Leukemia: Up-to-Date Information from Path-ogenesis to Management-ft

Science Insights Medicine, 30 March 2017
2017: e00077
Doi: 10.15354/sim.17.co025
 
Consensus (Narrative)
Leukemia: Up-to-Date Information from Pathogenesis to Management
The Medical Therapeutic Consensus Task Force (MTCTF)*​
 
Author Affiliations
*: The Medical Therapeutic Consensus Task Force (MTCTF), Division of Medicine and Public Health, The BASE, Chapel Hill, nc 27012, USA
* Correspondence to: MTCTF, Email: consensus.med@basehq.org
 
Sci Insigt Med. 2017;2017:e00077. doi:10.15354/sim.17.co025
 
SUMMARY

Leukemia is a type of cancer that affects bone marrow, it’s characterized by presence of high number of abnormal white blood cells in the blood that affects nearly all body organs and tissue and give rise to multiple symptoms and complications. Despite the high number of research studies in the field of leukemia, it’s yet not clear how the disease forms, and there’s no proven mechanism that explains leukemia. Prognosis and responsiveness to treatment is better in children than in adults. There are four main types of leukemia: Acute Lymphocytic leukemia, acute myeloid leukemia, Chronic Lymphocytic leukemia, and chronic myeloid leukemia. Leukemia isn’t linked to any specific preventable risk factors, and that’s why it’s totally unpreventable. Non-specific risk factors predisposing to leukemia include irradiation, some types of viral infections, tobacco, benzene, chloramphenicol, phenybutazone, hair dyes, and chromosomal factors. Main symptoms of leukemia include anemia with dyspnea, thrombocytopenia with bleeding tendency, leucopenia with recurrent infections, weight loss, fever, fatigue, anorexia, lymphadenopathy, hepatosplenomegaly, night sweating, bone pain, weakness, and shortness of breath. Diagnosis of leukemia depends on complete blood picture to detect the decreased number of normal blood cells and the increased number of the abnormal leukemic cells. Also bone marrow biopsy, CSF examination, blood chemistry testing, and radiology are useful diagnostic and confirmatory methods. Supportive treatment of leukemia aims aid compensation for the decreased body functions, such as packed RBCs transfusion to compensate anemia, platelet transfusion to compensate thrombocytopenia, antibiotics to compensate for neutropenia, and allopurinol to treat gout. Specific treatment of leukemia depends mainly on chemotherapy, such as busulphan in treatment of CML. The Chinese leukemia treatment “a combination between Chinese & western medicine “is remarkably becoming a popular alternative to chemotherapy.

Keywords:  Labor Pain; Novel Technique; Analgesia; Opioid; Drug Delivery

 

BOX 1. 15 INTERESTING GENERAL FACTS ABOUT LEUKEMIA

[1] About 1 million Americans are either suffering or re-covering from blood cancer.
[2] Nearly each ten minutes, an American citizen dies from leukemia.
[3] Approximately a combined total of 171,550 are ex-pected to be diagnosed with one of the three Main types of blood cancer [Lymphoma, Myeloma, Leukemia] by the end of 2016.
[4] Those who are older than 67 years are the most prone to get leukemia. However about 1/3 of Leukemia patients are kids and teens. Survival rates of leukemia are so low as it usually affects old people who have already reached The natural end of human life.
[5] Leukemia affects male patients more than female ones.
[6] According to rate of occurrence, leukemia type of can-cer comes 10th or 11th [ranked after endometrial tumors that affect uterus]
[7] Blood cancer as a whole accounts for a percent of 10% of newly-diagnosed cancer in USA.
[8] The five-years survival rate of leukemia from 2005 – 2011 was about 62%.
[9] The five-year survival rate have tripled or even quad-rated in the last 50 years.
[10] Leukemia nearly affects every important organ in the body.
[11] Despite the high number of research studies in the field of leukemia, it’s yet not clear how the Disease forms, and there’s no proven mechanism that explains leukemia.
[12] Many researches have shown that there is no clear connection between any groups of risk Factors and suffer-ing from leukemia, that’s why leukemia is nearly 100% unpreventable. 
[13] About $70-$90 million are spent every year on leu-kemia researches.
[14] The Chinese leukemia treatment “a combination be-tween Chinese & western medicine “is remarkably becom-ing a popular alternative to chemotherapy.
[15] It’s believed that leukemia wasn’t discovered until the 18th century.
    
