Precursor-B Lymphoblastic Leukemia / Lymphoma

(B-ALL / B-LBL)

Epidemiology:

· Children >> adults

o 75% < 6 y

· Down Synrdome predisposition

Common sites:

• bone marrow
• blood
• extramedullary sites are common:
• lymph nodes
• spleen
• CNS
• Liver
• Testis
• B-LBL:
• Skin
• Soft tissue
• Bone
• Lymph nodes
• Infrequently mediastinal masses

Histologic features:

· > 25% blasts in bone marrow is often used to define “leukemia” for many treatment protocols

o > 20% BM blasts is generally required (but no agreed-upon figure)

o < 25% for B-LBL

· Lymphoblasts obliterating normal architecture

o Intermediate size cells (10-20um)

o Scant to moderate amount of cytoplasm – very high N:C ratio (7:1 to 4:1)

§ Moderately to deeply basophilic

§ Agranular usually

· Coarse azurophilic granules (10%)

§ Vacuoles may be present

§ Cytoplasmic pseudopod (hand mirro cells) in some cases

o Nuclei somewhat larger than regular lymphocyte

§ Round to oval; occasinonally clefted, folded, convoluted, oblong, or angular

§ Fine and lacy chromatin, but more granular than myeloblasts

§ multiple nucleoli – variably prominent

· single-file growth often

· High rate of mitosis

o Focal starry sky pattern in some cases

· Lymph node:

o Diffuse or paracortical pattern of involvement

• FAB classification (3 types):
• B-ALL:
• L1:
• Small blasts
• Scant cytoplasm
• L2:
• Variation in size
• A bit more cytoplasm
• L3 (Burkitt’s):
• Dark blue cytoplasm with multiple vacuoles
• Nuclei with irregular outlines, folded

Immunophenotype and Special Stains:

Marker:	Sensitivity:	Specificity:
TdT	>95%
CD19, 22, 79a	Almost always	Some cases of T-ALL are positive
CD20	-/+
CD24	Most
PAX5	Most	Most specific in tissue sections (but t(8;21) AML is positive)
CD10	+/-*	+ in normal haematogones
Cytoplasmic mu	-/+
Surface Ig	Usually -ve
PAS	Sometimes, coarse granules	Not very specific (erythroid as well)
MPO (neg)	Always – positivity excludes this diagnosis
sIg (neg)	Characteristically, but not all	Normal B-cell precursors at the more mature stage are positive
HLA-DR
CD34	+/-
CD13	-/+
CD33	-/+
CD45	+/-

• Immunophenotype of precursor B-ALL differs in almost all cases from that seen in normal B-cell precursors (eg. haematogones)
• Prognostic impact:
• the strong correlation observed between certain immunophenotypic subgroups (e.g. CD10- prepre-B-ALL, pre-B-ALL) and unfavourable cytogenetic or clinical features (see above) has called into question the value of immunophenotyping as an independent predictor of treatment outcome (Ludwig et al. 1994)
• Pro-B ALL (pre-pre-B ALL) (GEIL pre-B1-ALL) (immature stage) (~10% of adults):
• CD19+, cyCD22+, CD24+, cyCD79a+, TdT+
• CD10-, cyIgM-, sIg-
• Associated with 11q23 translocations
• Older
• Higher WBC counts
• Poor prognosis for both children and adults
• Most studies in both childhood and adult ALL have reported a worse prognosis for patients whose leukaemic blasts express an immature CD10- pre-pre-B or null-ALL phenotype
• “can be, especially in infant ALL, explained by the association of this immunophenotype with adverse biological (ex. 11q23 rearrangements) and clinical features (eg. Hyperleukocytosis), occurring in up to 50% of patients.”
• prognosis and response to “classical therapeutic protocols” are more similar to T-lineage ALL, especially in children (Lenormand et al.)
• the worse prognosis of the pre-pre-B or pre-B phenotype could be attributed mainly to the distinct biological and clinical features of these subgroups, and the independent value of immunophenotyping in predicting outcome has not yet been established. In addition, a number of studies have shown that more effective treatment may lessen the negative prognostic impact of immunophenotypic features (e.g. in B-ALL). (Ludwig et al, 1994)
• Common ALL (intermediate stage)
• CD10+
• CD34+ (or +/-?)
• Pre-B-ALL (most mature precursor B differentiation stage)
• c-µ (cytoplasmic µ chains
• sIg- characteristically
• An unusual subtype is CD10- pre-B ALL (poor prognosis in Gleissner et al.)
• TdT+
• CD19+
• cyIgM+
• CD10-
• High prevalence of MLL rearrangements
• MLL-rearranged are poor prognosis while MLL not rearranged had survival ranging within standard-risk adult ALL
• GEIL immunophenotypic classification:
• GEIL pre-B1-ALL are CD10- (worse prognosis)
• GEIL pre-B2-ALL are CD10+
• GEIL pre-B3-ALL are CD20+
• GEIL pre-B4-ALL are cµ+
• GEIL B-ALL are sIg+
• Myeloid antigen expression (CD13, CD33) (10-40 % in adults)
• Controversial prognostic value
• Early studies suggested an inferior outcome
• Other series with protocols based on high-dose chemotherapies have failed to confirm a prognostic correlation
• The aberrant expression of myeloid markers CD13 and CD33 on either T or B cell blasts does not appear to confer a poor prognosis in adult ALL (Fielding 2011)
• myeloid antigen (CD13 and/or CD33) coexpression is not associated with a worse prognosis in adult ALL (Myron et al.)
• controversial
• Almost 50% of cases with a CD10- pre-pre-B phenotype expressed myeloid antigens (usually CDw65) as opposed to less than 20% (adults) or 10% (children) in the other BCP-ALL and most T-lineage subgroups

