the initial recovery. These outpatient programs also offer cost savings to the payer

for health services.

24,25 Successful outpatient care during autologous HCT requires

careful development and implementation of the necessary supportive-care strategies

to prevent or minimize infection, chemotherapy-induced nausea and vomiting,

infection, pain, and transfusion requirements. It is also necessary to develop

admission criteria for patients with more severe complications.

Use of prophylactic oral antibiotics and once-daily IV antibiotics to prevent or

treat febrile neutropenia has facilitated outpatient care and prevented many patients

from being hospitalized.

26

In addition, outpatient care during autologous HCT demands that HCT centers have

appropriate resources, facilities, and staff to provide 24-hour patient care coverage.

Patients undergoing outpatient care must meet eligibility criteria, including the

availability of caregivers 24 hours a day and housing within close proximity to the

HCT center.

Hematopoietic Growth Factors After Autologous

Peripheral Blood Progenitor Cell Infusion

CASE 101-1, QUESTION 6: Ten days after the collection of PBSC, P.J. is admitted for his autologous

HCT. He receives a myeloablative preparative regimen with cyclophosphamide, carmustine, and etoposide with

an autologous PBPC graft. An order is written to begin filgrastim 5 mcg/kg/day subcutaneously, beginning on

day 0 and continuing until the ANC has recovered to 500 cells/μL for two consecutive days. What is the

rationale for filgrastim in P.J. after the transplant procedure?

Autologous HCTs, regardless of the stem cell source, are associated with

profound aplasia due to the myeloablative preparative regimen (Table 101-3).

Aplasia typically lasts 14 to 21 days after an autologous BMT and 10 to 14 days after

an autologous PBPCT.

21 During this period of pancytopenia, patients are at high risk

for complications such as bleeding and infection. In order to lessen the complications

of pancytopenia, hematopoietic growth factors, such as filgrastim and sargramostim,

may be used. These drugs exert their effects by stimulating the proliferation of

committed progenitor cells. The benefits of the hematopoietic growth factor have

been shown in several large multicenter, randomized, double-blind, placebocontrolled trials.

27–29 The majority of the trials suggest hematopoietic growth factor

administration is associated with a shorter time to neutrophil engraftment (by 4–7

days), less infectious complications, shorter hospitalization after autologous BMT,

and therefore decreased resource utilization.

27,28,30 However, the use of these agents

does not affect overall survival.

27,29

Although studies in the autologous PBPCT setting note more rapid neutrophil

recovery after hematopoietic growth factor use, others report no difference in

infection rates and minimal decreases in associated resource use such as the duration

of hospitalization.

28,30–32 Although clinical practice guidelines for hematopoietic

growth factors support their use after autologous transplant, pharmacoeconomic

analyses are needed to further evaluate the true benefit of hematopoietic growth

factors after autologous PBPCT.

Filgrastim is preferred for accelerating neutrophil engraftment in clinical practice.

The reason most commonly cited is the desire to avoid febrile reactions associated

with sargramostim, which complicates interpretation of febrile neutropenia. Although

sargramostim or filgrastim theoretically may stimulate proliferation of leukemia

myeloblasts, no evidence to date suggests that the incidence of leukemia relapse is

higher in patients who receive these hematopoietic growth factors after autologous or

allogeneic HCT.

33,34

Although both filgrastim and sargramostim successfully hasten neutrophil

recovery, neither agent stimulates platelet production or augments platelet

recovery.

27,28 At this time, there is no established role for erythropoietin stimulating

agents or platelet growth factors in the care of these patients. In summary, P.J. is

undergoing autologous PBPCT for the treatment of a lymphoid malignancy. Thus,

either sargramostim or filgrastim is an acceptable option for accelerating

engraftment. Whether the addition of either agent will reduce infection and improve

other clinically relevant outcomes is debatable.

14 A complete blood cell (CBC) count

with differential should be obtained daily. Filgrastim should be continued until

neutrophil recovery is achieved.

ALLOGENEIC HEMATOPOIETIC STEM CELL

TRANSPLANTATION

Allogeneic HCT involves the transplantation of hematopoietic stem cells obtained

from a donor’s bone marrow, PBPCs, or umbilical cord blood to a patient. Fifty-one

percent (51%) of all transplants performed in North America in 2008 used unrelated

donors.

1 Thus, to understand the application of and complications after allogeneic

HCT, a working knowledge of immunology and the major histocompatibility complex

(MHC) and human leukocyte antigen (HLA) in humans is necessary.

Indications for Allogeneic Hematopoietic Stem Cell

Transplantation

CASE 101-2

QUESTION 1: B.S., a 22-year-old man, has acute myelogenous leukemia (AML) in first remission after

induction chemotherapy with standard doses of cytarabine and daunorubicin and consolidation with high-dose

cytarabine. B.S. has poor risk cytogenetics, with abnormalities of 11q23 and inversion 3. Thus, he will receive

an allogeneic HCT as part of postremission therapy. Typing performed on family members has identified a fully

HLA-matched sibling donor. B.S. returns to the clinic today for a pretransplantation workup. At this time, his

physical examination is noncontributory. All laboratory values are within normal limits. A bone marrow biopsy

reveals less than 5% blasts. B.S. has a normal electrocardiogram and cardiac wall motion study. His renal,

hepatic, and pulmonary function tests are normal. Is an allogeneic HCT indicated for B.S.?

