Handout for lecture on lymphoblastic neoplasms presented by Rob McKenna

Transcription

1 Handout for lecture on lymphoblastic neoplasms presented by Rob McKenna The following slides represent a near final version of the presentation that will be given in Maui, January 23,2018. Minor changes in slides and order of slides may appear in the actual lecture. Lymphoblastic Neoplasms Presented by: Robert W. McKenna Notice of Faculty Disclosure In accordance with ACCME guidelines, any individual in a position to influence and/or control the content of this CME activity has disclosed all relevant financial relationships within the past 12 months with commercial interests that provide products and/or services related to the content of this CME activity. The individual below have responded that they have no relevant financial relationship with commercial interest to disclose: Robert W. McKenna, MD 1

2 Lymphoblastic Leukemia / Lymphoma (Acute Lymphoblastic Leukemia ALL) Morphology and Immunophenotype Genetics WHO Classification 2016 Prognostic indicators MRD Current status and future Lymphoblasts in two Patients with ALL Lymphoblasts in two Patients with ALL 2

3 Cytoplasmic Granules in Lymphoblasts in ALL t(9;22) B ALL Down Syndrome-B ALL Bone marrow B cell precursors Hematogones Size and morphology bridge mature lymphocytes and neoplastic lymphoblasts Large percentages seen in healthy infants and young children Increased in Regenerating marrows Autoimmune or congenital cytopenias Lymphoma, neuroblastoma AIDS Immunophenotyping Distinguishes ALL from AML and B from T ALL Identifies subsets of both B and T ALL Immunophenotypic prognostic / treatment groups T lymphoblastic higher risk than B lymphoblastic Early T cell precursor leukemia, CD10( ) B ALL, etc. MRD detection B ALL T ALL 3

4 Cytogenetics in ALL Defines prognostic and treatment groups one of the most important factors in riskstratification treatment Defines categories of B lymphoblastic leukemia in WHO classification Karyotype Abnormalities 75% of all cases 80% of B lymphoblastic leukemia 50 60% of T lymphoblastic leukemia Significantly higher by molecular cytogenetics (FISH) Frequency of specific genotypes in childhood lymphoblastic leukemia Pui C et al. JCO 2011;29: Relationship of Cytogenetics to Prognosis in B ALL Prognostic Group Cytogenetic Abnormality Low Risk Hyperdiploidy >50 t(12;21) Intermediate Risk Hyperdiploidy Diploid, 6q, t(1;19) 9p abnormalities High Risk Hypodiploid Near Haploid t(9;22), t(4;11), t(5;14) t(17;19) 4

5 B Lymphoblastic Leukemia with Hyperdiploidy B Lymphoblastic Leukemia with t(9;22)(q34;q11.2), BCR ABL1 Gene Expression Profile of 132 Pediatric ALL Blood. 2003; 102:

6 Complex genomic alterations and gene expression in acute lymphoblastic leukemia with intrachromosomal amplification of chromosome 21 Jon C. Strefford*, Frederik W. van Delft, Hazel M. Robinson*, Helen Worley*, Olga Yiannikouris, Rebecca Selzer, Todd Richmond, Ian Hann**, Tony Bellotti, Manoj Raghavan, Bryan D. Young, Vaskar Saha, and Christine J. Harrison* We have previously identified a unique subtype of acute lympho- blastic leukemia (ALL) associated with a poor outcome and char- acterized by intrachromosomal amplification of chromosome 21 including the RUNX1 gene (iamp21). In this study, array-based comparative genomic hybridization (acgh) (n 10) detected a common region of amplification (CRA) between and Mb and a common region of deletion (CRD) between 43.7 and 47 Mb in 100% and 70% of iamp21 patients, respectively. High- resolution genotypic analysis (n 3) identified allelic imbalances in the CRA. Supervised gene expression analysis showed a distinct signature for eight patients with iamp21, with 10% of overex- pressed genes located within the CRA. The mean expression of these genes was significantly higher in iamp21 when compared to other ALL samples (n 45). Although genomic copy number correlated with overall gene expression levels within areas of loss or gain, there was considerable individual variation. A unique subset of differentially expressed genes, outside the CRA and CRD, were identified when gene expression signatures of iamp21 were compared to ALL samples with ETV6-RUNX1 fusion (n 21) or high hyperdiploidy with additional chromosomes 21 (n 23). From this analysis, LGMN was shown to be overexpressed in patients with iamp21 (P ). Genomic and expression data has further characterized this ALL subtype, demonstrating high levels of 21q instability in these patients leading to proposals for mechanisms underlying this clinical phenotype and plausible alternative treatments. PNAS (2006); 103: Contributions of Newer Technologies in Molecular Genetics High resolution genome wide analysis Provides new insights into pathobiology of ALL Identifies novel subtypes of leukemia, especially markers of high risk disease Potential targets for molecular based therapy N Engl J Med 2009; 360:

7 Deletion of IKZF1 in ALL Encodes lymphoid transcription factor IKAROS Frequent event (80%) in BCR ABL1 positive ALL Associated with MRD at day 29, relapse and poor outcome Poor outcome in both BCR ABL1 (+) and BCR ABL1 ( ) [ BCR ABL1 like ] ALL Blood 2010;115: WHO Classification of Lymphoblastic Leukemia/Lymphoma 2017 B lymphoblastic leukemia/lymphoma, NOS B lymphoblastic leukemia/lymphoma with recurrent genetic abnormalities (9 categories) T lymphoblastic leukemia/lymphoma (1 subset) Natural killer cell leukemia/lymphoma (provisional) 7

8 B Lymphoblastic Leukemia/Lymphoma (B LL/L) With Recurrent Genetic Abnormalities B LL/L with t(9;22)(q34.1;q11.2); BCR ABL1 B LL/L with t(v;11q23.3); KMT2A/MLL rearranged B LL/L with t(12;21)(p13.2;q22.1); ETV6 RUNX1/TEL AML1 B LL/L with hyperdiploidy BLL/L with hypodiploidy* Near haploid Low hypodiploid B LL/L with t(5;14)(q31.1;q32.1); IGH/IL3 B LL/L with (1;19)(q23;p13.3); TCF3 PBX1/E2A PBX1 B LL/L BCR ABL1 like (provisional)* B LL/L with iamp21 (provisional)* B Lymphoblastic Leukemia/Lymphoma with Hypodiploidy (hypodiploid ALL) 5% of ALL; 1% with<45 chromosomes Near haploid (23 29 chromosomes) RAS or receptor tyrosine kinase mutations Poor prognosis Low hypodiploid (33 39 chromosomes) TP53 (some germline) and/or RB1 mutations? Is low hypodiploid ALL a form of Li Fraumeni syndrome Poor prognosis High hypodiploid (40 43 chromosomes) Near diploid (44 45 chromosomes) B Lymphoblastic Leukemia/Lymphoma with iamp21 2% of B ALL; more common in older children Detected with FISH probe to RUNX1 5 or more copies of RUNX1 or 3 or more on a single abnormal chromosome 80% have other chromosome abnormalities (gains in X, abnormalities of 7) Deletions of RB1 and ETV6; rearrangement of CRLF2 Constitutional Robertsonian translocation rob(15;21)q10;q10)c has 3000 fold increase in this leukemia; appears to involve chromothripsis Relatively poor prognosis with standard therapy 8

9 B Lymphoblastic Leukemia/Lymphoma, BCR ABL1 like Lack the BCR ABL1 translocation but have a very similar gene expression profile to ALL with BCR ABL % of B ALL Frequency lowest in children with standard risk ALL Higher in those with high risk ALL, adolescents, and adults Higher in children with Downs, Hispanics and native Americans Genetics of B lymphoblastic Leukemia/Lymphoma, BCR ABL1 like Different types of chromosomal rearrangements Many different genes and partners involved May require complex laboratory analysis to identify these CRLF2 rearrangements account for about half Often show interstitial deletion of pseudoautosomal region Xp22.3 and Yp11.3 Half of these have mutations of JAK2 or JAK1 TK type translocations, ABL1 or other kinases Over 30 different partner genes described Many BCR ABL1 like ALL show deletions or mutations in genes important to leukogenesis IKZF1 and CDKN2A/B Treatment and Prognosis of B Lymphoblastic Leukemia/lymphoma, BCR ABL1 like Overall poor prognosis Other high risk features Older age; High WBC; MRD (+) High risk of relapse independent of all other risk factors Most have targetable lesions involving ABL or JAK STAT signaling pathways ABL, PDGFRB, etc Dasatinib CRLF2, JAK2, etc Ruxolitinib 9

