Preparative Regimens Used in Hematopoietic Cell Transplantation and Chimeric Antigen Receptor T-Cell Therapies

Hematopoietic Cell Transplant Preparative Regimens

Goals of the Preparative Regimen

Hematopoietic cell transplant (HCT) is a therapy that has the potential to cure or prolong the life of patients with hematologic malignancies as well as certain solid tumors and nonmalignant conditions. High-dose chemotherapy (HDC) preparative regimens are a critical part of the HCT process. The preparative regimen is administered before the HCT and is selected based on patient-, disease-, and transplant-specific factors.

Preparative regimens use myeloablative (MA) properties to eradicate the malignancy or provide sufficient tumor reduction and create space in the bone marrow via ablation. The goal is to use agents that provide synergistic cytotoxicity yet avoid overlapping toxicities. HDC before an allogeneic transplant should also provide an adequate degree of immunosuppression and lymphodepletion to prevent graft rejection and graft-versus-host disease (GVHD).

In the infancy of HCT, classic HDC preparative regimens included cyclophosphamide (Cy) and total body irradiation (TBI). Recently, a variety of agents such as busulfan (Bu), melphalan (Mel), and fludarabine (Flu) have been added to the armamentarium of cytotoxic agents used in preparative regimens. Today, alkylating agents still make up the MA backbone of most HDC preparative regimens. In addition to chemotherapy or TBI, preparative regimens can also include monoclonal/polyclonal antibodies and/or targeted therapies.

The preparative regimen selected is dependent on:

Fitness of recipient
- Age
- Performance status
- Comorbidities
Graft source
Type of disease or malignancy and chimerism required to cure/mitigate disease
Stage of disease or malignancy
Graft versus tumor/malignancy (GVT) potential
Pediatric patient—consideration of impact on growth/fertility/development

Preparative Regimen Intensity

The preparative regimen is given to reduce tumor burden and facilitate engraftment. Increasing dose intensity can improve outcomes by securing prompt donor chimerism (allogeneic) and heightened disease control (in the malignant setting); however, increased intensity yields increased nonrelapse mortality (NRM) and therefore has little impact on overall survival.

Historically, dose intensity was the focus of HCT, but the field has evolved as knowledge of GVT has increased. Since the early 2000s, efforts were made to exploit GVT while minimizing regimen-related toxicity. These efforts resulted in lowering of TBI dose and/or alkylating agent doses.

Regimen intensity is divided into three categories including MA, reduced toxicity/intensity (RIC), and nonmyeloablative (NMA). Guidance relative to defined TBI and chemotherapy doses for regimen intensity are in Fig. 10.1 .

Fig. 10.1, Definitions of myeloablative (MA), reduced toxicity/intensity (RIC), and nonmyeloablative (NMA) regimens ATG , Antithymocyte globulin; Ben , bendamustine; Bu , busulfan; Cy , cyclophosphamide; Flu , fludarabine; Gy , gray; IV , intravenous; Mel , melphalan; PO , oral; TBI , total body irradiation; TLI , total lymphocyte irradiation

Myeloablative Regimens

MA regimens typically consist of a combination of TBI and/or alkylating agents. The doses of these agents cause profound cytopenia that is observed within 7 to 21 days. With MA HDC, autologous recovery does not occur, therefore a stem cell graft is required for count recovery. In addition to pancytopenia, they are also associated with alopecia, stomatitis/esophagitis, diarrhea, and sterility.

MA regimens facilitate rapid and complete engraftment of donor cells; however, these regimens are associated with extreme tissue damage, which leads to increased toxicity and transplant-related mortality (TRM) as well as higher rates of GVHD. The risk of TRM increases with patient age and hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score, which often limits its use in elderly patients and in those with multiple comorbidities.