DIFFERENT TYPES OF LEUKEMIA
Acute means the disease progresses rapidly, and the symp-toms are more sever.
Acute Lymphocytic Leukemia [ALL]
Also Called: Acute lymphoblastic leukemia or acute lym-phoid leukemia.
Incidence: can occur at any age, but most commonly oc-curs under the age of 15 [Teens] Or above the age of 65, and characterized by formation of Thymic Mass.
Pathology: Build-up and accumulation of lymphoblastic cells in bone marrow 
[present in the shaft of long bone, and responsible for syn-thesis of different blood cells]
►Those abnormal cells cannot differentiate into neither T-Cells [the immune cells that kills the infected cells, pre-venting spread of the pathogen to the healthy cells], Nor B-Cells [the immune cells that are responsible for produc-ing the antibodies which give our bodies protection against re-infection with the same pathogen again]
►Also, those abnormal malignant cells limits the bone marrowability to produce 
Other types of blood cells, for example:
↓ Red Blood Cells Synthesis → Anemia → Fatigue. 
↓ Platelets → Thrombocytopenia → Bleeding tendency. 
↓ Immune Cells → ↓Resistance to microbes → Recur-rent infections
Standard treatment : Chemotherapy and radiology
Survival Rate : 85% in children & 50% in adults
Subtypes: B-lymphoblastic leukemia T-lymphoblastic leu-kemia Burkett’s leukemia Acute Bi-phenotypic leukemia
 
Acute Myeloid Leukemia [AML]
Also Called : Acute myelogenous leukemia or acute mye-loblastic leukemia.
Prevalence : It’s the most common type of leukemia
Incidence : adults aging from 50 – 60 years
Mechanism : Build-up and accumulation of myeloblastic cells in bone marrow 
►Those abnormal cells cannot differentiateinto neither Red Blood Cells [the cells that carry hemoglobin and play a very important role in respiration and gas.
►Also, those abnormal malignant cells migrate to differ-ent organs and tissues where they develop and replicate causing the characteristic clinical symptoms.
Standard treatment: Unfortunately, it’s incurable, but there are many effective supportive treatment.
Survival : the 5-years survival rate is 40% 
Subtypes :  Acute myeloblastic leukemia Acute megakar-yocytic leukemia Acute Monocytic leukemia Acute pro-myelocytic leukemia [90% Survival]
 
Chronic Lymphocytic Leukemia[CLL]
Incidence : adults above the age of 55 “almost never af-fects kids”
Survival : the 5-years survival rate is 75% 
Subtype :  B-cell prolymphocytic leukemia [more aggres-sive]
 
Chronic Myeloid Leukemia [CML]
Incidence : usually affects adults [children can be affected, but this’s rare]
Standard treatment : treated with imatinib (under the name of Gleevec in USA, Glivec in Europe)
Survival : the 5-years survival rate is 90% 
Subtype : chronic myelomonocytic leukemia.
    
OTHER TYPES OF LEUKEMIA
Hairy cell leukemia
T-cell prolymphocytic leukemia 
Large granular lymphocytic leukemia
Adult T-cell leukemia.
    
CAUSES OF LEUKEMIA

Genetic “chromosomal” factors
Philadelphia Chromosome : in CML, Congenital Diseases with abnormalities : such as Down’s syndrome, Fanconi anemia, Klinefilter syndrome.
Radiation
Retroviruses 
 HTLV-1 [Human T-cell Leukemia Virus-1]
 EBV [Epstein-Barr Virus]
Viruses
Retroviruses 
 HTLV-1 [Human T-cell Leukemia Virus-1]
 EBV [Epstein-Barr Virus]
Chemical and Drugs
Hydrocarbons [Benzene]. Alkylating agents. 
Chloramphenicol. Phenylbutazone.
Tobacco. Hair dyes.
Mother to fetus transmission 
Only a few cases has been of sick babies to sick moms have been reported.
    

