Kathryn Jackson

Outcomes and prognostic factors for patients with acute myeloid leukemia admitted to the intensive care unit

Abstract Patients receiving treatment for acute myeloid leukemia (AML) commonly experience life-threatening complications requiring intensive care unit (ICU) support. This is a retrospective study of 505 patients with newly diagnosed AML who were treated with intensive chemotherapy between January 1999 and December 2010. Eighty-three patients (16.4%) were identified who had required 92 ICU admissions. The indication for ICU admission was hemodynamic instability in 47.0% of patients and respiratory impairment in 42.2%. The underlying pathology was most commonly infection (77.1%). Vasopressors were required in 67.5% of admissions, mechanical ventilation in 60.2% and hemodialysis in 15.7%. Rates of survival to hospital discharge and 12 months were 59.0% and 41.3%, respectively. Mechanical ventilation use and higher fibrinogen were independently associated with mortality prior to hospital discharge, and mechanical ventilation use and AML cytogenetic risk group were predictive of mortality within 12 months of ICU admission. By providing a more accurate estimation of a patients chance of recovery, such prognostic factors may contribute to decision-making about the appropriateness of admission to the ICU or continuation of intensive life-sustaining measures.

A novel mutation of the erythropoietin receptor gene associated with primary familial and congenital polycythaemia

Primary familial and congenital polycythaemia (PFCP) is a rare form of inherited erythrocytosis caused by heterozygous mutations in the erythropoietin receptor gene (EPOR). We present a novel mutation in the EPOR in a 15-year-old male who was referred to our clinic for investigation of a persistently elevated haemoglobin level. A significant family history of unexplained erythrocytosis spanning four generations of the patient’s family was established. The family history was also significant for an apparent increased rate of cerebrovascular disease in individuals with erythrocytosis. The mutation detected in our patient resides in exon 8 of EPOR, similar to all other EPOR mutations responsible for PFCP. These mutations result in truncation of the cytoplasmic domain of the receptor and impair down-regulation of signalling via the erythropoietin receptor (EPOR). Clinical manifestations in published cases have varied widely and there is a paucity of firm recommendations regarding the management of affected patients. Given the strong family history of complications attributable to erythrocytosis we have recommended venesection with a haematocrit target of ≤0.45 for our patient.

Intensive chemotherapy and reduced‐intensity allogeneic hematopoietic stem cell transplantation for acute myeloid leukemia in elderly patients

Acute myeloid leukemia (AML) incidence increases with age, yet treatment of elderly patients has reduced efficacy compared with younger patients and is often poorly tolerated. This retrospective study assessed the outcomes of older patients with AML treated with intensive chemotherapy with or without allogeneic hematopoietic stem cell transplantation (HSCT).

Alemtuzumab as salvage therapy for steroid and ATG/etanercept-refractory acute GVHD

