Amer M. Zeidan

Current therapy of myelodysplastic syndromes

After being a neglected and poorly-understood disorder for many years, there has been a recent explosion of data regarding the complex pathogenesis of myelodysplastic syndromes (MDS). On the therapeutic front, the approval of azacitidine, decitabine, and lenalidomide in the last decade was a major breakthrough. Nonetheless, the responses to these agents are limited and most patients progress within 2 years. Allogeneic stem cell transplantation remains the only potentially curative therapy, but it is associated with significant toxicity and limited efficacy. Lack or loss of response after standard therapies is associated with dismal outcomes. Many unanswered questions remain regarding the optimal use of current therapies including patient selection, response prediction, therapy sequencing and combinations, and management of resistance. It is hoped that the improved understanding of the underpinnings of the complex mechanisms of pathogenesis will be translated into novel therapeutic approaches and better prognostic/predictive tools that would facilitate accurate risk-adaptive therapy.

HLA-Haploidentical Donor Lymphocyte Infusions for Patients with Relapsed Hematologic Malignancies after Related HLA-Haploidentical Bone Marrow Transplantation

Treatment of relapse after related HLA-haploidentical T cell-replete bone marrow transplantation (haploBMT) with post-transplantation cyclophosphamide (PTCy) using haploidentical donor lymphocyte infusion (haploDLI) is not documented. All patients who received haploDLI after haploBMT with PTCy between June 2003 and October 2012 were identified and assessed for graft-versus-host disease (GVHD) and outcomes. Forty patients received 52 haploDLI doses. Sixteen patients had acute myeloid leukemia, 11 had lymphomas, and 34 had nonmyeloablative conditioning before haploBMT. The median time from haploBMT to relapse was 183 (range, 0 to 1399) days. The median age at haploDLI was 48 (range, 3 to 70) years. The first haploDLI doses were 1 × 10(5) CD3(+) cells/kg with subsequent escalation. The most commonly used first haploDLI dose was 1 × 10(6) CD3(+) cells/kg. The median follow-up after haploDLI was 7 (mean, 15.4; range, .5 to 96) months for the entire cohort, and 17.5 (mean, 28; range, 2.4 to 96) months for the responders. Acute GVHD developed in 10 patients (25%), 6 patients had grade 3 to 4, and 3 developed chronic GVHD. Twelve (30%) patients achieved a complete response (CR) with a median duration of 11.8 (mean, 22.5; range, .4 to 94) months. At last follow-up, 8 responders were alive in CR; 6 for over a year. HaploDLI for relapse after haploBMT is associated with acceptable toxicities and can result in durable responses.

Impact of a venous thromboembolism prophylaxis “smart order set”: Improved compliance, fewer events

Venous thromboembolism (VTE) affects over 700,000 Americans annually. Prophylaxis reduces the risk of VTE by 60% but many patients still do not receive risk‐appropriate VTE prophylaxis. To improve our institutions VTE prophylaxis performance, we developed mandatory computerized clinical decision support‐enabled “smart order sets” that required providers to assess VTE risk factors and contraindications to pharmacologic prophylaxis. Using provider responses, the order set recommends evidence‐based risk‐appropriate VTE prophylaxis. To study the impact of our “smart order set” on prescription of risk‐appropriate VTE prophylaxis and clinical outcomes, we conducted a retrospective chart review of consecutive patients admitted to the Medicine service during one month immediately prior to (November 2007) and a single month subsequent to (April 2010) order set launch. Data collection included patient demographics, VTE risk factors, and the use and type of VTE prophylaxis. The pre‐ and post‐implementation cohorts contained 1,000 and 942 patients, respectively. After implementation of the “smart order set”, the prescription of risk‐appropriate VTE prophylaxis increased from 65.6% to 90.1% (P < 0.0001). Orders for any form of VTE prophylaxis increased from 76.4% to 95.6% (P < 0.0001). Radiographically documented symptomatic VTE within 90 days of hospital discharge declined from 2.5% to 0.7% (P = 0.002). Preventable harm was completely eliminated (1.1% to 0%, P = 0.001) with no difference in major bleeding or all‐cause mortality. A VTE prophylaxis computerized clinical decision support‐enabled “smart order set” improved prescription of risk‐appropriate VTE prophylaxis, reduced symptomatic VTE and eliminated preventable harm from VTE without increasing major bleeding. Am. J. Hematol. 88:545–549, 2013.

