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Abstract Background: FOP is an ultra-rare, severely disabling genetic disorder characterized by episodic flare-ups and heterotopic ossification (HO) leading to restricted movement, physical disability, and early death. FOP may initially be misdiagnosed in ~90% of individuals leading to unnecessary and often harmful interventions. Patients with FOP are diagnosed and managed by multiple specialties, including endocrinologists. Data from an ongoing, prospective, longitudinal, global, natural history study (NCT02322255) were used to investigate the progression of FOP, HO formation, and impact on physical functioning over time. We present results from the first 12 months of the 3-year study. Methods: Males and females with FOP and a documented ACVR1 R206H mutation participated. HO volume was assessed by low-dose whole body computed tomography (WBCT) scan, excluding the head. All imaging was interpreted at a blinded, central laboratory using pre-specified procedures. Functional outcomes were evaluated using the Cumulative Analogue Joint Involvement Scale (CAJIS; for each joint: score=0 represents <10% involvement, score=1 represents 10–90% involvement, and score=2 represents >90% ankylosed across 15 major joints; total score range 0 to 30 [higher scores indicate more severe mobility limitations]) and the FOP Physical Function Questionnaire (FOP-PFQ; percent total score). Changes from Baseline at Month 12 were evaluated for new HO volume, CAJIS, and FOP-PFQ. Results: Of 114 participants (pts) with Baseline data, 99 (4 to 56 years at enrollment; mean 17 years of age; 56% male) also had a Month 12 assessment. A total of 93 pts had evaluable WBCT scans at Baseline and Month 12 and were included in the HO analysis. In total, 40% (37/93) of pts had new HO over 12 months; the mean volume of new HO in these pts was 57,706 mm3 (SD=100,079 mm3; median=20,753 mm3; range: 522 to 438,826 mm3). Of the pts with new HO, 65% (24/37) reported at least one flare-up (mean rate of 2.3 flare-ups/year). Over 12 months, 60% (56/93) of pts did not have new HO; 43% (24/56) of them reported at least one flare-up (mean rate of 1.8 flare-ups/year). Mean changes from Baseline in CAJIS and FOP-PFQ were minimal: CAJIS: 0.6 (SD=2.4; median=1.0; n=99) and FOP-PFQ: 4.4% (SD=11.2; median=3.7%; n=90); and were similar across pts with or without new HO. Conclusions: In participants with FOP, although deterioration of physical function is expected over a patient’s lifetime, CAJIS and FOP-PFQ scores did not worsen significantly in the relative short-term of this study. However, HO volume, quantified by WBCT, increased over the course of 12 months. These results show that measuring HO may be a viable way to monitor changes in FOP over short periods of time.

Abstract High-risk acute promyelocytic leukemia (APL) remains a therapeutic challenge, with higher associated rates of early mortality and relapse than standard-risk APL. All-trans retinoic acid (ATRA) plus arsenic trioxide (ATO) is a well-established treatment for patients with standard-risk APL, but it is not well defined for those with high-risk APL. In a prior study of patients with high-risk APL, the addition of gemtuzumab ozogamicin (GO) to ATO plus ATRA suggested benefit. The SWOG Cancer Research Network conducted a phase 2 study to confirm the efficacy and safety of the combination of ATRA plus ATO plus GO in treating high-risk APL patients. The primary end points were 3-year event-free survival (EFS) and early (6-week) death rates associated with this combination. Seventy patients were treated. With a median follow-up of 3.4 years, the 3-year EFS and overall survival estimates were 78% (95% confidence interval [CI], 67%-86%) and 86% (95% CI, 75%-92%), respectively. Overall, 86% of patients achieved complete response. The 6-week mortality rate was 11%. The most common treatment-emergent toxicities during the induction phase included febrile neutropenia, aspartate aminotransferase/alanine aminotransferase elevation, hyperglycemia, hypoxia, headache, and prolonged QT interval corrected for heart rate. Retinoic acid syndrome occurred in 9% of patients. Approximately 37% of patients did not complete all planned courses of postremission therapy. The combination of ATRA plus ATO plus GO in high-risk APL patients was effective and generally well tolerated, suggesting an opportunity to offer a chemotherapy-free induction platform for patients with this disease. This trial was registered at www.clinicaltrials.gov as #NCT00551460.

