Meera Yogarajah

Leukemic Transformation in Myeloproliferative Neoplasms: A Literature Review on Risk, Characteristics, and Outcome

Abstract Myeloproliferative neoplasms (MPNs) operationally include essential thrombocythemia, polycythemia vera, primary myelofibrosis (PMF), and prefibrotic PMF. All 4 MPN variants might progress into blast‐phase disease (MPN‐BP). For essential thrombocythemia, reported risk factors for leukemic transformation include advanced age, extreme thrombocytosis, anemia, leukocytosis, and sequence variants/mutations involving TP53 and EZH2 (for expansion of gene symbols, see www.genenames.org); for polycythemia vera, advanced age, leukocytosis, abnormal karyotype, mutations involving SRSF2 and IDH2, and treatment with pipobroman, chlorambucil, or P32; and for PMF, increased blast percentage, thrombocytopenia, abnormal karyotype, triple‐negative driver mutational status, and sequence variants/mutations involving SRSF2, RUNX1, CEBPA, and SH2B3. The reported median survival figures for MPN‐BP range from 1.5 to 2.5 months in patients treated with supportive care only, from 2.5 to 10 months in those receiving hypomethylating agents or low‐dose chemotherapy, and from 3.9 to 9.4 months in those receiving induction chemotherapy. Three‐year survival after allogeneic stem cell transplant was reported in 16% to 33% of patients. These observations validate the extremely poor prognosis associated with MPN‐BP and the lack of effective drug therapy and highlight the need for urgent assessment of therapeutic values of investigational agents. In the meantime, affected patients might be best served with aggressive chemotherapy followed by allogeneic stem cell transplant after adequate blast clearance.

Blast phase myeloproliferative neoplasm: Mayo-AGIMM study of 410 patients from two separate cohorts

A total of 410 patients with blast phase myeloproliferative neoplasm (MPN-BP) were retrospectively reviewed: 248 from the Mayo Clinic and 162 from Italy. Median survival was 3.6 months, with no improvement over the last 15 years. Multivariable analysis performed on the Mayo cohort identified high risk karyotype, platelet countu2009<u2009100u2009×u2009109/L, ageu2009>u200965 years and transfusion need as independent risk factors for survival. Also in the Mayo cohort, intensive chemotherapy resulted in complete remission (CR) or CR with incomplete count recovery (CRi) rates of 35 and 24%, respectively; treatment-specified 3-year/5-year survival rates were 32/10% for patients receiving allogeneic stem cell transplant (AlloSCT) (nu2009=u200924), 19/13% for patients achieving CR/CRi but were not transplanted (nu2009=u200924), and 1/1% in the absence of both AlloSCT and CR/CRi (nu2009=u2009200) (pu2009<u20090.01). The survival impact of AlloSCT (HR 0.2, 95% CI 0.1–0.3), CR/CRi without AlloSCT (HR 0.3, 95% CI 0.2–0.5), high risk karyotype (HR 1.6, 95% CI 1.1–2.2) and platelet countu2009<u2009100u2009×u2009109/L (HR 1.6, 95% CI 1.1–2.2) were confirmed to be inter-independent. Similar observations were made in the Italian cohort. The current study identifies the setting for improved short-term survival in MPN-BP, but also highlights the limited value of current therapy, including AlloSCT, in securing long-term survival.

Splanchnic vein thrombosis in patients with myeloproliferative neoplasms: The Mayo clinic experience with 84 consecutive cases

