Hematologic Malignancies

Kim Robien, PhD, RD, CSO, FADA INTRODUCTION

The term “hematologic malignancies” refers to cancer of the blood, bone marrow, and lymph nodes. The primary forms of hematopoietic malignancies are leukemias, lymphomas, and multiple myelomas. Several related disorders— namely, myelodysplastic syndromes (MDS), myelofibrosis, amyloidosis, and the myeloproliferative disorders polycythemia vera and essential thrombocytosis— are not cancers, but may eventually evolve into hematologic malignancies. Table 12.1 lists the various types of hematologic malignancies, along with Table 12.1 Incidence and Mortality Rates of Hematologic Malignancies in

the United States

Cancer Types

New Cases per Year*

Deaths per Year*

Leukemia

Acute myelogenous leukemia

5,200

8,990

Chronic myelogenous leukemia

4,570

490

Acute lymphocytic leukemia

5,200

1,420

Chronic lymphocytic leukemia

15,340

4,500

Lymphoma

Hodgkin’s lymphoma

8,190

1,070

Non-Hodgkin’s lymphoma

63,190

18,660

Multiple myeloma

19,900

10,790

Myelodysplastic syndrome

10,300*

35% 3-year survival*

*Unless otherwise noted, data are for 2007 and come from the following source: American Cancer Society. Cancer Facts and Figures 2007. Atlanta, GA: American Cancer Society; 2007.

*Data are for 2003 and come from the following source: Ma X, Does M, Raza A, Mayne ST. Myelodysplastic syndromes: Incidence and survival in the United States. Cancer. 2007;109(8):1536—1542.

incidence and mortality data for the United States. Data on incidence and survival for myelofibrosis, amyloidosis, and the myeloproliferative disorders are not well documented, as these nonmalignant diseases are not reportable to large, population-based cancer monitoring programs.

Leukemias encompass a number of cancers arising from hematopoietic cell lines. Genetic translocations, inversions, or deletions in hematopoietic cells disrupt the normal function of the genes at these locations, altering normal blood cell development.1 As a result, dysfunctional or nondifferentiated leukemic cells accumulate in the bone marrow space and progressively replace normal hematopoietic cells. Signs and symptoms of leukemia include anemia, fatigue, bleeding, and infections. Leukemias can be either acute or chronic. They can arise from myeloid or lymphoid cell lines, or both, as in the case of myeloid/lymphoid or mixed-lineage leukemia (MLL). The four major forms of leukemia are acute lymphocytic leukemia (ALL), acute myelogenous leukemia (AML), chronic lymphocytic leukemia (CLL), and chronic myelogenous leukemia (CML).2

Leukemias are relatively rare cancers, accounting for only 3% of all new cancer cases each year.3 Approximately 13,290 individuals are diagnosed with AML and 5,430 with ALL annually in the United States.3 ALL occurs more commonly among children and young adults, with a median age at diagnosis of 10 years, whereas the median age of onset for AML is 65 years.4 CLL is the most common form of leukemia in adults in Western countries, affecting approximately 15,100 individuals each year in the United States.3 CML affects approximately 4,500 individuals per year in the United States,5 with a median age of onset between ages 45 and 55.6 Leukemia is the most common type of cancer among children, with ALL accounting for 75% of all pediatric leukemia cases, AML for 20% of such cases, and CML for less than 5%.7

Advances in the treatment of childhood ALL over the past 50 years have resulted in current 5-year survival rates exceeding 80% for this disease.89 Adult leukemias are associated with somewhat less optimistic survival statistics. Among adults with AML, 15-25% can be expected to survive 3 or more years, and some may achieve complete remission with appropriate therapy.10 Among adults with ALL, 35-40% can expect to survive 2 years with appropriate treatment, and some researchers report 3-year survival rates as high as 50%.11 Overall 5-year survival rates for chronic myelogenous leukemia have increased from 27% in 1990-1992 to 49% in 2002-2004 following the introduction of new tyrosine kinase inhibitors, such as imatinib (described later in this chapter).12 Mean survival for adult chronic lymphocytic leukemia is 8-12 years.13

Lymphomas—that is, cancer of lymphocytes—are often broadly categorized into two main categories: Hodgkin’s disease (HD) and non-Hodgkin’s lymphoma (NHL). The presence of Reed-Stemberg cells, distinctive giant cells derived from B lymphocytes, is the hallmark abnormality associated with HD. All other types of lymphoma are considered NHL, a category that the World Health Organization has further organized into B-cell tumors, T-cell and natural-killer-cell tumors, and immunodeficiency-associated lympho-proliferative disorders.14

