5 - High-Dose Chemotherapy and Hematopoietic Stem Cell Transplantation

Editors: Skeel, Roland T.

Title: Handbook of Cancer Chemotherapy, 7th Edition

Copyright 2007 Lippincott Williams & Wilkins

> Table of Contents > Section II - Chemotherapeutic and Biotherapeutic Agents and Their Use > Chapter 5 - High-Dose Chemotherapy and Hematopoietic Stem Cell Transplantation in Hematologic Malignancies

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Chapter 5

High-Dose Chemotherapy and Hematopoietic Stem Cell Transplantation in Hematologic Malignancies

Roberto Rodriguez

Chatchada Karanes

The clinical practice of bone marrow transplantation was not widely used in the United States until the early 1970s although the first successful allogeneic hematopoietic stem cell transplantation (HCT) occurred in 1959. Earlier data demonstrated that allogeneic HCT can cure patients with leukemia and aplastic anemia and there was evidence supporting the concept of graft-versus-leukemia (GVL) effect. Subsequently, high-dose chemotherapy and autologous HCT have produced durable remission in non Hodgkin's lymphoma (NHL), Hodgkin's lymphoma (HL) and multiple myeloma. The availability of hematopoietic growth factors in mid-1980 resulted in increasing numbers of autologous HCT in hematologic malignancies and later in breast, ovarian, and testicular cancer.

During the last 10 years, the number of transplants performed has grown exponentially. According to the Center for International Blood and Marrow Transplant Research (CIBMTR), 485 transplant centers worldwide performed 16,900 transplantations in 2003, of which 6,900 were autologous transplantations. Since 2000, there has been slowdown in the growth of both autologous and allogeneic transplants. The drop in autotransplants was due to a decrease in their use for breast cancer. The successful treatment of chronicmyelogenous leukemia (CML) with imatinib has significantly decreased the numbers of patients receiving allogeneic HCT for this disease. However, the use of allogeneic transplants for other indications continues to increase. In the last 10 years, criteria for the transplantation of hematopoietic stem cells (HSCs) have changed dramatically. These include the concept of tandem autologous transplant in multiple myeloma, reduced-intensity regimens for patients with impaired organ function, or older patients who would not be able to tolerate a full myeloablative conditioning regimen, and the use of donor lymphocytes to eradicate minimal residual diseases. Choices of stem cell sources now include marrow, peripheral blood stem cells (PBSCs), and umbilical cord blood (UCB). Newer immunosuppressive drugs are available for prevention and treatment of graft-versus-host disease (GVHD), resulting in less morbidity and mortality during the post-transplant period. With improved supportive care, the indications for transplantation continue to increase. Selected groups of patients can receive high-dose therapy (HDT) with HCT as outpatients.

Clinical trials during the last 30 years have demonstrated that high-dose chemotherapy with or without the addition of

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radiation therapy can result in improved response and overall survival (OS) rates for patients with various malignant and nonmalignant diseases. High-dose chemotherapy enables the clinician to exploit the steep dose response curves observed with many chemotherapeutic agents. The line representing log kill of malignant cells remains linear or slightly curvilinear for many chemotherapeutic agents, particularly for the alkylating agents. Most of the alkylating agents can be dose-escalated 4- to 10-fold; some alkylators such as thiotepa can be escalated 30-fold when supported with HCT. Most nonalkylating agents cannot be dose-escalated more than twofold; some exceptions include cytarabine, etoposide, mitoxantrone, and paclitaxel. Improved supportive modalities including antibiotics, antiemetics, and hematopoietic cytokines and the availability of a variety of blood products have improved the safety of HDT. However, hematopoietic progenitor cells (HPCs) derived from bone marrow, peripheral blood, or cord blood are required to rescue the patient from myeloablative therapy. Therefore, the clinician can continue to escalate the doses of chemotherapy or radiation therapy beyond marrow toxicity to the next level of toxicity, the nonhematologic dose-limiting toxicity.

Although dose escalation is possible with hematopoietic stem cell rescue, not all malignancies can be cured with this treatment modality. In some diseases, the doses necessary to achieve complete tumor cell kill exceed the nonmarrow lethal doses of chemotherapy or radiation therapy. In other malignancies, dose escalation beyond the marrow lethal dose results in only modest increases in cell kill. Metastatic melanoma, non small cell lung cancer, and colon cancer are examples of malignancies that HDT with hematopoietic stem cell rescue cannot cure.

Even with dose intensification, many patients ultimately experience disease relapse, which probably results from either failure to eradicate residual tumor cells or, in the case of autotransplantation, the reinfusion of hematopoietic stem cells (HSCs) containing contaminating tumor cells. With the use of molecular techniques, the latter has been proved to be the case in some hematologic diseases such as acute myelogenous leukemia (AML) and low-grade lymphoma. It is clear that performing the transplant early in the course of the disease results in better outcome. The role of graft manipulation such as purging or CD34 selection is rarely used for autologous transplantation. Patients with significant marrow involvement should be considered for allogeneic stem cell transplantation.

Allogeneic transplantation provides a source of HSCs that is devoid of contaminating tumor cells. Growing clinical experience supports an immunotherapeutic (graft-versus-tumor) effect of the donor immune system to eradicate minimal residual disease after transplant. This immunoreactivity can be exploited following nonmyeloablative HCT for residual disease or at the time of disease relapse by donor lymphocyte infusions (DLIs), inducing complete remission in many hematologic malignancies. Unfortunately, transplant-related morbidity and mortality remain problematic because of GVHD and prolonged immunosuppression.

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I. Scientific background

A. High-dose therapy (HDT) rationale

The cytocidal effect of chemotherapy in cell culture and animal models follows first-order kinetics. Each treatment kills a set fraction of cancer cells, irrespective of the starting number. The degree of kill in these experimental systems is dose dependent. Tumor cell viability decreases in a logarithmic manner, with a linear increase in drug dose. A modest escalation in the dose may result in a much higher fractional kill of tumor cells. Sublethal chemotherapy selects for and encourages development of resistant cells. The use of several chemotherapeutic agents in combination with different mechanisms of action inhibits the development of resistance. In addition, combinations of agents selected for nonoverlapping extramedullary dose-limiting toxicities should be used in maximal doses. Therefore, the optimal approach uses the highest possible doses of non cross-resistant agents with steep dose response curves as early as possible in the patient's disease course to achieve the highest tumor cell kill and reduce the development of drug resistance. Eradication of tumor (cure) usually requires an 8- to 12-log kill of cancer cells. A complete clinical remission can be obtained with as little as a 4-log cell kill and a partial remission (50% tumor cytoreduction) with as little as a 1- or 2-log kill. Complete remissions are the surrogate short-term markers of potentially successful therapy.

The dosages of many active agents are limited by myelosuppression, even with the use of hematopoietic growth factors. The use of hematopoietic stem cell support allows for increased dosage and combination therapy with agents that would normally produce an unacceptable degree of myelosuppression.

B. Graft-versus-tumor effect

The eradication of leukemia after allogeneic HCT results both from the cytotoxic chemoradiotherapy administered before transplant and the immunologic mechanisms. The first clinical demonstration of graft-versus-leukemia (GVL) activity was observed after allogeneic HCT for advanced leukemia, in which the probability of leukemic relapse was found to be significantly lower in those patients who developed acute and/or chronic graft-versus-host disease (GVHD). Analysis of patients with leukemia treated with either allogeneic unmodified HCT, allogeneic T-cell depleted HCT, or syngeneic HCT showed that the risk of relapse was lowest for patients who received allogeneic unmodified HCT and developed acute and/or chronic GVHD. However, GVHD is not a prerequisite for GVL activity. With current approaches to allogeneic HCT, however, it has not been possible to separate the beneficial GVL (or graft-versus-cancer) effect from deleterious GVHD. The association of GVL activity with GVHD has implicated donor T cells reacting with minor histocompatibility antigens expressed by recipient cells as major contributors to the GVL effect. Other effector mechanisms such as natural killer cells may also contribute to GVL activity either directly or as a consequence of inflammation induced by allogeneic T cells.

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Three important clinical applications in stem cell transplantation have evolved from GVL effect. The first application is the use of donor lympholyte infusion (DLI) to treat patients with post-transplant leukemic relapse. Patients with CML showed best responses to DLI followed by low-grade lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia (CLL). AML, intermediate-grade lymphoma, multiple myeloma, HL, renal cell carcinoma, and breast cancer show intermediate sensitivity. Acute lymphoblastic leukemia (ALL) and high-grade lymphoma are insensitive to GVL effect. The second application is the use of nonmyeloablative or reduced-intensity allogeneic conditioning regimens in older and less fit patients. With this approach, low doses of irradiation and chemotherapy, which alone are not sufficient to eradicate tumors, are administered to facilitate graft acceptance, and tumor regression is induced by donor immune cells. The third application is the tandem stem cell transplant using nonmyeloablative allogeneic HCT after reduction of tumor burden by autologous transplants. Several clinical trials using autologous HCT followed by allogeneic HCT in multiple myeloma, low-grade NHL, and HL are in progress.

II. Indications for HDT with hematopoietic stem cell transplantation

A. Disease

During the last 15 years, the indications for HDT and HCT have changed markedly. The most common indications for allogeneic and autologous transplants differ (Fig. 5.1). For acute and chronic leukemias, myelodysplastic syndromes (MDSs), and nonmalignant diseases (aplastic anemia, immune deficiencies, inherited metabolic disorders), allogeneic transplantation is the predominant approach. Autotransplants are most commonly used for multiple myeloma, non-Hodgkin's lymphoma (NHL), and Hodgkin's lymphoma (HL) and less commonly for AML, neuroblastoma, and breast cancer. Fifteen years ago, autologous transplants were performed almost exclusively for NHL and HL. In 2003, multiple myeloma was the most common indication for autologous transplants, followed by NHL, HL, and AML. The use of autotransplants performed in solid tumors are decreasing due to low efficacy in these diseases and the availability of potentially less toxic and more effective therapy using newer classes of antineoplastic agents. Although most allogeneic transplantations continue to be performed for acute and chronic leukemias, there has been a recent increase in allogeneic transplantations for immunodeficiency disorders, inherited disorders of metabolism, thalassemia, and sickle cell diseases. New data using autologous and allogeneic HCT in autoimmune diseases are encouraging.

B. Stem cell sources

Bone marrow was used as the only source of stem cells until the mid-1980s. The introduction of hematopoietic growth factors has made it possible to mobilize the stem cells from the bone marrow into the peripheral blood, resulting in the ability to collect large numbers of stem cells through apheresis and accelerate the engraftment. Currently, PBSCs are the major stem cell source of all autologous transplants. Traditionally, allogeneic transplants use bone marrow grafts. From 1997 to 2004, there was a steady increase in

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the use of peripheral blood stem cell (PBSC) grafts, which accounted for 70% of grafts used in adults. Among pediatric recipients 20 years old or younger, marrow is still used in 61%, PBSC in 30%, and cord blood in 9%. For recipients of unrelated stem cell sources, cord blood is now used in 34% of recipients 20 years old or younger whereas cord blood is only used in 4% of adult recipients. In addition to differences in their stem cell content, transplants from the three sources differ in the composition and state of activation of immune cells. As a consequence, bone marrow, UCB, and PBSC transplants have different kinetics of hematologic recovery, the most rapid engraftment being observed with PBSCs and the slowest with UCB. Stem cell source also confers different risks for developing GVHD. PBSC transplants show similar incidence of acute GVHD and a possible increase in chronic GVHD compared with bone marrow. UCB transplants have a favorably low risk of GVHD even in one or two antigen-mismatched transplants. Stem cell dose is an independent factor in transplants from any source, determining engraftment rate, transplant-related mortality (TRM), and risk of leukemic relapse. Higher marrow and PBSC cell dose correlated with improved transplant outcome, although PBSC dose of 8 million CD34 cell dose/kg of recipient body weight resulted in increased GVHD. An understanding of the impact of stem cell source and dose is essential to obtain optimum conditions for a successful outcome after transplant.

