ADVERSE EVENTS ASSOCIATED

WITH INFUSION OF HSC

1. Dr.Indhumathi
2. Post Graduate
3. DEPT OF IHBT
4.
INTRODUCTION

 Hematopoietic stem cells(HSC) are clonal precursor cells that are

capable of self-renewal and multipotent i.e., formation of all lines of
blood cells restoring hematopoiesis and immunity.

 The intent of HSC transplant is to achieve long term engraftment of the

cells infused.

 Advancement in supportive care – newer antibiotics and the

development of pretransplant conditioning regimens with lower
nonhematologic toxicities widen the use of HSC transplant.
 AUTOLOGOUS Patient serve as a self
TRANSPLANTATION donor

TYPES OF SYNGENETIC Donor is a genetically

HSCT TRANSPLANTATION identical twin

ALLOGENEIC From related or

TRANSPLANTATION unrelated donor
STEM CELL SOURCE

 HSCs can be collected through harvesting the marrow via multiple

aspirations

 HSCS are collected from the peripheral blood by Leukapheresis

termed peripheral blood stem cell collection.

 Hematopoietic growth factors such as G-CSF were given to mobilize

the HSC to peripheral blood.
  HSCs can be mobilized during recovery after cytoreductive
chemotherapy (chemomobilization)

 Often performed to collect PBSCs for autologous HSCT.

MOBILIZATION

 Most centers require at least 2×106 CD34+ cells/kg body

weight and optimal recovery occurs with infusion ≥ 5×106
CD34+ cells/kg
After collection, HSCs can be cryopreserved
to store for extended periods of time

To avoid damage to cells a cryoprotective CRYOPRESERVATION

agent is used i.e., DMSO.

Thawed immediately prior to infusing the

patient.
  The combination of chemo, radio and biologic therapies
given prior to HSCT referred to as preparative regimen
CONDITIONING
REGIMEN IN  The sole role in autologous transplant is eradication of
AUTOLOGOUS any residual cancer
SETTING
 Combination therapies are used to minimize overlapping
toxicity and mechanism of resistance.
 Alkylating agents such as Busulfan, Melphalan and Nitrosoureas are
commonly used because of their steep dose response curve and
myelosuppression as their dose limiting toxicity.

 Dose escalation not feasible when extramedullary toxicity occurs at the

same or lower dose levels of myelosuppression.

 Regimens such as high dose melphalan used for the treatment of

patients with multiple myeloma and Carmustine based regimens for the
treatment of lymphoma
  For eradication the underlying malignancy and
induction of state of immune tolerance to allow for the
donor cells to engraft and expand
PREPARATIVE
REGIMEN IN  Chemotherapy based protocols or total body irradiation
ALLOGENIC (TBI) based protocols.
TRANSPLANT
 TBI provides both immunosuppressive and
myeloablative effects.
TBI BASED REGIMENS

 The use of fractionated regimens and organ shielding has lowered the
toxicity.

 TBI often combined with high-dose cyclophosphamide, a potent

immunosuppressive agent

 TBI + etoposide with or without cyclophosphamide

  Busulfan(Bu) and Cyclophosphamide regimens are used
extensively

NON TBI
 Also Fludarabine and Busulfan regimens produce high
BASED rates of engraftment with low non relapse mortality
REGIMENS
 The dose limiting toxicity of oral Bu is hepatotoxicity
with veno-occlusive disease of the liver.
REDUCED INTENSITY CONDITIONING
REGIMENS

 Non myeloablative and reduced intensity regimens developed as less

toxic alternative conditioning regimens

 Lower doses of chemo or radiotherapy to allow for engraftment and

rely on GVT effect to prevent relapse.

 Implied in older or medically infirm patients who could not tolerate

myeloablative regimens.
 Due to underlying disease,
previous treatments that have
been administered, toxicity In allogenic transplants,
ADVERSE
from the preparative regimen,
infections resulting from
the immunological
complication of
EFFECTS OF
granulocytopenia or post-
transplant immunodeficiency,
transplantation i.e., HSC
transplant rejection and
hemorrhage caused by
thrombocytopenia and tissue GVHD INFUSION
toxicity
  Mild infusion reactions such as hypotension, skin
flushing, dyspnea, abdominal cramping , nausea or
AE ON diarrhoea triggered by histamine release by DMSO.