NHL is the fifth most common cancer diagnosis among both men and women in the United States,3 and most common form of hematologic malignancy. In 2008, the American Cancer Society estimated that more than 66,000 new cases of NHL and more than 8,000 cases of HD would be diagnosed.3 Survival rates for adults diagnosed with HD have improved dramatically over the past few decades, and now 75% of these patients can expect to achieve complete remission after receiving combination chemotherapy with or without radiation.15 Overall 5-year survival rates for NHL are in the range of 55—65%.3 Currently, 30—60% of aggressive forms of NHL can be cured, although survival rates are less predictable for indolent, slowly progressing forms of NHL, which are associated with higher relapse rates.16

Multiple myeloma is a cancer of plasma cells. The malignant plasma cells secrete proteins that stimulate the osteoclasts to break down bone, resulting in the characteristic bone lesions, bone pain, hypercalcemia, and loss of stature associated with this type of malignancy.17 Approximately 20,000 new cases are diagnosed in the United States annually.3 Multiple myeloma is rarely diagnosed in individuals younger than 40 years.17 The disease responds well to treatment, but is rarely curable.18 Current treatment modalities aim to lengthen survival time with the disease. Five-year survival rates are currently 32%.19

Many hematologic malignancies are now classified by cytogenetic profiling (specific genetic abnormality) or immunophenotyping (membrane surface protein expression profile) of the cancer cell. These subclassifications allow for use of more targeted treatment regimens and better estimates of patients’ prognosis. An example of a genetic marker that is helpful in this regard is the Philadelphia chromosome (Ph+), the hallmark cytogenetic abnormality seen in 95% of CML cases.20 Ph+ is a translocation of the long arms of chromosomes 9 and 22, which transfers the Abelson (abl) oncogene from chromosome 9 to the breakpoint cluster region (bcr) on chromosome 22.21 22 Transcription of this bcr-abl fusion gene produces an abnormal tyrosine kinase protein, which in turn activates a number of cytoplasmic and nuclear signal-transduction pathways, ultimately leading to the disordered myelo-proliferation seen in CML.23

Nutritional Interventions for Hematologic Malignancies

In general, nutrition assessment and development of a nutrition care plan for patients with any type of cancer should include consideration of two broad issues: the effects on nutritional status caused by the cancer itself and the effects on nutritional status caused by the treatment.

Impact of the Disease Process on Nutritional Status

Hematologic malignancies themselves tend not to have significant effects on an individual’s nutritional status. Cancer-induced anorexia and cachexia are less common in the early phases of hematologic malignancies compared with other types of cancer, but may occur in the later stages and as side effects of certain treatments. A 1980 study by the Eastern Cooperative Oncology Group reported that weight loss in the 6 months prior to initiation of treatment occurred in only 4% of patients with AML, 10% of patients with NHL (favorable prognosis), and 15% of patients with more aggressive forms of NHL.24 Anemias related to the cancer process, rather than nutrient deficiencies, may occur as the malignant hematopoietic cell lineage crowds out erythrocytes.

Cancer-associated hypercalcemia is most frequently described with multiple myeloma, HD and NHL, but may also occur with other hematologic malignancies. Tumor cells can disrupt the body’s normally tight control of calcium homeostasis through secretion of various endocrine proteins, such as parathyroid hormone-related protein and 1,25-(OH)2cholecalciferol, which in turn can lead to increased osteoclastic bone resorption and hypercalcemia.25 Treatment for cancer-associated hypercalcemia most commonly consists of intravenous hydration to rehydrate the patient and promote renal calcium excretion, followed by bisphosphonates to inhibit bone resorption.25 Calcium supplementation (from parenteral or oral sources) should be discontinued, and phosphorus replacement may be necessary.26

Impact of Treatment Regimens on Nutritional Status

Registered dietitians and other nutrition practitioners with specialized and advanced skills in oncology nutrition are able to anticipate the nutrition-related impacts of planned treatment regimens, and work with the individual to prevent or minimize these side effects.27 Because treatment regimens are constantly evolving, the reader is referred to the National Cancer Institute’s Comprehensive Cancer Database, called the Physician Data Query (PDQ; http://www.cancer.gov/cancertopics/pdq/cancerdatabase), for current recommendations by cancer type, stage, and grade.

Treatment for hematologic malignancies may include several stages of combination chemotherapy regimens: induction chemotherapy to decrease the tumor burden and assess response to chemotherapeutic agents, followed by consolidation/intensification therapy, and finally maintenance chemotherapy to keep the cancer in remission. This treatment course may extend over a lengthy period, sometimes for many months or even years.

More recently, a new class of small-molecule drugs has been developed to target the specific aberrant proteins or pathways involved in certain hematologic malignancies. These drugs, with their more specific targets, hold promise as being able to provide for better drug tolerance with improved outcomes. One of the first drugs introduced in this class, imatinib, is a tyrosine kinase inhibitor developed specifically to inhibit the abnormal tyrosine kinase that is transcribed from the Ph+ chromosome in CML. Its side effects include nausea, vomiting, diarrhea, anorexia, rash, and muscle pain, but these tend to be minor compared to the side effects observed with other chemotherapeutic agents used to treat CML.

