







2 months
PTA
• intermittent fever (undocumented temperature) with no associated colds, cough, diarrhea
• accompanied by easy fatigability, decreased level of activity and loss of appetite
• Paracetamol 250mg/5mL, 5 mL every
4 hours (14.7 mkd)
• slight relief

• pallor in the palms, nail beds, face and conjunctivae
• (-) bleeding
• intermittent fever
• consulted at the local health center
• CBC: Hgb 80g/dl, Hct 0.23, WBC 9.8, segmenters 0.3, lymphocytes 0.7, plt 248
• “UTI”
• Co-amoxiclav 250mg/5mL, 5mL every 8 hours for 7 days (44mkd)
• No relief
• Ferrous gluconate + Vitamin B-complex
129.5mg/5mL, 5mL once a day for 1 month
(7.6mkd)

• follow up consult
• Undocumented weight loss
• palpable cervical lymphadenopathies
• Chest Xray: Primary Tuberculosis Infection
• Isoniazid + Pyridoxine HCl 200mg/10mL, 5 mL OD (5.9mkd)
• Rifampicin 200mg/5mL, 7.5 mL OD
(17.6mkd)
• CBC: Hgb 81 g/dl, Hct 0.24, RBC 3.7, WBC
7, segmenters 0.3, lymphocytes 0.7, plt 191
• Urinalysis: light yellow, sl turbid, pH6, sp gr 1.015, sugar (-), albumin (-), WBC 1-
3/hpf, RBC 0-2

• 5 episodes of loose watery stools
• accompanied by abdominal pain
• (-) vomiting
• consulted at the local health center
• CBC: Hgb 54.4, Hct 0.16, WBC 6.35, segmenters 0.15, lymphocytes 0.85, plt 175
• Urinalysis: normal
• referred to our institution due to persistent anemia


Cutaneous: (-) rash, pigmentation, hair loss

HEENT: (-) lacrimation, (-) hearing loss, (-) aural discharge, (-) nasal discharge, (-) epistaxis, (-) toothache, (-) salivation, (-) sore throat

Respiratory: (-) dyspnea

Cardiovascular: (-) orthopnea, (-) cyanosis,

Gastrointestinal: (-) constipation, (-) jaundice,
(-) pica


Genitourinary: (-) polyuria, (-) hematuria

Musculoskeletal: (-) bone pain, (-) limitation of movement

Nervous/Behavior: (-) tremors, (-) convulsions (-) mood/behavioral change

Endocrine: (-) breast asymmetry, (-) pain or discharge (-) heat/cold intolerance

Food CHO (g) CHON (g) FATS (g) Calories
Breakfast 5 tbsp corned beef
1 cup rice
Lunch Canned tuna
1 cup rice
Dinner ½ cup pork adobo
1 cup rice
TOTAL
RENI
%
-
23
-
23
2
23
40
2
22
2
28
2
24
-
21
-
-
1
430
100
103
100
314
100
1147
1410
81%

 average prep student before he started getting absent from school due to easy fatigability
 can read and write, draw a person with hands and clothes, knows morning and afternoon, and knows right and left sides

At par with age


No previous hospitalizations

No past surgeries

No food or drug sensitivities


Unrecalled


(-) HPN, DM, PTB, cancer, hematologic disorders

JF
RF
Name Age Relation Educational
Attainment
Occupation Health
32 Father College undergraduate
Driver Healthy
32 Mother HS graduate Housewife Healthy
JF
JF
11 Sister
7 Brother
Student Healthy
Student Healthy

 lives in Nueva Ecija with his parents and siblings in a one-storey house made of wood and concrete, well-lit, well-ventilated
 drink tap water and water supply at home is from
NAWASA.