CLINICAL MANIFESTATIONS OF LEUKEMIA

Bone Marrow Failure
Overcrowding of the bone marrow with abnormal leuke-mia cells, significantly diminishes The ability of bone marrow to synthesize other blood cells, leading to : 
Anemia
 The total hemoglobin level becomes below 12 g/dl in ♀ or 14 g/dl in ♂.
Anemia decreases the blood ability to carry oxygen lead-ing to fatigue, weakness.
Dyspnea, shortness of breath, tiredness and decreased abil-ity to exercise.
In severe cases other symptoms like confusion and uncon-sciousness may occur.
Also the heart may try to compensate the decreased tissue oxygenation by ↑
COP [Cardiac output] through increasing both contractility force and rate, which
Can lead to palpitation, murmurs, angina, ventricular hy-pertrophy or heart failure.

Thrombocytopenia
Due to decreased number of platelets below 150.000 / μl.
The decrease in the number of thrombocytes, hinders the body ability to stop 
Bleeding from injured blood vessels, which can manifest as bleeding gums, nose Bleed, purpura,or petechia.
Also, it may manifest by heavier longer periods or break-through bleeding in female leukemic patients.

Granulocytopenia & Lymphocytopenia:
The abnormal immature leucocytes cannot differentiate into the useful functional 
Types of wbcs, which leads to :
 ↓ T-lymphocytes → ↓ Ability to control viral infections & mutated cells.
 ↓ B-lymphocytes → ↓ Ability to form antibodies → recurrent infections.
 ↓ pmnls [polymorph-Nuclear Lymphocytes]→ ↓ Body resistance to Infections, and generalized lowered body immunity.  May manifest as throat and mouth ulcers, en-larged cervical lymph nodes, Parotiditis, pneumonia, cellu-litis, or even bacteremia [Bacteria invade the blood]. Man-ifestations due to infiltration of body organs by leukemia cells  When the abnormal leukemia cells are disseminated into blood, they migrate to Several tissues and organs giv-ing rise to several symptoms that differ according To the affected organ .
 
Central Nervous System “CNS” 
Symptoms include ↑ ICT [increased Intra-Cranial Ten-sion] which can lead to nausea, headache, tremors, cranial nerve palsy, or spinal compression.
 
Lungs
Symptoms include parenchymal infiltration, pleural effu-sion [presence of excess fluid around the lungs which im-pairs lung expansion], dyspnea, shortness of breath, or mediastinal syndrome
 
Reticulo-Endothelial System
Leukemia causes generalized lymphadenopathy [inflam-mation of lymph nodes And lymph vessels], for example :-
Enlarged mediastinal lymph nodes →Mediastinal Syn-drome :
 - Obstructed Superior Vena Cava
 - Severe edema
 - Cough and headache
Enlarged porta hepatis lymph nodes → obstructive jaun-dice
Due to obstruction of bile outflow, that leads abnormal yellowish
Discoloration of skin and mucous membranes (e.g.: white-ness of eye), 
Together with dark urine, dark stool, and severe itching.
Hepato – Splenomegaly [enlarged liver and spleen] → Nausea and pain.
 
Gastro-intestinal Tract
 Hypertrophy of gums, mouth ulcers, pain, diarrhea, colic and hemorrhage. 
 
Kidney and genital system
Hematuria [presence of blood in urine], UTI [Urinary Tract Infection], Ureteric Obstruction [By urate stones], Testicular Swelling [in ALL].
 
Musculo-skeletal
Sub-periosteal infiltration [the abnormal leukemia cells infiltrates under the Membrane that covers the outer sur-face of the bone “Periosteum”] causing Bone and joint pain, together with tenderness and muscle weakness.
 
