- Miriam Frech1,*,
- Lutz B. Jehn1,*,
- Kathleen Stabla1,
- Stephan Mielke2,
- Björn Steffen3,
- Hermann Einsele2,
- Stephan K. Metzelder1 and
- Andreas Neubauer1,*⇑
- 1Department of Internal Medicine and Hematology, Oncology and Immunology, Philipps University Marburg, and University Hospital Giessen and Marburg, Baldingerstrasse, Germany
- 2Department of Internal Medicine II, University Hospital Würzburg, Oberdürrbacher Straβe 6, Germany
- 3Department of Medicine, Hematology/Oncology, Goethe University of Frankfurt, Theodor-Stern-Kai 7, Germany
The addition of tyrosine kinase inhibitors (TKI) to treatment regimens of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) has significantly improved overall survival.160 However, allogeneic stem cell transplantation (allo-SCT) offers the only curative option in the established therapeutic armamentarium for patients with Ph+ ALL. Ph+ ALL is characterized by the translocation t(9;22)(q34;q11.2), leading to the expression of the fusion protein BCR-ABL1. Treatment with TKI, such as imatinib or dasatinib, targets the ABL1 tyrosine kinase portion of the fusion protein, thereby inhibiting proliferation and inducing apoptosis.2 However, several genes other than BCR have been identified to form rearrangements with ABL1 in B-cell ALL, including RCSD1, ETV6, NUP214, RANBP2, FOXP1, SFPQ, SNX2 and ZMIZ1.2–4 Here, the RCSD1-ABL1 rearrangement is characterized by the fusion of the N-terminal portion of the RCSD1 gene to ABL1 exon 4, a feature unique for the ABL1 fusion partner genes SFPQ and RCSD1.4 This unusual breakpoint of the ABL1 gene retains only a part of the SRC homology 2 (SH2) domain regulating autophosphorylation, and lacks the SH3 inhibitory module.2,4 The RCSD1 gene encodes the phosphoprotein CapZ-interacting protein (CapZIP) that contributes to regulation of actin filament assembly, and is found in immune cells, splenocytes and muscle tissue.5 There is growing evidence that Ph-negative (Ph−) patients showing ABL1 translocations also might benefit from treatment with TKI. However, sustained molecular remissions, even with the incorporation of TKI to treatment protocols, have rarely been reported, and patients frequently die from early relapse or refractory disease.3 In particular, the capacity of alloimmune effects complementing TKI-based targeted therapy to induce long-term remissions in patients with RCSD1-ABL1 rearrangements is unclear. Moreover, the prognostic impact of minimal residual disease (MRD) levels preceding allogeneic stem cell transplantation (allo-SCT) remains elusive in this context. We here show sustained molecular remission in a highly pretreated elderly patient with a refractory RCSD1-ABL1-positive B-cell ALL; molecular remission was achieved via multimodal treatment, including the sequential use of dasatinib and the bispecific T-cell engager blinatumomab followed by consolidation with allo-SCT. A 61-year old female presented in August 2012 with increasing fatigue and pallor. Peripheral blood counts revealed hemoglobin of 9.7 g/dL, white blood cell count of 2.5 × 109/L with 2% blasts and 66 × 109/L platelets. The bone marrow (BM) aspirate showed 70% blasts, and was consistent with acute leukemia (AL). Immunophenotyping revealed the blasts to be positive for CD10, CD19, CD22, CD79a, CD34 and HLA-DR. Of the blasts, 46% were positive for TdT, and the cells were negative for CD20. No myeloid or T-cell markers could be detected. Based on these results, a common-B-cell-ALL was diagnosed.