Other chemotherapeutic classes under development for use in hematologic malignancies include biological therapies (also known as immunotherapy), such as monoclonal antibodies. Pharmacologic derivatives of vitamins A and D are also being studied for their ability to induce abnormal hematopoietic progenitor cells to differentiate normally and produce functional blood cells (known as differentiation therapy). All-trans retinoic acid (ATRA) and vitamin D analogs have demonstrated success at achieving remissions when combined with other chemotherapeutic agents, especially in acute promyelocytic leukemia (ATRA) and MDS (vitamin D analogs).28 Hematopoietic cell transplantation (HCT) is also used in the treatment of hematologic malignancies; it is discussed in more detail later in this chapter.

Table 12.2 summarizes the chemotherapeutic agents commonly used in treating hematologic malignancies, as well as the potential nutritional implications of each agent.

Medication

Potential Side Effects ivith Nutritional Implications

Additional Nutrition-Related Concerns

Alkylating Agents

Busulfan

Nausea, vomiting (<10%*), mucositis, hyperglycemia, hypomagnesemia, hypophosphatemia, weight loss

Food may inhibit absorption of the drug.

Cyclophosphamide

Nausea, vomiting (>30%*)

Maintain adequate hydration.

Dacarbazine

Nausea, vomiting (>90%*), anorexia

Avoid alcohol while taking this drug.

Ifosfamide

Nausea, vomiting (30-90%*), xerostomia, abdominal pain

Maintain adequate hydration.

Mechlorethamine

Nausea, vomiting (<90%*)

Maintain adequate hydration.

Procarbazine

Nausea, vomiting, diarrhea, mucositis

Avoid alcohol while taking this drug.

Avoid high-tyramine foods (such as fermented or aged foods, anchovies, caviar, liver, raisins, bananas, chocolate, avocados, fava beans, soy sauce, tofu, miso), which can cause hypertension while taking this drug.

Antimetabolites

Cytarabine

Nausea, vomiting (10—90%*), diarrhea, mucositis, anorexia

Maintain adequate hydration.

Avoid alcohol while taking this drug.

Fludarabine

Anorexia, nausea, vomiting (<10%*), fatigue, edema

Hydroxyurea

Constipation

Mereaptopurine

Diarrhea, intestinal ulcers

Maintain adequate hydration.

Methotrexate

Nausea, vomiting (10—30%*), diarrhea, anorexia, mucositis

Maintain adequate hydration.

Thioguanine

Nausea, vomiting, diarrhea, mucositis

Maintain adequate hydration.

Avoid alcohol while taking this drug.

incidence of emesis without antiemetics for intravenous administration of the drug, according to the following source: Kris MS, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for anti emetics in oncology: Update 2006.J Clin Oncol. 2006;24:2932-2947.

Medication

Potential Side Effects ivith Nutritional Implications

Additional Nutrition-Related Concerns

Anthracyclines

Daunorubicin

Nausea, vomiting (30—90%*), xerostomia, dysgeusia

Doxorubicin

Nausea, vomiting (30-90%*)

Idarubiein

Nausea, vomiting (30—90%*), diarrhea, abdominal cramping

Mitoxantrone

Diarrhea, nausea, vomiting (10—30%*), mucositis

Antimitotic Drugs

Etoposide

Nausea, vomiting (10—30%*), diarrhea, anorexia

Avoid alcohol while taking this drug.

Vinblastine

Vomiting (<10%*), constipation, jaw pain

Vincristine

Nausea, vomiting (<10%*), constipation, hyponatremia

Tyrosine Kinase Inhibitors

Dasatinib

Abdominal pain, constipation, diarrhea, anorexia, nausea, vomiting, weight gain or loss, abdominal distention, fatigue

Do not eat grapefruit or grapefruit juice while taking this drug.

Imatinib

Nausea, vomiting, diarrhea, anorexia, weight gain, fatigue

Take drug with meals and a large glass of water.

Do not eat grapefruit or grapefruit juice while taking this drug.

Nilotinib

Nausea, vomiting, diarrhea, constipation, hyperglycemia, hypophosphatemia

Avoid food 2 hours before and 1 hour after taking this drug.

Do not eat grapefruit or grapefruit juice while taking this drug.

* Incidence of emesis without antiemetics for intravenous administration of the drug, according to the following source: Kris MS, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: Update 2006.J Clin Oncol. 2006;24:2932-2947.