Garbage is collected every day, no segregation done
 do not own any pets
 no factories nearby
 exposed to second hand cigarette smoke from his father


General Survey

Conscious, coherent, ambulatory, not in cardiorespiratory distress, well-nourished and wellhydrated








2

Physical Examination

Skin

Warm, moist skin, no active dermatoses, good skin turgor, (+) pallor, no jaundice

HEENT


no unusual facies, no facial asymmetry
pale palpebral conjunctivae, anicteric sclerae, no tears, pupils 3-4 mm ERTL

Physical Examination

HEENT


 no tragal tenderness, nonhyperemic external auditory canal, intact tympanic membrane, no discharge nasal septum midline, no nasal discharge, turbinates nonhyperemic and not congested moist buccal mucosa, no dental caries, nonhyperemic posterior pharyngeal wall, tonsils not enlarged

Physical Examination

Neck

Supple neck, no limitation of movement,
(+) palpable cervical lymph nodes,< 1 cm firm, rubbery, nonmatted ,non tender

Lungs
 symmetrical chest expansion, no retractions, equal vocal and tactile fremiti, resonant on percussion, clear breath sounds

Physical Examination

Heart
 adynamic precordium, apex beat at 4 th LICS MCL, no heaves/lifts, no thrills, normal rhythm, S1 louder than S2 at apex, S2 louder than S1 at the base, no murmurs

Abdomen
 soft and flat, normoactive bowel sounds, tympanitic, no tenderness, no palpable masses, liver span 8 cm, spleen was palpable at 3cm below the subcostal margin

Physical Examination

Genitourinary
 genitalia grossly male, no discharge

(+) inguinal lymphadenopathies

Extremities


 pulses full and equal on all extremities, no edema, no cyanosis, no clubbing, no joint swelling or tenderness, no limitation of motion, capillary refill <2 seconds
Pale nail beds no skin dimpling, no tufts of hair

Neurologic Examination

Mental Status: Conscious, coherent, oriented to time, place and person, follows commands

Cranial nerves: intact

Motor: no atrophy, no fasciculations, no spasticity or rigidity, MMT 5/5 on all extremities

Cerebellar: can do APST and FTNT with ease

Sensory: no sensory deficit

Reflexes: DTRs ++ on all extremities, (-) Babinski

Meningeal signs: (-) nuchal rigidty, (-)
Brudzinski, (-) Kernig’s









6 year old male
Pallor
Intermittent low grade fever easy fatigability
Decreased level of activity loss of appetite
Weight loss
Chest X-ray: Primary Tuberculosis Infection, on treatment






(+) pallor
Persistent anemia pale palpebral conjunctivae, nail beds
Palpable CLN, inguinal lymphadenopathies hepatosplenomegaly

-Fever
Hepatosplenomegaly
-Pallor
-Easy fatigability
-
-Palpable CLN
-CBC: Blast cells

Overview
Infectious Mononucleosis Tuberculosis
• Most common hematologic disease of childhood
• Dietary deficiency
• Blood loss- milk-protein induced inflammatory colitis, peptic ulcer
• Hookworm infestation
• Chronic diarrhea
• Genetic disorder in globin chain production
• 3% world population carries gene for bthalassemia
• In SEA, 5-10% carries gene for α-thalassemia
• 6 y/o M
Patient
Clinical
Manifestati ons diagnosis
•
•
Pallor
Hemoglobin <5g/dl, irritability, anorexia, tachycardia
• Neurologic: attention span, alertness, learning
• Dec Serum ferritin & serum iron
• Inc serum transferrin
• Inc reticulocyte count
• typical facies ( maxillary hyperplasia, flat nasal bridge, frontal bossing), pathologic bone fractures hepatosplenomegaly, cachexia
• Pallor, hemosiderosis, jaundice
• CC: pallor
• intermittent fever
(undocumented) easy fatigability, increased sleepiness, anorexia
• PE: pallor in the palms, nail beds, face & conjunctivae
• palpable cervical lymphadenopathies
• liver span 8 cm, spleen was palpable at 3cm below the subcostal margin
• Severe anemia, few reticulocytes, microcytosis

Overview
Clinical
Manifestati ons
•
•
•
Lymphoma
• Most common hematologic disease of childhood
• Dietary deficiency
• Blood loss- milk-protein induced inflammatory colitis, peptic ulcer
• Hookworm infestation
• Chronic diarrhea
• 6 y/o M
Pallor
Hemoglobin <5g/dl, irritability, anorexia, tachycardia
Neurologic: attention span, alertness, learning
Patient
• CC: pallor
• intermittent fever
(undocumented) easy fatigability, increased sleepiness, anorexia
• PE: pallor in the palms, nail beds, face & conjunctivae
• palpable cervical lymphadenopathies
• liver span 8 cm, spleen was palpable at 3cm below the subcostal margin diagnosis • Dec Serum ferritin & serum iron
• Inc serum transferrin
• Inc reticulocyte count