Is diabetes mellitus associated with increased incidence and disease-specific mortality in endometrial cancer? A systematic review and meta-analysis of cohort studies

OBJECTIVE To assess the association between diabetes mellitus (DM) and the incidence and disease-specific mortality of endometrial cancer (EC). METHODS MEDLINE, EMBASE and conference abstracts of the 2011-2013 Annual Meetings of Society of Gynecological Oncology were searched for reports of original cohort studies that enrolled diabetic and non-diabetic women who were free of EC at baseline to compare the incidence and disease-specific mortality of EC by DM status. The included reports were examined for demographic characteristics of study populations, study design, effect measures and risk of bias. Statistical heterogeneity was evaluated with Chi-square test of the Cochrane Q statistics at the 0.05 significance level and I(2) statistic. Publication bias was assessed by visual examination of a funnel plot and the Eggers test for small-study effects. RESULTS Twenty-nine cohort studies (17 prospective, 12 retrospective) were eligible for this review, 23 of which reported EC incidence, five reported disease-specific mortality and one reported both. For incidence of EC among women with versus without DM, the summary relative risk (RR) was 1.89 (95%CI, 1.46-2.45; p<0.001) and the summary incidence rate ratio was 1.61 (95%CI, 1.51-1.71; p<0.001). The pooled RR of disease-specific mortality was 1.32 (95%CI, 1.10-1.60; p=0.003), while results in the studies reporting standardized mortality ratios were inconsistent. There remains considerable amount of clinical and methodological heterogeneity among the included studies; moreover, the hazard ratios for incident EC showed significant statistical heterogeneity and therefore were not quantitatively synthesized. CONCLUSIONS There is consistent evidence for an independent association between DM and an increased risk of incident EC, while the association between DM and EC-specific mortality remains uncertain. Further studies with better considerations for selection bias, information bias and confounding will further facilitate causal inference involving DM and EC.

Hepatosplenic T-cell lymphoma in a patient with Crohn's disease who received infliximab therapy

Hepatosplenic T-cell lymphoma (HSTL) is a rare form of aggressive non-Hodgkin’s lymphoma. About one fourth of HSTL cases have been associated with immunosuppressive therapy for various reasons, mostly for solid organ transplantation. So far, four cases of HSTL [1 – 4] have been reported in the literature in association with Crohn’s disease (CD); one of these patients was treated with anti-tumor necrosis factor alpha antibody (infliximab). We are reporting another case of HSTL in a patient with CD who received infliximab. A 31-year-old white male presented to the emergency room in January 2005 with three-day history of fevers, chills, and malaise. The patient had a 6-year history of Crohn’s disease (CD), primarily involving the small bowel. He was maintained on mesalamine and 6-mercaptopurine (6-MP), although he was not fully compliant with the latter. He also received several courses of steroids for periodic flares. The patient received a single 300 mg dose of anti-tumor necrosis factor alpha antibody (infliximab) 51 months prior to presentation. However, he continued to experience recurrent flares of active disease, eventually requiring ileo-cecectomy and resection of 2 small bowel segmental strictures. His 6-MP was not resumed following surgery because of prolonged post-operative neutopenia. On presentation, the physical examination was notable for the presence of splenomegaly but absence of hepatomegaly or lymphadenopathy. The WBC was 1600/ml (4000 – 11,000/ml), HCT 19% (35 – 47%) and platelet count 54,000/mL (150,000 – 400,000/mL). A complete blood count done two months earlier showed only mild anemia. A blood smear showed hypochromic microcytic RBCs but no abnormal circulating cells. LDH was 264 IU/L (90 – 200 IU/L), ALT 78 IU/L (20 – 65 IU/L), AST 56 (7 – 37 IU/L). Abdominal CT scan confirmed the presence of splenomegaly but was otherwise normal. The bone marrow was hypercellular with trilineage dysplasia but no malignant cells were identified. Bone marrow cytogenetics were normal at that time. The cytopenias were considered to be secondary to autoimmunity and splenomegaly. The bone marrow dysplasia was believed to be secondary to the prior use of 6-MP. Subsequently, the patient was started on high dose steroids with subsequent normalization of the CBC, LDH and the liver enzymes. Over the next few weeks, he continued to have recurrent fevers and worsening cytopenias whenever the steroids were tapered although the LDH and liver enzymes remained normal. Subsequently, he received two more doses of infliximab, each of 300 mg (in March and April 2005) with no evident response. A repeat abdominal CT scan done in May 2005 showed progression of the splenomegaly. Subsequently, the patient underwent splenectomy. The spleen was markedly enlarged (2247 grams) with no discrete lesions. The spleen had diffuse expansion of the red pulp with an atypical lymphoid population (Figure 1). The atypical lymphoid population was positive for CD3, CD16, CD56, CD2, CD7, gamma

