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Editorial theme | Nutritional support for improved clinical outcomes post HSCT

Nov 2, 2022
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Learning objective: After reading this article, learners will be able to describe developments in nutritional supportive care for patients who have undergone a stem cell transplant.

The nutritional status of patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat a hematologic condition can be affected at any stage of their treatment. Pretreatment characteristics, such as cachexia and weight loss, can negatively impact quality of life, physical activity, therapeutic response, and prognosis.1

At the stage of allo-HSCT, most patients will have received chemotherapy and may have experienced symptoms related to intensive conditioning chemotherapy, such as mucositis and anorexia.2 Following allo‑HSCT, graft-versus-host disease (GvHD), as well treatments such as glucocorticoids and immunosuppressants, can limit the success of transplant, with GvHD being associated with significant morbidity and mortality. Subsequently, novel approaches that minimize the severity and incidence of GvHD, as well as the nutritional deficiencies that may arise from its treatment, are needed.

One such area for these novel approaches is nutritional support and optimizing the nutritional status in patients who have undergone allo-HSCT, including performing research to understand how nutrition effects and can improve clinical outcomes. This topic was recently covered by GvHD Hub; preliminary data from the phase III NEUTRODIET trial were summarized, which explored the effect of diet on infection in patients post-HSCT.

In the coming months, the GvHD Hub will be exploring the importance of supportive care in patients with GvHD, both during and after transplant. For the first piece in this editorial theme, we are pleased to present a summary of the role and effect of nutrition on clinical outcomes in patients undergoing HSCT.

The past, present, and future of nutritional support for improving GvHD and clinical outcomes in patients post HSCT

In this article, we summarize findings and data from three studies that have explored current clinical practices, novel therapeutics, and future research strategies relating to the nutritional management of patients receiving HSCT.

It is established that insufficient energy and nutrient intake in patients with hematologic malignancies can be prevented and treated following onset with oral, enteral, and parenteral nutrition.2 However, even with recommendations on how and when to use nutritional support, malnutrition and weight loss can progress due to delayed or ineffective clinical management.2 For example, the prevalence of malnutrition in multiple myeloma is ~23% prior to treatment, with this often worsening during the course of therapy.2 To determine what nutritional support patients with multiple myeloma receive, how it compares to accepted guidance, and whether this affects clinical outcomes, Kuypers, et al.2 conducted a retrospective analysis of patients who received HSCT and published their findings in Supportive Care in Cancer.

Our current knowledge on improving nutritional status in patients is largely based on research limited to different types and routes of nutritional support. Moving forwards, research in the field is looking to incorporate novel medicines and therapies. One such novel approach is the administration of an oral polymeric formulation enriched with transforming growth factor-β2 (TGF-β2; referred to as TE-OPF) for nutritional support.3 TGF-β2 is an anti-inflammatory cytokine with diverse roles, including gut flora modulation, homeostasis of gut inflammation, immune system regulation (including white cell activation, differentiation, and proliferation), immune tolerance, and prevention of autoimmunity.3 TGF-β2 is the most studied bioactive peptide for nutritional support in patients with chronic inflammatory bowel disease (IBD), the clinical manifestations of which may closely resemble gastrointestinal acute GvHD.3 In August 2022 in Nutrients, Morello, et al.3 presented data from a clinical trial exploring the use of TE-OPF in patients who had undergone allo-HSCT, to evaluate both its anti-inflammatory effects and potential for calorific support.

Frequently considered outcomes in nutritional assessment in patients post-HSCT include survival data, GvHD rates, treatment comorbidities (e.g., infection), physical function, and weight.2,3 However, an important consideration that is often overlooked is how nutrition can support and improve exercise and physical performance, which can both directly improve clinical outcomes and health-related quality of life in patients.4 The GvHD Hub has previously presented the study design of the IRENE-G study, which looked to increase our understanding of these relationships.

Does parenteral and nutritional support affect clinical outcomes in patients who have undergone allo-HSCT?1

The aim of the study by Kuypers, et al.2 was to investigate the associations between prolonged inadequate calorie intake, nutritional status type, and clinical outcomes in adults with multiple myeloma post HSCT.

The study was a retrospective case note analysis of patients treated at a single center between 2015 and 2022. All patients were aged ≥18 years, had a diagnosis of multiple myeloma, and a had an Eastern Cooperative Oncology Group performance status of ≤2.

Data on the following were collected:

  • demographics;
  • height, weight, and weight changes;
  • diet, including nutrition support type (e.g., enteral, oral, or parenteral);
  • transplant, including engraftment time and length of stay; and
  • adverse events, including episodes of infection.

Nutritional risk was scored using the Malnutrition Screening Tool (not at risk, 0–1; at risk, ≥2) and nutritional status was classified using the Subjective Global Assessment (SGA) or Patient-Generated SGA (PG-SGA), which are both established and validated measures. Nutritional support provided was reviewed according to the American Society for Parenteral and Enteral Nutrition (ASPEN) and European Society of Clinical Nutrition and Metabolism (ESPEN) guidelines on nutritional support in HSCT.