Overview
Acute lymphoblastic leukemia
• Males>females, at all ages
• Peaks 2-6 years old
• Occurs 5x than AML
• Idiopathic
• Exposure to radiation
• B-cell ALL & EBV infection
Acute myelogenous leukemia
• 11% of leukemia
• Idiopathic
• Exposure to ionizing radiation, chemotherapeutic agents
• 6 y/o M
Patient
Clinical
Manifestati ons diagnosis
•
•
•
•
Initially non-specific &brief
Anorexia, fatigue, irritability, low grade fever, bone pain
• Hx of URTI (1-2 mos)
Pallor, fatigue, bruising, epsitaxis, fever
PE: pallor, purpuric/petechial lesion, mucous membrane hemorrhage
• Lymphadenopathy, splenomegaly, deep bone pain
• Peripheral smear & bone marrow examination
• >25% lymphoblast
• Anemia & thrombocytopenia
• Staging: CSF exam
• S & Sxs is 2⁰ to bone marrow failure
• uncommon in ALL: subcutaneous nodules or “blueberry muffin” lesions, infiltration of gingiva, signs of DIC, discrete mass
(granulocytic sarcomas)
• CNS symptoms more common than ALL
• Peripheral smear & bone marrow examination
• Myeloperoxidase containing cell
• CC: pallor
• intermittent fever
(undocumented) easy fatigability, increased sleepiness, anorexia
• PE: pallor in the palms, nail beds, face & conjunctivae
• palpable cervical lymphadenopathies
• liver span 8 cm, spleen was palpable at 3cm below the subcostal margin

1 st Hospital day

Request for:



CBC with platelet
Reticulocyte count
Peripheral blood smear

Hgb
RBC
Hct
MCV
MCH
MCHC
RDW
MPV
Platelet
Reference range 9/13/2010
115-155 g/L
4-6x10^12/L
0.35-0.45
87
34
±
±
5 U^3
25-33 pg/cell g/dL
11.6-14.6
7.4-10.4 fL
150-450x10^9/L
WBC
Differential count
Neutrophils
Metamyelocyte
5.5-15.5x10^9/L
0.50-0.70
Bands
Segmenters
Lymphocytes
Blast
Reticulocyte count
0.50-0.70
0.20-0.40
34.3
36.3
27.5
8.2
43
46
1.34
0.13
94.5
5.1
0.11
0.01
0.03
0.07
0.7
0.19
28

Peripheral Smear



WBC: presence of immature cells (blast cells)
RBC: Anisochromia with
Anisocytosis and
Poikilocystosis
Platelet decrease
ANC=561

2 nd Hospital day

Patient was scheduled for BMA

Transfusion of 1 satellite bag properly typed and cross matched over 4 hours

Started on IVF D5 0.3% NaCl 14-15 gtts/min

3 rd Hospital day

Transfused with 1 satellite bag PRBC properly typed and cross matched over 4 hours after Bone marrow aspiration


BMA was done. Obtained 2 ml bone marrow aspirate.

Specimen was sent for flow cytometry

4 th Hospital day

Request for:







CBC with platelet
Total bilirubin
BUN, Creatinine
Na, K
Total Calcium, iPO4, BUA
Alkaline phosphatase, LDH
CXR (PA, Lat)

Hgb
RBC
Hct
MCV
MCH
MCHC
RDW
MPV
Platelet
WBC
Differential count
Neutrophils
Metamyelocyte
Bands
Segmenters
Lymphocytes
Blast
Reticulocyte count
Reference range 9/16/2010
115-155 g/L 81
4-6x10^12/L
0.35-0.45
2.66
0.24
87 ± 5 U^3
25-33 pg/cell
34 ± g/dL
88.7
30.5
34.4
11.6-14.6
7.4-10.4 fL
150-450x10^9/L
5.5-15.5x10^9/L
19
8.9
24
11
0.50-0.70
0.50-0.70
0.20-0.40
0.07
0.01
0.06
0.75
0.18
ANC=770
Blood Chemistry
Test Reference Range
Urea Nitrogen
Uric Acid
Creatinine
Alkaline phosphatase
Total bilirubin
Direct bilirubin
9-23 mg/dL
4-8.5 mg/dL
0.32-0.59 mg/dL
40-129 U/L
0.5-1.5 mg/dL
0.1-0.4 mg/dL
Indirect bilirubin 0.3-1.1 mg/dL
LDH 100-190 U/L
Result
5.06
6.35
0.28
63.12
0.4
0.06
0.34
416.82

