Cameron Curley

Outcomes after major or bidirectional ABO‐mismatched allogeneic hematopoietic progenitor cell transplantation after pretransplant isoagglutinin reduction with donor‐type secretor plasma with or without plasma exchange

BACKGROUND: Major ABO mismatch in hematopoietic progenitor cell transplantation (HPCT) is associated with a range of immunohematologic consequences including progenitor cell infusion (PCI)‐related hemolysis, delayed red blood cell engraftment, and pure red cell aplasia (PRCA). Although pretransplant (recipient) isoagglutinin reduction may be associated with decreased immunohematologic complications in this setting, there is no consensus with respect to strategies for isoagglutinin reduction.

Acute myeloid leukemia, the 3q21q26 syndrome and diabetes insipidus: a case presentation.

Diabetes insipidus (DI) is a rare presenting complication of acute myeloid leukaemia (AML). Typically, the combination of DI and AML is associated with structural abnormalities of the neurohypophysis. We present a case of AML and DI presenting without any abnormalities of the neurohypophysis on radiological scanning and with normal cerebrospinal fluid examination. The AML karyotype at presentation was characterized by the presence of a t(3; 3)(q21; q26) translocation and monosomy 7. After treatment with induction chemotherapy, the patient achieved a complete remission and his DI resolved. At subsequent AML relapse, characterized by a complex karyotype without the t(3; 3)(q21; q26) translocation or monosomy 7, DI did not recur. Our case provides clinical support to the hypothesis that the t(3; 3)(q21; q26) translocation and/or monosomy 7 in AML may directly result in dysregulation of transcription factors resulting in development of DI in AML patients.

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.

Is extramedullary relapse of acute myeloid leukemia after allogeneic hematopoietic stem cell transplantation associated with improved survival

Recent reports have suggested that extramedullary (EM) relapse of acute myeloid leukemia (AML) post‐hematopoietic stem cell transplantation (HSCT), unlike isolated bone marrow (BM) relapse, is associated with improved prognosis. We reviewed the outcomes of relapsed AML post‐HSCT at our institution to determine whether survival for patients with EM relapse was truly improved in comparison to patients suffering BM relapses treated in a similar (active) way.

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

Acute myeloid leukaemia relapsing after allogeneic haemopoietic stem cell transplantation: prognostic factors and impact of initial therapy of relapse

We sought to determine factors associated with the overall survival from relapse (OSR) of acute myeloid leukaemia (AML) after allogeneic haemopoietic stem cell transplantation (alloHSCT) and the effect of first salvage therapy and subsequent graft‐versus‐host disease (GVHD) on OSR.

Pharmacokinetics and immunological outcomes of alemtuzumab-based treatment for steroid-refractory acute GvHD

Pharmacokinetics and immunological outcomes of alemtuzumab-based treatment for steroid-refractory acute GvHD

Immunotherapy following relapse of acute leukaemia after T-cell-replete allogeneic peripheral blood progenitor cell transplantation: importance of new onset chronic graft-versus-host disease

To further define the relative impact of immunotherapy and subsequent development of graft‐versus‐host disease (GVHD) on survival in patients with relapsed acute leukaemia postallogeneic hematopoietic stem cell transplant (SCT), we performed a single‐centre retrospective analysis of 32 actively treated patients between 2003 and 2011.

Use of brentuximab vedotin as salvage therapy pre-allogeneic stem cell transplantation in relapsed/refractory CD30 positive lympho-proliferative disorders: a single centre experience

The role of brentuximab peri‐allogeneic transplantation in patients with relapsed and/or refractory CD30 positive lymphomas remains poorly defined.

The role of hematopoietic stem cell transplantation for relapsed and refractory Hodgkin lymphoma

running dose in an attempt to standardize dosing strategies amongst prescribers of different disciplines. The reduction in titrations required to reach a therapeutic aPTT goal showed the superiority over an empiric, prescriber-based strategy. There were no significant differences in the safety endpoints; however, our study was not designed or powered for these outcomes. This is the first published protocol to compare DTI therapy following a guideline that allows prescribers to choose between three therapeutic aPTT goals vs. a historic control and demonstrate an improvement in achievement of therapeutic goal values. There are several limitations to our study. Our analysis was observational in nature and as such unable to account for all forms of bias that may have affected the results. Unlike previously published guidelines that have been nurse-managed, our dosing guideline requires diligence of the prescriber to follow-up and order each dose change and subsequent monitoring frequency. Dosing titrations were enforced by clinical pharmacy staff. The implementation of a direct thrombin inhibitor dosing and titration guideline was associated with an increase in patients who achieved therapeutic aPTT goal, as well as achieving therapeutic aPTT goal on initial dose when compared to a historic cohort of patients managed by the prescriber. These findings were presented in abstract form at the 43rd Society of Critical Care Medicine Annual Congress and received the Hematology Specialty Award.