This article is part of the 2018 NMJ Oncology Special Issue. Download the full issue here.
Ren G, Zhang J, Li M, et al. Protein blend ingestion before allogeneic stem cell transplantation improves protein-energy malnutrition in patients with leukemia. Nutr Res. 2017;46:68-77.
To determine whether the addition of supplemental whey and soy protein could mitigate muscle wasting and loss of muscle strength typically seen following allogeneic stem cell transplantation for acute lymphoblastic and acute myelogenous leukemia
Double-blind, randomized, controlled clinical trial
Participants were recruited from the Bone Marrow Transplantation Center at Hebei Yanda Lu Daopei Hospital in Hebei, China. Participants included both males and females and ranged in age from 9 to 50; all were diagnosed with either acute lymphoblastic leukemia (ALL) or acute myelogenous leukemia (AML). All participants underwent an allogeneic stem cell transplant during the study period utilizing the same protocol: busulfan, total body irradiation, and cyclophosphamide.
Eighty patients were enrolled; 77 had complete information. Of these, 27 were excluded due to other hematopoietic disease or infections. Out of the remaining 50, 26 were not included in the final study results due to either a change in their protocol or missing specimen(s). Thus, 24 participants completed the study.
The control group (n=12) consumed a “natural foods” diet that consisted of standard nutritionist-designed daily meals. The intervention group (n=12) was provided the same natural foods diet in addition to 1.5 g/kg per day of a whey and soy protein blend. Actual dietary intake was monitored daily.
Participants in the intervention group were instructed to drink 0.5 g/kg protein powder (50% protein from whey protein isolate and 50% protein from soy isolate) 30 minutes after each of the 3 main meals of the day, for a total of 1.5 g/kg/day. The study was conducted from patient enrollment (0-30 days prior to transplant) through 30 days after transplant.
Study Parameters Assessed
Routine monitoring of dietary intake, anthropomorphic variables, and biochemical indicators was performed on a daily and weekly basis from enrollment (0-30 days prior to transplant) through the conclusion of the study (30 days posttransplant). Time to engraftment, a measure of transplant success, was also tracked for all participants.
Even with declining caloric intake in the posttransplant period, the additional protein may have an impact on maintaining and gaining muscle mass, and supporting serum markers of protein status.
Dietary intake was assessed with a 24-hour dietary recall questionnaire, a food nutrition composition table, and nutritionist software. Blood samples were collected to assess biochemical indicators: serum albumin, globulin, and total protein levels. Muscle strength was tested at 3 points during the study: at baseline (time of enrollment into study), pretransplantation, and posttransplantation.
Anthropomorphic measures were taken by the same clinical nutritionist at each weekly interval and included the following:
- Height in centimeters using a wall-mounted stadiometer
- Weight in kilograms using an electronic scale
- Triceps skinfold thickness (TSF) with a dial calibrated to 0.2 mm at the halfway point between the acromion and the olecranon process of the right upper arm
- Upper arm circumference (AC) using flexible tape at the nearest 0.1 cm halfway between the right acromion and olecranon process
- Muscle mass, measured as upper arm muscle circumference (AMC)
- Calf girth and thickness of the thenar eminence
Primary Outcome Measures
Changes in anthropometric measurements, changes in muscle strength, and changes in serum protein composition from enrollment through the conclusion of the study at 30 days posttransplantation.
Three time points were used for the final analysis: baseline (time of enrollment; varied from 0-30 days before transplant); pretransplant; and posttransplant. Time to engraftment was a secondary outcome measure.
Pretransplant and posttransplant energy (caloric) intake and protein intake from natural food diets was similar between the control and intervention groups. Energy intake decreased dramatically and proportionally in both groups in the posttransplant period. The majority of patients in control and intervention groups showed no statistically significant weight change in the posttransplant period. However, the majority of patients in the intervention group (n=9, or 75%) had improved muscle mass in the posttransplant period as measured by upper arm circumference (AC), while the majority of patients in the control group (75%) had a loss in muscle mass/AC. Similarly, 100% of the participants in the treatment group who consumed additional protein during the period from baseline to pretransplant (n=6) showed an increase in muscle strength.
Measures of albumin, globulin, and total protein assessed in both the pretransplant and posttransplant periods were consistently higher in a majority of the intervention group participants compared to the control group. From baseline to pretreatment, albumin levels increased in 75% of the intervention group and only 25% of the control group; globulin levels increased in 75% of the intervention group and 41% of the control group; and total protein levels increased in 75% of the intervention group and only 25% in the control group.
From pretreatment to posttreatment, globulin levels increased in 66% of the intervention group and 41% of the control group; total proteins increased in 58% of the intervention group and 33% of the control group.
Secondary outcome measures also showed notable differences between control and intervention groups. Engraftment is a reliable measure of transplant success, marking the end of the most critical portion of the transplant period and the beginning of a return to immune competence. There was a statistically significant difference in time to engraftment between the 2 arms of this study. Time to engraftment was 12.2±2.0 days in the intervention group and 15.1±2.9 days for the control group (P<0.05). Time to engraftment for 2 patients in the intervention group was as short as 10 days. As one might expect with a shortened time to engraftment, the incidence of pulmonary infections was lower in the intervention group (41%) than the control group (66%). Baseline incidence of infection was 0 in both groups.