Acute GVHD (aGVHD) refractory to initial treatment with corticosteroids is associated with high rates of morbidity and mortality. Although several different agents have been proposed as therapy for steroid-refractory aGVHD, there remains no consensus as to optimal management following failure of corticosteroids. At our institution, steroid-refractory aGVHD is routinely treated with antithymocyte globulin (ATG), etanercept±mycophenolate mofetil. Although this approach is able to salvage a significant proportion of patients, prognosis is historically dismal in those patients refractory to second-line therapy. Given the reports of steroid-refractory aGVHD responding to alemtuzumab, we have incorporated this agent as third-line therapy in patients failing the above strategies. Herein, we report the outcome of 13 patients with steroid and ATG/etanercept-refractory aGVHD treated with alemtuzumab as third-line therapy at our institution. Patients were identified retrospectively from an institutional database and clinical outcomes determined by review of medical records. GVHD diagnosis was biopsy proven and clinically graded according to the Gluksberg criteria. Steroid-refractory aGVHD was defined as progressive GVHD after 3 days of methylprednisolone X2mg/kg/ day, no change in GVHD grade after 7 days of methylprednisolone, ocomplete response (CR) after 14 days of methylprednisolone or recurrence of GVHD on steroid taper while receiving 450mg of prednisolone per day. In second-line therapy with ATG, etanercept±mycophenolate mofetil was delivered as previously published. Alemtuzumab was administered at 10mg s.c. daily for five consecutive days in patients who failed to respond to second-line therapy, as defined by progressive GVHD at any time post ATG/etanercept, no response at 14 days or oCR at 28 days post second-line therapy. Response to alemtuzumab was assessed after 28 days or at the time of death if earlier; CR was defined as resolution of all signs and symptoms of aGVHD (Grade 0) and PR as reduction in severity of GVHD by at least 1 overall grade. Between August 2007 and October 2009, a total of 13 patients received alemtuzumab as third-line therapy for refractory aGVHD. Overall 2 patients (15%) had grade 3 and 11 patients (85%) had grade 4 GVHD, with the predominant site of involvement being the gastrointestinal tract in 11 patients (85%) and skin in 2 (15%). Overall response rate was 23%, with two CR and one PR observed. However, infectious complications were common, with 12 patients (92%) experiencing at least one clinically significant infectious event. Bacterial infections occurred in 9 patients (69%), with multiple episodes reported in 5 (38%). Viral infections occurred in 8 patients (62%), including CMV reactivation in 6 of 9 CMV seropositive donor and/or recipient pairs, and polyomavirus (BKV) viral cystitis in 2 (15%); note that rates of EBV and/or adenoviral reactivation could not be defined as routine screening for these viruses was not performed. Invasive fungal infection occurred in 4 patients (31%), including confirmed aspergillus infections in 2 patients that contributed to subsequent mortality. Of concern, apparent non-infectious pulmonary toxicity was also common, occurring in 9 patients (69%), including development of diffuse alveolar haemorrhage (DAH) in 2 of 3 patients with alemtuzumab-responding disease (1 CR and 1 PR patient, respectively). Overall mortality rate was 92%, with only one survivor on long-term follow-up. Median survival was 41 days (range 21–910 days); all deaths occurred within 3 months of alemtuzumab treatment. Causes of death included progressive GVHD in 5 patients (38%), infection in 4 patients (31%) and non-infectious pulmonary toxicity in 3 (23%). There are an increasing number of reports on the use of alemtuzumab as second-line therapy to treat steroidrefractory aGVHD. However, these reports vary in terms of patient selection as well as alemtuzumab administration, including route of administration, dose and dose schedule, making comparison of results difficult. In general terms, based on relatively small patient numbers, the published data to date suggest that a majority of patients appear to respond to alemtuzumab therapy (overall response rate 50–83%), but CR rates are somewhat lower (20–40%) and OS limited (0–56% of patients). In one report, several patients actually received alemtuzumab as third-line therapy after failing steroids and alternative immunosuppressive agents. Although overall response to alemtuzumab in this subgroup of patients appeared high (overall response rate 71 with 57% PR and 14% CR), survival was more modest (14% overall survival), with significant infection-related mortality noted. Indeed, similar to our experience, even in a second-line setting, the use of alemtuzumab to treat refractory aGVHD is associated with high rates of infectious complications, including from atypical pathogens. However, unlike our experience, previous publications of alemtuzumab therapy in refractory GVHD have not reported significant rates of noninfectious pulmonary toxicity. Whether the pulmonary complications seen in our patient cohort simply reflect the more advanced GVHD status of our patients in comparison with other series, or other undefined factors, is unknown. Given the variable dosing and administration Bone Marrow Transplantation (2011) 46, 1579–1580 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11

Addition of etoposide to standard acute myeloid leukaemia induction chemotherapy does not improve survival

Addition of etoposide to standard acute myeloid leukaemia induction chemotherapy does not improve survival We read with interest the article by Low et al., which found that addition of etoposide to high-dose cytarabine and idarubicin for acute myeloid leukaemia (AML) induction chemotherapy increased gastrointestinal toxicity without improvement in complete remission (CR) rate or survival. This observation occurs in the setting of ongoing debate regarding optimal cytarabine and anthracycline doses, and the role of additional agents in AML induction strategies. Their cohort of 53 patients included 22 who received ICE and 31 who received HiDAC-3 induction chemotherapy. Comparison of ICE to HiDAC-3 demonstrated no improvement in CR rate after one cycle, relapse-free survival or overall survival (OS). However, there was a significant increase in grade 3–4 nausea and vomiting, grade 3–4 diarrhoea, and enterocolitis in ICE-treated patients. We reviewed the outcomes of patients with newly diagnosed AML treated with ICE or HiDAC-3 induction chemotherapy at our institutions between February 1999 and July 2011. Patients were identified from institutional databases and outcomes determined by retrospective review of medical records. In general, choice of ICE versus HiDAC-3 induction was institutional-based. The Princess Alexandra Hospital generally utilised the ICE protocol (cytarabine 3 g/m IV BD days 1, 3, 5, 7, idarubicin 9 mg/m IV days 1–3, etoposide 75 mg/m IV days 1–7), while the Royal Brisbane and Women’s Hospital used HiDAC-3 (cytarabine 3 g/m IV BD days 1, 3, 5, 7, idarubicin 12 mg/m IV days 1–3) more frequently. When patients treated at these institutions were compared, no significant differences in baseline characteristics, AML response rates or survival outcomes were found, allowing their data to be combined for this analysis. Cytarabine was dose-reduced to 1 g/m per dose for the five patients ≥60 years treated with either of these regimens. In total, 87 patients had received ICE and 30 patients HiDAC-3. Median age was 45 years (range 16–67 years). When patients were stratified into cytogenetic risk groups (according to South West Oncology Group criteria), 7.7% had favourable-risk, 73.5% had intermediate-risk, and 14.5% had adverse-risk disease. There were no significant differences between groups for baseline characteristics, including age (P = 0.60), cytogenetic risk group (P = 0.14) or initial white cell count (P = 0.15). Following one cycle of induction chemotherapy, CR rate was 86.2% for ICE and 73.3% for HiDAC-3 (P = 0.16). Induction death, defined as death from any cause within 30 days of starting induction chemotherapy, occurred in 6.9% and 6.7% of patients respectively (P = 1.00). There were no induction deaths for those patients ≥60 years who received dose-reduced cytarabine. Allogeneic stem cell transplantation was undertaken in CR1 for 25.3% of ICE patients and 23.3% of HiDAC-3 patients (P = 1.00). At a median follow-up of