The primary indications for allogeneic HCT include treatment of otherwise fatal

diseases of the bone marrow or immune system (Table 101-2). The optimal role and

timing of allogeneic HCT, in contrast to other therapies, remains controversial,

35

especially because treatment options for AML have increased. The National

Comprehensive Cancer Network treatment guidelines for AML include the use of

allogeneic HCT. A matched sibling or alternative donor (e.g., matched unrelated

donor [MUD]) HCT is recommended as part of postremission therapy in patients

with preceding hematologic disease (e.g., myelodysplasia, secondary AML) or poor

risk cytogenetics, as in the case of B.S.

36 Current research efforts focus on the use of

reduced-intensity preparative regimens and the utility of HCT relative to novel

targeted agents in the hope of improving the outcome of allogeneic HCT.

36 B.S. is

eligible for allogeneic HCT by virtue of his cytogenetics and the availability of a

histocompatible donor. In addition, he meets age and organ function eligibility

requirements and is in complete remission with minimal residual disease.

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p. 2107

Histocompatibility

CASE 101-2, QUESTION 2: Why is histocompatibility important in selection of the donor in patients like B.S.

who undergo an allogeneic HCT?

Because the tissue transplanted in allogeneic HCT is immunologically active, there

is potential for bidirectional graft rejection.

2

In the first scenario, cytotoxic T cells

and natural killer (NK) cells belonging to the host (recipient) recognize MHC

antigens of the graft (donor hematopoietic stem cells) and elicit a graft rejection

response. This results in ineffective hematopoiesis (i.e., inadequate ANC and/or

platelet counts) post-transplant. In the second scenario, immunologically active cells

in the graft recognize host MHC antigens and elicit an immune response, referred to

as GVHD. Therefore, an essential first step for patients eligible for HCT is finding

an HLA-compatible graft with an acceptable risk of rejection and GVHD.

Determination of histocompatibility between potential donors and the patient is

completed before allogeneic HCT.

37

Initially, HLA typing is performed using tissue

(buccal swab) and blood samples. Compatibility at class I MHC antigens (HLA-A,

HLA-B, and HLA-C) is determined through serologic and DNA-based testing

methods.

38,39 Currently, most clinical and research laboratories are also performing

molecular DNA typing.

38–47 A donor–recipient pair with different HLA antigens (i.e.,

“antigen mismatched”) always has different alleles, whereas pairs with the same

allele always have the same antigen and are termed “matched.” However, some pairs

have the same HLA antigen but different alleles and are thus “allele mismatched.”

(See Chapter 34, Kidney and Liver Transplantation, for additional discussion of

histocompatibility.)

Graft rejection is least likely to occur with a syngeneic donor, meaning that the

recipient and host are identical (monozygotic) twins. Identical twins occur

spontaneously in nature in approximately 1 in 100 births; thus, it is unlikely that a

patient would have a syngeneic donor. In those patients without a syngeneic donor,

initial HLA typing is conducted on family members because the likelihood of a

complete histocompatibility match between unrelated individuals is remote. Siblings

are the most likely to be histocompatible within a family; however, only 25% of

potential HCT recipients will have an HLA-identical sibling.

38

Lack of an HLA-matched sibling donor can be a barrier to allogeneic HCT.

Alternative sources of allogeneic hematopoietic stem cells, such as related donors

mismatched at one or more HLA loci, or MUDs, are used.

40 Establishment of the

National Marrow Donor Program has helped increase the pool of potential donors

for allogeneic HCT.

40 Through this program, an HLA-matched unrelated volunteer

donor might be identified. Recipients of an unrelated graft are more likely to

experience graft failure and acute GVHD relative to recipients of a matched sibling

donor.

41 Thus, work is ongoing to identify factors that predict graft failure or GVHD

to improve the availability and safety of unrelated donor transplants (see Graft

Rejection section).

42

The preparative regimen and/or GVHD prophylaxis may be altered based on the

mismatch between the donor and the recipient. The risk of graft failure decreases

with better matches, and although mismatching in a single HLA allele does not

appear to impact overall survival, mismatching in more than one allele significantly

impairs overall survival. The most important alleles to match are the HLA class I

antigens (HLA-A, HLA-B, HLA-C) and the HLA class II antigens (HLA-DRB1,

HLA-DPB1, HLA-DQB1).

43–45 This field is continually evolving with current data

suggesting that mismatches at HLA-DPB1confer an increased risk of mortality.

46

Eligibility criteria for allogeneic HCT vary between institutions. Having a

matched sibling donor is no longer a requirement for allogeneic HCT, because

improved immunosuppressive regimens and the National Marrow Donor Program

have allowed an increase in the use of unrelated or related matched or mismatched

HCT.

41 Potential donors also include haploidentical donors, who are a parent,

sibling, or child of a parent with only one identical HLA haplotype. Hematopoietic

cell transplant with a haploidentical donor was initially associated with high rates of

graft failure and GVHD, but recent technologic advances have improved outcomes.

Haploidentical HCT involves another alloreactive mechanism involving NK cells,

which may be associated with reduced relapse rates in AML patients.