10 T Lymphoblastic Leukemia/Lymphoma (T LL/L) T lymphoblastic leukemia/lymphoma (T LL/L) Early T cell precursor LL/L* Natural killer cell leukemia/lymphoma (provisional)* T Lymphoblastic Leukemia T Lymphoblastic Lymphoma 10

11 T Lymphoblastic Lymphoma-Low Level BM Involvement Flow Cytometry Histograms of BM From a Patient with Low Level Involvement with T Lymphoblastic Lymphoma T Lymphoblastic leukemia/lymphoma Improved prognosis with intensive chemotherapy regimens 65% to 75% overall survival in children Conventional cytogenetics studies are less contributory in identifying risk groups Immunophenotype and gene expression profile identify A sub set of TLL/L: Early T Cell Precursor Leukemia (ETP ALL) 11

12 Lancet Oncol. 2009; 10: Early T Cell Precursor (ETP) Leukemia 10% to 15% of T ALL Derived from a subset of thymocytes that retain stem cell like features Distinctive phenotype CD1a, CD8,CD5 weak with stem cell/myeloid agns. ETP related gene expression signature Early T Cell Precursor Leukemia Coustan Smith MS, etal. Lancet Oncol. 2009, 10:

13 Prognosis of Early T cell Precursor ALL (ETP ALL) Initial descriptions reported a very poor outcome compared with other T ALL More recent larger studies with more effective therapy show little or no effect on outcome for ETP ALL This despite higher rates of MRD following induction therapy Prognostic Indicators In ALL Clinical Age Leukocyte count CNS involvement Immunophenotype Cytogenetics Rapidity and degree of cytoreduction and MRD Minimal Residual Disease (MRD) Early treatment response is most important prognostic factor in ALL Early response reflects: Leukemic cell genetics Host pharmacodynamics and pharmacogenetics Effectiveness of treatment regimen Assessed by measurements of MRD 13

14 Sensitivity of Methods for Detection of Lymphoblasts in Bone Marrow Flow Cytometry 0.01% to 0.005% Molecular (PCR) 0.01% to % Minimal Residual Disease in a Patient with B ALL (t(9;22)(q34;q11.2); BCR/ABL1) Diagnostic Marrow Following Induction Rx 0.01% B Lymphoblasts Courtesy of Steven H. Kroft, M.D. Prognostic Significance of End of Induction MRD in Patients with ALL Borowitz MJ, etal. (2008) Blood; 111:

15 Prognostic Significance of End of Consolidation MRD in Patients with ALL 197 relapsed 33 relapsed Borowitz MJ, etal. (2008)Blood; 111: COG Risk Classification of B ALL First assigned to standard or high risk Patient age White blood cell count Cytogenetic abnormalities and MRD then refine risk classification Low High hyperdiploidy, t(9;21) Standard/intermediate High Age, WBC Very high Hypodiploidy, Ph+ ALL, Ph like ALL, iamp21, t(17;19) High level MRD after induction and persistent MRD at later time points Five year survival rates for children less than 15 years old with ALL: SEER Cancer Statistics Review. 15

16 Prognosis for Children with ALL to 20% of children with B ALL and 25 to 35% with T ALL are not cured Relapsed ALL remains the 4 th commonest childhood malignancy Most common cause of cancer deaths in kids Further improvement by dose escalation will be limited by toxicities To improve cure rates further less toxic targeted approaches are necessary Eg., tyrosine kinase inhibitors, JAK inhibitors, CAR T cells (anti CD19 engineered T cells), etc. Thank you! Questions? Natural Killer(NK) Cell Lymphoblastic Leukemia/Lymphoma (provisional) Difficult to define Many (CD56 +) reported cases are now recognized as blastic plasmacytoid dendritic neoplasms May have a primitive immunophenotype indistinguishable from AMLminimally differentiated (myeloid/nk acute leukemia) Early NK cell progenitors lack specific markers or overlap with T ALL (CD7, CD2, even CD5 and CD3 epsilon) distinction may be difficult More mature markers (CD16) are rarely expressed (CD94 or CD161 are not commonly tested May be considered in cases expressing CD56 and T associated antigens such as CD7, CD2 and even ccd3 if T cell and IG receptor genes are germline and blastic plasmacytoid dendritic cell leukemia is excluded Hopefully wider availability of more specific NK markers such as panels against KIRs will help clarify the disease Best considered a provisional entity 16