Acute Lymphoblastic

Leukemia
Definition
• Neoplastic disease which results from a mutation in a single
lymphoid progenitor cell at one of several discrete stages of
development
• B Cell or T Cell
Epidemiology

• Most common childhood acute leukemia, ~80%

• Incidence in adults ~20%
• Bimodal distribution of occurrence:
• Peak at age 2-5
• Second increased incidence after age 50
Etiology
• Unknown
• Genetic Predisposition
• Increased incidence amongst monozygotic and dizygotic twins
• Down Syndrome
• Disorder with chromosomal fragility:
• Fanconi’s anemia
• Bloom Syndrome
• Ataxia-Telangiectasia
• Infections
• HTLV1 in T cell leukemia/lymphoma
• EBV in mature B cell ALL
• HIV in lymphoproliferative DO
Presentation

• Nonspecific Symptoms
• Fatigue/decreased energy
• Fever
• Easy bruising
• Bleeding
• Dyspnea
• Dizziness
• Infection
• Joint, extremity pains
• CNS involvement
Clinical Presentation

• Physical Exam • Lab Abnormalities

• Pallor • anemia
• Ecchymoses • wbc vary
• Petechiae • 0.1 (20-40%) - >100 k (10-16%)
• LAD • Platelets – usually ↓
• ↑ LD, uric acid
• Hepatosplenomegaly
• CXR: eval for thymic mass
• CSF to eval for involvement
Diagnosis
Differential Diagnosis

• ITP
• Aplastic Anemia
• Infectious mononucleosis
• Rheumatoid Arthritis
• Rheumatic Fever
• Collagen Vascular Disease
Treatment
• 1 – Remission Induction
• 2 – Intensification (Consolidation) Therapy
• 3 – Maintenance Therapy
• 4 – CNS Prophylaxis
• 5 – Allogeneic Stem Cell Transplant
Treatment

• Remission Induction
• Goals: restore normal hematopoiesis, induce a complete remission rapidly in
order to prevent resistance to drugs
• Standard induction regimen
• 4 or 5 drugs: vincristine, prednisone, anthracycline, L-asparaginase, +/-
cyclophosphamide
• Intensification
• High doses of multiple agents not used during induction or re-administration
of the induction regimen
Treatment

• Maintenance Therapy
• Daily po 6MP, weekly MTX, monthly pulses of vincristine and prednisone for
2-3 yrs
• CNS Prophylaxis
• Given during induction and intensification
• Intrathecal: MTX, Cytarabine, corticosteroids
• Systemic: high dose mtx, cytarabine, L-asparaginase
• +/- Cranial Irradiation
Treatment

• Stem Cell Transplant

• Done during first CR
• Indications:
• Ph Chromosome
• t(4;11) mutation
• Poor initial response to induction therapy
• Other
• Adolescents benefit significantly from pediatric ALL regimens vs. adult
regimens
Relapse & Prognosis

• Relapse
• Most occur during treatment or within the first 2 years
• Bone Marrow is the most common site
• Poor prognostic factors in patients previously treated:
• Relapse on therapy
• Short initial remission after intense therapy
• T-cell immunophenotype
• Ph Chromosome
• Circulating blasts
• High leukocyte count at relapse
Prognosis

