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Infection Risk Associated with Daratumumab

Authors:

Abstract

Background Daratumumab is an IgG kappa monoclonal antibody (mAB) against CD38 which is expressed on myeloma cells. It has recently been approved for treatment of patients with relapsed refractory multiple myeloma. Our objective was to identify the potential infectious complications associated with daratumumab use. Methods We conducted a retrospective analysis of myeloma patients who received daratumumab at our institution from October 2015 to December 2016. Patients were divided into four groups based on administration regimen of daratumumab: (1) single agent with dexamethasone; (2) triple therapy with proteasome inhibitor (PI), immune-modulating drug (IMiD), mitogen-activated protein kinase (MEK) inhibitor or mAB; (3) quadruple therapy with IMiD + PI ± mAB or cyclophosphamide; (4) with high-dose chemotherapy. For each group, we evaluated the incidence of infection, neutropenia (defined as ANC <1,000), hospitalization, and 90-day survival. Results A total of 171 patients (63% male, 37% female) were included in the study and received a total of 343 cycles of daratumumab. Median age was 68 years. A total of 151 infections occurred in 121 of the 343 cycles (40% bacterial; 52% viral). There was a significant association between development of infection and chemotherapy regimen used (χ² = 17, P ≤ 0.001). Patients developed neutropenia in 129 of 254 cycles (51%). There was a significant association between the development of neutropenia and chemotherapy regimen used (χ² = 43.51, P < 0.00001). Discontinuation of chemotherapy occurred in 65 cycles (19%), mainly due to progression of disease (54%). Eighty subjects (23%) required hospitalization, infection being the main cause (51%). Ninety-day survival was 91.8%. Conclusion Infection is common among myeloma patients who receive daratumumab. Myeloma patients who receive daratumumab in conjunction with multidrug chemotherapy regimens have an increased risk of infection and neutropenia. Because daratumumab is given predominantly as outpatient therapy, a greater understanding of the potential immunomodulatory effects of daratumumab will lead to increased vigilance in identifying and treating clinically significant infections. Disclosures F. Davies, Janssen: Consultant, Speaker honorarium. G. Morgan, Janssen: Consultant and Research Contractor, Research support and Speaker honorarium.
S702 • OFID 2017:4 (Suppl 1) • Poster Abstracts
Results. A total of 260 patients (mean age 55±17 years; 37.5% female) pre-
sented to the EC 363 times. Eighty-four percent of patients had neutropenia >7days
in duration and the median ANC at presentation was 0 cells/mm3 (range: 0–490
cells/mm3). e majority of patients had acute myeloid leukemia (64%) and 50%
had relapsed disease. Fiy-eight of 363 (16%) presented with PNA, 34/363 (9.3%)
with SSTI, 12/363 (3.3%) with UTI, 11/363 (3 %) with IAI, and 7/363 (2%) with
sinusitis. Among patients directly admitted to the ICU, PNA occurred in 3/22
(14%). Five of 7 patients (71%) who were subsequently transferred to the ICU had
PNA. PNA was more common in patients who died in hospital vs. those who sur-
vived (9/20 [45%] vs. 47/324 [15%], P < 0.01) and 9/56 (16%) of patients with PNA
died in hospital.
Conclusion. PNA was the most common diagnosis in leukemia patients present-
ing to the EC with NF and was associated with high morbidity and mortality. ese
data highlight PNA as a target for further investigation in this population with regards
to the role of timely diagnosis and treatment.
Disclosures. R. Chemaly, Gilead: Consultant and Investigator, Consulting fee
and Research grant. Ansun: Investigator, Research grant. GSK: Investigator, Research
grant
2356. Lymphopenia after Radiotherapy and Risk of Infection
CynthiaTerrones, MD1; LenaSpecht, MD, DMSc2; Maja V.Maraldo, MD, PhD2;
JensLundgren, MD, DMSc, Professor1 and MarieHelleberg, MD, PhD, DMSc3;
1Centre of Excellence for Health, Immunity and Infections (CHIP), Department
of Infectious Diseases, Copenhagen University Hospital, Copenhagen, Denmark,
2Department of Oncology, Section of Radiotherapy, Copenhagen University
Hospital, Copenhagen, Denmark, 3Copenhagen University Hospital, Rigshospitalet,
Copenhagen, Denmark
Session: 253. Transplant Infections - Epidemiology
Saturday, October 7, 2017: 12:30 PM
Background. Radiotherapy may cause lymphocyte depletion; although extent,
duration, and possible associated excess risk of infection from lymphopenia are
unknown. ese questions were addressed in a recently established cohort of consecu-
tive cancer patients undergoing radiotherapy and with complete long-term nation-
wide follow-up.
