Laura Finn

Therapy for metastatic melanoma: the past, present, and future

Metastatic melanoma is the most aggressive form of skin cancer with a median overall survival of less than one year. Advancements in our understanding of how melanoma evades the immune system as well as the recognition that melanoma is a molecularly heterogeneous disease have led to major improvements in the treatment of patients with metastatic melanoma. In 2011, the US Food and Drug Administration (FDA) approved two novel therapies for advanced melanoma: a BRAF inhibitor, vemurafenib, and an immune stimulatory agent, ipilimumab. The success of these agents has injected excitement and hope into patients and clinicians and, while these therapies have their limitations, they will likely provide excellent building blocks for the next generation of therapies. In this review we will discuss the advantages and limitations of the two new approved agents, current clinical trials designed to overcome these limitations, and future clinical trials that we feel hold the most promise.

Association of Therapy for Autoimmune Disease With Myelodysplastic Syndromes and Acute Myeloid Leukemia

Importance Therapy-related myeloid neoplasms are a potentially life-threatening consequence of treatment for autoimmune disease (AID) and an emerging clinical phenomenon. Objective To query the association of cytotoxic, anti-inflammatory, and immunomodulating agents to treat patients with AID with the risk for developing myeloid neoplasm. Design, Setting, and Participants This retrospective case-control study and medical record review included 40 011 patients with an International Classification of Diseases, Ninth Revision, coded diagnosis of primary AID who were seen at 2 centers from January 1, 2004, to December 31, 2014; of these, 311 patients had a concomitant coded diagnosis of myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML). Eighty-six cases met strict inclusion criteria. A case-control match was performed at a 2:1 ratio. Main Outcomes and Measures Odds ratio (OR) assessment for AID-directed therapies. Results Among the 86 patients who met inclusion criteria (49 men [57%]; 37 women [43%]; mean [SD] age, 72.3 [15.6] years), 55 (64.0%) had MDS, 21 (24.4%) had de novo AML, and 10 (11.6%) had AML and a history of MDS. Rheumatoid arthritis (23 [26.7%]), psoriasis (18 [20.9%]), and systemic lupus erythematosus (12 [14.0%]) were the most common autoimmune profiles. Median time from onset of AID to diagnosis of myeloid neoplasm was 8 (interquartile range, 4-15) years. A total of 57 of 86 cases (66.3%) received a cytotoxic or an immunomodulating agent. In the comparison group of 172 controls (98 men [57.0%]; 74 women [43.0%]; mean [SD] age, 72.7 [13.8] years), 105 (61.0%) received either agent (P = .50). Azathioprine sodium use was observed more frequently in cases (odds ratio [OR], 7.05; 95% CI, 2.35- 21.13; P < .001). Notable but insignificant case cohort use among cytotoxic agents was found for exposure to cyclophosphamide (OR, 3.58; 95% CI, 0.91-14.11) followed by mitoxantrone hydrochloride (OR, 2.73; 95% CI, 0.23-33.0). Methotrexate sodium (OR, 0.60; 95% CI, 0.29-1.22), mercaptopurine (OR, 0.62; 95% CI, 0.15-2.53), and mycophenolate mofetil hydrochloride (OR, 0.66; 95% CI, 0.21-2.03) had favorable ORs that were not statistically significant. No significant association between a specific length of time of exposure to an agent and the drug’s category was observed. Conclusions and Relevance In a large population with primary AID, azathioprine exposure was associated with a 7-fold risk for myeloid neoplasm. The control and case cohorts had similar systemic exposures by agent category. No association was found for anti–tumor necrosis factor agents. Finally, no timeline was found for the association of drug exposure with the incidence in development of myeloid neoplasm.

