TRIPASS XR تري باس

 

OVERVIEW

Worldwide, more than 32,000 autologous and 25,000 allogeneic hematopoietic cell

transplantations (HCTs) are performed annually.

1 The rationale behind the use of

HCT is based on the steep dose response of chemotherapy; however, with increasing

doses of chemotherapy, bone marrow suppression becomes a dose-limiting side

effect. The administration of HCT provides recovery of the bone marrow.

Hematopoietic stem cell transplant is a procedure that involves the infusion of

hematopoietic stems cells into patients who have received high doses of

chemotherapy and/or radiation. Variations of this procedure depend on the donor of

these stem cells, self- versus nonself, and the source of the stem cells. Autologous

stem cell transplants are ones in which the patient serves as the donor of

hematopoietic stem cells whereas, in allogeneic transplants, the donor is another

related individual such as a sibling, or an unrelated donor. The source of the

hematopoietic stem cells may be from peripheral blood progenitor cells (PBPCs),

bone marrow (BM), or umbilical cord blood.

The type of HCT performed depends on a number of factors, including type and

status of the disease, patient age, performance status, and organ function and, if

allogeneic transplant is needed, the availability of a compatible donor.

Characteristics of autologous and allogeneic transplantation, with either

myeloablative or nonmyeloablative preparative regimens, are compared in Table

101-1.

2 Many diseases are treated with autologous or allogeneic HCT and are listed

in Table 101-2.

2 Modifications to the basic schema for HCT are necessary based on

the immunologic source (i.e., allogeneic or autologous) and the anatomic source (i.e.,

bone marrow, PBPCs, or umbilical cord blood) of the hematopoietic stem cells

infused.

Hematopoietic cell transplantation (HCT) may be the only treatment available to

many patients; however, it is associated with considerable morbidity and mortality,

with approximately 40% of advanced cancer patients who undergo HCT dying of its

complications.

2 The basic schema for HCT is illustrated in Figure 101-1. A

combination of chemotherapy and/or radiation administered before infusion of the

hematopoietic stem cells is referred to as the preparative or conditioning regimen.

2

The days leading up to the infusion of the hematopoietic stem cells are counted in the

negative (i.e., −3, −2, −1), the day of HCT infusion is termed day 0, and the days

following the transplant are counted in the positive (+1, +2, etc.). Although the

preparative regimen may use the same agents that are used in conventional

chemotherapy regimens, the doses are higher. The purpose of the preparative regimen

is to eradicate the residual malignancy and, in the setting of an allogeneic HCT, to

suppress the recipient’s immune system.

2 Only myeloablative preparative regimens

are used for autologous HCT; however, myeloablative, reduced-intensity or

nonmyeloablative preparative regimens may be used with allogeneic HCT.

Myeloablative preparative regimens involve administration of near-lethal doses of

chemotherapy and/or radiation, which ablate the bone marrow; this may be followed

by a 1- to 2-day rest. After completion of the preparative regimen, the HCT takes

place. Myeloablative preparative regimens have significant regimen-related toxicity

and morbidity and thus are usually limited to healthy, younger (i.e., usually younger

than 60 years) patients.

3 Alternatively, reduced-intensity or nonmyeloablative

transplants are performed with the hope of curing more cancer patients without the

complication of preparative-related toxicity. Nonmyeloablative regimens make use

of the graft-versus-tumor (GVT) effect allowing for donor lymphocyte-induced tumor

eradication (see graft-vs.-tumor section). For most chemotherapy-based preparative

regimens, a rest period is necessary to allow for elimination of toxic metabolites

from the chemotherapy that could damage infused cells. After chemotherapy and/or

radiation, a period of pancytopenia lasts until the infused hematopoietic stem cells

re-establish functional hematopoiesis. Engraftment, when functional hematopoiesis is

established, is commonly defined as the point at which a patient can maintain a

sustained absolute neutrophil count (ANC) of more than 500 cells/μL and a sustained

platelet count of at least 20,000/μL lasting three consecutive days without

transfusions.

4 Graft rejection occurs when the patient cannot maintain functional

hematopoiesis and may occur after autologous or allogeneic HCT.

AUTOLOGOUS HEMATOPOIETIC STEM CELL

TRANSPLANTATION

The defining characteristic of autologous HCT is that the donor and the recipient are

the same individual, making post-transplantation immunosuppression unnecessary.

