INTERESTING CASE

PRESENTATION
Hematology
• 32 year old male, diagnosed case of paroxysmal
nocturnal haemoglobinuria on treatment since 5
years
• Patient had poorly controlled disease . He was
started on tablet cyclosporin 100 mg once a day.
• The patient required multiple blood transfusions.
• He was referred to higher centre for bone marrow
transplantation
• Donor was his sister. Histocompatiblity match was
found. Peripheral blood was harvested.
• The patients blood group was A positive and his
sister's was O positive.
• So this was an ABO incompatible hematopoietic
bone marrow transplant.
• The transplant procedure was well tolerated by the
patient .
• Post transplant the patient's blood group changed
from A positive to O positive .
• As recipient marrow is completely ablated , donor
marrow cells from the red blood cells .
• The patient also has developed a herpes zoster
infection on trunk involving T2 dermatome.
• Patient has not required further transfusions, no
evidence of thrombosis of haemoptysis is seen.
BONE MARROW TRANSPLANT
• Hematopoietic cell transplantation (HCT) is an
important and potentially curative treatment
option for a wide variety of malignant and
nonmalignant diseases.
• HSCs are multipotent and have the capacity to
differentiate into the cells of all blood lineages:
erythrocytes, platelets, neutrophils, eosinophils,
basophils, monocytes, T and B lymphocytes, natural
killer cells, and dendritic cells
• The most primitive human hematopoietic cells are
CD34+ and CD38- . However, CD34+ cells comprise
approximately 2 to 5 percent of nucleated cells in
bone marrow, while HSC are much more rare
(about 1 per 20,000 bone marrow cells).
• Clinical trials using highly purified populations of
CD34+, Thy-1+ cells have demonstrated that this
cell population alone is capable of rapid and
sustained hematopoietic engraftment.
Source of stem cells
• Hematopoietic stem cells can be found in several
different human tissues: bone marrow; peripheral
blood, especially following mobilization; and
umbilical vein cord blood obtained at the time of
delivery.
• Bone marrow is generally aspirated from the
posterior iliac crests under either regional or
general anesthesia. Additional bone marrow can be
obtained from the anterior iliac crest.
How to harvest stem cells
• 5 to 10 mL of marrow from each puncture site, with a
goal of collecting up to 10 to 15 mL of marrow per
kilogram of recipient body weight (between 700 and 1500
mL of bone marrow for an adult recipient).
• Guidelines established by the National Marrow Donor
Program (NMDP) limit the volume of bone marrow
removed to 20 mL/kg of donor weight.
• Either heparin or acid-citrate-dextran-A can be used to
anticoagulate bone marrow products.
• If the product is to be cryopreserved, red cells are washed
off prior to freezing.
• An alternative to collection of unstimulated bone
marrow is to prime with granulocyte colony-
stimulating factor (G-CSF) prior to bone marrow
harvest (10 to 16 mcg/kg SQ per day for three
days).
• There have been some suggestions that this
approach may result in decreased incidence and
severity of graft-versus-host disease.
• A nucleated cell dose of 2 x 108/kg is generally
considered to be adequate.
• This generally requires between 700 and 1500 mL
of bone marrow for an adult recipient.
• PBPC products account for the majority of donor
hematopoietic stem cells for allogeneic HCT.
Following the completion of studies comparing the
relative efficacy of different hematopoietic stem
cell sources, transplantation with mobilized PBPCs
is more common.
• Both granulocyte colony-stimulating factor (G-CSF) and
granulocyte-macrophage colony-stimulating factor (GM-CSF),
either administered alone or in combination with chemotherapy
or other stimulating agents (eg, plerixafor), can be used to
mobilize a mixture of stem and other cells from the bone marrow,
referred to as peripheral blood progenitor or stem cells (PBPCs).
• Usual approach is to use G-CSF alone for the mobilization of
allogeneic donors and to use cyclophosphamide plus G-CSF for
autologous mobilization.
• The use of plerixafor is for patients who fail to mobilize adequate
numbers of CD34+ cells with either G-CSF alone or G-CSF plus
chemotherapy.