Figure 5.1. Indications for blood and marrow transplantation in North America, 2003. NHL, non Hodgkin's lymphoma; AML, acute myelogenous leukemia; ALL, acute lymphoblastic leukemia; MDS, myelodysplastic syndrome; CML, chronic myelogenous leukemia; CLL, chronic lymphocytic leukemia. (Permission from Center for International Blood and Marrow Transplant Research.)

III. Patient eligibility

A. Host factors

Autologous transplants can be conducted safely in patients up to 75 years of age if they have adequate performance status, physiologic organ function, and HSCs.

There had been a trend of increasing transplant recipient age since 1996. According to CIBMTR data, 60% of autologous transplant recipients between 2001 and 2004 are older than 50 years and 10% of them are older than 60 years. Nineteen percent of patients undergoing allogeneic transplantation are older than 50 years. The risk of death after allogeneic HCT depends on the underlying disease, stage of disease at the time of transplantation, type of conditioning regimen, and donor type. The Seattle transplant team reported that the risk for overall grade 4 toxicity and nonrelapse mortality among nonmyeloablative and ablative allogeneic HCT increased in direct relation to increasing pretransplantation comorbidities as assessed by Charlson comorbidity score. In their series, the 1-year nonrelapse mortality was 20% in nonablative patients compared with 32% in ablative patients. Although nonmyeloablative patients had a higher pretransplantation comorbidity score, were older, and had more often failed preceding ablative transplantation, they experienced fewer grade 3 to 4 toxicities than ablative patients. For allogeneic transplantation, the usual upper age limit is 60 years, although some centers perform human leukocyte antigen (HLA) identical sibling transplants in selected patients up to 60 to 65 years old. For unrelated or mismatched related donors, the usual age limit is 60 years depending on the recipient performance status and comorbid illness. For both autologous and allogeneic transplants, patients must meet a minimum physiologic organ

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function. Common criteria include pulmonary function test results (forced vital capacity, forced expiratory volume, and corrected diffusing capacity) more than 50% of predicted, cardiac function results with a left ventricular ejection fraction more than 40% to 45%, no active infections, liver function test results less than two to four times normal, performance status more than 60% on the Karnofsky scale of less than 2 on the Eastern Cooperative Oncology Group scale, and serum creatinine level of less than 2 mg/dL. In certain diseases, patients with impaired renal function could also be considered for autotransplantation (e.g., multiple myeloma patients treated with high-dose melphalan).

B. Disease factors

In general, patients with malignant disease should show at least a partial response (PR) to standard-dose chemotherapy before being considered for HDT with hematopoietic stem cell transfusion (HSCT). Practicing hematologists and oncologists should refer high-risk patients early for transplant evaluation. This allows adequate time to identify matched related or unrelated donors for allogeneic stem cell transplant candidates or in case of autologous transplantation, it enables patients to avoid exposure to stem cell toxic treatment before autologous stem cell collections. A recommended timing for HCT referral to transplant centers is shown in Table 5.1.

IV. Chemotherapeutic agents for dose-intensive strategies

Agents are chosen for dose intensification based on the steepness and linearity of their dose response curve, the absence of nonhematologic toxicity that prevents dose escalation (preferably allowing a 5- to 10-fold dose escalation over conventional doses), and, when combined with other agents, a synergistic antitumor effect with a minimum of overlapping nonhematologic toxicity. The doses of alkylating agents are often reduced by 20% to 40% when combined as compared with use as a single agent in high-dose conditioning regimens. Therefore, the choice of chemotherapeutic agents is arbitrary, based largely on anecdotal data and a matter of personal experience and preference. Extramedullary toxicities of the most commonly used conditioning agents are listed in Table 5.2. In most cases, drug doses are limited by gastrointestinal toxicity (mucositis, diarrhea) or major organ toxicity (e.g., heart, lung, kidney, or central nervous system [CNS]). When combining drugs in a conditioning regimen, particular attention must be given to overlapping toxicities. Pre-existing renal or hepatic insufficiency or both may seriously reduce drug clearance. This can result in higher drug levels and further end-organ toxicity.

A. Alkylating agents

  • BCNU (carmustine) is a nitrosourea with clinical activity against a number of tumors. It is formulated in 10% alcohol solution, which may account for the hypotension seen during or shortly after administration. BCNU, which undergoes spontaneous hydrolysis, should be protected from light and is usually administered as a 2-hour infusion. At high dose, pulmonary and hepatic toxicity are dose limiting. Nonhematologic toxicities are delayed and cumulative. BCNU doses exceeding 300 mg/m2 are associated with acute or late pneumonitis in at least 20% of patients.

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    Patients should be informed to monitor exercise tolerance; if tolerance diminishes, further evaluation should be performed (chest radiograph, arterial blood gas, pulmonary diffusion capacity). If drug-induced pneumonitis is confirmed, prednisone should be started with a taper over 2 to 3 months. BCNU is also occasionally associated with an increased incidence of veno-occlusive disease.

    Table 5.1. Recommended timing for transplant consultation

    AML
    • High-risk AML including
      Antecedent hematologic disease (e.g., myelodysplasia)
      Treatment-related leukemia
      Induction failure
    • CR1 with poor-risk cytogenetics
    • CR2 and beyond
    ALL
    • High-risk ALL including
      Poor-risk cytogenetics (e.g., Philadelphia chromosome positive, 11q23)
      High WBC (>30,000 50,000) at diagnosis
      CNS or testicular leukemia
      No CR within 4 weeks of initial treatment
      Induction failure
      CR2 and beyond
    Myelodysplastic syndromes
    • Intermediate-1, intermediate-2 or high IPSS score which includes
      >5% marrow blasts
      Other than good risk cytogenetics (good risk includes 5q- or normal)
      >1 lineage cytopenia
    Chronic myelogenous leukemia
    • No hematologic or minor cytogenetic response 3 months post imatinib initiation
      No complete cytogenetic response 6 to 12 months post imatinib initiation
      Disease progression
      Accelerated phase
      Blast crisis (myeloid or lymphoid)
    Non Hodgkin's lymphoma
    • Follicular lymphoma
      Poor response to initial treatment
      Initial remission duration <12 months
      Second relapse
      Transformation to diffuse large B-cell lymphoma
      Diffuse large B-cell lymphoma
      At first or subsequent relapse
      CR1 for patients with high or high-intermediate IPI risk
      No CR with initial treatment
      Mantle cell lymphoma
      Following initial therapy
    Hodgkin's lymphoma
    • No initial CR
    • First or subsequent relapse
    Multiple myeloma
    • After initiation of therapy
    • At first progression

  • Busulfan (Myleran [PO], Busulfex [IV]) has a more marked effect on myeloid cells than on lymphoid cells and can cause prolonged aplasia. The major nonhematologic toxicities are veno-occlusive disease of the liver, pneumonitis, and mucositis. Busulfan rapidly enters the CNS and may cause seizures. Patients should receive prophylactic phenytoin (with doses sufficient to achieve therapeutic levels) before initiation of high-dose busulfan, and the phenytoin should be continued for 24 hours after the final dose. Busulfan is available in oral and, recently, in IV formulation. The IV formulation is dissolved in polyethylene glycol and N,N-dimethylacetamide to a final concentration of 6 mg/mL. The usual adult dose of Busulfex is 0.8 mg/kg of ideal body weight or adjusted body weight, whichever is lower, administered as a 2-hour infusion through a central venous catheter every 6 hours for 4 days. Ninety-three percent of patients achieve an area under the curve (AUC) below the target of 1,500 mol/L/minute with no dosage adjustments. If vomiting occurs within 30 minutes of an oral administration or if pill fragments are present in the emesis, most institutions repeat the dose. Busulfan is well absorbed after oral administration, exhibits low protein binding, and is metabolized through conjugation with glutathione to form a thiophenium ion. At a given dose, there is considerable variability in the systemic exposure of oral busulfan, typically expressed as AUC or average concentration at steady state. Relative to that in adolescents and adults, patients younger than 4 years have an increased apparent oral clearance of busulfan and a higher conjugation rate of busulfan with glutathione in the enterocyte. An increased risk of serious hepatic veno-occlusive disease has been reported when the AUC level exceeds 1,500 mol/L/minute. Busulfan administration through the IV route ensures complete bioavailability and reliable systemic drug exposure with more predictable blood levels and less veno-occlusive disease.

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    Table 5.2. Toxicity of common chemotherapeutic agents

    Drug (Dose) Extramedullary Dose-Limiting Toxicity Other Toxicities
    BCNU (carmustine) (300 600 mg/m2) Interstitial pneumonitis Renal insufficiency, encephalopathy, N/V, VOD
    Busulfan (12 16 mg/kg) Mucositis, VOD Seizures, rash, N/V, hyperpigmentation, pneumonitis
    Cyclophosphamide (120 200 mg/kg) Cardiomyopathy Hemorrhagic cystitis, SIADH, N/V, interstitial pneumonitis
    Cytarabine (ara-C) (4 36 g/m2) CNS ataxia, mucositis Pulmonary edema, conjunctivitis rash, fever, hepatitis
    Cisplatin (150 180 mg/m2) Renal insufficiency, peripheral neuropathy Renal tubular acidosis, hypomagnesemia, hypokalemia, ototoxicity
    Carboplatin (600 1,500 mg/m2) Ototoxicity, renal insufficiency Hepatitis, hypomagnesemia, hypokalemia, peripheral neuropathy
    Etoposide (600 2,400 mg/m2) Mucositis N/V, hepatitis, fever, pneumonia
    Ifosfamide (12 16 g/m2) Encephalopathy, renal insufficiency Hemorrhagic cystitis
    Melphalan (140 200 mg/m2) Mucositis N/V, hepatitis, SIADH, pneumonitis
    Mitoxantrone (30 75 mg/m2) Cardiomyopathy Mucositis
    Paclitaxel (Taxol) (500 775 mg/m2) CNS, ataxia, peripheral neuropathy Anaphylaxis, mucositis
    Thiotepa (500 800 mg/m2) Mucositis Intertriginous rash, N/V, hyperpigmentation
    Fludarabine (90 180 mg/m2) CNS visual disturbances, peripheral neuropathy N/V, tumor lysis syndromes, immunosuppression
    N/V, nausea/vomiting; VOD, veno-occlusive disease; SIADH, syndrome of inappropriate antidiuretic hormone; CNS, central nervous system.

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  • Cyclophosphamide (Cytoxan) is probably the most widely used chemotherapeutic agent for dose intensification. Cyclophosphamide requires activation in the liver, but there is no evidence that the P-450 system necessary for that activation is saturated at the doses used in intensification. Clearance of cyclophosphamide increases quickly after the first dose, and there is considerable interpatient variability in plasma concentrations with repeated dosing. Total doses as high as 5,000 to 7,000 mg/m2 divided over 1 to 4 days can be safely administered as 1- to 2-hour infusions each day. Aggressive hydration (hyperhydration) and diuresis or administration of mesna as an uroprotectant is necessary to prevent hemorrhagic cystitis (also used for ifosfamide). The dose-limiting toxicities are cardiac and pulmonary. The cardiac effect, some degree of which occurs in up to 25% of patients, is a potentially fatal hemorrhagic myocarditis that may occur acutely or within days or may manifest as heart failure or pericardial effusions as long as 3 to 4 weeks after completion of treatment. The risk of cardiac toxicity is not cumulative, and repeated doses are tolerated in the patients who recover. This toxicity occurs most often in patients who receive more than 200 mg/kg (>7,500 mg/m2), are older than 50 years, and have a previous history of congestive heart failure. The pulmonary toxicity of cyclophosphamide consists of proliferation of atypical type II pneumocytes with fibrosis. It usually manifests clinically within 4 to 6 weeks of therapy as progressive dyspnea, nonproductive cough, hypoxia, and interstitial radiographic changes. Even at high doses, cyclophosphamide is not myeloablative, and its antitumor effect as a single agent is limited. In autologous transplant, cyclophosphamide, alone or in combination with hematopoietic growth factors, is often used for PBSC mobilization. In allogeneic transplantation, cyclophosphamide is included predominantly as an immunosuppressive agent owing to its lymphocytotoxic effects.