2

Normal renal, hepatic, pulmonary, and cardiac functions are necessary for

eligibility at most centers. Historically, patients older than 55 years were excluded

from allogeneic HCT because they were more likely to succumb to transplantationrelated complications. However, many centers are now considering patients up to 65

years old and basing their selection criteria on physiologic rather than biologic age.

Harvesting, Preparing, and Transplanting Allogeneic

Hematopoietic Stem Cells

CASE 101-2, QUESTION 3: What methods can be used to harvest hematopoietic stem cells from B.S.’s

histocompatible sibling and prepare them for transplant? Are there any advantages to the use of bone marrow,

PBPCs, or umbilical cord blood as a source for hematopoietic stem cells?

The method of harvesting allogeneic hematopoietic stem cells varies according to

the site of harvest (i.e., bone marrow, peripheral blood, or umbilical cord blood).

ABO incompatibility increases the complexity of HCT, but is not an obstacle to

HCT. The hematopoietic stem cells may need additional processing to reduce the

RBCs infused with the HCT product if the donor and recipient are ABOincompatible, which occurs in 30% to 40% of sibling donor HCTs and is higher in

unrelated donor HCT.

47 Various strategies post-transplant used to manage blood

support for ABO-incompatible HCT recipients include the infusion of donor-type

fresh frozen plasma to provide a noncellular source of A or B antigens, as well as

transfusing-type volume reduced RBCs and platelets or O RBCs to minimize the risk

of immune-mediated hemolytic anemia and thrombotic microangiopathic

syndromes.

47

BONE MARROW

Harvesting bone marrow entails a surgical procedure in which marrow is obtained

from the iliac crests. Allogeneic bone marrow is obtained from the donor under local

or general anesthesia on day 0 of BMT.

2 The number of nucleated marrow cells

harvested varies depending on disease being treated, conditioning regimen, and

preinfusion manipulation, and is usually 1 to 3 × 10

8

infused cells/kg of recipient

weight.

17 These cells are obtained through multiple aspirations of marrow from the

posterior iliac crests. The marrow is then processed to remove fat or marrow emboli

and is usually immediately infused intravenously into the patient. If immediate

transplant is not possible, the bone marrow is frozen until it can be infused. Once

infused into circulation, through the mechanism of the chemokine SDF-1/CXCR4

receptor, the stem cells migrate to the bone marrow compartment where they will

eventually reside.

PERIPHERAL BLOOD PROGENITOR CELLS

As mentioned earlier, hematopoietic stem cells continuously detach, enter the

circulation, and return to the marrow; thus, the peripheral blood is a convenient

source of hematopoietic

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p. 2108

stem cells. The number of PBPCs is estimated by using the cell surface molecule

CD34 as a surrogate marker. The number of circulating CD34

+ cells in blood is

increased by mobilizing them from the marrow. The most commonly used regimen to

mobilize allogeneic (healthy) donors is a 4- to 5-day course of filgrastim 10 to 16

mcg/kg/day subcutaneously, followed by pheresis on the fourth or fifth day when

peripheral blood levels of CD34

+ cells peak.

9 An adequate number of hematopoietic

stem cells is usually obtained with one to two pheresis collections. The optimal

number of CD34

+

required is 4 to 10 × 10

6 cells/kg of recipient body weight for a

HLA-identical sibling donor transplant with haploidentical transplants requiring

greater numbers.

10,48,49 Higher cell doses have been associated with not only more

rapid engraftment but also fewer fungal infections and improved overall survival.

50

Hematopoietic stem cells obtained from the peripheral blood are processed like bone

marrow-derived stem cells and may be infused immediately into the recipient or

frozen for future use. Compared to bone marrow, PBPC infusions are associated with

quicker neutrophil and platelet engraftment.

2

In patients with a hematologic

malignancy and a matched sibling donor, PBPCT is also associated with lower

relapse rates and increased disease-free survival rates.

51 However, PBPC grafts

contain more T cells than do bone marrow grafts.

2 Therefore, PBPCT has a similar

incidence of acute GVHD, but an approximately 20% higher incidence of extensive

stage and overall chronic GVHD.

51

UMBILICAL CORD BLOOD

Blood from the umbilical cord and the placenta is rich in hematopoietic stem cells

but limited in volume.

52 Thus, umbilical cord blood offers an alternative stem cell

source to those patients who do not have a suitable related donor. After consent is

obtained, the cord blood cells are obtained in the delivery room after birth, typically

after the delivery of the placenta.

53

The cord blood is then processed, and, if it matches certain pre-established

criteria (e.g., minimum nucleated cell content, sterility), a sample is sent for HLA

typing and cryopreserved for future use. An estimated 20,000 HCTs with cord blood

donors have been performed with more than 300,000 cord blood units banked

worldwide. It is unknown how long cryopreserved cord blood is viable.

54

HCT with an unrelated cord blood donor has several potential advantages over

unrelated marrow or PBPC donors.

52 Specifically, (a) cord blood is readily

available, which leads to a more rapid time to HCT; (b) lack of stem cell exposure to

the thymus allows for greater degrees of HLA disparity as compared to bone marrow

or PBPC

53

; and (c) despite the less-stringent HLA matching, mismatched cord blood

cells are less likely to cause GVHD while still maintaining GVT activity. The lessstringent HLA requirements increase the likelihood of identifying a suitable

allogeneic donor, which is particularly beneficial for minority populations who are

underrepresented in adult registries and often lack matched stem cell sources.

