1. B-ALL as the Initial Presentation of a Hematopoietic Neoplasm with t(8;22)/BCR-FGFR1 The University of Texas MD Anderson Cancer Center Department of Hematopathology Wei Wang

2. Background  FGFR1-associated hematopoietic neoplasm, also known as 8p11 myeloproliferative syndrome, is a rare entity.  Present as a chronic myeloproliferative neoplasm with eosinophilia, with increased risk of blast transformation.  Blast phase: often myeloid or T-lymphoid, rarely B- lymphoid.  The most common translocation is t(8;13)(p11;q12)/ ZNF198, present in 50% of the cases.  Here, we present a case with t(8;22)(p11;q11)/BCR-FGFR1 and discuss the significance of clonal evolution.

3. Initial presentation A 55-year-old female presented with 48x10 9 /L WBC and 22% circulating blasts. BM biopsy: B-lymphoblastic leukemia (B-ALL) with 52% blasts.

4. Bone marrow Biopsy

6. 46,XX,t(8;22)(p11.2;q11.2)[9]/47,XX,t(8;22)(p11.2;q11.2),+der(22)t(8;22)[10]/ 46,XX[1] Karyotype Three patterns:

7. FGFR1dual color breakapart probe  1, lymphocyte (not labeled) : two normal fusion signals, C/W 46,XX  2, myeloid cells (arrows) : one fusion, one green and one red, C/W 46,XX,t(8;22)(p11.2;q11.2)  3, lymphoblasts (arrowheads): one fusion, one green, and two red, C/W 47,XX,t(8;22)(p11.2;q11.2),+der(22)t(8;22) FISH Three patterns: Dr. Guilin Tang

8. Clinical course Induction therapy with hyper-CVAD. Achieved complete remission. Flow MRD for B-ALL was negative. Consolidation therapy with POMP, followed by single agent blinatumomab maintenance therapy. 11 months after B-ALL diagnosis, the patient presented with rising WBC (up to 44x10 9 /L). Flow MRD for B-ALL was negative.

9. Bone marrow Biopsy

10. Cytogenetic during B-ALL remission Karyotype: two patterns: 46,XX,t(8;22)(p11.2;q11.2)[13]/46,XX[7]

11. FISH during B-ALL remission Two patterns:  1, a subset of myeloid cells : one fusion, one green and one red, C/W 46,XX,t(8;22)(p11.2;q11.2)  2, others: two normal fusion signals, C/W 46,XX

12. Diagnosis Myeloproliferative neoplasm with t(8;22)/BCR-FGFR1, chronic phase.

13. B-ALL diagnosis Hyper-CVAD + Ofatumumab POMP therapy Blinatumomab Ponatinib Hydrea SCT B-ALL MRD negative by flow Clinical course and WBC count POMP: 6-mercaptopurine, vincristine, methotrexate, and prednisone

14. Model Hematopoietic stem cells t(8;22) Myeloid progenitor cells Lymphoid progenitor cells T B +der(22)t(8;22)

15. Literature review: t(8;22) CaseAge/SexChronic phaseBlast phase Serdy et al.78/FN/At(8;22)(p11.2;q11.2), del(11)(q13q23), add(9)(p22),-7 Wakim et al.43/Mt(8;22)(p11.2;q11.2)45,XY,t(6;11)(q11;p13),−7,t(8;22)(p11.2;q11.2),del(9)(p13p22) Baldazzi et al.70/Ft(8;22)(p11;q11) 46, XX, t(8;22)(p11;q11) [10]/45, idem, del(3)(p11p21),del(7)(p12p15), add(8)(p23),-9[6]/46, XX[4] Haslam et al.21/M46,XY,t(8; 22)(p12;q11)[30] 46,XY,t(8; 22)(p12; q11)[8]/45,idem,der(3; 9)(q10;q10),dic(7; 11)(p11; q13),+r [cp3] Matikas et al.74/FN/A46,XX,del(5)q33q35,t(8;22)(p11;q11) Fioretos et al.75/MN/A46,XY,t(8;22)(p11;q11),t(9;21)(q34;q22) Kim et al.59/MN/A47,XY,t(8;22)(p11.2;q11.2),+19[16]/46,XY[1] Lee, et al.50/F 46,XX,t(8;22)(p11;q11)[9]/46,XX,t(8;22)(p11;q11),i(9)(q10)[1 1] 46,XX,t(8;22)(p11;q11)[21] Shimanuki et al.58/FN/A45,XX,t(8;22)(p11;q11),-16,add(19)(p13)[16] Morishige et al.50/MN/A46, XY, t(8;22)(p11.2;q11.2)[20] Richebourg et al. 56/F46,XX,t(8;22)(p11.2;q11.2)[20]47,XX,t(3;21)(q26;q22),t(8;22)(p11;q11),+der(22)t(8;22)[9] Murati et al.68/Mt(8;22)(p12;q11)N/A Demiroglu et al.65/Ft(8;22)(p11.2;q11.2)N/A Demiroglu et al.51/Ft(8;22)(p11.2;q11.2)N/A Pini et al.74/Ft(8;22)(p11;q11)N/A Patnaik et al.57/F46,XX,t(8;22)(p11.2;q11.2)[20]N/A Dolan et al.8/M46,XY,inv(4)(p15.2q13),t(8;22;14)(p11.2;q11.2;q24)[19]N/A 82% (9/11) of cases in blast phase had additional cytogenetic abnormalities. In contrast, only 18% (2/11) of cases in chronic phase had additional cytogenetic abnormalities

16. Take home message 1.Hematopoietic neoplasm with FGFR1 rearrangement can have acute leukemia as the initial presentation. 2.Different from other fusion partners, t(8;22) is often:  No eosinophilia  Blast Phase: B-ALL instead of AML and T-ALL.