General Manifestations
Fever : due to opportunistic bacterial infection enhanced by lowered body immunity together
With tissue destruction and increased metabolic rate “hy-permetabolism” Weight loss 
Prostration & Asthenia
 
Other Manifestations
Other clinical disorders caused by leukemia may include :
Gout : due to increased serum uric acid.
Hypokalemia [decreased blood Potassium Level] : due to renal tubular dysfunction.
Hyponatremia : due to ↑ADH [Syndrome of Inappro-priate Anti-Diuretic Hormone].
Mickulicz’s Syndrome : enlarged salivary & lacrimal glands.
Chloroma : Soft tissue masses occurring at any site 
Leukostasis : due to excess blasts which lead to obstruc-tion of blood capillaries, with
Subsequent ischemia or rupture of those obstructed capil-laries
    

DIAGNOSIS & INVESTIGATIONS OF LEUKEMIA

Diagnosis of Acute Leukemia 
(1)    Complete Blood Count [CBC]
Red Blood Cells : severe normocytic normochromic anemia [may require BM transplant]
Low hemoglobin levels below 12 g/dl in male or 14 g/dl in female.
Platelets : thrombocytopenia with low platelets level be-low 150.000 / μl.
Leucocytes [Leucocytosis] :
Total Leucocytic Count [TLC] : abnormally increased and may exceed 100.000/mm3
Predominant blast cells consists 30-90% (normally 1-3%), [maybe lympho or myeloblas].
Sub-leukemic Leukemia : TLC is normal or subnormal with presence of Blast
Aleukemic leukemia : TLC is normal or subnormal with absence of Blast
In this case, blood tests cannot reveal that a person has leukemia despite Having clear leukemia clinical picture. 
This occurs mainly during early stages or remission.
This case can be diagnosed only by bone marrow exami-nation.
Differentiation between leukemic cells is important, and can be done by :
Morphology
Surface markers : immunophenotyping
Cytoplasmic markers
Myeloblasts are Myeloperoxidase + Ve
Lymphoblasts are PAS + Ve
(2)    Bone Marrow Examination
Bone marrow is hyper-cellular, full of abnormal blast cells [30 - 90 % or even 100% of BM] 
Very important in diagnosis of aleukemic leukemia.
(3)    Lymph Node Biopsy
Lymph Node Biopsy is used to diagnose specific types of leukemia under certain conditions
(4)    Cerbro – Spinal Fluid Examination [CSF exam.]
Used for detection of abnormal leukemic cells
(5)    Radiology
X-ray : reveals bone osteoporosis, periosteal elevation, and exclude mediastinal mass.
MRI : reveals the extent of brain and nervous damage due to leukemia.
Ultrasound : For organs in abdominal cavity, e.g.: kid-ney, liver, and spleen.
CT : rarely used to check mediastinal [chest] lymph nodes.
(6)    Blood Chemistry Tests
Used for checking the degree of liver & kidney damage caused by leukemia.
Can also be used to check the effect of chemotherapy on patients.
Blood Shows :
 ↑ Uric acid level [may lead to gout] ↑ LDH [Lactate Dehydrogenase level]
↓ K+ level [Hypokalemia]  ↓ Na+ level [Hypo-natremia] 
(7)    FAB classification
French – British – American classification of Acute Leu-kemia :
Myeloid Lymphoid
M1 → M7 L1 → L3
(8)    Leukemoid Reaction[Leukemoid Blood Picture]
It’s a condition characterized by marked leukocytosis (< 25.000 /mm3) 
± immature forms, either :
Lymphatic Leukemoid Reaction
Viral : infectious mononucleosis, herpes simples, hepatitis, and HIV
Bacterial : Pertussis “whooping cough”, TB, and brucello-sis
Protozoal : Toxoplasmosis 
Myeloid Leukemoid Reaction
Ch.Ch. By ↑wbcs < 50.000 /mm3, and/or presence of immature leukocytes.
Occurs in :-
Bone Marrow overstimulation [Hyperactive BM] :-
Occurs in acute hemolysis, acute hemorrhage, and acute hypoxia.
Bone Marrow infiltration [Leucoerythroplastic Anemia]
Presence of both immature rbcs & immature wbcs
 
