Rationale pooled plasma product containing mainly Immunoglobulin G subtype

Rationale              Chroniclymphocytic leukemia (CLL) affected roughly one million people globally in2015, and resulted in 60,000 deaths (1, 2). Leukemia isthe 6th most common cancer in Jordan.

It was estimated that chroniclymphocytic leukemia made up 8% of the total leukemiacases in Jordan in 2012 (3). Following the global aging trends the rate of CLL cases is expectedto increase which would increase the socioeconomic burden associated withmanaging those patients especially in a low-resource country such as Jordan.            CLL causes aderangement in the immune system and immunoglobulin production, predisposingpatients to recurrent infections (4, 5). Infectionshave been known to be a major cause of morbidity and mortality in CLL patientswith a mortality rates reaching 50% (6, 7)             Intravenousimmunoglobulin (IVIG) is a pooled plasma product containing mainlyImmunoglobulin G subtype (IgG) which plays a central role in the body’s defenseagainst bacterial infection. IVIG is commonly used in CLL patients to reducethe risk of bacterial infections (8). Theestimated cost of 5 grams of IVIG at the University of Jordan hospital is 300$USD, a 70 kg patient will require roughly 28 grams of IVIG with a cost ofroughly 1700$USD for a single infusion session.              Another plasmaproduct is cryo-depleted plasma, which also contains IgG and otherimmunoglobulin subtypes (IgA, IgM).

It is readily available in blood banks butusually discarded. Cryo-depleted plasma use in the case of CLL was neverstudied before. In this trial we aim to study cryo-depleted plasma useas an affordable, effective alternative to IVIG.

  Specific Aims Aim 1: Compare the number of bacterial infection episodes inpatients on IVIG vs cryo-depleted plasma    The primary outcome of this trial will be the difference inbacterial infection rate between IVIG and cryo-depleted plasma.Hypothesis 1: The bacterial infection ratesbetween the two groups will be comparable  Aim 2: Compare the rate of fungal infection in patients on IVIG vscryo-depleted plasmaDifferent immunoglobulins are essential to protect against viraland fungal infections, though IgG is the major component of IVIG, IgM and IgAare not present. Cryo-depleted plasma on the other hand has the three majorimmunoglobulin components (IgG, IgM, and IgA); these immunoglobulins play animportant role in protecting the mucosal surfaces against fungal, viral andbacterial infections.            Hypothesis 2: Patients in cryo-depleted arm willhave a lower fungal infection rate compared to IVIG arm Aim 3: Compare the time to the first bacterial infection betweenIVIG and cryo-depleted armsHypothesis 3:      Background and Significance              ChronicLymphocytic Leukemia is a type of cancer that arises from lymphocytes in thebone  marrow, commonly affecting olderpatients with a median age of  70 yearsat the time of diagnosis(9). The clinicalcourse of CLL is usually indolent, the majority of CLL cases arise in B celllymphocytes, these cells are responsible for secreting antibodies, presentantigens to other immune cells and secrete cytokines (10). CLL cellshave been shown to be capable of inhibiting normal B lymphocytes by inhibitingthe interaction with T lymphocytes(11). Moreovernormal lymphocyte differentiation and development is dependent on CD40 ligand-mediated helper signal that is suppressed by CLL cells.

(12). FurthermoreCLL cells secrete inhibitory cytokines such as TGF- ?,which inhibit B cell proliferation. (13). All thesecellular interactions with malignant B cells result in a state of reducedimmunoglobulins (5).

In CLLpatients the prevalence of hypogammaglobulinemia ranges from 10-100%.(5)              Though thepathogenesis of infection in CLL patients is probably multifactorial (14), the reducedimmunoglobulin level is an important factor predisposing patients with CLL to infections(4, 5). Severalreports and trials of administering IVIG in patients with CLL showed asignificant reduction of bacterial infections risk, but no significantdifference in the incidence of viral and fungal infections was seen (8, 15, 16)             Theuse of IVIG as a prophylaxis against bacterial infection though effective istremendously expensive, making it a less attractive option to physicians andpatients alike in a country with very limited resource like Jordan.

            Plasma is a bloodproduct that is readily available in most hospitals; it is divided into cryo-precipitateplasma or cryo-supernatant plasma (cryo-depleted plasma). Cryo-depleted plasmais prepared from slowly thawing the frozen plasma that is then centrifuged toseparate the plasma from the insoluble cryoprecipitate. The insolublecryoprecipitate is removed and the remaining plasma is refrozen.(17). Thecryo-depleted plasma is rich with immunoglobulins IgG, IgA and IgM. Cryo-depletedplasma collection and processing comes at an almost no added expense.             The pathogenesisof infections in CLL is multifactorial. The major risk factors in thosepatients are directly related to the primary disease process (18, 19).

