Acute leukemia

Acute Leukemia

Dr Anil Kumar GAsst Prof Dept of Medicine MVJ MEDICAL COLLEGE

- Is a group of malignant (neoplastic) disorders , characterized by the clonal expansion and accumulation of one or more blood cell line(s) , with eventual involvement of all hematopoietic organs and other organs.

Leukemia

• Prolonged life (immortal) resistant to apoptosis • Growth factor independent growth• Insensitivity to growth-inhibitory signals • Ability to invade and metastasize• Blockage of intracellular differentiation

Tow or more Mutations within the genome of HSC or multipotential progenitors/precursors

Activation of specific proto-oncogene De-activation of tumor suppressor genes

Leukemia

Clone of cells with characteristics of a malignant cell

Leukemia• CBC and blood film examination : - Normocytic normochromic anemia (mild to severe) - Platelets count: reduced to normal - WBC’s count: decreased mature leukocytes - The appearance of abnormally circulating blood cells (malignant

cells)

• BM aspirate and/or biopsy - B.M. hyperactivation and hyperplasia - Blasts : represents greater than 20 - 30% depends on the type of

Classification and type of Leukemia .

Hematopoieticstem cell

Neutrophils

Eosinophils

Basophils

Monocytes

Platelets

Red cells

Myeloidprogenitor

Lymphoidprogenitor

B-lymphocytes

T-lymphocytes

Plasmacells

naïve

ALL

AML

Leukemia• Cytochemistry:

Blasts Identified Cellular Element Stained Cytochemical Reaction

Myeloblasts strong positive; monoblasts faint positiveLymphoblast Negative

Neutrophil primary granules Myeloperoxidase (MPO)

Myeloblasts strong positive; monoblasts faint positiveLymphoblast Negative

Phospholipids Sudan Black B (SBB)

Promyelocyte stage positive Cellular enzyme Specific esterase

Monoblasts strong positiveOthers Negative Cellular enzyme Nonspecific esterase

(NSE)

lymphoblast's and pronormoblasts Negative to Positive .Myeloblasts usually negative.Metamyelocyte & PMN Strong +ve

Glycogen and related substances Periodic acid-Schiff

Acute Myeloid Leukemia- Malignant neoplastic proliferation and accumulation of immature and nonfunctional myeloid line of blood cells in the bone marrow .

- Also known as acute myelogenous leukemia or acute nonlymphocytic leukemia (ANLL)

- Most common Acute Leukemia affecting adults.

- As an Acute Leukemia, AML progresses rapidly and is typically fatal within weeks or months if left untreated .

Myeloid maturation

myeloblast promyelocyte myelocyte metamyelocyte band neutrophil

MATURATION

Adapted and modified from U Va website

Etiology

• Heredity– Down syndrome– Fanconi anemia– Bloom syndrome– ataxia-telangiectasia– Congenital neutropenia (Kostmann syndrome)

• Radiation– High-dose radiation (atomic bombs survivors)

• chemical and occupational exposures– Benzene– petroleum products– Paint– embalming fluids– ethylene oxide– Herbicides– smoking

•

• Drugs– Alkylating agent– Topoisomerase II inhibitor– Chloramphenicol– Phenylbutazone– Chloroquine– methoxypsoralen

Acute Myeloid LeukemiaPathophysiology

- In AML, a single myeloblast genetic changes which "freeze" the cell in its immature state and prevent differentiation.

- When such a "differentiation arrest" is combined with other mutations which disrupt genes controlling proliferation, the result is an uncontrolled growth of an immature clone of cells, leading to the clinical entity of AML .

-

Acute Myeloid Leukemia

- Thegrowth of leukemic clone cells, which tends to displace or interfere with the development of normal blood cells in the bone marrow .

- This leads to neutropenia, anemia, and thrombocytopenia. The symptoms of AML are often due to the low numbers of these normal blood elements.

Pathophysiology

Clinical Presentation

• Nonspecific symptoms • Fatigue• Anorexia • Weight loss • Fever • Bleeding, easy bruising• Bone pain, lymphadenopathy, nonspecific

cough, headache, or diaphoresis

Physical Findings

• Fever• Splenomegaly• Hepatomegaly• Lymphadenopathy• Sternal tenderness• Evidence of infection and hemorrhage

Gum hypertrophy

Leukemia cutis

Acute Myeloid LeukemiaLaboratory findings:

1- Peripheral Blood:

- The leukocyte count ranges from < 1X109 to >100X109 .

- Presence of blast on the blood smear.

- Neoplastic blast have few granules in the RNA rich cytoplasm.

Acute Myeloid Leukemia

- Erythrocyte decreased, Hb less than 10g/dl

- Slightly Macrocytic because of the inability to compete the neoplastic cell for folate and vitB12 or early release of Retic cells.

2- Bone marrow:

- Typically, hypocellular with increased fat content .

