Leukemia , causes, clinical features, raktarbud

Leukemia
Dr. Arjun Upadhyaya
MD Kayachikitsha II year
IOM,TUATH, Nepal

Definition
Leukemia is a type of cancer of the blood or bone
marrow characterized by an abnormal increase of
immature white blood cells called "blasts".
Leukemia is a broad term covering a spectrum of
diseases. In turn, it is part of the even broader group
of diseases affecting the blood, bone marrow, and
lymphoid system, which are all known as tumors of
the hematopoietic and lymphoid tissues.
Leukemia is a treatable disease. Most treatments
involve chemotherapy, medical radiation therapy, or
hormone treatments.

Classification
There are several types of leukemia. The different types
of leukemia are grouped in two ways. One way is by how
quickly the disease develops and gets worse. The other
way is by the type of blood cell that is affected.
By how quickly the disease develops
• Chronic
• Acute
By the type of blood cell that is affected
• Lymphoid cells
• Myeloid cells

Types
I. Acute lymphoblastic leukemia (ALL)
II. Acute myeloid leukemia (AML)
III.Chronic lymphoblastic leukemia(CLL)
IV.Chronic myeloid leukemia (CML)
Other types
• Hairy cell leukemia (HCL)-
• T-cell prolymphotic leukemia (T-PLL)-
• Larger granular lymphocytic leukemia – T-cell or NK cell
• Adult T-cell leukemia – C/A Human T-lymphotropic virus
(HTLV)

Pre –leukemia
Transient myeloproliferative disease, also termed
transient leukemia, involves the abnormal proliferation
of clone of non-cancerous megakaryoblasts.
The disease is restricted to individuals with down
syndrome .
Resolves within 3 months or ,in 10 % of cases ,progresses
to acute megakaryoblastic leukemia .

Differential diagnosis
Leucocytosis
• Normally responding bone marrow
- infection
- inflammation : tissue necrosis , infraction ,
burns , arthritis
- Stress : overexertion , seizure, anxiety,
anaesthesia,
- Drugs : corticosteroids, lithium, beta agonists
- Trauma : splenectomy
- Hemolytic anaemia

• Abnormal bone marrow
- AML
-ALL
-CML
-CLL
- Myeloproliferative disorders

Leukemia V/S Lymphoma
• Malignant cells diffusely
invade the bone marrow
and get spilled into the
peripheral circulation
• Peripheral blood film can
be diagnostic
• Bone marrow is almost
always involved
• Malignant cells form a
soft tissue mass in some
tissues or organs
• Do not spill into
peripheral blood
• Peripheral blood film is
often not diagnostic
• Bone marrow is not
always involved
• Biopsy of the mass is
often needed for
diagnosis

Acute V/S Chronic leukemia
• Leukemia may be acute or chronic
• Acute leukemia are more aggressive and the
patient may die in few months
• Chronic leukemia have more indolent course
of many years

Causes of leukemia
The aetiology of Leukaemia is not known in most patients. However,
a number of factors have been implicated.
1. Genetic factor:
There is high concordance rate among identical twins if acute leukaemia
develops in the first year of life. Families with excessive incidence of
leukaemia have been identified. Acute leukaemia occur with increased
frequency with a variety of congenital disorder such as Down‟s, Bloom‟s,
Klinefelter‟s and WiskottAldrich‟s syndrome, Fanconi„s anaemia and ataxia
telangiectsia.
2. Environmental factors:
Certain environmental factors are known to play a role in the aetiology of
leukaemia. These include the following;
a. Ionising radiation-e.g.-in individuals exposed to occupational radiation
exposure, patients receiving radiation therapy, and Japanese survivors of
the atomic bomb explosions. Radiation exposure is related to the
development of CML, AML and all but not to CLL or HCL.
b. Chemical carcinogens-e.g. Benzene and other aromatic hydrocarbons
are associated with the development of AML.

3. Infection- Induction of Leukaemia‟s in experimental animals by RNA viruses
(retro viruses) has been studied for quite some time but more recently viral
aetiology of adult T-cells Leukaemia –Lymphoma (ATLL) by a human retro virus
called human T cells leukaemia –lymphoma virus I (HTLV-I) and (HTLV-II) for T
cells variant of hairy cells leukaemia has been established
4. Cigarette, cigar, and pipe smoking have been associated with cancers of the
lung, mouth, bladder, colon, kidney, throat, nasal cavity, voice box,
oesophagus, lip, stomach, cervix, liver, and pancreas, and with leukemia

