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The establishment of primary tumor cells in distant organs, termed metastasis, is the principal cause of cancer mortality and is a crucial therapeutic target in oncology. Thus, it is critical to establish a better understanding of metastatic progression for the future development of improved therapeutic approaches. Indeed, such development requires insight into the timing of tumor cell dissemination and seeding of distant organs resulting in occult lesions. Following dissemination of tumor cells from the primary tumor, they can reside in niches in distant organs for years or decades, following which they can emerge as an overt metastasis. This timeline of metastatic dormancy is regulated by interactions between the tumor, its microenvironment, angiogenesis, and tumor antigen-specific T-cell responses. An improved understanding of the mechanisms and interactions responsible for immune evasion and tumor cell release from dormancy would help identify and aid in the development of novel targeted therapeutics. One such mediator of dormancy is myeloid derived suppressor cells (MDSC), whose number in the peripheral blood (PB) or infiltrating tumors has been associated with cancer stage, grade, patient survival, and metastasis in a broad range of tumor pathologies. Thus, extensive studies have revealed a role for MDSCs in tumor escape from adoptive and innate immune responses, facilitating tumor progression and metastasis; however, few studies have considered their role in dormancy. We have posited that MDSCs may regulate disseminated tumor cells resulting in resurgence of senescent tumor cells. In this review, we discuss clinical studies that address mechanisms of tumor recurrence including from dormancy, the role of MDSCs in their escape from dormancy during recurrence, the development of occult metastases, and the potential for MDSC inhibition as an approach to prolong the survival of patients with advanced malignancies. We stress that assessing the impact of therapies on MDSCs versus other cellular targets is challenging within the multimodality interventions required clinically. [ABSTRACT FROM AUTHOR]

Survival benefit associated with intensive over low-intensity chemotherapy in older adults with acute myeloid leukemia (AML) is controversial. Geriatric assessment and genetic risk categories correlate with survival following intensive chemotherapy in older adults with AML and can guide treatment selection. In a single-center trial, we integrated both geriatric assessment, and genetic risk categories to personalize selection of intensive versus low-intensity chemotherapy in older adults ≥60 years with AML (NCT03226418). In the present report, we demonstrate feasibility of this approach. Broad eligibility criteria and co-management of patients with community oncologists allowed enrollment of 45% of all patients with AML treated at our center during the study period. The median time from enrollment to therapy initiation was two days (range 0–9). Over half of the trial patients had a score of ≥3 on hematopoietic cell transplantation comorbidity index, impairment in physical function (Short Physical Performance Battery), and Montreal Cognitive Assessment. Three fit patients received intensive chemotherapy, whereas other patients received low-intensity chemotherapy. Mortality at 30 days from diagnosis was 3.7% (95% confidence interval [CI] 0.7–18.3%) and at 90 days was 29.6% (95% CI 15.9–48.5%). One-year overall survival was 66% (95% CI 60–87%). Our data demonstrate the feasibility of integrating geriatric assessment in precision oncology trials to define fitness for intensive chemotherapy. Broad eligibility criteria and academic-community collaboration can expand access to clinical trials. [ABSTRACT FROM AUTHOR]

There is a high incidence of antiphospholipid antibodies, detected by assays for anticardiolipin or lupus-like anticoagulant, in HIV disease. However, a link to the antiphospholipid syndrome, with clinical thrombosis, is tenuous. We report a case of a 25-year-old man with undetermined risk factors for HIV presenting with possible antiphospholipid syndrome manifesting as necrotic skin lesions as the initial clinical presentation for HIV. We also review the literature exploring the association between HIV and antiphospholipid syndrome.