EPIDEMIOLOGY OF ADULT ACUTE MYELOID LEUKEMIA: IMPACT OF EXPOSURES ON CLINICAL PHENOTYPES AND OUTCOMES AFTER THERAPY

BACKGROUND An increased risk of adult myeloid leukemia (AML) has recently been associated with lifestyle and environmental exposures, including obesity, smoking, some over the counter medications, and rural/farm habitats in case control studies. The association of these exposures with AML cytogenetic categories, outcomes after therapy, and overall survival is unknown. METHODS Relevant exposures were evaluated in a cohort of 295 consecutive AML patients diagnosed and treated at Mayo Clinic in Florida and Arizona. Standard cytogenetic risk categories were applied and reviewed in a central cytogenetic laboratory. The association of epidemiologic exposures with cytogenetic risk, complete remission after therapy, and overall survival was evaluated using logistic and Cox regression models. RESULTS A significant association between obesity and intermediate-abnormal cytogenetics was identified (OR: 1.94, P=0.025). Similarly, those with secondary AML were more likely to have poor risk (OR: 2.55, P<0.001) and less likely to have intermediate normal (OR: 0.48, P=0.003) cytogenetics. In multivariate analysis, overall survival was improved for patients ≥ 60 years receiving intensive (RR: 0.21, P<0.001) and non-intensive therapy (RR: 0.40, P<0.001 compared to no treatment, and was lower for users of tobacco (RR 1.39, P=0.032), and those with poor risk cytogenetics (RR: 3.96, P=0.002) or poor performance status (RR: 1.69, P<0.001). Furthermore, an association between statin use at the time of diagnosis (OR: 2.89, P=0.016) and increased complete remission after intensive chemotherapy was identified, while prior solid organ transplantation was associated with significantly lower complete remission rate after therapy (OR: 0.10, P=0.035). CONCLUSION Our results provide evidence that specific epidemiologic exposures, including obesity, are significantly associated with unique AML cytogenetic risk categories and response to therapy. This supports a link between patient lifestyles, clinical exposures, and leukemogenesis.

Second primary acute lymphoblastic leukemia in adults: a SEER analysis of incidence and outcomes

We conducted a surveillance epidemiology and end results (SEER)‐based analysis to describe the incidence and characteristics of second primary acute lymphoblastic leukemia (sALL) among adults (≥18 years) with a history of primary malignancies (1M). Standardized incidence ratios (SIRs) of sALL cases were calculated by site and 1M stage. We also evaluated the differences in 5‐year sALL survival by age, site, and extent of 1M, latency of sALL after 1M, and evidence of underlying racial/ethnic disparity. We identified 10,956 patients with de‐novo/primary acute lymphoblastic leukemia (1ALL) and 772 with sALL. Women (49.1% vs. 42.9%), white patients (72.0% vs. 59.5%), older patients (58.8% vs. 25.2%; age ≥65 years), and patients diagnosed between 2003 and 2012 (66.8% vs. 53.9%) had a higher proportion of sALL compared with 1ALL. There was a significantly inferior median 5‐year survival for sALL patients compared to 1ALL (6 vs. 15 months; HR 1.20, 95% CI 1.10–1.31, P < 0.001). The median latency period was 60.0 months; the most common 1M among sALL patients were breast (17.9%) and prostate (17.4%). Patients with any 1M were at increased risk of developing sALL (SIR 1.76, 95% CI 1.58–1.95, P < 0.001). Hematological‐1M sites had significantly higher SIRs (hematological‐SIR 7.35; solid‐SIR 1.33; P < 0.001). We observed a significant increase in sALL incidence after a 1M and a significantly worse 5‐year survival with different demographic characteristics from 1ALL. There is a need to define appropriate screening methods for patients surviving their primary cancer.

Combined plasma exchange and platelet transfusion in immune-mediated thrombocytopenic emergencies

Refractory immune-mediated thrombocytopenia (ITP) can be very difficult to manage, especially if associated with a hemorrhagic or surgical emergency. We report two cases of refractory ITP that were unresponsive to routine therapeutic interventions and frequent platelet transfusions. A combination of plasma exchange and platelet transfusion successfully raised the platelet count to a level that permitted life-saving surgical interventions. Plasma exchange in these two cases likely reduced platelet antibodies significantly, decreasing platelet destruction. We propose that a trial of combination plasma exchange and platelet transfusion can be attempted in emergent thrombocytopenic situations with an underlying immune mechanism.

