and used for patients receiving imatinib in the same way as in the ‘pre imatinib era’.[17]
- Number of cytogenetic and molecular markers that may reflect a certain prognosis or risk-profile in patients with CML have been developed in the last few years.[18]
- Among those are:[19]
- Novel cytogenetic defects
- Point mutations or amplifications of BCR/ABL or other genes
- The quantitative amount of BCR/ABL after STI571 treatment
- Various hypermethylation patterns
- Silencing of tumor suppressor genes
- It is also likely that some of the previous markers will be used in the near future using more accurate techiniques. Such as:
- Quantitative PCR testing using light cycler technique.[20]
- COBRAFISH.[21]
- A novel FISH technique that may be helpful in the detection of cryptic translocations occurring during disease evolution.
- COBRAFISH.[21]
- The counting of basophils may be improved by using specific antibodies or by measurement of cellular histamine levels. [22]
- Using such tests, both, the mature basophils as well as the immature basophils (that may escape conventional blood counting especially in patients with CML-AP, can be measured more accurately for prognostic calculations.
References
- ↑ 1.0 1.1 1.2 Canadian Cancer Society.2015.http://www.cancer.ca/en/cancer-information/cancer-type/leukemia-chronic-myelogenous-cml/finding-cancer-early/?region=ab
- ↑ Jabbour E, Kantarjian H (November 2012). "Chronic myeloid leukemia: 2012 update on diagnosis, monitoring, and management". Am. J. Hematol. 87 (11): 1037–45. doi:10.1002/ajh.23282. PMID 23090888.
- ↑ Thompson PA, Kantarjian HM, Cortes JE (October 2015). "Diagnosis and Treatment of Chronic Myeloid Leukemia in 2015". Mayo Clin. Proc. 90 (10): 1440–54. doi:10.1016/j.mayocp.2015.08.010. PMC 5656269. PMID 26434969.
- ↑ 4.0 4.1 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.
- ↑ National Cancer Institute. Physician Data Query Database 2015.http://www.cancer.gov/types/leukemia/hp/cml-treatment-pdq#link/_381_toc
- ↑ Medline Plus.2015.https://www.nlm.nih.gov/medlineplus/ency/article/000570.htm
- ↑ Radivoyevitch T, Jankovic GM, Tiu RV, Saunthararajah Y, Jackson RC, Hlatky LR, Gale RP, Sachs RK (March 2014). "Sex differences in the incidence of chronic myeloid leukemia". Radiat Environ Biophys. 53 (1): 55–63. doi:10.1007/s00411-013-0507-4. PMC 3943788. PMID 24337217.
- ↑ Deininger MW (2015). "Diagnosing and managing advanced chronic myeloid leukemia". Am Soc Clin Oncol Educ Book: e381–8. doi:10.14694/EdBook_AM.2015.35.e381. PMID 25993200.
- ↑ American Society of Clinical Oncology. Leukemia - Chronic Myeloid - CML: Symptoms and Signs. 11/2016. Accessed at www.cancer.net/cancer-types/leukemia-chronic-myeloid-cml/symptoms-and-signs on May 14, 2018
- ↑ Wadhwa J, Szydlo RM, Apperley JF, Chase A, Bua M, Marin D, Olavarria E, Kanfer E, Goldman JM (April 2002). "Factors affecting duration of survival after onset of blastic transformation of chronic myeloid leukemia". Blood. 99 (7): 2304–9. PMID 11895760.
- ↑ Hasford J, Ansari H, Pfirrmann M, Hehlmann R (May 1996). "Analysis and validation of prognostic factors for CML. German CML Study Group". Bone Marrow Transplant. 17 Suppl 3: S49–54. PMID 8769702.
- ↑ Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, Ansari H (June 1998). "A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group". J. Natl. Cancer Inst. 90 (11): 850–8. PMID 9625174.
- ↑ Sokal JE, Cox EB, Baccarani M, Tura S, Gomez GA, Robertson JE, Tso CY, Braun TJ, Clarkson BD, Cervantes F (April 1984). "Prognostic discrimination in "good-risk" chronic granulocytic leukemia". Blood. 63 (4): 789–99. PMID 6584184.
- ↑ Hasford J, Pfirrmann M, Hehlmann R, Allan NC, Baccarani M, Kluin-Nelemans JC, Alimena G, Steegmann JL, Ansari H (June 1998). "A new prognostic score for survival of patients with chronic myeloid leukemia treated with interferon alfa. Writing Committee for the Collaborative CML Prognostic Factors Project Group". J. Natl. Cancer Inst. 90 (11): 850–8. PMID 9625174.
- ↑ Kantarjian HM, Keating MJ, Smith TL, Talpaz M, McCredie KB (January 1990). "Proposal for a simple synthesis prognostic staging system in chronic myelogenous leukemia". Am. J. Med. 88 (1): 1–8. PMID 2294759.
- ↑ Gratwohl A, Hermans J, Goldman JM, Arcese W, Carreras E, Devergie A, Frassoni F, Gahrton G, Kolb HJ, Niederwieser D, Ruutu T, Vernant JP, de Witte T, Apperley J (October 1998). "Risk assessment for patients with chronic myeloid leukaemia before allogeneic blood or marrow transplantation. Chronic Leukemia Working Party of the European Group for Blood and Marrow Transplantation". Lancet. 352 (9134): 1087–92. PMID 9798583.
- ↑ Goldman JM, Druker BJ (October 2001). "Chronic myeloid leukemia: current treatment options". Blood. 98 (7): 2039–42. PMID 11567987.
- ↑ Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U, Gschaidmeier H, Druker BJ, Hehlmann R (November 2002). "Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy". Leukemia. 16 (11): 2190–6. doi:10.1038/sj.leu.2402741. PMID 12399961.
- ↑ Hochhaus A, Kreil S, Corbin AS, La Rosée P, Müller MC, Lahaye T, Hanfstein B, Schoch C, Cross NC, Berger U, Gschaidmeier H, Druker BJ, Hehlmann R (November 2002). "Molecular and chromosomal mechanisms of resistance to imatinib (STI571) therapy". Leukemia. 16 (11): 2190–6. doi:10.1038/sj.leu.2402741. PMID 12399961.
- ↑ Merx K, Müller MC, Kreil S, Lahaye T, Paschka P, Schoch C, Weisser A, Kuhn C, Berger U, Gschaidmeier H, Hehlmann R, Hochhaus A (September 2002). "Early reduction of BCR-ABL mRNA transcript levels predicts cytogenetic response in chronic phase CML patients treated with imatinib after failure of interferon alpha". Leukemia. 16 (9): 1579–83. doi:10.1038/sj.leu.2402680. PMID 12200666.
- ↑ Barbouti A, Johansson B, Höglund M, Mauritzson N, Strömbeck B, Nilsson PG, Tanke HJ, Hagemeijer A, Mitelman F, Fioretos T (October 2002). "Multicolor COBRA-FISH analysis of chronic myeloid leukemia reveals novel cryptic balanced translocations during disease progression". Genes Chromosomes Cancer. 35 (2): 127–37. doi:10.1002/gcc.10099. PMID 12203776.
- ↑ Bühring HJ, Simmons PJ, Pudney M, Müller R, Jarrossay D, van Agthoven A, Willheim M, Brugger W, Valent P, Kanz L (October 1999). "The monoclonal antibody 97A6 defines a novel surface antigen expressed on human basophils and their multipotent and unipotent progenitors". Blood. 94 (7): 2343–56. PMID 10498606.