Cytogenetic analysis showed two coexisting clones with an abnormal karyotype of 47,XX,+17,t(1;9)(q22;q34)/46,XX,der(6)t(6;17)(p23; q21),t(1;9)(q22;q34) and, in the molecular analysis, no evidence for BCR-ABL1 was found. Figure 1A illustrates the patient’s course of disease and treatment. The patient was enrolled on GMALL elderly (01/2003) and treated accordingly. After two induction courses (Figure 1A, 1), her BM evaluation on day 36 revealed primary induction failure with progressive disease, and 90% of leukemic blasts. She therefore continued chemotherapy with high-dose methotrexate and asparaginase three months after induction therapy was initiated (Figure 1A, 2). Her disease achieved first complete remission (Figure 1A, CR 1) in January 2013, and high-dose cytarabine was administered (Figure 1A, 3). At the same time, an unrelated donor search was initiated. Donor search, however, was futile, and the patient experienced a BM relapse with 20% of leukemic blasts in April 2013. Re-induction chemotherapy with one cycle of FLAG-Ida comprising fludarabine, cytarabine, G-CSF and idarubicin was administered (Figure 1A, 4), but BM revealed residual disease with 70% of leukemic blasts one month later, in May 2013. The patient was included in the BEZ235 study and treated with an oral PI3K/mTOR inhibitor (Figure 1A, 5), but no remission could be achieved. The patient was transferred to our hospital. Due to the patients progressive disease and the suspicion of an ABL1-activating fusion gene based on the translocation t(1;9)(q22;q34), salvage therapy with single agent dasatinib was initiated at a dose of 100 mg once daily, in July 2013 (Figure 1A, 6). The RCSD1-ABL1 t(1;9)(q22;q34) fusion between exon 3 of RCSD1 and exon 4 of ABL1 could be validated by RT-PCR and sequencing of the fusion transcript (Figure 1B). A stable disease with partial remission in the BM was achieved (Figure 2A). This was confirmed by a decrease of RCSD1-ABL1 amplicon in RT-PCR (Figure 2B, lanes 2 and 3). Moreover, inhibition of RCSD1-ABL1 activity by dasatinib was shown by Western analysis of phosphorylated ABL1 and its downstream target CRKL (Figure 2C). Treatment with dasatinib was complemented with two cycles of chemotherapy, including clofarabine and cyclophosphamide (Figure 1A, 7). CR 2 was achieved in October 2013, whereas minimal residual disease (MRD) levels still remained positive. In this regard, treatment with blinatumomab was started within the MT103-203 study in January 2014 (Figure 1A, 8), and MRD levels became negative. Flow cytometric analysis revealed no further evidence of any CD10+/CD19+ BM cells. In March 2014, allo-SCT was performed successfully (Figure 1A, 9). Since then, there is an ongoing remission that, to date, has lasted 30 months. During this period, the patient has not recieved any antileukemic treatment. Clinical monitoring of the patient is performed via RT-PCR of the RCSD1-ABL1 fusion transcript, followed by nested PCR of the amplicon, to detect early relapse or MRD (Figure 2B, E). As positive control for clinical monitoring, the plasmid PCR2.1-TOPO_ RCSD1-ABL1(626bp) was synthesized encoding RCSD1-ABL1 amplicon with the fusion site (Figure 2D, E).
For the management of elderly patients with refractory ALL and ABL1-activating fusion genes not involving BCR, the present case provides several important implications. In addition to this report, ten cases with B-cell precursor ALL and a molecular genetically confirmed RCSD1-ABL1 gene rearrangement have been reported in literature to date.2,3,6–12 To our knowledge, this is the first reported case of a patient with relapsed and refractory RCSD1-ABL1-positive B-cell ALL in whom salvage therapy with single-agent dasatinib induced a meaningful response and a durable molecular remission, which was consolidated with allo-SCT. TKI-based treatment of patients with RCSD1-ABL1-positive B-cell ALL has been described before. Thus, Perwein et al. (2016) described an imatinib-induced long-term remission in a pediatric patient with RCSD1-ABL1-positive B-cell precursor (BCP) ALL. In contrast to our case, imatinib complemented relapse chemotherapy, but its sole antileukemic efficacy could not be proved. Furthermore, no consolidation with allo-SCT was performed.12 Moreover, Mustjoki et al. (2009) presented a 40-year old patient who achieved morphological remission after addition of dasatinib to a modified CVAD regimen and allo-SCT was performed. However, at 12 months from allo-SCT, their patient relapsed.7 We here show that dasatinib monotherapy seems to be an effective treatment option in RCSD1-ABL1-positive cases to increase the number of patients who can proceed to allo-SCT. The single-agent antileukemic activity of dasatinib was further intensified with a clofarabine-cyclophosphamide combination, as this approach induced significant response in adult patients with advanced ALL, even in the presence of adverse prognostic factors like the BCR-ABL1 rearrangement.13 The administration of blinatumomab, resulting in negative MRD levels, might also have contributed to this long-term remission. In patients with Ph+ ALL, the MRD status before allo-SCT is a strong predictor of relapse.14 As described by Kolb et al. (1995), patients with Ph+ disease benefit from adoptive immunotherapy.15 Thus, contrary to Perwein et al. (2016), we consider the graft-versus-leukemia effect in our patient to be critical for curative therapy. Of note, dasatinib was not continued as maintenance due to concerns about its potential vascular toxicity, since our patient has a medical history of arterial hypertension, hypercholesterolemia, and coronary artery disease with stent implantation in 2009. In particular, the high non-relapse mortality (NRM) of allo-SCT in the group of elderly patients and preexisting comorbidities remains a significant problem. The uncertainty in the management of these patients often withholds them from definitive therapy. In conclusion, the present case demonstrates that monotherapy with TKI, such as dasatinib, is effective in refractory RCSD1-ABL1 ALL. In addition, our case should encourage clinicians to consider allo-SCT even for elderly patients with uncommon cytogenetic abnormalities and preexisting comorbidities as the only curative treatment option.
↵* MF and LBJ share first authorship
Funding: this work was supported by grants from the Deutsche Forschungsgemeinschaft (DFG) [grant numbers KFO 210 #3, SPP1463, NE310/18-1] and the Deutsche José-Carreras Leukämie-Stiftung [grant number AH06/01]. We thank the patient and the physicians contributing patient samples to this study.
Information on authorship, contributions, and financial & other disclosures was provided by the authors and is available with the online version of this article at www.haematologica.org.
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