Kirk Morris

Diagnostic and prognostic utility of the serum free light chain assay in patients with AL amyloidosis

Background: Organ dysfunction in AL amyloidosis is related to the production and deposition of amyloidogenic monoclonal light chains. These pathological light chains can now be quantified using the recently developed serum free light chain assay.

Oral ribavirin for treatment of respiratory syncitial virus and parainfluenza 3 virus infections post allogeneic haematopoietic stem cell transplantation

The prognosis for patients with respiratory syncytial virus (RSV) or parainfluenza virus type 3 (PIV3) respiratory tract infection post allogeneic haematopoietic progenitor cell transplant (HPCT) is historically poor. The use of oral ribavirin (RBV) has not been widely studied in this patient population. We examined the outcomes of 15 consecutive patients (RSV, n=13 and PIV3, n=2) treated with oral RBV post HPCT. Oral RBV was commenced at a starting dose of 10 mg/kg/day, increasing to a maximum dose of 60 mg/kg/day depending on response and tolerance. At diagnosis, seven patients had upper respiratory tract infection (URTI) and eight had lower respiratory tract infection (LRTI). The starting RBV dose of 10 mg/kg/day did not prevent the progression of URTI to LRTI in any patient. However, with dose escalation, six of the seven patients responded to RBV therapy and survived their infective episode. Of the eight patients presenting with LRTI, six patients survived their infection, again after dose escalation of RBV. There was no dose-limiting toxicity seen in any patient. Our results indicate that oral RBV has clinical efficacy in the treatment of RSV/PIV3 infection post HPCT. However, a starting dose of 10 mg/kg/day appears ineffective; we recommend a starting dose of 20 mg/kg/day in this patient group.

Outcome of treatment of adult acute lymphoblastic leukemia with hyperfractionated cyclophosphamide, doxorubicin, vincristine, dexamethasone/methotrexate, cytarabine: results from an Australian population

The optimal initial therapy for treatment of adult acute lymphoblastic leukemia is yet to be defined. Hyper-CVAD has become a widely used treatment for adult acute lymphoblastic leukemia, although publication of outcomes is largely limited to single-center experience. We performed a retrospective analysis of 63 patients treated with Hyper-CVAD at two Australian institutions between 1995 and 2007. Complete remission was obtained in 86% of patients, with an induction mortality of 8%. Treatment-related toxicity was high, resulting in premature cessation of planned treatment in 29% of patients achieving CR. Survival estimates were comparable to previously published experience, with estimated 5-year overall and progression-free survival of 48% and 42%, respectively. Allogeneic stem cell transplant was performed in 22% of patients in first complete remission, with encouraging survival outcomes (estimated 5-year overall survival 75%, progression free survival 82%). Hyper-CVAD is an effective and tolerable induction strategy for adult ALL, and is suitable for use prior to allogeneic stem cell transplant in first complete remission.

Incidence and outcomes of invasive fungal disease in adult patients with acute lymphoblastic leukemia treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone: implications for prophylaxis.

Invasive fungal disease (IFD) is a common complication of therapy for acute leukemia. Whilst the effi cacy and safety of prophylactic strategies to prevent IFD during induction chemotherapy for acute myeloid leukemia are relatively well defi ned, very few data are available with respect to IFD incidence in adult acute lymphoblastic leukemia (ALL) [1]. Over the last decade the intensity of induction protocols in adult ALL have increased signifi cantly [2], resulting in increased corticosteroid exposure and prolonged neutropenic episodes, both well-defi ned risk factors for the development of IFD [3]. Consequently, the adequacy of fl uconazole-based prophylactic strategies to prevent IFD during therapy of ALL is increasingly debatable. However, due to the potential for interactions between various chemotherapy agents used in ALL induction and the extended-spectrum azoles [4,5], fl uconazole continues to be used for standard IFD prophylaxis, despite its lack of anti-mold activity. More data with respect to the actual incidence and/or burden of IFD within adult ALL is needed to better defi ne the risks and benefi ts of implementing anti-mold prophylaxis in this setting. We reviewed the outcome of consecutive adult patients diagnosed with ALL and treated with hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone (Hyper-CVAD) at our institution between May 2005 and December 2010. Hyper-CVAD was administered as previously published [6]. Patients were identifi ed from an institutional database and data with respect to diagnosis and treatment of potential IFD collected from individual medical records. Identifi ed cases of IFD were then retrospectively defi ned as proven, probable or possible as per the 2008 European Organisation for Research and Treatment of Cancer/ Mycoses Study Group (EORTC-MSG) consensus criteria [3]. As per protocol, fl uconazole 200 mg OD PO was used for primary IFD prophylaxis [6]. Th e routine clinical approach to potential IFD was “ pre-emptive, ” where patients with persistent culture-negative fevers unresponsive to broad-spectrum antibiotics underwent computed tomography (CT) scanning of the chest and upper abdomen sinuses (if clinical signs/ symptoms of potential sinusitis) and in the presence of any radiological change consistent with potential IFD commenced on antifungal agents with anti-mold activity. Indirect tests for fungal elements (i.e. galactomannan antigen or β - d -glucan) were not used during the time period under review. Although the choice of empiric anti-mold agent was at the treating physicians ’ discretion, lipid amphotericin 1 – 3 mg/kg/day was used routinely until 2008/2009, with patients changed