Immunoglobulins play a critical role of the immune response by specificallyrecognizing and binding to antigens such as bacteria, fungus and viruses andaid in their destruction. The common occurrence of hypoglobulinemia in CLLpatients puts them at a particular risk.(5)             Immunoglobulinsubtypes have a wide range of roles. IgG provides the majority ofantibody-based immunity against invading pathogens, IgA on the other had is themajor immunoglobulin found in mucosal areas such as gut, urogenital tract andrespiratory tract. Finally IgM is expressed in two forms either as a monomer(on the surface of B cells) or pentamer (secreted form), it functions toeliminate pathogens in the early stages of exposure before there is sufficientIgG (20). Usingcryo-depleted plasma will not only enhance IgG function but will also increaseIgA and IgM levels, something that cannot be done with IVIG.

            Preliminary data              Our team: I ama medical graduate from the University of Jordan (UJ) and currently working asresearch fellow at the Cell Therapy Center (CTC)-UJ. I am currently enrolled asa student at the Global Clinical Scholar Research Training program- HarvardMedical School. My mentor; professor Abdalla Abbadi is a consultantHemato-Oncologist and is the director of the Hemato-Oncology division and Bonemarrow transplant unit at UJ. Our team also includes three Hemato-Oncology clinicalfellows and two senior internal medicine residents and one pharmacists and abiostatistician.            The twoparticipating institutes are the King Hussain Cancer Center (KHCC), the largestspecialized cancer center in Jordan and the Jordan University Hospital, atertiary referral university hospital. The two institutes see and manage around50-60 CLL patients annually.      Methods  Trial design            The planned trialwill be a double-blinded randomized controlled trial.

Randomization feature of REDCapsoftware will be used; block randomization with block sizes of 4 combinedwith stratification according to the stage (based on Rai staging criteria) willallocate patients with a 1:1 ratio to one of the intervention arms. Since thedesign is a double-blinded study, the nature of each infusion will only beknown to the pharmacist. Both IVIG and cryo-depleted plasma will be packed inidentical bags, enclosed in opaque wrappers to prevent frothing from IVIG orcolor of the cryo-depleted plasma from un-blind the intervention arms. Serumimmunoglobulins assessments performed at each visit will be withheld from thoseattending to the patient or analyzing the data.

All plasma products given; willbe collected, stored and tested as per WHO and hospital guidelines prior tobeing given to the participants (21). ABO bloodgroup matched cryo-depleted plasma will be used.             Patientsrandomized to the IVIG arm (arm 1) will receive 400 mg per kg of body weight ofIVIG infusion every three weeks for one year. Patients randomized to thecryo-depleted plasma arm (arm 2) will receive 10 mL per kg of body weight ofcryo-depleted plasma every three weeks for one year.            Infections will beassessed both clinically and by patient reported symptoms. Patients will beasked to report to the hospital at the first symptoms or sign suggestive ofinfection.

Patients will also be asked to keep a daily diary noting anysymptoms and the presence or absence of fever; this will be done to evaluatepossible infectious episodes that may be deemed trivial by the patients. Diaryentries and hospital evaluation will be reviewed every three weeks when thepatients come to the clinic for an infusion.             Patientspresenting with features suggestive of infection will undergo a fullexamination and appropriate investigations and cultures. If no etiologicalagent is documented, the classification of that episode will be based onclinical grounds.

Infections will be graded as either serious (infectionsrequiring hospital admission, parenteral antibiotic therapy or both) or asmoderate (infections requiring oral antibiotic therapy) (4), the numberand severity of infectious episodes will also be collected.     Inclusion/exclusion criteria:            Patients olderthan 18 years who are able to provide informed consent, with a confirmeddiagnosis of CLL (maybe only stage 1 and 2) that doesn’t require chemotherapytreatment will be considered eligible to participate in the trial.Patients who become symptomatic or display evidence of rapidprogression of disease necessitating chemotherapy initiation will bedisqualified from the study.

Patients with previous anaphylaxis reaction to blood or any bloodproduct 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 6weeks and cbc and chemistryVirology every 6 month baseline, 6month and end.             Limitations:            Potentiallimitations in this trial includes, xxxxxx in order to address this xxxx willbe done1) confounding: randomization2) generalizability: the KHCC and JUH receive a wide range ofpatient population that is a good representation of the local population