Rationale pooled plasma product containing mainly Immunoglobulin G subtype

Rationale

 

            Chronic
lymphocytic leukemia (CLL) affected roughly one million people globally in
2015, and resulted in 60,000 deaths (1, 2). Leukemia is
the 6th most common cancer in Jordan. It was estimated that chronic
lymphocytic leukemia made up 8% of the total leukemia
cases in Jordan in 2012 (3).

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Following the global aging trends the rate of CLL cases is expected
to increase which would increase the socioeconomic burden associated with
managing those patients especially in a low-resource country such as Jordan.

            CLL causes a
derangement in the immune system and immunoglobulin production, predisposing
patients to recurrent infections (4, 5). Infections
have been known to be a major cause of morbidity and mortality in CLL patients
with a mortality rates reaching 50% (6, 7)

            Intravenous
immunoglobulin (IVIG) is a pooled plasma product containing mainly
Immunoglobulin G subtype (IgG) which plays a central role in the body’s defense
against bacterial infection. IVIG is commonly used in CLL patients to reduce
the risk of bacterial infections (8). The
estimated cost of 5 grams of IVIG at the University of Jordan hospital is 300
$USD, a 70 kg patient will require roughly 28 grams of IVIG with a cost of
roughly 1700$USD for a single infusion session.  

            Another plasma
product is cryo-depleted plasma, which also contains IgG and other
immunoglobulin subtypes (IgA, IgM). It is readily available in blood banks but
usually discarded. Cryo-depleted plasma use in the case of CLL was never
studied before. In this trial we aim to study cryo-depleted plasma use
as an affordable, effective alternative to IVIG.

 

Specific Aims

 

Aim 1: Compare the number of bacterial infection episodes in
patients on IVIG vs cryo-depleted plasma   

The primary outcome of this trial will be the difference in
bacterial infection rate between IVIG and cryo-depleted plasma.

Hypothesis 1: The bacterial infection rates
between the two groups will be comparable

 

Aim 2: Compare the rate of fungal infection in patients on IVIG vs
cryo-depleted plasma

Different immunoglobulins are essential to protect against viral
and fungal infections, though IgG is the major component of IVIG, IgM and IgA
are not present. Cryo-depleted plasma on the other hand has the three major
immunoglobulin components (IgG, IgM, and IgA); these immunoglobulins play an
important role in protecting the mucosal surfaces against fungal, viral and
bacterial infections.           

Hypothesis 2: Patients in cryo-depleted arm will
have a lower fungal infection rate compared to IVIG arm

 

Aim 3: Compare the time to the first bacterial infection between
IVIG and cryo-depleted arms

Hypothesis 3:

 

 

 

 

 

Background and Significance

 

            Chronic
Lymphocytic Leukemia is a type of cancer that arises from lymphocytes in the
bone  marrow, commonly affecting older
patients with a median age of  70 years
at the time of diagnosis(9). The clinical
course of CLL is usually indolent, the majority of CLL cases arise in B cell
lymphocytes, these cells are responsible for secreting antibodies, present
antigens to other immune cells and secrete cytokines (10). CLL cells
have been shown to be capable of inhibiting normal B lymphocytes by inhibiting
the interaction with T lymphocytes(11). Moreover
normal lymphocyte differentiation and development is dependent on CD40 ligand-
mediated helper signal that is suppressed by CLL cells. (12). Furthermore
CLL cells secrete inhibitory cytokines such as TGF- ?,
which inhibit B cell proliferation. (13). All these
cellular interactions with malignant B cells result in a state of reduced
immunoglobulins (5).In CLL
patients the prevalence of hypogammaglobulinemia ranges from 10-100%.(5) 

            Though the
pathogenesis of infection in CLL patients is probably multifactorial (14), the reduced
immunoglobulin level is an important factor predisposing patients with CLL to infections
(4, 5). Several
reports and trials of administering IVIG in patients with CLL showed a
significant reduction of bacterial infections risk, but no significant
difference in the incidence of viral and fungal infections was seen (8, 15, 16)

            The
use of IVIG as a prophylaxis against bacterial infection though effective is
tremendously expensive, making it a less attractive option to physicians and
patients alike in a country with very limited resource like Jordan.

            Plasma is a blood
product that is readily available in most hospitals; it is divided into cryo-precipitate
plasma or cryo-supernatant plasma (cryo-depleted plasma). Cryo-depleted plasma
is prepared from slowly thawing the frozen plasma that is then centrifuged to
separate the plasma from the insoluble cryoprecipitate. The insoluble
cryoprecipitate is removed and the remaining plasma is refrozen.(17). The
cryo-depleted plasma is rich with immunoglobulins IgG, IgA and IgM. Cryo-depleted
plasma collection and processing comes at an almost no added expense.