Reduced-Intensity Regimens

RIC regimens are considered an intermediate category and do not fit the definition of MA nor NMA. Compared to MA regimens, RIC regimens have lower TRM and use at least a 30% dose reduction of TBI and alkylating agents. They still result in pancytopenia, alopecia, esophagitis/stomatitis, and sterility; however, the severity and duration of these toxicities may be reduced. The “Champlin Criteria” defines RIC regimens as any regimen that does not require stem cell support for autologous recovery to occur within 28 days, has low nonhematologic toxicity, and produces mixed donor-recipient chimerism in a large proportion of patients by day 30. While autologous recovery is possible without stem cell support, doing so would cause significant morbidity and mortality.

Nonmyeloablative Regimens

NMA regimens result in minimal cytopenias and do not require stem cell support. These regimens are only used in the allogeneic setting since NMA regimens rely heavily on the GVT effect.

These regimens cause very little early toxicity, which affords elderly patients and those with comorbidities access to HCT. Acute GVHD may be delayed and can develop after day +100. Still, GVHD is still a significant factor in NRM after NMA HCT. Additional distinct differences compared to MA regimens include: less inflammatory cytokine release, immune tolerance from mixed chimerism, shorter duration of immunosuppression, and more antigen presenting cells present after the preparative regimen is complete.

The NMA regimen should be sufficiently immunosuppressive to allow full engraftment using peripheral blood stem cell transplant. Therefore purine analogues and/or antithymocyte globulin is often included in these regimens to aid with immunosuppression.

Graft Versus Malignancy/Tumor Effect in Hematopoietic Cell Transplant

When selecting the intensity of the preparative regimen, it is important to assess the malignancy for sensitivity to GVT effect as described in Fig. 10.2 . NMA regimens are not as effective in malignancies less sensitive to GVT.

Fig. 10.2, Graft versus tumor effect/sensitivity in relation to malignancy 9 ALL , Acute lymphoblastic leukemia; AML , acute myeloid leukemia; CLL , chronic lymphocytic leukemia; CML , chronic myeloid leukemia; MCL , mantle cell lymphoma; MM , multiple myeloma

Malignant cells derived from antigen presenting cells, B-lymphocytes, and dendritic cells are often sensitive to GVT effect. A prime example is chronic myeloid leukemia, which possesses all of these features. Lack of costimulatory molecules could contribute to lack of immune response and malignancies with rapid rates of proliferation could be faster than the time to immune response, which is seen with acute lymphoblastic leukemia.

Nonchemotherapy Agents

Characteristics of HDC preparative regimens for HCT include a steep dose-response curve. The ability to use stem cells as rescue allows the HDC regimen to exceed standard doses and maximize myelosuppression. Since TBI has both a steep response curve and myelosuppression, it was one of the first MA agents used in preparative regimens and is commonly used today.

Total Body Irradiation

TBI has been used in HCT since the late 1950s and continues to be used today in MA, RIC, and NMA regimens. TBI can eradicate malignant cells, including those in sanctuary sites (testes, brain, etc.) and is also immunosuppressive enough to prevent graft rejection. More details about TBI will be covered in Chapter 15 .

Radioisotopes and Radioimmunotherapy

Radioisotope use in HCT was first reported in the mid 1990s in patients with multiple myeloma (MM). A beta-emitting radioisotope, holmium-166 1,4,7,10-tetraazycyclodecane-14,7,10-tetramethylenephosphate, was used but it was never studied further in the autologous setting, possibly because of the late toxicities and newer maintenance approaches available post-HCT in MM.

Radioimmunotherapy (RIT) became a therapeutic option for CD20+ B-cell malignancies in the 1990s. RIT agents studied in HCT include ⁹⁰ Y-ibritumomab tiuxetan ( ⁹⁰ Y-IT) and ^I,131 I-tositumomab ( ¹³¹ I-T); however, ¹³¹ I-T is no longer available. Both ⁹⁰ Y-IT and ¹³¹ I-T have been reported in the autologous and allogeneic settings coupled with HDC preparative regimens. Though the regimens were well tolerated, facilitated engraftment, and responses were promising, no randomized trials were performed to assess survival compared to standard HDC preparative regimens.

