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Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts.

Acquired aplastic anaemia is a rare, serious, immunologically mediated bone marrow failure syndrome, characterised by marrow hypoplasia of varying severity and significant pancytopenia. Careful attention and investigation, including molecular testing, is required to confirm the diagnosis and exclude other mimicking conditions, such as inherited bone marrow failure syndromes. In a proportion of patients, the disease evolves to myelodysplasia or acute myeloid leukaemia and in some there is an association with paroxysmal nocturnal haemoglobinuria. The disease has a major impact on patient quality of life. Haemopoietic stem/progenitor cell transplantation for eligible patients with an available donor is the only current curative therapy. Other patients may receive immunosuppression, most commonly with anti-thymocyte globulin and cyclosporin. An initial response to immunosuppression is often encouraging, but relapse is common. Supportive care, including management of transfusion requirements and infections, is central to management. Promising new diagnostic tools and emerging therapies will likely transform approaches to this important, chronic and life-threatening condition.

Background: WHIM (Warts, Hypogammaglobulinemia, Infections, and Myelokathexis) syndrome is a rare, autosomal-dominant primary immunodeficiency. Gain-of-function (GOF) mutations in the CXCR4 gene are the most common cause of WHIM syndrome, manifesting as panleukopenia with severe neutropenia, lymphopenia, and monocytopenia, recurrent bacterial infections, unusual susceptibility to human papillomavirus infections with intractable mucocutaneous warts, and increased risk of malignancy (McDermott DH, et al. Immunol Rev. 2019;2878:91-102). Mavorixafor is an investigational, small-molecule, selective antagonist of the CXCR4 receptor being developed as an oral, once-daily (QD) treatment for patients with WHIM syndrome (Dale DC, et al. Blood. 2020;136(26):2994-3003). Objective: We present an update on the clinical outcomes of patients with WHIM syndrome who continued in the long-term extension of the phase 2 study, highlighting long-term safety and efficacy. Methods: A long-term extension is ongoing as part of the open-label, prospective, dose-escalation, phase 2 study evaluating the safety and efficacy of mavorixafor (NCT03005327) in adults with WHIM syndrome. Individuals with a pathogenic GOF CXCR4 mutation and absolute neutrophil count ≤400/μL and/or absolute lymphocyte count ≤650/μL were included. All provided written informed consent. The primary objectives were to evaluate safety and tolerability and assess safe dosage. Exploratory efficacy end points included changes in infection rates, number of cutaneous warts, and white blood cell counts, compared to baseline. Researchers completed detailed interviews of 4 participants continuing in the study to assess their overall study experience and perceived treatment effects. Results: Five of 8 patients in the dose-finding phase 2 study entered into the long-term extension (LTE); median treatment duration was 148.4 weeks. One patient left the LTE because of study fatigue, and all 5 patients had dose escalation to 400 mg oral QD as of May 2021. As of the November 2020 data cutoff, annualized infection rates decreased from 5.6/year at study baseline to 2.2/year at 40 months' treatment, providing evidence of persistent reduction of infections over time. At doses of 300 and 400mg QD (n=7), the mean time above threshold for ANC and ALC were 12.7 hours (SD ± 9.8) and 16.9 hours (SD ± 5.9) compared to 2.1 hours (SD ± 3.3) and 11.5 hours (SD ± 5.9) at doses ≤200 mg QD, respectively. One patient experienced a 79% reduction in warts. Safety data review at May 2021 showed that there were 12 minor treatment-emergent adverse events (grade 1) with long-term treatment (46 months), no treatment-related infections of grade 3 or higher, no treatment-related serious adverse events, and no clinically significant laboratory abnormalities with mavorixafor treatment. Patient interviews revealed that all 4 LTE participants experienced good tolerability of mavorixafor and decreased frequency, severity, and duration of infections and decreased hospital/doctor visits. Three of 4 participants reported previous need for prophylactic treatment to prevent infection of minor wounds, but with mavorixafor, minor wounds healed without infection or need for prophylaxis. The mechanism of action of mavorixafor was of interest to 3 of 4 participants, who found it important that treatment address the underlying cause of disease, not simply the symptoms. Two participants reported a QOL improvement, and the other 2 reported that WHIM syndrome never affected their QOL Conclusion: Ongoing long-term treatment of adults with WHIM syndrome with mavorixafor 300 to 400mg shows durable increase in neutrophils and lymphocytes and sustained improvements in infections and warts. Detailed patient interviews for patient global impression of changes are consistent with sustained clinical benefit of long-term treatment. Mavorixafor has the potential to be a safe, effective, and long-term therapy targeting the underlying cause of WHIM syndrome. A global phase 3 registrational study is ongoing. Disclosures Dale: X4 Pharmaceuticals: Consultancy, Honoraria, Research Funding. Firkin: X4 Pharmaceuticals: Research Funding. Bolyard: X4 Pharmaceuticals: Research Funding. Tang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Jiang: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. MacLeod: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Cadavid: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company. Hu: X4 Pharmaceuticals: Current Employment, Current equity holder in publicly-traded company.

