Moshe Chaim Ornstein

Combination strategies in myelodysplastic syndromes

The myelodysplastic syndromes (MDS) consist of an array of clonal hematological malignancies resulting from disorders of pluripotent hematopoietic stem cells. MDS is associated with a poor overall prognosis and patients are categorized as higher risk and lower risk on the basis of the International Prognostic Scoring System. Currently, lenalidomide, azacitidine, and decitabine are the only three FDA-approved drugs for MDS. Traditional therapies for MDS involve the administration of single agents providing either supportive measures or disease-modifying effects directed to slowing progression to acute myeloid leukemia (AML) and improving survival. Recently, however, there has been increasing evidence suggesting that the combination of drugs with different mechanisms of action offers substantial benefit in the form of diminished side effects, improved overall survival, and delayed progression to AML. Multiple studies indicate that when compared with traditional monotherapies, combining various medications with non-overlapping mechanisms of action and toxicities may result in significant benefit for patients with MDS. A variety of combination therapies with growth factors, DNA methytransferase inhibitors, histone deacetylase inhibitors, and immunosuppressant treatments provide encouraging data indicating that the successful future of MDS treatment rests in the combination of multiple treatments modalities to achieve improved clinical outcomes.

State of the evidence: mechanical ventilation with PEEP in patients with cardiogenic shock

The need to provide invasive mechanical ventilatory support to patients with myocardial infarction and acute left heart failure is common. Despite the large number of patients requiring mechanical ventilation in this setting, there are remarkably few data addressing the ideal mode of respiratory support in such patients. Although there is near universal acceptance regarding the use of non-invasive positive pressure ventilation in patients with acute pulmonary oedema, there is more concern with invasive positive pressure ventilation owing to its more significant haemodynamic impact. Positive end-expiratory pressure (PEEP) is almost universally applied in mechanically ventilated patients due to benefits in gas exchange, recruitment of alveolar units, counterbalance of hydrostatic forces leading to pulmonary oedema and maintenance of airway patency. The limited available clinical data suggest that a moderate level of PEEP is safe to use in severe left ventricular (LV) dysfunction and cardiogenic shock, and may provide haemodynamic benefits as well in LV failure which exhibits afterload-sensitive physiology.

A Phase II Study of Intermittent Sunitinib in Previously Untreated Patients With Metastatic Renal Cell Carcinoma

Purpose Sunitinib is a standard initial therapy in metastatic renal cell carcinoma (mRCC), but chronic dosing requires balancing toxicity with clinical benefit. The feasibility and clinical outcome with intermittent sunitinib dosing in patients with mRCC was explored. Patients and Methods Patients with treatment-naïve, clear cell mRCC were treated with four cycles of sunitinib (50 mg once per day, 4 weeks of receiving treatment followed by 2 weeks of no treatment). Patients with a ≥ 10% reduction in tumor burden (TB) after four cycles had sunitinib held, with restaging scans performed every two cycles. Sunitinib was reinitiated for two cycles in those patients with an increase in TB by ≥ 10%, and again held with ≥ 10% TB reduction. This intermittent sunitinib dosing continued until Response Evaluation Criteria in Solid Tumors-defined disease progression while receiving sunitinib, or unacceptable toxicity occurred. The primary objective was feasibility, defined as the proportion of eligible patients who underwent intermittent therapy. Results Of 37 patients enrolled, 20 were eligible for intermittent therapy and all patients (100%) entered the intermittent phase. Patients were not eligible for intermittent sunitinib because of progressive disease (n = 13), toxicity (n = 1), or consent withdrawal (n = 3) before the end of cycle 4. The objective response rate was 46% after the first four cycles of therapy. The median increase in TB during the periods off sunitinib was 1.6 cm (range, -2.9 to 3.4 cm) compared with the TB immediately before stopping sunitinib. Most patients exhibited a stable sawtooth pattern of TB reduction while receiving sunitinib and TB increase while not receiving sunitinib. Median progression-free survival to date is 22.4 months (95% CI, 5.4 to 37.6 months) and median overall survival is 34.8 months (95% CI, 14.8 months to not applicable). Conclusion Periodic extended sunitinib treatment breaks are feasible and clinical efficacy does not seem to be compromised.