Chemotherapy Agents

Chemotherapy agents are classified as either cell cycle specific or cell cycle nonspecific. The cell cycle has phases including G0; resting phase, G1; growth phase, S; synthesis phase, G2; second growth phase, or M; mitosis phase. A cell cycle specific agent is only able to exert its cytotoxic effect in a certain phase of the cell cycle whereas cell cycle nonspecific agents can kill cells in any phase of the cell cycle. Alkylating agents are cell cycle nonspecific, whereas purine and pyrimidine analogs are cell cycle specific, see Table 10.1 . (See Table 10.3 for pharmacologic properties and toxicities of agents used in preparative regimens and Table 10.4 for examples of commonly used HDC preparative regimens.)

Table 10.1

Chemotherapy Agents in Hematopoietic Cell Transplant and the Cell Cycle

Cell Cycle Specific	Cell Cycle Nonspecific
S phase Cladribine Clofarabine Cytarabine Etoposide Fludarabine Gemcitabine	Busulfan Bendamustine Carboplatin Carmustine Cyclophosphamide Ifosfamide Melphalan Thiotepa
M Phase Docetaxel
G2 Phase Etoposide

Cell Cycle Specific

Cell Cycle Nonspecific

S phase

Cladribine
Clofarabine
Cytarabine
Etoposide
Fludarabine
Gemcitabine

Busulfan
Bendamustine
Carboplatin
Carmustine
Cyclophosphamide
Ifosfamide
Melphalan
Thiotepa

M Phase

Docetaxel

G2 Phase

Etoposide

Table 10.3

Dosing, Pharmacokinetics, and Toxicity of Chemotherapy Used in Preparative Regimens