Assessment of Drug Sensitivity in Hematopoietic Stem and Progenitor Cells From Acute Myelogenous Leukemia and Myelodysplastic Syndrome Ex Vivo

Current understanding suggests that malignant stem and progenitor cells must be reduced or eliminated for prolonged remissions in myeloid neoplasms such as acute myelogenous leukemia (AML) or myelodysplastic syndrome (MDS). Multicolor flow cytometry has been widely used to distinguish stem and myeloid progenitor cells from other populations in normal and malignant bone marrow. In this study, we present a method for assessing drug sensitivity in MDS and AML patient hematopoietic stem and myeloid progenitor cell populations ex vivo using the investigational Nedd8‐activating enzyme inhibitor MLN4924 and standard‐of‐care agent cytarabine as examples. Utilizing a multicolor flow cytometry antibody panel for identification of hematopoietic stem cells, multipotent progenitors, common myeloid progenitors, granulocyte‐monocyte progenitors, and megakaryocyte‐erythroid progenitors present in mononuclear cell fractions isolated from bone marrow aspirates, we compare stem and progenitor cell counts after treatment for 24 hours with drug versus diluent. We demonstrate that MLN4924 exerts a cytotoxic effect on MDS and AML stem and progenitor cell populations, whereas cytarabine has more limited effects. Further application of this method for evaluating drug effects on these populations ex vivo and in vivo may inform rational design and selection of therapies in the clinical setting. Stem Cells Translational Medicine 2017;6:840–850

Vancomycin Induced Neutropenia: A Case Report

Vancomycin is a glycopeptide antibiotic with widespread use since 1958. Vancomycin is clinically indicated for the treatment of methicillin-resistant strains of coagulase negative and coagulase positive staphylococcal infections, gram-positive penicillin-resistant infections and as an alternative treatment for penicillin-allergic patients. Vancomycin induced neutropenia is a rare side effect. We present the case of a 23 year old man with recurrent fevers and persistently positive blood cultures growing viridans group streptococci. He was found to have endocarditis requiring aortic valve replacement. Due to the patient’s allergies he was treated with IV vancomycin therapy. This resulted in the uncommon adverse event of vancomycin induced neutropenia. The patient subsequently responded to granulocyte colony stimulating factor. Vancomycin induced neutropenia is an uncommon but serious adverse reaction with the potential for morbidity and mortality. Further guidelines are needed for leukocyte monitoring during vancomycin therapy and the use of granulocyte colony stimulating factor to treat this adverse effect.

Correction of factor XI deficiency by liver transplantation.

Orthotopic liver transplantation for other diseases typically results in a coincidental cure for hemophilia A and B; however, long-term outcomes of liver transplant in hemophilia C are not very well described. Herein, the authors report a patient of severe congenital factor XI (FXI) deficiency who received an orthotopic liver transplant. The authors discuss the perioperative management and long-term outcomes. The normalization of his FXI levels confirms that the liver is the most clinically relevant site of synthesis of FXI.

Are we curing more older adults with acute myeloid leukemia with allogeneic transplantation in CR1

Purpose of reviewDespite the fact that acute myeloid leukemia (AML) is most common in older adults aged at least 60 years, curative therapy remains elusive in this population. Here we examine the data for predicting which patients are candidates for ‘curative therapy’, available therapeutic options, and the utilization of reduced intensity allogeneic stem cell transplantation in first remission. Recent findingsIncorporation of geriatric assessment tools to assess patient frailty, in addition to evaluation of comorbid conditions, improves patient selection for intense therapy. The majority of patients eligible for and treated with induction chemotherapy achieve complete remission, and overall survival in the older AML population is superior after allogeneic stem cell transplant. However, population-based studies continue to demonstrate the undertreatment or lack of treatment of older AML patients. SummaryNew patient assessment tools, ability to offer more successful outcomes after induction chemotherapy, and improved survival after allogeneic transplantation has not yet translated to increased ‘curative’ treatment on a population level of older AML patients. It is critical that the tools and therapies available be put into practice while older patient enrollment in well designed therapeutic clinical trials which include the option of allogeneic transplantation is increased.