scans to report the visualized needle track as well as any complications. Study protocol was approved by institutional review board. The average age of the 25 study patients was 64 years, 56% were male, and the average BMI was 25.7 kg/m. All patients had successful BMP’s under local anesthesia. In 3 (12%) patients, the needle track traversed the ilium and penetrated the sacro-iliac joint and the sacrum (Figure 1). The needle track in these cases was at approximately 90 degrees to the coronal plane of the body. None of the 3 patients with sacral penetration reported significant pain or neurological symptoms. In 6 cases, the needle tracks were visualized at various angles in the ilium. In 16 scans, no needle track was seen. Of the 25 CT scans, none revealed a significant hematoma or other vascular complication. The lengths of the biopsy cores have been reported elsewhere. There is little data available on the safest techniques for the BMP. In a study on cadavers, Konda et al demonstrated that advancement of the biopsy needle perpendicular to the body’s coronal plane was associated with increased risk of injury to the iliac and iliolumbar arteries, femoral and obturator nerves, and the sacro-iliac joint, if penetration of the inner table of the ilium occurred. Retroperitoneal hemorrhage following a BMP, although uncommon, likely occurs due to traversal of the ilium by the needle. In contrast, penetration of the inner iliac cortex while advancing the biopsy needle laterally towards the ASIS is significantly less likely to result in neurovascular damage or trauma to the sacroiliac joint. It seems reasonable to conclude that fewer neurovascular injuries will occur by targeting the ASIS. In our study, 3 patients (12%) had penetration of the inner table of the ilium through the sacro-iliac joint and into the sacrum. Analysis of CT scans shows that a 9 degree change in needle angulation can lead to penetration of the sacrum (Figure 1). No adverse consequences of inadvertent penetration of the sacrum were noted in this small series. Study limitations include the relatively small sample size and lack of control for objectively comparing the technique and tools used. Despite these limitations, this study presents novel information about real-world visualization of needle tracks after a blind BMP. Further studies are needed to determine the safest and most efficacious technique for the BMP.

A concise review of BCL-2 inhibition in acute myeloid leukemia

ABSTRACT Introduction: Acute myeloid leukemia (AML) is a heterogeneous disease characterized by clonal proliferation of myeloid precursors with impaired ability to differentiate to mature cells causing accumulation of leukemic blasts in bone marrow, peripheral blood, and extramedullary tissue. Our understanding of the genomic landscape of AML has improved prognostic accuracy and lead to the development of targeted therapies. In 2017 the Food and Drug Administration (FDA) approved midostaurin, gemtuzumab ozogamicin, CPX-351 and enasidenib for the treatment of AML. There are many novel agents under investigation for treatment of AML, but those that inhibit the anti-apoptotic molecule BCL-2 are of particular interest due to strong pre-clinical data and early promising clinical results. Areas covered: This article provides an overview of the pathophysiology of BCL-2 inhibition in AML, biomarkers and resistance mechanisms to BCL-2 inhibition and an update of results of the preclinical and clinical trials. Expert commentary: Venetoclax-based combination treatment for newly diagnosed elderly patients for whom intense chemotherapy is not an option may be the first setting in which this agent may be employed in AML. Based on pre-clinical evidence, BCL-2 inhibition may be useful in relapsed/refractory disease in conjunction with cytotoxic therapy, but has modest single agent activity.

Clonal evolution of Philadelphia chromosome in acute myeloid leukemia after azacitidine treatment