Autologous hematopoietic stem cells must be obtained (i.e., harvested) before the

myeloablative preparative regimen is administered and subsequently stored for

administration after the preparative regimen. Essentially, these hematopoietic stem

cells are administered as a rescue intervention to re-establish bone marrow function

and avoid long-lasting, life-threatening marrow aplasia that results from the

myeloablative preparative regimen.

5

Incomplete tumor eradication by the highintensity treatment prior to transplant remains the main cause of relapse after

transplant.

6

Table 101-1

Comparison of Types of Hematopoietic Cell Transplants

Risk

a

Myeloablative Nonmyeloablative

Autologous Allogeneic Allogeneic

Relapse after HCT +++ + +

Rejection – + ++

Delayed engraftment ++ + +

GVHD – + ++

Infection + ++ to +++

b ++ to +++

b

Transplant-related morbidity + +++ ++

Transplant-related mortality + ++ +

Cost of procedure ++ +++ ++ to +++

aRisk varies depending on underlying disease, patient characteristics, and previous medical history.

bRisk of infection increases with intensity and duration of immunosuppression and/or chronic GVHD.

GVHD, graft-versus-host disease; HCT, hematopoietic cell transplants.

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Table 101-2

Diseases Commonly Treated with Hematopoietic Cell Transplantation (HCT)

Allogeneic

Nonmalignant

Aplastic anemia

Thalassemia major

Severe combined immunodeficiency disease

Wiskott–Aldrich syndrome

Fanconi anemia

Inborn errors of metabolism

Malignant

AML

Acute lymphoblastic leukemia

Chronic myeloid leukemia

Myelodysplastic syndrome

Myeloproliferative disorders

NHL

Hodgkin disease

Chronic lymphocytic leukemia

Multiple myeloma

Juvenile myelomonocytic leukemia

Autologous

Malignant

NHL

Multiple myeloma

AML

Hodgkin disease

Neuroblastoma

Germ-cell tumors

Other diseases

Autoimmune disorders

Amyloidosis

Timing of HCT relative to diagnosis varies with disease.

AML, acute myelogenous leukemia; NHL, non-Hodgkin lymphoma.

Source: Copelan EA. Hematopoietic stem-cell transplantation. N Engl J Med. 2006;354:1813; Vaughan W et al.

The principles and overview of autologous hematopoietic stem cell transplantation. Cancer Treat Res.

2009;144:23.

Indications for Autologous Hematopoietic Cell

Transplantation

CASE 101-1

QUESTION 1: P.J., a 46-year-old man, has diffuse large B-cell non-Hodgkin lymphoma (NHL) in first

relapse after a complete remission of 1 year. An 80% reduction in measurable disease is noted after two cycles

of dexamethasone, high-dose cytarabine, and cisplatin (DHAP) salvage chemotherapy. P.J.’s bone marrow

biopsy and lumbar puncture are negative for malignant cells. Is a myeloablative preparative regimen with

autologous HCT indicated for P.J.?

Autologous HCT is used to treat a variety of malignancies (Table 101-2). NHL

and multiple myeloma are the most common indications for this procedure and

represent more than two-thirds of all autologous HCT.

2 Nearly all patients who

undergo autologous HCT have failed standard chemotherapy regimens; therefore,

their hematopoietic stem cells have been exposed to prior chemotherapy leading to

less abundant and viable stem cells.

The primary use of autologous HCT is in diseases that have aggressive features but

are still chemotherapy-sensitive.

7

In a randomized, controlled trial,

8 autologous bone

marrow transplant (BMT), compared with conventional chemotherapy with DHAP,

resulted in a 5-year event-free survival of 46% versus 12%, respectively (p =

0.001). Overall 5-year survival was 53% in the BMT group and 32% in the

conventional chemotherapy patients (p = 0.038).

8

Whereas HCT is delayed until relapse after primary treatment in NHL, in some

malignancies, autologous HCT is indicated as primary therapy to improve overall

survival and progression-free survival.

7,9–10

Prospective studies comparing preparative regimens, stem cell mobilization

techniques, and stem cell source (i.e., BMT vs. PBPCT) are not available; however,

autologous PBPCT has become the preferred source of stem cells, most likely owing

to the improved outcomes with PBPCT in other disease settings.