  • Ifosfamide, a closely related analog of cyclophosphamide, is also a prodrug that must undergo hepatic metabolism. As with cyclophosphamide, hyperhydration, and protection with mesna are required to prevent hemorrhagic cystitis. Unlike cyclophosphamide, the dose-limiting toxicity of ifosfamide is toxic encephalopathy manifested as lethargy, confusion, seizures, or stupor. Renal toxicity may also manifest as metabolic acidosis due to accumulation of metabolic by-products resulting in proximal renal tubular acidosis. No definite antitumor advantage of ifosfamide over cyclophosphamide has yet been established.

  • Melphalan alkylates target tissues after spontaneous formation of a (nitrogen) mustard-type reactive intermediate in vivo. It is administered rapidly in two daily doses of 70 to 100 mg/m2 or one dose of 140 to 200 mg/m2. Because less than 15% of the intact drug is excreted renally, melphalan can be administered safely in patients with renal insufficiency. The dose-limiting toxicities are gastrointestinal toxicity (mucositis, diarrhea) and, less commonly, hepatitis and pneumonitis.

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  • Platinum compounds (cisplatin, carboplatin) covalently bind to deoxyribonucleic acid (DNA) bases and disrupt DNA function. Cisplatin can be escalated only two- to threefold owing to renal and neurologic toxicity. Cisplatin must be reconstituted in a chloride-containing solution to minimize spontaneous hydrolysis. Aggressive hydration and diuresis with normal saline loading and maintenance of good urine output are required to avoid renal tubular toxicity. Magnesium wasting commonly leads to hypocalcemia and hypokalemia. Peripheral neuropathy and high-frequency hearing loss are potential long-term side effects. Carboplatin has less renal and neurologic toxicities; myelosuppression and hepatic and gastrointestinal (mucositis and diarrhea) toxicities are more common with carboplatin. Some clinicians use the AUC (Calvert formula) of 20 to 28 for target drug dosing of carboplatin in high-dose preparative regimens.

  • Thiotepa has one of the steepest dose response curves of all the alkylating agents and is not cross-resistant with cyclophosphamide. It has therefore been included in many different dose-intensity regimens. Thiotepa penetrates the blood brain barrier better than most alkylating agents. Mucositis is the dose-limiting toxicity, with CNS toxicity being observed only at very high doses. It may increase the risk of hepatic veno-occlusive disease when used with other agents known to have that toxicity.

B. Nonalkylating and less commonly used agents

  • Cytarabine is an analog of deoxycytidine and has multiple effects on DNA synthesis. It is used in high doses for the treatment of leukemia and in some regimens for NHL. At high doses, cytarabine causes neurologic toxicity, manifested by cerebral and cerebellar dysfunction. Renal dysfunction increases the risk of neurotoxicity substantially. This toxicity may present as dysarthria, gait disturbances, dementia, and coma. These toxicities are usually reversible but may be fatal. If neurologic symptoms develop, the cytarabine should be stopped immediately. Another rare but life-threatening complication is noncardiogenic pulmonary edema. Pulmonary symptoms, when they develop, are often fatal. Cytarabine conjunctivitis is responsive to topical steroids, which should be used prophylactically.

  • Etoposide is a topoisomerase II inhibitor that shows synergism with platinum compounds. It has high single-agent activity in the treatment of leukemia, lymphomas, and testicular cancer. Its primary nonhematologic toxicities are mucositis, liver toxicity, and hypotension from the lipid formulation if administered rapidly.

  • Paclitaxel is a taxane that stabilizes microtubules, leading to mitotic arrest. It has activity against breast and ovarian cancers. One phase I study reported a maximum tolerated dose of 725 mg/m2. At higher doses, unacceptable CNS, renal, mucosal, and pulmonary toxicities were observed. Peripheral neuropathy was tolerable and not associated with motor weakness. Because paclitaxel is eliminated through hepatic metabolism, hepatic insufficiency can prolong elimination and increase toxicity.

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  • Fludarabine is a nucleotide analog of adenine arabinoside and inhibits DNA synthesis by inhibiting DNA polymerase , ribonucleotide reductase, and DNA primase. The drug is converted rapidly to the active metabolite 2-fluoro-ara-A when given IV. The half-life is approximately 10 hours. The drug is eliminated through the kidneys; 23% of the active drug is excreted unchanged in the urine. Therefore, it should be administered cautiously in patients with renal insufficiency. It produces lymphocytopenia and substantial immunosuppression and is approved for the treatment of B-cell chronic lympholyte leukemia (CLL). Owing to its immunosuppression, it is used in combination with alkylating agents or low-dose total-body irradiation (TBI) to enhance engraftment of allogeneic hematopoietic progenitors. At this time, it is available only in IV formulation; the oral form is in clinical trials. The dose recommended for CLL is 25 mg/m2/day IV over 30 minutes for 5 days; however, the dosage used for conditioning in nonmyeloablative HSCT varies from 25 to 50 mg/m2 over 30 minutes once a day for 3 to 5 days. Once reconstituted, the drug should be used in 8 hours owing to a lack of antimicrobial preservative. The dose-dependent toxicities include myelosuppression and immunosuppression. Visual disturbances and CNS symptoms have been reported at very high doses.

V. Total-body irradiation (TBI)

TBI is an integral component of several conditioning regimens, particularly for hematologic malignancies requiring allogeneic or autologous transplantation. It has been used since the earliest days of bone marrow transplantation for both immunosuppression (prevention of allograft rejection) and antitumor effect. However, the therapeutic ratio of TBI is small. The usual dosage of TBI is 10 to 14 Gy given in twice- or thrice-daily doses over 3 to 4 days (e.g., 2 Gy b.i.d. for 3 days). Fractionation (and hyperfractionation) substantially reduces the risk of both interstitial pneumonitis and veno-occlusive disease of the liver. Above that dose, pulmonary, hepatic, and gastrointestinal toxicities become limiting and life threatening with little therapeutic gain. Acute and chronic toxicities with TBI are summarized in Table 5.3.

VI. Preparative regimens

The regimens used for dose intensification are largely empiric, and few have been compared in randomized trials. Important issues such as optimum combination or doses, the benefit of an induction regimen immediately preceding intensification, and the benefit of repeated cycles of dose intensity have shown benefit only in multiple myeloma and possibly HL. TBI-based regimens result in more regimen-related toxicity and are used for NHL, ALL, HL, AML, and multiple myeloma. Examples of commonly employed preparative regimens are shown in Tables 5.4 and 5.5.

A. Allogeneic transplant myeloablative regimen

Standard myeloablative preparative regimens must provide effective antitumor activity and suppress host immunity to prevent graft rejection. Commonly used cytotoxic agents include TBI, cyclophosphamide, busulfan, cytarabine, and etoposide. Immunosuppression is necessary for allogeneic HCT to prevent graft-versus-host diseases (GVHD) and graft rejection.

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The combined toxicity of preparative regimen and GVHD prophylaxis in these patients increases early morbidity and mortality in the first month of transplant compared with those receiving autologous HCT. The treatment-related mortality of 10% to 30% depends on diagnosis, disease stage, patient age, and donor type. In this model, it has been thought that myeloablation was necessary to create a marrow space, although immunosuppression prevented rejection and GVHD.

Table 5.3. Total-body irradiation associated acute and chronic toxicities

System Acute Symptoms and Signs Acute Onset Chronic Symptoms and Signs Onset and incidence
Gastrointestinal Nausea and vomiting, diarrhea 24 48 h
Hepatic Veno-occlusive disease 6 21 days
Mucosal tissues Parotitis, decreased lacrimation, sore throat, mucositis 24 48 h Sicca syndrome, cataracts 20% with fractionation at 0.5 to 3 4 years
Endocrine Acute pancreatitis, steroid-induced hyperglycemia 7 21 days Gonadal failure
Hypothyroidism
Delayed bone growth
>90%
40% 50%
Pulmonary, renal Pneumonitis 1 3 months Pulmonary fibrosis
Bone marrow transplantation nephropathy
Uncommon
Skin, second malignancies Erythema, alopecia 5 10 days Secondary leukemia
Solid tumors
5% 10%
2% at 10 years, 7% at 15 years

Table 5.4. Common preparative regimens for high-dose therapy with total-body irradiation

Drug Total Dose Daily Dose Schedule (Day)a Indications Autologous or Allogeneic
Single cytotoxic drug regimens
Cyclophosphamide 120 mg/kg 60 mg/kg -5, -4 Leukemia, NHL Both
 TBI 1,200 cGy 200 cGy b.i.d. -3, -2, -1 aplastic anemia
Etoposide 60 mg/kg 60 mg/kg -3 Leukemia, NHL Allogeneic
 TBI 1,320 cGy 120 cGy t.i.d. -7, -6, -5, -4
Cytarabine (ara-C) 36 g/m2 3 g/m2b.i.d. -9, -8, -7, -6, -5, -4 Leukemia, NHL Allogeneic
 TBI 1,200 cGy 200 cGy b.i.d. -3, -2, -1
Melphalan 140 mg/m2 140 mg/m2 -4, Leukemia, multiple Both
 TBI 1,200 cGy 200 cGy b.i.d. -3, -2, -1 myeloma
Combination cytotoxic drug regimens  
Cytarabine (ara-C) 18 g/m2 3 g/m2b.i.d. -8, -7, -6 Leukemia, NHL Allogeneic
 Cyclophosphamide 90 mg/kg 45 mg/kg -5, -4
 TBI 1,200 cGy 200 cGy b.i.d. -3, -2, -1
Etoposide 60 mg/kg 60 mg/kg -4, Leukemia, NHL Both
 Cyclophosphamide 120 mg/kg 60 mg/kg -3, -2
 TBI 1,320 cGy 120 cGy t.i.d. -8, -7, -6, 5b
Thiotepa 10 mg/kg 5 mg/kg -5, -4 Leukemia, NHL Allogeneic
 Cyclophosphamide 120 mg/kg 60 mg/kg -3, -2
 ATG 120 mg/kg 30 mg/kg -5, -4, -3, -2
 TBI 1,375 cGy 125 cGy t.i.d. -9, -8, -7, -6b
Fludarabine 90 mg/m2 30 mg/m2 -4, -3, -2 Leukemia, NHL Allogeneic
 TBI 200 cGy 200 cGy once -1
TBI, total-body irradiation; NHL, non Hodgkin's lymphoma; ATG, antithymocyte globulin.
aDay 0 is day of transplantation, day -5 is 5 days before transplantation, etc.
bTBI given twice on this day.