Medication

Potential Side Effects ivith Nutritional Implications

Additional Nutrition-Related Concerns

Monoclonal Antibodies

Rituximab

Nausea, vomiting (<10%*)

Miscellaneous

Asparaginase

Nausea, vomiting, anorexia, hyperglycemia, hepatoxicity, renal insufficiency

Bleomycin

Nausea, vomiting (<10%*), mucositis

Avoid alcohol while taking this drug.

Bortezomib

Nausea, anorexia, diarrhea, constipation

Maintain adequate hydration.

Cyclosporine

Renal insufficiency, hypomagnesemia, hyperlipidemia

Maintain adequate hydration.

Magnesium supplementation is often required.

Oral magnesium supplementation may cause GI upset.

Hyperlipidemia often resolves with discontinuation of medication. If duration of therapy is prolonged, the patient may benefit from modification of dietary fat intake.

Interferon

Nausea, vomiting, diarrhea, anorexia, dysgeusia, fatigue

Maintain adequate hydration.

Prednisone

Altered body composition (increased body fat, decreased

Encourage daily low-impact exercise.

muscle stores, fluid retention), decreased bone mineralization,

Adequate dietary calcium, vitamins D and K intake to

hyperglycemia, hyperphagia, weight gain, hypokalemia and

maximize bone density.

other electrolyte disturbances, hyperlipidemia

Diet modification and insulin may be needed to manage blood glucose levels.

Hyperlipidemia often resolves with discontinuation of medication. If duration of therapy is prolonged, the patient may benefit from modification of dietary fat intake.

Thalidomide

Nausea, constipation, hypocalcemia

Avoid alcohol while taking this drug.

Take drug at bedtime, and at least one hour after eating.

incidence of emesis

without antiemetics for intravenous administration of the drug, according to the following source: Kris MS, Hesketh PJ, Somerfield MR, et al. Ameri-

can Society of Clinical Oncology guideline for anti emetics in oncology: Update 2006.J Clin Oncol. 2006;24:2932-2947.

Impact of Supportive Treatments on Nutritional Status

Supportive treatments can also have nutritional implications. Transfusion iron overload can occur in patients requiring frequent red blood cell (RBC) transfusions, such as patients with myelodysplastic syndrome or patients undergoing HCT. Each unit of RBCs contains 200-250 mg iron, and with estimated daily losses of only 1-2 mg/day for the average person without blood loss,29 iron overload can quickly become an issue for patients requiring frequent transfusions. In addition to the potential for organ damage, increased serum iron levels can increase the risk of bacterial infections.30

For patients with documented transfusion iron overload, or those for whom prolonged RBC support is anticipated, dietary and supplemental iron restrictions may be necessary. Multivitamin supplements without iron are increasingly available now that the major manufacturers have developed separate product lines for “seniors”—these products tend to be iron free. Dietary and supplemental vitamin C should also be limited to the Recommended Dietary Allowance for the patient’s life-stage and gender, as this vitamin has been found to act as a pro-oxidant in the presence of iron.31

Hematopoietic Cell Transplantation

Hematopoietic cell transplantation (HCT) involves the use of chemotherapy with or without radiation, followed by infusion of donor (allogeneic) or previously stored patient (autologous) hematopoietic cells. HCT is used to treat a variety of hematologic malignancies, including leukemia and lymphoma, as well as nonmalignant conditions such as aplastic anemia, autoimmune diseases, and immune deficiency diseases. Despite significant advances in treatments over the past 40 years, HCT is associated with considerable treatment-related morbidity, prolonged hospitalizations, and long-term health problems.32 Typical medical and nutritional issues that may arise during the myeloablative HCT process are outlined in Table 12.3.

Conditioning (Day —10 to Day O)1

Neutropenia (Days 0 to 20)

E ngraftme nt!Early Recovery (Days 20 to 100)

Long-Term Recovery (Beyond Day 100)

Possible Medical Issues with Nutritional Implications

Tumor lysis

Opportunistic infections

Mucositis, esophagitis, gastritis

Sinusoidal obstructive syndrome

Nausea, vomiting, diarrhea

Altered taste, smell acuity

Changes in consistency, volume of saliva

Acute GVHD

Opportunistic infections

Altered taste acuity

Drug-induced nephrotoxicity

Transfusion-related iron overload

Chronic GVHD

Opportunistic infections

Delayed growth and development

Relapse, secondary tumors

Cataracts

Osteopenia/osteoporosis

Transfusion-related iron overload

Possible Nutrition Diag

noses*

Increased/decreased nutrient needs: electrolytes (N1-5.1/5.4) related to tumor lysis

Inadequate oral food/beverage intake (N1-2.1) related to mucositis, nausea, vomiting, intolerance to certain foods (especially lactose, citrus, fat)