Diagnosis of Chronic Leukemia 
(1)    Complete Blood Count [CBC]
Red Blood Cells : early increased, but later on → normocytic normochromic anemia.
Platelets : early increased, but later on → thrombocyto-penia with low platelets level.
Leucocytes [Leucocytosis] 
Total Leucocytic Count [TLC] : ranges between 100.000/mm3 – 500.000/mm3
Neutrophils mainly ↑, but also eosinophils and baso-phils can ↑.
Myelocytes range from 20-50% 
Leukocyte alkaline phosphatase is low [may reach zero]
(2)    Bone Marrow Examination
Bone marrow is hyper-cellular, full of abnormal myelo-cytes & myeloblasts. 
BM examination can also demonstrate Philadelphia Chromosome 
Philadelphia Chromosome 
Specific chromosomal abnormality in myeloid cells found in 80-90 % Of Chronic Myeloid Leukemia Cases.
Philadelphia +Ve patients tend to have better prognosis & response to treatment. 
(3)    Blood Chemistry Tests
Lymph Node Biopsy is used to diagnose specific types of leukemia under certain conditions
↑ Uric acid level ↑ Transcobalamin II  ↑ Vitamin B12]
(4)    Rai’s staging of Chronic Lymphocytic Leukemia [Prognositc]
Stage 0    Absolute Lymphocytosis – Normal Hb & platelets
Stage 1    Stage 0 + Lymphadenopathy
Stage 2    Stage 0 + Lymphadenopathy + Hepatosplenomeg-aly
Stage 3    Stage 0, 1, or 2+Anemia (Hb > 11 g/dl)
Stage 4    Stage 0,1, or 2+Thrombocytopenia (Platelets > 100.000/mm3).
    

TREATMENT OF LEUKEMIA

Supportive Treatment of Leukemia
Supportive Treatment of Leukemia 
Anemia : packed rbcs transfusion.
Bleeding : platelets transfusion. 
Infections : granulocyte transfusion, antibiotics, antifungal, or antiviral.
Gout : Allopurinol.
Leukostasis : removal of leukemia cell from blood by leu-kopharesis.
Prevention of acute tumor lysis syndrome “that follows chemotherapy”, by :-
Adequate hydration, allopurinol, and dialysis. 
 
Supportive Treatment of Leukemia 
Aim : sensitization of immune system to enable it to detect and remove tumor cells.
Methods : Bacillus-Calmette-Guerin vaccine, levimazol, monoclonal abs,
 Subcutaneous irradiated allogeneic leukemic cells.
 
Oncotherapy of ALL
(1)    Remission induction[4-6 w]
Prednisone [orally]  Vincristin [IV]
 Criteria of Remission:-
 - Absent clinical manifestations
 - Bone Marrow : Lymphoblast > 5 %
 - Blood : Absent blast, PNLS < 5.000/mm3, 
Platelets < 75.000/mm3.
(2)    CNS Prophylaxis[2-5 w]
Cranial irradiation ± Spinal irradiation + Methotrexate [intrathecal]
(3)    Consolidation
Similar to remission induction. 
(4)    Maintenance for 2 years at least
Prednisone / Vincristin [every 3 monthes]
(5)    Follow up via clinical symptoms and hematologi-cal exams
Testicular biopsy for men may be needed.
 
Oncotherapy of AML
(1)    Remission induction
Either : 6-Mercatopurine + Methotrexate + Cyclophos-phamide 
Or : Cytosine arabinoside + 6-thioguanine + Doxorubicin
(2)    CNS Prophylaxis[usually not used]
(3)    Consolidation[7-10 monthes]
Usually not useful.
Bone Marrow transplantation usually needed.
(4)    Bone Marrow Transplantation
Especially in patients > 45 years
 
Treatment of CML
(1)    Chemotherapy
Busulphan [Myleran]. 
Hydroxyurea [Hydrea]. 
(2)    X-ray total or local radiotherapy 
(3)    Recent approaches
Early splenectomy followed by aggressive chemotherapy alpha-interpheron – Imatinib mesylate 
Bone marrow transplantation. 
 