Abstract Background While consensus guidelines regarding VTE prophylaxis for hospital inpatients have been available for more than 15 years, the number of US inpatients who are potentially eligible for prophylaxis is unknown. Such data are required for estimating the potential costs and benefits of prophylaxis in reducing VTE incidence. Objective To estimate the number of Y2002 US acute-care hospital inpatients who are potentially eligible for VTE prophylaxis. Methods We applied the 7th (2004) American College of Chest Physician (ACCP) Consensus Conference VTE prophylaxis guidelines (Geerts et al. Chest2004;126:338S–400S) to inpatients with hospital discharge International Classification of Disease (ICD-9) codes for major surgery or medical illness identified from the Healthcare Utilization and Cost Database (HCUP), a national acute-care hospital database supported by the US Agency for Health Care Quality Research. Results Of a total of 37.8 million inpatients discharged from US acute-care hospitals in Y2002, 13.4 million (35%) met ACCP guideline criteria for VTE prophylaxis (Table). Table. Inpatients Discharged from US Acute-Care Hospitals with ACCP Guideline Defined Risk of VTE in Y2002 Surgical VTE Risk N Highest risk surgery 744,465 High risk surgery 3,031,318 Moderate risk surgery 2,019,696 Surgical subtotal 5,795,479 Medical VTE Risk N Heart failure 1,867,576 Cancer 1,017,356 Stroke 515,370 Other medical conditions 4,196,343 Medical subtotal 7,596,645 Grand Total 13,392,124 Among the 37.8 million Y2002 discharged inpatinets, 7.7 million were defined by HCUP criteria as having had a major operative procedure. When ACCP surgical risk criteria were applied to this population, 1.9 (25%) were at low VTE risk, while 5.8 million (75%) were at moderate (26%), high (39%) or highest (10%) VTE risk. Among the patients without a major operative procedure, 7.6 million met the ACCP criteria for VTE prophylaxis based on medical illness risk factors. Conclusions In total, 13.4 million US residents meet ACCP criteria for VTE prophylaxis annually due to hospitalization for either major surgery or medical illness. Given that almost 60% of all VTE events occurring in the community are related to recent acute-care hospitalization, providing universal, safe and effective VTE prophylaxis to this population affords an important opportunity to significantly reduce the incidence of VTE. These data provide support for developing and monitoring compliance with hospital-wide guidelines for VTE prevention.

Abstract Background The total annual number of VTE events and related deaths in the US is unknown, largely because the complete spectrum of disease (including asymptomatic events and sudden deaths) occurring in the community is under-recognized. Objective To estimate the total annual number of non-fatal and fatal deep vein thrombosis (DVT) and pulmonary embolism (PE) events (incident and recurrent) in the US. Methods We developed an incidence-based model that included both hospital- and community-acquired VTE events as well as death from recognized and unrecognized VTE. We estimated the annual number of community-acquired events using the average age-, sex-, and event-specific incidence rates in Olmsted County, MN (1966–1990) and Y2000 US census data. We estimated the annual number of hospital-acquired events using patient age and Y2002 International Classification of Disease (ICD-9) discharge diagnosis codes for major surgery types or acute medical illnesses within the Healthcare Utilization and Cost Database, which includes major discharge diagnoses from all US acute-care hospitals. Patients were included in the hospital model if they were deemed at risk of VTE according to current American College of Chest Physicians definitions. The hospital at-risk population was divided into categories according to type of surgery or medical diagnosis on admission. We estimated the annual number of VTE events based on the published probability of VTE with and without prophylaxis, and US prophylaxis rates, by risk group. Fatal and recurrent events were estimated based on published data. The effects of VTE and prophylaxis rate uncertainty on our estimates were tested using sensitivity analyses. Results The estimated total annual number of symptomatic VTE events in the US exceeded 600,000, (DVT, n=376,365; PE, n=237,058. Table). Table. Annual Number of Non-Fatal and Fatal, Community- and Hospital-Acquired Symptomatic VTE Events in the US Event Type Community Hospital Total Non-Fatal ---------n---------- DVT 108,240 268,125 376,365 PE 85,358 151,700 237,058 Total 193,598 419,825 613,423 Fatal DVT 649 1,609 2,258 PE 105,902 188,210 294,112 Total 106,550 189,819 296,370 VTE-related deaths were estimated at 296,370 annually. Of these deaths, 21,223 (7%) patients were diagnosed with VTE and treated, 101,032 (34%) were sudden fatal PE and 174,115 (59%) followed undetected PE. Approximately two-thirds of symptomatic VTE events were hospital-acquired and one-third were community-acquired. Conclusions Our study confirms that VTE is a major US health problem. Given that effective VTE prophylaxis and expert consensus prophylaxis guidelines are widely available, these data suggest that universal, safe and effective prophylaxis could significantly reduce US VTE incidence and related deaths. Future studies should address the impact of universal VTE prophylaxis on VTE incidence and survival.