Plerixafor
• Plerixafor reversibly inhibits binding of stromal cell-derived factor-
1-alpha (SDF-1α), expressed on bone marrow stromal cells, to the
CXC chemokine receptor 4 (CXCR4), resulting in mobilization of
hematopoietic stem and progenitor cells from bone marrow into
peripheral blood.
• This is given after patient has received filgrastim (10 mcg/kg once
daily) for 4 days; plerixafor, filgrastim, and apheresis should be
continued daily until sufficient cell collection up to a maximum of
4 days.
• Usual approach is to treat the donor with G-CSF at a dose of 10 to
16 mcg/kg per day, with hematopoietic stem cell mobilization
usually occurring between days four and six .
Donors
• An identical twin (syngeneic, HLA identical)
• A sibling, relative, or unrelated donor (allogeneic,
which can be HLA identical, haploidentical, or
mismatched)
• Umbilical cord blood (allogeneic, which can be HLA
identical, haploidentical, or mismatched)
• The patient (autologous, HLA identical)
HLA typing
• Molecular typing, used for allele matching, defines
HLA genes by their DNA sequences. Molecular
typing is necessary for HLA-matching in unrelated
donor transplants and preferred by most centers
for HLA-matching in related donor transplants.
• Antigen typing is gradually being replaced by
molecular typing
Donor recipient mismatch
• A 12 of 12 HLA match refers to donor-recipient pairs matched for HLA-A,
HLA-B, HLA-C, HLA-DRB1, HLA-DQB1, and HLA-DP1 at the allele level.
• A 10 of 10 HLA match refers to donor-recipient pairs matched for HLA-A,
HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 at the allele level.
• A 9 of 10 HLA match refers to pairs with a single allele or antigen mismatch
at either HLA-A, HLA-B, HLA-C, HLA-DRB1, or HLA-DQB1.
• An 8 of 8 HLA match refers to donor-recipient pairs matched for HLA-A, HLA-
B, HLA-C, and HLA-DRB1 at the allele level.
• 7 of 8 HLA match refers to pairs with a single allele or antigen mismatch at
either HLA-A, HLA-B, HLA-C, or HLA-DRB1.
• 6 of 6 HLA match refers to donor-recipient pairs matched for HLA-A, HLA-B,
and HLA-DRB1 at the allele level.
• Antigen mismatches can be further characterized as being in
the "graft-versus-host" direction or the "host-versus-graft"
direction:
• graft-versus-host direction mismatch means that the patient
possesses one or more alleles not present in the donor. In such
a mismatch, the donor T cells from the graft would be
expected to mount an alloreactive response towards the
patient (host) tissue.
• host-versus-graft direction mismatch means that the donor
possesses one or more alleles not present in the patient. In
such a mismatch, the patient's T cells (host T cells) would be
expected to mount an alloreactive response towards the
donor (graft) cells
• Type of graft planned and mismatched HLA gene – For patients
undergoing bone marrow transplant, allele or antigen mismatch
at HLA-B or HLA-C may be better tolerated than HLA-A or HLA-DR
. In contrast, for patients undergoing peripheral blood progenitor
cell transplant, HLA-C antigen mismatch appears to convey a
worse prognosis [9].
• Other HLA genes – Typing for HLA-DP, -DQB1, and -DRB 3/4/5
may improve outcomes. If the grafts are otherwise considered
equal, donors with the greatest number of matches for these
genes are preferred.
• Donor-specific HLA antibodies – The presence of donor-specific
HLA antibodies is associated with an increased risk of graft failure
and should be avoided
• A choice among several equally matched donors can
then take into account other donor characteristics such
as age, CMV status (matching for CMV status
preferred), gender (males and nulliparous females
preferred), and blood type
• The best outcomes are seen in CMV negative recipients
with a CMV negative donor. If the recipient is CMV
seropositive, some centers advocate for the use of a
CMV seropositive donor with the hope that this will
result in a faster restoration of CMV immunity.