Na
K iPO4
Total
Calciu m
Reference range
137-147 mmol/L
3.8-5 mmol/L
2.4-4.7 mmol/L
8.8-11 mg/dL
Result
138.52
2.9
4.84
8.31

CXR:



There is haziness over the right lung bases and the retrocardiac region
Confluent densities are seen over the paratracheal and peribronchial regions
Impression: Above findings may be suggestive of Primary
Koch’s Infection


2D echo was requested as baseline studies prior to
Doxorubucin

Initial reading: Ejection fraction 69; mild pericardial effusion

5 th Hospital day

Patient was started Prednisone 10 mg/5 ml,
10 ml BID on full stomach

Patient was scheduled for intrathecal chemotherapy
(Methotrexate 25 mg/ml)

Started on NaHCO3 325 mg/tab, 1 tab now then TID;
Allopurinol 100 mg/tab, 1 tab BID

For 5 days only
6 th Hospital day

Transfuse with 2 ‘u’ type specific Platelet concentrate


Intrathecal chemotherapy was done

2 ml CSF fluid was obtained


Cell cytology
CSF differential count
CSF
Physical characteristics
Color
Volume
Transparency
Supernatant colorless
0.75 ml
Clear colorless, clear
Total RBC
Total WBC
None found
None found

Reduction below normal in the concentration of hemoglobin or RBCs in the blood


Age/Sex
At birth
Childhood
Adolescence
Adult man
Adult woman
(menstruating)
Adult woman
(postmenopausal)
During pregnancy
Hemoglobin g/dl Hematocrit %
17 52
12 36
13
16(+2)
13(+2)
40
47(+6)
40(+6)
14(+2)
12(+2)
42(+6)
37(+6)

•
•
•
Disorders of Proliferation
Disorders in Erythrocyte Maturation
Disorders due Primarily to Erythrocyte
Destruction or Red Cell Loss

S
O

Acute Lymphocytic Leukemia
Introduction
-The leukemias are the most common malignant neoplasms in childhood:
41% of all malignancies that occur in children [<15 yrs].
-Acute lymphoblastic leukemia (ALL) 77%.
-Acute myelogenous leukemia (AML) 11%.
-Chronic myelogenous leukemia (CML) for 2–3%.
-Juvenile chronic myelogenous leukemia (JCML) for 1–2%.

Acute Lymphocytic Leukemia
Introduction
Leukemias may be defined as:
-a group of malignant diseases in which genetic abnormalities in a hematopoietic cell give rise to a clonal proliferation of cells.

-Increased rate of proliferation, a decreased rate of spontaneous apoptosis, or both.

-Disruption of normal marrow function and, ultimately, marrow failure.

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Epidemiology:
-It has a striking peak incidence between 2–6 yr of age.
-Occurs slightly more frequently in boys than in girls.
-More common in children with certain chromosomal abnormalities such as Down syndrome, Bloom syndrome, ataxia-telangiectasia, and
Fanconi syndrome.

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Etiology:
-The etiology of ALL is unknown, although several genetic and environmental factors are associated with childhood leukemia.
-Exposure to medical diagnostic radiation both in utero and in childhood.
-Association between B-cell ALL and Epstein-Barr viral infections in certain developing countries.

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Factors Predisposing to Childhood Leukemia
GENETIC CONDITIONS
Down syndrome
Fanconi syndrome
Bloom syndrome
Diamond-Blackfan anemia
Schwachman syndrome
Klinefelter syndrome
Turner syndrome
Neurofibromatosis
Ataxia-telangiectasia
Severe combined immune deficiency
Paroxysmal nocturnal hemoglobinuria
Li-Fraumeni syndrome

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Factors Predisposing to Childhood Leukemia
ENVIRONMENTAL FACTORS
Ionizing radiation
Drugs
Alkylating agents
Nitrosourea
Epipodophyllotoxin
Benzene exposure
Advanced maternal age

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Pathogenesis:
-The classification of ALL depends on characterizing the malignant cells in the bone marrow to determine the morphology, phenotypic characteristics as measured by cell membrane markers, and cytogenetic and molecular genetic features.
-Morphology alone is usually adequate to establish a diagnosis, but the other studies are essential for disease classification, which may have a major influence on both the prognosis and the choice of appropriate therapy.