Chronic myelomonocytic leukemia (CMML) is a rare but distinct hematological neoplasm with overlapping features of myelodysplastic syndrome (MDS) and myeloproliferative neoplasm (MPN). Individuals with CMML have persistent monocytosis and bone marrow dyspoiesis associated with various constitutional symptoms like fevers, unintentional weight loss, or night sweats. It is established that there is a strong association of CMML with preceding or coexisting autoimmune diseases and systemic inflammatory syndromes affecting around 20% of patients. Various molecular abnormalities like TET2, SRSF2, ASXL1, and RAS are reported in the pathogenesis of CMML, but no such mutations have been described to explain the strong association of autoimmune diseases and severe inflammatory phenotype seen in CMML. Germline mutation in SH2B adaptor protein 3 (SH2B3) had been reported before to affect a family with autoimmune disorders and acute lymphoblastic leukemia. In this report, we describe the first case of a female subject with many years of preceding history of multiple sclerosis before the diagnosis of CMML. We outline the evidence supporting the pathogenic role of SH2B3 p.E395K germline mutation, connecting the dots of association between autoimmune diseases and CMML genesis. [ABSTRACT FROM AUTHOR]

Polypharmacy, usually defined as taking ≥5 prescribed medications, increases chances of drug–drug interactions and toxicities, and may harm cancer patients who need multiple chemotherapeutic agents and supportive medications. We analyzed the effects of polypharmacy in overall survival (OS) in acute myeloid leukemia (AML). A total of 399 patients were divided into two groups: patients with polypharmacy (≥5 medications) versus without polypharmacy (<5 medications). Polypharmacy was associated with age ≥60 years, Karnofsky Performance Status of ≤80, hematopoietic cell transplant (HCT) comorbidity index of ≥5, and adverse cytogenetics. Patients with polypharmacy were less likely to receive intensity chemotherapy or HCT. One-year OS of patients with polypharmacy versus those without polypharmacy was 29 vs. 49% (p<.001). Polypharmacy conferred worse OS in patients <60 years (37 vs. 65% at 1 year, HR 1.95, 95% CI 1.21–3.15) but not in patients ≥60 years (26 vs. 27% at 1 year, HR 1.12, 95% CI 0.81–1.57). Thus, polypharmacy has negative impact on OS in AML, particularly among patients aged <60 years. [ABSTRACT FROM AUTHOR]

Aim: This study evaluated the overall survival (OS) of older patients (≥60 years) with acute myeloid leukemia based on the intensity of treatment. Methods: This single center, retrospective study included 211 patients diagnosed between 2000 and 2016, who received 10-day decitabine, low-intensity therapy or high-intensity therapy. Cox regression examined the impact of therapy on OS. Results: Younger patients were more likely to receive high-intensity therapy. Patients who received low-intensity therapy had worse OS compared with high-intensity therapy (median OS: 1.2 vs 8.5 months; p < 0.01). OS was similar with 10-day decitabine (median OS of 6.3 months) compared with either low-intensity therapy or high-intensity therapy. Conclusion: Ten-day decitabine is an effective alternative in older patients with newly diagnosed acute myeloid leukemia. [ABSTRACT FROM AUTHOR]

The expression of checkpoint blockade molecules PD-1, PD-L1, CTLA-4, and foxp3+CD25+CD4+ T cells (Tregs) regulate donor T cell activation and graft-vs-host disease (GvHD) in allogeneic hematopoietic stem cell transplant (allo-HSCT). Detailed kinetics of PD-1-, CTLA-4-, and PD-L1 expression on donor and host cells in GvHD target organs have not been well studied. Using an established GvHD model of allo-HSCT (B6 → CB6F1), we noted transient increases of PD-1- and CTLA-4-expressing donor CD4+ and CD8+ T cells on day 10 post transplant in spleens of allo-HSCT recipients compared with syngeneic HSCT (syn-HSCT) recipients. In contrast, expression of PD-1- and CTLA-4 on donor T cells was persistently increased in bone marrow (BM) of allo-HSCT recipients compared with syn-HSCT recipients. Similar differential patterns of donor T cell immune response were observed in a minor histocompatibility (miHA) mismatched transplant model of GvHD. Despite higher PD-1 and CTLA-4 expression in BM, numbers of foxp3+ T cells and Tregs were much lower in allo-HSCT recipients compared with syn-HSCT recipients. PD-L1-expressing host cells were markedly decreased concomitant with elimination of residual host hematopoietic elements in spleens of allo-HSCT recipients. Allo-HSCT recipients lacking PD-L1 rapidly developed increased serum inflammatory cytokines and lethal acute GvHD compared with wild-type (WT) B6 allo-HSCT recipients. These data suggest that increased expression of checkpoint blockade molecules PD-1 and CTLA-4 on donor T cells is not sufficient to prevent GvHD, and that cooperation between checkpoint blockade signaling by host cells and donor Tregs is necessary to limit GvHD in allo-HSCT recipients. [ABSTRACT FROM AUTHOR]