• At present, there are over 18 million donors
registered worldwide [28]. These potential donors
have undergone HLA-A and -B serologic typing. A
significant percentage has also undergone
molecular typing.
• The sorting order is for HLA-A, B and DRB1
• ABO and Rh status — ABO and Rh compatibility are not required
between the donor and recipient. Hemolysis, delayed
erythropoietic engraftment, and pure red cell aplasia (PRCA) may
complicate ABO-incompatible transplantation after either marrow
or PBPC transplantation. However, these complications are not
common.
• A meta-analysis of available studies has concluded that there was
no adverse association between any ABO mismatching and
survival following allogeneic hematopoietic cell transplantation
(HCT).
• Cases of delayed hemolysis and/or PRCA have been described in
patients with pre-existing alloantibodies against Rh or ABO
antigens,
ABO incompatibility
• ABO incompatibility can be major or minor.
• Patients with blood group A receive from group B
or vice a verse, this is a major incompatibility.
• Groups A and B with O and are considered minor.
• Typically, type O blood is utilized if there is a major
ABO mismatch between donor and recipient until
engraftment of donor RBCs is confirmed.
Role of atorvastatin
• statin use by the HCT donor and not the recipient was associated with a
significantly decreased risk of grades III to IV acute GVHD Statin-
associated GVHD protection was limited to those patients receiving
cyclosporine-based postgrafting immunosuppression, and was not
observed among those treated with tacrolimus
• .In a phase II trial, atorvastatin (40 mg daily by mouth) was administered
to 30 sibling donors starting two to three weeks prior to stem cell
collection.Atorvastatin was administered at the same dose to the HCT
recipient in addition standard GVHD prophylaxis with tacrolimus and a
short course of methotrexate. Atorvastatin was well tolerated by the
donors, and the cumulative incidence rates of acute and chronic GVHD
were 11 and 52 percent, respectively. There did not appear to be
increased rates of infection, relapse, or mortality.
Post transplant care
• Virtually all patients undergoing transplantation require blood
product support in the form of red blood cell and platelet
transfusions until the transplanted marrow cells engraft
sufficiently to support hematopoiesis. This generally requires
14 to 21 days or more with bone marrow but is accelerated
with peripheral blood progenitor cells with engraftment
typically requiring 10 to 14 days.
• All cytomegalovirus (CMV)-negative patients who receive bone
marrow cells from a CMV-negative donor should receive
seronegative blood products. In addition, it is highly
recommended to use irradiated blood products with or
without leukodepletion methods
• Many centers use a threshold of 7 to 8 g/dL of hemoglobin.
• prophylactic transfusion for patients with platelets ≤10,000/microL is
reasonable. Further enhancing platelet recovery is not likely to have a
significant impact on 60-day mortality but could significantly decrease
health care costs .
• In post-transplant setting the usual dose is 5 mcg/kg per day for G-CSF
(filgrastim), which we prefer, or 250 mcg/m2 per day for GM-CSF
(sargramostim) .Therapy is usually begun one to five days after
transplantation and continued until the absolute neutrophil count
reaches 10,000/microL; however, a shorter duration until clinically
adequate neutrophil recovery is achieved is a reasonable alternative.
Subcutaneous injection is preferred to intravenous injectiond potentially
improve patient quality of life.
•
Role of erythropoetin
• Most centers do not routinely employ EPO early after
allogeneic transplantation. Instead, EPO is generally
reserved for those patients with prolonged anemia (eg,
transfusion requirements after day 28) and those who
develop recurrent anemia after an initial hemoglobin
recovery.
• Post-transplant anemia may be multifactorial and
impacted by transplant complications (eg, GVHD) and
medications (eg, ganciclovir, cyclosporine). EPO
treatment may decrease the requirements for red
blood cell transfusions in patients with GVHD.
Thrombocytopenia in HCT
• The development of antibodies, resulting in
significant thrombocytopenia, has limited the use
of thrombopeitin in these patients.