Molecular features:

• Acute leukemia testing guidelines
• Clonal DJ rearrangements of the IgH gene (nearly all)
• IgL gene rearrangement (some)
• TCR gene rearrangement (up to 70%)
• High hyperdiploidy (51-65 chromosomes, mode 55) (25% - up to 1/3 in children, < 10 % in adults) (good prognosis in adults, best prognosis in children) (higher incidence by FISH)
• 21 (99 %), X, 6, 14, 4, 18, 17, and 10 are most common
• Perhaps specific duplications are important
• Least common are 1, 2, and 3
• Flow and FISH may be used
• 21 is tetrasomic in ~70 %
• 14 and 18 may be tetrasomic
• Structural abnormalities (50 %) (unlikely to be of prognostic importance)
• 1q abnormalities (15 %) (specifically does not alter prognostic implications of high hyperdiploidy)
• Usually partial duplication
• 6q deletion (7 %)
• Isochromosomes (4 %)
• i(17)(q10) is most frequent (2 %)
• previous suggestion of association with relapse, but not confirmed
• Very good (best) prognosis in children
• > 90% cure rate
• 4, 10 (and previously17) together have the best prognosis
• Structural abnormalities are unlikely to be of prognostic importance in high-hyperdiploid ALL
• Childhood
• Not seen in infants
• Arises in utero (?always)
• Adults
• Younger adults
• No unique morphologic or cytochemical features
• Early pre-B / common immunophenotype
• CD19+ CD10+ and other typical markers, CD34+ CD45- often
• Associated molecular findings:
• PAX5 mutations and deletions common in childhood
• Other mutations: (1/3, mutually exclusive)
• FLT3
• NRAS
• KRAS
• PTPN11
• Evidence that most cases arise through a simultaneous gain of chromosomes in a single cell division
• Surprisingly high incidence in cases with a failed or normal karyotype
• Low hyperdiploidy (47-49 chromosomes)
• ?good prognosis as well
• Near triploidy:
• Note: rule out a duplicated hypodiploid clone
• Included within the low-hyperdiploid group for prognosis
• May harbor a hidden low-hyperdiploid clone (evident by FISH or DNA index)
• Near tetraploidy (84-100 chromosomes) (1% of childhood B-ALL):
• 90% have an ETV6-RUNX1 fusion in one study
• 6% of ETV6-RUNX1 fusion leukemias have near-tetraploidy
• Good prognosis which is attributed to the ETV6-RUNX1 fusion
• Hypodiploidy (5%)
• <46 chromosomes
• Perhaps < 45 or 44 is more important (~1%)
• Note endoreduplication may occur resulting in a hyperdiploid karyotype
• Discrepancy between FISH and karyotype is a clue
• Low hypodiploidy (30-39 chromosomes) and near triploidy (60-78 chromosomes) may be found together and are thought to represent the same process (high risk / poor prognosis in adults)
• Structural abnormalities maybe as well
• Children and adults
• Near haploid (23-29 chromosomes) is limited to childhood
• Poor prognosis
• 44-45 is better
• Near haploid is worst in some studies
• Low hypodiploidy and near triploidy both had significantly inferior EFS and OS compared with other Ph- adult ALL
• Similar curve to Ph+ve and complex and t(4;11) cases
• No unique morphologic or cytochemical features
• CD19+ CD10+ typically
• t(12;21)(p13;q22) (25%)
• TEL-AML1 (ETV6-RUNX1)
• Fusion protein interferes with normal function of RUNX1 (dominant negative)
• Very good prognosis
• > 90% cure rate
• childhood
• not seen in infants, rare in adults
• arises in utero (sometimes or always?) with development of leukemia years later
• necessary but not sufficient for development of leukemia