Acute leukemia
• Increased proliferation of immature cells
(blast cells)
• Only proliferation but no maturation or
differentiation
• Functionless blast cells accumulate in bone
marrow and finally spills into the peripheral
circulation
• No space for normal cells in bone marrow
• Decreased normal functional cells

Acute lymphocytic leukemia
ALL is the most common type of leukemia in young
children. It also affects adults, especially those 65 and
older.
Subtypes include precursor B acute
lymphoblastic leukemia, precursor T acute
lymphoblastic leukemia, Burkitt's leukemia,
and acute biphenotypic leukemia.
While most cases of ALL occur in children, 80% of
deaths from ALL occur in adults

Treatment of ALL
Management of ALL is directed towards control of bone marrow and systemic
(whole-body) disease. Additionally, treatment must prevent leukemic cells from
spreading to other sites, particularly the central nervous system (CNS) e.g.
monthly lumbar punctures. In general, ALL treatment is divided into several
phases:
Induction chemotherapy to bring about bone marrow remission. For adults,
standard induction plans include prednisone, vincristine, and
an anthracycline drug; other drug plans may include L-
asparaginase or cyclophosphamide. For children with low-risk ALL, standard
therapy usually consists of three drugs (prednisone, L-asparaginase, and
vincristine) for the first month of treatment.
Consolidation therapy or intensification therapy to eliminate any remaining
leukemia cells. There are many different approaches to consolidation, but it is
typically a high-dose, multi-drug treatment that is undertaken for a few months.
People with low- to average-risk ALL receive therapy with antimetabolite drugs
such as methotrexateand 6-mercaptopurine (6-MP). People who are high-risk
receive higher drug doses of these drugs, plus additional drugs.
]

CNS prophylaxis (preventive therapy) to stop the cancer from
spreading to the brain and nervous system in high-risk people.
Standard prophylaxis may include radiation of the head and/or
drugs delivered directly into the spine.
Maintenance treatments with chemotherapeutic drugs to prevent
disease recurrence once remission has been achieved.
Maintenance therapy usually involves lower drug doses, and may
continue for up to three years.
Alternatively, allogeneic bone marrow transplantation may be
appropriate for high-risk or relapsed people.

Acute myeloid leukemia
(AML) occurs far more commonly in adults than in children, and
more commonly in men than women. It is treated with
chemotherapy. The five-year survival rate is 20%.
One subtype is APL (Acute Promyelocytic Leukemia), which has a
survival rate greater than 90%. Subtypes of AML include acute
promyelocytic leukemia, acute myeloblastic leukemia, and acute
megakaryoblastic leukemia.

Treatment of AML
Many different anti-cancer drugs are effective for the treatment of
AML. Treatments vary somewhat according to the age of the person
and according to the specific subtype of AML. Overall, the strategy is
to control bone marrow and systemic (whole-body) disease, while
offering specific treatment for the central nervous system (CNS), if
involved.
In general, most oncologists rely on combinations of drugs for the
initial, induction phase of chemotherapy. Such combination
chemotherapy usually offers the benefits of early remission and a
lower risk of disease resistance.
Consolidation and maintenance treatments are intended to prevent
disease recurrence. Consolidation treatment often entails a repetition
of induction chemotherapy or the intensification chemotherapy with
additional drugs. By contrast, maintenance treatment involves drug
doses that are lower than those administered during the induction
phase

Chronic leukemia
• Malignant cells are able to differentiate and
are functional

Chronic Myeloid Leukemia
• Clonal Myeloproliferative disorder
• Incidence is 1.5 per 100,000 people per year
• Constitute about 20% of all leukemia
• Male > Female
• Increases slowly with age until the middle
forties, when it starts to rise rapidly
• The median age of diagnosis is 45 to 55 years
• No etiologic agent is incriminated in CML

• CML is a/w Philadelphia
chromosome
• The Ph chromosome is an
abnormal chromosome
22, resulting from a
reciprocal translocation
between part of the long
arm of chromosome 22
and chromosome 9.
• The resulting karyotype is
described as
t(9;22)(q34;q11)

• This translocation
results in fusion of
Break point cluster
region (BCR) gene of
Chr 22 with Abelson
1(Abl) gene of Chr 9
resulting in Ongogenic
BCR-Abl fusion gene
located in Ph
chromosome

• The new BCR-Abl fusion gene is capable of
being expressed as a messenger RNA &
encodes the Bcr-abl fusion protein.
• The translated p210 protein has tyrosine
kinase activity and enhanced phosphorylating
activity compared with the normal protein
resulting in altered cell growth, stromal
attachment and apoptosis ultimately leading
to CML

Clinical Presentations
• CML can present as one of the three phases
– Chronic Phase
– Accelerated Phase
– Blast Crisis

• Asymptomatic to severely symptomatic
• Symptoms due to splenic enlargement
– Early satiety and left upper quadrant pain or mass
• Symptoms due to hypermetabolic state
– fatigue, malaise, weight loss, night sweats
• Symptoms due to leukostatic manifestations due to
severe leucocytosis
– CVA, MI, venous thrombosis, priapism, visual disturbances,
pulmonary insufficiency
• Less common are features related to granulocyte or
platelet dysfunction
– infections, thrombosis, or bleeding.