Increased nutrient needs: fluids (N1-5.1) due to drug-induced nephrotoxicity

Increased/decreased nutrient needs: electrolytes (N1-5.1/5.4) related to drug-induced nephrotoxicity and altered electrolyte excretion or retention

Inadequate oral food/beverage intake (N1-2.1) related to GI GVHD, altered taste acuity, transition from IV to PO medications

Increased nutrient needs: fluids (N1-5.1) related to drug-induced nephrotoxicity

Involuntary weight gain (NC-3.4) related to fluid retention

Increased/decreased nutrient needs: electrolytes (N1-5.1/5.4) related to drug-induced nephrotoxicity and altered electrolyte excretion or retention

Impaired nutrient utilization (NC-2.1) related to malabsorption as a result of chronic GI GVHD and/or pancreatic insufficiency

Altered nutrition-related laboratory values: hyperglycemia (NC-2.2) related to chronic use of steroids

Altered nutrition-related laboratory values: hypertriglyceridemia (NC-2.2) related to chronic use of steroids, immunosuppressants

(continues)

Altered nutrition-related laboratory values: hyperglycemia (NC-2.2) related to chronic use of steroids

Decreased nutrient needs: iron (N1-5.4) related to blood transfusions

Increased nutrient needs: calcium, vitamin D (N1-5.1) related to chronic use of steroids

Involuntary weight gain (NC-3.4) related to chronic use of steroids

Decreased nutrient needs: iron (N1-5.4) related to blood transfusions

Chewing difficulty (NC-1.2) related to oral strictures

Swallowing difficulty (NC-1.1) related to esophageal strictures GI = gastrointestinal, GVHD = graft-versus-host disease, IV = intravenous, PO = per os (Latin for “by mouth”).

*Patients receiving autologous, syngeneic, non-myeloablative, or reduced-intensity transplants may be at lower risk of both medical and nutritional complications because of lower toxicity of conditioning and immunosuppressive regimens. tThe day of transplant is traditionally referred to as day 0.

*Data from International Dietetics and Nutrition Terminology (IDNT) Reference Manual: Standardized Language for the Nutrition Care Process. American Dietetic Association, 2008. Parentheses indicate applicable nutrition diagnosis code.

Source: Adapted from Hasse JM, Robien K. Nutrition support guidelines for therapeutically immunosuppressed patients. In: Kudsk KA, Pichard C, eds. From Nutritional Support to Pharmacologic Nutrition in the ICU. Heidelberg, Germany: Springer-Verlag; 2000:361—383.

Disease eradication following myeloablative HCT is due not only to the chemotherapy and/or radiation given during the conditioning regimen, but also to the effect of the donor cells attacking and destroying the host malignant cells in what is known as the graft-versus-malignancy effect. Non-mye-loablative and reduced-intensity treatment regimens, which utilize lower doses of radiation and chemotherapy in an attempt to utilize the graft-versus-malignancy effect to a greater degree, have made HCT feasible for patients who otherwise would not be expected to tolerate the more intense myeloablative regimens. As a result, the HCT population has expanded, to the point that older patients, patients with comorbid conditions, and patients with some premalignant diseases may receive transplants.

The current literature related to nutritional support of HCT patients relates primarily to traditional myeloablative HCT regimens. Very few studies have gathered data on non-myeloablative or reduced-intensity regimens. It is expected that these less intensive regimens will result in fewer and less intense nutritional symptoms, and will require parenteral nutrition (PN) less frequently or for shorter duration. One notable exception is that the frequency of acute and chronic graft-versus-host disease (GVHD) has been shown to be similar between myeloablative and non-myeloablative regimens, and may occur later post-transplant among patients treated with non-myeloablative regimens.3334 GVHD can have severe nutritional effects, as will be discussed later in this section.

Nutritional Requirements of the HCT Patient

Because of the intensity of the treatment regimens, patients undergoing HCT—and especially allogeneic myeloablative treatment regimens—may have increased energy, protein, and fluid requirements. Whenever possible, clinicians should use indirect calorimetry to measure resting energy expenditure for patients undergoing HCT. When indirect calorimetry is not available, studies have indicated that patients receiving myeloablative treatment regimens generally require dietary intake of 30—35 kcal/kg to maintain nitrogen balance and body weight during the cytoreduction and neutropenic phases of the transplant.35, 36 Patients receiving reduced-intensity or autologous treatment regimens may have lower energy requirements. The evidence supporting a specific protein recommendation for HCT patients is more limited, but seems to indicate that more than 2.2 g protein/kg body weight may be needed to maintain positive nitrogen balance in the early post-transplant period.35-38