INFUSION
 Patients should be adequately pre-medicated with
antihistaminic medications prior to the infusion
 Severe reactions including respiratory distress, bronchospasm, heart
block or arrhythmias, cardiac arrest hemolysis , encephalopathy and
seizure also can occur
 Many of this reaction are related to amount of DMSO administered
 Minimizing the DMSO administered may reduce the risk of such
reactions
 Although idiosyncratic responses may occur at DMSO doses that
could be tolerated.
MYELOSUPPRESSION

 High dose chemotherapy directly destroys the bone marrow’s ability

to produce white blood cells, red blood cells and platelets

 Patients usually need blood and platelet transfusions until the new
graft being producing blood cells.

 Duration can be shortened by infusing an optimum number of stem

cells and growth factors that hasten the recovery
Blood components must be irradiated to minimize the
possibility of graft-versus host reactions mediated by blood
donor T cells.

For most patients marrow cellularity can be demonstrated

within 14 days of transplantation .
  Is an inflammation of the lining of the mouth or
gastrointestinal(GI) tract.

 Due to intensive therapy that precedes stem cell

transplantation.
MUCOSITIS
 Chemotherapy and radiation therapy are effective at
killing rapidly dividing cells in cancer. Unfortunately
many normal cells in body also rapidly dividing such as
entire GI tract including mouth and throat
 Usually occurring within 10 to 14 days after transplantation

 Administration of keratinocyte growth factor may reduce the

incidence and severity of mucositis

 Palifermin is a type of growth factor, first FDA approved drug for the
prevention and treatment of oral mucositis
  Is manifested as unexplained fever and rash in the peri-
engraftment period.

ENGRAFTMENT  Patients also have weight gain, hypoxemia and

SYNDROME pulmonary infiltrates in the absence of fluid overload or
cardiac disease.

 May progress to multiorgan failure and death

 The clinical features of ES have been defined according to Spitzer
criteria developed from a broad literature review

 The major criteria include fever > 101̊ F, erythrodermatous rash over
more than 25% of the body that cannot be linked to medication and
non cardiogenic pulmonary edema
 ES is characterized by hepatic dysfunction
( bilirubin ≥2mg/dl or a 2 fold increase in
transaminase over baseline).

 Renal insufficiency( 2 fold increase in serum

creatinine over baseline), weight gain (2.5 %
increase) and unexplained transient
encephalopathy
ENGRAFTMENT
SYNDROME
 Mechanism behind ES was not fully understand.

 Pro inflammatory cytokines (IL-1, TNF-α, IFN-γ) and

innate immune cells likely play a role

 These cytokines predispose patients to heightened

antigen presentation and T cell activation

 May also contribute to break in peripheral tolerance

First step in management is to exclude
alternative causes.

Treatment with corticosteroids was

initiated to ameliorate the symptoms.
 Also referred to as sinusoidal obstruction
syndrome

HEPATIC
VENO- High dose chemotherapy regimens, high intensity
conditioning regimens, mismatched or unrelated
OCCLUSIVE donor transplants result in direct injury to the
DISEASE hepatic venous endothelium
(VOD) Characterize by tender hepatomegaly, jaundice,
noncardiogenic weight gain, hyperbilirubinemia
from fluid retention and ascites.
The incidence ranges from 5% to 50%

Treatment is usually best supportive care although

defibrotide is currently approved for the treatment of
severe VOD

Oral busulfan is productive of increased VOD

secondary to hepatic first-pass effect, unpredictable
absorption kinetics and variable bioavailability with
sinusoidal obstruction as terminal events
  Acute or delayed complication of the conditioning
regimen and previous treatments

 Direct toxicity can result from the conditioning regimen

and radiation induced lung injury
LUNG
COMPLICATI
 Diffuse alveolar hemorrhage may occur in immediate
ONS post transplant period during pancytopenia

 Bronchiolitis obliterans is a pulmonary manifestation of

chronic GVHD and can be triggered by some lung
infections particularly viral infections.
INTERSTITIAL PNEUMONIA SYNDROME

 May occur following allogenic transplant

 It is diffuse non infectious pneumonia appears to be immune mediated

process induced by toxicity of the conditioning regimens

 Patient may have a dry non-productive cough or shortness of breath .