Genetically manipulated T cells can be endowed with novel functions to obtain desired in vivo effects after adoptive transfer. This genetic approach is being used to introduce genes such as chimeric immunoreceptors and tumor-specific T cells are being evaluated in early phase clinic trials. However, the ability to alter the genetic programming of T cells also presents opportunities to remove unwanted T-cell functions in order to augment an anti-tumor effect or endow resistance such as to HIV infection. Specifically, the use of RNA interference (RNAi) to disrupt gene expression by targeting either the mRNA or the promoter, provides investigators with many new opportunities to genetically modify T cells that should prove useful in future applications of adoptive immunotherapy. [ABSTRACT FROM AUTHOR]

High-dose melphalan 140 mg/m2 is the standard of care for patients with multiple myeloma (MM) with renal insufficiency (RI). Palifermin as a cytoprotective agent has demonstrated efficacy in reducing the intensity and duration of oral mucositis (OM) in patients who receive intensive chemotherapy/radiotherapy. There is no prospective data on the use of palifermin in patients with MM with RI. Eligibility criteria: creatinine clearance ≤60 mL/minute/1.73 m2, age >18 years, no dialysis, no active OM, and a suitable candidate for autologous stem cell transplant (ASCT). Melphalan dose ranged from 140 to 200 mg/m2 and escalated at the increment of 20 mg/m2. Six dosages of palifermin 60 mcg/kg/day were given intravenously between day –5 to day +3. Dose escalations were to stop if dose-limiting toxicities (DLTs) occurred at melphalan dose in ≥2 of 3 patients, with that dose declared as the maximal administered dose and the level below where ≤1 of 6 patients had DLTs was considered the maximally tolerated dose (MTD). Nineteen patients were enrolled from June 2007 to June 2011. Data on 15 evaluable patients is reported as 4 patients were removed. Median age was 59 years (range, 36-67 years). The overall incidence of OM ≥ grade 3 was 53% (8 of 15) and a median duration of ≥grade 3 OM was 6.5 days (range, 3-42 days). One patient in L2 (melphalan 160 mg/m2) developed atrial fibrillation on day +9. Two patients in L4 (melphalan 200 mg/m2) developed grade 4 OM, hence reaching DLT. No DLT was observed in 6 patients enrolled in L3 (melphalan 180 mg/m2). Palifermin has permitted safe dose escalation of melphalan up to 180 mg/m2 in patients with RI. [ABSTRACT FROM AUTHOR]