• Physical findings
– Also depends upon the phase of CML
– Mild anemia to severe anemia
– Splenomegaly
– Hepatomegaly
– Lymphadenopathy unsual but can be present at
late stages (blast crisis)
– Bleeding disorders and Infections are rare unless
in blast crisis

Chronic Phase
• Majority of CML are diagnosed in chronic phase
• Defined by
– Elevated WBC >50,000 (10,000-5,00,000) with left
shift extending to blasts
– Blasts <10% in peripheral blood or bone marrow
– Thrombocytosis and increased Basophils, Eosinophils
– Mild normocytic normocromic anemia
– Low leucocyte alkaline phosphatase score
• Median duration is 4-5 years

Accelerated Phase
• Second and intermediate phase
• Defined by
– 10-20% blast cells blood or marrow
– basophils ≥20%, platelet count <100,000
– Progressive anemia
– General worsening of the symptoms
• Median duration is 3-18months

Blast Crisis
• Final phase of the disease
• Transformation into Acute leukemia with
blasts ≥ 20% (Myeloid 70% and lymphoid 30%)
• Increased symptomatology
– Fatigue due to severe anemia
– Bleeding, infections
– Lymphadenopathy
– CNS involvement
• Rapidly fatal

• Diagnosis of CML is not difficult
– Leucocytosis with left shifting extending to blasts
– Splenomegaly
– Presence of Philadelphia chromosome (90-95%) or
BCR-Abl mRNA in bone marrow sample or blood

Treatment of CML
• Treatment of chronic phase
– Tyrosine kinase inhibitors
– Allogenic stem cell transplantation
– Interferon alpha based treatment
– Chemotherapy to reduce WBC counts with
hydroxyurea or busulphan

• Tyrosine kinase inhibitors
– Imatinib ( 1st gen), Dasatinib, Nilotinib (newer gen)
– First-line therapy in chronic-phase CML
– Inhibit BCR-ABL tyrosine kinase activity and reduce the
uncontrolled proliferation of WBC
– Complete cytogenetic response is seen in 76% at 18
months of therapy
– Therapy is continued for life in those with complete
cytogenetic response
– Patients are monitored by repeated bone marrow
examination at 6, 12 and 18 months for complete
cytogenetic response then 3-monthly real-time
quantitative polymerase chain reaction (PCR) for BCR ABL
mRNA transcripts in blood.

• Tyrosine kinase inhibitors
– Those who don’t obtain complete cytogenetic
response at 18 months of treatment are labeled as
treatment failure with imatinib
– These pts are treated with either newer
generation TKIs (desatinib, nilotinib) or allogenic
stem cell transplantation

• Allogenic stem cell transplantation
– Reserved for treatment failure patients with
imatinib
• Interferon alpha with cytarabine, hydroxyurea
or busulphan are being obsolete
• `3

Treatment of CML
• Treatment of accelerated phase
– Imatinib is indicated if the patient has not already
received it but the response is poor
– Hydroxyurea can be used as palliative therapy

Treatment of CML
• Treatment of blast crisis
– Type of blast should be determined and treated as
acute leukemia
– Lymphoblastic transformation is better treated
than myeloblastic
– Supportive management should be considered in
very old pts with myeloid transformation due to
very poor response to treatment

CLL
• Most common type of leukemia
• Male to female ratio is 2 : 1
• Median age at presentation is 65–70 years
• It results from the clonal expansion of small
lymphocytes and is almost invariably (95%) B cell in
origin
• B lymphocytes fail to transform to plasma cells or
produce antibodies
• An ever-increasing mass of immuno-incompetent cells
accumulates resulting in decrease immunity and bone
marrow failure

Clinical features of CLL
• The onset is usually insidious.
• In most cases the diagnosis is made incidentally
on a routine CBC.
• In the late stages the patient may present with
features of
– Bone marrow failure,
– Anemia due to autoimmune hemolysis,
– Increased susceptibility to infection,
– Painless lymphadenopathy and
– Systemic symptoms like night sweats and weight loss.

