University of Santo Tomas Hospital Department of Pediatrics Grand Rounds Ang.Ang.Aningalan....

University of Santo Tomas HospitalDepartment of Pediatrics

Grand RoundsAng.Ang.Aningalan.Antonio.Aramburo.

General Data JPF 6 year old, male Birthdate: September 9, 2004 Religion: Roman Catholic Address: Nueva Ecija Informant: Mother Reliability: Good

PALLORCHIEF COMPLAINT:

History of Present Illness:

History of Present Illness:

Admission

Review of System:

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

Review of System: 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

24 hour food recallFood CHO (g) CHON (g) FATS (g) Calories

Breakfast 5 tbsp corned beef1 cup rice

-23

402

24-

430100

Lunch Canned tuna1 cup rice

-23

222

1-

103100

Dinner ½ cup pork adobo1 cup rice

223

282

21-

314100

TOTAL 1147

RENI 1410

% 81%

Developmental history 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

Past Illnesses No previous hospitalizations No past surgeries No food or drug sensitivities

Immunization History Unrecalled

Family History (-) HPN, DM, PTB, cancer, hematologic

disorders

Family profile

Name Age Relation Educational Attainment

Occupation Health

JF 32 Father College undergraduate

Driver Healthy

RF 32 Mother HS graduate Housewife Healthy

JF 11 Sister Student Healthy

JF 7 Brother Student Healthy

Socioeconomic and Environmental History

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

Physical Examination General Survey

Conscious, coherent, ambulatory, not in cardiorespiratory distress, well-nourished and well-hydrated

Physical Examination BP : 90/50 mmHg HR : 120 bpm RR : 24 cpm Temp :36.9C Wt : 17kg (WFA : z score below -1, normal) Lt: 112 cm (LFA : z score below 0 normal) BMI 13.6 kg/m2 (BFA: z score -1, normal)

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, non-hyperemic 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 4th 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

Salient Features: Subjective 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

Salient Features: Objective (+) pallor Persistent anemia pale palpebral conjunctivae, nail beds Palpable CLN, inguinal lymphadenopathies hepatosplenomegaly

Approach To Diagnosis

Infectious Mononucleosis Tuberculosis Patient

Overview •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 b-thalassemia•In SEA, 5-10% carries gene for α-thalassemia

•6 y/o M

Clinical Manifestations

•Pallor•Hemoglobin <5g/dl, irritability, anorexia, tachycardia•Neurologic: attention span, alertness, learning

• 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

diagnosis •Dec Serum ferritin & serum iron•Inc serum transferrin•Inc reticulocyte count

•Severe anemia, few reticulocytes, microcytosis

Lymphoma Patient

Overview •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


diagnosis •Dec Serum ferritin & serum iron•Inc serum transferrin•Inc reticulocyte count

Acute lymphoblastic leukemia Acute myelogenous leukemia

Patient

Overview •Males>females, at all ages•Peaks 2-6 years old•Occurs 5x than AML•Idiopathic•Exposure to radiation•B-cell ALL & EBV infection

•11% of leukemia•Idiopathic•Exposure to ionizing radiation, chemotherapeutic agents

•6 y/o M


•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

• 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


diagnosis •Peripheral smear & bone marrow examination•>25% lymphoblast•Anemia & thrombocytopenia•Staging: CSF exam

•Peripheral smear & bone marrow examination•Myeloperoxidase containing cell

Course in the Ward

1st Hospital day Request for:

CBC with plateletReticulocyte countPeripheral blood smear

Reference range

9/13/2010

Hgb 115-155 g/L 46

RBC 4-6x10^12/L 1.34

Hct 0.35-0.45 0.13

MCV 87±5 U^3 94.5

MCH 25-33 pg/cell 34.3

MCHC 34±g/dL 36.3

RDW 11.6-14.6 27.5

MPV 7.4-10.4 fL 8.2

Platelet 150-450x10^

9/L

43

WBC 5.5-15.5x10^

9/L

5.1

Differential count

Neutrophils 0.50-0.70 0.11

Metamyelocyte

0.01

Bands 0.03

Segmenters 0.50-0.70 0.07

Lymphocytes

0.20-0.40 0.7

Blast 0.19

Reticulocyte count

28

Peripheral Smear WBC: presence of

immature cells (blast cells)

RBC: Anisochromia with Anisocytosis and Poikilocystosis

Platelet decrease

ANC=561

2nd 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

3rd 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

4th Hospital day Request for:

CBC with plateletTotal bilirubinBUN, CreatinineNa, KTotal Calcium, iPO4, BUAAlkaline phosphatase, LDHCXR (PA, Lat)

