In Focus
58th American Society of Hematology Annual Meeting
Gene therapy for haemophilia B
Lindsey George (The University of
Pennsylvania, Philadelphia, PA, USA)
presented results from a clinical
trial where seven patients with
haemophilia B were treated with
SPK-9001, a gene therapy treatment
using a bioengineered AAV capsid
with liver specic tropism containing
a transgene encoding FIX Padua,
a naturally occurring variant with
much greater specific activity than
wild-type FIX. All patients received
a dose of 5 10 vg/kg, and steady-
state FIX expression was reached by
12 weeks after vector infusion. All
patients saw an increase in FIX activity,
with a mean increase of 323%. No
patients developed an inhibitor
against FIX, and only one patient
required FIX concentrate infusion for
a bleed 2 days after vector infusion.
Four of the patients who required
regular prophylaxis before treatment
were able to safely stop following
treatment.
Targeting of FLT3 mutations in
AML
Gilteritinib is an oral FLT3 and AXL
inhibitor with preclinical activity
against both FLT3-ITD activating
muta tions and FLT3-Asp835
resistance mutations. Alexander Perl
(University of Pennsylvania-Abramson
Comprehensive Cancer Center,
Philadelphia, PA, USA) presented
the results of an open-label dose-
escalation study (NCT02014558)
of gilteritinib in adult patients with
relapsed or refractory acute myeloid
leukaemia (AML). 252 patients were
enrolled in the study with 177 (70%)
of patients having two or more lines
of prior therapy. Although having a
FLT3 mutation was not an inclusion
criterion of the study, 194 patients
had a locally conrmed FLT3 mutation.
When restricting the analysis to
patients who received 80 mg or more
gilteritinib, and had a conrmed FLT3
mutation (n=169), 18 patients had a
www.thelancet.com/haematology Vol 4 January 2017
Downloaded from ClinicalKey.com at The Regents of the University of Michigan January 31, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
complete response, 51 had a complete
response with incomplete blood
count recovery, and 19 had a partial
response (overall response, 88 [52%]).
Median overall survival in these
patients was 31 weeks (range 261).
For all enrolled patients, progressive
disease (n=75), lack of ecacy (n=44),
adverse events (n=34), and death
(n=29) were the most common
reasons for treatment discontinuation.
Seven deaths were considered
possibly related to treatment, from
pul monary embolism, respiratory
failure, haemoptysis, intracranial
bleeding, ventricular brillation, septic
shock, and neutropaenia. The most
commonly reported treatment-related
adverse events of any grade were
diarrhoea (16%) and fatigue (15%).
Ibrutinib for cGVHD
David Miklos (Stanford University,
Stanford, CA, USA) presented
the results of a phase 2 study
of ibrutinib in for patients with
chronic graft versus host disease
(cGVHD) who were unsuccessfully
treated with corticosteroids.
42 patients were treated with
ibrutinib, and had a median of two
(range one to three) prior treatments.
After a median follow-up of
139 months, 28 (67%) of 42 patients
had a cGVHD response based on
the 2005 NIH consensus response
criteria (nine complete response,
19 partial response). 20 (71%) of the
28 patients had a response lasting
20 weeks or longer, and 12 (48%) of
25 patients with available data had a
response lasting 32 weeks or longer.
Serious adverse events occurred in
22 patients (52%), and the most
common adverse events (AEs) of all
grades were fatigue (57%), diarrhoea
(36%), muscle spasms (29%), nausea
(26%), and bruising (24%).
Catheter related thrombosis
There is limited evidence regarding
risk factors for paediatric patients and
central venous catheter-associated
thrombosis. Julie Jaray (University of
Southern California, Los Angeles, CA,
USA) presented the interim results of
a prospective, observational cohort
study including 1096 patients who
had 1233 central venous catheters
inserted. Peripherally inserted
Lan-Lan Smith
central catheters (PICC) were placed
in 827 (67%) cases and there were
406 (33%) centrally inserted tunnelled The 58th American Society of
lines. The cumulative incidence of Hematology Annual Meeting
was held in San Diego, CA, USA
venous thromboembolism (VTE) on Dec 36, 2016.
for the whole population was
57% (75% PICC, 2% in tunneled
lines). In a multivariate analysis of
883 placements, risk of VTE was
associated with type of central venous
catheter (tunnelled lines vs PICC, odds
ratio 34 [95% CI 1482]), number
of lumens (single vs multiple 27
[1553]), history of VTE (no vs yes 28
[1265]), and gender (female vs male
05 [0309]).
Mycosis fungoides and Szary
syndrome
Malignant T-cells in patients with
mycosis fungoides and Szary syn-
drome can express PD-1 and PD-L1/
PD-L2. Michael Khodadoust (Stanford
University School of Medicine,
Stanford, CA, USA) presented
the results of a phase 2 study of
pembrolizumab, which included
24 relapsed or refractory patients
who received at least one dose of
the drug. Most were heavily treated
with a median of four prior systemic
therapies (range 111). Nine patients
(38%) had an objective response with
one complete response and eight
partial responses, and an additional
nine patients had stable disease. In
particular, improvements in skin
disease were observed in six patients.
An adverse event which had not
been observed in previous trials
with pembrolizumub was immune-
mediated skin flare reaction, seen
exclusively in patients with Szary
syndrome. Two patients had a
e13
 In Focus
grade 2 reaction and four patients had
grade 3.