• Overall better in children than in adults

• In adults, worse outcomes with:
• Increasing age, >60
• Increased wbc count at presentation
Acute Lymphoblastic
Leukemia
In Pregnancy
SEMUA dalam kehamilan
Leukemia akut jarang terjadi selama kehamilan. Ini mempengaruhi sekitar 1
dari 75.000 kehamilan.
Sebanyak 28% dari kasus leukemia didiagnosis selama kehamilan adalah ALL
sementara leukemia myeloid akut (AML) dan leukemia myeloid kronis (CML)
mewakili sisanya [Terek et al. 2003].
Tinjauan literatur laporan kasus SEMUA selama kehamilan ditunjukkan pada
Tabel 1. Sebanyak 17 pasien menerima kemoterapi dosis tinggi antara usia
kehamilan 15 dan 33 minggu. Kemoterapi terutama diberikan selama trimester
kedua dan ketiga. Regimen kemoterapi bervariasi, dengan sebagian besar
rejimen termasuk anthracyclines, vincristine dan steroid. Meskipun sebagian
besar hasil jangka panjang pasien tidak jelas, sekitar separuh perempuan
dalam ulasan ini mencapai remisi dan separuh lainnya mengalami kekambuhan
atau meninggal karena perkembangan penyakit. Beberapa bayi dilahirkan
dengan beberapa hasil yang merugikan termasuk pansitopenia sementara,
gangguan pernafasan dan kelahiran prematur.
ALL in pregnancy
Acute leukemia is uncommon during pregnancy. It affects approximately
1 in 75,000 pregnancies [Terek et al. 2003]. A total of 28% of leukemia
cases diagnosed during pregnancy are ALL while acute myeloid
leukemia (AML) and chronic mye- loid leukemia (CML) represent the
remainder [Terek et al. 2003]. A literature review of case reports of ALL
during pregnancy is shown in Table 1. A total of 17 patients received
high-dose chemotherapy between gestational age of 15 and 33 weeks.
Chemotherapy was mainly given dur- ing the second and third trimester.
Chemotherapy regimens varied, with most regimens including
anthracyclines, vincristine and steroids. While most patients’ long-term
outcomes are unclear, about half of the women in this review achieved
remission and the other half either relapsed or died from progression of
the disease. Some of the infants were born with few adverse outcomes
including transient pancytopenia, respiratory dis- tress and preterm
delivery.
Penggunaan inhibitor tirosin kinase selama
kehamilan
Ada beberapa laporan kasus wanita yang diobati dengan tirosin kinase inhibitor (TKI)
selama kehamilan. Karena sejarah yang lebih lama dari pasien yang diobati dengan
imatinib, ada lebih banyak laporan tentang hasil kehamilan setelah paparan kehamilan
untuk imatinib dibandingkan dengan TKI yang lebih baru. Sebuah tinjauan hasil
kehamilan dari 180 wanita yang terpapar imatinib selama kehamilan dilakukan [Pye et
al. 2008]. Ulasan ini menemukan 50% pasien dengan hasil yang diketahui (125 dari
180) melahirkan bayi normal, dan 28% menjalani terapi elektif, 3 setelah identifikasi
kelainan. Abnormalitas diidentifikasi pada 12 bayi dengan 9 dari defek yang terjadi
pada bayi dengan paparan trimester pertama yang diketahui pada imatinib. Tinjauan
menyimpulkan bahwa sebagian besar kehamilan yang terpapar imatinib cenderung
memiliki hasil yang sukses tetapi malformasi janin tetap merupakan risiko.
Kasus paparan TKI baru selama kehamilan juga telah dilaporkan. Satu kasus paparan
nilotinib selama trimester pertama dijelaskan pada pasien yang secara tidak terduga
menjadi hamil saat mengambil nilotinib 200 mg secara oral dua kali sehari sampai 7,4
minggu kehamilan [Conchon et al. 2009]. Dia melahirkan bayi tanpa cacat bawaan
diidentifikasi. Bayi terbukti memiliki perkembangan normal ketika mengikuti longitudinal
Tyrosine kinase inhibitor use during
pregnancy
There are few case reports of women being treated with tyrosine kinase inhibitors
(TKI) during pregnancy. Owing to the longer history of patients treated with imatinib,
there are more reports on pregnancy outcome after gestational exposure to imatinib
compared with the newer TKIs. A review of pregnancy outcomes of 180 females exposed to
imatinib during pregnancy was performed [Pye et al. 2008].The review found 50% of the
patients with known outcomes (125 out of 180) delivered normal infants, and 28%
underwent elective ter- minations, 3 following identification of abnormal- ities. Abnormalities
were identified in 12 infants with 9 of those defects occurring in the infants with known first
trimester exposure to imatinib. The review concluded that most pregnancies exposed to
imatinib are likely to have successful outcome but fetal malformations remain a risk.
Cases of exposure to newer TKI’s during preg- nancy have also been reported. One case of
expo- sure to nilotinib during the first trimester was described in a patient who unexpectedly
became pregnant while taking nilotinib 200 mg orally twice a day until 7.4 weeks of
pregnancy [Conchon et al. 2009]. She delivered a baby with no congenital malformation
identified. The baby was shown to have normal development when fol- lowed longitudinally
[Conchon et al. 2009].
Hasil jangka panjang anak-anak setelah terpapar kemoterapi di uterus
Risiko paparan in utero untuk kemoterapi diharapkan untuk memasukkan kelainan
dalam pertumbuhan, organogenesis, intelek dan reproduksi [Garber, 1989]. Secara
keseluruhan, laporan tindak lanjut jangka panjang menunjukkan beberapa efek
samping. Sebagian besar laporan ini berasal dari observasi setelah pengobatan
pasien hamil dengan kanker payudara, limfoma, leukemia dan tumor padat lainnya
[Gulati et al. 1986; Partridge dkk. 2000; Aviles dkk. 2001; Peres dkk. 2001; Hahn dkk.
2006; Ali et al. 2009; Cardonick dkk. 2010]. Banyak penelitian melaporkan bahwa
anak-anak ini memiliki tinggi dan berat badan normal dibandingkan dengan kontrol,
tidak memiliki perilaku abnormal atau defisit belajar, dan memiliki evaluasi psikologis
dan neurologis yang normal [Peres et al. 2001; Hahn dkk. 2006; Cardonick dkk. 2010].
Regimen kemoterapi selama kehamilan untuk kanker payudara, limfoma dan leukemia
termasuk anthracyclines, antimetabolites dan agen alkylating. Doxorubicin telah
menjadi obat yang paling umum digunakan selama kehamilan dengan sebagian besar
laporan yang menunjukkan tidak ada kelainan jantung yang terkait, meskipun satu
Long-term outcomes of children after exposure to chemotherapy in utero
The risks of in utero exposure to chemotherapy are expected to include
abnormalities in growth, organogenesis, intellect and reproduction [Garber, 1989].
Overall, long-term follow-up reports show few side effects. Most of these reports
come from observation following the treatment of pregnant patients with breast
cancer, lymphomas, leukemia and other solid tumors [Gulati et al. 1986; Partridge et
al. 2000; Aviles et al. 2001; Peres et al. 2001; Hahn et al. 2006; Ali et al. 2009;
Cardonick et al. 2010]. Many of the studies reported that these children have normal
height and weight compared with controls, have no abnormal behavior or learning
deficit, and have normal psychological and neurological eval- uations [Peres et al. 2001;
Hahn et al. 2006; Cardonick et al. 2010].
Chemotherapy regimens during pregnancy for breast cancer, lymphoma and leukemia
included anthracyclines, antimetabolites and alkylating agents. Doxorubicin has been the
most com- mon drug used during pregnancy with most reports showing no associated
cardiac abnor- malities, although one study reported on a trend towards a reduction in both
wall thick- ness and left ventricular mass index [Aviles et al. 2006; Van Calsteren et al. 2006].
Some studies reported on children exposed to chemo- therapy in utero developing reactive
airway dis- ease and recurrent otitis media [Garber, 1989; Aviles et al. 2001; Hahn et al.