The leukemias are a group of malignant disorders of the haemopoietic tissues characteristically associated with increased number of leucocytes in the blood.   Or 

Leukemias are a heterogeneous group of neoplasm arising from malignant transformation of haemopoitic cells. 
Leukemic cells proliferate primarily in the bone marrow and lymphoid tissues where they interfere with normal haemopoesis and immunity. Ultimately they emigrate in to the peripheral blood and infiltrate other tissues. Thus leukemias are progressive and fatal condition resulting in death most often from hemorrhage or infections. The course may vary from a few days or week to many years depending on the type. 

EPIDEMIOLOGY 
Leukemia account for 0.15 – 0.6% of the total medical admission in many General hospitals in India. C.L.L. is less common in India and neighboring countries when compared to West. 
Males are affected more frequently (both acute and chronic) than females.
Male to female ratio-
Acute leukemia -- 3: 2
Chronic lymphocytic leukemia -- 2: 1
Chronic myeloid leukemia -- 1.3: 1 
Frequency of leukemia seen in India:
C.M.L 25 – 30 %
A.M.L       20 - 25 %
A.L.L. 15 - 25 %
C.L.L. 1 – 2 %
Other varieties 1 -2 % 
Age incidence:
Acute lymphoblastic leukemia is primarily a disease of children and young adult, where as AML occurs primarily in adults. (ALL shows a peak incidence in the 1- 5 age group.) Chronic lymphocytic leukemia tends to occur in the elderly. 

ETIOLOGY: 
In majority of the patients the cause of the leukemia is unknown.
There are certain factors associated with development of leukaemia. They are as follows: 
1. Ionising radiation: A significant increase in myeloid leukemia
followed the atomic bombing of Japanese cities. An increase in leukemia was observed after the use of radiotherapy for ankylosing spondylitis and diagnostic X ray of the fetus in pregnancy. Individual with occupational exposure, patients receiving radiation therapy or Japanese survivors of the atomic bomb explosion have a predictable and dose related increased incidence of leukemia. Radiation exposure increases the risk of developing CML, AML and possibly ALL, but there is no known relationship to CLL or to hairy- cell leukemia. 
2. Cytotoxic drugs: Cytotoxic drugs particularly alkylating agent, may
Induce myeloid leukemia usually after a latent period of several years. It had been noticed that in patients undergone alkylating agent therapy for cancer of ovary, lung and breast had develop acute leukemia after several months. Multiagent anti cancerous chemotherapy may produce leukemia.
3. Exposure to benzene in industry: (chronic benzene exposure)
Exposure to other aromatic hydrocarbons may result in AML. 
4. Retro viruses: One rare form of T cell leukemia lymphoma appears to
be associated with a retrovirus- Human T Cell Leukemia Virus (HTLV) 
5. Genetic and congenital disorders: There is increased incidence of
leukemia in the identical twin of the patient with leukemia. Increased incidence occurs in Down’s syndrome and other genetic disorders like Bloom’s, Klinefelters, Fanconi’s and the Gonadal dysgensis (xxy) 
Wiskott- aldrich syndromes (due to defective nucleotide in the platelet. Sex linked recessive. Bleeding from various sites.), Ataxia telangiectasia and congenital agamma globulinemia are also prone to terminate in acute leukemia. 
6.Immunological: Immune deficiency states are associated with an increase in haematological malignancy.
7.Predisposing hematologic diseases: Some haematological diseases acquired during life have a remarkable tendency to terminate as acute leukemia. Primary thrombocytopenia, polycythemia vera, paroxysmal nocturnal hemoglobinuria and hemopoietic stem cell disease may terminate in acute leukemia. 
 
PATHOPHYSIOLOGY 
Acute leukemia is characterised by proliferation of immature myeloid or lymphoid cells. The leukemia arises following malignant transformation of a single hemopoitic or lymphoid progenitor followed by cellular replication and expansion of the transformed clone. A fundamental characteristic of the malignant cells in acute leukemia is their failure to mature beyond the myeloblast or promyelocyte level in AML and the lymphoblast level in ALL. Leukemic cells accumulate in bone marrow due to excessive proliferation and to a defect in terminal differentiation. The failure to mature to non-replicating end cells is the primary reason for accumulation of leukemic cells in AML. The leukemic cells proliferate primarily in the bone marrow, circulating in the blood and may infiltrate in to other tissue such as lymph node, liver, spleen, skin, viscera and the central nervous system. 