Drug	Doses in HCT	Metabolism	Elimination	Select Toxicities*	Clinical Pearls	Interactions and Mechanism
Alkylating Agents
Busulfan	0.8 mg/kg/dose IV Q6h for 2–4 days -or- 3.2 mg/kg IV daily or 100–130 mg/m IV daily for 2–4 days Target AUC of 16.4–24.6 mg*h/L/day for 2–4 days	Hepatic (conjugation with GSH followed by oxidation)	Urine (<2% as unchanged drug)	Hepatic Dermatalogic Neurologic	PK monitoring improves TRM Hyperpigmentation “busulfan tan” Requires seizure prophylaxis	Acetaminophen-GSH depletion 3A4 inhibitors (e.g., azoles) 3A4 inducers (e.g., phenytoin) Metronidazole-3A4 inhibition and GSH depletion
Bendamustine	100–200 mg/m ² IV daily for 2 days -or- 130 mg/m ² IV daily for 3 days	Hepatic to active metabolites	Urine and feces (<3% as unchanged drug)	Hepatic Gastrointestinal Dermatologic	Multiple formulations, which have different storage/stability, concentration, and infusion times	1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, OCPs) 1A2 inducers (e.g., phenytoin, rifampin, ritonavir)
Carmustine	300–400 mg/m ² IV once	Hepatic (CYP 1A2) to active and inactive metabolites	Urine and lungs (as CO ₂ )	Pulmonary Hepatic Gastrointestinal	Diluent contains ethanol Infusion reactions include headache, pain, flushing
Cyclophosphamide	50–60 mg/kg IV daily for 2–4 days -or- 14.5–50 mg/kg IV once -or- 750–1000 mg/m ² IV daily for 3 days	Requires bioactivation Hepatic (CYP) to active and inactive metabolites	Urine (~10% as unchanged drug) and feces	Cardiac Gastrointestinal SIADH Pulmonary Urinary	Concomitant mesna and hydration reduces incidence of hemorrhagic cystitis. Required for ifosfamide. Recommended for some cyclophopshamide containing regimens	CYP 2B6 and to lesser degree 2C19, 3A4, 2C9 inhibition has potential to reduce prodrug activation
Ifosfamide	10–12 grams/m ² divided over 4–5 days		Urine (amount excreted unchanged is dose dependent)	Neurologic Gastrointestinal Cardiac Renal Urinary		CYP 3A4 and to lesser degree 3A5, 2C9, 2B6 inhibition has potential to reduce prodrug activation
Melphalan	Single agent: 140–200 mg/m ² IV once Combination: 100– 140 mg/m ² IV once -or- 70–90 mg/m ² IV daily for 2 days	Spontaneous hydrolysis	Urine (~10% as unchanged drug)	Gastrointestinal Hepatic Secondary Malignancy	Cryotherapy for 2 hours lessens mucositis Short stability- infusion should be complete within 60 min of reconstitution
Propylene-glycol free melphalan	Single agent: 100 mg/m ² IV daily for 2 days	Spontaneous hydrolysis	Urine (~10% as unchanged drug	Gastrointestinal Hepatic Secondary Malignancy	Cryotherapy for 2 hours lessens mucositis
Thiotepa	5–10 mg/kg/dose (max 20 mg/kg total) -or- 250–300 mg/m ² IV daily for 3 days	Hepatic (CYP 3A4 and 2B6) to active metabolite	Urine (2%–10% as thiotepa and TEPA)	Hepatic Gastrointestinal Neurologic Dermatologic	Excreted in sweat, frequent showers required. Avoid lotions and occlusive dressings	3A4 and 2B6 inhibition has potential to reduce prodrug activation Inhibits 2B6 (could inhibit cyclophosphamide activation)
Nucleoside Analogs
Clofarabine	30–40 mg/m ² IV daily for 4 doses (course max of 160 mg/m ² )	Intracellularly to active metabolite	Urine (49%–60% as unchanged drug)	Hepatic Dermatologic Capillary leak syndrome	Renally dose adjusted per package insert
Cytarabine	100–200 mg/m ² /dose IV Q12h for 8 total doses	Intracellularly to active metabolite	Urine (80%–90%) as inactive metabolite	Gastrointestinal Neurotoxicity	Distributes into tear ducts and CSF. Steroid eye drops recommended for high dose
Fludarabine	25–40 mg/m ² IV daily for 3–5 days (course max of 200 mg/m ² )	Dephosphorylated then phosphorylated to active metabolite	Urine (60% as dephosphorylated metabolite)	Neurotoxicity Pulmonary	Renally dose adjusted per package insert
Gemcitabine	800 mg/m ² IV once -or- 1500 mg/m ² IV daily for 4 days -or- 75 mg/m ² IV push followed by 2400– 2700 mg/m ² IV daily for 2 doses 5 days apart (course max of 5500 mg/m ² )	Intracellularly to active metabolite	Urine (~90% as inactive metabolites)	Hepatotoxicity Dermatologic	Deoxycytidine kinase is quickly saturated. Prolonged infusion can maximize metabolism to active drug	Is a radiosensitizer, avoid within 7 days of radiation
Topoisomerase II Inhibitors
Etoposide	100–200 mg/m ² /dose IV Q12h for 8 doses -or- 750 mg/m ² IV daily for 3 days -or- 30–60 mg/kg IV once	Hepatic (CYP 3A4, 3A5)	Urine (~50% as unchanged drug) and feces	Hepatic Hypotension Gastrointestinal	Diluent contains ethanol, polysorbate 80, and polyethylene glycol. Unstable at concentrations > (0.4 mg/mL) May infuse doses ≥ 30 mg/kg as undiluted drug Renally dose adjusted per package insert	1A2 inhibitors (e.g., fluvoxamine, ciprofloxacin, OCPs) 1A2 inducers (e.g., phenytoin, rifampin, ritonavir)
Etoposide phosphate		Water soluble prodrug. Rapidly converted to etoposide	Urine (~50% as unchanged drug) and feces	Hepatic Gastrointestinal	Does not cause hypotension as it does not contain ethanol or polyethylene glycol
Platinum Agents
Carboplatin	300–700 mg/m ² IV daily for 3 days	Minimal	Urine (~70% as unchanged drug)	Renal Gastrointestinal Ototoxicity	Multiple renal dose adjustment formulas	Carboplatin decreases phenytoin and fosphenytoin levels
Taxanes
Docetaxel	275 mg/m ² IV once	Hepatic (CYP 3A4, 3A5) to inactive metabolites	Feces (~70% as metabolites)	Dermatologic Hypersensitivity Fluid retention	Premedicate with steroids and antihistamine	CYP 3A4 inhibitors/inducers have the potential to influence metabolism