Laboratory findings:

- Special Stains and Percentage of Blasts aid in the Diagnosis .

Acute Myeloid LeukemiaClassification :

1- FAB Group Classification , Based on : - The Morphological criteria of PB and BM . - The Immunophenotyping of Leukemic cells . - The cytochemistry of Leukemic Cells . - For Diagnosis, Blast count in PB or BM is >30% .

2- WHO Classification : - Molecular/Genetic Features of Malignancies . - FAB Class. Incorporated into WHO Class. - For Diagnosis, Blast count in PB or BM is >20% .

FAB Classification: AML

M0: Acute myeloblastic leukemia with minimal differentiation

• Most common in adult patients• 5% of AML• Leukocytosis in 40% and > 50% with leukocytopenia• Diagnosis

Less than 3% of the blasts are positive for peroxidase or the Sudan black B reaction

Blasts are positive for the myeloid-associated markers CD13, CD14, CD15 or CD33, CD34 and negative for B or T lineage marker (CD3, CD10, CD19 and CD5)

Almost no mature myeloid cells are seen

• Morphology: The blasts are small to medium-

sized round cells with an eccentric nucleus

The nucleus has a flattened shape and sometimes lobulated or cleaved and contain fine chromatin with several distinct nucleoli

The cytoplasm is lightly basophilic without granules

Auer rods are not found

M1: Acute myeloblastic leukemia without maturation

• Highest incidence seen in adult and in infants less than a year old

• 10% AML cases

• Predominant cell in the peripheral blood is usually a poorly differentiated myeloblast with fine reticular chromatin and prominent nucleoli

• Auer rods are found in 50% of blasts

M2: Acute myeloblastic leukemia with maturation

• Presenting symptoms for M2 AML are similar to those of the M1 type

• 30% to 45% of cases of AML

• Blasts show azurophilic granules and Auer rods

• Evidence of maturation is present, with >10% of the marrow cells being promyelocytes, myelocytes,and mature neutrophils and <20% being monocytes

M3: Acute promyelocytic leukemia (APML)

• Younger adults• Median survival is about 18 months • Fusion of a truncated retinoic acid receptor alpha (RAR-alpha)

gene on chromosome 17 to a transcription unit called PML (for promyelocytic leukemia) on chromosome 15

• The blasts are large with abundant cytoplasm, completely occupied by closely packed large granules, staining bright pink, red or purple

• The nucleus is often bilobed or markedly indented with a prominent nucleolus

• Cells containing bundles of Auer rods "faggots" randomly distributed in the cytoplasm are characteristic, but are not present in all cases

• Cytochemistry: MPO and Sudan black B are strong

positive PAS is negative and NSE is weak

positive• IHC: positive for CD13, CD15, CD1

and CD33 myeloid antigens• Cytogenetic studies: 50% cases

show translocation t(15; 17)

M4: Acute myelomonocytic leukemia (AMML)

• 15% to 25%• Usually in the elderly • Sometimes in patients who have had preceding chronic

myelomonocytic leukemia• Both neutrophilic and monocytic cells and their precursors are

present, each constituting at least 20% of the marrow cells• Monocytosis (≥5×10⁹/l)• Serum and urine levels of muramidase (lysozyme) are usually

elevated because of the monocytic proliferation• Positive reactions for Sudan black B, MPO and both specific and

non-specific esterase• Positivity for CD13, CD33, CD11b and CD14• inv(16) (p13; q22) and del (16)(q22)

• Morphology: Monoblasts: large cells with

round nuclei, one or more prominent nucleoli and abundant basophilic cytoplasm, sometimes with fine azurophilic granules, vacuoles, and pseudopod formation

Promonocytes: less basophilic and more granulated cytoplasm, occasional vacuoles and azurophilic granules. The nuclei are irregular and indented

M5: Acute monoblastic leukemia (AMoL)

• M5a: (Acute monoblastic Leukemia) Granulocyte <20% and monocytes >80%; >80% monoblasts Children

• M5b: (Acute monocytic leukemia) Granulocyte <20% and monocytes >80%; <80%

monoblasts; all developmental stages of monocytes seen Adults

• Serum and urinary muramidase levels are often extremely high• Cytochemistry: NSE positive and PAS is negative• IHC: positivity with CD11b and CD14

M5a

M5b

M6: Acute erythroid leukemias• Erythroleukemia: 5% of AML cases

Both erythroid and myeloid cells At least 50% of the nucleated cells in the bone marrow are erythroid

and at least 20% of the non-erythroid cells are myeloblasts Erythroid cells are dysplastic, megaloblastoid nuclei, the cytoplasm

often possessing poorly delineated, coalescing vacuoles Myeloblasts are similar to those in AML with and without maturation

• Pure erythroid leukemia: very rare >80% of the marrow cells are erythroid Erythroblasts have deeply basophilic, often agranular, cytoplasm may

contain poorly delineated vacuoles. The nuclei have fine chromatin and one or more nucleoli