• CD19+ CD10+ CD34+ CD9- CD20- CD66c-
• Frequent myeloid antigen expression esp. CD13 (doesn’t indicate mixed phenotype leukemia)
• t(9;22)(q34;q11.2) – Philadelphia chromosome – BCR-ABL fusion transcript (25 % in adults)
• 25% of adult ALL (>50% over 55 y.), 2-5% of pediatric ALL, 95-100% of CML, 5% of AML
• ~1/2 of adult cases produce the same size fusion protein as in CML
• worst prognosis in ALL
• high WBC
• leukemia presentation (lymphomatous presentation rare)
• CD25+ (highly associated) CD10+ CD19+ TdT+, CD34+, more frequent myeloid antigens (CD13 and CD33), CD117-
• MLL rearrangements – t(v;11q23) (70%)
• Translocation between MLL gene (11q23) and any one of a large number of different fusion partners
• AFF1 (AF4/MLLT2/PBM1) on 4q21 is most common
• ENL (19p13)
• AF9 (9p22)
• t(4;11)(q21;q23) (30-50% in infants) (5% in adults) (high-risk / poor prognosis in adults)
• AFF1 (AF4/MLLT2/PBM1)
• der(11) has the pathogenetically essential transcript (MLL-AFF1)
• additional chromosomal changes often (30%) (no prognostic impact in childhood B-ALL)
• +X
• i(7)(q10)
• +8
• Lenormand et al. found no specific feature or different outcome for t(4;11) patients, who shared the clinical and biological characteristics of the whole series of pre-B1-ALL studied (children and adults)
• May occur in utero – frequently presents in very young infants (most common leukemia < 1 y)
• For adults, more common in younger adults
• Early B-precursor immunophenotype:
• CD10-
• CD19+
• CD24- or weak
• Myeloid-associated antigens often:
• CD15
• CD65s
• (not CD13 or CD33)
• Hyperleukocytosis
• Younger
• M > F
• High WBC count
• organomegaly
• Prognosis:
• t(4;11) MLL-AF4 translocations have a poor prognosis
• controvery whether MLL translocations other than MLL-AF4 have as poor a prognosis
• infants with MLL translocations, particularly < 6 months, have a particularly poor prognosis
• Very high WBC counts (> 100 x 10⁹ often)
• High frequency of CNS involvement at diagnosis
• Ludwig et al. found that “a portion of patients may achieve long-term remission and probably cure, after having received intensive postremission treatment”
• NG2+ (relatively specific)
• CD19+ CD10- CD24- CD15+ pro-B immunophenotype
• FLT3 overexpression
• MYC rearrangements
• t(8;14)(q24;q32) (high risk / poor prognosis in adults) and variants
• ?classified as Burkitt today?
• t(5;14)(q31;q32) (<1%)
• IL3-IGH
• Resulting in constitutive overexpression of IL3
• Functional consequences not understood
• Karyotype is best to detect
• Variable eosinophilia
• Increase in circulating eosinophils (reactive population)
• BM blast count may be low
• May present with an asymptomatic eosinophilia without any blasts in PB
• Children and adults
• CD19+ CD10+ (blasts)
• Finding of even a small number of blasts with this phenotype in a patient with eosinophilia should strongly suggest this diagnosis
• Prognosis similar to other ALL likely
• t(1;19)(q23;p13.3) (6%)
• E2A(TCF3) on 19 and PBX1 on 1
• Fusion gene on der(19) is a transcriptional activator
• Likely interferes with the normal transcriptional activity of E2A and PBX1
• May be loss of der(1)
• Standard risk on current treatment regimens (adults also standard risk in BCR-ABL1- group)
• previously bad prognosis
• children mostly
• for adults, younger adults mostly
• no unique morphologic or cytochemical features
• CD19+ CD10+ cytoplasmic mu+ heavy chain+ pre-B cell phenotype
• CD9+ (strong) CD34- or minimal