Results

In total, 113 patients were included in the final analysis. Demographic and clinical data for the patients recruited to the study are presented in Table 1. Of note, only 3% of patients were underweight prior to HSCT.

Table 1. Characteristics of patients included in the retrospective study*

Characteristic, % (unless otherwise stated)

All patients
(N = 113)

Median age (range), years

62 (3371)

Sex

 

              Male

61

              Female

39

R-ISS stage

 

              I

19

              II

41

              III

10

              Relapsed disease

15

              Unstageable

15

Number of comorbidities

 

              1

83

              ≥2

17

Transplant number

 

              1

90

              2

10

R-ISS, revised International Staging System.
*Adapted from Kuypers, et al.2

The use of different types of nutrition can be seen in Table 2, demonstrating varying adherence to guidelines.

Table 2. Use of nutritional support in patients receiving stem cell transplant*

Recommendation

Patients in which used, %

Nutrition support used in malnourished patients anticipated to be unable to consume and/or absorb adequate nutrients for 714 days

100

Enteral nutrition used in patients with a functioning gastrointestinal tract in whom oral intake is inadequate to meet nutritional requirements

10

Parenteral nutrition used in patients with severe mucositis, ileus, severe malabsorption, protracted diarrhea, or intractable vomiting

37

Parenteral nutrition ceased as soon as toxicities resolved after stem cell engraftment

100

*Adapted from Kuypers, et al.2

Parenteral nutrition was associated with a shorter platelet engraftment time by 2.7 days (p = 0.036) and a longer hospital stay by 6.1 days (p < 0.001) compared with enteral/oral nutrition. The type of nutrition support was not associated with neutrophil engraftment time (p = 0.365) and inadequate energy intake for ≥7 days was not associated with any clinical outcomes (p > 0.05).

TGF-β2-enriched oral polymeric formulation to prevent malnutrition in patients post HSCT2

Morello, et al.3 conducted a single-center, prospective, interventional trial. Patients undergoing allo-HSCT were given TE-OPF from the day of admission to their discharge following HSCT. All patients were aged ≥18 years, with no history of gastrointestinal problems, including fistulas, perforations, or intractable vomiting.

TE-OPF dosing was calculated according to body mass index and calorific need and was adjusted through the course of transplant according to changes in weight using a predetermined schema. No minimal dose was defined, but 50% of the prescribed dose was considered adequate for ongoing trial participation. Based on a power calculation (power, 75%; α-level, 0.05), recruitment was stopped when 24 subjects had received ≥50% of the prescribed TE-OPF.

The primary outcomes were:

  • to reduce the rate of severe malnutrition to <50% at Day 28 post HSCT (based on an observed rate of 75% in a prior study); and
  • to evaluate safety, including adverse events reported during TE-OPF administration.

Nutritional status was assessed using the PG-SGA scale on admission, Day 0 (day of transplant), and Days 7, 14, 21, and 28, and scored as Grade A (good nutritional status), Grade B (moderate malnutrition), or Grade C (severe malnutrition respect). A second score was given based on weight loss, food intake, symptoms, and physical activity. Secondary outcome data included development of GvHD, treatment cessation, and median overall survival. Cytokine levels were measured at defined timepoints to determine any association with clinical outcomes.

For analysis, patients were divided into:

  • Group A (received >50% of prescribed TE-OPF); or
  • Group B (received <50% of prescribed TE-OPF).

Results

Overall, 51 patients who underwent allo-HSCT were included in the study, with patient characteristics presented in Table 3.

Table 3. Demographic and clinical characteristics of trial participants*

Characteristic, % (unless otherwise stated)

All patients
(N = 51)

Median age (range), years

55 (20−72)

Median follow-up (range), days

279 (29−564)

Diagnosis

 

              ALL/AML/MDS/MPN

78.5

              Lymphoma/myeloma

21.5

Disease status as remission

 

              CR

43.2

              MRD

41.1

              Advanced disease

15.7

Donor type

 

              Matched related

41.2

              Matched unrelated

39.2

              Haploidentical

15.7

Stem cell source

 

              Peripheral blood

94.1

              Bone marrow

5.9

Nutritional status at admission

 

              PG-SGA A

74.5

              PG-SGA B

23.5

              PG-SGA C

2.0

ALL, acute lymphoblastic leukaemia; AML, acute myeloid leukaemia; CR, complete remission; MDS, myelodysplastic syndromes; MPN, myeloproliferative neoplasms; MRD, minimal residual disease; PG-SGA, Patient Generated-Subjective Global Assessment Score.
*Adapted from Morello, et al.3

At the end of the study, after a median follow-up of 416 days, the estimated median overall survival was 734 days for well or moderately nourished patients (PG-SGA A/B) in comparison to 424 days for malnourished patients (p = 0.03).