Interest in the use of glutamine in the HCT population was stimulated by animal studies that found decreased mucosal atrophy, more rapid mucosal recovery, and decreased incidence of bacteremia following high-dose chemotherapy with oral glutamine or glutamine-supplemented PN.39, 40 Initially, the use of glutamine in the oncology patient population had been an area of controversy owing to concerns that tumors are avid glutamine consumers. Ultimately, these concerns were allayed when studies using rat models suggested that glutamine-enhanced PN solutions did not increase tumor size compared to unsupplemented controls.41

Unfortunately, research into the role of glutamine supplementation in the HCT population has not lived up to the promise suggested by the earlier animal studies. While Ziegler et al42 reported significantly improved nitrogen balance, decreased incidence of infection, and shortened length of stay among patients receiving glutamine-enhanced PN solutions compared to those who did not receive glutamine supplementation, numerous subsequent studies have failed to replicate those findings.43-47 Therefore, the use of glutamine-enhanced PN solutions is not currently recommended because of the solutions’ cost and lack of demonstrated benefit.35 Similarly, the use of oral glutamine has failed to show a convincing benefit in improving oral intake or reducing the incidence and severity of oral mucositis or diarrhea in the HCT population48, 49 and, therefore, is not recommended.35

Fluid requirements, especially in patients receiving myeloablative regimens, are also elevated because of the use of nephrotoxic conditioning regimens, immunosuppressive agents, and antimicrobial agents. Fluid requirements have been estimated to be 1,500 mL/m2,32 but may vary based on the individual’s medical condition. Fluid restrictions may be necessary if the patient develops sinusoidal obstruction syndrome (discussed later in this chapter). Conversely, fluid requirements may increase if the patient develops renal insufficiency or has significant gastrointestinal losses from diarrhea or GVHD.

Parenteral Nutrition Support

Many HCT patients—but especially those undergoing myeloablative treatment regimens—experience significant oral mucositis, taste changes, nausea, vomiting, and diarrhea in the early post-transplant phase as a result of the conditioning regimens. These side effects can result in a significant reduction in dietary intake. PN is commonly used as the sole source of nutrition support or to supplement oral intake. However, the American Dietetic Association’s evidence-based guideline on the use of PN following HCT recommends PN be used only in selected patients because of the increased risk of complications, increased cost, and lack of significant improvement in treatment outcomes.35 Prophylactic PN is not recommended. Whenever possible, it is best to work closely with the patient and/or caregivers during this stage to find acceptable foods in an attempt to maintain oral intake and gastrointestinal integrity.

In a retrospective cohort study of 20 patients with AML undergoing HCT, Iestra et al. found that only 60% of patients required PN support based on the following criteria: (1) severe malnutrition at admission, (2) a prolonged period of minimal oral intake (7—10 days), or (3) weight loss of more than 10% of total body weight.50 Calvo et al found that the costs associated with intensive nutritional monitoring and daily assessment of oral intake were approximately one-half of the potential cost savings achieved by avoiding inappropriate PN use and the infectious complications that could accompany unneeded PN.51

Concerns regarding the use of PN following HCT include the potential for intravenous lipids to contribute to an increase in infectious complications, the potential for glucose-based solutions to exacerbate efforts to maintain normal blood glucose levels and further increase infection risk, the potential for inhibiting oral intake needed to maintain gastrointestinal mucosal integrity, and the possibility of contributing to post-transplant hepatic complications as evidenced by elevated serum transaminase, alkaline phosphatase, and bilirubin levels.52 These liver function parameters, if related to PN, often improve with discontinuation or cycling of the PN infusion.

Infectious complications, while increasingly treatable, remain a significant cause of transplant-related mortality.53 One of the first reports suggesting PN may contribute to infectious complications following HCT came from Weisdorf et al. in 1987; in their study, these authors found that among patients receiving allogeneic HCT, bacteremias occurred in 72% of patients receiving PN and 48% of patients who did not receive PN.54 Several studies in the late 1970s and early 1980s demonstrated that 20% intravenous lipid emulsions could inhibit phagocytosis and alter neutrophil chemotaxis in healthy volunteers,55-57 potentially increasing the risk of infection. However, a randomized trial of 512 patients undergoing allogeneic or autologous HCT for hematologic malignancies found no significant differences in the incidence of bacterial or fungal infections between intravenous lipid emulsions (of 20% linoleic acid) at either 6-8% or 25-30% of total daily energy.58 Similarly, a randomized trial of 66 patients receiving allogeneic HCT for hematologic malignancies comparing isocaloric glucose-based (100% glucose as nonprotein calories) and lipid-based (80% lipids and 20% glucose as nonprotein calories) PN solutions found no significant differences between the 2 groups for incidence of fever or positive blood cultures.59