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 prospective phase II randomized study of deferasirox to prevent iatrogenic iron overload in patients undertaking induction/consolidation chemotherapy for acute myeloid leukaemia

This prospective randomized phase II study aimed to determine the safety and efficacy of deferasirox in preventing iatrogenic iron overload in patients receiving induction/consolidation chemotherapy for acute myeloid leukaemia (AML) ize. Serum ferritin, transferrin saturation and CRP were measured pre‐, mid‐ and post‐ each chemotherapy cycle. Patients were randomized to receive either therapy with deferasirox vs. no deferasirox therapy once serum ferritin increased to >500 μg/l. The trial was stopped prematurely due to excess gastrointestinal (GI) and infectious toxicity demonstrable in the deferasirox arm, after 10 patients had been randomized to deferasirox and 6 patients to the control arm. Overall, deferasirox was poorly tolerated, with median maximum tolerated dose only 13·8 mg/kg/d and no patient able to tolerate doses >20 mg/kg/d. Median duration of deferasirox therapy was only 72 d (range 19–130 d), with 9/10 patients requiring unplanned dose interruptions and 4/10 patients unable to continue the drug predominantly due to GI effects. Although all 3 treatment‐related deaths occurred in the deferasirox arm (P = 0·25), median overall survival was similar between treatment arms. Use of deferasirox to prevent iatrogenic iron overload in AML patients undertaking induction/consolidation is poorly tolerated and appears to be associated with excess GI and infectious toxicity.

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).

‘Real-world’ Australian experience of pomalidomide for relapsed and refractory myeloma

Ashleigh Scott , Nicholas Weber, Campbell Tiley, Kerry Taylor, John Taper, Simon Harrison, Kah-Lok Chan, Richard Stark, Cindy Lee, Kirk Morris, P. Joy Ho, Anthony Dodds, Sundra Ramanathan, Raj Ramakrishna, Anne-Marie Watson, Bradley Auguston, Fiona Kwok, Hang Quach, Pauline Warburton, Philip Rowlings and Peter Mollee Princess Alexandra Hospital, Woollongabba, Brisbane, Australia; University of Queensland, St Lucia, Brisbane, Australia; Royal Brisbane and Women’s Hospital, Herston, Brisbane, Australia; Gosford Hospital, Gosford, New South Wales, Australia; Icon Cancer Care, South Brisbane, Australia; Nepean Hospital, Nepean, Sydney, Australia; Peter MacCallum Cancer Centre, Melbourne, Australia; Port Macquarie Base Hospital, Port Macquarie, New South Wales, Australia; Royal Adelaide Hospital, Queen Elizabeth Hospital, Adelaide, Australia; Royal Prince Alfred Hospital, Sydney, Australia; St Vincent’s Hospital, Sydney, Australia; St George Hospital, Kogarah, Sydney, Australia; Southern Sydney Haematology, Kogarah, Sydney, Australia; Liverpool Hospital, Liverpool, Sydney, Australia; Sir Charles Gairdner Hospital, Perth, Australia; Westmead Hospital, Sydney, Australia; St Vincent’s Hospital, Melbourne, Australia; Wollongong Hospital, Wollongong, New South Wales, Australia; Calvary Mater Hospital, Newcastle, New South Wales, Australia

Pretransplant platelet transfusion refractoriness is not associated with platelet nonengraftment in T-replete hematopoietic progenitor cell transplantation for hematologic malignancies.

Cellular engraftment after allogeneic hematopoietic progenitor cell transplantation (HPCT) can be affected by pre‐HPCT antibodies against donor human leukocyte antigen (HLA; donor‐specific antibodies [DSAs]), which are commonly acquired by either pregnancy or transfusion. Issues regarding high assay sensitivity and variable interpretation limit routine screening for DSAs. Platelet (PLT) transfusion refractoriness (PTR) is relatively common in patients with hematologic malignancies, and anti‐HLA alloantibodies can be identified in up to 20% of cases. For patients with PTR undergoing subsequent allogeneic HPCT, however, the effect if any on subsequent PLT nonengraftment is unknown.