• Unique gene expression profile
• Note that some hyperdiploid B-ALL have a karyotypically identical t(1;19) involving different genes and with a different phenotype
• poor prognosis originally but modern ALL therapy is effective
• t(17;19)(q22;p13) (rare)
• E2A and HLF on 17
• Extremely poor prognosis
• Rare recurrent translocations:
• t(8;14)(q11;q32)
• IGH at 14q32
• CEBPD at 8q11
• Transcription factor
• Overexpressed as a result of the translocation
• Note 4 other CEBP gene family members have been described in ALL
• Down syndrome association
• t(9;22)(q34;q11) has been associated in non-Down syndrome patients
• older children and adults
• overall no increased risk of relapse (limited data available)
• cytogenetic alterations correlate with immunophenotype, gene expression patterns, and sometimes predict prognosis
• many of these aberrations dysregulate the expression and function of transcription factors required for normal hematopoietic cell development
• del(6)(q) (5-13% of ALL, both B and T)
• considerably variable breakpoints
• critical region has not been found; likely multiple genes involved
• GRIK2 (6q16) is a candidate
• most common are 6q15-q21
• terminal deletions are actually interstitial
• characteristic of lymphoid malignancies in general (NHL and CLL)
• usually in association with other abnormalities
• no evidence for impact on prognosis
• del(9)(p) (?improved prognosis as sole abnormality compared to other Ph- patients – see GIMEMA)
• dic(9;20)(p13.2;q11.2) (~2% pediatric (2-3y peak), ~0.5% adult)
• subtle on karyotype – may be mistaken for simple monosomy 20 and/or del(9p)
• breakpoints cluster to 9p13.2 and 20q11.2
• variable; no fusion genes identified; loss of material may be the important event
• CDKN2A lost
• Female predominance
• del(12)(p)
• t(17;19) (very rare)
• E2A-HLF
• Poor prognosis
• +21 (20%) (1% as a sole anomaly)
• Note: if found as the sole cytogenetic abnormality, look fro the presence of the ETV6-RUNX1 fusion by FISH or RT-PCR
• +5 (as a sole anomaly) (rare)
• Poor prognosis
• Pre-B immunophenotype
• i(21)(q10) (rare)
• associated with t(12;21)(p13;q22)
• ider(21)(q10)t(12;21)(p13;q22)
• if found as the sole cytogenetic change, look for the presence of the ETV6-RUNX1 fusion by FISH or RT-PCR
• clinical and prognostic associations are unclear
• AML1 amplification (chr. 21) (5%)
• iAMP21
• Poor prognosis
• dup(1)(q12-21q31-32) (no known prognostic effect – specifically no effect in high hyperdiploidy)
• mostly a secondary abnormality
• t(8;14)(q24;q32) in 1/3 of cases
• high hyperdiploid (1/3)
• often as the sole structural abnormality
• appears only in relapse
• may arise from an unbalanced translocation giving rise to a der(1)t(1;1)(p?;q?)
• proximal breakpoint near-centromeric (1q12-21.1)
• distal breakpoint heterogeneous
• 57.4 Mb minimally
• Normal karyotype (30 % of adults) (best prognosis in SWOG & GIMEMA)
• Complex karyotype (5 or more unrelated chromosomal abnormalities) (high risk)
• Extremely poor prognosis
• LOH:
• MLL (45% of pediatric acute leukemia)
• Down Syndrome:
• Don’t differ substantially from those seen in non-Down syndrome individuals
• Normal karyotype (40%)
• High hyperdiploidy (11%)
• t(12;21)(p13q22)(10%) (likely higher if molecular / FISH included)
• +X (40%) (sole in about 20%)
• t(8;14)(q11;q32) (3%)
• upregulation of CEBPD
• 9p deletion (sole in about 20%)
• t(9;22)(q34;q11) (1%)