The American Dietetic Association’s evidence-based guideline on the use of lipids in PN formulations following HCT calls for providing 25-30% of energy as lipids to prevent fatty acid deficiency and improve blood glucose control.35 The guideline also recommends monitoring triglyceride levels regularly while patients are receiving PN solutions containing lipids, and notes that the lipid infusion should be discontinued if the patient develops hyperlipidemia.35

Infections related to hyperglycemia in HCT patients receiving PN are also a concern. In a retrospective chart review of 208 patients undergoing HCT (including both autologous and allogeneic patients as well as those receiving myeloablative and reduced-intensity conditioning regimens), Sheean and Braunschweig found that patients who received PN were 4 times more likely to experience hyperglycemia (defined as glucose > 110 mg/dL) compared to than those who did not receive PN (OR = 3.9; 95% confidence interval: 2.7-5.5).60 No association was observed between the dextrose administration dose (range: 1.3—3.9 mg/kg/min) and serum glucose concentrations. Sheean and colleagues also reported that the likelihood of infection was 2 times higher among patients receiving PN who had hyperglycemia compared to those who did not have hyperglycemia (OR = 2.1; 95% confidence interval: 1.3-3.5) after excluding patients on steroids.61 Clearly, careful blood glucose monitoring and management while on PN is vital in this immunosuppressed population at increased risk of infection complications.

The potential for PN to delay resumption of oral intake is also a concern. Charuhas et al. found that providing PN once the patient has been able to transition from the hospital to the ambulatory setting (roughly corresponding to the transition from the neutropenic to the engraftment/early recovery phase) resulted in delayed resumption of oral intake.62 In their study of 258 HCT patients, the patients who were randomized to receive intravenous hydration were able to meet more than 85% of their estimated caloric requirements an average of 6 days earlier than members of the group receiving PN.62

Enteral Nutrition Support

Enteral feedings are the preferred route of nutrition support in any patient population, as the presence of nutrients in the intestinal tract is thought to maintain mucosal integrity and prevent bacterial translocation. However, the use of nasoenteric feeding tubes is challenging in the early post-transplant period because of the potential for tube displacement and the risk of aspiration as a result of treatment-induced vomiting,63- 64 increased risk of bleeding complications during tube placement, and increased risk of ulceration at contact points with the tubing.

Despite these obstacles, a small number of studies have reported successful enteral feedings in the early post-transplant period, primarily in children. In a study of 15 adult patients undergoing HCT for a variety of hematologic malignancies,65 nasojejunal feeding tubes were placed prior to initiation of chemotherapy. Eight of the 15 patients tolerated the enteral feedings and were able to maintain their feeding tubes until the day of engraftment. One patient refused tube placement, 4 patients lost their tubes due to vomiting, and 2 patients experienced epistaxis.

Papadopoulou et al66 reported that of 21 children undergoing HCT who elected to receive enteral feedings, only 8 patients stopped the feedings prematurely. Seven vomited the tube after an average of 10 days, and 1 stopped the enteral feeding because of diarrhea. The timing of feeding tube placement in this study is not described.

Langdana et al reported that of 49 children undergoing HCT who received nasogastric tubes during conditioning or the first week post-transplant, 42 were able to be maintained exclusively on enteral feedings.67 Conversely, Hopman et al reported that of 12 patients who agreed to enteral feedings when they were unable to meet at least 75% of estimated caloric needs by oral intake, only 3 could be maintained exclusively by enteral feedings.68 The researchers did note that patients who received enteral feedings for a longer time pre-transplant seemed to tolerate enteral feedings better in the post-transplant period, and that cholestasis was less common among patients who received enteral feedings compared to a group who received parenteral nutrition.

Taken collectively, these small studies suggest that enteral feedings during HCT may be possible. Clearly, though, the factors associated with successful enteral feedings require further study.

Graft-versus-Host Disease

Graft-versus-host disease (GVHD) is a common post-transplant complica-tion.69 Although we refer to the condition as a “disease,” it actually is a normal physiologic response in which host tissue cells that were damaged during the conditioning regimen begin secreting immunostimulatory cytokines. These cytokines enhance expression of MHC antigens and adhesion molecules, thereby inducing a cascade of immune responses in the newly transplanted donor hematopoietic cells, including activation of cytotoxic T cells and natural killer cells.69 These activated donor T cells interact with the host antigen-presenting cells, resulting in an amplification of local tissue injury and destruction.69 The skin, liver, and intestinal tract are most often affected, as demonstrated by symptoms ranging from a mild skin rash or elevated liver function tests to fatal organ failure.

To prevent this complication, transplant patients are given immunosuppressive medications, such a cyclosporine or tacrolimus, until the donor cells are able to develop a tolerance to the host tissues. Corticosteroids are commonly used in the treatment of GVHD, and typically require a prolonged tapering schedule. Hyperglycemia and osteopenia/osteoporosis are common complications of these treatment schedules. Patients should be counseled to participate in daily weight-bearing exercise, and to consume adequate calcium and vitamin D through both diet and supplements.