• TMA may occur following allogeneic or autologous
HCT, although the latter is much rarer. The cause
may be multifactorial and include effects of
radiation, cytotoxic chemotherapy, disseminated
infection, and/or administration of a calcineurin
inhibitor for graft versus host disease (GVHD)
prevention.
When to suspect TMA
• Schistocytes account for more than 4 percent of red
blood cells
• De novo prolonged or progressive thrombocytopenia
(ie, platelet count <50,000/microL or ≥50 percent lower
than previous values)
• Sudden and persistent increase in serum lactate
dehydrogenase concentration
• Decrease in hemoglobin concentration or increase in
transfusion requirement
• Decrease in serum haptoglobin
• Management of post-transplant TMA is supportive, and may
include treatment of infection, transfusions if needed (eg, platelet
transfusion for major bleeding), and dialysis if renal failure is
severe. Discontinuation of implicated drugs, especially calcineurin
inhibitors (eg, cyclosporin, tacrolimus), is essential.
• There is no convincing evidence to support the use of plasma
exchange therapy in post-transplant TMA. This contrasts with
management of thrombotic thrombocytopenic purpura (TTP; a
TMA caused by severe ADAMTS13 deficiency), for which plasma
exchange may be life-saving.
• Most patients will recover following withdrawal of calcineurin
inhibitors.
Mucositis
• The majority of patients who undergo either autologous or
allogeneic hematopoietic cell transplantation (HCT) with a
myeloablative preparative regimen develops significant
mucositis and has difficulty maintaining an adequate caloric
intake.
• intravenous amifostine be used, at a dose of ≥340 mg/m2, to
prevent radiation proctitis in patients receiving radiation
therapy (II).
• octreotide, at a dose of ≥100 µg subcutaneously twice daily, be
used to treat diarrhea induced by standard- or high-dose
chemotherapy associated with hematopoietic stem cell
transplantation (HSCT), if loperamide is ineffective .
Newer agents for mucositis
• recombinant human keratinocyte growth factor-1
(KGF-1/palifermin) be used to prevent oral
mucositis (at a dose of 60 µg/kg per day for 3 days
prior to conditioning treatment and for 3 days after
transplant) .
• low-level laser therapy
• patient-controlled analgesia with morphine
• benzydamine mouthwash
TPN
The following criteria were used to define the need for
TPN:
• Severe malnutrition at admission
• A prolonged period (7 to 10 days) of minimal oral
intake
• Clinical weight loss during treatment exceeding 10
percent of body weight
• Using these definitions, TPN was judged to be
necessary in only 55 percent of patients undergoing
HCT,
Oral of glutamine
• Glutamine is an important precursor for nucleotide synthesis, and
an important fuel source for rapidly dividing cells, such as the
lining epithelia of the GI tract. Furthermore, glutamine is
postulated to facilitate healing of the GI mucosa following
damage by either radiation therapy (RT) or chemotherapy .
• Impact of oral glutamine supplementation to prevent gut atrophy
and decrease mucositis and infectious complications in patients
undergoing HCT remains controversial.
• Parenteral TPN with glutamine supplementation (0.57 g/kg per
day) was associated with significantly lower infection and
colonization rates, better nitrogen balance, a decreased incidence
of infection, and a shorter length of stay.
Antiemetics
• The use of high-dose chemotherapy in association
with a bone marrow or peripheral blood stem cell
transplant presents a special challenge to achieving
good antiemetic control
• The updated 2017 antiemetic guidelines from ASCO
and the 2016 Multinational Association of Supportive
Care in Cancer (MASCC)/European Society for
Medical Oncology (ESMO) guidelines recommend a 5-
HT3 receptor antagonist plus dexamethasone with
consideration of aprepitant in this setting
Diarrhoea in post HCT
• Acute graft-versus-host disease
• infections
• medications (eg, mycophenolate mofetil)
• mucosal damage due to the conditioning regimen
• neutropenic enterocolitis
• post-transplantation lymphoproliferative disease
involving the gastrointestinal tract
• recipients of umbilical cord blood transplantation may
develop a culture-negative, antibiotic-responsive
diarrhea termed cord colitis syndrome
Cord colitis syndrome
• Patients with cord colitis most commonly presented with a
persistent (>7 days) watery, nonbloody diarrhea starting a
median of 131 days after HCT.