• Howell-Jolly bodies, ring sideroblast, megaloblastoid and dyserythropoietic changes

• Coarse positivity of PAS

• IHC: glycophorin A

M7: Acute megakaryoblastic leukemia (AMkL)

• Rare • 5% of AML• At least 50% of the blasts are from the megakaryocytic

lineage.• The megakaryoblasts are often pleomorphic and have a

basophilic, agranular cytoplasm that may demonstrate pseudopod and bleb formation, indicating budding platelets

• Dysplastic platelets may be visible in the blood• Circulating micromegakaryocytes and megakaryocyte

fragments

Acute Myeloid LeukemiaWHO Classification of AML

1- AML with recurrent Cytogenetic abnormalities - usually translocation, in most cases the chromosomal rearrangement create a fusion gene, encoding a novel fusion protein.

I. AML with t(8;21)(q22;q22);(ETO/AML1):- Present morphological as AML with maturation.

- The fusion protein blocks the normal function of CBF, and induce abnormal gene activation and gene repression, this will lead to increase proliferation with blocked differentiation.


II. AML with abnormal B.M eosinphils inv (16)(p13;q22) or t(16;16)(p13;q22)(CBFB/MYH11):

- Present morphology as AML with monocytic and granulocytic maturation and presence of abnormal eosinphils in B.M.

- Combination of acute myelomonocytic leukemia (AMML) with abnormal eosinphilis is morphologically AMML Eo.

- Abnormal immature ( basophilic ) granules in the eosinphils, promyelocyte, and myelocyte stages.

-


III . AML with t(15;17)(q22;q12)(PML/RARa) and variants:

- it is acute promyelocytic leukemia(APL), an AML in which abnormal promyelocyte predominate.

- The presenting signs are DIC and bleeding .

- The typical t(15;17) gene rearrangement result in the fusion of (PML/RARa) gene and reciprocal ( RARa/PML) gene.


- PML is growth suppressor nuclear protein normally found in complex macromolecular structure.

- The PML/RARa fusion protein leads to formation of co-repressor complex molecules that enhance the oncogenesis of APL .


IV. AML with 11q23(MLL) abnormalities:

- These leukemia associated with monocytic features ( monoblasts and promonocyte).

- The MLL protein is a DNA binding protein that interact with other nuclear protein and permits the association of transcription factor which regulate transcription.


2- AML with multilinage Dysplasia ( with or without prior MDS)

-It is an Acute leukemia ( >20% blast) with dysplasia in more than 50% of the cells in two or more myeloid cell lines.

-It is occurs with or following MDS / MPD.

-examples of dysplasia include: hypogranular PMNs, psuedo-pelger-Huet anomaly, megaloblastic erythrocyte, ringed sideroblast.

- - poor prognosis.


3- AML and Myelodysplastic syndrome, therapy releated:

-These disorder arise as a result of cytotoxic chemotherapy and / or radiation therapy.

Two major subtypes:

I. Alkylating agent/ radiation treatment: initially it start with MDS and eventually evolving AML.

II. Topoisomerase II inhibitor treatment.


4- Acute Myeloid leukemias not otherwise categorized:- Include all AML cases that not fulfill criteria for any of other described.- The subtypes of this AML are classified according to differentiated on morphology and cytochemical features.

I. AML Minimally DifferentiatedII. AML without MaturationIII. AML with MaturationIV. Acute Myelomonocytic leukemia (AMML)V. Acute monoblastic leukemia and Acute monocytic leukemiaVI. Acute Erythroid leukemia (AEL)VII. Acute Megakaryoblastic leukemia


VIII. Acute Basophilic leukemia

- The most characteristic feature by cytochemistry is metachromatic positivity with toluindine blue.

IX. Acute panmyelosis with mylofibrosis

- it is occur with or following chemo and radio therapy.

X. Myeloid Sarcoma

- a tumor of myeloblast or immature myeloid cells occures in the extramedullary site or in the bone.

AMLCytogenetics & Prognosis

Favorablet(8;21), t(15;17),

inv(16)

Intermediate (Most patients)normal, +8, +21,

+22, del(7q), del(9q),

Adverse-5, -7, del(5q),

abnormal 3q, complex karyotype

(> 3 -5 abnormalities)

Group CR 5 year survival

Favorable 91% 65-75%

Intermediate 86% 40-50%Adverse 63% <15%

AML Treatment:Induction Chemotherapy

Anthracycline (Idarubicin) for 3 days and Cytosine arabinoside (Ara-C) for 7 days (3+7, Younger/fit patients only)

Supportive care red cell and platelet transfusions, prophylactic antibacterial, antifungals and antivirals

AML:Response to Induction

Remission status determined by bone marrow at end of month following induction therapy (e.g. Day 14 & 28)

Complete remission:CR is defined-Blood neutrophil count -1000/L Platelet count 100,000/L.Circulating blasts - absent. The bone marrow <5% blastsAuer rods -absent.Extramedullary leukemia -absent