Inadequate TE-OPF was associated with an increase in gastrointestinal GvHD cumulative incidence, with a rate of 38% in Group B vs 0% in Group A (p = 0.006). No differences were found in the incidences of chronic GvHD or acute GvHD between the two groups.

Pneumonia was more common in patients in Group B (48.1%) compared with those in Group A (12.5%); other key outcome data can be seen in Table 4. No adverse events relating to TE-OPF intake were observed.

Table 4. Key clinical outcome data for patients in Group A and Group B*

Clinical outcome

Group A
(n = 24)

Group B
(n = 27)

p value

PG-SGA Grade C, %

12.5

88.9

0.000

Acute GvHD, %

29.1

51.8

NS

GI acute GvHD, %

0

29.6

0.005

Pneumonia %

12.5

48.1

0.006

Median overall survival after allo-HSCT (range), days

734 (580881)

424 (347501)

NS

Allo-HSCT, allogeneic hematopoietic stem cell transplantation; GI, gastrointestinal; GvHD, graft-versus-host disease; NS, not significant; PG-SGA, Patient Generated-Subjective Global Assessment Score.
*Adapted from Morello, et al.3

Of the cytokines measured, mean insulin-like growth factor-1 was lower in Group B than Group A at Day 14 (109.16 vs 165.56 ng/mL; p = 0.024) and Day 28 (109.52 vs 153.64 ng/mL; p = 0.013). Cumulative incidence of acute gastrointestinal GvHD was lower in patients with higher values of insulin-like growth factor-1 at 14 and 28 days (p = 0.021 and 0.032, respectively).

IRENE-G trial: Impact of resistance exercise and nutritional endorsement on physical performance in patients with GvHD4

The IRENE-G trial represents a novel approach to assessing the importance of nutrition for exercise and physical performance and improved overall clinical outcomes and GvHD. The main hypothesis is that while physical performance should be improved in both study groups after 24 weeks, the effect will be significantly greater in the experimental group. This would suggest a benefit for patients receiving structure rather nutritional support. It is anticipated that patients in the experimental group will experience less fatigue, a reduced GvHD symptom burden, improved quality of life, increased muscle strength, a better nutritional status, and better endurance capacity.

Discussion

Kuypers, et al.2 identified that patients undergoing HSCT who received parenteral nutrition achieve platelet engraftment sooner than those who do not, but also remain in hospital longer. However, patients who experience inadequate energy intake for ≥7 days do not experience poorer clinical outcomes. The study also established that despite clear guidelines for the optimal use of nutritional support in patients undergoing HSCT, there can be significant deviation from this is in clinical practice.

In the novel interventional study by Morello, et al.3, TE-OPF appears to show efficacy in reducing the incidence of malnutrition in patients who have received allo-HSCT. In particular it exerts a protective role in reducing acute gastrointestinal GvHD and pneumonia. Larger, prospective controlled clinical studies will be needed to validate these findings.

Finally, as stated by the authors, the IRENE-G study will be the first prospective, randomized, controlled clinical trial to evaluate the role of exercise and guided nutritional support in the management and treatment of GvHD.4 The comparison of exercise with nutritional management of patients with GvHD relative to nutritional management alone, should provide valuable insights into the complications that patients with GvHD may experience after allo-HSCT. In addition, it is hoped that the clear protocol guiding the adjustment of nutritional support will correct the variability in patient management identified by Kuypers, et al.2

Conclusion

Diet and nutrition are fundamental to supporting patients through allo-HSCT and to help manage nutritional deficiencies in GvHD, a major complication of allo-HSCT. Strategies, including parenteral nutrition, bioactive medicinal products, exercise, and adherence to best practice guidelines, are important factors that may help improve clinical outcomes for patients with hematologic malignancies. Further, large-scale and randomized clinical trials are needed to validate these considerations and inform us of what approaches to nutritional support are optimal for patients in this cohort.

  1. Kim DH. Nutritional issues in patients with cancer. Intest Res. 2019;17(4):455-462. DOI: 5217/ir.2019.00076
  2. Kuypers J, Simmance N, Quach H, et al. Nutrition support use and clinical outcomes in patients with multiple myeloma undergoing autologous stem cell transplant. Support Care Cancer. Online ahead of print. DOI: 10.1007/s00520-022-07358-y
  3. Morello E, Arena F, Malagola M, et al. Malnutrition prevention after allogeneic hematopoietic stem cell transplantation (alloHSCT): A prospective explorative interventional study with an oral polymeric formulation enriched with transforming growth factor beta 2 (TGF-β2). 2022;14(17):3589. DOI: 10.3390/nu14173589
  4. Rivera J, Kühl R, Zech U, et al. Impact of resistance exercise and nutritional endorsement on physical performance in patients with GvHD (IRENE-G study) - design and rational of a randomized controlled trial. BMC Cancer. 2022;22(1):440. DOI: 1186/s12885-022-09497-1