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Pathogenesis :
-
Chromosomal abnormalities are found in most patients with ALL.
-The abnormalities provide important prognostic information.
-Specific chromosomal findings, such as the t(9;22) translocation, suggest a need for additional, molecular genetic studies.
-The PCR and fluorescence in situ hybridization techniques offer the ability to pinpoint molecular genetic abnormalities and to detect small numbers of malignant cells during follow-up.

Acute Lymphoblastic Leukemia
Common Chromosomal Abnormalities in the Acute Leukemias of Childhood
Disease, Subtype
ALL, pre-B
ALL, pre-B
ALL, pre-B
ALL, B-cell
ALL (general)
Chromosomal
Abnormality
Trisomy 4 and
10
Influence on Prognosis
Favorable t(12;21) t(4;11) t(9;22) t(8;14)
Unfavorable
Unfavorable
None
Hyperdiploidy Favorable
ALL (general)
AML, M1 *
AML, M4 *
AML, M3 *
AML (general)
Hypodiploidy Unfavorable t(8;21) inv(16) t(15;17) del(7)
Favorable
Favorable
Favorable
Unfavorable
AML, infant t(4;11) Unfavorable
ALL = acute lymphoblastic leukemia; AML = acute myelogenous leukemia.
French-American-British classification

Acute Lymphoblastic Leukemia Acute Lymphocytic Leukemia
Clinical Manifestations:
-The initial presentation of ALL is usually nonspecific and relatively brief:
•Anorexia
•Fatigue
•Irritability
•Intermittent low-grade fever
-Bone or joint pain, particularly in the lower extremities, may be present.
-Patients often have a history of an upper respiratory tract infection in the proceeding 1–2 mo.

Acute Lymphoblastic Leukemia Acute Lymphocytic Leukemia
Clinical Manifestations:
-symptoms may be of several months' duration, may be predominantly localized to the bones or joints
-As the disease progresses, signs and symptoms of bone marrow failure become more obvious:
• pallor, fatigue, bruising, epistaxis, fever may be caused by infection
-Physical examination reflecting bone marrow failure:
•Pallor
•purpuric and petechial skin lesions
•mucous membrane hemorrhage

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Clinical Manifestations:
-The proliferative nature of the disease may be manifested as:
• lymphadenopathy
• splenomegaly
• hepatomegaly
-Signs of increased intracranial pressure that indicate leukemic involvement of the CNS:
• papilledema
• retinal hemorrhages
• cranial nerve palsies

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Diagnosis:
-Strongly suggested by peripheral blood findings indicative of bone marrow failure.
-Anemia and thrombocytopenia are seen in most patients.
-Leukemic cells are often not observed in the peripheral blood in routine laboratory examinations.
-Most patients with ALL present with total leukocyte counts of less than
10,000/μL:
The leukemic cells are often initially reported to be atypical lymphocytes.

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Diagnosis:
-When the results of an analysis of peripheral blood suggest the possibility of leukemia, a bone marrow examination should be done promptly to establish the diagnosis.
-Bone marrow aspiration alone is usually sufficient, but sometimes a bone marrow biopsy is needed to provide adequate tissue for study or to exclude other possible causes of bone marrow failure.

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Diagnosis :

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Treatment:
-Three of the most important predictive factors are:
•Age of the patient
•Initial leukocyte count
•The speed of response to treatment
-Patients between 1–10 yr of age and with a leukocyte count of less than 50,000/μL is widely used to define average risk.
-Patients considered to be at higher risk are children who are older than
10 yr of age or who have an initial leukocyte count of more than
50,000/μL.