The leukemic blast cells accumulate in the bone marrow and suppress the growth and differentiation of normal haemopoitic cells. Thus AML &ALL result in the diminished production of normal erythrocytes, gametocyte & platelets. These deficiencies of normal cells leads to the most important manifestation of this disease. Weakness, fatigue and pallor as a result of anaemia. Infection as result of granulocytopenia and hemorrhage as a result of thrombocytopenia.  

CLASSIFICATION 
According to the cell type primarily involved leukemia are classified into two. They are
1. Myeloid leukemia
2. Lymphoid lukaemia 
According to the clinical behavior of the disease lukeamias are classified into two.
1.Acute lukaemia
2. Chronic lukeamia. 
Lukeamia      Acute     Chronic

 1.Lymphoid 2.Myloid 1.Lymphoid 2.Myloid
(Lymphoblastic) (Myloblastic) (Lymphocytic) (Mylocytic) 
 
SUB CLASSIFICATION
AML (F A B Classification) 
M1 - Undifferentiated myeloblast
M2 - Differentiated myeloblast
M3 - Promyelocytic
M4 - Myelomonocytic
M5 - Monocytic
M6 - Erythrocytic
M7 - Megakaryocytic. 

A L L 
L1 - Blast cells are small and there is no appreciable variation in size and shape. The nuclear chromatin is smooth and the nucleoli are indistinct. 
L2 -The blast cells vary in size with prominent nucleoli and a variable amount of cytoplasm. 
L3 - The cells are deeply basophilic with vacuolated cytoplasm. 
C L L 
1. Common B cell
2. Rare T cell
3. Hairy cell
4. Prolymphocytic
 
C M L 
1. Philadelphia chromosome positive
2. Philadelphia negative, Break point cluster region positive
3. Philadelphia negative, Break point cluster region negative
4. Eosinophilic leukemia 
 
SUBLEUKEMIC AND ALEUKEMIC LEUKEMIA 
Not all leukemias are associated with an increased leucocyte count or even the appearance of abnormal cells in the blood. The sub leukemic is used when the leucocyte count is with in or below normal limits but abnormal cells are seen in the blood. 
Aleukemic is used when there are no abnormal cells to be seen and leucocyte count is normal or subnormal.
Almost all patients who present with sub leukemic or aleukemic disease have acute leukemias. The diagnosis is made from the marrow. 

ACUTE UNDIFFERENTIATED LEUKEMIA (AUL) 
In ALL the predominant cells are agranular blast cells. Similarly granular blast cells are predominant in AML But in rare cases of leukemia cells can not be classified by current technique in to one of these two major categories and can be referred to as AUL. 
Note: Although leukemias are divided in to lymphoid and myeloid varities recent advances have shown that this division may be artificial since in acute leukemias both type may co exist in the same patient. 
 
ACUTE LEUKEMIAS 
There is a failure of cell maturation in acute leukemias. Proliferation of cells which do not mature leads to an increasing accumulation of useless cells which take up more and more marrow space at the expense of the normal haemopoitic elements. Eventually this proliferation spills in to the blood.

CLINICAL FEATURES:
The patient usually present with non-specific flu- like symptoms or vague malaise and tiredness. Bleeding manifestation such as purpura, gum bleeding, mouth ulcers, herpes labialis and sore throat etc are common to many disorders. 
Symptoms of more diagnostic importance, which may reflect the growth, or infiltration of leukaemic cells in the marrow include persistent or recurrent skeletal pain or tenderness especially the lower sternum and occasionally swelling of the large joint. 
Hepatosplenomegaly in advanced stage Cervical lymphadinopathy secondary to pharyngeal sepsis. But enlarged lymph node due to the disease is a common feature of the lymphoblastic form. 
 