Outcomes in umbilical cord blood recipients are improved with fewer HLA

mismatches and greater numbers of CD34

+ cells.

55 However, the limited number of

hematopoietic stem cells in cord blood is a disadvantage in particular when

considering adult patients.

56

In order to overcome the cell dose limitation and

improve engraftment, researchers have been studying infusing two cord blood units,

57

coinfusing a cord blood unit with highly purified CD34

+ cells from haploidentical

donors,

58 and ex vivo expansion of cord blood progenitors,

59 delivery of the cord

blood unit directly into the bone marrow space,

60–62 and priming of cord blood with

agents that may facilitate homing to the bone marrow.

63

As an adequate cell dose is critical for engraftment after cord blood

transplantation and the cell dose of a single cord blood unit is limited, progress in the

field of cord blood transplantation for the treatment of adults has been slower.

56

However, recent data showed that when a single cord blood unit with an adequate

cell dose is available, the outcomes of adults with leukemia are similar to those

receiving unrelated bone marrow or peripheral blood grafts.

64

Moreover, for those adults with leukemia who do not have a single cord blood unit

with a suitable cell dose, the use of two partially matched cord blood units to

compose the graft also provides outcomes similar to that of related and unrelated

donors.

65 These data associated with the promising outcomes when using umbilical

cord blood in the context of reduced-intensity conditioning have significantly

increased the utilization of cord blood as a source of hematopoietic progenitors for

the treatment of adult patients.

66,67

In summary, the utilization of cord blood as a source of hematopoietic stem cells

for transplantation has substantially expanded in the last decade. Novel

methodologies to improve engraftment, promote immune reconstitution, and improve

outcomes after cord blood transplantation are under investigation and are likely to

further extend its availability to patients who require a potentially curative allogeneic

transplant but lack a suitable related donor.

Therefore, it is most reasonable to harvest PBPCs from B.S.’s sibling to use for

his myeloablative HCT because his sibling is fully HLA-matched. A PBPC transplant

is preferred to BMT due to the expectations of increased speed of neutrophil and

platelet engraftment and disease-free survival rate and lower relapse rate.

Graft-versus-Tumor Effect

CASE 101-2, QUESTION 4: B.S. will receive an allogeneic HCT from his histocompatible sibling with the

hope of inducing GVT effect to help in treating his malignancy. What is the GVT effect? Which tumors are

most responsive to this effect?

Graft-vs.-tumor refers to the phenomenon where the donor’s cytotoxic T

lymphocytes suppress or eliminate the recipient’s malignancy. Initial clinical

evidence of a GVT effect came from the observation that patients with GVHD had

lower relapse rates compared with those who did not.

68,69 This suggested a GVT

effect due to the donor lymphocytes. Lymphocyte involvement in GVT was further

supported by the effectiveness of donor lymphocyte infusions in treating patients who

experienced relapse of their malignancies after allogeneic HCT.

70,71 Eradication of

the recurrent malignancy is due to either specific targeting of the tumor antigens or to

GVHD, which may affect cancer cells preferentially. Different illnesses vary in their

responsiveness to donor lymphocyte infusions, with chronic myelogenous leukemia

(CML) and acute leukemias being the most and least responsive, respectively.

72

Patients with certain solid tumors (e.g., renal cell carcinoma) also appear to benefit

from a GVT effect.

73 These data are the platform on which the use of reducedintensity and nonmyeloablative preparative regimens are based.

Preparative Regimens for Allogeneic Hematopoietic

Stem Cell Transplantation

MYELOABLATIVE PREPARATIVE REGIMENS

CASE 101-2, QUESTION 5: What is the rationale for using myeloablative preparative regimens for patients

like B.S. who are to receive an allogeneic HCT? What types of regimens are used, and what is recommended

for B.S.?

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p. 2109

The combination of chemotherapy and/or radiation used in allogeneic HCT is

referred to as the preparative or conditioning regimen. The rationale for high-dose

myeloablative preparative regimens is similar to that discussed in the Autologous

Hematopoietic Stem Cell Transplantation section. Infusion of hematopoietic stem

cells restores hematopoiesis induced by dose-limiting myelosuppression of

chemotherapy, maximizing the potential value of the steep dose–response curve to

alkylating agents and radiation

18

, and suppressing the host immune system. The

preparative regimen is also designed to eradicate immunologically active host tissues

(lymphoid tissue and macrophages) and to prevent or minimize the development of

host-versus-graft reactions (i.e., graft rejection). Conversely, patients undergoing

syngeneic transplantation do not require immunosuppressive preparative regimens

before HCT because the donor and the patient are genetically identical; thus, there is

no potential for host-versus-graft reactions. Therefore, preparative regimens are

tailored to the primary disease and to HLA compatibility between the recipient–

donor pair.

Examples of common preparative regimens for allogeneic HCT are shown in

Table 101-3.

8,20,74 Table 101-4 lists the common toxicities associated with

myeloablative allogeneic HCT. Most allogeneic preparative regimens for the

treatment of hematologic malignancies contain cyclophosphamide, radiation, or both.

The combination of cyclophosphamide and total body irradiation (TBI) was one of

the first preparative regimens used, and it is still used widely today. This regimen is

immunosuppressive and has inherent activity against hematologic malignancies (e.g.,

leukemias, lymphomas). TBI is myeloablative and immunosuppressive, does not have

cross-resistance to chemotherapy, and reaches sites not affected by chemotherapy

(e.g., the central nervous system).