Investigations
• CBC
– WBC is increased with lymphocytosis ( > 5 X 109/L is
criteria for diagnosis)
– RBC may be normal or decreased
– Plts may be normal or decreased
• Peripheral blood smear
– Small or medium sized mature and normal appearing
lymphocytes.
– Smudge cells may be seen
– No immature blasts are evident.

Investigations
• Immunophenotyping
– Monoclonal B cells expressing the B cell antigens
CD19 and CD23, with either kappa or lambda
immunoglobulin light chains
• Serum immunoglobulin
– levels should be estimated to establish the degree
of immunosuppression

Investigations
• Bone marrow examination
– Not essential for the diagnosis of CLL
– For prognosis (patients with diffuse marrow
involvement have a poor prognosis)
– Monitoring treatment
• Other
– Retics
– Direct Coomb’s test

Treatment
• Treatment is only required if
– there is evidence of bone marrow failure
– massive or progressive lymphadenopathy or
splenomegaly
– systemic symptoms such as weight loss or night
sweats
– rapidly increasing lymphocyte count
– autoimmune haemolytic anaemia
– thrombocytopenia

Treatment
• Stage A CLL
– No treatment is needed apart from the proper
counselling about the disease

Treatment
• Stage B and C CLL
– Oral chemotherapy with chlorambucil
– Purine analogue fludarabine in combination with
cyclophosphamide
– Anti-CD20 monoclonal antibody rituximab
– Corticosteroids for autoimmune cytopenias

Treatment
• Supportive treatment
– Transfusions of blood for symptomatic anaemia or
thrombocytopenia
– prompt treatment of infections or
immunoglobulin replacement.
– Radiotherapy for lymphadenopathy which is
causing discomfort or local obstruction
– Splenectomy

Prognosis
• The success of treatment depends on the type of leukemia and the age of
the person. Outcomes have improved in the developed world.
• The average five-year survival rate is 61% in the United States. In children
under 15, the five-year survival rate is greater (60 to 85%), depending on
the type of leukemia. In children with acute leukemia who are cancer-free
after five years, the cancer is unlikely to return.
• Outcomes depend on whether it is acute or chronic, the specific abnormal
white blood cell type, the presence and severity
of anemia or thrombocytopenia, the degree of tissue abnormality, the
presence of metastasis and lymph node and bone marrow infiltration, the
availability of therapies and the skills of the health care team.
• Treatment outcomes may be better when people are treated at larger
centers with greater experience

Complications
• Tumor lysis syndrome
• Neutropenic fever, sepsis, overall increased risk of infection
• Neutropenic enterocolitis (typhlitis)
• Hyperviscosity syndrome (HVS)
• Treatment related complications
- Chemotherapy induced nausea and vomiting (CINV)
- Cytokine release syndrome (CRS)
- Tunnel infection

Raktarbud
According to vagbhat, Vitiated Dosha will constricted and compress the blood
within the Venous (siras). This will be mature it before time hence obstruction of
bleeded blood produce lump of mamsa covered with muscular sprouts and grow
very fast along with bleedings. This vitiated Shonit (blood) along with circulating
blood within vessels produced Blood cancer. This make the patients suffer from
pandu (Anaemia) and complication of blood
Cancer originates due to a metabolic crisis, i.e. aggravation of vata forces and
suppression of kapha forces, both interacting with one another resulting in
proliferation. However, the abnormal cancerous growth at a specific organ
(Ekadesavriddhi) is managed by compensation from other parts of the body
(Anyasthaniyakshaya), e.g. body weight loss (cachexia) .
Sushruta has proposed six stages in the pathogenesis of all diseases but his
concept suits more to the pathology of the tumour than pathogenesis itself.

Stages of tumour according to Ayurveda
1. Sanchaya: early stages of localized neoplastic changes.
2. Prakopa: transformation of primary growths into metastatic tumours.
3. Prasara: metastasis.
4. Sthana samsraya: complete metastasis and secondary growth.
5. Vyakti: clinical signs and symptoms are expressed.
6. Bheda: the stage where differentiation of growth occurs on the basis of
histopathology

Treatment modalities in Raktarbud
During the 7th century BC, Atreya and Dhanwantari used ayuveda medicines for
treating the early stages of cancer and surgery in advanced cases.
In the 8th century AD, Vagbhata, a Buddhist physician composed two texts:
Astanga Hrdaya and Astanga sangraha where new methods for cancer treatment
were introduced.
Other Ayurvedic texts of internal medicine, viz., Chakradatta composed by
Chakrapani (10th century AD), the Sarangadhara Samhita by Sarangadhara (14th
century AD), the Bhavaprakasha Samhita by Bhavamisra (15th century AD), the
Satmya Darpan Samhita by Viswanath (16th century AD), the Vaisajya Ratnabali
by Binoda Lala Sen Gupta (18th Century AD), the Rasatarangini by Sadananda
Sharma (19th century AD), etc. explain numerous remedies to treat internal and
external neoplasms.