  Hepatic veno occlusive disease from high dose
regimens
ORGAN  Interstitial Pneumonitis (BCNU) Carmustin induced
TOXICITY  Cardiomyopathy and hemorrhagic cystitis (CY)
cyclophosphamide induced
 More prone to variety of infections as a result of
 myelosuppression
INFECTIONS  delayed immune reconstitution
 immunosuppression
 PHASE I PHASE II
• The period following the • Following engraftment
preparative regimen and upto Day 100
while awaiting
engaftment
THREE
PHASES PHASE III
• From day 100 to months
and years following
transplantation
  Risks varies for each of the periods depending on degree
of tissue toxicity, length of neutropenia and presence of
GVHD
EARLY
RECOVERY  Bacterial, fungal and herpes simplex virus(HSV)
PHASE infections pose the greatest risk
 Bacterial infections predominate in the early post-transplant period
when the absolute neutrophil count is less than 100 per microliter and
the mucosal and skin barriers are most compromised

 The majority(70%) of bacterial pathogens are gram positive with

gram negative incidence decreasing significantly
  Bacterial prophylaxis with a quinolone antibiotic in an
effort to suppress intestinal flora and prevent gram
negative infections
PROPHYLAXIS
 Prompt administration of broad spectrum antibiotics
following a neutropenic febrile event is important in
preventing morbidity of bacterial infections
 The prophylactic use of fluconazole has been shown to
reduce the incidence of systemic and superficial fungal
infections

 Posaconazole, Voriconazole , Echinoocandins had

greater activity against molds and advocated for high
risk patients
 HSV reactivation is seen commonly in seropositive patients during
the first six weeks after transplantation

 Acyclovir prophylaxis has shown to prevent reactivation, reduce

morbidity and lower the incidence of antibiotic resistance
  Begins immediately after engraftment when profound
depression of cellular and humoral immunity occurs

MID
 Viral pathogens especially CMV are the major causes of
RECOVERY infections
PHASE
 Prophylactic use of Ganciclovir has largely eliminated
the CMV disease after transplantation
  Prophylaxis against Pneumocystis carinii(PCP) is
LATE recommended for a minimum of six months
RECOVERY
PHASE  Trimethoprim-Sulfamethoxazole is agent of choice for
PCP prophylaxis
 Fludarabine or TBI based preparative regimens were associated with
higher risk of late infections

 Viral infections mainly Varicella zoster virus and Pneumonia are

common

 Delayed immune reconstitution is probably more important than

marrow hypoplasia as a factor contributing to infectious deaths
  The failure to recover hematologic function or loss of
marrow function after initial reconstitution
GRAFT
FAILURE(GF)  Generally takes place within 60 days of transplantation
although late graft failures known to occur
GF IN ALLOGENIC TRANSPLANT

Risk factors:
 low nucleated cell count infused
Increasing HLA disparity between donor and host
T-cell depleted graft
Inadequate immunosuppression of the host
• * High as 35% in patients undergoing transplantation
for aplastic anemia
•
• * Caused in larger part by alloimmunization from prior
transfusions

• * Minimized to 10% by application of leukofiltered

irradiated blood components
 Evidence implicating host T cells as the mediators of an
active immune response against minor alloantigens
expressed by the donor T cells

 Fludarabine, antithymocyte globulin (ATG), are

intensive immunosuppressive agents added to eliminate
host T cells .
GF IN Recipient HLA- Avoid selecting donors
HAPLOIDENTICAL specific antidonor whom the recipient
SETTING antibodies have been has anti-HLA
implicated antibodies against
  Is extremely rare

GRAFT  Occurs when bone marrow function does not return

FAILURE IN
AUTOLOGOUS  May occur in patients with extensive marrow fibrosis
SETTING before transplantation, a viral illness or use of some
drugs(Methotrexate)
 In some cases , the reasons for graft failure is unknown
 If present repeat
Depends on whether infusion of donor
donor cells detected cells can be attempted
in patient’s marrow with or without
further conditioning
TREATMENT When no donor
OF GF hematopoietic cells are
detected, a second How-ever
conditioning regimen outcomes in this
may be administered
followed by infusion of
setting is poor
donor HSCs
  ABO incompatibility in allogenic bone marrow
transplant may be associated with incomplete or delayed
erythroid engraftment

 Persistent anti-donor isoagglutinins after major ABO

PURE RED mismatch transplant may cause PRCA
CELL
APLASIA  Treatment may be done with Erythropoietin or Anti
thymocyte globulin or plasmapheresis with relative
success considering PRCA was immunologically
mediated
 The three
requirements to be
met