AUC , Area under the curve; CSF , cerebrospinal fluid; GSH , glutathione; HCT , hematopoietic cell transplant; IV , intravenous; OCPs , oral contraceptive pill; PK , pharmacokinetic; SIADH , syndrome of inappropriate antidiuretic hormone; TEPA , N,N’,N’’-triethylenephosphoramide; TRM , transplant-related mortality.

Table 10.4

Common HDC Preparative Regimens for Hematologic Malignancies

Myeloablative Regimens
Name	Regimen Details	Transplant Type	Disease
Cy-TBI	Cy 60 mg/kg/day IV for 2 days Fractionated TBI 10–14.25 Gy	Allogeneic	AML, ALL, CML
TBI-Etoposide	Fractionated TBI 10–14.25 Gy Etoposide 60 mg/kg IV for one day	Allogeneic	ALL, AML
BuCy2	Bu 1 mg/kg/dose every 6 hours orally for 4 days Cy 50 mg/kg IV for 2 days	Allogeneic Autologous	Heme
BuCy4	Bu 4 mg/kg/day orally for 4 days Cy 50 mg/kg/day for 2–4 days	Allogeneic Autologous	Heme
Bu-Flu	Bu 100–130 mg/m ² IV daily for 4 days (AUC 16.4–20.5 mgh/L/day)* Flu 40 mg/m ² IV for 4 days	Allogeneic	AML, MDS, CML
BEAM or BEAM + R	BCNU 300 mg/m ² IV for 1 day Etoposide 100–200 mg/m ² /dose IV q12h for 4 days AraC 100–200 mg/m ² /dose IV q12h for 4 days Mel 140 mg/m ² IV for 1 day +/- Rituximab 375 mg/m ² /dose IV weekly × 2–3 doses (pre- and/or post-HCT for CD20+ malignancies)	Autologous Allogeneic	Lymphoid malignancies
Be-EAM	Ben 100–200 mg/m ² IV daily for 2 days Etoposide 200 mg/m ² IV daily for 4 days AraC 200 mg/m ² /dose IV q12h for 4 days Mel 140 mg/m ² IV for 1 day	Autologous	Lymphoid malignancies
CBV	Cy 1500–1800 mg/m ² IV for 4 days BCNU 300–600 mg/m ² IV for 1 day Etoposide 600–2400 mg/m ² IV total dose given over 4 days	Autologous	Lymphoid malignancies
Thiotepa-BCNU	BCNU 400 mg/m ² IV for 1 day Thiotepa 5 mg/kg/dose IV q12h for 2 days	Autologous	CNS lymphoma
Mel	140–200 mg/m ² IV for 1 day -or- 70–100 mg/m ² IV daily for 2 days	Autologous	Myeloma Amyloid Waldenströms
Captisol-enabled; PG-free Mel	100 mg/m ² IV daily for 2 days	Autologous	Myeloma
Bu-Flu-Clo	Flu 10 mg/m ² IV daily for 4 days Clo 30 mg/m ² IV daily for 4 days Bu 130 mg/m ² IV daily for 4 days (AUC 24.6 mgh/L /day)*	Allogeneic	AML MDS
Bu-Clo	Clo 40 mg/m ² IV daily for 4 days Bu 100–130 mg/m ² IV daily for 4 days (AUC 16.4–22.6 mgh/L/day)*	Allogeneic	ALL AML MDS
Gem-BuMel +/- SAHA +/- R	Gem 2475 mg/m ² IV for 2 total doses given 5 days apart Bu 105 mg/m ² IV daily for 4 days (AUC 16.4 mgh/L/day)* Mel 60 mg/m ² IV daily for 2 days +/- SAHA 1000 mg/day orally daily for 7 days +/- rituximab 375 mg/m ² IV once before Gem	Autologous	Refractory HD or lymphoma