Methods. e cohort constitutes patients who received rst course of radio-
therapy in the period 2005–2016 at Copenhagen University Hospital. Lymphocyte
counts at radiotherapy start and at 1, 6, 12 and 24months thereaer allowed for
classifying those with lymphopenia (<1.0× 103 cells/µL). Whether this condition
was associated with excess risk of subsequent rst hospital admission with a diag-
nosis of infection was assessed by Poisson regression analysis, adjusted for age, sex,
and calendaryear.
Results. During the study period 22,151 patients had a rst course of radi-
otherapy, of whom 14,823 had a lymphocyte count, measured in at least one of the
pre-dened time points. Median duration of radiotherapy was 28days (IQR, 12–39).
Lymphocyte counts declined in the rst month aer initiation of radiotherapy then
increased gradually during follow-up. At month 24, 28.6% of cohort in follow-up had
lymphopenia (Figure1). During 39,620 per 1,000 person-years of follow-up, 3,644
(24.6%) patients had a hospital admission with an infection; most frequently a respira-
tory infection (48.2%), followed by urinary tract (13.8%) and gastrointestinal infec-
tions (8.5%). Lymphopenia at 0, 6, 12 and 24months aer radiotherapy start, but not
at month 1, was associated with increased risk of subsequent admission with infection
(Table1).
Conclusion. e majority of cancer patients develop lymphopenia aer radio-
therapy, which persist in a fraction of the population for several months. Radiotherapy-
associated lymphopenia was associated with increased risk of subsequent hospital
admission with an infection, suggesting clinically relevant impairment of immune
function in a subgroup of the treated population.
Disclosures. All authors: No reported disclosures.
2357. Trypanozoma cruzi Infection in Patients Undergoing Solid Organ
Transplantation
NoeliaMañez, MD1; ManuelAlderete Jr., MD2; JoseBenso, MD2; AlejandraValledor,
2; AstridSmud, MD1; AlejandroSchijman, PhD3; SusanaBesuschio, Chem3 and
LauraBarcan, MD1; 1Internal Medicine, Hospital Italiano de Buenos Aires, Buenos
Aires, Argentina, 2Hospital Italiano de Buenos Aires, Buenos Aires, Argentina,
3Instituto INGEBI, Buenos Aires, Argentina
Session: 253. Transplant Infections - Epidemiology
Saturday, October 7, 2017: 12:30 PM
Background. It is estimated that 1.5 million people are infected with T.cruzi in
Argentina (4%). Chagas reactivation rate (R) in patients with solid organ transplanta-
tion (SOT) is around 33%, being higher in cardiac transplantation (Tx).
Objective: To describe the clinical characteristics, evolution, mortality, to evalu-
ate reactivation risk factors and to analyze the usefulness of molecular tests in patients
undergoing at SOT with Chagas’ disease risk (ChR) (R or Donor-derived transmission,
-DT-), in a hospital in our country.
Methods. Retrospective cohort from all the patients who received an SOT in our
hospital from January 1988 to March 2017. All patients with ChR: either R or DT were
analyzed. Inclusion: survival more 30days and 6months of follow-up or until death.
We performed post-Tx monitoring with parasitaemia (Strout), and serial whole blood
polymerase chain reaction (PCR) testing, weekly until 2months, every 2 weeks until
the sixth month and monthly until the year, later annual. PCR monitoring is done
since2006.