Background: WHIM (Warts, Hypogammaglobulinemia, Infections, Myelokathexis) Syndrome is a serious, ultrarare genetic disorder caused by a gain-of-function mutation in CXCR4 that causes profound neutropenia and lymphopenia associated with increased rates of bacterial and viral infections. Long-term sequelae include hearing loss, bronchiectasis, and HPV-associated malignancies. The cancer risk in WHIM patients is estimated at 30% by age 40. There is currently no treatment that addresses the underlying mechanism of disease. G-CSF increases neutrophil counts but does not appear to reduce infection rates; use of parenteral gamma globulin has had mixed reports of benefit, but no controlled trials have been reported; Plerixafor, a CXCR4 antagonist, has been shown to increase leukocyte counts and reduce infection rates when absolute neutrophil counts (ANC)>600 mm-3 and absolute lymphocyte counts (ALC)>1000 mm-3, but is a parenteral agent that must be administered twice daily. X4P-001 is an orally available, allosteric inhibitor of CXCR4 that is being developed to treat WHIM. We report here the PK/PD data from the Phase 2 portion of Phase 2/3 trial X4P-001 MKKA (NCT03005327) in WHIM patients that led to selection of the dose for Phase 3 development. Methods: Study X4P-001 MKKA is a Phase 2/3 study. The primary objective of Ph2 portion was to assess the dose required to achieve a consistent increase in circulating neutrophils and lymphocytes. Adult patients with WHIM syndrome, with documented WHIM-associated genotype, and either ANC Results: Eight patients were enrolled and were evaluable for efficacy. 6 of 8 were female, and the mean (SD) age was 35.5 (13.37). Two patients started treatment with 50 mg, then received, 100, 150, 300 and 400 mg; 2 started at 100 and then received 200 and 300 mg; 2 started at 200 mg; 1 escalated to 300 and 400 mg while the other terminated after 1 week due to an adverse event (AE). Two started at 300 mg and did not escalate. Doses of at least 300 mg/day were needed to achieve success criteria for ANC, while at doses ≥100 mg/day, 50-100% met success criteria for ALC. (Figure 1) Two patients discontinued: 1 due to an AE of grade 1 rash, and 1 voluntarily withdrew. No serious AEs were reported. One patient had unrelated cholecystitis (grade 3). All other AEs were grade 1 or 2. Conclusions: Treatment of WHIM patients with X4P-001 results in meaningful increases in ANC at doses ≥300 mg, and in ALC at doses ≥100 mg per day for at least 5 weeks. These doses are anticipated to be associated with clinically meaningful outcomes in terms of infections and warts. X4P-001 appeared to be safe and well-tolerated at doses of 50-400 mg per day.4 Disclosures Dale: Athelas, Inc.: Equity Ownership; Amgen: Consultancy, Research Funding; Sanofi-Aventi: Consultancy, Honoraria; Cellerant: Other: Scientific Advisory Board; Hospira: Consultancy; Prolong: Consultancy; Beheringer-Ingelheim: Consultancy; Coherus: Consultancy. Hartmann:Cetara: Employment; X4P Pharmaceuticals: Consultancy. Brown:Certara: Employment; X4P Pharmaceuticals: Consultancy. Ebrahim:X4Pharmaceuticals: Employment. Gorelick:X4 Pharma: Consultancy; PIN Pharma: Consultancy; Shire: Consultancy; NGN Capital: Consultancy, Other: Venture partner; IntraBio: Consultancy; Zymo Consulting Group LLC: Employment.