Subcutaneous daratumumab
for myeloma
Saad Usmani (Levine Cancer Institute/
Carolinas HealthCare System,
Charlotte, NC, USA) presented the
results of a phase 1b study on patients
with relapsed or refractory multiple
myeloma, examining whether
the combination of subcutaneous
daratumumab along with admini-
stration of recombinant human
hyaluronidase enzyme (rHuPH20)
could facilitate systemic absorption
of daratumumab (NCT02519452).
Focusing on the patients in the
dose-escalation part of the study,
41 patients were treated with the
combination at 1200 mg (n=8) or
1800 mg (n=33) dose levels. Nine
(22%) of the 41 patients reported
infusion-related reactions, which were
mostly grade 1 or 2 in severity, which
including, fever, rigors, vomiting,
itching, oedema of the tongue, non-
cardiac chest pain and wheezing. All
of these AEs developed during the
first infusion and were controllable.
AEs observed in the study were
similar to those seen with intravenous
daratumumab. Five patients reported
grade 3 or higher drug-related AEs,
including fatigue (n=2), influenza,
hypertension, dyspnoea, and tumour
lysis syndrome. The second part of the
trial will randomise patients to receive
either subcutaneous daratumumab
with rHuPH20 versus intravenous
daratumumab.
Managing upper extremity
DVT in patients with cancer
Upper extremity deep vein thrombosis
(UEDVT) is often associated with
central venous catheter placement in
patients receiving chemotherapy for
cancer. Gwynivere Davies (University
of Calgary, Calgary, AB, Canada)
presented results of a multicentre
prospective cohort study of adult
patients with active malignancy
and symptomatic proximal UEDVT,
e14
Downloaded from ClinicalKey.com at The Regents of the University of Michigan January 31, 2017.
For personal use only. No other uses without permission. Copyright 2017. Elsevier Inc. All rights reserved.
treated with rivaroxaban. Among the
70 patients included, 54 (77%) had
a PICC with 16 (23%) having a port-
a-cath line. The primary objective
was an estimate of the proportion
of catheter survival at 3 months,
dened as infusion failure that does
not respond to tissue plasminogen
activator. Catheter survival was 586%
(95% CI 469694) at 12 weeks and
no catheters were removed due to
thrombosis. The 3-month incidence of
recurrent VTE was 143% (025766),
one of which was a fatal pulmonary
embolism. There were 11 bleeding
events in nine patients.
Recombinant ADAMTS13
Replacement of defective ADAMTS13
in patients with hereditary thrombotic
thrombocytopenic purpura (TTP) with
a recombinant version of the protein
may provide an alternative treatment
option to plasma transfusions. Marie
Scully (University College London
Hospitals NHS Trust, London, UK)
presented data from a dose-escalation
study of a recombinant ADAMTS13
(BAX930), which was manufactured
using a plasma-free method.
15 patients were treated on the study
(three received 5 U/kg, three received
20 U/kg, and nine received 40 U/kg).
There were no binding or inhibitory
anti-ADAMTS13 antibodies related to
rADAMTS13 infusion detected, and
no serious adverse events. There was
evidence of cleaved von Willebrand
factor, and based on data from seven
patients treated with 40 U/kg, a
comparable pharmacokinetic profile
to that from plasma infusion studies.
Liposome delivery for AML
drugs
Changing the delivery method can
be a way of improving tolerability of
chemotherapy drugs. Jeffrey Lancet
(H Lee Moffitt Cancer Center &
Research Institute, Tampa, FL, USA)
presented results from an exploratory
analysis of patients who received an
allogeneic stem cell transplantation
in a phase 3 trial of CPX-351, a
liposomal formulation of cytarabine
and daunorubicin encapsulated at
a 5:1 molar ratio. Patients enrolled
were aged 6075 years with newly
diagnosed secondary AML or AML
with MDS-related cytogenetic
abnormalities. 153 patients were
randomised to receive CPX-351, and
156 to receive a standard 7+3 regimen.
91 patients of the 125 eligible patients
received a transplantation, 52 (34%)
of those treated with CPX-351 and
39 (25%) of those treated with 7+3.
Overall survival, landmarked for time
of stem-cell transplantation showed
that patients treated with CPX-351
had significantly improved survival
compared with those treated with
7+3 (HR 046, p=00046). Median
overall survival was not reached in
the CPX-351 group, and a median of
1025 months (95% CI 6211669)
was noted for those in the 7+3 group.
Stopping TKIs in CML
Francois-Xavier Mahon (University
of Bordeaux, Bordeaux, France)
presented results from the European
stop TKI (EURO-SKI) trial, which
included 755 patients in chronic-
phase CML who had achieved a
deep molecular response (BCR-ABL
<001%, MR4) for at least a year, who
had assessable molecular data for
estimating molecular recurrence-free
survival (MRFS). MRFS was 61% (95%
CI 5865) at 6 months, 55% (5158)
at 12 months, and 50% (4754) at
24 months, indicating that stopping
TKIs can be feasible and safe. Mhairi
Copland (University of Glasgow,
Glasgow, UK) presented results from
the British De-Escalation and Stopping
Therapy with Imatinib, Nilotinib or
sprYcel (DESTINY) study, which looked
at de-escalating treatment, including
49 patients who had only achieved
MR3 (BCR-ABL <01%). They found
that decreasing TKI treatment to half
the standard dose appeared to be safe,
and was associated with improvement
in TKI-related side eects.
Lan-Lan Smith
www.thelancet.com/haematology Vol 4 January 2017