Recent advances in the biology and treatment of B-cell acute lymphoblastic leukemia

Figures & data

Table 1 Common genomic abnormalities in B-cell acute lymphoblastic leukemia and their prognostic significance

Risk class	Involved gene	Frequency
		Adults	Children
Favorable risk
Cytogenetic (numerical change)
Hyperdiploid	TP53, CREBBP	2%–15%	10%–26%
Tetraploid
Cytogenetic (translocation)
t(12;21)(p12;q22)	ETV6-RUNX1	<1%	20%–25%
High risk
Cytogenetic (numerical change)
Hypodiploid	RAS, IKZF2, TP53	5%–10%	5%–10%
Near-triploid	Unknown/unidentified	3%–5%	1%
Trisomy 8	Unknown/unidentified	10%–12%	2%
Monosomy 7	Unknown/unidentified	6%–11%	4%
Cytogenetic (translocation)
t(9;22)(q34;q11)	BCR-ABL, IKZF, CRLF2	15%–25%	2%–6%
t(4;11); t(9;11); t(19;11); t(3;11)	MLL with various partners	5%–10%	<5%
t(8;14); t(8;22); t(2;8)	C-MYC with various partners	5%	2%–5%
t(17;19)	E2A-HLF	<5%	<5%
Cytogenetic (other)
Complex cytogenetic		5%–10%	2%
iAMP21	RUNX1	–	2%
7 p deletion	Unknown/unidentified	5%–10%	<5%
17 p deletion	TP53	8%	2%
9 p deletion	CDKN2A, CDKN2B	7%–11%	6%–30%
Molecular genetics
CRLF2 overexpression	CRLF2	5%–10%	5%–10%
IGH rearrangement	IGH	<3%	10%
JAK mutations	JAK1, JAK2	7%–18%	2%
Gene expression
BCR-ABL1-like	CRLF2, IKZF1, JAK2, ABL1, ABL2, PDGFRB, EPOR, RAS, NTRK3	25%–30%	10%
Intermediate risk Cytogenetics
t(1;14); t(10;14); t(5;14)	TCR with various oncogenes	~35%	~35%

Note: Data from Mrózek et al.¹¹⁸

Table 2 Characteristics of conventional and new high-throughput MRD techniques

Technique	Target	Applicability	Sensitivity	Advantages	Disadvantages
RQ-PCR (Ig/TCR)	Ig/TCR gene rearrangement	Up to 90%	10^−4–10^−5	• High sensitivity • Large applicability • Well-standardized	• Time-consuming • Target instability • Require more experience
RQ-PCR (fusion gene)	Fusion gene transcripts	30%–40%	10^−4–10^−6	• High sensitivity • Rapidity and easy use • Target stability	• Cross-contamination risk • Applicable for specific leukemia subgroups
MFC	Leukemic cell immunophenotype	>90%	10^−3–10^−4	• Relative high sensitivity • Rapidity • Large applicability	• Difficult to standardize • Require more experience • Phenotype switch
NGS	Ig/TCR gene rearrangements	>90%	10^−5–10^−6	• Highest sensitivity • Large applicability	• Not yet standardized • Expensive
EuroFlow-based flow cytometry (≥8 colors)	N-dimension-based deviations from normal leukocytes	>90%	10^−4–10^−5	• Rapidity (within 3–4 hours) • High applicability • Highly standardized • Many labs in Europe	• Require more experience • Many cells needed • Still limited in the US • Validation ongoing
Ig/TCR HTS	Ig/TCR gene rearrangements	>95%	10^−4–10^−6	• High sensitivity • High applicability • Not dependent on primers • Identifies oligoclonality	• Time-consuming • No standardization • Limited number of labs • Validation ongoing

Abbreviations: HTS, high-throughput sequencing; MFC, multicolor flow cytometry; MRD, minimal residual disease; NGS, next-generation sequencing.

Figure 1 Monoclonal antibodies under investigation for treatment of B-cell acute lymphoblastic leukemia.

Note: List is not comprehensive.
Abbreviations: ADC, antibody drug conjugate; AYA, adolescents and young adults; B-ALL, B-cell acute lymphoblastic leukemia; BFM, Berlin-Frankfurt-Munster; BiTE, bispecific T-cell engager; chemo, chemotherapy; HCVAD, hyperfractionated cyclphosphamide, vincristine, adriamycin, dexamethasone; HCT, hematopoietic cell transplantation; mAb, monoclonal antibody; Ph, Philadelphia; R/R, relapsed/refractory.

Figure 2 Overall survival in adults with relapsed or refractory acute lymphoblastic leukemia treated with blinatumomab vs chemotherapy (TOWER Study).

Note: From the New England Journal of Medicine, Kantarjian H, Stein A, Gökbuget N, et al, Blinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic Leukemia, 376(9):836–847. Copyright © (2017) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.⁹⁴

Figure 3 Overall survival in adults with relapsed or refractory ALL treated with inotuzumab ozogamicin vs standard intensive chemotherapy (INO-VATE Trial).

Note: From the New England Journal of Medicine, Kantarjian HM, Deangelo DJ, Stelljes M, et al, Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia, 375(8):740–753. Copyright © (2016) Massachusetts Medical Society. Reprinted with permission from Massachusetts Medical Society.¹⁰⁵

MrózekKHeeremaNABloomfieldCDCytogenetics in acute leukemiaBlood Rev200418211513615010150

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KantarjianHSteinAGökbugetNBlinatumomab versus Chemotherapy for Advanced Acute Lymphoblastic LeukemiaN Engl J Med2017376983684728249141

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KantarjianHMDeangeloDJStelljesMInotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic LeukemiaN Engl J Med2016375874075327292104

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