Abstract Over the past decade several prospective studies of post-remission therapy in AML have compared allogeneic hematopoietic stem cell transplantation (HSCT), autologous HSCT and chemotherapy. The data are appropriately presented by intention-to-treat analyses. However, such analyses do not provide information to the clinician or patient as to outcome from the initiation of post-remission therapy, be it HSCT or chemotherapy. Furthermore, such analyses are impossible to interpret when a significant percentage of patients do not receive their intended therapies (for example, only 54% of patients randomized to autologous HSCT; Cassileth, NEJM, 1998). Finally, such studies present survival data that may not be relevant to current practice where the mortality from autologous HSCT has decreased sharply (for example, 14% non-relapse mortality from autologous HSCT; Cassileth, NEJM, 1998). In the current analysis, results from 4 consecutive ECOG studies that included autologous HSCT were analyzed and the data collated. In PC486 patients received standard induction followed by allogeneic HSCT if they had a compatible sibling; otherwise they were to undergo an autologous HSCT without any prior consolidation (Cassileth, JCO, 1993). E4995 studied standard induction with added high-dose cytarabine (HiDAC) intensification on D 8–10, followed by 2 courses of HiDAC consolidation. All patients were to undergo an autologous HSCT after induction and consolidation (Cassileth, Leuk Lymph, 2005). E3489 was a US Intergroup study in which patients received standard induction (3 + 7). If in CR, all patients received an attenuated course of induction (2 + 5). Patients who had a histocompatible sibling were assigned to allogeneic HSCT; those without a donor were randomized to an autologous HSCT or chemotherapy (Cassileth, NEJM, 1998). E1900 is an ongoing phase III study in which patients receive standard induction followed by allogeneic HSCT or two courses of HiDAC followed by autologous HSCT. The latter study is ongoing; therefore, only data describing transplant-related mortality (TRM) are presented. The relapse rate from start of each post-remission regimen in these studies, based on therapy actually received and not on intention-to-treat analysis, is presented in table 1 and the TRM is presented in table 2. Table 1. Relapse Rate from Start of Post-Remission Therapy Cytogenetics Allogeneic HSCT (n=85) Autologous HSCT (n=113) Chemotherapy (n=109) Favorable 11.8% (2/17) 10.5% (2/19) 60% (12/20) Intermediate 20.5% (8/39) 32.3% (10/31) 53.7% (22/41) Unfavorable 16.7% (2/12) 41.7% (5/12) 83.3% (15/18) Unknown 23.5% (4/17) 33.3% (17/51) 56.7% (17/30) Table 2. Treatment-Related Mortality after Post-Remission Therapy Allogeneic HSCT Autologous HSCT – Marrow Autologous HSCT – Blood Chemotherapy Study E3489, E4995, E1900 E3489, PC 486 E4995, E1900 E3489 Treatment-related mortality 15.3% (18/117) 11% (16/85) 1.5% (2/135) 2.7% (3/109) In conclusion: The TRM after autologous HSCT using mobilized peripheral blood has decreased substantially in recent years. As shown in table 2, in PC486 and E3489 where bone marrow was harvested and treated with perfosfamide (4-HC) prior to cryo-preservation, the TRM was significantly greater than in the later studies, E4995 and E1900, where peripheral blood was harvested after priming with chemotherapy and/or cytokines. The lower relapse rate post autologous transplant, together with the lower procedural mortality with current practice, may confer a survival advantage in future prospective studies of autologous HSCT versus chemotherapy. While absolute comparisons cannot be made, as the timing of each therapy may not be identical, these data provide crucial information for informed and patient/physician discussions prior to initiation of postremission therapy.