Treatment modalities
Though there is no basic line of treatment of Leukaemia has found in Ayurveda, as
it is Asadhya (incurable), but principle of treatment is as follows :
• Sodhana chikitsha
• Saman chikitsha
• Rasayan chikitsha
• Dhatwagni chikitsha
• Vyadhipratyanika chikitsa (specific anti-cancerous drugs)
• Lakshanika chikitsa (symptomatic treatment)

Herbs used in leukemia
 Sandpushpa juice (10-20ml) and paste (10gm) of whole plant, leaf
and root will be useful to cured Leukaemia.
 Bhallatak will be cutted and boil in 200 ml milk after then it will be
keeping for cool automatically and then ingested orally after
application of Dharat in to mouth.
 Vanpalandu tuber churna(120-200mg), syrup(30-60 ml) and
tincture (5-30) drop will be useful in curing Leukaemia.
 Vantrapush root churn (250-500mg) and root abstract (15-60mg)
will be useful in curing Leukaemia.
 Gugulunirayas(2-4gm) will be useful to cure Leukaemia.
1. A.charyap. Sharma, hindi commentary, Drayva Guna Vigyan. Vol (II), Chaukhamba Bharti Academy Varanasi, Reprint edition-2009; 832.
2. Acharyap. Sharma, hindi commentary, Drayva Guna Vigyan. Vol (II), Chaukhamba Bharti Academy Varanasi, Reprint edition- 2009;
168-169.
3. Acharyap. Sharma, hindi commentary, Drayva Guna Vigyan. Vol (II), Reprint edition Chaukhamba Bharti Academy Varanasi, Reprint
edition- 2009; 207.
4. Acharyap. Sharma, hindi commentary, Drayva Guna Vigyan. Vol (II), Chaukhamba Bharti Academy Varanasi, Reprint edition- 2009; 834.
5. . Ambikadatt Shastri, hindi commentary, Susuhrut Samhita. Chikitsha Sthan 5/ 40-45, Chaukhambha Publication Varanasi, Reprint
edition- 2011; 45.

Polyherbal and herbomineral compound used in Raktarbud
• Rodhra ras
• Vradha dharu
• Vradhadaru yoga
• Nityanada ras
• Kanchanar gugulu
• Hargauri ras
There are also clinical researches of certain Ayurvedic herbs and a mineral on
Leukaemia has published recently:
1. Navjeevan Ras
2.Kamdudha Ras
3.Keharubapisti having content Trinakantamanichurn, Gulab ark (for mardan)
4. Semicarpusana cardium has resulted in significant clearance of the leukemic cells from the bone marrow
and internal organs in Leukaemia animals with compare standreddrug imatinib mesylate. [4]
5. Semi synthetic anti cancerous drug of Podophyllum hexandrrum and lead compound namely etoposide,
teniposide, etopophes, which are used for the treatment of cancer including Leukaemia.[5,6]
6. Gugulipid mediated suppression of cancer cell proliferation reported significant in Leukaemia cell.[7,8]
1. http://www.jaim.in. [IP: 117.239.29.130]
2. http://www.jaim.in. [IP: 117.239.29.130]
3. http://www.jaim.in., [IP: 117.239.29.130]

4. P.K. Raveedran Nair et.al, Isolation and characterization of an anticancer catechol compound from
Semecarpusana cardium. Journal of Ethnopharmacology journal,2009;1-7
5. Imbert Tf, Discovery of Podophyllotoxin, Biochimie, 80 (1998); 207-222.
6. Stahelin HF & Wartburg VA, The chemical and biological route from Podophyllotoxinglucoside to etoposide:
Ninth cain memorial award lecture, cancer Res, 51 (1991);5-15.
7. Samudio I, Konopleva M, Safe S, McQueen T, Andreeff M () Guggulsterone induce apoptosis and
differentiation in acute myeloid leukemia: identification of isomer-specific antileukemic activities of the
pregnadienedione structure. Mol Cancer Ther2005, Vol.4; 1982-1992.
8. Shishodia S, Aggarwal BB Guggulsterone inhibits NF-kappaB and Ikappa Balpha kinase activation, suppresses
expression of anti-apoptotic gene products, and enhances apoptosis. J BiolChem2004, 279 (4); 7148-4715

2/10/2020
Dr. Arjun Upadhyaya/ An Approach to the
patient of cough
62

Leukemia , causes, clinical features, raktarbud

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