AML Treatment:Consolidation

Following induction into Complete Remission

3-4 cycles of high dose cytosine arabinoside (HiDAC) administered approximately every 5-6 weeks

ORBone marrow (peripheral blood stem cell)

transplant (Depends on degree of risk)

AML-M3 or APLAcute Promyelocytic Leukemia (APL M3)

Blasts and promyelocytes heavily granulated, Auer rods often abundant

Disseminated intravascular coagulation (DIC) common

Treatment differs from all other AML subtypes

once had the worst prognosis now the best prognosis

AML-M3 or APL

Treated with a derivative of Vitamin A (all trans retinoic acid or ATRA)

Favorable prognosis if diagnosed just prior to starting chemotherapy (>80% cured)

Has chromosomal translocation, t(15;17) involving the retinoic acid receptor-a gene that blocks normal granulocyte differentiation

Dan Longo, Anthony Fauci, Dennis Kasper et al Harrison's Principles of Internal Medicine 18th Ed. 2011

Acute Lymphoid Leukemia

Malignant neoplastic proliferation and accumulation of immature and nonfunctional Lymphoid line of blood cells in the bone marrow

Acute lymphocytic leukemia is the most common type of cancer in children.

Acute Lymphoid LeukemiaSigns and Symptoms- Generalized weakness and fatigue- Anemia- Frequent or unexplained fever and infection- Weight loss and/or loss of appetite- Bone pain, joint pain (caused by the spread of "blast" cells to the surface of the bone or into the joint from the marrow cavity)- Breathlessness- Enlarged lymph nodes, liver and/or spleen-Pitting edema (swelling) in the lower limbs and/or abdomen- Petechiae, which are tiny red spots or lines in the skin


- Damage to DNA that leads to uncontrolled cellular growth and spread throughout the body.

Pathophysiology

- This damage may be caused by environmental factors such as chemicals, drugs or radiation.

- Some evidence suggests that secondary leukemia can develop in individuals treated for other cancers with radiation and chemotherapy as a result of that treatment

- Damage can be caused through the formation of fusion genes, as well as the dysregulation.

Initial Laboratory finding characteristic of ALL

Peripheral Blood: 1- Leukocyte count usually increased but may be normal or decreased. 2 -Neutropenia

3 -Lymphoblast 4 -Thrombocytopenia

Bone Marrow: 1- Hypercellular 2> -20% lymphoblast ( WHO)

Other laboratory finding: 1- associated with increased cellular metabolism and turn over such: Hyperuricemia.

incrased serum LD. hypercalacemia due to increased BM resorption.

2 -Renal failure.

3 -increased CSF lymphblast.

Acute Lymphoid Leukemia- Terminal Deoxynucleotidyl transferase (TdT): - - TdT, is the most important enzyme that is helpful in the identifying cellular subtypes.- TdT is a DNA polymerase found in cell nuclei , this enzyme not present in the normal mature lymphocyte but can be found in 65% of the thymic population of lymphocyte.

Acute Lymphoid LeukemiaClassification

- Based on FAB classification, ALL is categorized into three catergories ALL-L1, ALL-L2 and ALL-L3 .

- Immunohistochemistry and immunophenotyping are almost always necessary to distinguish ALL from AML.

- On other hand WHO identify of malignant cell as T, B and on the degree of maturation.


- Blasts in ALL-L1 are with high N/C ratio.- Delicate diffuse chromatin pattern and small prominent nucleoli. - Scant cytoplasm . - Affects primarily children

FAB classificationALL-L1

Acute Lymphoid LeukemiaFAB classification

ALL-L2- The blasts are larger than those of L1, have more plentiful cytoplasm and are more pleomorphic. - Abundant cytoplasm, predominant nucleoli, nuclear clefting .

-Affects adults

Acute Lymphoid LeukemiaFAB classification

ALL-L3 : Burkitt's type- L3 blasts cells are fairly regular in shape with strong basophilic cytoplasm and prominent cytoplasmic vaculation .

Affects adults and children

FAB Classification of ALL

Morphology TdT CD10

ALL-L1 Small lymphocyte scant cytoplasm+ + ; Moderately clumped chromatin;

Inconspicuous nucleoli

ALL-L2 Small and medium size lymphblast+ + ; Mixed chromatin patterns;

Inconspicuous nucleoli

ALL-L3Burkitt- type Large lymphblast; large nucleus with-/+ - nucleoli; cytoplasm vacuolization;

Intense cytoplasm basophilia

Acute Lymphoid LeukemiaWHO classification

- WHO classification considers ALL and lymphblastic lymphoma to be single disease with different clinical presentation.

- Precursor T- and B-cell neoplasm with B.M and peripheral blood involvement are ALL, while precursor T- and B-cell neoplasm presenting solid tumors are lymphoma.