Table 5.5. Common preparative regimens for high-dose therapy without total-body irradiation

Drug Total Dose Daily Dose Schedule (Day) Indications Autologous or Allogeneic
Big BU/CY
  Busulfan 16mg/kg 1 mg/kg q.i.d. -9, -8, -7, -6 Leukemia, NHL Allogeneic
  Cyclophosphamide 200 mg/kg 50mg/kg -5, -4, -3, -2
Little BU/CY
  Busulfan 16 mg/kg 1 mg/kg q.i.d. -7, -6, -5, -4 Leukemia, NHL, Both
  Cyclophosphamide 120 mg/kg 60mg/kg -3, -2 myeloma, breast cancer
CPB STAMP I
  Cisplatin 165 mg/m2 55 mg/m2 -6, -5, -4 Breast cancer Autologous
  Cyclophosphamide 5,625 mg/m2 1,875 mg/m2 -6, -5, -4
  BCNU 600 mg/m2 600 mg/m2 -3
TC
  Thiotepa 500 mg/m2 125 mg/m2 -7, -6, -5, -4 Breast cancer Autologous
  Cyclophosphamide 6 g/m2 1.5 g/m2 -7, -6, -5, -4
CBV
  BCNU 300 600 mg/m2 300 600 mg/m2 -6 HL Autologous
  Etoposide 900 2,400 mg/m2 300 800 mg/m2 -6, -5, -4
  Cyclophosphamide 6 7.2 g/m2 1.5 1.8 g/m2 -6, -5, -4, -3
BEAM
  BCNU 300 mg/m2 300 mg/m2 -6 HL, NHL Autologous
  Etoposide 800 mg/m2 200 mg/m2 -5, -4, -3, -2
  Cytarabine 800 1,600 mg/m2 200 400 mg/m2 -5, -4, -3, -2
  Melphalan 140 mg/m2 140 mg/m2 -1
ICE
  Ifosfamide 16 g/m2 4 g/m2 -6, -5, -4, -3 NHL, testicular cancer Autologous
  Carboplatin 1.8 g/m2 600 mg/m2 -6, -5, -4
  Etoposide 1.5 g/m2 500 mg/m2b.i.d. -6, -5, -4
BEAC
  BCNU 300 mg/m2 300 mg/m2 -6 NHL, HL Autologous
  Etoposide 800 mg/m2 200 mg/m2 -5, -4, -3, -2
  Cytarabine 800 mg/m2 200 mg/m2 -5, -4, -3, -2
  Cytoxan 140 mg/kg 35 mg/kg -5, -4, -3, -2
MEL
  Melphalan 200 mg/m2 100 mg/m2 -3, -2 Multiple myeloma Autologous
MCC
  Mitoxantrone 75 mg/m2 25 mg/m2 -8, -6, -4 Ovarian cancer Autologous
  Carboplatin AUC 28 1/5 total dose -8, -7, -6, -5, -4
  Cytoxan 120 mg/m2 40 mg/m2 -8, -6, -4
CBDA/VP
  Carboplatin 2.25 g/m2 750 mg/m2 -6, -5, -4 Testicular cancer Autologous
  Etoposide 2.1 g/m2 700 mg/m2 -6, -5, -4
Fludarabine 90 mg/m2 30 mg/m2 -6, -5, -4 NHL Allogeneic, reduced intensity
  Cyclophosphamide 2,250 mg/m2 750 mg/m2
Fludarabine 150 mg/m2 30 mg/m2 -6, -5, -4, -3, -2 Leukemia Allogeneic, reduced intensity
  Melphalan 140 mg/m2 70 mg/m2 -3, -2
Fludarabine 180 mg/m2 30 mg/m2 -10, -9, -8, -7, -6, -5 Leukemia Allogeneic, reduced intensity
Busulfan 8 mg/kg 4 mg/kg -6, -5 NHL Allogeneic, reduced intensity
ATG 40 mg/kg 10 mg/kg -4, -3, -2, -1 MDS Allogeneic, reduced intensity
ATG, antithymocyte globulin; MDS, Myelodysplastic syndromes; HL, Hodgkin's lymphoma; NHL, non-Hodgkins lymphoma; BCNU, carmustine.

B. Reduced-intensity nonmyeloablative regimens

Increasing recognition of the role of graft-versus-tumor effect has shifted the emphasis from delivery of myeloablative therapy aiming at maximum tumor destruction to optimizing engraftment, thereby providing the platform for further adoptive immunotherapy with DLI. This has resulted in the emergence of new concepts and procedures that allow replacement of the patient bone marrow and immune system with that of the donor by a transplant procedure with markedly reduced intensity of the preparative regimen. The true nonmyeloablative regimen used low-dose TBI of 200 cGy alone or in combination with fludarabine or fludarabine plus cyclophosphamide. This type of preparative regimen provides sufficient immunosuppression to allow engraftment of allogeneic blood progenitor cells without causing profound neutropenia and severe organ toxicity of myeloablative radiochemotherapy. It is suitable only for patients in remission or with more indolent disease, because it takes several weeks to achieve full donor T-cell chimerism to result in graft-versus-tumor effect. To maintain the continued presence of donor cells following nonmyeloablative transplant, it is occasionally necessary to give the recipient posttreatment infusions of additional donor T cells. This is referred to as donor lymphocyte infusion (DLI). However, DLI also carries a significant risk of GVHD development. There are several approaches to improving the safety of DLI, including selective removal of the alloreactive T cells and/or induction of tolerance in the donor lymphocytes to the recipient tissues to prevent GVHD. Such an approach is used in the follow-up phase of treatment for patients who need DLI to further consolidate/maintain the presence of the donor hematopoietic cells. Immunosuppressive agents used in this type of transplant are combinations of oral cyclosporine or tacrolimus with mycophenolate mofetil (MMF) (Table 5.6), avoiding the debilitating oral mucositis from the use of methotrexate as in conventional stem cell transfusion (SCT). This approach reduces the toxicity of the transplant procedure and makes it possible to treat debilitated patients and possibly extend the use of transplantation to older patients (55 to 70 years old) who are not presently eligible for HCT procedures. Other possible indications include treatment of nonmalignant disorders and induction of tolerance for solid organ transplantation. The procedure can be performed in an outpatient setting. Although a potentially lower level of inflammatory cytokines may be present after nonmyeloablative therapies, fatal GVHD still occurs.

C. Reduced-intensity conditioning myeloablative regimens

These regimens result in more myelosuppression than does a true nonmyeloablative regimen. They are used more frequently because most patients still have active disease

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that requires rapid eradication of the underlying diseases. These regimens are usually fludarabine-based combinations, with melphalan 140 to 200 mg/m2 or busulfan. Some groups have added alemtuzumab for additional immunosuppression. In this setting, complete chimerism is rapidly achieved and antitumor responses can be expected immediately. Regimen-related mortality has been lower than expected for a high-risk population, between 30% and 40% 1 year post-transplant. These regimens may be selected for more aggressive malignancies where cytoreduction is expected to contribute to eradicating the disease.

Table 5.6. Common graft-versus-host disease (GVHD) prophylactic drugs, mechanism of action, toxicity, dosage, target serum levels, and usual combination regimens

Drug Mechanism of Action (see Fig. 5.1) Toxicity Dosage, Schedule Target Serum Level Usual Combinations
CSA Calcineurin inhibitor Hypertension, azotemia, tremors, TTP, hyperlipidemia, hyperglycemia, CNS 3 5 mg/kg/day, from day -3 or day -1 until day +100, taper over 3 months 100 300 ng/mL CSA/MTX, CSA/MMF
FK-506 Calcineurin inhibitor Same as CSA 0.002 0.03 mg/kd/day, schedule as CSA 5 10 ng/mL FK-506/MTX, FK-506/sirolimus
MTX Dihydrofolate reductase inhibitor Mucositis, cytopenias, liver 5 15 mg/m2 days 1, 3, 6, 11 NA CSA/MTX, FK-506/MTX, CSA/MMF/MTX
MMF IMPDH inhibitor Cytopenias, nausea, diarrhea, bowel perforation 30 45 mg/kg/day, day 0 to day + 28, tapered variably NA CSA/MMF, CSA/MMF/MTX
Sirolimus mTOR inhibitor Thrombocytopenia, TTP, hyperlipidemia 12 mg PO loading dose, day -3; 4 mg PO/day, day -2 to 100, tapered over 3 months 3 12 ng/mL FK-506/sirolimus
CSA, cyclosporine-A; TTP, thrombotic thrombocytopenic purpura; CNS, central nervous system; MTX, methotrexate; MMF, mycophenolate mofetil; FK-506, tacrolimus; NA, not applicable; IMPDH, inosine monophosphate dehydrogenase; mTOR, mammalian target of rapamycin.

D. Autologous transplant

In autologous transplant, non cross-resistant cytotoxic agents with nonoverlapping extramedullary toxicities are often combined. Combination regimens of two or more agents are generally more effective than single-agent regimens; many of the newer regimens rely on the synergistic effect of alkylating agents with agents such as topoisomerase inhibitors. Immunosuppression is not required.

VII. Type of hematopoietic cell transplant

A.

Allogeneic transplant is used mostly for the treatment of leukemia and other hematologic malignancies. Less than 5% of allogeneic transplants are used for nonmalignant diseases such as aplastic anemia, immunodeficiency syndromes, or hemoglobinopathies. Most adult allogeneic transplants now use PBSC more often than marrow donation from an HLA-identical sibling, unrelated donors, and mismatched family donors. Until recently, donors were identified by serologic phenotype testing for class I and class II major histocompatibility complex molecules HLA-A, -B, and -DR on lymphocytes. Mendelian inheritance predicts a 25% likelihood of identifying an HLA-identical sibling donor within a family; another 5% of patients have a one-antigen mismatched family donor. Through the efforts of the National Marrow Donor Program (NMDP), 5 million volunteer donors and more than 45,000 unrelated cord blood units (CBUs) are available for patients without matched family members. Because of HLA polymorphism, most transplant centers now perform high-resolution HLA typing that includes HLA-C, -DRB1, and -DQ; occasionally, HLA sequence based typing is required to confirm compatibility for both class I and class II HLA antigens. This is particularly important in evaluating potential unrelated donors. With the use of this technology, an acceptable match can be identified in 80% of white patients in the NMDP. Minorities have less chance of finding suitable unrelated donors. However, cord blood transplant is another alternative for patients who cannot find suitable unrelated donors. Most pediatric patients should be able to find one or two antigen-mismatched CBUs with adequate cell dose for transplant. The pilot data using double cord blood transplants for children and adults showed consistent engraftment for most patients. Transplantation-related mortality (TRM) rates range from20% to 30% in HLA-identical sibling transplant recipients and are significantly higher in recipients of mismatched unrelated grafts and haploidentical grafts (40% 45%) compared with recipients of matched unrelated marrow grafts (23%). Therefore, patients who lack a closely matched family donor

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should be offered a phenotypically matched unrelated donor if available.

  • GVHD prophylaxis. GVHD is a serious complication after allogeneic HCT, accounting for approximately half of nonrelapse mortality causes, whereas graft rejection is uncommon (<10%). GVHD, engraftment, and graft-versus-tumor reactions are mediated by donor T cells; therefore, removing T cells from the graft (T-cell depletion) can prevent GVHD at the expense of more frequent graft failure and relapse. There is growing evidence that different T-cell subsets mediate these processes and identifying them has been considered the Holy Grail of HCT. Standard drugs used for GVHD prophylaxis have been cyclosporine and methotrexate, which had been shown in a randomized trial to be more effective in GVHD prevention than cyclosporine alone. Later data on tacrolimus, a newer calcineurin inhibitor, has been shown to have equal or better activity than cyclosporine and has been adopted by many, along with methotrexate, as a preferred combination. The addition of corticosteroids has not been shown to improve rates of acute GVHD, and may increase opportunistic infections. Recently, new immunosuppressive drugs have been tested in this setting. MMF is an IMPDH (inosine monophosphate dehydrogenase) inhibitor, inhibiting the de novo synthesis of purines; in contrast to other cells, lymphocytes are dependent on the de novo pathway for purine synthesis, thereby being selectively affected by MMF. The combination of cyclosporine and MMF is synergistic in animal models and has been used with success in nonmyeloablative transplants as GVHD prophylaxis; however, high rates of GVHD with this regimen were seen in conventional transplants and unrelated donor transplants. Sirolimus, an oral immunosuppressive drug that inhibits the mammalian target of rapamycin (mTOR), a critical step in the activation of T cells, has been shown to have promising GVHD prevention activity when combined with tacrolimus; this regimen has been associated with a greater risk of thrombotic microangiopathy thrombotic thrombocytopenic purpura/hemolytic uremic syndrome (TTP/HUS). A large national randomized study in patients receiving sibling transplants will compare this combination with tacrolimus plus methotrexate, considered by most to be the best standard prophylaxis. Table 5.6 lists the most commonly used immunosuppressive drug and their side effects.