Treatment of CLL
It’s delayed till appearance of symptoms, as it’s believed that drugs doesn’t affect mortalitiy
(1)    Chemotherapy
Chlorambucil [Leukeran]. 
Prednisone. 
Alternative treatment includes :
Combined Chemotherapy. Cyclophosphamide [endoxan].
Fludarabine. Monoclonal Antibodies. 
(2)    Lymph Node & Spleen Radiotherapy.■
 

ARTICLE INFORMATION

Author Affiliations: The Medical Thera-peutic Consensus Task Force (MTCTF), Division of Medicine and Public Health, The BASE, Chapel Hill, NC 27012, USA
Author Contributions: The Medical Ther-apeutic Consensus Task Force (MTCTF) had full access to all of the data in the study and takes responsibility for the in-tegrity of the data and the accuracy of the data analysis.
Study concept and design: MTCTF.
Acquisition, analysis, or interpretation of data: MTCTF.
Drafting of the manuscript: MTCTF.
Critical revision of the manuscript for im-portant intellectual content: MTCTF.
Statistical analysis: N/A.
Obtained funding: N/A.
Administrative, technical, or material sup-port: MTCTF.
Study supervision: MTCTF.
Conflict of Interest Disclosures: The au-thors declared no competing interests of this manuscript submitted for publication.
Funding/Support: N/A
Role of the Funder/Sponsor: N/A
How to Cite This Paper:  The Medical Therapeutic Consensus Task Force (MTCTF). Leukemia: Up-to-date infor-mation from pathogenesis to manage-ment. Sci Insigt Med. 2017;2017:e00077.
Digital Object Identifier (DOI): http://dx.doi.org/10.15354/sim.17.co025.
Article Submission Information: Received, February 09, 2017; Revised: March 04, 2017; March: March 21, 2017 
 
 

REFERENCES

1.    Https://en.wikipedia.org/wiki/Leukemia
2.    Http://www.dosomething.org/facts/11-facts-about-leukemia-and-other-blood-cancers
3.    Http://www.lls.org/http%3A/llsorg.prod.acquia-sites.com/facts-and-statistics/fa...
4.    Http://www.fascinatingplanet.com/10-little-known-facts-about-leukemia-worth-kno...
5.    Http://www.cancercenter.com/leukemia/types/
6.    Http://www.youtube.com/watch?V=Ya8IzYwguVM
7.    Http://en.wikipedia.org/wiki/Anemia
8.    Http://www.mayoclinic.org/diseases-condi-tions/leukemia/basics/symptoms/con-200...
9.    Http://www.cancer.gov/types/leukemia
10.    Http://www.healthline.com/health/leukemia#Symptoms4
11.    Https://www.liverandpancreas.co.uk/the-management-of-obstructive-jaundice.php
12.    Http://www.medicinenet.com/leukemia/article.htm
13.    Http://www.webmd.com/cancer/tc/leukemia-topic-overview 
14.    Http://www.cancer.org/cancer/leukemiainchildren/detailedguide/childhood-leukemi...
15.    Http://nihseniorhealth.gov/leukemia/whatisleukemia/01.html
16.    Http://www.emedicinehealth.com/leukemia_health/viewer-comments_em-1857-page2.htm
17.    Http://www.nhs.uk/Conditions/leukaemia-chronic-lymphocytic/Pages/Introduction.aspx
18.    Http://my.clevelandclinic.org/health/diseases_conditions/hic_Leukemia
19.    Http://my.clevelandclinic.org/health/diseases_conditions/hic_Leukemia
20.    Http://www.cancer.net/cancer-types/leukemia-acute-myeloid-aml/diagnosis
21.    Http://www.cancer.net/cancer-types/leukemia-acute-myeloid-aml/treatment-options
22.    Http://www.cancervic.org.au/about-can-cer/cancer_types/leukaemia/treatment_for_....