Lineage Switch Under Blinatumomab of a Relapsed Common ALL Co-Expressing Myeloid Markers without MLL Rearrangement
Authors: Zoghbi Annabel , Winkler Beate , zur Stadt Udo , Müller Ingo , Escherich Gabriele 
Published: October 2019

Abstract
Lineage switch under Blinatumomab of a relapsed Common ALL co-expressing myeloid markers without MLL rearrangement
Annabel Zoghbi, Udo zur Stadt, Beate Winkler, Ingo Müller and Gabriele Escherich
Background
The bispecific antibody blinatumomab induces T cell-mediated B cell lysis by adhering to CD3 positive cytotoxic T cells and attaching to CD19, a marker which is commonly seen in lymphoblastic malignancies of the B cell lineage. It has been proven to be an effective therapeutic option for adult and pediatric refractory or relapsed B cell precursor acute lymphoblastic leukemia (ALL).
Lineage switch from ALL to a CD19 negative myeloid phenotype is well known in patients with mixed lineage leukemia (MLL) gene rearrangements and has been recently described following blinatumomab treatment in an infant with MLL rearrangement as well as for two patients with MLL rearrangement who were treated with CAR-T cells.
Case description
A nine year old girl with common ALL ( strong positivity for CD 10,19, 24,34,45, 52 and 79a) with the coexpression of myeloid markers (CD13 86% and CD66c 56%) was treated according to CoALL 08-09 high risk protocol and showed a very slow MRD response. Cytogenetic studies showed a hyperdiploid karyotyp without evidence of a MLL, BCR/ABL or TEL/AML rearrangement. Only one month into maintenance therapy she relapsed with the phenotype of the initial blasts. Because of non-response (M3 marrow) after the first two cycles of treatment accorting to the IntReALL protocol with a M3 marrow. The patient became aplastic for 2 months and developed aspergillus pneumonia, which was treated by combination of antifungals and granulocyte infusions. Nevertherless, blinatumomab treatment was initiated. The patient tolerated treatment well and did not develop a cytokine release syndrome, but eventually recovered granulopoiesis under blinatumomab treatment. Leukemic blasts below the 1% border, however, were detectable throughout immunotherapy. In the absence of other opportunities, we planned on a HSCT and in the event of relapse thereafter re-initiation of Blinatumomab in the allogeneic setting with the new immune system developing. Hence, the patient underwent an uneventful MUD-HSCT in March 2016 following conditioning with TBI/VP-16 and serotherapy with alemtuzumab due to CD52 expression of the blasts. On day 29 after transplant, a routine bone marrow aspiration revealed a second molecular relapse at the order of 2 x 10-3with the same immunophenotype. Thus, immunosuppression with cyclosporine A was drastically lowered and a grade II skin GvHD developed, which was controlled by topic treatment, before CsA was discontinued.
Blinatumomab was reinitiated on day 49 after SCT. After two and a half weeks on therapy, an increase in LDH and leukocytes was visible. Bone marrow aspiration showed disease progression with 70% blasts, which now were CD19 negative with the immunophenotypical and morphological attributes of myeloid leukemia. Nevertheless, initial MRD markers still were strongly positive, indicating the common precursor with the initial phenotype. Detailed analysis will be presented. Cytogenetic analysis of the relapse samples revealed no changes.
With no curative approach remaining, palliative therapy with cytarabine and thioguanine was initiated which could not control the fulminant expansion of leukemic cells, leading to the patient's death within four days from diagnosis.
Conclusion
CD19 negative relapses following blinatumomab therapy have been perceived in recent treatment studies, while reports on immunologic and morphologic presentation of a myeloid phenotype are scarce. Our patient coexpressed myeloid markers, CD13 and CD66c, from the start, thus, it is possible that subclones who did not carry CD19 had a pronounced selection advantage during blinatumomab treatment, leading to their vast expansion.

Disclosures
No relevant conflicts of interest to declare.