  • Umbilical cord blood (UCB) transplantation. Transplantation of UCB was successfully performed for the first time in 1988 to treat a boy with Fanconi's anemia. Transplantation of unrelated UCB permits a greater degree of HLA mismatching without an unacceptably high incidence of GVHD. Graft characteristics known to allow rapid donor engraftment in recipients of conventional allografts include cell dose, CD34 content, and HLA matching. The higher primary graft failure rates and delayed donor myeloid recovery in UCB recipients are due to the low graft HSC dose, which include up to 10-fold fewer nucleated and CD34 cells as compared with adult donor grafts.

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    UCB graft variables that have a predictive value for time to donor myeloid engraftment include cryopreserved and reinfused total nucleated graft cell content, CD34 content, and infused colony-forming units (CFUs). Most of the published results on cord blood transplant focus primarily on pediatric patients with hematologic malignancies. Donor myeloid engraftment is delayed compared with conventional allogeneic grafts, and ranges from 22 to 30 days. The probability of donor engraftment ranges from 65% to 88%. Acute GVHD of grades II IV has ranged from 35% to 40%, despite most receiving grafts being disparate at two or more HLA loci. High peritransplant mortality is attributed in part to delayed donor myeloid recovery. Transplant outcomes for patients allografted with related UCB has been similar or slightly better compared with unrelated UCB grafts. Data regarding cord blood transplant in adults is limited. Initially, a minimum cryopreserved UCB cell dose of 1 x 107 nucleated cells/kg recipient body weight was suggested but a high (>40%) day 100 mortality led to a higher minimum dose more than 2 x 107/kg. The majority of adult UCB recipients have received grafts mismatched at two or more HLA loci. Cord blood transplant is now accepted as an alternative stem cell source in pediatric patients with hematologic malignancies. Two recent large European and North American retrospective studies describe transplants of UCB or bone marrow from unrelated donors in adults with acute leukemia. Multivariate analysis showed UCB to yield lower risks of grade II IV acute GVHD, but neutrophil recovery was significantly delayed. The incidence of chronic GVHD, TRM, and relapse- and leukemia-free survival were not significantly different in the two groups.

    Barker and coinvestigators at the university of Minnesota had conducted a phase I clinical trial testing the safety of combined transplantation of two partially HLA-matched UCB in adult recipients using myeloablative conditioning in order to overcome the cell dose barrier. All 21 evaluable patients engrafted at a median of 23 days (range, 15 41 days). At day 21, engraftment was derived from both donors in 24% of patients and a single donor in 76% of patients, with one unit predominating in all patients by day 100. An advantage of cord blood over adult marrow for allogeneic transplantation is that the cells are readily available in cord blood banks, are routinely typed for HLA antigens and ABO blood groups, and are tested for infectious agents. This reduces the time required to search for and identify a suitable donor, which is crucial for patients in desperate need of a transplant. The age and weight of the recipient are not obstacles, as long as the unit of cord blood contains more than 2 x 107 nucleated cells/kg of the recipient's weight at the time of collection. A simultaneous search of registries of bone marrow donors and cord blood banks for appropriate matches and adequate cell numbers should be initiated for patients without related family donors. The final choice of the source of stem cells must take into account the degree of HLA identity, the

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    availability of the donor, the urgency of transplantation, and the number of cells in the unit of cord blood.

B.

Autologous transplants and the number of centers performing them are increasing at a striking rate. Currently, most centers use autologous PBSCs as the source of HPCs to support high-dose therapy (HDT). With the advent of PBSCs and hematopoietic growth factors, the duration of marrow aplasia has been significantly shortened compared with that of autologous bone marrow transplants. Randomized trials have demonstrated that the use of PBSCs has resulted in fewer infectious complications, shorter hospitalizations, and lower costs. Many centers are performing autologous transplants in the outpatient setting.

  • Autologous peripheral stem cell collection. PBSCs are collected by a process called leukapheresis. This is usually coordinated with the transplantation center's blood bank. Patients require insertion of a large-bore central venous catheter before initiation of apheresis. PBSCs are collected after mobilization by hematopoietic growth factors (e.g., granulocyte colony-stimulating factor (G-CSF) or granulocyte macrophage colony-stimulating factor [GMCSF]) with or without chemotherapy. Although cyclophosphamide (1.5 to 2 g/m2) is the most common single chemotherapeutic agent reported in stem cell mobilization regimens, a number of other agents have been used either alone or in combination with cyclophosphamide or with other agents. Several investigators have found that the infusion of at least 2.5 x 106 CD34+ cells/kg resulted in timely hematopoietic recovery. In addition, more recently it was observed that the infusion of at least 5.0 x 106 CD34+ cells/kg was consistently associated with more predictable and rapid recovery, particularly of platelets. Most patients reach their target CD34+ cell goal within two to five collections. However, in heavily pretreated patients, this minimum requirement is often difficult to achieve. AMD3100, a new selective CXCR4 (CXC chemokine receptor 4) antagonist, rapidly mobilizes CD34+ cells from marrow to peripheral blood in 6 to 8 hours with minimal side effects. The addition of a single dose of AMD3100 to G-CSF produces consistent mobilization of CD34+ cells in particularly poor mobilizers. More patients receiving AMD3100 reached their CD34+ cell dose targets with fewer leukapheresis procedures. Clinical trials to optimize the use of AMD3100 for stem cell mobilization are ongoing.

VIII. Hematopoietic growth factors and cytokines after HCT

A.

Hematopoietic myeloid growth factors shorten the time to bone marrow or PBSC engraftment after high-dose chemotherapy. They act by binding to specific cell surface receptors, stimulating proliferation, differentiation, commitment, and selected end-cell functions. Two commercially available hematopoietic growth factors are G-CSF (filgrastim) and GM-CSF (sargramostim). For HPC mobilization with growth factors alone, most clinicians start the growth factor on day 1, with initiation of apheresis on day 5. For chemotherapy

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plus growth factor mobilization, the growth factor administration begins the day after completion of the chemotherapy, and apheresis commences when the peripheral blood CD34 count is more than 20 cells/ L or white blood cell count is more than 1,000. After transplantation, the growth factors are usually started after hematopoietic stem cell infusions; growth factor support is continued daily until the absolute neutrophil count is more than 3,000 for a minimum of 1 day.

B.

Erythropoietin is not routinely used during the post-transplant period. It has been shown to accelerate the red cell engraftment in patients receiving ABO incompatible grafts.

C.

Palifermin, a recombinant human keratinocyte growth factor when given on three consecutive days before conditioning regimen and repeated daily for 3 days after HCT, has shown significant reductions in grade 4 oral mucositis, patient-reported soreness of mouth and throat, reductions in the use of opioid analgesics, and the use of total parenteral nutrition.

IX. Toxicities

Toxicities of dose-intensive regimens can be formidable and life threatening. They vary considerably with the different preparative regimens, type of transplant (autologous versus allogeneic, related versus unrelated versus mismatched), and the patient's physiologic organ function and performance status. Some of the toxicities associated with transplant preparative regimens are outlined in Tables 5.2 and 5.3. As indicated, some of the toxicities are acute, whereas others are chronic. Stomatitis, esophagitis, and diarrhea can be severe with some regimens. Hepatic, renal, or pulmonary toxicities can occur in 20% to 30% of patients. Most patients require blood product support in the peritransplant period. Central venous catheter infections or thrombosis can be problematic. Most centers use prophylactic antibiotics to prevent bacterial, viral, and fungal infections. Guidelines for the post-transplant care are covered at the end of the chapter.

A. Graft-versus-host diseases (GVHD)

GVHD may occur in two different forms, known as acute and chronic GVHD, arbitrarily defined as occurring before and after 100 days post-transplant, respectively. Acute GVHD is characterized by rash, diarrhea, and elevated liver enzymes in varying degrees; chronic GVHD resembles some autoimmune disorders, frequently presenting as dry eye, lichenoid changes of the mouth and skin, sclerodermatous changes of the skin, and elevated liver enzymes. GVHD occurs in approximately 50% of all patients, varying in severity from not requiring treatment to fatal, and being more common in the elderly, in unrelated ormismatched transplants, using peripheral blood cells as opposed to bone marrow, and when donors are multiparous women.

B. Treatment of GVHD

The standard treatment for newly diagnosed acute GVHD is with prednisone or methylprednisolone, 1 to 2 mg/kg/day for 1 week, tapered gradually over several weeks/months, depending on the response. Most patients will respond to this approach; however, approximately 20% of patients will be refractory; to improve on these results, a national study is currently investigating, in a randomized fashion, the concurrent use of steroids in four different combinations as up-front therapy for acute GVHD: MMF, denileukin diftitox (Ontak), pentostatin, or etanercept. To date,

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no single drug or antibody has been proved of benefit in steroid-refractory acute GVHD, the mortality remaining very high. Numerous new immunosuppressive drugs and monoclonal antibodies are currently in trial, based on encouraging pilot data. Examples include purine analogs (pentostatin), antibodies targeting T-cell alloreactivity (anti CD-3 antibodies; costimulatory molecule inhibitors such as CTLA-4 and anti- CD154; anti IL-2 receptor/CD25 such as denileukin diftitox (Ontak) and daclizumab; anti-adhesion molecule antibodies such as S-1-P receptor antibodies), and anti tumor necrosis factor (anti-TNF) antibodies such as etanercept.

The initial treatment of chronic GVHD is also with prednisone, usually with a calcineurin inhibitor. The adjunct use of MMF in that setting is currently being tested in a multicenter study. Second-line therapy has not been proved to be of benefit, but similar drugs used as in acute GVHD are being tested.

X. Response and long-term outcomes

With a few exceptions, the goal of HDT with HSCT is to cure or substantially prolong good-quality survival. The short-term surrogate marker for improved survival or cure is complete remission. Partial remission rarely translates into important increases in survival and represents only a 1- to 3-log kill of malignant cells. Therefore, partial remission rates have little meaning in dose-intensive regimens. Less than 50% of patients with advanced malignancy obtain durable remissions with current dose-intensive regimens, stimulating major research efforts to eradicate minimal residual disease after transplantation.

A. Leukemia

  • Acute myelogenous leukemia (AML). The risk of relapse in AML varies according to the cytogenetic risk.

    • HCT is generally not recommended for patients in first complete remission with cytogenetic favorable subtypes of AML where the relapse probability is 35% or less. This applies to most patients with the so-called core binding factor leukemias AML t(8; 21), AML inv(16), and acute promyelocytic leukemias with t(15; 17). In these conditions, the risk of procedure-related death (approximately 10% 20%) does not outweigh the potential benefit of the transplant. In the favorable-risk category, it seems reasonable to reserve the option of an allogeneic HCT for an eventual relapse.