Other features:

· BM failure:

o anemia

o thrombocytopenia

o neutropenia

· leukocytes may be decreased, normal or markedly elevated

· Very aggressive

· Good prognosis in kids

o > 95% CR

o 80 % cure rate

· 60-85% CR in adults

o < 50 % cure rate (~40 %)

· In adults, complex karyotype (5 or more unrelated chromosomal abnormalities) have been associated with a extremely poor prognosis

· COG risk groups for children (1-22 years): cytogenetics component

o Very high

§ Hypodiploidy with < 44 chromosomes

§ t(9;22)

§ induction failure

o high:

o standard:

§ t(1;19)(q23;p13.3)

o lower risk:

§ t(12;21)

§ simultaneous trisomies of chromosomes 4, 10, and 17 (high hyperdiploidy?)

· cytogenetic risk groups for adults:

o BCR-ABL1+ (highest-risk)

o High-risk (UK group):

§ t(4;11)

§ t(8;14)

§ HoTr (low hypodiploidy / near triploidy)

§ Complex (>=5 abnormalities if not fitting into other category)

o SWOG risk groups for adults (Pullarkat et al):

§ Proposed risk groups for adult ALL (including T-ALL):

· Standard risk:

· High hyperdiploidy (51-65 chromosomes)

· Intermediate risk:

· Normal

· Abnormality of 11q (not MLL rearrangement)

· 6q-

· 17p-

· 9p-

· 12p-

· -13

· 13q-

· 14q32 rearrangement

· t(10;14)

· low hyperdiploidy (47-50 chr)

· other TCR translocations

· tetraploidy (>80) (with no structural changes)

· all others

· high risk:

· -7 (Ph neg)

· 7p-

· +8

· other 11q23/MLL rearrangement aside from t(4;11)

· t(1;19)

· t(17;19)

· t(5;14)/TLX3 or CALM-AF10 in T-cell ALL

· very high risk:

· t(4;11)/AF4/MLL+

· t(8;14)/MYC/IGH+

· Complex (>= 5 abn) without translocations

· Low hypodiploidy (30-39) / near triploidy (60-78)

§ Used originally in their study:

· t(9;22) (worst OS and RFS)

· other unfavourable

· -7

· +8

· 11q23 rearrangement

· Miscellaneous

· Normal diploid (best OS and RFS)

o CALGB risk groups for adult ALL:

§ Unfavourable:

· t(9;22)

· t(4;11)

· -7

· +8

· Poor prognostic factors (other than cytogenetics)

o Infancy

o Age

§ > 10 y.

§ Also strong prognostic factor for adults

· Treating physicians are very much aware that age has, arguably, the most significant impact on outcome. (Fielding 2011)

· the incidence of “very high risk” cytogenetic categories, such as Philadelphia chromosome positive (Ph pos) ALL, increases with advancing age.

· In addition, the clearly documented biological differences tolerance of treatment is also generally poorer with advancing age.

§ But not significant in multivariate in SWOG for OS or RFS (?younger group)

o Higher WBC count

§ Percentage of blasts in the PB

§ for the purposes of stratification, cutoff levels for poor prognosis have been drawn at levels of 30 × 10^9 /L for those with B precursor ALL

§ Presenting WBC often predicts for any or all of the outcome measures tested, both for initial response, that is, achievement of complete remission (CR) after initial therapy, and for longterm outcome measures, such as event-free survival (EFS), disease-free survival (DFS), and overall survival (OS). (Fielding, 2011)

§ Not significant in multivariate in SWOG for OS or RFS

o Cytogenetic subgroup

o Day 14 marrow response (morphology)

§ Recent reports in childhood ALL have suggested that a response within 7–14 days is associated with the best prognosis [25]. However, this has never been prospectively confirmed in adult ALL. (Fielding 2011)

o Achievement of CR at 4 weeks (typically) for adults

o Minimal residual disease after therapy (PCR / flow cytometry)

§ Studies in both childhood and adult ALL have shown a significant correlation between MRD levels and subsequent relapse risk (Fielding 2011)

o CNS disease at diagnosis (5% of adults)

o Relapse:

§ Once ALL has relapsed in adults, survival is generally very poor (Fielding 2011)

o Presence or absence of mediastinal tumour

o Immunophenotype

o CNAs:

§ Abnormalities in key pathways, including lymphoid differentiation, cell cycle regulation, and tumor suppression, have all been identified as relating to outcome (Fielding, 2011)