Abstract Results from clinical trials may change with time. Data presented in initial abstracts or early reports are often different from what appears in subsequent publications, sometimes due to a more rigorous analysis (as in initial response rates) or to maturity of data (as in reports of survival). Survival curves usually provide projected data based on Kaplan-Meier analyses. Such data may change with time when unexpected events occur (as, for example, relapse after T-cell depleted allogeneic transplants) or more patients advance to the initially projected time point. For AML, several groups have reported that there are very few relapses beyond 3 years. At issue is the optimal time for reporting these survival data. Table 1 reports data from 6 consecutive clinical trials addressing induction and post-remission questions in AML patients performed by ECOG. These data compare the 3-year overall survival (OS) and disease-free survival (DFS) for the identical cohorts of patients as presented at 1 year and at 3 years after completion of the study accrual. PC 486 was a phase II study of induction therapy followed by allogeneic or autologous transplant without prior consolidation. E 3489 was a US intergroup study in which patients received post-induction therapy using an allogeneic transplant (allo), an autologous transplant (auto) or chemotherapy (chemo). E1490 was a study in older adults of induction and consolidation with GM-CSF or placebo. E2491 was an intergroup study comparing ATRA induction versus standard chemotherapy in patients with APL. After consolidation, patients were randomized to maintenance with ATRA versus observation (obs). E3993 was a study in older adults comparing priming with GMCSF or placebo. E4995 was a phase II study of intensified induction and consolidation followed by an autologous transplant. For the same cohorts of patients the 3-year OS tends to decrease as the time from completion of study accrual increases. When looking at the DFS, while a decrease may also occur, in several studies there was an improved DFS with time (for example, in E2491, chemo to ATRA, or in E3993 with GM-CSF priming). There were no changes in either OS or DFS beyond 3 years (data not shown). Table 1: Three-year OS and DFS Presented at Different Time Points OS (%) DFS (%) Study One year Three years One year Three years PC 486 auto or allo HSCT 42 → 38 45 → 39 E 3489 allo HSCT 50 → 50 48 → 47 auto HSCT 47 → 46 39 → 39 chemo 56 → 51 36 → 36 E 1490 Induction / consolidation GM-CSF 23 → 22 23 → 24 placebo 15 → 12 16 → 15 E2491 APL induction+ maintenance ATRA + ATRA 87 → 84 72 → 73 ATRA + obs 83 → 80 61 → 60 chemo + ATRA 81 → 75 43 → 58 chemo + obs 54 → 45 16 → 18 E 3993 Induction/consolidation GM-CSF priming 13 → 11 5 → 10 placebo 14 → 14 9 → 9 E 4995 Induction / consolidation / auto HSCT 54 → 48 63 → 53 In conclusion: For large cooperative group studies, treatment results in AML presented one year from conclusion of study accrual are unlikely to dramatically alter the overall results. Nonetheless, some differences may occur, both in OS and DFS, warranting caution in interpreting the data and comparing with other published reports. Such differences are likely to be even greater if data are presented upon completion of study accrual, prior to one year - although, in a cooperative group setting, this should be balanced against the need to release data for future planning. Publication of interim data, before conclusion of the study accrual, may be misleading and are to be strongly discouraged. Three years appear to be the appropriate time for the publication of definitive survival data.

Abstract Wiskott-Aldrich syndrome (WAS) is an X-linked disease caused by mutations in the WAS gene, leading to thrombocytopenia, eczema, recurrent infections, autoimmune disease, and malignancy. Hematopoietic cell transplantation (HCT) is the primary curative approach, with the goal of correcting the underlying immunodeficiency and thrombocytopenia. HCT outcomes have improved over time, particularly for patients with HLA-matched sibling and unrelated donors. We report the outcomes of 129 patients with WAS who underwent HCT at 29 Primary Immune Deficiency Treatment Consortium centers from 2005 through 2015. Median age at HCT was 1.2 years. Most patients (65%) received myeloablative busulfan-based conditioning. With a median follow-up of 4.5 years, the 5-year overall survival (OS) was 91%. Superior 5-year OS was observed in patients <5 vs ≥5 years of age at the time of HCT (94% vs 66%; overall P = .0008). OS was excellent regardless of donor type, even in cord blood recipients (90%). Conditioning intensity did not affect OS, but was associated with donor T-cell and myeloid engraftment after HCT. Specifically, patients who received fludarabine/melphalan-based reduced-intensity regimens were more likely to have donor myeloid chimerism <50% early after HCT. In addition, higher platelet counts were observed among recipients who achieved full (>95%) vs low-level (5%-49%) donor myeloid engraftment. In summary, HCT outcomes for WAS have improved since 2005, compared with prior reports. HCT at a younger age continues to be associated with superior outcomes supporting the recommendation for early HCT. High-level donor myeloid engraftment is important for platelet reconstitution after either myeloablative or busulfan-containing reduced intensity conditioning. (This trial was registered at www.clinicaltrials.gov as #NCT02064933.)

Background. Critical limb ischemia (CLI) is limb pain occurring at rest or impending limb loss as a result of lack of blood flow to the affected extremity. CLI pain is challenging to control despite multimodal pharmacologic analgesia and surgical intervention. We described the successful use of a continuous local anesthetic infusion via a popliteal nerve catheter to control severe refractory ischemic lower limb pain in a patient who failed surgical intervention and performed a brief narrative literature review on regional anesthesia for ischemic pain.Case Presentation. A 74-year-old female with acute myelogenous leukemia presented with CLI after experiencing left popliteal artery occlusion. Palliative medicine service was consulted for pain management in the setting of escalating narcotic dose requirements. She experienced a complicated hospital course with several failed attempts at surgical revascularization due to arterial rethrombosis. In accordance with the patient’s goals of care, a continuous popliteal nerve catheter was placed, despite the high risk nature of an intervention in an immunocompromised patient with thrombocytopenia (platelet count of 30,000 platelets/microliter) and ongoing therapeutic anticoagulation. The patient experienced immediate relief while transitioning to comfort care.Conclusion. This is the first report of successful analgesia for CLI via a continuous popliteal catheter in a patient with rethrombosis and failed surgical revascularization. Based on our collaborative experience, we recommend the development of partnerships between the acute pain service and palliative care service to facilitate the early evaluation and decision to utilize regional anesthesia for treatment of CLI.