• The diarrhea was associated with weight loss (91 percent)
and fever (64 percent)
• computed tomography of the abdomen demonstrated focal
or diffuse thickening of the colonic wall. Colonoscopy
revealed erythematous mucosa with or without ulcerations,
but no pseudomembranes.
• negative viral and bacterial cultures and a colon biopsy that
demonstrated chronic active colitis, frequently with
associated granulomas.
• All cases demonstrated a response to antibacterial
treatment (usually metronidazole with or without a
fluoroquinolone) with a median treatment duration
of 14 days. While approximately half of the patients
relapsed after the discontinuation of antibiotics, all
responded to subsequent courses of antibiotics.
• A newly discovered bacterium, provisionally called
Bradyrhizobium enterica, has been proposed as the
underlying cause of cord colitis syndrome.
Neutropenia
• The definition of neutropenia varies from institution to
institution, but neutropenia is usually defined as an
absolute neutrophil count (ANC) <1500 cells/microL,
and severe neutropenia is usually defined as an ANC
<500 cells/microL or an ANC that is expected to
decrease to <500 cells/microL over the next 48 hours
• Fever in neutropenic patients is defined as a single oral
temperature of ≥38.3°C (101°F) or a temperature of
≥38.0°C (100.4°F) sustained over a one-hour period.
• Fever in a neutropenic patient should be
considered a medical emergency. Broad-spectrum
antibacterials should be given as soon as possible
(within 60 minutes of triage) and at full doses,
adjusted for renal and/or hepatic function.
• Bathing patients daily with chlorhexidine gluconate,
an antiseptic agent with broad-spectrum activity
against many organisms, has been shown to be an
effective method of decreasing both hospital-
acquired infections and colonization with drug-
resistant organisms, primarily among patients in the
intensive care unit (ICU).
• the reduction in bloodstream infections with
chlorhexidine use was greatest for coagulase-
negative staphylococci and fungal infections
• First check immunoglobulin G (IgG) levels in allogeneic
HCT recipients with bacteremia or recurrent
sinopulmonary infections and administer IVIG to those
with levels <400 mg/dL [1]. The dose and frequency are
varied to maintain levels >400 mg/dL. The half-life of
IVIG in HCT recipients is shorter (approximately 1 to 10
days) than in other patients (approximately 18 to 23
days) [1,41-43].
• The efficacy of IVIG is best illustrated by reports of
patients with common variable immunodeficiency
(CVID)
Immunization of recipient
• Usually recommended vaccines are
• H influenza
• Hepatitis A and B
• Diphtheria toxoid
• HPV
• meningococcal
• Polio
• HCT candidates should receive live virus vaccines ≥4 weeks
prior to the initiation of the conditioning regimen and
inactivated vaccines ≥2 weeks prior to the initiation of the
conditioning regimen.
• Nonimmune HCT candidates ≥12 months of age should receive
the varicella vaccine (a live virus vaccine) if they are not
immunocompromised and if the interval until initiating the
conditioning regimen is ≥4 weeks [10]. If there is sufficient
time prior to HCT, two doses of the varicella vaccine should be
given; for individuals 1 to 12 years of age, the doses should be
separated by at least three months and, for individuals ≥13
years of age, the doses should be separated by at least four
weeks.
• HCT recipients should be immunized against a number
of pathogens such as pneumococcus, Haemophilus
influenzae, tetanus, and others once they are likely to
mount an immune response.