    • For patients with intermediate or poor cytogenetic risk, the risk of leukemic recurrence after first remission is approximately 50% to 80%. Furthermore, the chance of salvage after the leukemia recurs is low. When applied as first-line postremission therapy, allogeneic HCT represents the best option for prevention of relapse in these patients. The low rate of relapse has been confirmed in all studies comparing allogeneic and autologous HCT but has not translated into a consistent survival advantage. When there is an HLA-matched sibling donor, allogeneic HCT should be recommended for patients in this group up to 60 to 65 years of age. With the use of reduced-intensity regimen, some investigators have raised the upper age limit

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      to 65 to 70 years. Allogeneic HCT provides the best antileukemic effect with a probability of a 3-year survival of 61% when performed in CR1 and 48% in CR2 patients.

    • For patients who received autologous HCT, 3-year survival probabilities in first remission were 62% in those younger than 20 years and 48% among those older than 20 years. Corresponding survival probabilities after transplantation in second remission were 48% 8% and 37% 4%. It is recommended that those patients going on to autologous HCT should receive prior intensive chemotherapy as the best method of in vivo purging. PBSCs collected after consolidation therapy for autologous transplants indicate a very lowmortality rate and faster engraftment. For patients with unfavorable cytogenetic risk, allogeneic HCT from either a family matched donor or an unrelated donor is recommended. Recent data from a randomized EORTC/GIMEMA AML-10 trial comparing allogeneic versus autologous HCT in first remission AML showed that performing early allo-HCT led to better overall results than auto-HCT, especially for younger patients or those with bad/very bad risk cytogenetics. The role of reduced-intensity regimens before allogeneic transplantation is under active investigation; preliminary results suggest similar survival compared with conventional regimens, albeit in older and sicker patients, underscoring the lower toxicity of these regimens. Recently, a nonmyeloablative regimen of total lymphoid irradiation (TLI) and antithymocyte globulin (ATG) developed at Stanford showed very promising results for patients with AML in first remission, with very low rates of GVHD, TRM, and relapse. Larger studies are under way to confirm these results. Dose intensity may still be important in some instances (such as higher tumor burden at transplantation); one retrospective analysis showed less relapse with a reduced-intensity/myeloablative regimen compared with a truly nonmyeloablative regimen.

  • Acute lymphoblastic leukemia (ALL) is curable in 60% to 75% of affected children but in only 20% to 30% of adults. Even in high-risk patients, there are no clinical trials proving that early transplant is beneficial if complete remission is achieved with standard induction therapy. Because of the rarity of ALL in adults, few institutions have enough patients for randomized trials properly analyzed according to risk factors (e.g., CNS leukemia, high white blood cell count at presentation, male gender, hepatosplenomegaly, Philadelphia chromosome positive [Ph+] cytogenetics, immunophenotype). Most clinicians agree, even without substantial clinical trial data, that patients with Ph+ ALL should proceed to transplant in the first complete remission. Patients who undergo transplant to consolidate the first complete remission have a 50% leukemia-free survival rate as compared with 40% in the second complete remission and beyond and 20%in relapse using HLA-identical sibling donors; again, lower rates are observed with alternative donors. Reduced-intensity regimens for ALL have been

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    rarely reported, but a higher rate of relapse is likely, given the low GVL effect for this disease. The outcome of autologous transplantation in ALL is inferior to that of allogeneic transplants.

  • Chronic myelogenous leukemia (CML) is no longer the most common indication for allogeneic transplantation since the introduction of imatinib mesylate as a first-line therapy for CML patients. The IRIS study has shown that at 42 months, 84% of newly diagnosed CML patients treated with imatinib achieved complete cytogenetic remission (CCR) with progression-free survival (PFS) of 94%. Progression to accelerated phase or blast crisis had occurred in 6.1%, whereas 6.9% of patients had lost complete hematologic response or major cytogenetic response. Although the overall rate of progression had peaked in the second year of therapy (7.6%), the incidence of progression to advanced phase was practically constant over the years, at an average of 2% per year. Analysis of the IRIS study showed that the Sokal score (which is based on age, spleen size, and platelet and peripheral blood blast count) is well correlated with the likelihood of achieving a CCR of 91% for low-, 84% for intermediate-, and 69% for high-risk patients.

    Currently, there is a debate as to whether any subgroup of patients with newly diagnosed chronic phase CML should be treated by HCT as primary therapy. It has been suggested that patients classified as poor risk by Sokal and good risk for allografting should be transplanted without preceding treatment with imatinib. The same has been suggested for children regardless of their Sokal score. As HCT in accelerated phase or blast crisis carries a much poorer prognosis than in chronic phase, early detection of relapse is critical. However, even meticulous monitoring will not always detect relapse early, as some patients have progressed directly to accelerated phase or blast crisis, even from CCR. Therefore, patients with a low-risk transplant option, for example, young patients with an HLA-matched sibling donor, should be informed that according to currently available data, imatinib does not eradicate leukemia, that life-long therapy is required, and that there is small risk of progression to advanced phase even in those with an excellent response and sometimes without advance warning. Most patients are now referred for transplantation after the disease has transformed to accelerated and blast crisis. Although alternative Abl kinase inhibitors show promising activity, these patients should be offered allogeneic HCT. Our recommendation is to perform HLA typing of the sibling and search for unrelated donors early in patients with high-risk Sokal score or in patients who do not achieve major cytogenetic response after 12 months of 400 mg of imatinib.

  • Chronic lymphocytic leukemia. A significant number of patients with newly diagnosed CLL are relatively young with up to 20% being younger than 55 years. Although the overall median survival for these patients is approximately the same (10 years) as for the older cohort, they are far more likely to die as a result of CLL, particularly in

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    the presence of adverse prognostic features. These are advanced clinical stage, extensive marrow involvement, high lymphocyte count and short doubling time, CD38 positivity, and adverse genetic abnormalities (del 11q, del 17p, and/or unmutated status of the variable region of the immunoglobulin [Ig] heavy-chain gene). Approximately 60% of younger patients with CLL have progressive disease and this group has a median survival of 5 years from therapy. Autologous hematopoietic cell transplantation (HCT) is feasible in young patients with CLL and results in long-lasting clinical and molecular remissions. The transplantation-related mortality (TRM) rate is less than 10%, with complete response (CR) rates of approximately 80%; a risk-matched case control study revealed a prolongation of survival compared with conventional therapy. However, these results have never been confirmed in prospective randomized studies, and it is becoming evident that most patients attaining complete remissions after autograft will eventually experience relapse. Previous studies have examined autologous transplantation used as salvage therapy. There are also concerns about the ability to mobilize adequate numbers of progenitor cells in patients with CLL, particularly after fludarabine therapy. The UK Medical Research Council (MRC) assessed the response to fludarabine as a first-line chemotherapeutic agent, evaluated the feasibility of progenitor cell mobilization after this treatment, and safety and efficacy of autologous stem cell transplantation in CLL patients younger than 60 years with newly diagnosed stage B, C, and progressive stage A disease. The initial response rate to fludarabine in 115 patients was 82%. Stem cell mobilization was attempted in 88 patients and was successful in 59 (67%). Overall, 65 of 115 patients (56%) entered into the study proceeded to autologous transplantation. The early TRM rate was 1.5%. The number of patients in complete remission after transplantation increased from37% to 74%, and 63% who were not in complete remission at the time of their transplantation achieved a complete remission after transplantation. The 5-year overall and disease-free survival (DFS) rates from transplantation were 77.5% and 51.5% respectively. Sixteen of 20 evaluable patients achieved a molecular remission on a polymerase chain reaction (PCR) for Ig heavy-chain gene rearrangements in the first 6months following transplantation. Allogeneic SCT for CLL is associated with significant morbidity and mortality, both from regimen-related toxicity and from GVHD and infection. Despite this, there is evidence that patients who survive can have long-term disease control. The Seattle Group has recently reported on 64 patients diagnosed with advanced CLL treated with nonmyeloablative conditioning with (n = 53) or without (n = 11) fludarabine, who also received a transplant from related (n = 44) or unrelated (n = 20) donors. The overall response rate in 61 evaluable patients was 67% (50% CR). The 2-year incidence of relapse/ progression was 26%, whereas the 2-year relapse rate and nonrelapse mortality rate were 18% and 22%, respectively. Although the number is small, unrelated transplants

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    resulted in higher CR and lower relapse rates than related transplants, suggesting more effective GVL activity. We recommend allogeneic transplantation with myeloablative conditioning for patients younger than 50 years. In patients between 50 and 65 years of age and in all those relapsing after an autologous transplantation, an allogeneic stem cell transplantation with a reduced-intensity conditioning regimen is offered.

B. Lymphoma

  • Hodgkin's lymphoma. The use of autologous HCT (auto-HCT) for relapsed Hodgkin's lymphoma (HL) is now considered the standard of care. Two randomized trials showed significant benefit in freedom from treatment failure (FFTF) for auto-HCT over conventional therapy for relapsed disease. The results of these trials, together with improved tolerability of the procedure, have resulted in the recommendation of auto-HCT at the time of first relapse for even the most favorable patients. The lack of a survival benefit in these randomized trials has been attributed to patients in the nontransplant arm undergoing transplant at the time of second relapse. Investigators for the German Hodgkin Study Group (GHSG) and European Group for Blood and Marrow Transplantation (EBMT) reported on 161 patients with relapsed HL randomized to standard-dose Dexa-BEAM or high-dose BEAM and transplantation with HSCs (BEAM-HCT). Of the 117 patients with chemosensitive relapse, there was a significant improvement in 3-year FFTF for patients undergoing auto-SCT compared with 4 cycles of Dexa-BEAM (55% vs. 34%, p = 0.019). Three-year FFTF was significantly better for patients treated with BEAM-HCT, regardless of whether first relapse occurred early (<12 months) (41% vs. 12% p = 0.007) or late (>12 months) (75% vs. 44%, p = 0.02). A variety of preparative regimens have been reported; the BEAM, CBV, and BEAC regimens listed in Table 5.5 are the most commonly employed. In patients receiving nitrosoureas (e.g., BCNU), the clinician must pay particular attention to respiratory symptoms (dry cough, shortness of breath, hypoxia, and interstitial infiltrates on chest radiograph) 4 to 12 weeks after transplant because these symptoms are suggestive of BCNU pulmonary toxicity, a potentially fatal complication that can be reversed with prompt initiation of corticosteroids. Allogeneic HCT has been used in the past for patients relapsed after autologous HCT. A recent review of International Bone Marrow Transplant Registry/Autologous Blood and Marrow Transplant Registry (IBMTR/ABMTR) data identified 114 patients (79 NHL, 35 HD) who underwent a conventional allo-HCT (1990 1999) after failing an auto-HCT. The PFS rates at 1, 3, and 5 years of 32%, 25%, and 5%, respectively, with no difference in HL and NHL, and TRM was 21% at 100 days. The EBMT collected data on 94 patients who received reduced-intensity conditioning with allogeneic HCT (RIC-allo) for HL. Approximately 50% had failed previous autograft. Three-year OS, PFS, and TRM rates were 45%, 35%, and 18%, respectively. The only significant prognostic

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    factor for OS and DFS was chemosensitive disease, with a median survival of less than 1 year for patients with resistant disease, although the median had not yet been reached at 2 years in patients with sensitive relapse. The role of tandem auto-HCT as well as tandem auto-HCT followed by reduced-intensity HCT is under investigation. There was a continuing risk of relapse or secondary AML and MDS for 12 years after autologous bone marrow transplant, whereas there were no cases of secondary AML/MDS or relapses beyond 3 years after allogeneic bone marrow transplant.