The Philadelphia (Ph) chromosome occurs due to a balanced translocation between chromosomes 9q34 and 22q11, resulting in a fusion protein BCR-ABL1 with differing protein sizes depending on the break point, p210 (e13a2 or e14a2), p190 (e1a2) and p230 (e19a2). Ph chromosome is pathognomonic of chronic myeloid leukemia (CML). It is also present in approximately 2–3% of children and 20–30% of adults with acute lymphoblastic leukemia (ALL). Acute myeloid leukemia (AML) with BCRABL1 is a rare entity with an incidence of approximately 2% and has been included in the 2016 World Health Organization classification as a provisional entity [1]. It is clinically challenging to differentiate de novo CML-myeloid blast crisis from AML with BCR-ABL1. The absence of a history of a hematologic disorder, basophilia or splenomegaly may favor AML with BCR-ABL1 over CML blast crisis. Nonetheless, the secondary acquisition of the Ph chromosome in treated AML patients is an extremely rare event. We describe the first known report of a secondary Ph chromosome occurring in an AML patient after treatment with azacitidine. A 62-year-old female with a history of cirrhosis secondary to nonalcoholic steatohepatitis, hypothyroidism, diabetes mellitus-2, obstructive sleep apnea, hypertension and hyperlipidemia presented with significant joint pains and myalgias over a period of 5 months. At presentation, her white blood cell count (WBC)1⁄4 2.8 10/L, absolute neutrophil count (ANC)1⁄4 0.6 10/L, hemoglobin1⁄4 9.6 g/dL, hematocrit1⁄4 29.0, and platelet count1⁄4 29 10/L. A bone marrow biopsy revealed a hypercellular (80%) bone marrow with reduced trilineage hematopoiesis, 51% blasts consistent with AML. Flow cytometry revealed 27% aberrant myeloblasts expressing CD34, CD117, CD71, HLA-DR, CD13, dim CD33 and partial myeloperoxidase positive. Cytogenetics revealed a normal female karyotype with normal FISH for AML/MDS. A targeted molecular panel revealed no evidence of Fms-like tyrosine kinase 3 (FLT3) or nucleophosmin-1 (NPM1) mutations consistent with intermediate-1 risk de novo AML based on the 2010 European Leukemia Net classification [2], although there was no CEBPa mutational analysis performed at diagnosis. She was initiated on 7þ 3 induction with continuous infusion cytarabine (100mg/ m IV days 1–7) and idarubicin (12mg/m IV days 1–3). She achieved a complete remission (CR1) and then received consolidation therapy on an institutional trial with high dose lenalidomide 50mg, followed by maintenance at 10mg daily (NCT01578954). The patient was not interested in allogeneic stem cell transplant in CR1. She received 3 cycles of maintenance lenalidomide and then developed cytopenias. A bone marrow biopsy revealed 40% cellularity and 31% blasts consistent with relapsed AML. Cytogenetics revealed two abnormal clones: an addition of chromosome 12 and a subclone with a t(3;20)(p23;q11.2). A molecular analysis was not performed at the time of relapse. She was treated with salvage cladribine 5mg/m IV days 1–5, cytarabine 2 gm/m IV days 1–5 and G-CSF days 0–6 (CLAG) and a recovery bone marrow biopsy revealed a normocellular (40%) bone marrow with 3% blasts consistent with a CR2. Cytogenetics/FISH revealed absence of the original trisomy 12 clone but two abnormal unrelated clones consisting of t(11;20)(p11.2;q11.2) and t(1;6)(q44;q21), respectively, of unclear significance. She then received two cycles of consolidation chemotherapy with high-dose cytarabine dose reduced for age (1.5 gm/m IV Q12 hours days 1, 3 and 5). Bone marrow biopsy after recovery from cycle 2 of consolidation therapy revealed variably cellular bone marrow (10–80%) with 13% blasts consistent with recurrent AML (second relapse). Cytogenetics revealed a trisomy 12 clone in 1/20 metaphases consistent with her previous documented karyotypic abnormality. The patient then received azacitidine 75mg/m SQ days 1–7 for her relapsed AML. A repeat bone marrow biopsy after 3 cycles of azacitidine revealed stable disease with 8% blasts and cytogenetics evolved to an abnormal clone

Hemophagocytic lymphohistiocytosis (HLH) secondary to Ehrlichia chaffeensis with bone marrow involvement

Dear Editor, Hemophagocytic lymphohistiocytosis (HLH) is a rare lifethreatening clinical syndrome of hyper inflammation that leads to a dysregulated and ineffective immune activation [1]. Patients can often present similar to a sepsis-like syndrome with multi-organ dysfunction, and despite treatment, a high mortality rate is observed [2]. HLH is classified as primary or familial when a gene mutation is identified and secondary or sporadic in its absence. Common triggers for either entity include infections, the most common being Epstein-Barr virus, and immunodeficiency states like inherited syndromes, malignancy, autoimmune disorders, or HIV infection [1, 2]. Very little is known about Ehrlichia as an etiology for HLH. We present a rare case of secondary HLH due to Ehrlichia chaffeensis (E. chaffensis) with bone marrow involvement in a patient with HIV. A 66-year-old African American female with a history of HIV and noncompliance with anti-retroviral medications presented with septic shock requiring vasopressors. On admission, the temperature was 38.2 °C; heart rate was in the 140 s; examination was remarkable for lethargy and diffuse abdominal pain. A computed tomography scan of the abdomen/ pelvis was unrevealing. Complete blood count was notable for pancytopenia with a white cell count of 3.0 × 10/μl, platelet count of 22 × 10/μl, and hemoglobin of 12.2 g/dl. Metabolic profile demonstrated multi-organ dysfunction with serum creatinine elevated at 4.89 mg/dl and transaminitis with AST of 132 U/L and ALT of 518 U/L. Both CD-4 and CD-56 NK cells were 0.00/μl. HIV viral load was 8113 copies/ml. Serum triglycerides were elevated at 358 mg/dl. Ferritin was > 40,000 ng/ml. She was empirically started on broad spectrum antibiotics along with liposomal amphotericin-B. Due to her clinical presentation and the