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

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.

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.

Bone marrow Biopsy

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:

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

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.

Bone marrow Biopsy

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

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

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

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

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

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

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.