11 PBPCs, defined as

cells that express the CD34 antigen (e.g., CD34

+

), are continuously circulating in the

blood; however, their numbers are too low to easily collect the amount needed in

transplant. Mobilization refers to the techniques used to move the stem cells out of

the bone marrow compartment, increasing their numbers in circulation. Mobilization

can be accomplished using growth factors or chemotherapy (see Mobilization and

Collection of Autologous Peripheral Blood Progenitor Cells section).

P.J. has minimal residual disease that has demonstrated chemotherapy sensitivity

(i.e., he had an 80% response to chemotherapy). His long-term prognosis will be

improved with autologous PBPCT rather than with further conventional

chemotherapy, as described previously. Thus, autologous PBPCT is indicated, owing

to the greater likelihood that higher-dose chemotherapy may eradicate his tumor.

Figure 101-1 Basic schema for hematopoietic stem cell transplantation. Day 0 = bone marrow, peripheral blood

progenitor cell (PBPC), or umbilical cord blood infusion. Postgraft immunosuppression or graft-versus-host disease

(GVHD) prophylaxis for allogeneic grafts only.

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Harvesting Autologous Hematopoietic Stem Cells

CASE 101-1, QUESTION 2: What is the best way to harvest and preserve harvested hematopoietic stem

cells for P.J.?

PBPCs have essentially replaced bone marrow as the source of stem cells at many

HCT centers, accounting for 98% of autologous transplants in adults from 2004 to

2008.

1 PBPCs result in more rapid engraftment than bone marrow and fewer days of

neutropenia.

12 Collection of PBPCs occurs before administering the preparative

regimen; thus, autologous hematopoietic stem cells must be cryopreserved.

2

Hematopoietic stem cells are frozen below −120°C and used within a few weeks;

although, when frozen, they are viable for years.

2 Dimethyl sulfoxide (DMSO) is the

cryopreservative commonly used to protect hematopoietic stem cells from damage

during freezing and thawing. Infusion of hematopoietic stem cells stored in DMSO

can be associated with toxicities due to the DMSO itself. During infusion, DMSO is

associated with skin flushing, nausea, diarrhea, dyspnea, hypotension, arrhythmias

and, rarely, anaphylactic reactions.

13 The presence of undetectable tumor cells in the

transplanted cells contributes to relapse of hematologic cancers; unfortunately,

purging the grafts of tumor cells does not improve survival.

2

Relative to bone marrow harvest, collection of PBPCs requires less invasive

collection methods and contains up to 5 times more hematopoietic stem cells. This

results in a PBPC HCT having more rapid neutrophil and platelet recovery (i.e., a

shorter duration of neutropenia or thrombocytopenia), fewer platelet transfusions,

fewer days of intravenous antibiotics, and a shorter duration of hospitalization

compared to a bone marrow HCT. Thus, the shift to the use of PBPCs instead of bone

marrow for autologous HCT is primarily because of the more rapid engraftment and

less invasive collection methods.

11 Therefore, it would be best for P.J. to undergo

pheresis for PBPC collection. These cells would be bathed in DMSO and frozen at –

120°C.

Mobilization and Collection of Autologous Peripheral

Blood Progenitor Cells

CASE 101-1, QUESTION 3: For PBPC mobilization, P.J. received one dose of cyclophosphamide 4 g/m

2

IV

on day 1, followed by filgrastim 10 mcg/kg/day subcutaneously (SC) beginning on day 2 and continuing through

completion of pheresis. Twelve days after receiving cyclophosphamide, P.J.’s white blood cell count recovered

to 3,000 cells/μL and pheresis was begun. An adequate number of PBPCs is collected after two pheresis

sessions. P.J.’s cells are processed and stored. What was the rationale for administering filgrastim and

cyclophosphamide? What determines the duration of pheresis?

Normally, low numbers of PBPCs are found in the peripheral circulation;

therefore, it is necessary to “mobilize” PBPC from the marrow compartment into the

systemic circulation. Mobilization leads to a collection of sufficient numbers of

autologous PBPCs in most patients, although a minority of patients may still have

poor mobilization.

11 Multiple methods can be used to mobilize PBPCs.

Hematopoietic growth factors alone or in combination with myelosuppressive

chemotherapy are used to mobilize PBPCs.

11 After administration of the mobilizing

agent(s), the patient undergoes pheresis, an outpatient procedure similar to dialysis in

order to collect PBPCs.