More is better: Combination therapies for myelodysplastic syndromes

The myelodysplastic syndromes (MDS) are a heterogenous collection of clonal hematopoietic malignancies that exist as a subgroup of the myeloid neoplasms as classified by the World Health Organization (WHO). They are characterized by ineffective hematopoiesis, subsequent cytopenias, transformation to acute myeloid leukemia (AML), and poor overall survival. There are currently three FDA-approved medications for MDS; lenalidomide, azacitidine, and decitabine. The role of these agents is to diminish the clinical impact of MDS and delay its progression to AML. However, despite known results with these monotherapies, recent clinical trials with a variety of combinations for MDS have demonstrated promising results. These trials include combinations of hypomethylating agents, histone deacetylase inhibitors, growth factors, and chemotherapy among others. In this paper we review the current literature on combination therapies in MDS, analyze on-going and concluded trials, and suggest future possibilities for combination strategies in MDS.

Clinical Effect of Dose Escalation After Disease Progression in Patients With Metastatic Renal Cell Carcinoma

Micro‐Abstract Patients taking tyrosine kinase inhibitors (TKIs) for metastatic renal cell carcinoma might benefit from dose escalation at the occurrence of progressive disease (PD). The data from patients who underwent TKI dose escalation at PD were retrospectively reviewed. The median duration of therapy after PD (10.1 months) was longer than that before PD (6.8 months), suggesting an antitumor effect with TKI dose escalation at PD. Background: Given the variability in drug levels with tyrosine kinase inhibitors (TKIs) in patients with metastatic renal cell carcinoma (mRCC), dose escalation at the occurrence of progressive disease (PD) might have antitumor effects. Patients and Methods: The data from patients with mRCC who were treated at the Cleveland Clinic with TKIs and received a dose escalation after PD in accordance with Response Evaluation Criteria In Solid Tumors (RECIST), version 1.1, were retrospectively reviewed. Patient‐ and disease‐related data were collected and summarized as frequency counts and percentages or medians and ranges. The Kaplan‐Meier method was used to summarize the treatment duration for the escalated doses. Results: Twenty‐two patients were identified. Most patients (82%) were men; the median age at diagnosis was 58 years (range, 40‐71 years). The most common histologic type was clear cell (73%). Axitinib was the most frequently escalated agent after PD (17 patients), followed by sunitinib (3 patients), and pazopanib (2 patients). Before PD, the median treatment duration was 6.8 months (range, 1.6‐50.6 months). Of the 18 patients with evaluable tumor measurements after dose escalation, 14 (78%) had a decrease in tumor burden. The median decrease in tumor burden after dose escalation was 14% (range, 2%‐58%); 4 patients (22%) had decreases ≥10%, 2 (11%) ≥20%, and 4 (22%) >30% (RECIST partial response). At the last follow‐up examination, 5 patients (23%) continued to be treated at escalated doses. The median duration of escalated therapy was estimated at 10.1 months (range, 0.6 to 37.9 months). Conclusion: Dose escalation of TKIs after PD for select patients with mRCC can lead to a reduction in tumor burden and extend the duration of therapy.

The safety and efficacy of nivolumab for the treatment of advanced renal cell carcinoma

ABSTRACT Introduction: Despite a variety of therapies for advanced advanced renal cell carcinoma (RCC) including vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitors (TKIs) and mammalian target of rapamycin (mTOR) inhibitors, outcomes for these patients are still not optimal. Immunotherapy with checkpoint inhibitors such as nivolumab, a fully human immunoglobulin (Ig) G4 PD-1 inhibitor antibody, is a promising development in RCC and provides a new therapeutic option for patients with advanced disease. Areas Covered: This article reviews safety and efficacy data from the phase I, II, and III clinical trials that have led to the approval of nivolumab for the treatment of patients with advanced RCC who have previously been treated with VEGF-directed therapy. Expert Commentary: Given the overall survival advantage with nivolumab compared to previously approved therapy, nivolumab is a new standard of care in the second-line setting for patients with advanced RCC. Additional studies are underway to answer important questions including the identification of biomarkes and the use of nivolumab in treatment-naïve patients.

Predictive factors for latency period and a prognostic model for survival in patients with therapy-related acute myeloid leukemia