Symptoms  
Sign 
Lab abnormalities 
Cause
Fatigue/
Weakness
Pallor
Anaemia, hypocalcemia, Hyper calcemia & hypomagnesemia
Marrow failure, release of cellular ions and metabolits.
Weight loss
Weight loss  
Reduced food intake, anaemia, increased catabolism
Bleeding from skin, mucus membrane, gums, gastrointestinal tract, and genito urinary tract.
Purpura, gum oozing, or hypertrophy haematuria or melena.  
Thrombocytopenia, hypofibrinogenemia, reduced factor 5 & 8 and increased fibrin split products.
Marrow failure and disseminated intra vascular coagulation
Infection of skin, throat, gums, respiratory or urinary tract
Fever, chills and pyodermis gangrinosum
Granulocytopenia, X-ray evidence of infection like pneumonia Sinusitis etc. positive cultures.
Marrow failure, granulocytopenia and immunodeficiency
Headache, nausea, vomiting, blurred vision and cranial nerve dysfunction
Papilledema, cranial nerve palsy and meningeal irritation. 
Spinal fluid pleocytosis, reduced CSF sugar and increased CSF Protein
Meningeal, CNS or nerve infiltration and or compression. 
Bone pain and tenderness 
Increased bone tenderness
Abnormal bone marrow, X-ray (bone destruction)  
Local leukemic infiltration
Abdominal fullness and anorexia
Hepatosplenomegaly, abdominal tenderness
Hyperfibrinigenemia, elevated SGOT, SGPT and alkaline Phosphates  
Infiltration of abdominal viscera  
Enlarged lymph node or tumour mass
Enlarged lymph node mass in node areas, skin, breast, testis.  
Abnormal biopsy-liver, spleen, bone and gums.  
Local tumor growth or infiltration  
Oliguria 
------------------
Constipation.
--------------------------
Concentrated urine, elevated BUN, and elevated uric acid
-------------------------
Dehydration, uric acid nephropathy, DIC

INVESTIGATION 
Blood 
Peripheral smear- blast cell
Anemia- normochromic type
MCV- either normal or raised.
Leukocyte count -may varies from as low as 1 X 109/l to as high as 500 X 109/l or more.
The blood film appearance of blast cells and other primitive cells are usually diagnostic. 
In aleukemic form a bone marrow is necessary to establish the diagnosis. Severe Thrombocytopenia is usual but not invariable. 
Bone marrow 
The bone marrow is the most valuable diagnostic investigation
The marrow is usually hypercellular with replacement of normal elements by leukemia blast cells in varying degrees. The presence of Auer rods in the cytoplasm of the blast cells indicates a myeloblastic leukemia. Presence of blast cells in excess of 30% of the total cells in the marrow confirms the diagnosis of acute leukemia. Elevation above 5% should be noted with suspicion.

OTHER INVESTIGATIONS 
Renal functions: Blood urea, creatinine.
Liver functions: Total protein, albumine, bilirubine, alkaline phosphates, AST/ALT, gamma-GT
Hemostatic function: Coagulation screan, fibrinogen, and d-dimers.
Cellular proliferation: Plasma LDH, Plasma urate. 
 
MANAGEMENT 
Specific therapy: Bone marrow transplantation is a therapeutic option for young patient who has histocompatibile sibling donor. It is generally offered to the patient with AML in first remission and those with ALL in first, second, or subsequent remission. 
Supportive therapy: Thrombocytopenic bleeding- requires platelet transfusion.
Anemia: blood transfusion.
Infection: (unexplained fever >380c lasting over 6 hours in neutropenic patient indicative the possible septicemia) Patients with lymphoblastic leukemia are susceptible to infection with pneumocystis carini, which causes severe pneumonia
Fungal infection: Oral or pharyngeal monilial infection is common. Systemic fungal infection with candida or pulmonary aspergillosis.
Viral infection: Herpes simplex infection occurs frequently around the lips and nose.  
Renal & Hepatic function should be monitored closely particularly if the patient is receiving antibiotic, which is also, nephrotoxic. 
Protected environment 
Psychological support 
Isolation is often psychologically stressful for the patient. Psychological support is important. An optimistic attitude from the staff is vital. Delusion, hallucination and paranoia are not uncommon during periods of severe bone marrow failure and septicemic episodes and should be met with patience and understanding.  
Supportive observation:  
Continuous monitoring of renal, hepatic, hemostatic function is necessary together with fluid balance measurements. The patient is often severely anorexic and may find drinking difficulty. The necessary fluids and electrolytes often have to be given intravenously as long as necessary.