Milder cases of gastrointestinal GVHD may, in part, be managed through use of diets that are low in GI stimulants or irritants, such as caffeine, lactose, acids, fats, and dietary fiber. It is especially important that patients with gastrointestinal GVHD closely follow food safety guidelines to avoid bacterial translocation across the damaged gastrointestinal mucosa. Higher grades of gastrointestinal GVHD may require PN and complete bowel rest to slow fluid losses from diarrhea and allow the gastrointestinal mucosa time to heal. The Seattle Cancer Care Alliance has developed patient education materials on its “gastrointestinal diets,” which are available through the organization’s website at http://www.seattlecca.org/patientsandfamilies/ nutrition/nutritionDietsguidelines/.

Chronic GVHD (cGVHD), typically defined as GVHD occurring after day 100 post-transplant, is a major cause of morbidity and mortality following HCT, though the pathobiology of the disease is not well understood.70 Nutritional concerns typically arise in conjunction with oral, hepatic, and gastrointestinal cGVHD, which can cause mouth pain, esophageal strictures, malabsorption, and weight loss.7172 In particular, oral ulcerations and pain may limit oral intake.73 Malabsorption can occur for a variety of reasons, including alterations of the intestinal mucosa, bile acid deficiency, pancreatic enzyme deficiency, or bacterial overgrowth.72

Low-fat diets and pancreatic enzymes may be effective in managing GI symptoms in patients with cGVHD. Patients should be evaluated for fat-soluble vitamin deficiencies, and supplements should be used as needed. Dietary intake should be monitored regularly and evaluated for nutritional adequacy.

Sinusoidal Obstruction Syndrome

Hepatic sinusoidal obstruction syndrome (SOS), previously known as veno-occlusive disease, can occur when sinusoidal epithelial cells are damaged by high-dose conditioning regimens. The damaged cells swell and eventually slough, causing congestion and obstruction of blood flow through the sinusoid.74 SOS is characterized by hepatomegaly, fluid retention, ascites, and jaundice.74 Fluid and sodium restrictions may be needed to limit the rapid fluid weight gain that often occurs with SOS. If hyperbilirubinemia persists for longer than a week and the patient is receiving PN, trace element solutions containing copper and manganese should be discontinued to avoid accumulation of these elements, which are normally excreted through bile.75 Manganese toxicity can lead to neurotoxicity, whereas copper toxicity can further exacerbate hepatic damage and cause gastrointestinal side effects, such as abdominal pain, cramping, nausea, vomiting, and diarrhea.76

Food Safety

Because the hematopoietic system plays a significant role in the immune system, treatment for hematologic malignancies often results in neutropenia. Food-borne illnesses could easily occur, and could significantly affect a patient’s recovery. Such illnesses are potentially avoidable with proper training of the patient and caregivers. Many institutions have developed neutropenic diet guidelines that are intended to exclude foods that carry a higher likelihood of bacterial contamination. These guidelines often vary from institution to institution, however, and they are rarely based on actual microbiological testing of the food items in question.

Even foods that are approved for inclusion in neutropenic diets can be a source of food-borne illness if proper food sanitation, storage, preparation, and serving procedures are not followed. In a randomized trial comparing adherence to either a neutropenic diet or the Food and Drug Administration’s (FDA’s) food safety guidelines among pediatric oncology patients receiving myelosuppressive chemotherapy, Moody et al. found no difference in infection rates between the two study arms.77 The study reported a greater adherence rate with the food safety guidelines (100%) than with the neutropenic diet (94%), suggesting that the food safety guidelines, which are less restrictive regarding food choice, but more global with regard to hygiene, are more appropriate as a patient and caregiver education tool. The websites of the Centers for Disease Control and Prevention’s (CDC’s) Food Safety Office (http://cdc.gov/foodsafety/) and the FDA’s Center for Food Safety and Applied Nutrition (http://www.cfsan .fda.gov/) offer the most current food safety guidelines and patient/client education materials.

SUMMARY Treatment-related complications will likely have a greater impact on nutritional status than will disease-related issues for patients with hematologic malignancies. The nutritional concerns of this patient population run the gamut from fairly minor implications for patients who can be successfully treated with new small-molecule drugs such as imatinib, to some of the most challenging nutrition issues encountered in oncology among patients who receive myeloablative HCT. Food safety is a special concern for people being treated for hematologic malignancies, as these individuals are often in an immunocompromised state, either as a result of the disease or the treatment. Clinicians interested in specializing in oncology nutrition should develop their skills in anticipating nutrition-related effects of planned treatment regimens, and working with patients and caregivers to minimize the impact of treatment on nutritional status.

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