WHO classification defines two subgroups of ALL:

1- Precursor B- and T-cell neoplasm ( leukemia/ lymphoma) which include L1 and L2 . 2- Burkitt type ALL (L3).


1- Precursor B- cell leukemia:

- it is a neoplasm of lymphoblast committed to the B- cell linage, involve B.M, peripheral blood - some cases may present with primary involvement of lymph node and exranodal site ( lymphoma).- Rearrangement of immunoglobulin genes can be detected by molecular testing.- Additional markers of B linage commitment required for dignosis. CD10/CD19/CD20/CD22 , TdT = +ve


1- Precursor B- cell leukemia:

- Cytogenetic abnormalities associated with B-ALL include translocation, hypodiploidy, and hyperdiploidy.

- The most common is t(12;21)(p13;q22)- Produce TEL-AML1 fusion gene.- Hyperdiploid B-ALL have a mutation in the receptor tyrosine Kinase FLT-3 , resulting in constitutive activation of the receptor.- t(1;19) PBX1-E2A , t(4;11) AF4-MLL- Precursor B- cell has good prognosis.


2- Precursor T- cell leukemia:

- It is a neoplasm of lymphoblasts committed to T- cell linage, involving B.M and peripheral blood. - High WBC count, lymphoblast and cytochemistry similar to B-cell, but acid phosphatase shoe intense positivity in T-ALL.

- T- cell linage can be detected by rearrangement of the T cell receptor genes by molecular studies.- There are four TCR genes capable of rearranging, coding for the a ,B, Y and & chain of the TCR.


- Cytogenetic studies show translocation involving alpha and Delta TCR loci (14q11.2), the beta locus (7q35) or gamma locus (7p14-15).

- Transcription factors.

CD2/CD3/CD5/CD7/CD10 = +ve

2- Precursor T- cell leukemia:


3- ALL- Burkitt type :

- Cell Large in size.- Nuclear chromatin : fine and homogeneous- Nuclear shape : Regular, oval to round.- Nucleoli prominent, one or more.- Cytoplasm amount : Moderately Abundant.- Vaculation Often prominent.- This tumor has a high proliferation rate and many mitotic figures may be seen in the B.M smear.


- Burkitt's cell show clonal rearrangement of the immunoglobulin heavy and light chain genes

3- ALL- Burkitt type :

All cases have translocation of the MYC gene (8q14) to the:1. heavy chain region on chromosome 14{t(8;14)} or2. light chain loci on chromosome 2p12{t(2;8)} or3. chromosome 22q11{t(8;22)}.

AML ALL

Common in adult Common in children Age

Anemia, neutropenia, thrompocytopenia,

myeloblast, Promyelocyte .Anemia, neutropenia,

thrompocytopenia, Lymphoblast, Prolymphcytes

Hematologic prsentation

Medium to large myeloblast with distinct nucleoli, fine

nuclear chromatin and abundant basophilic

cytoplasm, Auer rod can be present

Small to medium lymphoblast, fine chromatin with scanty to

abundant cytoplasm, indistinct nucleoli

Prominent cell morphology

PAS negative, Peroxidase and SBB are positive,TdT may

positive or negative

PAS and TdT are Positive, Peroxidase and SBB are

negative Cytochemistry

Acute LeukemiaPrognosis :

1- ALL :- Prognosis Varies from Poor to Good According to : 1- Type of Cytogenetic abnormalities 2- Diploidy , Hyper or Hypo 3- Metastasis

Cytogenetic change Risk categoryt(4;11)(q21;q23) Poor prognosist(8;14)(q24.1;q32) Poor prognosis

Complex karyotype (more than four abnormalities) Poor prognosis

Low hypodiploidy or near triploidy Poor prognosis

High hyperdiploidy (specifically, trisomy 4, 10, 17) Good prognosis

del(9p) Good prognosis

Treatment of ALL:• Induction phase I (4 weeks)

– Prednisone, vincristine, daunorubicin, L-asparaginase– No benefit to adding cyclophosphamide, high-dose

cytarabine, or high-dose anthracycline • Induction phase II (4 weeks)

– Cyclophosphamide, cytarabine, 6-mercaptopurine• Consolidation

– 4-7 cycles of intensive multiagent chemotherapy– Delayed reinduction

Central Nervous System Prophylaxis• Less than 10% of ALL presents with CNS involvement

however, with no CNS prophylaxis CNS relapse can occur in 60% of patients.

• Risk factors for CNS involvement in adults – mature B-cell ALL– high serum lactate dehydrogenase levels > 600 U/L)– presence of a high proliferative index at diagnosis ( >14% of lymphoblasts in the

S and G2/M phase of the cell cycle)

• If symptomatic CNS disease present at diagnosis concurrent cranial irradiation + IT chemotherapy

• For CNS prophylaxis in all other cases : – IT-MTX and systemic high-dose MTX or some regimens

incorporate “triple” therapy ( IT MTX +ARA-C+Corticosteroids)

ALL - Supportive care• Cytopenias : .

