br Discussion Case reports of successful chemotherapy desens

Discussion Case reports of successful chemotherapy desensitizations have been described for platinum agents, taxanes, anthracyclines, rituximab [8], and cytarabine [9], but not specifically clofarabine. For older patients with relapsed AML that are not candidates to receive anthracycline therapy, options include clofarabine/cytarabine, hypomethylating agents, and low-dose cytarabine [10], which gives the clinician relatively few treatment options aside from clinical trial enrollment. Thus it may be preferable to maintain the option of using clofarabine despite encountering capillary-leak syndrome or hypersensitivity during administration. Our successful desensitization approach avoided a severe reaction and led to a favorable response in this patient. As with any desensitization, the decision to retry therapy must be approached cautiously, especially if capillary leak syndrome alone is suspected in the absence of hypersensitivity. Batzlaff and Dulohery recently presented a case of clofarabine-induced capillary leak syndrome in a 70-year-old patient with AML, who experienced tachycardia, hypotension, and renal injury leading to death [11]. Capillary leak syndrome and clofarabine hypersensitivity have common signs [12]; however, inflammatory responses to clofarabine leading to endothelial injury thought to result in capillary leak syndrome [13] present after several days of therapy [11–13]. Elements of both capillary leak syndrome as well as an allergic reaction were felt to be present in our patient [14]. Though drug desensitization protocols are meant to stave off immediate hypersensitivity reactions, it is possible that this approach could also reduce the cytokine release which provokes symptoms of capillary leak syndrome. Prior studies show clofarabine-associated AKI with higher doses of 30–40mg/m2; Faderl et al. reported a 5% incidence of Grade 3 or 4 acute renal failure [15]. Younger patients with better baseline renal function are less likely to experience AKI with clofarabine [16]. In our patient, AKI occurred previously in the setting of dehydration, concomitant angiotensin-converting enzyme inhibitor and metformin use, and hypotension. During desensitization we ensured that good hydration was maintained, lisinopril and metformin were held, and clofarabine-induced hypotension was avoided, all of which likely contributed to the absence of AKI during the process.
Philadelphia (Ph) chromosome results from the reciprocal R 568 hydrochloride t(9;22)(q34.1;q11.2), and is a diagnostic feature for chronic myeloid leukemia (CML). In most cases, the breakpoint in occurs in M-bcr region, leading to production of e13a2 and/or e14a2 fusion transcripts. The breakpoints infrequently occur in either m-bcr or μ-bcr, producing e1a2 or long e19a2 fusion transcripts. Several other variant transcripts, such as e8a2, e13a3, e14a3, and e6a2 have also been identified and account for <1% of CML cases. Late appearing Ph chromosome may be acquired over the course of myelodysplastic/myeloproliferative neoplasm (MDS/MPN) or MDS, representing disease progression and often signifying poor prognosis. In this report we describe a patient with chronic myelomonocytic leukemia (CMML), a subtype of MDS/MPN, which progressed to AML with gain of the rare BCR-ABL1 fusion transcript e6a2 and died shortly of tumor lysis syndrome. The patient is a 58 year old man who presented on 9/2012 at an outside institution with WBC 24.3K/ul, Hgb 7.6g/dl, and Platelets 56.0K/ul; differential: neutrophils 53%, lymphocytes 10%, monocytes 35%, eosinophils 2%, and blasts 0%. The aspirate smear was hemodilute and inadequate for differential, but showed dysgranulopoiesis. The bone marrow (BM) biopsy was markedly hypercellular (approximately 100%) with hyperplastic granulopoiesis and dysplastic megakaryocytes (monolobation, widely separated nuclei). Immunohistochemistry revealed 5-10% blasts expressing CD34 and CD117, which by flow cytometry were also positive for CD13, CD33, and MPO; but negative for B/T-lymphoid markers. The karyotype was normal. FISH study was negative for t(9;22) and chromosome 5, 7, 8, and 20 aberrations. Molecular studies were positive for RUNX1 and TP53 mutations, but negative for fusion transcripts and FLT3, NPM1, ASXL1, EZH2, and ETV6 mutations. Based on these findings and a history of persistent monocytosis, a diagnosis of CMML-1 was rendered. He was refractory to 4 cycles of azacytidine and vorinostat and rapidly progressed to AML 8 months later in 5/2013 with 20% marrow blasts, which by flow cytometry were positive for CD34 (small subset), CD13, and CD33; while negative for CD117 and B/T-lymphoid markers including CD19 and cCD3, thereby excluding mixed phenotype acute leukemia. Cytogenetics study again showed a normal karyotype: 46,XY[20]. No molecular testing was performed. Despite an AML induction with cytarabine and idarubicin (standard “7+3” regimen) on 5/16/2013, his disease further progressed with 41% marrow blasts, which responded with re-induction with high-dose cytarabine on 5/30/2013 with reduction of blasts to 5%. Although he never achieved complete remission, his blast count remained stable and he did not receive further treatment or had interval biopsies until 9/2013, when his disease progressed again with 83% marrow blasts and 63% circulating blasts, and received fludarabine, cytarabine, idarubicin, and G-CSF (FLAG-IDA salvage regimen) and hydroxyurea. The patient was transferred to our institution on 9/30/2013 where a bone marrow biopsy showed 34% blasts. Karyotype analysis detected Ph chromosome: 46,XY,t(9;22)(q34.1;q11.2)[11]/46,XY[9]; and FISH showed BCR/ABL1 fusion signal in 6% cells: nuc ish(ABL1x3,BCRx3)(ABL1 con BCRx1)[30/500]. RT-PCR was negative for p210 and p190 fusion transcripts, but revealed a much larger product (~800bp) suggesting a variant fusion with estimated molecular weight of 191kDa (A). Sanger sequencing confirmed a fusion of BCR exon e6 and ABL exon a2, generating e6a2 fusion transcript (B). Molecular/NGS studies were positive for DNMT3A, RUNX1, and SUZ12 mutations; and negative for FLT3, NPM1, CEPBA, NRAS, KRAS, TET2, ASXL1, IDH1/2, and JAK2 mutations. Dasatinib (140mg/day) was initiated on 10/28/2013. However, FISH study from a 11/5/2013 blood sample showed BCR/ABL1 in 475/500 (95%) of the cells, indicating expansion of the Ph+ clone. Due to dasatinib-induced pneumonitis dasatinib (3 doses received) was discontinued on 11/17/2013 and switched to nilotinib (800 mg/day) on 11/19/2013. His WBC was 17.6K/uL in pre-dasatinib and 4.6K/uL pre-nilotinib (but post- dasatinib) periods, during both of which ABL kinase mutation by Sanger sequencing of ABL exon 4–9 were negative. His WBC further increased to 91.3K/uL with 80% circulating blasts on 11/24/2013. However, FISH revealed fusion in only 17/508 (3.4%) of peripheral blood cells. The patient was given palliative care and expired on 12/04/13 from tumor lysis syndrome.