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Treatment:
-The initial therapy is designed to eradicate the leukemic cells from the bone marrow and is known as remission induction.
-During this phase, therapy is usually given for 4 wk and consists of:
•vincristine weekly.
•corticosteroid such as dexamethasone or prednisone.
•either repeated doses of native l-asparaginase or a single dose of a long-acting asparaginase preparation.
•Intrathecal cytarabine or methotrexate, or both, may also be given.

Acute Lymphoblastic Leukemia Acute Lymphocytic Leukemia
Treatment:
-The second phase of treatment is consolidation/intensification
Once remission has been achieved, systemic treatment in conjunction with central nervous system (CNS) sanctuary therapy follows.
-intensity varies depending on risk group assignment
-Intensification may involve use of the following:
•Intermediate or high-dose methotrexate
•Drugs similar to those used to achieve remission
•Different drug combinations with little known crossresistance
•L-asparaginase for an extended period of time
•Combinations of the above

Acute Lymphoblastic Leukemia Acute Lymphocytic Leukemia
Treatment:
-After remission induction, many regimens provide 14–28 wk of multiagent therapy
-Finally maintenance phase of therapy, lasts for 2–3 yr, depending on the protocol used:
• daily mercaptopurine and weekly methotrexate, usually with intermittent doses of vincristine and a corticosteroid.
-Poor prognostic features:
• those with the t(9;22) translocation
-may undergo bone marrow transplantation during the first remission.

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Treatment:
-The major impediment to a successful outcome is relapse of the disease.
-Relapse occurs in the bone marrow in 15–20% of patients with ALL and carries the most serious implications, especially if it occurs during or shortly after completion of therapy.
-Intensive chemotherapy with agents not previously used in the patient followed by allogeneic stem cell transplantation can result in long-term survival for a few patients with bone marrow relapse.

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Treatment:
-Testicular relapse occurs in 1–2% of boys with ALL, usually after completion of therapy.
-Such relapse presents as painless swelling of one or both testes.
-The diagnosis is confirmed by biopsy of the affected testis.
-Treatment includes systemic chemotherapy and local irradiation.
-A high proportion of boys with a testicular relapse can be successfully re-treated, and the survival rate of these patients is good.

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
SUPPORTIVE CARE:
-Close attention to the medical supportive care needs of the patients is essential in successfully administering aggressive chemotherapeutic programs.
-Patients with a large tumor burden are prone to tumor lysis syndrome
-may produce severe myelosuppression ,
•may require erythrocyte and platelet transfusion
•always requires a high index of suspicion and aggressive empirical antimicrobial therapy for sepsis in febrile children with neutropenia.
-prophylactic treatment of Pneumocystis carinii pneumonia during chemotherapy and for several months after

Acute Lymphoblastic Leukemia
Acute Lymphocytic Leukemia
Prognosis:
-Most children with ALL can now be expected to have long-term survival, with the rate greater than 80% after 5 yr.
-The most important prognostic factor is the choice of appropriate risk-directed therapy, with the type of treatment chosen according to the type of ALL, the stage of disease, the age of the patient, and the rate of response to initial therapy.
-Characteristics generally believed to adversely affect outcome include:
•an age younger than 1 yr or older than 10 yr at diagnosis.
•a leukocyte count > 100,000/μL at diagnosis.
•a slow response to initial therapy.

Journal: Risk-adjusted therapy of acute lymphoblastic leukemia can decrease treatment burden and improve survival: treatment results of 2169 unselected pediatric and adolescent patients enrolled in the trial ALL-BFM 95
Anja Möicke et al. The American Society of Hematology. 2008




Impressive improvements of survival rates in pediatric acute lymphoblastic leukemia (ALL) have been achieved during the last decades.
Today, a long-term cure can be attained for approximately 75% of patients.
ALL-Berlin-Frankfurt-Münster (BFM) trials, the so-called prednisone response (PR, for definition see “Response and relapse criteria”) evolved as one of the strongest prognostic factors.


Patients with “prednisone good-response” (PGR) comprised 90% of all patients with a cure rate of more than 80%.
Patients with inadequate PR (“prednisone poor-response,” PPR) had an unfavorable outcome with a probability of event-free survival (pEFS) of less than 50%.


In trial ALL-BFM 95






Age white blood cell count (WBC) at diagnosis immunophenotype
Prednisone response response to induction treatment unfavorable translocations t(9;22) and t(4;11).