  • Non Hodgkin's lymphoma (NHL)

    • Diffuse large B-cell lymphoma (DLBCL). Autologous HCT remains the standard of care for patients with relapsed DLBCL following CHOP or similar chemotherapy, provided the disease is sensitive to second-line chemotherapy. Although there are few data to confirm the benefit of this approach in patients relapsing after rituximab-based therapy, it is likely to remain the standard. Early studies of HDT and SCT demonstrated the importance of chemosensitivity as a predictive factor for outcome after transplantation. Other favorable factors identified in many studies include initial remission duration of more than 12 months and the absence of bulky disease at the time of SCT. Poor outcome with less than 20% OS and PFS was reported in patients with age adjusted International Prognostic Index (aaIPI) score of 2 or 3 at the time of auto-HCT. Therefore, for those patients with high aaIPI scores at the time of relapse, and for those with chemorefractory disease at the time of relapse, other alternative therapy should be considered due to poor survival after auto-HCT. Commonly used second-line regimens used before auto-HCT for relapsed DLBCL include DHAP, ESHAP (etoposide, methylprednisone, cisplatin), mini-BEAM (carmustine, etoposide, cytarabine, melphalan), and ICE (ifosfamide, carboplatin, etoposide). These regimens produce CR rates of 25% to 35%. The addition of rituximab to ICE (R-ICE) increases the CR rate to 53% compared with 27% for patients treated with ICE in a previous study. The PFS after transplantation was noted to be slightly longer in patients treated with R-ICE compared with historical patients receiving ICE (54% vs. 43% at 2 years) although this did not reach statistical significance. The pilot data using high-dose yttrium 90 (90Y)-ibritumomab tiuxetan in combination with high-dose BEAM and auto-HCT is effective and did not delay engraftment in patients with CD20+ NHL. Allogeneic transplantation does not appear to be superior to autologous transplantation in treating intermediate-grade lymphomas. Although fewer relapses are observed after allogeneic transplant, presumably because of a graft-versus-lymphoma effect, the TRM offsets the lower relapse rate. The use of reduced-intensity regimen in NHL has increased the 1-year OS rate after allo-HCT from 23% to 67% in one study. This strategy is particularly appealing for patients who have failed previous autologous transplants,

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      given a very high nonrelapse mortality of more than 70% for these patients after conventional preparative regimens. A high rate of relapse of close to 50% after reduced-intensity regimens has been reported in two retrospective analyses of aggressive lymphomas, with disease sensitivity predicting for better outcome. These data provide limited insight into the potency of the GVL effect in this setting, and it remains unclear if reducing the intensity of the regimen compromises disease control. A more encouraging report with the non-myeloablative regimen of fludarabine/TBI from the Seattle Consortium for aggressive lymphomas suggests that patient selection (chemosensitive disease)may be important for successful transplantation for those patients.

    • Low-grade NHL. Chemotherapy at conventional doses for the treatment of patients with recurrent follicular NHL is likely to produce consecutive remissions of shorter duration each time. Several phase II studies suggest that salvage treatment followed by consolidation with auto-HCT can result in prolonged disease-free survival (DFS). Freedman and colleagues reported the largest single-institution experience. A total of 153 patients were treated with auto-HCT using autologous bone marrow purged in vitro with anti B-cell monoclonal antibody. At a median follow-up of 5 years (range 2 13 years), the estimated 8-year DFS and OS were estimated as 42% and 66%, respectively. All trials suggested an improved median duration of PFS compared with historic controls treated with conventional chemotherapy and prolonged PFS in a fraction of patients. However, recurrence rate of more than 50% is generally observed. The German Low-Grade Lymphoma Study Group randomized patients younger than 60 years with chemosensitive indolent NHL (mostly follicular NHL) in first partial or complete remission to auto-HCT versus maintenance interferon (IFN) therapy. At a median follow-up period of 4.2 years, 27.2% relapses were observed in the auto-HCT study arm versus 60.3% in the IFN arm. The 5-year PFS was also significantly better in the auto-HCT arm (67% vs. 33%). The exact role of allo-HCT in follicular NHL is difficult to define. Allotransplant was initially used in patients thought not to be candidates for auto-HCT because of extent of disease or marrow involvement. Several retrospective studies suggest that allo-HCT is associated with a very low relapse rate and might be a curative treatment for follicular lymphoma (FL). Results from the registry data demonstrate that allogeneic bone marrow transplantation is associated with high morbidity and mortality, attributable largely to GVHD. In this patient population, however, the probability of relapse appears low, with a 50% DFS rate 5 years after transplant. This approach has the advantage of the absence of contaminating tumor cells and a graft-versus-lymphoma effect. These observations, along with cases of disease regression after DLI and withdrawal of immunosuppression, suggest a powerful GVL

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      effect for low-grade lymphomas. Therefore, reduced intensity regimens are an appealing strategy for these patients, and initial clinical experience confirms this, with low relapse rates (0% 21%) and treatment-related mortality (5% 30%) in single institution and registry series.

    • Mantle cell lymphoma. One area of controversy is mantle cell lymphomas. These are aggressive intermediate-grade lymphomas with a median survival of approximately 2 years using conventional therapy. There is currently no definite evidence of a survival advantage using autologous or allogeneic transplant for primary refractory disease, relapsed disease, or after the second complete remission. Few single-institution data reported event-free survival of 36% to 48% at 3 to 4 years. Blastic morphology and heavily pretreated patients are associated with worse prognosis. Few investigators reported encouraging results with the use of rituximab after auto-HCT or using an intensive-chemotherapeutic regimen, hyper-CVAD, cytarabine, and methotrexate to induce molecular remission followed by auto-HCT. Because most patients with mantle cell lymphoma relapse even after HDT, current emphasis is focused on post-transplant immunotherapy to eradicate minimal residual disease. This includes low-dose IL-2, IFNs, idiotype-specific vaccines, and dendritic cell vaccines, and intensification of the preparative regimen with radioimmunoconjugates.

      The literature is limited regarding allogeneic transplantation for mantle cell lymphoma. Conventional myeloablative regimens have led to long-term survival for this disease, usually in the setting of chronic GVHD, suggesting a GVL effect. Reduced-intensity regimens for this disease have been associated with lower toxicity but the long-term disease control is still unknown.

C. Plasma cell dyscrasias

  • Multiple myeloma is an incurable B-cell malignancy that constitutes 10% of all hematologic malignancies. The treatment of multiple myeloma is rapidly evolving. Before the use of thalidomide and dexamethasone as initial treatment, the standard therapy with VAD or melphalan and prednisone resulted in amedian survival of 30 to 36months. It has been shown previously in two randomized trials that high-dose therapy (HDT) plus autologous transplant compared with standard therapy resulted in improved DFS and overall survival (OS). The use of tandem autologous transplant early in the management of multiple myeloma using total therapy I by the Arkansas group produced a CR rate of 41% and OS of 79 months. The IFM94 trial was the first randomized trial comparing single and tandem auto-HCT in multiple myeloma. The 7-year probability of event-free survival doubled from 10% to 20% with a concomitant improvement of OS from 21% to 42%. The data indicate that tandem auto-HCT improves PFS with a variable effect on OS. Two trials suggest that the second procedure provides

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    the most benefit in patients not achieving a CR, near complete response (nCR), or very good PR (>90% reduction in serummonoclonal protein). Melphalan 200 mg/m2 is considered standard high-dose regimen for auto-HCT in myeloma as a regimen with multiple chemotherapy and TBI produced more toxicity without increasing antitumor benefit. Post-transplant use of IFN after auto-HCT did not demonstrate an advantage of PFS or OS. The use of thalidomide and alternative agent, lenalidomide, post-AHCT is under investigation. Allogeneic transplant, in contrast, may be curative in 20% to 25% of patients but is associated with extremely high TRM rates, approaching 40% to 50% in most reports. There is no advantage of allo-HCT compared with auto-HCT. The French and Spanish group recently reported the use of reduced-intensity regimen allo-HCT performed after auto-HCT as a consolidation measure and showed higher response rate with allo-HCT compared with second auto-HCT but the TRM was greater, leading to comparable survival rates in the two groups.

  • Primary amyloidosis is a plasma cell dyscrasia associated with light-chain deposition in one or more organ systems. With standard therapy, the median survival time is 18 to 24 months, but it is less than 1 year for patients with cardiac amyloidosis. Recent reports from Boston University and the Mayo Clinic indicate that HDT with autotransplantation can effect high remission rates and improve survival rates. Changes in organ function and performance status at 1 year post-auto-HCT correlated with hematologic response. Improvement in at least one organ function was seen in 66% of patients with hematologic response. Improvements in cardiac, renal, liver, and neurologic symptoms were observed. Further improvements were seen after 1 year.

D. Myelodysplastic syndrome (MDS)

MDS is a clonal disorder of HPCs. There is no effective standard therapy for this disorder. Allogeneic transplantation can produce longterm disease-free survivors: approximately 40% of patients younger than 40 years but only 15% to 20% of patients older than 40 years. The analysis of MDS transplants reported to the EBMT showed both the estimated DFS and risk at 3 years to be 36% for patients transplanted with stem cells from matched siblings. Age and stage of disease had independent prognostic significance for DFS, survival, and TRM. Patients transplanted at an early stage of disease had a significantly lower risk of relapse than patients transplanted at more advanced stages. The estimated DFS at 3 years was 25% for patients with voluntary unrelated donors, 28% for patients with alternative family donors, and 33% for patients autografted in first complete remission. The relapse rate is lowest for nonidentical related donors and highest in autologous recipients. For patients younger than 55 years with MDS, allo-HCT offers the best effective treatment. The data using a reduced-intensity regimen are encouraging but need long-term follow-up.

E. Myelofibrosis

With conventional therapies being often ineffective, with a median survival of 3 to 5 years, myelofibrosis

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has the worst prognosis of all the chronic myeloproliferative diseases. Recently, a report on 55 patients younger than 55 years with myelofibrosis who underwent allo-HCT indicated that 48% of the recipients of an HLA-identical transplant survived event-free at 5 years. Nevertheless, the 1-year TRM in this study was 27% in spite of the relatively young age (median 42 years) of the patients receiving transplants. Further, a recent follow-up from this same group of investigators noted only a 14% 5-year OS in a subgroup of transplant recipients older than 45 years compared with 62% for younger patients.

F.

Other diseases in which HDT with transplantation has reported efficacy include aplastic anemia and MDSs. Aplastic anemia has a guarded prognosis because of the risk of infection and fatal hemorrhage. The 1-year survival rate for severe aplastic anemia is less than 20%. Allogeneic transplantation results in a long-term survival rate ranging from 50% to 90%. Favorable prognostic factors are younger age (<16 years), no prior transfusions, short interval from diagnosis to transplant, and no evidence of infection. The preparative regimen consists of immunosuppressive agents: cyclophosphamide alone or with antithymocyte globulin or with TBI. Patients who do not have a compatible sibling donor may be considered for a matched unrelated donor transplantation. Approximately 15% to 30% of patients survive with engraftment.

A new arena of clinical interest is autoimmune diseases. Although published predominantly in case reports, there appears to be clinical improvement or stabilization in disease parameters after HDT with autologous transplant for multiple sclerosis, systemic lupus erythematosus, scleroderma, and rheumatoid arthritis. Preparative regimens focus on immunosuppression with cyclophosphamide with TBI or antithymocyte globulin.

XI. Guidelines for long-term care of hematopoietic-cell transplantation survivors

Patients who survive HCT remain at greater risk than the average populations for certain diseases, most notably related to immune and endocrine dysfunction, and second malignancies. The magnitude of the problem is greater after allogeneic transplantation than after autologous transplantation, because of slower immune reconstitution and GVHD, which should be cared for by physicians knowledgeable with this complication.