Azacitidine with or without Entinostat for the treatment of therapy-related myeloid neoplasm: further results of the E1905 North American Leukemia Intergroup study

Therapy‐related myeloid neoplasms (tMN) are serious late effects of the treatment of cancer with poor response to conventional treatment. Azacitidine (AZA) has been used to treat patients with tMN but current data are retrospective. We present here 47 tMN patients prospectively enrolled as a specific cohort in the E1905 study. TheE1905 study was a randomized phase 2 study (NCT00313586) testing 10 d of AZA (50 mg/m2/d) +/− the histone deacetylase inhibitor entinostat (4 mg/m2/d PO day‐3 and day‐10). A total of 47 patients [29 therapy‐related myelosyspastic syndrome (t‐MDS) and 18 therapy‐related acute myeloid leukaemia (t‐AML)] were recruited to the study. 24 patients were treated with AZA monotherapy and 23 with AZA+entinostat. The median number of administered cycles was 4, significantly higher in patients treated with AZA (6 cycles vs. 3 cycles, P = 0·008). Haematological normalization rates were 46% in monotherapy and 17% in the combination arm. Median overall survivals were 13 and 6 months, respectively. The novel 50 * 10 schedule of azacitidine appears effective, with response rates, when given as single agent, comparable to those for patients with de novo MDS/AML treated on the same protocol. However, the combination of AZA and entinostat was associated with increased toxicity and could not be recommended for treatment of tMN.

There’s Risk, and Then There’s RISK: The Latest Clinical Prognostic Risk Stratification Models in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) include a diverse group of clonal hematopoietic disorders characterized by progressive cytopenias and propensity for leukemic progression. The biologic heterogeneity that underlies MDS translates clinically in wide variations of clinical outcomes. Several prognostic schemes were developed to predict the natural course of MDS, counsel patients, and allow evidence-based, risk-adaptive implementation of therapeutic strategies. The prognostic schemes divide patients into subgroups with similar prognosis, but the extent to which the prognostic prediction applies to any individual patient is more variable. None of these instruments was designed to predict the clinical benefit in relation to any specific MDS therapy. The prognostic impact of molecular mutations is being more recognized and attempts at incorporating it into the current prognostic schemes are ongoing.

Lenalidomide performance in the real world: patterns of use and effectiveness in a Medicare population with myelodysplastic syndromes.

Lenalidomide is approved for the treatment of anemia with transfusion dependence (TD) in patients with lower‐risk myelodysplastic syndrome (MDS) with 5q deletion (del5q‐MDS), but its “real‐life” use and effect on transfusion needs are unclear. In the current study, the authors examined its use in the Medicare population.

Iron chelation therapy in myelodysplastic syndromes: where do we stand?

Anemia leading to transfusion dependency (TD) and iron overload (IO) is commonly observed in patients with myelodysplastic syndromes (MDS). In MDS, TD and IO have been retrospectively associated with inferior survival and worse clinical outcomes, including cardiac, hepatic and endocrine dysfunction, and, in some analyses, with leukemic progression and infectious complications. Although suggested by retrospective analyses, clear prospective documentation of the beneficial effects of iron chelation therapy (ICT) on organ function and survival in MDS patients with TD and IO is currently lacking. Consequently, the role of ICT in MDS patients with TD and IO remains a very controversial aspect in the management of MDS. In this review, the authors summarize the current knowledge regarding IO in MDS and the role of ICT.

Hepatocellular carcinoma: systemic therapies and future perspectives

Hepatocellular carcinoma is (HCC) the most common primary malignancy of the liver in adults. It is also the fifth most common solid cancer worldwide and the third leading cause of cancer-related deaths. Treatment options for HCC include liver transplantation, surgical resection, locoregional therapies and chemotherapy. The median survival time of patients following the diagnosis of unresectable disease is approximately 6–20 months, whereas the 5-year survival is less than 5%. Given the projected increase in incidence of HCC due to hepatitis C virus infection and obesity related cirrhosis, there is an urgent need for more intensive research in this cancer. In this article, we review the systemic options available for patients with HCC, its molecular pathogenesis and future therapeutic directions with special emphasis on immune-based and molecularly-targeted therapy.