Purpura fulminans in a patient with paroxysmal nocturnal haemoglobinuria.

Paroxysmal nocturnal haemoglobinuria (PNH) is a clonal haemolytic disease with a propensity for causing thrombotic complications. Purpura fulminans (PF) has only rarely been described in association with PNH. We report a case of PF in a patient with PNH; however, in contrast to previous cases, cessation of anticoagulation did not result in recurrent thrombotic complications. A 21-year-old male with PNH that developed during follow-up of immunosuppression refractory severe aplastic anaemia presented with a widespread purpuric rash. He had been unwell for several days prior to initial presentation with non-specific URTI symptoms, treated with oral amoxicillin. He had also been commenced escitalopram several weeks beforehand. His PNH was manifest by stable moderate thrombocytopenia (platelet count 50 ¥ 10/L) but normal Hb and WCC/differential. On flow cytometry, his PNH clone affected 100% neutrophils, 70% monocytes but <5% RBC. The patient had never suffered haemolysis or prior thromboembolic disease, and as such had never been treated with eculizumab. There was no family history of blood or clotting disorders. At presentation, the patient exhibited a classic PF rash over his face, back and chest. Skin biopsies displayed classic PF features with prominent haemorrhage throughout the dermis and focal necrosis of the epidermis in association with widespread thrombi in dermal blood vessels. Repeat FBC was unchanged. Coagulation profile and thrombotic screen were normal with no evidence of DIC. Protein C levels were mildly reduced (0.62 U/mL; RR 0.7 to 1.3 via chromogenic activity assay); protein S levels, blood cultures, vasculitic screen and liver and renal function tests were all normal. The patient was treated with FFP, prednisone (1 mg/ kg/day), enoxeparin 1 mg/kg BD, platelet transfusions (to maintain platelet count >50 ¥ 10/L), vitamin K and empirical Tazocin. Skin lesions rapidly improved, and no new lesions developed after the first 48 h. Once vasculitic screen results were available, prednisolone was weaned. Repeat protein C levels performed 7 days after presentation, after active PF manifestations had clinically resolved, were normal (0.91U/mL). Due to persistent thrombocytopenia, warfarin therapy was felt to be relatively contra-indicated, and given the possibility of either a viral or a drug trigger for the PF, enoxeparin was ceased 8 weeks after all skin lesions fully healed, 18 weeks post-initial presentation. After 12mths the patient remains well with no change in his PNH and no further thrombotic events including no recurrence of his PF. Given the lack of family history of clotting disorders and the normalisation of protein C levels after PF treatment, the mildly low protein C levels at PF presentation were felt secondary to an acquired deficiency in the setting of active PF. Only two cases of PF associated with PNH have been previously published. In both cases, infectious triggers (non-specific febrile illness and presumed meningococcal sepsis) preceded the onset of PF. In one case, despite anticoagulation and resolution of PF lesions, the patient continued to suffer recurrent venous thrombosis. In the other case, the patient died from presumed meningococcal sepsis. Our case is unique in that despite cessation of anticoagulation, the patient remains well with no recurrent thrombotic events. Although the underlying PNH was presumably a significant contributing factor in development of the PF, the lack of recurrent PF despite cessation of anticoagulation and ongoing PNH suggests that the trigger for the PF may have been either infection (viral) or drug (amoxicillin or escitalopram) related. We are unaware of any previous reports of escitalopram-related PF. In conclusion, PF is a rare though recognised complication of PNH. However, PF occurring in PNH appears to require a precipitating event or ‘trigger’ to manifest. Our case highlights that PF occurring in PNH may fully resolve without the development of ongoing thrombotic disease.