Results. We performed 1932 SOT in 29years: 54 SOT in patients with ChR,
46 chagasic recipients (CR) and 8 chagasic donors (CD) to negative recipient 24/46
(52%) presented R, (see Table1), 4 had more than one episode. Time to rst R was
67days (r=3–296, median 30days). At the time of the R Strout was performed in 19
episode 13 were negative, PCR was positive in 10/10 of perfcormed test, 32% vs. 100%
(P=0.001). Clinical R: 5 episode in 4 patients (panniculitis 3, 1 with myocarditis, 1
myocarditis). Strout was negative in 2 of these, in the other episode monitoring had
not been performed. Immunosuppression (IS): there were no dierences in the IS,
(induction and treatment of rejections). Reactivation: 21/24 responded to treatment,
2 spontaneously PCR-negative, 1 died. Mortality: 6/24 (25%) in pt. R and 2/17 (12%)
in pt no R (P=ns), not related mortality. DT occurred in 1/ 3 liver and in 0/5 renal
recipients.
Type of Tx All Reactivation Clinic
Liver (L) 786 7/26 (27%) 1/7 (14%)
Heart 241 13/23 (56%) 2/13 (15%)
Kidney (K) 613 2/5 (40%) 1/2 (50%)
Lung 105 1/2 (50%) 0
LK 26 1/1 (100% 0
Others 161 0 0
Conclusion. PCR was more sensitive than Strout for detection of R or transmission.
ere was no clinical R in pt monitored by PCR. Also PCR sensitivity allow safe accept-
ance of Chagasic organs.
Disclosures. Al l authors: No reported disclosures.
2358. Infection Risk Associated with Daratumumab
Joyce JJohnsrud, MD1; SandraSusanibar, MD2; JorgeJo-Kamimoto, MD2; Andrew
JJohnsrud, MD3; AtulKothari, MD1; Mary JBurgess, MD1; CarolinaSchinke,
MD2; Sharmilananendrarajan, MD, PhD2; MaurizioZangari, MD2; FaithDavies,
MBBCh, MRCP, MD, FRCPath2; GarethMorgan, PhD2; FritsVanrhee, MD, PhD2
and Juan Carlos RicoCrescencio, MD1; 1Division of Infectious Diseases, University of
Arkansas for Medical Sciences, Little Rock, Arkansas, 2Myeloma Institute, University
of Arkansas for Medical Sciences, Little Rock, Arkansas, 3Division of Hematology and
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Poster Abstracts • OFID 2017:4 (Suppl 1) • S703
Oncology, University of Arkansas for Medical Sciences, Little Rock, Arkansas
Session: 253. Transplant Infections - Epidemiology
Saturday, October 7, 2017: 12:30 PM
Background. Daratumumab is an IgG kappa monoclonal antibody (mAB)
against CD38 which is expressed on myeloma cells. It has recently been approved for
treatment of patients with relapsed refractory multiple myeloma. Our objective was
to identify the potential infectious complications associated with daratumumabuse.
Methods. We conducted a retrospective analysis of myeloma patients who received
daratumumab at our institution from October 2015 to December 2016. Patients were
divided into four groups based on administration regimen of daratumumab: (1) sin-
gle agent with dexamethasone; (2) triple therapy with proteasome inhibitor (PI),
immune-modulating drug (IMiD), mitogen-activated protein kinase (MEK) inhibitor
or mAB; (3) quadruple therapy with IMiD + PI ± mAB or cyclophosphamide; (4) with
high-dose chemotherapy. For each group, we evaluated the incidence of infection, neu-
tropenia (dened as ANC <1,000), hospitalization, and 90-day survival.
Results. A total of 171 patients (63% male, 37% female) were included in the
study and received a total of 343 cycles of daratumumab. Median age was 68years.
Atotal of 151 infections occurred in 121 of the 343 cycles (40% bacterial; 52% viral).
ere was a signicant association between development of infection and chemother-
apy regimen used (χ2=17, P ≤ 0.001). Patients developed neutropenia in 129 of 254
cycles (51%). ere was a signicant association between the development of neu-
tropenia and chemotherapy regimen used (χ2=43.51, P < 0.00001). Discontinuation
of chemotherapy occurred in 65 cycles (19%), mainly due to progression of disease
(54%). Eighty subjects (23%) required hospitalization, infection being the main cause
(51%). Ninety-day survival was91.8%.