The host must

express tissue The transplanted
antigens that are not graft must contain
GVHD present in transplant
donor and can be
immunocompetent
cells
recognized as foreign

The host must be

incapable of rejecting
the transplanted
alloreactive cells
  Usually occur within the first 100 days

 Organs involved include skin, gastrointestinal tract, and

ACUTE liver; involvement of skin is most common
GVHD
 No laboratory studies, including tissue biopsies, are
available to confirm or exclude this diagnosis
Acute GVHD (aGVHD) can be considered a three-step process:
(1) damage to host tissues from chemotherapy/radiotherapy inducing
the secretion of inflammatory cytokines
(2) activation and amplification of donor T cells interacting with host
antigen-presenting cells along with increased expression of major
histocompatibility complex (MHC) antigens and
(3) target cell apoptosis via both cellular and inflammatory mediators
  The risk of developing aGVHD increases primarily with
* HLA disparity between donor and recipient,
* but also with increasing age of donor and recipient,
* gender disparity, and
RISK
* infusion of T cell–replete HSC products.
FACTORS
 Conditioning with reduced-intensity regimens, with
lower regimen-related toxicities to nonhematologic
tissues, also results in a lower risk of aGVHD
 T lymphocytes are primary mediators of the GVH
reaction, and multiple studies have demonstrated lower
risks of aGVHD for recipients of T cell–depleted grafts

 Unfortunately, T-cell depletion increases the risks of

engraftment failure and relapse after disease, as a result
of the loss of the beneficial effects

 Selective T-cell subset depletion and “addback” of allo-

depleted T cells are strategies that may be effective for
reducing the risk of acute GVHD while preserving the
GVT effect.
  Acute GVHD is graded clinically using a standardized
system that takes into account clinical changes in the
primarily affected organs: skin, liver, and
gastrointestinal tract.
GRADING
 This grading system allows for quantitative estimates of
disease severity, transplant-related mortality, and
response to therapy with scoring consisting of Grades I
to IV
  Corticosteroids remain the standard initial treatment, but
even with prompt initiation of such therapy, the
treatment is suboptimal
TREATMENT
 The outcome for patients with steroid refractory GVHD
is poor, with a mortality rate of 70%;
 A number of drugs including ATG, pentastatin,
switching to tacrolimus from cyclosporine, and newer
monoclonal antibodies have shown (limited) activity in
the salvage treatment of patients with steroid-refractory
aGVHD.
 Extracorporeal exposure of peripheral blood
mononuclear cells to the photosensitizing agent 8-
methoxypsoralen and UVA radiation (photopheresis) has
been shown to be effective in the treatment of selected
diseases mediated by T cells, including both aGVHD
and cGVHD and

 Is a novel approach to the treatment of patients with

steroid-refractory GVHD
 Most patients receive a
combination of a calcineurin
Pharmacologic agents are the inhibitor (tacrolimus or
mainstay of prophylaxis of cyclosporine) along with an
aGVHD. antimetabolite such as
methotrexate or mycophenylate
mofetil (MMF)
PROPHYLAXIS
The addition of antithymocyte
globulin (ATG) to the
conditioning regimen lowers the
GVH and HVG reactions
because of the persistence of
this agent for several days after
HSC infusion.
CHRONIC GVHD

 Chronic GVHD is the leading cause of late treatment-related deaths

among recipients of allogeneic BM and stem cell transplants.

 cGVHD resembles autoimmune disorders

 A falling performance status, progression weight loss, or recurrent

infections are usually signs of clinical extensive cGVHD.
 50% of long-term survivors will develop this
complication of transplantation at a median of 9 months,
and patients must be monitored closely for at least 2
years after transplantation so that appropriate treatment
can be initiated before extensive tissue damage develops
Factors predicting the development of cGVHD include
*degree of HLA disparity
* source of HSCs (PBSC transplantation conveys a higher risk
compared with marrow or cord blood transplantation)
 The manifestations of chronic GVHD are extensive with
nearly every organ potentially affected.

 The consequences for affected patients can be

profound, with its presence or absence being the most
significant determinant of long-term outcome and
quality of life
 Patients who develop cGVHD have a higher risk of
TRM but a lower risk of relapse as a result of the
immunologic GVD effect.
 Most patients require at least two drugs for
treatment of cGVHD.

Glucocorticoids along with a calcineurin

TREATMENT inhibitor are the standard initial treatment.