            The pathogenesis
of infections in CLL is multifactorial. The major risk factors in those
patients are directly related to the primary disease process (18, 19).
Immunoglobulins play a critical role of the immune response by specifically
recognizing and binding to antigens such as bacteria, fungus and viruses and
aid in their destruction. The common occurrence of hypoglobulinemia in CLL
patients puts them at a particular risk.(5)

            Immunoglobulin
subtypes have a wide range of roles. IgG provides the majority of
antibody-based immunity against invading pathogens, IgA on the other had is the
major immunoglobulin found in mucosal areas such as gut, urogenital tract and
respiratory tract. Finally IgM is expressed in two forms either as a monomer
(on the surface of B cells) or pentamer (secreted form), it functions to
eliminate pathogens in the early stages of exposure before there is sufficient
IgG (20). Using
cryo-depleted plasma will not only enhance IgG function but will also increase
IgA and IgM levels, something that cannot be done with IVIG.     

   

 

 

 

Preliminary data

 

            Our team: I am
a medical graduate from the University of Jordan (UJ) and currently working as
research fellow at the Cell Therapy Center (CTC)-UJ. I am currently enrolled as
a student at the Global Clinical Scholar Research Training program- Harvard
Medical School. My mentor; professor Abdalla Abbadi is a consultant
Hemato-Oncologist and is the director of the Hemato-Oncology division and Bone
marrow transplant unit at UJ. Our team also includes three Hemato-Oncology clinical
fellows and two senior internal medicine residents and one pharmacists and a
biostatistician.

            The two
participating institutes are the King Hussain Cancer Center (KHCC), the largest
specialized cancer center in Jordan and the Jordan University Hospital, a
tertiary referral university hospital. The two institutes see and manage around
50-60 CLL patients annually. 

    

Methods

 

Trial design

            The planned trial
will be a double-blinded randomized controlled trial. Randomization feature of REDCap
software will be used; block randomization with block sizes of 4 combined
with stratification according to the stage (based on Rai staging criteria) will
allocate patients with a 1:1 ratio to one of the intervention arms. Since the
design is a double-blinded study, the nature of each infusion will only be
known to the pharmacist. Both IVIG and cryo-depleted plasma will be packed in
identical bags, enclosed in opaque wrappers to prevent frothing from IVIG or
color of the cryo-depleted plasma from un-blind the intervention arms. Serum
immunoglobulins assessments performed at each visit will be withheld from those
attending to the patient or analyzing the data. All plasma products given; will
be collected, stored and tested as per WHO and hospital guidelines prior to
being given to the participants (21). ABO blood
group matched cryo-depleted plasma will be used.

            Patients
randomized to the IVIG arm (arm 1) will receive 400 mg per kg of body weight of
IVIG infusion every three weeks for one year. Patients randomized to the
cryo-depleted plasma arm (arm 2) will receive 10 mL per kg of body weight of
cryo-depleted plasma every three weeks for one year.

            Infections will be
assessed both clinically and by patient reported symptoms. Patients will be
asked to report to the hospital at the first symptoms or sign suggestive of
infection. Patients will also be asked to keep a daily diary noting any
symptoms and the presence or absence of fever; this will be done to evaluate
possible infectious episodes that may be deemed trivial by the patients. Diary
entries and hospital evaluation will be reviewed every three weeks when the
patients come to the clinic for an infusion.

            Patients
presenting with features suggestive of infection will undergo a full
examination and appropriate investigations and cultures. If no etiological
agent is documented, the classification of that episode will be based on
clinical grounds. Infections will be graded as either serious (infections
requiring hospital admission, parenteral antibiotic therapy or both) or as
moderate (infections requiring oral antibiotic therapy) (4), the number
and severity of infectious episodes will also be collected.

 

 

 

 

Inclusion/exclusion criteria:

            Patients older
than 18 years who are able to provide informed consent, with a confirmed
diagnosis of CLL (maybe only stage 1 and 2) that doesn’t require chemotherapy
treatment will be considered eligible to participate in the trial.

Patients who become symptomatic or display evidence of rapid
progression of disease necessitating chemotherapy initiation will be
disqualified from the study.

Patients with previous anaphylaxis reaction to blood or any blood
product or a documented IgA deficiency will be excluded.  

 

Sample size and recruitment:

cbc, immunoglobulin ( to check level if had any influence on rx),
chemistry (baseline), Xray (noninvasive way to make sure no initial infection),
+- hiv hbv hbc.

Baseline and end of study,

Immunoglobulin before second injection (trough level), every 6
weeks and cbc and chemistry

Virology every 6 month baseline, 6month and end.

 

           

Limitations:

            Potential
limitations in this trial includes, xxxxxx in order to address this xxxx will
be done

1) confounding: randomization

2) generalizability: the KHCC and JUH receive a wide range of
patient population that is a good representation of the local population

x

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