Reduction of the daunorubicin dose in induction treatment by 50% in the SR group
The extension of the maintenance therapy by 12 months in
SR boys to prevent the late relapses observed in this patient group randomized intensification of the extracompartment
/consolidation phase with intermediate-dose (ID) cytarabine in addition to high-dose methotrexate in the MR group omission of pCRT in all MR patients with non-T-ALL; modification of consolidation/reinduction in HR patients by intensification in the block elements and reintroduction of protocol II.


Patients

April 1, 1995, until June 30, 2000, a total of 2283 patients younger than 18 years with ALL were enrolled into the trial ALL-BFM 95.



Patients were treated in 82 participating study centers in Austria, Switzerland, and Germany.
The median follow-up period for the analyzed patients was 7.2 years.
Thirty-seven patients were considered lost to followup after a median follow-up time of 3.0 years.


Diagnosis


 diagnosis of ALL was established if at least 25% lymphoblasts were present in the bone marrow (BM).
Central nervous system (CNS) involvement was diagnosed
 more than 5 cells/ μ L were counted in CSF and lymphoblasts were identified



CNS3- intracerebral infiltrates were detected on cranial computed tomography
CNS2- blasts were identified in CSF cytospin preparations although CSF cell count was less than or equal to 5 cells/ μ L in the case of traumatic lumbar puncture with identification of blasts, CNS status was categorized as TLP+, and as TLP- if no blasts were identified
Immunophenotyping, determination of cellular DNA content using flow cytometry, and definition of DNA index was performed


Response and relapse criteria


PR was determined after 7 days of monotherapy with prednisone and one intrathecal dose of methotrexate on day 1 and was centrally reviewed in the study center.


PPR (predisone poor response) - presence of 1 x 10 9 blasts/L or more in
PB on day 8,
PGR (prednisone good response)- fewer than 1 x 10 9 blasts/L
BM response was evaluated in aspiration smears on day 33 of induction treatment.

Complete remission (CR)- less than 5% blasts in the regenerating BM, the absence of leukemic blasts in blood and CSF, and no evidence of localized disease.


Resistance to therapy (nonresponse)- was defined as not having achieved
CR by the start of the fourth pulsatile high-dose block.
Relapse- was defined as recurrence of 25% or more lymphoblasts in BM or localized leukemic infiltrates at any site.




Stratification
Patients were stratified into 3 risk groups according to the following criteria:



High Risk (HR): PPR, and/or no CR on day 33, and/or evidence of t(9;22) (or BCR/ABL), and/or evidence of t(4;11) (or MLL/AF4).
Medium Risk (MR): No HR criteria, and initial WBC 20 x
10 9 /L or more and/or age at diagnosis less than 1 or 6 years or older, and/or T-ALL.
Standard Risk (SR): No HR criteria, and initial WBC less than 20 x 10 9 /L, and age at diagnosis between 1 and 6 years, and no T-ALL.
CNS status was no stratification criterion.


Survival was defined as the time of diagnosis to death from any cause or last follow-up.
For analysis of randomized patient subsets, disease-free survival (DFS) was calculated from time of randomization to the first event or the last follow-up date.

The Kaplan-Meier method was used to estimate survival rates


Remission failures. Deaths. Relapse


Estimated 6-year event-free survival (6y-pEFS) for all
2169 patients was 79.6% ( ± 0.9%). The large standard-risk (SR) group (35%of patients) achieved an excellent 6y-EFS of 89.5% ( ± 1.1%) despite significant reduction of anthracyclines.

In the medium-risk (MR) group (53% of patients), 6ypEFS was 79.7% ( ± 1.2%); no improvement was accomplished by the randomized use of additional intermediate-dose cytarabine after consolidation.



Omission of preventive cranial irradiation in non–T-
ALL MR patients was possible without significant reduction of EFS, although the incidence of central nervous system relapses increased. In the high-risk
(HR) group (12% of patients), intensification of consolidation/reinduction treatment led to considerable improvement over the previous ALL-BFM trials yielding a 6y-pEFS of 49.2% ( ± 3.2%).
Compared without previous trial ALL-BFM90, consistently favorable results in non-HR patients were achieved with significant treat ment reduction in the majority of these patients.