Photopheresis has an overall response rate

of 50% to 60%
  PLS is a specific type of graft versus host disease
resulting in an immune mediated hemolysis in the post
transplant(solid organ & stem cell) patient.
PASSENGER
LYMPOCYTE  PLS occurs when viable donor B-lymphocytes are
passively transferred to the recipient within the allograft.
SYNDROME
 The passenger lymphocyte syndrome is due to the
production of antibodies by the donor B lymphocytes
“passenger lymphocytes” in a primary or secondary
immune response against the recipient’s red blood cell
antigen resulting in red blood cell destruction.
 PLS usually results from antibodies active against the
ABO and Rh systems

 Rarely, it may occur due to non-ABO/Rh antibodies, if

the organ donor has been previously sensitized to other
red cell antigens by transfusion or pregnancy
 Viable lymphocytes from the donor can temporarily
reside in the recipient, and if they are stimulated shortly
after transplant by recipient or transfused red cell
antigens, they can start producing antibodies during
their life.
  Immunosuppression used post transplantation has an
important etiologic role.

 Cyclosporine and tacrolimus without Methotrexate for

GVHD prophylaxis can permit rapid proliferation of
RISK spared B lymphocyte , which produce antibodies.
FACTORS
 Better HLA matching will result in less effective
clearing of B-lymphocytes from the recipient, increasing
the risk of PLS.
 PLS typically presents 1-3 weeks post-transplant.

 Clinical syndrome mild and self-limited in most of the cases.

 However, rarely acute renal failure, disseminated intravascular

hemolysis, hypotension, and multiorgan system failure may occur.
  Treated by transfusion of blood products.

 Red blood cell products are of donor’s ABO type.

TREATMENT  Plasma products should be of recipient’s ABO-type.

 Using the donor’s ABO-type replaces susceptible red

cells that will not be hemolyzed.
Utilizing B-lymphocyte targeted
therapy such as Rituximab has been
used .

Other treatment modalities include

immunomodulation with IVIG and
corticosteroids
  Avascular necrosis (AVN) of bone is an uncommon
complication of HSC transplantation, with an average
time of onset of about 2 years after transplantation.

LATE  The hip joint being the most often affected

COMPLICATI
ONS  The cause of this complication is not defined,

 Although vasculitis involving intraosseous blood vessels

induced by GVHD has been proposed for patients
undergoing allogeneic HSC transplantation
  Cataract formation is a frequent long-term complication
CATARACT of HSC transplantation and is associated with
administration of TBI and corticosteroids
  The majority of dose-intense conditioning regimens
invariably cause gonadal failure, with only a minority of
patients able to regain gonadal function after HSCT.

GONADAL  Therefore, puberty and menarche are delayed or

FAILURE abrogated completely.

 For women, ovarian failure is guaranteed in the face of

busulfan and or TBI conditioning.
 The development of secondary cancers, including
myelodysplasia or secondary leukemia, is a well-
described complication of allogeneic or autologous
HSC transplant

SECONDARY Risk factors were prior radiation (especially to the

pelvis),heavily pretreated, slow PBPC mobilizers, or
CANCERS subject to TBI-containing conditioning regimens.

Both autologous and allograft recipients are at higher

risk for additional secondary cancers, especially bone,
head, neck, and connective tissue malignancies.
  Transplantation is given with curative intent,
and the proper management of the transplant
recipient includes lifelong monitoring for
complications

 Although patients may achieve a cure of the

CONCLUSION underlying disease with HSC transplantation,
these patients face a higher mortality rate
than the general population.

 Factors associated with poorer quality of life

include older age at time of transplantation,
presence of long-term sequelae of the
treatment, and presence of chronic GVHD
 • Blood Banking and Transfusion Medicine, 2nd edition, Hillyer,
Silberstein.
• Rossi’s Principles of Transfusion Medicine, 5th edition.
 Passenger Lymphocyte Syndrome; a Review of the Diagnosis,
Treatment, and Proposed Detection Protocol☆ Mitchell M.
Moosavi, Alexander Duncan, Sean R Stowell, John D. Roback,
Harold Clifford Sullivan
REFERENCES  Engraftment Syndrome following Autologous Stem Cell
Transplantation – an Update Unifying the Definition and
Management Approach .Robert Frank Cornell1 Parameswaran
Hari,2 and William R. Drobyski2
THANK YOU