Reduced Intensity Regimens
Name	Regimen Details	Transplant Type	Disease
FM100 or FM140	Flu 25 mg/m ² IV daily × 5 days or 30-40 mg/m ² IV daily × 4 days Mel 50–70 mg/m ² IV daily for 2 days or 100–140 mg/m ² for one dose	Allogeneic	AML, MDS, MPD, CML, lymphomas, Myeloma
Flu-Bu2	Flu 30 mg/m ² IV daily for 5–6 days Bu 1 mg/kg/dose every 6 hours orally for 2 days or 130 mg/m ² IV daily × 2 days Anti-T-lymphocyte globulin (fresenius) 10 mg/kg IV daily for 4 days	Allogeneic	AML MDS CML
Flu-Bu	Flu 40 mg/m ² IV daily for 4 days Bu 100 mg/m ² IV daily for 4 days or fractionated Bu given over 6 days (AUC 16.4 mgh/L/day or course AUC 16,000 micromol-min)*	Allogeneic	AML, MDS, MPD
Flu-Cy-Thiotepa	Thiotepa 5 mg/kg IV Q12h for 2 doses Cy 30 mg/kg IV daily for 2 days Flu 30 mg/m ² daily IV for 2 days	Allogeneic	Lymphoid malignancies
Cy-eATG	Cy 50 mg/kg IV daily for 4 days Antithymocyte globulin (equine) 30 mg/kg IV daily for 3 days	Allogeneic	Aplastic anemia (<40yo)

Nonmyeloablative Regimens
Name	Regimen Details	Transplant Type	Disease
Flu-Cy; Flu-Cy-R	Fludarabine 30 mg/m ² IV daily for 3 days Cy 750–1000 mg/m ² IV daily for 3 days +/- Rituximab 375 mg/m ² IV weekly for 4 doses (pre-/ post-HCT)	Allogeneic	CLL Lymphoid
Flu-TBI	Flu 30 mg/m ² IV daily × 3 days TBI 2 Gy once	Allogeneic	Lymphoid Myeloid Myeloma
Flu-Ben-R	Flu 30 mg/m ² IV daily × 3 days Ben 130 mg/m ² IV daily × 3 days Rituximab 375 mg/m ² IV weekly x 4 doses (pre-/post-HCT)	Allogeneic	Lymphoid
TLI + ATG	TLI 8 Gy (cumulative) over 11 days Antithymocyte globulin (rabbit) 1.5 mg/kg IV daily × 5 days	Allogeneic	Lymphoid Myeloid

ALL , Acute lymphoblastic leukemia; AML , acute myeloid leukemia; ara-C , cytarabine; AUC , area under the curve; BCNU , carmustine; Ben , bendamustine; Bu , busulfan; Clo , clofarabine; CML , chronic myeloid leukemia; Cy , cyclophosphamide; eATG equine antithymocyte globulin; Flu , fludarabine; Gem , gemcitabine; HD , Hodgkin disease; HDC , high-dose chemotherapy; MDS , myelodysplastic syndrome; Mel , melphalan; R , rituximab (may be added for CD20+ lymphomas); rATG , rabbit antithymocyte globulin; SAHA , vorinostat; TBI , total body irradiation; TLI , total lymphocyte irradiation.

Alkylating Agents

Alkylating agents (AAs) were the first agents used in HCT and remain the “backbone” of most preparative regimens because they possess a steep dose-response curve and result in significant myelosuppression. These agents work by crosslinking deoxyribonucleic acid (DNA), thereby preventing the division of cells, and can be either monofunctional (crosslink one DNA strand) or bifunctional (crosslink two DNA strands).