2 The toxicity of TBI and the scarcity of facilities

for its delivery have led to the development of radiation-free preparative regimens.

Modifications of the cyclophosphamide–TBI (CY/TBI) preparative regimen include

replacing TBI with other agents such as busulfan and adding other chemotherapeutic

or monoclonal agents such as alemtuzumab to the existing regimen. These measures

are designed to minimize the long-term toxicities associated with TBI (e.g., growth

retardation in children, cataracts) or to provide additional antitumor activity. The

long-term outcomes of busulfan/cyclophosphamide (BU/CY) and CY/TBI in patients

with AML and CML have been compared in a meta-analysis of four clinical trials.

75

Equivalent rates of long-term complications were present between the two

preparative regimens, except for a greater risk of cataracts with CY/TBI and

alopecia with BU/CY. Overall and disease-free survival rates were similar in

patients with CML although there was a trend for improved disease-free survival

with CY/TBI in AML patients. In the case of a mismatched allogeneic HCT with an

increased chance of graft rejection, antithymocyte globulin (ATG) may also be added

to the preparative regimen to further immunosuppress the recipient.

Based on these data, the CY/TBI preparative regimen is preferred for B.S.

because he has AML with poor cytogenetics and has a matched sibling available.

Because of the high relapse rates seen in AML, myeloablative allogeneic transplant

is indicated in first remission for patients less than 60 years old with good

performance status due to the decrease in likelihood of achieving a complete

response to reinduction chemotherapy and the expected reduced duration of a second

remission.

REDUCED-INTENSITY OR NONMYELOABLATIVE PREPARATIVE

REGIMENS

CASE 101-2, QUESTION 6: Describe the rationale for nonmyeloablative preparative regimens. Is B.S. a

candidate for such a regimen?

The regimen-related toxicity of a myeloablative preparative regimen (Table 101-

4) limits the use of allogeneic HCT to younger patients who have minimal

comorbidities. Because many patients with hematologic malignancies are older and

have comorbidities, myeloablative HCT cannot be offered to a substantial portion of

them.

76 The observation that patients with GVHD have less relapses and an improved

understanding of the GVT effect led to the development of strongly

immunosuppressive but not myeloablative (i.e., a reduced-intensity or

nonmyeloablative) preparative regimens.

2 Currently, reduced-intensity preparative

regimens account for 30% of allogeneic transplants.

77 More than 60% of patients

receiving reduced-intensity preparative regimens are older than 50 years.

1,77

There is a wide spectrum of reduced-intensity preparative regimens, with the

nonmyeloablative regimens causing the least amount of myelosuppression. In general,

more intensive preparative regimens are required for engraftment in the setting of

unrelated donor or HLA-mismatched related HCT.

78 Reduced-intensity regimens do

not completely eliminate the host’s normal hematologic and malignant cells and

therefore depend on the GVT effect to eradicate remaining cancer. The newly

transplanted donor cells slowly replace host hematopoiesis, and elicit GVT effects.

73

After engraftment, mixed chimerism is generally present. Chimerism can be defined

as the ability to detect both donor-derived and recipient-derived hematopoietic cells;

both donor and patient cells coexist together for a period of time in the patient. If the

graft is rejected, typically only recipient cells are present. After a reduced-intensity

preparative regimen, mixed chimerism (defined as 5%–95% donor T cells present in

the peripheral blood) between the host and recipient develops, allowing for a GVT

effect as the primary form of therapy. Chimerism is evaluated to monitor disease

response and engraftment post-transplant. Chimerism is assessed within T cells and

granulocytes in the peripheral blood and bone marrow using conventional (e.g., using

sex chromosomes for opposite sex donors) and molecular (e.g., variable number of

tandem repeats for same sex donors) methods. The methods used to characterize

chimerism after HCT are reviewed elsewhere.

79–81 A few months after HCT, donor

lymphocytes can be infused (called a “donor lymphocyte infusion”) to augment the

GVT activity.

2 The use of donor lymphocyte infusions is dependent on the

availability of the donor and is highly center specific. The challenge is to maximize

the GVT effect while minimizing the risk of GVHD. Therefore, GVHD prophylaxis,

although different from that used with myeloablative regimens, is still necessary.

Although reduced-intensity preparative regimens have led to lower treatment-related

mortality rates, they may be offset by higher relapse rates.

2,82 The safety and efficacy

of these regimens have led to their wider application to nonmalignant conditions.

2

Because most of the data for reduced-intensity preparative regimens are derived from

older patients or those with comorbid conditions, they cannot be compared with data

for myeloablative preparative regimens.

82

It is unclear if reduced-intensity

preparative regimens improve long-term survival of patients with malignant or

nonmalignant diseases who are younger or without comorbid conditions. Prospective

controlled trials are needed with stratification based on comorbidities, disease

characteristics, pretransplant therapy, and hematopoietic stem cell source.

82

There is a paucity of data regarding the optimal source of hematopoietic stem cells

after reduced-intensity preparative regimens. Most case series have combined data

from PBPC and marrow grafts. But some data suggest that, compared to bone marrow

grafts, PBPC is associated with quicker engraftment, earlier T-cell chimerism, longer

progression-free survival, and a lower risk of graft rejection.