– Transfusion support : Platelets and Packed red cell transfusion when necessary ( leukodepleted and irradiated to prevent GVHD)

– G-CSF Support

• Prevention of Tumor Lysis Syndrome ( Risk highest in Burkitt-ALL and T-Cell ALL) – Intravenos hydration 100ml/hr– Allopurinol– Rasburicase– Correction of electrolyte disturbances (Hypocalcemia, Hyperphospahtemia)

• Antibiotic Prophylaxis while on aggressive chemotherapies :– Acyclovir prophylaxis for all HSV seropositive adults– Prophylaxis with antibiotics (quinolones) and/or antifungals during neutropenia.– Trimtheoprim/sulfamethoxazole for PCP prophylaxis– Ganciclovir prophylaxis for CMV seropositive patients

Adult ALL: Maintenance Therapy

• Weekly methotrexate + daily 6-mercaptopurine – Monthly Vincristine/prednisone pulses

• Duration: 2-3 years• Appropriate for all cases except B-cell and Ph+

ALL• Poor outcome if omitted• No randomized trials in adults

ALL -SPECIAL GROUPS• All in older adults• Ph+ all• Mature b-cell / burkitt- all (l3)• T-cell all

ALL in Older Adults

• Low CR and survival rates• Lower rate of T-cell ALL• High rate of Ph-positive ALL ( more than 50%

of ALL in age > 65)• Often excluded from clinical trials• Often receive attenuated chemotherapy

Complications Observed in Older Adults With ALL

• Comorbid conditions• More severe mucositis related to pain medications• Events associated with specific chemotherapies

– Vincristine: neuropathy, constipation– Steroids: hyperglycemia, infections– L-asparaginase: encephalopathy ( more lethargy and

somnolence occur in older adults)• Low marrow reserve

– Adding G-CSF improves CR rate

Philadelphia Chromosome (Ph+) ALL• t(9;22) bcr/abl translocation • Precursor B cell• Incidence continuously increasing with age

• Associated with very poor outcome– No cure with intensive ALL chemotherapy (all ages).

Despite intensive chemotherapy, long term survival < 10%– Cure with SCT possible

• Allo SCT is recommended for all patients with PH+ ALL who achieve a CR.

Imatinib in Ph+ ALL

• Induces high response rate as single agent– Response generally not durable

• In combination with ALL chemotherapy ( preferred choice)for induction– Higher CR rate: 90% to 97% and improved outcome

compared with chemotherapy alone – Concurrent administration of imatinib +

chemotherapy superior to alternating schedule

B-Cell ALL (FAB L3): Burkitt’s Leukemia• Rapid cell proliferation and very high LDH • t(8;14), t(2;8), t(8;22)

– Rearrangement of myc protooncogene (ch 8) with Ig heavy chains (ch 14) or light chains (ch 2 or 22)

• High expression of CD20• Treatment option : Short intensive chemotherapy

– High-dose MTX and cyclophosphamide– Role of anti-CD20 : Addition of rituximab – Intensive CNS prophylaxis

• No maintenance required ( high cure rates after intensive chemotherapy)

• Cure rate: 60%; relapses are rare 6 months after CR

T-CELL ALL• Current therapies for T-cell acute lymphoblastic leukemia

(ALL) produce high responses,

• but approximately one half of patients will relapse within 2 years.

• Nelarabine demonstrates antineoplastic activity in patients with relapsed/refractory T-cell ALL. In a recent study by the Cancer and Leukemia Group B, nelarabine treatment produced complete remission rates of 26% with minimal toxicities in relapsed/refractory ALL patients.

Late Complications of therapy• Late complications of therapy

• Brain tumors (cerebral irradiation)• Secondary AML from topoisomerase inhibitors and alkylating

agents• Cardiomyopathy (anthracyclines)• Osteoporosis (corticosteroids)• Growth disturbances• Thyroid dysfunction (cranial irradiation)• Obesity (uncertain etiology)• Neuropsychiatric disturbances and seizures (IT MTX and cranial

irradiation)• Emotional problems• Discrimination with insurance, job applications and military service

ALL: New Chemotherapies

• Antimetabolites– Nelarabine (relapsed T-ALL)– Clofarabine– Trimetrexate (dihydrofolate reductase inhibitor)

• Liposomal or pegylated agents– Pegylated L-asparaginase– Liposomal daunorubicin– Liposomal vincristine

• Cytarabine liposome injection (IT)

ALL: Novel Management Approaches

• Minimal residual disease evaluation– Define prognostic groups for treatment selection

• Microarray analysis (gene expression profiles)– Prognosis – Identify new targets

Treatment of ALL: Summary and Future Directions

• Preferable to treat adult patients in clinical trials• Trials for young adults and adolescents needed• For patients not in trials, a number of existing

chemotherapy regimens available• Adult patients with Ph-positive ALL: imatinib

– Options in imatinib-resistant disease now available• Allo SCT appropriate in high-risk ALL