A. Immune dysfunction

Understanding immune reconstitution after HCT is essential to anticipate and prevent specific infections. Risks of potential complications after stem cell transplantation correlate with immune system recovery. For practical purpose, the following are recommendations by the Center of Disease Control and Prevention together with the Infectious Disease Society of America and American Society of Blood and Marrow Transplantation. Risks of complications and treatment guidelines vary according to period after and type of stem cell transplant.

B. Pre-engraftment period (days 0 30)

During the first month post-transplant, neutropenia and injury of mucosal barriers frequently lead to bacteremia, herpes simplex reactivation, and candidemia. Common bacterial organisms include

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mouth and gut organisms (e.g., Streptococcus viridans, gramnegative rods). Prophylactic antimicrobials help reduce some of these infections but emergence of resistant organisms must be considered; randomized studies proving conclusively the value of such strategies are scant.

C. Early postengraftment period, autologous transplants (after day 30)

Immunologic function usually recovers rapidly after the first month post-transplantation, and prophylactic antimicrobials are not recommended except for patients with lymphoma who remain at risk for Pneumocystis jiroveci (formerly carinii) pneumonia (PCP) and should receive prophylaxis, preferably with trimethoprim/sulfamethoxazole, for approximately 6 months. Reactivation of Varicella zoster is common for several months after transplant; routine use of acyclovir prophylaxis is common despite lack of solid data.

D. Early postengraftment period, allogeneic transplants (days 30-100)

Patients usually remain close to the transplant center during the second and third months post-transplant. Cytomegalovirus (CMV) reactivation is common during this period and is treated preemptively with ganciclovir (or foscarnet in resistant cases) when weekly screening tests become positive. Patients begin PCP prophylaxis during this time, and remain on it until immunosuppressive drugs are discontinued. Zoster and fungal prophylaxis are frequently given but data to support this practice is scant.

E. Late postengraftment period, allogeneic transplants (days >100) (Table 5.7)

Patients may return closer home during this period, and local oncologists will routinely care for them. Cellular and humoral immunity defects may not fully recover for 2 years or longer following allogeneic transplant, even in the absence of immunosuppressive drugs. These defects are more pronounced in the presence of GVHD; pneumococcal sepsis remains a leading cause of death in these patients, and prophylactic antibiotics (usually daily penicillin and twice or thrice weekly trimethoprim sulfamethoxazole) are recommended. Similarly, fevers should be treated promptly with empiric antibiotics pending culture results. Prophylactic Ig may be useful in patients who have hypogammaglobulinemia (IgG level <400 mg/dL) and recurrent respiratory infections. Fungal and viral infections are also frequent causes of death in patients with chronic GVHD; prophylactic antifungals and acyclovir are frequently given in this setting with few studies showing benefit. Patients should be re-immunized with inactivated vaccines (Haemophilus influenzae type B conjugate, polyvalent pneumococcal polysaccharide, diphtheria and tetanus toxoid, influenza virus, inactivated polio, and hepatitis B in patients at risk) beginning at 1 year post-transplant, and with live attenuated vaccines (measles, mumps, and rubella) at 2 months post-transplant, as long as chronic GVHD is not present.

F. Endocrine dysfunction

Hypothyroidism and hypogonadism are common complications after fractionated total-body irradiation (FTBI)-based conditioning regimens; screening for these problems is recommended 1 year post-transplant and as clinically indicated. Osteoporosis, avascular necrosis, and diabetes are common with steroid use; bone

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density scanning should be performed at 1 year and as clinically indicated thereafter. Stress doses of steroids should also be given during acute illness for such patients.

Table 5.7. Guidelines for long-term management after hematopoietic stem cell transplantation (HCT) (>day 100 post-HCT)

Complication Risk Factor Prevention/Screening Treatment Duration of Prophylaxis/Screening
PCP Lymphoma (auto), allo-HCT TMP/SMT 1 tablet PO b.i.d. 2 day/weeka TMP/SMT 6 months or active GVHD
Varicella zoster Auto- and allo-HCT Acyclovir 400 mg PO b.i.d. Acyclovir 800 mg PO 5 /day or 10 mg/kg IV 3 /day if systemic 6 12 months or active GVHD on steroids
Invasive fungal infections GVHD, steroids Unknown (azols commonly prescribed) Azols, amphotericins or echinocandins Unknown (active GVHD?)
Encapsulated organisms, respiratory infections GVHD, splenectomy, hypogammaglobulinemia TMP/SMT and/or Pen-V-K 250 mg PO b.i.d. Pooled -globulin if IgG <400 mg/dL Based on susceptibility Active GVHD or lifetime after splenectomy
Hypothyroidism Radiation TSH Thyroid hormone Annual
Hypogonadism Radiation FSH, LH, estrogen (women), testosterone (men) Testosterone (men); Gynecology consult (women) Annual for women and p.r.n. for men
Osteoporosis Steroids, radiation Bone densitometry Bisphosphonates, calcium, and vitamin D 1 year and p.r.n.
Graft dysfunction (cytopenias) Low cell dose, rejection, relapse, drugs, infections, GVHD (platelets), ABO mismatch (red cells only), MDS after auto CBC, platelet counts, bone marrow examination, call TC (chimerism analysis, rule out relapse and MDS after auto) Transfusions and/or growth factors; decision regarding second transplant or drug therapy per TC Monthly first year, q3 months second year, q6 months 5 year and yearly thereafter
Skin sensitivity, GVHD flare, skin cancer Sun exposure High-SPF sunscreen; physical examination; biopsy in selected cases Call TC, usually steroids needed p.r. n.
Dry eye GVHD Schirmer's test Lubrication, punctual plugs, ophthalmologic evaluation p.r. n.
cataracts Steroids, radiation Ophthalmologic examination Surgery 1 year and p.r.n.
Dry mouth/ulcers, GVHD Dental hygiene, culture to rule out HSV, Candida Saliva substitutes and stimulants; treat super-infection, call TC for topicals p.r. n.
Interstitial pneumonitis (autologous) BCNU, radiation Chest x-ray, bronchoscopy Start solumedrol 1 mg/kg/day, call TC p.r.n., usually occurs within 3 months post-HCT
Bronchiolitis obliterans GVHD PFT, high-resolution CT scan, lung biopsy in selected cases Bronchodilators, call TC (steroids needed) Day 100 and 1 year
Liver dysfunction GVHD, hepatitis, iron overload, drugs LFTs, hepatitis serologis, ferritin, ultrasound; call TC Iron chelation if iron overload, anti-virals,b ursodeoxycholic acid, call TC LFT q month 1 year, q3 months second year, others p.r. n.
Vulvovaginal dryness/dyspareunia GVHD, low estrogen levels Physical examination, estrogen levels, rule out super-infection Lubricants, topical estrogens/steroids, gynecology consult p. r.n.
Joint stiffness, skin thickening GVHD Physical examination Stretching exercises, emollients; call TC for topicals p. r.n.
PCP, Pneumocystis jiroveci (carinii) pneumonia; TMP/SMT, trimethoprim sulfamethoxazole; GVHD, graft-versus-host disease; TC, transplant center;
IgG, immunoglobulin G; TSH, thyroid stimulating hormone; FSH, follicle stimulating hormone; LH, luteinizing hormone; CBC, complete blood counts;
MDS, myelodysplastic syndrome; SPF, sun protection factor; HSV, herpes simplex virus; PFT, pulmonary function test; CT, computed tomography; LFT, liver function test.
aAtovaquone 750 mg b.i.d. or dapsone 100 mg/day for sulfa contraindication.
bInterferon is usually contraindicated.

G. Other organ dysfunction

Poor graft function is uncommon after autologous transplants; patients with grafts with low CD34 cell counts and who are heavily pretreated are at risk and may require transfusions and/or growth factors beyond 1 month; myelodysplasia should be ruled out in that setting. Allogeneic transplant recipients may have graft dysfunction from low cell dose, immunologic rejection (rare), drugs, infections (viral), GVHD (thrombocytopenia) and donor/recipient ABO mismatch (red cells only). Consultation with transplant physicians is recommended; growth factor support may be beneficial, but bone marrow biopsies are recommended to assess chimerism status and rule out relapse and myelodysplasia. Exacerbations of skin GVHD may occur after sun exposure in patients with GVHD and often require escalation of immunosuppression; high-SPF sunscreens and avoidance of direct sunlight are recommended. Oral cavity dryness and ulceration are common in chronic GVHD; twice yearly dental assessments and cleanings are recommended; exacerbations of GVHD should be discussed with transplant centers, and are usually managed with increased dose steroids, treatment of super-infections, and topical immunosuppressants. Ocular problems are also common, including cataracts after fractionated TBI-based regimens, and ocular sicca with chronic GVHD; in addition to aggressive lubrication with artificial tears and immunosuppressant, ophthalmologic evaluation is recommended for symptomatic patients. Pulmonary complications are most often related to regimen toxicity, most notably interstitial pneumonitis from BCNU and radiation, which should be treated promptly with steroids; idiopathic pneumonitis and bronchiolitis obliterans are serious complications that usually occur in the setting of GVHD and are usually managed with steroids and inhaled bronchodilators in coordination with transplant and pulmonary physicians. Liver dysfunction is also common in the setting of chronic GVHD; viral hepatitis and iron overload should be ruled out and managed accordingly. Hypertension is common with calcineurin inhibitors (CI); general guidelines to treat hypertension may be used in this setting. Azotemia may occur with CI and dose adjustments should be discussed with transplant centers. Vaginal dryness with discomfort may occur with GVHD and should be managed with lubricants, topical estrogens (if levels are low) and topical immunosuppressants.

H. Second cancers

The risk of secondary solid tumors is three times higher after allogeneic transplant than in control populations; risk factors include prior radiation, immunosuppression, and chronic GVHD. All types of malignancies have been described, but skin cancers and oral mucosa squamous cell carcinomas are most common. Avoidance of tobacco and excessive sunlight exposure are recommended. Yearly clinical assessments and other routine screening tests should be performed; the value of earlier and more frequent screening in this population is unclear. Secondary leukemia and myelodysplasia is more common after autologous transplant, with an

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incidence of 5% to 10%, being highest in patients exposed to alkylators, etoposide, and radiation.

XII. Future directions

The field of hematopoietic cell transplantation is evolving rapidly. Its use in the past had focused on hematologic malignancies and marrow failure. We are now starting to use stem cell transplantation to treat several autoimmune diseases and hemoglobinopathies. Indications for HCT in hematologic malignancies are also changing rapidly because of several new classes of new drugs with different mechanisms that now target molecular changes and result in better control of malignant cells. The preclinical studies showing ability of adult hematopoietic cells, umbilical cord blood, and embryonic stem cells to differentiate into osteoblasts, chondroblasts, myocytes, and neurons will potentially lead us to apply stem cell transplant in several areas of regenerative medicine in the future.

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Khouri IF, Saliba RM, Giralt SA, et al. Nonablative allogeneic hematopoietic transplantation as adoptive immunotherapy for indolent lymphoma: low incidence of toxicity, acute graft versus host disease, and treatment related mortality. Blood 2001;98:3595 3599.

K rbling M, Anderlini P. Peripheral blood stem cell versus bone marrow allotransplantation: does the source of hematopoietic stem cells matter? Blood 2001;98:2900 2908.

Lenz G, Dreyling M, Schiegnitz E, et al. Myeloablative radiochemotherapy followed by autologous stem cell transplantation in first remission prolongs progression-free survival in follicular lymphoma - results of a prospective randomized trial of the German Low-Grade Lymphoma Study Group (GLSG). Blood 2004;104: 2667 2674.

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Handbook of Cancer Chemotherapy
Handbook of Cancer Chemotherapy
ISBN: 0781765315
EAN: 2147483647
Year: 2007
Pages: 37

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