83,84

B.S. is young and healthy enough to receive a myeloablative allogeneic HCT.

Presently, reduced-intensity HCT is only indicated

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as first-line therapy for patients ineligible for myleoablative regimens due to age,

extensive prior treatments, or other contraindications. It is not an option for B.S.

Post-transplantation Immunosuppressive Therapy

CASE 101-2, QUESTION 7: What is the rationale for immunosuppressive therapy after an allogeneic HCT?

What is recommended for B.S.?

After infusion of hematopoietic stem cells, immunosuppressive therapy is

administered to prevent or minimize GVHD. Patients receiving syngeneic transplants

or a T-cell-depleted histocompatible allogeneic transplant generally do not receive

post-transplantation immunosuppressive therapy. In syngeneic transplantation, the

donor and the patient are genetically identical, and GVHD should not be elicited. In

T-cell-depleted transplantation, the volume of donor T cells infused into the patient

is usually insufficient to elicit significant GVHD.

70,85 Numerous immunosuppressive

agents given alone or in combination have been evaluated for the prevention of

GVHD. Commonly used regimens after myeloablative HCT include cyclosporine or

tacrolimus administered with a short course of low-dose methotrexate.

86 Graftversus-host disease (GVHD) prophylaxis varies in reduced-intensity protocols and

can be found in Table 101-5.

87 Corticosteroids may also be used to prevent GVHD,

but they are more commonly used to treat GVHD. In allogeneic HCT recipients

without GVHD, immunosuppressive therapy is slowly tapered and discontinued over

the course of 6 months to 1 year. Over time, the immunologically active tissue

between host and recipient become tolerant of one another and cease recognizing the

other as foreign, negating the need for immunosuppression. In contrast, solid organ

transplant recipients usually continue immunosuppressive therapy for the duration of

the recipient’s life.

In patients without a matched related or unrelated donor who undergo HCT with a

haploidentical donor, the use of cyclophosphamide posthematopoietic stem cell

infusion may be used. The cyclophosphamide is typically given approximately 4 days

after HCT. It has been shown that the cyclophosphamide does not affect the

hematopoietic stem cells but does exert its effect on alloreactive T cells, thereby

reducing the risk of GVHD development.

88 Current trials are ongoing to assess the

usefulness of this approach.

Table 101-5

Common Reduced-Intensity Preparative or Nonmyeloablative Regimens and

Post-grafting Immunosuppresion

102

Preparative Regimens Postgraft Immunosuppression

Fludarabine 30 mg/m

2

/day IV on 3 consecutive days

(−4, −3, −2), TBI 2 Gy as single fraction on day 0

Cyclosporine 6.25 mg/kg PO BID, days –3 to day +100

with taper from day +100 to +180

Fludarabine 25 mg/m

2

/day IV for 5 days and melphalan

90 mg/m

2

/d IV for 2 days

Mycophenolate mofetil 15 mg/kg PO BID or TID, day

+0 to +40 with taper from day +40 to +90

Fludarabine 25–30 mg/m

2

/day IV for 3–5 days,

busulfan ≤9 mg/kg/total dose

Tacrolimus to maintain trough blood concentration of

5–10 ng/mL with methotrexate 5 mg/m

2

/day IV days

+1, +3, +6, +11

BID, 2 times a day; IV, intravenous; PO, orally; TBI, total body irradiation; TID, 3 times a day.

B.S. is receiving a myeloablative preparative regimen with allogeneic transplant

and will receive cyclosporine administered for 6 months, followed by a taper, with a

short course of methotrexate 15 mg/m2 on day +1 and 10 mg/m2 on day +3, +6, and

+11 for post-transplant immunosuppression. This combination regimen will lower

the risk of GVHD. Assuming B.S. does not experience any serious complications, he

will likely be immunosuppressant free by 9 months post-transplant. The cyclosporine

will require therapeutic drug monitoring.

Comparison of Supportive-Care Strategies Between

Autologous and Allogeneic Myeloablative

Hematopoietic Stem Cell Transplantation

CASE 101-2, QUESTION 8: How do supportive-care strategies used for myeloablative preparative regimens

with an autologous graft differ from an allogeneic graft? What supportive care will B.S. likely require?

Supportive-care strategies common to patients receiving a myeloablative

preparative regimen, regardless of whether they have received an autologous or

allogeneic HCT, include use of indwelling central venous catheters; blood product

support; and pharmacologic management of chemotherapy-induced nausea and

vomiting, mucositis, and pain. These similarities are a function of the side effects of a

myeloablative preparative regimen.

Because of the different needs for immunosuppression with an autologous and

allogeneic HCT, the supportive care differs. Allogeneic HCT patients experience an

initial period of pancytopenia followed by a more prolonged period of

immunosuppression, which substantially increases the risk of bacterial infections, but

more importantly, fungal, viral, and other opportunistic infections.

4 The risk of

infection increases as additional immunosuppressive therapy is incorporated to

prevent or treat GVHD. Supportive strategies designed to minimize infection during

immunosuppression are essential after allogeneic HCT (see Infectious Complications

section).