– Role of auto SCT not yet defined

Biphenotypic Acute Leukemia• Single population of blasts coexpressing markers of two different lineages

• Rare

• Biphenotypic acute leukemia is defined when scores are >2 for the myeloid lineage and >1 for the lymphoid lineage

• The prognosis of biphenotypic acute leukemia patients is poor• • Higher incidence of CD34 antigen expression, complex

abnormal karyotype, extramedullary infiltration, relapse, and resistance to therapy after relapse

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AllRisk stratification

• After induction of complete remission (CR),

patients must be risk-stratified in order to identify the best post-remission strategy ( Consolidation therapy)

• Standard risk » Decreasing age (continuous variable; < 35 years)» Decreasing WBC (continuous variable)

• < 30,000 for B-cell lineage• < 100,000 for T-cell lineage

» T-cell lineage ( Thymic T-cell better, early T-cell is adverse risk)» CR within 4 weeks

• High Risk: any of the following: » High WBC at diagnosis (ie, >30,000 in B-ALL or >100,000 in T-ALL).» Clonal cytogenetic abnormalities — t(4;11), t(1;19), t(9;22), or bcr-abl

gene positivity. The prognostic value of t(1;19) in adult ALL is less clear than in pediatric ALL

» Time to attain CR after start of induction therapy > four weeks is of lesser importance.

» Older age — >60 years old is high risk, 30 to 59 years old is intermediate risk.

Prognostic Indicators

All - CONSOLIDATION

• Standard risk ALL in CR1– Proceed with consolidation and maintenance chemotherapy rather than either allogeneic or autologous HCT . – This preference places a relatively high value on avoiding the higher short-term mortality and long-term

morbidity associated with HCT and a low value on the potential, but uncertain, ability of the more intensive transplant therapy to eliminate residual disease.

• High Risk ALL – For young patients with high-risk ALL in CR1 who have an HLA-matched donor : allogeneic HCT preferred rather

than consolidation chemotherapy or autologous HCT – For patients with high-risk ALL in CR1 who are not candidates for allogeneic HCT ( older adults, co-morbidities),

consolidation chemotherapy preferred than autologous HCT . – For patients with Philadelphia chromosome positive ALL in CR1, a matched sibling HCT preferred than

consolidation chemotherapy or autologous HCT . In patients without an HLA-identical sibling, unrelated donor marrow transplantation is an effective option.

• For patients who are still in CR after completing consolidation chemotherapy proceed with two to three years of maintenance chemotherapy rather than observation The most commonly used regimen is daily 6-mercaptopurine , weekly methotrexate, and monthly pulses of vincristine and prednisone

(ie, POMP) or dexamethasone for three years.

Stem Cell Transplantation (SCT):CIMBTR Recommendations

• First CR– Allo SCT or MUD in high-risk patients– Role in standard-risk patients unclear but not

recommended– Auto SCT: no benefit over chemotherapy

• Second CR ( the CR after relapse)– Allo SCT

. CIBMTR, Center for International Blood and Marrow Transplant Research

ALL: SCT at First CR

Study Endpoint CHT Auto SCT Allo SCT ImprovedOutcome

CIBMTR vs German studies

LFS 32% -- 34% NS

JALSG 93 OS 40% -- 46% NSLALA 87 OS 35% 48% NSLALA 87 SR OS 45% 51% NSLALA 87 HR OS 20% 44% AlloLALA 94 HR OS 35% 44% 51% AlloGOELAL02 HR OS -- 40% 75% Allo

Several trials comparing chemotherapy vs. autologous stem cell transplant vs. Allo-SCT reveal improved survival with allo-SCT in High Risk patients as shown above.

Allo BMT vs Auto BMT in Patients With Ph- ALL: MRC UKALL XII/ECOG E2993

Rowe JM, et al. ASH 2006. Abstract 2.

Patients with Ph- ALL aged < 55 yrs

in complete remission after induction therapy

(N = 919)

Sibling Allo BMT(n = 389)

High-Dose Methotrexate

(3 doses)

HLA-matched sibling donor available?

Yes

High-Dose Methotrexate

(3 doses)

Auto BMT

Consolidation/Maintenance Chemotherapy:

2.5 years

(n = 530)

No

Allo BMT vs Auto BMT in Patients With Ph- ALL: 5-Year ResultsMRC/UK-ALL

• Improved OS with allo BMT vs auto BMT or postinduction chemotherapy in standard-risk Ph- patients– 5-year OS for allo BMT vs chemotherapy only: 54% vs 44%, respectively (P < .02)– No advantage in high-risk patients ( older patients, WBC > 30,000 [B cell] or >

100,000 [T cell])

Outcome by Risk Group, % Donor(n = 389)

No Donor(n = 530)

P Value

Overall 5-yr survival 53 45 .02 High risk 40 36 .50

Standard risk 63 51 .01

10-yr relapse rate High risk 39 62 < .0001 Standard risk 27 50 < .0001

Rowe JM, et al. ASH 2006. Abstract 2.