Busulfan

Role in HCT

Bu is a bifunctional AA and was only available in an oral dosage form until 1996. When used for allogeneic HCT, it has been combined with Cy (BuCy2 or BuCy4) or with Flu (BuFlu). Despite oral Bu’s success with regard to myelosuppression and engraftment, limitations such as erratic absorption and bioavailability led to an increased risk of sinusoidal obstruction syndrome (SOS) and resulted in a decrease in its use. Bu, when given intravenously (IV), 0.8 mg was equivalent to 1 mg of the oral formulation. In addition, IV Bu had more predictable pharmacokinetics. In 2000 the Bu in BuCy was replaced with the intravenous formulation and rates of SOS decreased.

In 2002, IV Bu was investigated as a once-daily dose rather than divided every 6 hours. Pharmacokinetic (PK) analysis revealed that the PK of Bu IV was linear, consistent throughout doses, and well tolerated and completely cleared within 24 hours.

Clinical Pearls

Newer dosing strategies aimed at further reducing toxicity, especially in older patients, by fractionating the Bu doses have recently been reported. In this setting, the Bu is given in a PK-guided fashion using a total course area under the curve (AUC) spread out over 6 total days of dosing starting 2 to 3 weeks before HCT.

PK monitoring has been shown to improve outcomes compared to weight-based dosing. Harmonization of Bu plasma exposure units (BPEU) was recently published and proposed using AUC reported in mg*h/L. Examples of AUC and concentration at steady state (Css) reported in Table 10.2 .

Table 10.2

Example of Busulfan Exposure Comparison After One Dose for Q6H vs. Q24H Using Different Units

AUC (mg × h/L Q6H) *	4.1	5.1	6.2
AUC (mg × h/L Q24H) *	16.4	20.5	24.6
AUC (μM × min Q6H)	1000	1250	1500
AUC (μM × min Q24H)	4000	5000	6000
Css (ng/mL)	684	855	1026

AUC , Area under the curve; Css , concentration at steady state; μM, micromolar; ng, nanogram.

* preferred units for reporting per BPEU

Bendamustine

Role in HCT

Ben was first reported in HCT with a regimen titled BeEAM , whereby Ben was substituted for carmustine in the BEAM regimen. Multiple analyses have since been conducted, and though the newer BeEAM regimen does not cause the unique pulmonary toxicity that is associated with BEAM, there are other notable toxicities, including a high rate of acute renal failure and higher rates of intensive care unit admissions.

Clinical Pearls

Risks for renal failure included higher doses of Ben (> 160 mg/m ² /day), previous renal injury, and patients over the age of 55 years. To prevent renal toxicity, hyperhydration with at least 3 L/day should be considered. In the allogeneic setting, Ben was given in combination with Flu, rituximab, and antithymocyte globulin-rabbit (for matched unrelated donor HCT) for allogeneic HCT in patients with chronic lymphocytic leukemia/lymphoma.

Carmustine

Role in HCT

Carmustine (BCNU) has long been used in the autologous HCT setting as part of the BEAM regimen. Coupled with thiotepa, it is used in autologous HCT in primary central nervous system lymphoma.

Clinical Pearls

Given its high lipid solubility, BCNU crosses the blood-brain barrier (BBB) and achieves cerebrospinal fluid levels > 50% of plasma.

Cyclophosphamide

Role in HCT

Cy was one of the first AAs used in preparative regimens for HCT, given in combination with TBI or Bu. In addition, it is also gaining popularity as part of the post-HCT GVHD prophylaxis regimen for certain HCTs.

Clinical Pearls

When given at high doses, 2-mercaptoethane (MESNA) and hyperhydration should be administered. MESNA doses vary, but should be at least 60% of the Cy dose, given intermittently or continuously. Patients should be instructed to void every 1 to 2 hours during Cy administration and consider checking for hematuria with each void. Monitor daily intake/output and weights and diareses as needed to maintain euvolemia. Monitor electrolytes, especially serum sodium and potassium. Hydration status should be assessed, particularly in pediatric patients, by ensuring a urine specific gravity of greater than 1.010 before initiating high-dose Cy.

Ifosfamide

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