B.S. received a myeloablative allogeneic transplant; therefore, he will have a

central venous catheter inserted at admission. He will most likely require multiple

RBC and platelet transfusions until engraftment occurs. He is at increased risk of

infection because he will be immunosuppressed for months after the transplant. Also,

if he were to develop GVHD, additional supportive care would be required. GVHD

prophylaxis with cyclosporine and methotrexate will place him at risk for additional

drug-related toxicities that will require monitoring. Had he received an autologous

transplant the duration of neutropenia would be less, no immunosuppressive

medications would be required, and the risk of developing complications from

GVHD would have been avoided.

Comparison of Supportive-Care Strategies Between

Allogeneic Myeloablative and Nonmyeloablative

Hematopoietic Cell Transplantation

CASE 101-2, QUESTION 9: How do supportive-care strategies used for myeloablative and

nonmyeloablative preparative regimens with an allogeneic graft differ?

p. 2110

p. 2111

A direct comparison of the toxicities between a myeloablative and

nonmyeloablative preparative regimen is difficult because the latter is offered only to

patients who are not candidates for myeloablative allogeneic HCT. The preparative

regimens differ substantially in terms of the chemotherapy agents used (Tables 101-3

and 101-5) and the degree of myelosuppression. Nonmyeloablative HCT may have a

different time pattern for infectious complications but there is a similar incidence and

severity of acute GVHD. This makes comparisons between the preparative regimens

challenging because of the differences in the pre-HCT health of the recipients.

78

Clinical research is focusing on designing optimal preparative regimens with

acceptable efficacy and toxicity. Thus, as compared to myeloablative HCT, the

preparative regimens and immunosuppression used after hematopoietic stem cell

infusion are more variable for reduced-intensity and nonmyeloablative HCT.

COMPLICATIONS ASSOCIATED WITH

HEMATOPOIETIC CELL TRANSPLANTATION

CASE 101-3

QUESTION 1: K.M. is a 36-year-old woman with CML in accelerated phase. After her initial diagnosis, a

successful search for an unrelated 6/6 HLA-matched allogeneic donor was conducted. K.M. is being admitted

for myeloablative allogeneic PBPCT. Orders for K.M.’s preparative regimen are written as follows: busulfan,

16 mg/kg total dose to be administered over 4 days (1 mg/kg/dose orally [PO] every 6 hours for 16 doses, days

−7, −6, −5, and −4). Cyclophosphamide 60 mg/kg/day IV to be administered on days −3 and −2. Day −1 is a

“rest” day, followed by infusion of PBPC on day 0. What toxicities associated with myeloablative preparative

regimen should be anticipated in K.M.? Are they similar to those anticipated after standard-dose

chemotherapy?

Myelosuppression is a frequent dose-limiting toxicity for chemotherapy when

administered in conventional doses used to treat cancer. However, because

myelosuppression is circumvented with hematopoietic rescue in the case of patients

receiving HCT, the dose-limiting toxicities of these myeloablative preparative

regimens are nonhematologic (i.e., extramedullary) in nature. The toxicities vary with

the preparative regimen used. Most patients undergoing HCT experience toxicities

commonly associated with chemotherapy, such as alopecia, mucositis, chemotherapyinduced nausea and vomiting, infertility, and pulmonary toxicity (see Chapter 94,

Adverse Effects of Chemotherapy and Targeted Agents). However, these drugrelated toxicities are magnified in the HCT population.

Table 101-4 depicts a range of toxicities that can occur after myeloablative

preparative regimen for HCT, and Figure 101-2 depicts the time course for

complications after HCT. Selected toxicities are discussed in the following sections.

Busulfan Seizures

CASE 101-3, QUESTION 2: In addition to her preparative regimen, the following supportive-care agents and

monitoring parameters are prescribed for K.M.: on the day of admission (day −8), administer levetiracetam 500

mg PO twice daily from days −8 to −3. Busulfan pharmacokinetic blood sampling is to occur after dose 1 to a

target busulfan concentration at steady state (CSS) greater than 900 ng/mL. Begin normal saline hydration

3,000 mL/m

2

/day 4 hours before cyclophosphamide and continue for 24 hours after the last cyclophosphamide

dose. Mesna is to be given concurrently with cyclophosphamide as 10% of the cyclophosphamide dose

administered intravenously 30 minutes before starting the cyclophosphamide dose, then as 100% of

cyclophosphamide dose administered as a continuous IV infusion for 24 hours after each dose of

cyclophosphamide. Beginning on day −5, weigh patient twice daily, check fluid input and urinary output every 4

hours, and monitor urine for RBCs daily until 24 hours after the last cyclophosphamide dose. If urine output

drops below 300 mL for 2 hours, administer an IV bolus of 250 mL normal saline and give furosemide 10

mg/m

2

, not to exceed 20 mg IV. What is the rationale for these supportive-care therapies and monitoring

parameters prescribed for K.M. as they relate to busulfan therapy?

Figure 101-2 Complications after hematopoietic stem cell transplantation (HCT) by time for patients undergoing

myeloablative allogeneic HCT only. CMV, cytomegalovirus; EBV, Epstein-Barr virus; GVHD, graft-versus-host

disease; HHV, human herpes virus; HSV, herpes simplex virus; PTLD, post-transplantation lymphoproliferative

disease; VOD, veno-occlusive disease; VZV, varicella-zoster virus.

p. 2111

p. 2112

Seizures occur in approximately 10% of patients receiving high-dose busulfan in

HCT preparative regimens. Busulfan is highly lipophilic and readily crosses the

blood–brain barrier with an average cerebrospinal fluid:plasma ratio of 1 or higher.