Reference range

9/16/2010

Hgb 115-155 g/L 81

RBC 4-6x10^12/L 2.66

Hct 0.35-0.45 0.24

MCV 87±5 U^3 88.7

MCH 25-33 pg/cell 30.5

MCHC 34±g/dL 34.4

RDW 11.6-14.6 19

MPV 7.4-10.4 fL 8.9

Platelet 150-450x10^

9/L

24

WBC 5.5-15.5x10^

9/L

11

Differential count

Neutrophils 0.50-0.70 0.07

Metamyelocyte

0.01

Bands

Segmenters 0.50-0.70 0.06

Lymphocytes 0.20-0.40 0.75

Blast 0.18

Reticulocyte count

ANC=770

Blood Chemistry

TestReference

RangeResult

Urea Nitrogen 9-23 mg/dL5.06

Uric Acid 4-8.5 mg/dL6.35

Creatinine0.32-0.59

mg/dL0.28

Alkaline phosphatase 40-129 U/L

63.12

Total bilirubin 0.5-1.5 mg/dL0.4

Direct bilirubin 0.1-0.4 mg/dL

0.06

Indirect bilirubin 0.3-1.1 mg/dL

0.34

LDH 100-190 U/L 416.82

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

Reference

range Result

Na137-147 mmol/L 138.52

K 3.8-5 mmol/L 2.9

iPO4 2.4-4.7 mmol/L 4.84

Total Calciu

m 8.8-11 mg/dL 8.31

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

pericardial effusion

5th 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

6th 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 colorless

Volume 0.75 ml

Transparency Clear

Supernatantcolorless, clear

Total RBC None found

Total WBC None found

ANEMIA

Reduction below normal in the concentration of hemoglobin or RBCs

in the blood

Changes in Normal Hemoglobin/Hematocrit Values with Age and Pregnancy

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

Anemia is not a diagnosis in itself, but merely an objective sign of disease.

First step in its diagnosis is detection of its presence.

3 FUNCTIONAL CATEGORIES OF THE ANEMIAS

• Disorders of Proliferation• Disorders in Erythrocyte Maturation• Disorders due Primarily to Erythrocyte

Destruction or Red Cell Loss

PROBLEM: ANEMIA

SSubjective Dataubjective DataOObjective Databjective Data

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

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.



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.



Factors Predisposing to Childhood Leukemia

GENETIC CONDITIONS Down syndromeFanconi syndromeBloom syndromeDiamond-Blackfan anemiaSchwachman syndromeKlinefelter syndromeTurner syndromeNeurofibromatosisAtaxia-telangiectasiaSevere combined immune deficiencyParoxysmal nocturnal hemoglobinuriaLi-Fraumeni syndrome



Factors Predisposing to Childhood Leukemia

ENVIRONMENTAL FACTORS Ionizing radiationDrugsAlkylating agentsNitrosoureaEpipodophyllotoxinBenzene exposureAdvanced maternal age



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.



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.



Common Chromosomal Abnormalities in the Acute Leukemias of Childhood

Disease, SubtypeChromosomal Abnormality

Influence on Prognosis

ALL, pre-B Trisomy 4 and 10

Favorable

t(12;21)

ALL, pre-B t(4;11) Unfavorable

ALL, pre-B t(9;22) Unfavorable

ALL, B-cell t(8;14) None

ALL (general) Hyperdiploidy Favorable

ALL (general) Hypodiploidy Unfavorable

AML, M1 t(8;21) Favorable

AML, M4 inv(16) Favorable

AML, M3 t(15;17) Favorable

AML (general) del(7) Unfavorable

AML, infant t(4;11) Unfavorable

ALL = acute lymphoblastic leukemia; AML = acute myelogenous leukemia.

French-American-British classification


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.




-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




-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



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.



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.



Diagnosis:

-ALL is diagnosed by a bone marrow evaluation that demonstrates more than 25% of the bone marrow cells as a homogeneous population of lymphoblasts.

-Staging of ALL is partly based on a CSF examination.

-If lymphoblasts are found and the CSF leukocyte count is elevated, overt CNS leukemia is present; a worse stage.



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.



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.



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 cross-resistance•L-asparaginase for an extended period of time•Combinations of the above



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.



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.



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.



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



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

Introduction 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 95Agewhite blood cell count (WBC) at diagnosis immunophenotype Prednisone response response to induction treatmentunfavorable translocations t(9;22) and

t(4;11).

Objectives 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.

Methods 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 follow-up 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/μL 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/ μL

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 109 blasts/L or

more in PB on day 8, PGR (prednisone good response)- fewer than 1 x 109 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 109 /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 109 /L, and age at diagnosis between 1 and 6 years, and no T-ALL.

CNS status was no stratification criterion.

Treatment

Statistical Analysis 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

Results

Event Free Survival

Events 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), 6y-pEFS 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.

Thank You

University of Santo Tomas Hospital Department of Pediatrics Grand Rounds Ang.Ang.Aningalan....

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