Conclusion. Infection is common among myeloma patients who receive daratu-
mumab. Myeloma patients who receive daratumumab in conjunction with multidrug
chemotherapy regimens have an increased risk of infection and neutropenia. Because
daratumumab is given predominantly as outpatient therapy, a greater understanding
of the potential immunomodulatory eects of daratumumab will lead to increased vig-
ilance in identifying and treating clinically signicant infections.
Disclosures. F. Davies, Janssen: Consultant, Speaker honorarium. G. Morgan,
Janssen: Consultant and Research Contractor, Research support and Speaker honorarium.
2359. Infectious Risks and Complications in Adult Acute Lymphoblastic
Leukemia (ALL) Patients Receiving Blinatumomab
WonheeSo, PharmD, Pharmacy1; ShuchiPandya, MD2; RodQuilitz, PharmD, BCOP,
Pharmacy3 and JohnGreene, MD, FACP, FSHEA1; 1Mott Cancer Center, Tampa,
Florida, 2University of South Florida, Tampa, Florida, 3H. Lee Mott Cancer Center,
Tampa, Florida
Session: 253. Transplant Infections – Epidemiology
Saturday, October 7, 2017: 12:30 PM
Background. Blinatumomab (BLN) is an anti-CD19 immunotherapy approved
for relapsed/refractory (R/R) B-cell ALL with signicantly increased survival rate.
While BLN showed lower rates of infection, neutropenia and mucosal barrier injury
(MBI) as compared with chemotherapy, its infection risks are not well described. BLN
may also cause cytokine release syndrome and hypogammaglobulinemia. Aretrospec-
tive review of the infectious risks and complications of BLN was performed for strate-
gic antimicrobial prophylaxis.
Methods. All patients who received BLN for ≥7days at an academic cancer cen-
ter from May 2015 to April 2017 were included. Patient characteristics pertinent to
infectious risks and complications were examined.
Results. Twenty patients with refractory (25%), relapsed (70%), or remitted (5%)
B-ALL who received a total of 35 cycles were included. Amedian of 2 previous chemo-
therapies were given (range 1–7). Ten of the 35 cycles were interrupted, none of which
were due to infections except in a patient who had hypotension with mild ground glass
pneumonia. Twenty-six infections (n) were observed with lower respiratory (9), gas-
trointestinal (6), and bacteremia (5) being most common. Four patients had nodular,
probable mold pneumonia, 3 of which were newly developed on BLN. Compared with
all patients, these patients had signicantly lower absolute neutrophil count (ANC) on
the rst day of BLN (1897 vs. 208/µL, P = 0.045) and prolonged days of ANC <100/
µL (3 vs. 8days, P = 0.047). Among the four bacteremic patients, two patients received
cytotoxic chemotherapy ≤ 3days of the last BLN; 1 patient was discharged with no
antibacterial since ANC recovered to >500/µL, but developed Pseudomonal bacter-
emia in a week with ANC ~ 100/µL. ere was one 30-day mortality (noninfectious).
Two patients were sent to hospice care <30days of BLN with progressive disease, one
of who also had infectious complications.
Conclusion. Despite lack of MBI and mild neutropenia by BLN, host factors (e.g., dur-
ation and degree of neutropenia/lymphopenia, stage of ALL, chemotherapy pre- and post-
BLN) play a key role in this population and should be considered in designing anti-mold
coverage. In R/R disease, ANC should be monitored closely both inpatient and outpatient
as neutropenia can worsen post BLN compounded by disease and other chemotherapy.
Disclosures. Al l authors: No reported disclosures.