Seizures are probably a direct neurotoxic effect

89

; therefore, seizure prophylaxis is

used. Many HCT centers have moved from phenytoin to levetiracetam for seizure

prophylaxis, although benzodiazepines (e.g., lorazepam or clonazepam) also have

been used.

90 Seizure prophylaxis is started at least 12 hours before the first busulfan

dose and is usually discontinued 24 to 48 hours after administering the last busulfan

dose. Seizures can occur despite the use of seizure prophylaxis, but they usually do

not result in permanent neurologic deficits.

Adaptive Dosing of Busulfan

CASE 101-3, QUESTION 3: What dosing strategies can be used to minimize busulfan toxicities?

Intravenous busulfan is commonly used in combination with cyclophosphamide as

a preparative regimen before allogeneic HCT for CML. The FDA-approved dose is

0.8 mg/kg IV every 6 hours for 16 doses, which is similar to the oral busulfan dose of

1 mg/kg, assuming a fraction absorbed of 90%.

91

Intravenous busulfan, at 0.8 mg/kg

of actual body weight, produces an average AUC of 1,200 μM/minute, within a wide

range of 900 to 1,500 μM/minute in 80% of patients.

92 Higher AUC values (>1,500

μM/minute) have been associated with an increased risk of developing venoocclusive disease (VOD) of the liver; therefore, monitoring of busulfan AUC is

warranted. Target AUCs are commonly between 900 and 1,350 μM/minute after the

first dose. This minimizes the risk of VOD and graft failure and minimizes the risk of

disease recurrence.

93

(See Case 101-3, Questions 7–9 for information on VOD.)

To minimize adverse events from IV busulfan, an AUC is obtained with the first

dose of busulfan to analyze K.M.’s exposure. Samples are drawn at the end of the 2-

hour infusion, then 1, 2, and 4 hours after the first sample. Many centers are not

capable of analyzing IV busulfan levels; therefore, prior arrangements must be made

for timely analysis of these samples in order to adjust the dose after the second or

third dose, if needed. K.M.’s AUC comes back 12 hours later at 1,225 μM/minute

and, therefore, her dose is not changed. Had the AUC been greater than 1,350

μM/minute; her dose could have been adjusted using the following formula:

Hemorrhagic Cystitis

CASE 101-3, QUESTION 4: What is the rationale for these supportive-care therapies and monitoring

parameters prescribed for K.M. as they relate to cyclophosphamide therapy?

In HCT patients receiving cyclophosphamide, moderate-to-severe hemorrhagic

cystitis occurs in 4% to 20% of patients receiving hydration alone.

94 Development of

hemorrhagic cystitis is thought to be due to the bladder toxin acrolein, a metabolite of

cyclophosphamide.

95 The chemoprotectant mesna donates free thiol groups which

bind acrolein and reduce its toxicity. The American Society of Clinical Oncology

(ASCO) Guidelines for the Use of Chemotherapy and Radiotherapy Protectants

recommends the use of mesna plus saline diuresis or forced saline diuresis to lower

the incidence of urothelial toxicity with high-dose cyclophosphamide in the setting of

HCT.

96

It is important to note that hematuria or hemorrhagic cystitis can occur despite

the use of any of these methods.

The optimal mesna dose with high-dose cyclophosphamide in preparation for

myeloablative HCT is unknown. A variety of different regimens have been used,

including intermittent bolus dosing (mesna dose 20%–40% of cyclophosphamide

dose, administered for up to five doses) or continuous infusion regimens (mesna dose

80%–160% of cyclophosphamide dose).

94,97,98 Mesna should be continued for 24 to

48 hours after the last cyclophosphamide dose, such that mesna is present within the

bladder at the same time as the urotoxic metabolite acrolein. After IV administration

of mesna, most of it (i.e., 60%–100%) is excreted within the urine over the course of

4 hours.

99 Cyclophosphamide has an average half-life of 7 hours after administration

of 60 mg/kg,

100 and acrolein may be present within the urine for 24 to 48 hours after

cyclophosphamide administration.

101

Thus, K.M. is receiving hydration with normal saline and mesna, administered as a

continuous infusion, to minimize her risk of hemorrhagic cystitis due to

cyclophosphamide. K.M. should be monitored for any RBCs present in the urine,

along with her urinary output, to allow for rapid intervention if hemorrhagic cystitis

occurs.

Chemotherapy-Induced Gastrointestinal Effects

CASE 101-3, QUESTION 5: What other end-organ toxicities must be watched for? Should any medications

be ordered for K.M. to prevent and treat the gastrointestinal (GI) effects associated with myeloablative

therapy?

The high doses of chemotherapy in preparative regimens cause most patients to be

nauseated and anorexic until day +10 to +15. Chemotherapy-induced nausea and

vomiting in HCT recipients can be due to highly emetogenic chemotherapy agents

(see Chapter 22, Nausea and Vomiting), TBI administration, and poor control of

nausea and vomiting prior to HCT. Thus, patients such as K.M. who are undergoing a

myeloablative HCT should be given prophylaxis with a serotonin antagonist plus a

corticosteroid.

102