Summary The risk of deep vein thrombosis and pulmonary embolism increases during, and for several weeks after, flights of four or more hours. Venous stasis due to prolonged immobility and obstruction to venous return from the legs is believed to accentuate any inherent predisposition of the traveller to venous thromboembolism. The incidence increases with flight duration, oestrogen ingestion, a prior episode of venous thromboembolism and coexisting medical or surgical conditions associated with increased risk. Clinically evident episodes occur at an incidence of about one per 4500 long-haul flights. The incidence increases in patients with other risk factors for thromboembolism, so prophylaxis with low molecular weight heparin can be considered. In people at low risk the adverse effects of prophylaxis outweigh the potential benefits.

Patients with suspected multiple myeloma should be investigated with screening tests. They may have a paraprotein in the serum, Bence-Jones protein in the urine, or both.

The treatment of acute promyelocytic leukemia has improved considerably after recognition of the effectiveness of all-trans-retinoic acid (ATRA), anthracycline-based chemotherapy, and arsenic trioxide (ATO). Here we report the use of all 3 agents in combination in an APML4 phase 2 protocol. For induction, ATO was superimposed on an ATRA and idarubicin backbone, with scheduling designed to exploit antileukemic synergy while minimizing cardiotoxicity and the severity of differentiation syndrome. Consolidation comprised 2 cycles of ATRA and ATO without chemotherapy, followed by 2 years of maintenance with ATRA, oral methotrexate, and 6-mercaptopurine. Of 124 evaluable patients, there were 4 (3.2%) early deaths, 118 (95%) hematologic complete remissions, and all 112 patients who commenced consolidation attained molecular complete remission. The 2-year rate for freedom from relapse is 97.5%, failure-free survival 88.1%, and overall survival 93.2%. These outcomes were not influenced by FLT3 mutation status, whereas failure-free survival was correlated with Sanz risk stratification (P[trend] = .03). Compared with our previously reported ATRA/idarubicin-based protocol (APML3), APML4 patients had statistically significantly improved freedom from relapse (P = .006) and failure-free survival (P = .01). In conclusion, the use of ATO in both induction and consolidation achieved excellent outcomes despite a substantial reduction in anthracycline exposure. This trial was registered at the Australian New Zealand Clinical Trials Registry (www.anzctr.org.au) as ACTRN12605000070639.

Severe iron overload is a reported complication of certain erythroid disorders which are characterized by increased erythropoietic activity. Proposed mechanisms include enhancement of iron absorption secondary to increased erythroid activity and coexistent heterozygosity or homozygosity for haemochromatosis. We performed PCR-based analysis for the haemochromatosis-related HFE C282Y mutation in an extended family with inherited haemolytic anaemia in which several members exhibited iron overload. The results demonstrated iron overload was associated with homozygosity but not heterozygosity for this mutation. Such an association may also exist in other erythroid disorders in which iron overload has been reported.

Most cases of iron deficiency can be diagnosed with simple tests. The concentration of serum iron