2360. Classification of Death Causes after Transplantation (CLASS): Evaluation of
Methodology and Initial Results
Neval EteWareham, MD1; CasparDa Cunha-Bang, MD, PhD1; Álvaro HBorges,
MD, PhD, MSc1; ChristinaEkenberg, MD1; JanGersto, MD, DMSc, professor1;
FinnGustafsson, MD, PhD, DMSc1; DitteHansen, MD, PhD2; MarieHelleberg, MD,
PhD, DMSc1; CarstenHeilmann, MD, DMSc, Professor1; JensHillingsø, MD1; Paul
SunoKrohn, MD1; Isabelle PaulaLodding, MD1; omas KromannLund, MD, PhD1;
LouiseLundgren, MD1; AmandaMocro, MSc, Professor3; MichaelPerch, MD4;
Søren LykkePetersen, MD, PhD1; IrmaPetruskevicius, MD5; AllanRasmussen, MD6;
KasperRossing, MD, PhD1; AndreasRostved, MD1; HenrikSengeløv, MD, DMSc7;
Vibeke RømmingSørensen, MD, PhD1; Søren SchwartzSørensen, MD, DMSc,
Professor8; JensLundgren, MD, DMSc, Professor9 and MATCH Program Study
Group; 1Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark,
2Copenhagen University Hospital, Herlev Hospital, Copenhagen, Denmark,
3University College London, London, UK, 4Department of Cardiology, Copenhagen
University Hospital, Copenhagen, Denmark, 5Aarhus University Hospital, Skejby
Hospital, Aarhus, Denmark, 6Department of Surgical Gastroenterology, Copenhagen
University Hospital, Copenhagen, Denmark, 7Department of Haematology,
Copenhagen University Hospital, Copenhagen, Denmark, 8Department of
Nephrology, Copenhagen University Hospital, Copenhagen, Denmark, 9Centre of
Excellence for Health, Immunity and Infections (CHIP), Department of Infectious
Diseases, Copenhagen University Hospital, Copenhagen, Denmark
Session: 253. Transplant Infections – Epidemiology
Saturday, October 7, 2017: 12:30 PM
Background. Correct classication of underlying causes of death is an impor-
tant outcome among transplant recipients. Deaths due to infections and adverse gra
function are oen misclassied. We aimed to develop and validate a system to code
causes of death in hematopoietic stem cell (HSCT) and solid organ (SOT) transplant
recipients and to identify characteristics that could identify deaths with a clearcause.
Methods. A standardized case record form (CRF) was used to collect clinical
information from consecutive recipients transplanted at a transplant hospital between
2004 and 2014, who died 2010–2013 (derivation cohort). Causes of death were deter-
mined through a centralized process involving two medical experts who independently
assessed each CRF. Factors associated with independent agreement between reviewers
were assessed and validated on patients who died 2013–2016 (validation cohort). All
cases without agreement were adjudicated. Death causes ascertained by our system
were compared with death causes in the Danish National Death Registry.
Results. 388 transplant recipients died during 2010 to 2016 (196 (51%) SOT and
192 (49%) HSCT). Using our methodology, leading underlying causes of death among
SOT and HSCT were classied as cancer (20%, 48%), gra rejection/failure/gra-vs.-
host-disease (35%, 28%) and infections (20%, 11%) (Figure1). Death causes were in
agreement with the Danish registry in only 37% of cases in derivation cohort. In the der-
ivation cohort, kappa was 0.64 (95% CI 0.56–0.69) for independent agreement between
the two experts (all remaining classied upon adjudication) (Figure2). Odds for inde-
pendent agreement were higher in cases with a history of cancer (aOR 3.20 (1.45–7.06));
among 174 with this characteristics, kappa was 0.71 (0.64–0.79). ese ndings were
reproducible in the validation cohort (kappa for overall independent agreement=0.63
(0.52– 0.73); among 54 recipients with a history of cancer, kappa=0.71 (0.57–0.84)).
Conclusion. We developed and validated a method able to systematically and
reliably classify underlying cause of death among transplant recipients. ere was a
high degree of discordance between this classication and that in the National Death
Registry. Our method can be applied to any cohort.
Disclosures. All authors: No reported disclosures.
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... Rituximab is known to induce a delayed response, and time between rituximab and daratumumab was short in patient 2 due to the dynamic worsening of his disease. While we did not observe significant adverse events, daratumumab treatment was associated with an increased risk of infection in systematic studies for multiple myeloma 16 and in case reports in autoimmune diseases. 9 17 Prospective clinical trials will be needed to investigate the safety and efficacy of daratumumab in AAV and to identify patients who could benefit from a plasma celltargeting drug. ...