12

Granulocyte–macrophage colony-stimulating factor (GM-CSF, sargramostim) and

granulocyte colony-stimulating factor (G-CSF, filgrastim) are both hematopoietic

growth factors and are used as mobilizing agents for PBPC collection.

11,14 Both

reliably mobilize PBPCs, with filgrastim providing a higher PBPC yield.

11 The most

frequently used filgrastim doses for autologous PBPC mobilization are in the range of

10 to 24 mcg/kg/day subcutaneously.

11,14 PBPC yield is higher when pheresis is

started at day 5 (vs. day 6), with the optimal yield being around 10 hours after

filgrastim administration.

11

Myelosuppressive chemotherapy stimulates stem cell and progenitor cell

proliferation. The combination of chemotherapy with filgrastim enhances PBPC

mobilization relative to filgrastim alone. A benefit of using chemotherapy is that it

also treats the underlying malignancy.

11 Examples of PBPC mobilization

chemotherapy regimens include single-agent cyclophosphamide or melphalan. No

mobilization chemotherapy regimen is clearly superior, which has led to

incorporating PBPC mobilization into a cycle of disease-specific chemotherapy, such

as using a single cycle of R-ICE (rituximab, ifosfamide, carboplatin, etoposide)

therapy as the mobilization regimen for a NHL patient whose disease is responsive to

R-ICE treatment.

11 By administering chemotherapy to the patient, the body’s repair

mechanism accelerates the cell division of stem cells and releases them into the

circulation. This is a delicate balance, because the more the chemotherapy that is

given to mobilize the stem cells the greater the potential for damage to the stem cells

and a decreased yield at collection. Stem cell toxic agents, such as carmustine,

should be avoided because they lower the quantity and quality of PBPCs. The

hematopoietic growth factor is initiated 24 to 72 hours after completion of

chemotherapy. Pheresis begins when the peripheral WBC count recovers to greater

than 1 to 3 × 10

3 cells/μL.

11

Certain patients fail to mobilize sufficient PBPC due to extensive prior therapy or

therapy with marrow toxic agents. In these patients, plerixafor, an inhibitor of the

CXCR4 chemokine receptor, can be used. Plerixafor was approved by the US Food

and Drug Administration (FDA) in 2008 for use in stem cell mobilization in

conjunction with filgrastim. It is known that CD34 is an adhesion molecule involved

in promoting adherence of hematopoietic stem cells to the bone marrow

microenvironment. Stromal cell-derived factor-1 (SDF-1) is a chemo-attractant agent

for hematopoietic stem cells; its presence in circulation causes rapid migration of

these stem cells to the peripheral blood.

11

Inhibition of the CXCR4 by plerixafor

blocks the ligand SDF-1 from binding to the CXCR4 receptor, thus releasing CD34

+

cells from the bone marrow. In two randomized studies, 59% of NHL patients and

72% of multiple myeloma patients had sufficient CD34

+ cell collection for

autologous transplant using plerixafor and filgrastim in four or fewer pheresis

sessions, compared to 24% and 34%, respectively, in those using filgrastim alone.

15

Plerixafor is administered to the patient approximately 10 to 18 hours prior to each

pheresis beginning four days after initiation of daily filgrastim 10 mcg/kg. Pheresis is

continued daily until the target number of PBPCs per kilogram of the recipients’

weight is obtained.

11 Typically, 1 to 2 large volume pheresis sessions are needed to

collect adequate numbers of CD34

+ cells.

16 For adult recipients, the number of cells

infused that are CD34

+

is the most reliable indicator of an adequate PBPC collection

and predictor of durable engraftment.

11 A variety of different thresholds have been

identified as the minimal number of CD34

+ cells needed for an autologous PBPCT to

produce rapid and complete (i.e., white blood cells, red blood cell, platelet)

engraftment in adults. The minimum threshold range has varied from 1 to 3 × 10

6

CD34

+ cells/kg of recipient weight, with more rapid platelet and neutrophil

engraftment occurring with greater than or equal to 5 to 8 × 10

6 CD34

+ cells/kg of

recipient weight.

11

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There are a number of factors that can affect the yield of CD34

+ cells, including the

timing and amount of myelosuppressive treatments received prior to mobilization;

both chemotherapy and radiation negatively impact mobilization. The type of

chemotherapy, number of different regimens, and overall duration of chemotherapy

treatment affect the ability to collect stem cells. Additionally, hypocellular marrow

and refractory disease can lead to a poor PBPC harvest.