ALL – SALVAGE THERAPY

Relapsed/ refractory all Prognostic Factors

Poor Prognostic Factors for CR Poor Prognostic Factors for Survival

Albumin level < 3 g/L* Albumin level < 3 g/L*Duration of first CR < 36 mos* Duration of first CR < 36 mos*Hemoglobin level < 10 g/dL Hemoglobin level < 10 g/dLPlatelet count ≤ 50 x 109/L* Platelet count ≤ 50 x 109/L*Percent bone marrow blasts > 50%

Percent bone marrow blasts > 50%*

Peripheral blood blasts ≥ 1% Percent peripheral blood blasts ≥ 1%White blood cell count > 20 x 109/L

Independent prognostic factors associated with achieving CR during salvage therapy include duration of first CR and platelet count. Several factors are associated with poor survival rates : - short duration of first CR, thrombocytopenia, elevated percent bone marrow blasts, and low albumin level

L-asparaginase in ALL

• Used only in ALL• Derived from bacterial enzyme• Enzyme that depletes serum L-asparagine ( Normal cells can reproduce

their own asparagine by asparagine synthetase but ALL cells can not and therefore, dependent on plasma asparagine depletion of plasma asparagine causes protein synthesis inhibition depletes synthesis of RNA and DNA apoptotic cell death of leukemic cells).

• Activity related to serum L-asparagine depletion• No myelosuppression• No late effects• Unique adverse effects

L-asparaginase: Mechanism of Action*

*Sensitivity of ALL cells to asparaginase due to low asparagine synthetase in leukemic cells.

Blood

L-asparagine

L-asparaginase

NH3 + L-aspartate

Cell

L-asparagine

Asparagine synthetase

Glutamine

L-aspartate L-asparagine+

Glutamate+

L-asparaginase in Adult ALL• No randomized trials in adults• Well tolerated in adults

– Usually given at lower total doses than in children • Importance in childhood disease suggests benefit of

increased treatment and longer schedules in adults• Antibody formation unknown

L-asparaginase: Toxicity

• Hypersensitivity– Neutralizing antibodies

• Liver dysfunction– Liver enzymes, bilirubin, low albumin

• Hemostasis– Bleeding: low clotting factors– Clotting: low antithrombin III, protein S

• Pancreatitis, diabetes mellitus, CNS effects (lethargy, somnolence)

Treatment of ALL: Summary and Future Directions (cont’d)

• Future treatment decision may be based on evaluation of MRD at critical time points– At CR and after CR

• Therapy selection through gene expression profiling

• Molecular markers with possible prognostic significance currently being investigated

ALL: Targeted Treatments

ALL Subtype Target TreatmentPh+ BCR/ABL Imatinib, dasatinib, nilotinib

T cell NUP214-ABL1NOTCH1 mutation

Imatinib, dasatinib, nilotinibGamma secretase inhibitor

Mature B cell CD20 RituximabPrecursor B cell CD20 RituximabAll subtypes CD52 AlemtuzumabMLL and hyperdiploidly FLT3 overexpression CEP701, PKC 212

• Targets include BCR/ABL, CD 20, and FLT3 overexpression, among others

Pegylated Asparaginase

• Pegylated E. coli L-asparaginase

• Less immunogenic • Long half-life

– Less frequent dosing– Continuous asparagine

depletion

• In children– More rapid reduction in

marrow blasts during induction

– Lower incidence of neutralizing antibodies

– Similar safety profile as native form

• In adults– Similar toxicity to native form

after single and multiple doses

.

Clofarabine in ALL• Approved in relapsed or refractory Pediatric ALL• Children (N = 61)[1]; median of 3 prior regimens

– 52 mg/m2 on Days 1-5• CR + CRp in 12 patients (20%); PR in 6 patients (10%)• Median survival:13 weeks• 9 responders proceeded to SCT

• Adults (N = 12)[2]

– Dose 40 mg/m2 on Days 1-5– CR in 2 patients (17%)

• Toxicity : hepatotoxicity, palmarplantar erythrodysesthesia, druf fever, rash 1. Jeha S, et al. J Clin Oncol. 2006;24:1917-1923.

2. Kantarjian H, et al. Blood. 2003;102:2379-2386.

T-Cell ALL: Gamma Secretase Inhibitor MK 0752

• NOTCH 1 gain-of-function mutations in 50% of T-ALL

• Gamma secretase inhibitors abrogate stimulatory effects of NOTCH 1

• Phase I trial– Gamma secretase inhibitor MK-0752– 4 patients: NOTCH1 activated mutations– 1 patient: decrease in size of mediastinal mass

DeAngelo D, et al. ASCO 2006. Abstract 6585.

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Acute leukemia

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