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Objective Treatment-refractory antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a life-threatening condition without evidence-based treatment options. One emerging treatment option for several antibody-mediated autoimmune diseases is the anti-CD38 antibody daratumumab, which depletes autoantibody-secreting plasma cells. Methods We treated two patients with severe life-threatening AAV with renal and pulmonary manifestation despite induction therapy with rituximab and cyclophosphamide with four to eight doses of 1800 mg daratumumab. We followed clinical and immunological responses. Results The first patient with myeloperoxidase-ANCA-positive microscopic polyangiitis had resolution of pneumonitis and pleuritis and stabilisation of kidney function after daratumumab. The second patient with proteinase 3-ANCA-positive granulomatosis with polyangiitis, diffuse alveolar haemorrhage necessitating extracorporeal membrane oxygenation (ECMO) and acute kidney failure, requiring kidney replacement therapy, was weaned off ECMO, mechanical ventilation and dialysis and discharged home after daratumumab. Clinical improvement was paralleled by a strong reduction in serum ANCA levels as well as total IgG, indicating depletion of plasma cells. Apart from the depletion of CD38 ⁺ natural killer cells, blood leucocyte levels were not notably influenced by daratumumab. Only mild adverse events, such as hypogammaglobulinaemia and an upper respiratory tract infection occurred. Conclusion Daratumumab was safe and effective in inducing remission in two patients with severe treatment-refractory AAV, warranting prospective clinical trials to establish safety and efficacy.
... The side-effect profile is well established, with common side effects including infusion related reactions. More important are the cytopenias and infections associated with daratumumab, with one study reporting a total of 11.7% of patients requiring hospitalizations due to infections in 171 patients treated with daratumumab with and without chemotherapy [19]. However, these infections were generally manageable with antivirals and antibiotics. ...
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Plasmablastic lymphoma (PBL) is a rare and aggressive form of large B-cell lymphoma (LBCL) most commonly seen in the setting of chronic immunosuppression or autoimmune disease. The prognosis is poor and CHOP-like regimens often fail to produce durable remission; therefore, there is no established standard of care treatment. However, PBL demonstrates substantial morphologic and immunophenotypic overlap with multiple myeloma (MM), suggesting that MM therapeutics might prove useful in treating PBL. We studied the effects of treatment using the first-in-class monoclonal antibody directed against CD38, daratumumab, in combination with chemotherapy in seven patients with advanced-stage LBCL with plasmablastic features. Treatment was safe and well-tolerated. Among six evaluable patients, six patients had complete response after treatment, and four patients who met strict WHO criteria for PBL had durable response (12–31 months and ongoing).
... Daratumumab has the following effects: neutropenia, lymphopenia, hyperglycemia, and decrease in natural killer cells, which play a major role in the immune clearance of virally infected cells [125,126]. The use of daratumumab in the treatment of MM patients is associated with the following infections: nasopharyngitis, pneumonia, and viral infections such as VZV [125][126][127][128]. ...
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Antibody deficiency or hypogammaglobulinemia can have primary or secondary etiologies. Primary antibody deficiency (PAD) is the result of intrinsic genetic defects, whereas secondary antibody deficiency may arise as a consequence of underlying conditions or medication use. On a global level, malnutrition, HIV, and malaria are major causes of secondary immunodeficiency. In this review we consider secondary antibody deficiency, for which common causes include hematological malignancies, such as chronic lymphocytic leukemia or multiple myeloma, and their treatment, protein-losing states, and side effects of a number of immunosuppressive agents and procedures involved in solid organ transplantation. Secondary antibody deficiency is not only much more common than PAD, but is also being increasingly recognized with the wider and more prolonged use of a growing list of agents targeting B cells. SAD may thus present to a broad range of specialties and is associated with an increased risk of infection. Early diagnosis and intervention is key to avoiding morbidity and mortality. Optimizing treatment requires careful clinical and laboratory assessment and may involve close monitoring of risk parameters, vaccination, antibiotic strategies, and in some patients, immunoglobulin replacement therapy (IgRT). This review discusses the rapidly evolving list of underlying causes of secondary antibody deficiency, specifically focusing on therapies targeting B cells, alongside recent advances in screening, biomarkers of risk for the development of secondary antibody deficiency, diagnosis, monitoring, and management.
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