• Live virus vaccines are avoided altogether during the
first 24 months following HCT, but certain ones (eg,
measles, mumps, and rubella vaccine) are indicated 24
months following HCT in patients who do not have
active graft-versus-host disease and who are not
receiving immunosuppressive agents
Donor immunization
• The possible benefit to HCT recipients of vaccinating donors has
been shown in studies with Pseudomonas aeruginosa
polysaccharide conjugate vaccine, diphtheria and tetanus toxoid
vaccines, and hepatitis B vaccine: adoptive transfer of specific
antibodies was achieved from immunized HCT donors to both
non–T cell– and T cell–depleted allogeneic HCT recipients
• Haemophilus influenzae B conjugate vaccine, and pneumococcal
conjugate vaccine have been shown to improve immunity in HCT
recipients
• There are case reports of attempts to clear chronically infected
HCT recipients by immunizing the donor with hepatitis B vaccine
and immunizing the recipient with hepatitis B vaccine in the early
posttransplant period
Hepatic complications
• increased concentrations of bilirubin and hepatic
enzymes
• hepatic graft-versus-host disease
• hepatic veno-occlusive disease
• Liver failure
• Hepatic sinusoidal obstruction syndrome (SOS) is a
syndrome characterized by painful hepatomegaly,
weight gain, ascites, and jaundice, which can progress
to fulminant hepatic failure. Pathologic changes include
necrosis of hepatocytes and perivenular fibrosis with
cholestasis,
• UDCA), a hydrophilic bile salt, has shown improved
survival in graft versus host disease (GVHD), and
hepatic sinusoidal obstruction syndrome (SOS)
after allogeneic hematopoietic cell transplantation
(HCT).
• 12 mg/kg per day divided into two oral doses),
starting one day before the first conditioning dose,
continuing until day 90 following HCT.
Psychiatric complications
• While the transplant procedure itself can be
physically and emotionally stressful, there does not
appear to be a substantially increased risk of a long-
term psychiatric disorder due to the procedure itself.
• At two weeks post-transplant, palliative care
consultation was associated with less depression,
anxiety, overall symptom burden, and impairment in
quality of life (QOL). Depression and QOL benefits
persisted at three months.
Delirium and encephalopathy
• Up to 50 percent of patients undergoing myeloablative HCT
experience an acute confusional state consistent with delirium at
some point during the first 30 days post-HCT.
• Risk factors for the development of delirium included higher pre-
HCT levels of alkaline phosphatase and/or blood urea nitrogen
and the use of high dose opioids post-HCT
• Transient, profound encephalopathy, with concurrent cardiac and
gastrointestinal effects, has been reported very rarely following
infusions of the hematopoietic stem cell product, perhaps due to
acute systemic toxicity from the dimethylsulfoxide (DMSO) used
as a cryopreservative
Social and psychological support
• One study examined whether the consistent presence
of an in-hospital lay care-partner (ie, someone present
at the bedside during the patient's hospitalization for
≥7 hours/day at least five days/week) had a significant
effect on overall survival following HCT
• 45 percent of the patients had an in-hospital lay care-
partner. Spouses and parents constituted 61 and 34
percent of these care-partners, respectively.At one year
post-HCT, overall survivals were 26 versus 75 percent
for those without or with a care-partner as defined
above
• More than 80 percent of survivors saw a physician
once per month or less.
• Approximately 60 percent of patients had returned
to work, school, or homemaking and agreed with
the statement: "Life has returned to normal."
• Forty-three percent of autologous and 25 percent
of allogeneic HCT patients were off all transplant-
related medications.
• The largest study of long-term follow-up evaluated 10,632
patients who were alive and disease-free two years after
receiving a myeloablative allogeneic HCT for acute
myeloid leukemia, acute lymphoid leukemia,
myelodysplastic syndrome, lymphoma, or severe aplastic
anemia before 2004
• After a median follow-up of nine years, there was an
estimated 10-year overall survival rate of 85 percent.
• The most common causes of death after HCT for
malignancy were late relapse, graft versus host disease,
and infection.
Bone marrow donation
• There are 3 main registrys in India
• MDRI: Marrow donation registry of India, centre at
Mumbai
• DATRI, Chennai
• Bharat registry, New Delhi
• MDRI has about 25000 registered donors. DATRI
has more than 3 lacs.
World marrow donation day
15 September 2018
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