Patients ≥55 years of age with active, relapsed or refractory acute myeloid leukemia (AML) who have failed standard induction and salvage therapies do not routinely undergo allogeneic hematopoietic cell transplantation due to their inability to receive myeloablative conditioning. The SIERRA trial is a prospective, randomized, phase 3, open-label, multicenter trial designed to address this significant unmet need. Preliminary results have shown that targeted conditioning with Iomab-B can lead to successful engraftment. Due to the activity level of infused 131I (300-1030 mCi, mean ∼600 mCi), patients are shielded from the public in a hospital room for 3-7 days. As a dedicated lead-lined isolation room is not always available, we present our experience from 6 SIERRA study sites demonstrating the feasibility of using mobile shielding in standard inpatient rooms to comply with radiation safety regulations. Six hospitals (1. Memorial Sloan Kettering Cancer Center, 2. Banner MD Anderson Cancer Center, 3. Medical College of Wisconsin, 4. Weill Cornell Medical Center, 5. University of Nebraska Medical Center, and 6. Stony Brook University Hospital) out of 20 sites have identified regular corner inpatient rooms (4 of them are on top floor) for isolation after Iomab-B therapeutic infusion. Shielding calculations were performed taking into consideration the patient room layout, bed position, surrounding areas (hall way, nursing station and adjacent rooms) and their occupancy to determine placement of mobile shielding. Radiation surveys were performed in identified areas following Iomab-B infusion and during the isolation period. As shown in Table 1, both calculation with 800 mCi of 131I and the survey immediately following therapeutic (time of maximum exposure) have shown that appropriate use of mobile shields can effectively decrease the exposure rate in surrounding public accessible areas to be less than the regulated limit of 2 mR/hour. Lead-lined rooms are not required for treating R/R AML patients with Iomab-B. The use of mobile shields enables treatment of patients in regular inpatient rooms. [ABSTRACT FROM AUTHOR]

Patients with rel/ref AML have very few options, despite novel targeted therapies (e.g. venetoclax, IDH inhibitors), other than allogeneic hematopoietic cell transplantation (HCT) to achieve a durable CR. In addition, patients ≥55 years of age cannot tolerate multiple cycles of intensive therapy trying to achieve a CR prior to transplant. Older patients are also unable to tolerate more intense myeloablative conditioning. The SIERRA trial is a prospective, randomized, phase 3 trial addressing the unmet need to improve access of older patients with active, rel/ref AML to HCT, the only potentially curative therapy available to them. Patients are randomized (1:1) to receive Iomab-B (day-12) followed by FLU/TBI and HCT, or to conventional care (CC). CC patients may receive investigator's choice of salvage therapy, including newly approved targeted agents and may proceed to standard HCT if they achieve CR. If patients do not achieve CR, the study allows cross-over (CO) to Iomab-B/HCT. Preliminary data are available from 75 (50%) patients (Table 1). Patients (median age 64) were heavily pretreated with 85% failing ≥2 induction therapies and 33% failing targeted therapies. All patients transplanted after Iomab-B engrafted. After randomization, 82% (31/38) patients in the CC arm failed salvage therapy, despite 32% (12/38) receiving targeted therapy. 73% (8/11) of the patients receiving venetoclax with HMA or LDAC did not achieve remission. Of the 31 patients, 9 were not CO transplant candidates. Of the 22 patients that crossed over for transplant, majority (91%, N=20) were able to receive Iomab-B/HCT, despite a median of 35% BM blasts. The most common reason preventing CO to transplant was disease progression. CC patients showed increased incidence of Grade 3 febrile neutropenia, compared to Iomab-B patients prior to CO or HCT (34% vs 8%). Iomab-B administration was generally well-tolerated with 1 Grade 3 and no Grade 4, infusion reaction. There were no Iomab-B-related deaths and 100-day non-relapse TRM was 3% on the Iomab-B arm (Table 1). Despite advanced age, active disease and heavily pre-treated patients, 100% (31/31) of all patients in the Iomab-B arm who received treatment with Iomab-B were able to undergo HCT and successfully engrafted. In comparison, only 18% (7/38) of the patients on the CC arm achieved remission and underwent conventional HCT despite a high percentage receiving recently approved agents and targeted therapies. Overall, including patients crossing over to receive Iomab-B/HCT after failure of salvage therapy in the CC arm, 68% (51/75) of all patients enrolled in the trial underwent HCT after Iomab-B. These preliminary results represent significant improvements in the current rates of transplantation in this patient population. This SIERRA trial is currently enrolling (www.sierratrial.com or clinicaltrials.gov NCT02665065). [ABSTRACT FROM AUTHOR]