§ genetic alteration of IKZF1, a gene that encodes the lymphoid transcription factor IKAROS, is associated with a very poor outcome in B-cell-progenitor ALL in patients who are otherwise characterized as standard-risk patients (Fielding 2011)

§ the nature and frequency of CNAs differ markedly among ALL genetic subtype (Fielding 2011)

§ There is no reason to suppose similar approaches will not yield exciting information in adult ALL, but data are presently lacking (Fielding 2011)

· B-LBL:

o Often asymptomatic

o Limited stage usually

o Favorable prognosis

· Treatment:

o Treatment of adult B-ALL

o To date, there are currently no data to suggest that the poor prognostic relevance of advanced age can yet be overcome by a “pediatric” therapeutic approach, but this is an active area of study.

o Several groups are already investigating the role of anti-CD20 antibodies in the treatment of ALL in adults. (Fielding 2011)

o

References:

· CAP Color Atlas of Hematology 1998

· Robbins and Cotran Pathologic Basis of Disease (2005)

· Swerdlow. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissue. 4th ed. WHO Publications; 2008.

· Forestier E, Gauffin F, Andersen MK, et al. Clinical and cytogenetic features of pediatric dic(9;20)(p13.2;q11.2)-positive B-cell precursor acute lymphoblastic leukemias: a Nordic series of 24 cases and review of the literature. Genes Chromosomes Cancer. 2008;47(2):149-158.

· Heim S, Mitelman F. Cancer Cytogenetics. 3rd ed. Wiley-Blackwell; 2009.

· Moorman AV et al. Karyotype is an independent prognostic factor in adult acute lymphoblastic leukemia (ALL): analysis of cytogenetic data from patients treated on the Medical Research Council (MRC) UKALLXII/Eastern Cooperative Oncology Group (ECOG) 2993 trial. BLOOD (2007);109(8):3181-3197.

· Moorman AV et al. A population-based cytogenetic study of adults with acute lymphoblastic leukemia. Blood 2010;115:206-214.

· Ludwig et al. Immunophenotypic and Genotypic Features, Clinical Characteristics, and Treatment Outcome of Adult Pro-B Acute Lymphoblastic Leukemia: Results of the German Multicenter Trials GMALL 03/87 and 04/89. Blood, Vol 92, No 6 (September 15), 1998: pp 1898-1909

· Gleissner B et al. CD10- pre-B acute lymphoblastic leukemia (ALL) is a distinct high-risk subgroup of adult ALL associated with a high frequency of MLL aberrations: results of the German Multicenter Trials for Adult ALL (GMALL). Blood 2005;106:4054-4056

· Lenormand B et al. PreBl (CD10-) Acute Lymphoblastic Leukemia: Immunophenotypic and Genomic Characteristics, Clinical Features and Outcome in 38 Adults and 26 Children. Leukemia and Lymphoma 1998; Vol. 28. pp. 329-342

· Pullarkat V et al. Impact of cytogenetics on the outcome of adult acute lymphoblasticleukemia: results of Southwest Oncology Group 9400 study. Blood 2008;111:2563-2572

· Czuczman MS et al. Value of Immunophenotype in Intensively Treated Adult Acute Lymphoblastic Leukemia: Cancer and Leukemia Group B Study 8364. Blood, Vol 93, No 11 (June 1), 1999: pp 3931-3939

· Wetzler et al. Prospective Karyotype Analysis in Adult Acute Lymphoblastic Leukemia: the Cancer and Leukemia Group B Experience. Blood 1999:93(11):3983-3993.

· Ludwig WD, RAGHAVACHAR A, THIEL E. Immunophenotypic classification of acute lymphoblastic leukaemia. Bailli~re' s Clinical Haematology Vol. 7, No. 2, June 1994.

· Vitale A, Guarini A, Ariola C, et al. Absence of prognostic impact of CD13 and/or CD33 antigen expression in adult acute lymphoblastic leukemia. Results of the GIMEMA ALL 0496 trial. Haematologica. 2007;92(3):342-348.

· Fielding AK. Prognostic Factors in Adult Acute Lymphoblastic Leukemia (ALL). In: Advani AS, Lazarus HM, eds. Adult Acute Lymphocytic Leukemia. Totowa, NJ: Humana Press; 2011:89-96. Available at: http://www.springerlink.com.myaccess.library.utoronto.ca/content/r28g8348721m176t/. Accessed September 8, 2011.

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