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Clinical evidence for a graft-versus-tumour effect following allogeneic HSCT for t(8;13) atypical myeloproliferative disorder

Bone Marrow Transplantation volume 44, pages 197–199 (2009)Cite this article

The 8p11 eosinophilic myeloproliferative syndrome (EMS) is a rare haematological malignancy characterized by myeloid hyperplasia and eosinophilia. It is associated with balanced translocations involving chromosome 8p11, most commonly t(8;13)(p11;q12).1, 2 The condition classically presents with lymphadenopathy, malaise and weight loss.1 The presence of the translocation in both myeloid and lymphoid cell lines suggests that it is a true stem cell disorder.3 Approximately 75% of cases present with or develop precursor T-cell lymphoblastic lymphoma, and most subsequently develop acute leukaemia, most typically of myeloid phenotype. The translocation most commonly involves the fusion of the fibroblast growth factor receptor 1 gene (FGFR1) with the N-terminal of zinc-finger 198 gene (ZNF198), causing constitutive activation of the FGFR1 tyrosine kinase. Rarer fusion partners include CEP110, FOP and BCR (associated with t(8;9)(p11;q33), t(6;8)(q27;p11) and t(8;22)(p11q22), respectively).3, 4 Treatment with chemotherapy alone has been unsuccessful with early relapse or progression to acute leukaemia reported in 10 of 13 cases in one series.1 The constitutively active fusion protein tyrosine kinases are attractive targets for targeted signal transduction therapy. Currently available tyrosine kinase inhibitors do not have significant activity against the FGFR1 tyrosine kinase. Although small molecule inhibitors with in vitro activity against FGFR are in phase I clinical trials (for example, TKI258, a multitargeted receptor tyrosine kinase inhibitor with activity against FGFR, VEGFR, PDGFR, FLT3 and KIT),5 presently only allogeneic haematopoietic SCT (HSCT) appears to be effective in eradicating or suppressing the malignant clone. The longest reported survival after HSCT is 3.3 years.6 We report the case of a patient with EMS and the t(8;13) translocation treated with allogeneic HSCT. Persistent minimal residual disease (MRD) was detected by PCR following transplantation and confirmed to be present within the CD34+ compartment. MRD was successfully eliminated with incremental doses of donor lymphocyte infusions (DLIs) and occurred coincident with the development of GVHD. He remains in remission at 5 years after transplantation. This is the first reported case of successful molecular remission induced by DLIs in this disorder, and the temporal association with development of GVHD suggests that graft-versus-tumor activity akin to that seen in CML may be an important therapeutic component of HSCT for EMS.

BM examination at 3 months showed morphological remission. PCR for the ZNF198-FGFR1 transcript detected MRD both by single-step and nested methodologies (Figure 1d). CYA was rapidly weaned without development of GVHD. By 9 months, the gene transcript was still present by both single-step and nested PCR in peripheral blood and BM (<1% blasts in the aspirate). To exclude the possibility that the positive signal was related to persistence in a more mature compartment that might not have the same malignant potential, we confirmed the presence of ZNF198-FGFR1 transcripts in CD34+ cells selected from a BM aspirate using the Miltenyi magnetic selection system. A programme of escalating doses of DLIs was initiated 10 months following transplantation in an attempt to eliminate MRD (Table 1). The probable reduction in disease burden following doses up to 3 × 107 T cells/kg prompted a ‘watch and wait’ policy, but 6 months later, the gene transcript was again detectable by both single-step and nested PCR indicating persistence and a possible increase in the level of residual disease.

Table 1 Programme of escalating doses of DLI and PCR results
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Authors and Affiliations

  1. Department of Haematology, University College Hospitals NHS Foundation Trust, London, UK

    W Townsend, K Somana, K Thomson & K Peggs

  2. and Human Genetics Division, Wessex Regional Genetics Laboratory, University of Southampton, Southampton, UK

    N C P Cross & K Waghorn

  3. Department of Histopathology, University College Hospitals NHS Foundation Trust, London, UK

    A Ramsay

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  1. W Townsend
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  2. N C P Cross
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Correspondence to K Peggs.

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Townsend, W., Cross, N., Waghorn, K. et al. Clinical evidence for a graft-versus-tumour effect following allogeneic HSCT for t(8;13) atypical myeloproliferative disorder. Bone Marrow Transplant 44, 197–199 (2009). https://doi.org/10.1038/bmt.2008.448

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