BACKGROUND The combination of ATRA and anthracycline-based chemotherapy has traditionally been regarded as the gold standard for induction and consolidation in previously untreated APL patients (pts), with ATO usually reserved for relapse. Recent data in Sanz low-risk (LR) and intermediate-risk (IR) APL indicate ATRA + ATO is superior to ATRA + chemotherapy (N Engl J Med 2013), but the optimal therapy for high-risk (HiR) pts remains unclear. In an attempt to improve anti-leukemic efficacy whilst limiting reliance on anthracyclines for all risk categories of APL, the ALLG incorporated ATO into an ATRA + reduced chemotherapy backbone, and the results of an interim analysis with a median follow-up of 2 years (yr) have been published (Blood 120:1570, 2012). Herein, we report results of the protocol-specified final analysis, conducted when all surviving pts had been followed for at least 2 yr after completion of consolidation. METHODS As published, APML4 protocol treatment comprised: (i) induction with ATRA (45 mg/m2 d1-36), IDA (12 mg/m2 d2,4,6,8), ATO (0.15 mg/kg d9-36), prophylactic prednisone (1 mg/kg d1-10) and aggressive hemostatic support; (ii) consolidation with ATRA and ATO (continuous in cycle 1, intermittent in cycle 2); (iii) 2 yr oral maintenance with ATRA, 6-mercaptopurine and methotrexate. Between 2004-2009, 124 evaluable pts were accrued, and median follow-up by the censor-reversing Kaplan-Meier method in this final analysis is 4.2 yr. RESULTS Median age was 44 (3-78) yr, median white cell count was 2.4 x 109/L (0.1-85.8), and median platelet count 22 x 109/L (2-173). Risk groups were 33 LR, 67 IR, 23 HiR, 1 unknown. FLT3 mutations were present in 44%, and 11% had ≥ 2 additional cytogenetic abnormalities (2+ACA). There were 4 (3.2%) deaths during induction (myocardial infarction d1, cerebral hemorrhage d3 and d7, cerebral edema and seizures d30). Grade 3-4 non-hematological adverse events included differentiation syndrome in 14%, and frequent but reversible biochemical hepatic and gastrointestinal toxicity. Q-Tc prolongation > 500 msec occurred in 14%, but there were no cases of ventricular arrhythmias or torsades de pointe. Significant neurological and cutaneous toxicity were infrequent. After induction, 118 pts (95%) achieved hematological complete remission; 112 commenced consolidation, and all were in molecular remission after cycle 2. A total of 5 relapses and 3 deaths have occurred post-induction, but none of the deaths were attributable to protocol therapy. Severe adverse events were less common during the chemotherapy-free consolidation cycles, especially cycle 2. The frequency of grade 3-4 neutropenia was 62% in cycle 1 and 27% in cycle 2, but there was no grade 3-4 thrombocytopenia. The following table lists event-free survival (EFS), disease-free survival (DFS), overall survival (OS) and cumulative incidence of relapse (CIR): Table All pts LR IR HiR 2 yr 5 yr 2 yr 5 yr 2 yr 5 yr 2 yr 5 yr EFS 92% 90% 97% 97% 93% 89% 83% 83% DFS 97% 95% 100% 100% 97% 93% 95% 95% OS 94% 94% 97% 97% 96% 96% 87% 87% CIR 3% 5% 0% 0% 3% 7% 5% 5% In univariate analysis, 2+ACA predicted for inferior DFS (P = .04), whereas age > 70 was associated with increased risk of early death (ED, P = .02), inferior EFS (P = .0002), and inferior OS (P = .001). Neither Sanz risk category nor FLT3 mutation status was significantly correlated with these outcome endpoints (all P > .05). In multivariate analysis, the significant associations of 2+ACA (P = .04 for DFS) and age > 70 (P = .0002 for EFS, P = .005 for OS) were retained. In addition, Sanz risk category was correlated with EFS (P[trend] = .003) and OS (P[trend] = .02). When compared with our previous ALLG APML3 trial (ATRA + IDA for induction and consolidation without ATO; Haematologica 2012), treatment with APML4 was associated with substantial and statistically significant improvements (see Figure) in EFS (P = .002), DFS (P = .001) and OS (P = .02). The significance of trial assignment was retained in multivariate analysis when APML3 and APML4 data were combined. CONCLUSIONS APML4 is a potent anti-leukemic regimen with manageable toxicity and a low ED rate. EFS and OS remain impressive with mature follow-up, and were influenced primarily by advanced age and Sanz risk category. The CIR was 5%, and was only associated with 2+ACA. Our results support the inclusion of ATO in induction and consolidation as front-line therapy for APL whilst simultaneously limiting cumulative anthracycline exposure. Figure 1 Figure 1. Disclosures Off Label Use: Arsenic trioxide is currently only registered in the US, Europe and Australia for the treatment of relapsed APL. This report includes its use in the initial treatment of APL.

Severe neutropenia due to selective loss from the bone marrow of cells of the entire neutrophil maturation sequence developed in a patient with Goodpasture's Syndrome and was associated with serious infections complicating continuous ambulatory peritoneal dialysis. Involvement of T-lymphocytes in the process affecting the neutrophil series was implicated by the relation between recovery from neutropenia and treatment with antithymocyte globulin (ATG). Azathioprine and corticosteroid administration failed to sustain recovery from neutropenia induced by ATG. It is concluded that ATG can provide a nonmyelotoxic form of therapy for pure white cell aplasia whose effectiveness is independent of responsiveness to other immunosuppressive agents.

The clinical course of a patient with chronic hepatitis and previous ulcerative colitis who subsequently developed pure red cell aplasia (PRCA) is described. The PRCA remitted initially with corticosteroid therapy. A subsequent relapse responded to cyclophosphamide therapy following splenectomy. This was followed by a fatal third episode of red cell aplasia associated with megakaryocyte aplasia.