Therapy‐related acute myeloid leukemia (t‐AML) is an increasingly recognized sequela in patients receiving chemotherapy or radiotherapy for a primary malignancy or autoimmune disease. This study assessed factors related to the latency period (LP) between the antecedent disorder (AD) and t‐AML diagnosis and developed a comprehensive prognostic model to predict overall survival (OS). We evaluated a cohort of newly diagnosed t‐AML patients treated with cytarabine‐based induction therapy from 2001 to 2011. Multivariable linear and proportional hazards models were used to assess the impact of different classes of chemotherapy on the LP and to identify independent prognostic factors for OS. Of 730 treated AML patients, 58 (7.9%) had t‐AML. Median LP to t‐AML was 5.6 years (range, 0.5–38.4). 64% of patients achieved CR and median OS was 10.7 months. Independent prognostic factors of short LP were age at AD (Pu2009<u20090.0001) and prior treatment with mitotic inhibitors (Pu2009=u20090.05). Unfavorable cytogenetics (Pu2009=u20090.004), antecedent hematologic or autoimmune disease (Pu2009=u20090.01), age >60 (Pu2009=u20090.03), and platelet count <30,000 μL (Pu2009=u20090.04) at the time of t‐AML diagnosis were prognostic for inferior OS. A prognostic model using these factors was developed that risk stratified t‐AML patients into two groups: favorable and unfavorable. Patients in the favorable group had a median OS of 37.6 months compared with 6.4 months in patients comprising the unfavorable group (Pu2009<u20090.0001). Multicomponent prognostic models integrating disease or treatment‐related covariates can help better understand how t‐AML evolves; and can be clinically useful in risk stratifying t‐AML patients undergoing induction therapy. Am. J. Hematol. 89:168–173, 2014.

Impact of vancomycin-resistant enterococcal bacteremia on outcome during acute myeloid leukemia induction therapy

This study aimed to identify the rate and impact of vancomycin-resistant enterococcal (VRE) bacteremia in patients with acute myeloid leukemia (AML) receiving induction chemotherapy (IC). Thirty-seven (10.6%) of 350 patients had VRE bacteremia during IC, with increasing rates of VRE bacteremia over the course of the study period. The overall complete remission (CR) rate for the cohort was 73%, and there was no difference in CR rate between the VRE bacteremia and non-VRE bacteremia cohorts (70% vs. 73%, p = 0.70). Unadjusted median overall survival (OS) was 12.8 months, and differed significantly between those with and without VRE bacteremia (7.1 months vs. 13.1 months, respectively; p = 0.03). The presence of VRE bacteremia during IC for AML was independently associated with increased all-cause mortality (hazard ratio 1.72, 95% confidence interval 1.13–2.63, p = 0.01).

Clinical activity of nivolumab in patients with non-clear cell renal cell carcinoma

BackgroundNivolumab is approved for patients with metastatic renal cell carcinoma (mRCC) refractory to prior antiangiogenic therapy. The clinical activity of nivolumab in patients with non-clear cell RCC subtypes remains unknown as these patients were excluded from the original nivolumab trials.MethodsPatients from 6 centers in the United States who received at least one dose of nivolumab for non-clear cell mRCC between 12/2015 and 06/2017 were identified. A retrospective analysis including patient characteristics, objective response rate according to RECIST v1.1 and treatment-related adverse events (TRAEs) was undertaken.ResultsForty-one patients were identified. Median age was 58xa0years (33–82), 71% were male, and majority had ECOG PS 0 (40%) or 1 (47%). Histology included 16 papillary, 14 unclassified, 5 chromophobe, 4 collecting duct, 1 Xp11 translocation and 1 MTSCC (mucinous tubular and spindle cell carcinoma). Among 35 patients who were evaluable for best response, 7 (20%) had PR and 10 (29%) had SD. Responses were observed in unclassified, papillary and collecting duct subtypes. In the entire cohort, median follow-up was 8.5xa0months and median treatment duration was 3.0xa0months. Median PFS was 3.5xa0months and median OS was not reached. Among responders, median time to best response was 5.1xa0months, and median duration of response was not reached as only 2 out of 7 responders had disease progression during follow-up. TRAEs of any grade were noted in 37% and most commonly included fatigue (12%), fever (10%) and rash (10%). Nivolumab treatments were postponed in 34% and discontinued in 15% of patients due to intolerance. No treatment-related deaths were observed.ConclusionsNivolumab monotherapy demonstrated objective responses and was well tolerated in a heterogeneous population of patients with non-clear cell mRCC. In the absence of other data in this treatment setting, this study lends support to the use of nivolumab for patients with metastatic non-clear cell renal cell carcinoma.

Emerging immunotherapy in advanced renal cell carcinoma

Immunotherapy has recently catapulted to the forefront of treatments for patients with solid tumors. Given its inherent immunogenic properties, renal cell carcinoma (RCC) has historically responded to immunotherapy and remains primed for further development. Although immunotherapy with high-dose interleukin 2 was a primary treatment for advanced RCC (aRCC), recent discoveries of key molecular and immunological alterations have led to the FDA-approval of nivolumab, an antiprogrammed cell death inhibitor, which has demonstrated an overall survival in patients with previously treated aRCC. However, despite recent therapeutic advances, aRCC remains an incurable disease for most patients. In this review, we assess the current landscape and future developments of immunotherapy in aRCC.