HOMOEOPATHIC MEDICINE 
Ars alb, Nat ars, Nat sulph +++ 
Aurum met, Ars iod, Calc, Calc phos, Carb sulph, Fer picricum, Nat mur, Nat phos, Picric acid, X-ray ++ 
Acetic acid, Aconite, Baryta iod, Baryta mur, Bry, Carbo veg, Chin sulph, Conium, Crot c, Crot h, Merc sol, Nux vom, opium, Phos, sulph, Thuja, Tuberculinum + 
 
PROGNOSIS 
Without treatment the survival of the patient with acute leukemia is about five weeks. This may extend to about ten weeks with supportive treatment. Patients who achieve remission with specific therapy have a better out look (about 79 % of adult patient with ALL and 60% with AML achieved remission. Survival for ALL patients is about 30 months and for AML patient about 13 months if remission is achieved.)  

BAD PROGNOSTIC FACTORS IN ACUTE LEUKEMIA 
1. Increasing age
2. Male sex
3. High leukocytes level at diagnosis.
4. Cytogenic abnormalities.
5. CNS involvement and diagnosis.
6. Thrombocytopenia below 1lakh.
7. Organomegaly.
8. T-cell ALL
9. Presence of mediastinal lymph node.
 
FAVORABLE PROGNOSTIC FACTORS 
1. Initial leukocyte count below 20,000/cc
2. Platelet counts above 1 lakh.
3. Absence of organomegaly.
4. Absence of mediastinal lymphadenopahty.
5. Younger age group.
6. Absence of complications 

Differences between acute and chronic leukemias 
Acute Chronic
Age
More in the first & second decade but can occur in all age group.
Mostly in the 4th, 5th and 6th decades. But even young children may be affected rarely 
Sex ratio 
Male: female-2: 1 
Male: female - 1: 1
Duration 
Weeks to months 
Several months to one year 
Presenting complaints
Anaemia, fever infections,
haemorrhagic tendencies or complications especially neurological.
Vague symptoms, loss of weight, mass in the abdomen or lymph - nodular masses
Organomegaly
Liver, spleen and lymph node are moderately enlarged in 70 - 80% of cases.
Moderate - gross spleenomegaly is the rule in CML. Moderate to gross lymphadenopathy in cases.
Blood picture
Total leucocyte count is moderately elevated. 15-30000/cmm. Blast cell from 10-90 % of the total. Platelets are often reduced
Total leucocyte count is grossly elevated. 150 –250000/cmm  
Bone marrow 
Shows depression of erithroiedcells, myeloid cells and megakaryocytes and infiltration by the abnormal cells. Blast cells from more than 30 %and may be even up to 90%
CML increase in myeloid cells, especially myelocytes, metamyelocytes and neutrophills. Infiltration by small lymphocytes is seen in CLL. Erythriod and megakaryocytic precursors may not be grossly suppressed in early stages. 
Chromosomal studies  
Variable
Philadelphia chromosome is demonstrable in 90 –95 % cases of CML  
Course& prognosis 
Untreated cases fatal within weeks to 6 months due to infection. Haemorrhage, anaemia or other complications
Untreated CML has median survival of 18 –24 months. CLL has a generally more prolonged course.  
Response totreatment
Spontaneous remission have rarely been reported. With treatment over 90 % of cases go in to remission and 60 – 70 % get complete cure.
With chemotherapy practically no case is cured. But the course is made more smooth and prolonged. With bone marrow transplantation at the ideal time cure rate exceed 50 %
 
LEUKEMOID REACTION: 
Leukemoid reaction is a non-neoplastic reactive leucocytosis characterised by the presence of immature cells of all stages in peripheral blood.
This may involve the myeloid, lymphatic or other cells types.
Childrens are affected more frequently than adults. 

CAUSES: 1. Acute infections
E.g.: - pneumonia, whooping cough, chicken pox,
Diphtheria, meningitis etc.
2.Chronic infections 
         E.g.: - tuberculosis, amoebic liver abscess. 
3. Haemolytic crisis and massive haemorrhages 
4. Metastatic carcinoma involving bone marrow (especially from neurofibroma, lungs etc.) 
5.other haematological malignancies like multiple myeloma and Hodgkin’s disease. 
6.Toxic states like eclampsia, burns and mercury poisoning
Blood picture myeloid in - pneumonia, TB, amoebic liver abscess, meningitis
metastatic carcinoma, multiple myeloma, post haemorrhage and hemolysis.
Blood picture lymphoid in- whooping cough and chicken pox. 
The bone marrow is normal with accelerated leucopoisis. No hepatospleenomegaly.