11 There is a paucity of

information regarding the parameters associated with engraftment in children

undergoing an autologous PBPCT.

17 After pheresis, the cells are cryopreserved,

stored, thawed, and infused into the patient as described in the Harvesting

Autologous Hematopoietic Stem Cells section. Because P.J. has been in remission

for a year after initial treatment for his disease, he received no radiation treatment,

and his salvage therapy did not contain alkylating agents, his cell collection can be

expected to be good and of short duration.

Myeloablative Preparative Regimens

CASE 101-1, QUESTION 4: What are the goals and characteristics of agents used for myeloablative

preparative regimens in patients like P.J.?

The primary goal of P.J.’s high-dose, myeloablative preparative regimen followed

by autologous transplant is to eradicate residual malignancy that is not treatable with

standard chemotherapy. With autologous HCT, there is no need for

immunosuppression because the donor and recipient are genetically identical.

2

Combination chemotherapy with multiple alkylating agents constitutes the most

common high-dose regimens before autologous HCT. Alkylating agents are used

because they exhibit a steep dose–response curve for various malignancies to

overcome resistance to treatment, and are characterized by dose-limiting bone

marrow suppression.

18

Ideally, combinations of antineoplastics should have

nonhematologic toxicities that do not overlap and that are not life-threatening.

Examples of common myeloablative regimens are illustrated in Table 101-3.

19–23 The

early and late toxicities to myeloablative regimens are listed in Table 101-4.

2–4

Table 101-3

Representative Myeloablative Preparative Regimens Used in Hematopoietic

Stem Cell Transplantation

Type of HCT Disease State Regimen Dose/Schedule

Allogeneic

75 Hematologic

malignancies

a

CY/TBI CY 60 mg/kg/day IV on

2 consecutive days

before TBI 1,000–1,575

rads fractionated for 1–

7 days

Autologous

92,93 Acute and chronic

leukemias

BU/CY BU adult 1 mg/kg/dose

PO or 0.8 mg/kg/dose

IV every 6 hours for 16

doses

BU children <12 kg 1.1

mg/kg/dose IV every 6

hours for 16 doses

CY 50 mg/kg/day IV

daily for 4 days or 60

mg/kg/day IV daily for 2

days after BU

Autologous

23 Non-Hodgkin

lymphoma, Hodgkin

disease

BEAM

(carmustine/etoposide/cytarabine/melphalan)

Carmustine 300

mg/m

2

/day IV, 1 dose

etoposide 200

mg/m

2

/day BID IV for

3 days

Cytarabine 200

mg/m

2

/day IV BID for

4 days

Melphalan 140 mg/m

2 1

dose

a

Includes acute myelogenous leukemia (AML), acute lymphocytic leukemia, chronic myelogenous leukemia, nonHodgkin lymphoma, and Hodgkin disease.

BID, twice a day; BU, busulfan; CY, cyclophosphamide; IV, intravenously; PO, orally; TBI, total body irradiation.

Table 101-4

Common Toxicities Associated with Myeloablative Allogeneic Hematopoietic

Stem Cell Transplantation

Early Post-transplant (<100 days) Late Post-transplant (>100 days)

Febrile neutropenia Increased susceptibility to infections

Nausea, vomiting, diarrhea

Mucositis

Veno-occlusive disease (VOD)

Renal dysfunction

Cardiotoxicity

Endocrine disorders (hypothyroidism, hemorrhagic

cystitis, infertility, growth retardation)

Neurocognitive changes

Pneumonitis Secondary malignant neoplasms

Graft rejection Chronic GVHD

Acute GVHD Cataracts

GVHD, graft-versus-host disease.

Complications of Autologous Hematopoietic Cell

Transplantation

CASE 101-1, QUESTION 5: What complications must be anticipated as a consequence of autologous HCT?

How can these be minimized? How can treatment be provided in an outpatient setting?

The most common cause of death after autologous HCT is relapse of the primary

disease. The most common toxicities seen during autologous HCT are the result of

the pancytopenia induced by high-dose chemotherapy. Because autologous HCT is

not complicated by profound immunosuppression or GVHD, supportive-care

strategies differ from allogeneic HCT. Isolation and use of laminar air flow rooms

are unnecessary. The use of autologous PBSCT is associated with shorter periods of

neutropenia and less need for clinical resources; thus, some HCT centers have

developed programs that incorporate outpatient care into

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