According to the Center for International Blood and Marrow Transplant Research, there were almost 9,000 allogeneic stem cell transplants performed in the United States in 2016, the most recent data available.1 Allogeneic stem cell transplantation involves the ablation of a patient’s immune system to rid the body of leukemia, lymphoma, or myeloma cell lines, followed by the infusion of hematopoietic stem cells from other related or unrelated donors with an acceptable human leukocyte antigen (HLA) match.2
Weight loss and malnutrition are common following allogeneic stem cell transplantation. In one study of almost 200 people who received an allogenic transplant, 55.6% of patients lost over 5% of their body weight, and there was a 1.6% rise in malnutrition.3 Longitudinal studies have demonstrated that loss of muscle mass associated with allogeneic transplants is extremely common and can last for as long as 6 years posttransplant.4,5 This loss in muscle mass has been positively correlated with graft-versus-host disease and decreased performance status.4
Serum measures of protein also tend to decline after bone marrow transplant. The decline in albumin, globulin, and total protein has been positively correlated with severe acute graft-versus host-disease and posttransplant mortality.6,7
Immunodeficiency is universal in patients who have received an allogeneic stem cell transplant, often persisting for months after the procedure. As a result, infectious complications are common in this posttransplant patient population, leading to significant morbidity and mortality.8
In the present clinical trial, the addition of 1.5 g/kg of a 1:1 combination of soy and whey protein powder was added to the recommended diet of patients undergoing allogeneic stem cell transplantation. The whey-soy combination was chosen based on the results of a prior study demonstrating its ability to augment the grasping force in a rat exercise model.9 An earlier human trial conducted by Reidy et al on the same whey-soy combination found that it promoted muscle protein synthesis in healthy individuals.10 Whey is unique in that it is rapidly degraded into branched-chain amino acids on ingestion. These branched chain amino acids, leucine in particular, have the ability to stimulate muscle protein synthesis through activation of the mammalian target of rapamycin (mTOR)-P70s6K pathway.11,12 Both whey and soy protein can also enhance the gastrointestinal microbiome. Soy protein has been documented to increase gastrointestinal microdiversity in a rat model, while soy has been shown to increase Lactobacillus species, while decreasing Clostridium in a mouse model.13,14
The present study demonstrates the feasibility of adding whey-soy protein to a recommended diet during the transplant period. Even with declining caloric intake in the posttransplant period, the additional protein may have an impact on maintaining and gaining muscle mass, and supporting serum markers of protein status. Evidence that this may positively impact morbidity associated with transplant comes in the form of secondary outcomes, with decreased time to engraftment and a decreased incidence of posttransplant infections in the experimental group. Notably, the experimental and control groups were otherwise comparable with respect to age, gender, leukemia type, and stem cell source.
While the results of this trial are encouraging, additional research is warranted. The patient population was relatively small (N=24), and patients were enrolled in the study anywhere between 0 to 30 days prior to transplant, adding inconsistency to the timing of the study.
- US Department of Health and Human Services. How many bone marrow or umbilical cord blood transplants are performed in the United States? Health Resources and Services Administration. Center for International Bone and Marrow Research. https://bloodcell.transplant.hrsa.gov/about/general_faqs/index.html#1990%20number%20tx%20inUS. Accessed September 14, 2018.
- Singh AK, McGuirk JP. Allogeneic stem cell transplantation: a historical and scientific overview. Cancer Res. 2016;76(22):6445-6451.
- Rieger CT, Wischumerski I, Rust C, et al. Weight loss and decrease of body mass index during allogeneic stem cell transplantation are common events with limited clinical impact. PLoS One. 2015;10(12):e0145445.
- Kyle UG, Chalandon Y, Mirabell R, et al. Longitudinal follow up of body composition in hematopoietic stem cell transplant patients. Bone Marrow Transplant. 2005;35(12):1171-1177.
- Iestra JA, Fibbe WE, Zwinderman AH, et al. Body weight recovery, eating difficulties and compliance with dietary advice in the first year after stem cell transplantation: a prospective study. Bone Marrow Transplant. 2002;29(5):417-424.
- Ferriera EE, Guerra DC, Baluz, K, et al. Nutritional status of patients submitted to transplantation of allogeneic hematopoietic stem cells: a retrospective study. Rev Bras Hematol Hemoter. 2014;36(6):414-419.
- Resvani AR, Storer BE, Storb RF, et al. Decreased serum albumin as a biomarker for severe acute graft-versus-host disease after reduced-intensity allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2011;17(11):1594-1601.
- Center for International Blood and Marrow Transplant Research. Guidelines for preventing infectious complications among hematopoietic cell transplant recipients: a global perspective. Bone Marrow Transplant. 2009;44(8):453-558.
- Ren G, Yi S, Zhang H, et al. Ingestion of soy-whey blended protein augments sports performance and ameliorates exercise-induced fatigue in a rat exercise model. Food Funct. 2017;8(2):670-679.
- Reidy PT, Walker DK, Dickinson JM, et al. Protein blend ingestion following resistance exercise promotes human muscle protein synthesis. J Nutr. 2013;143(4):410-416.
- Anthony JC, Yoshizowa F, Anthony TG, et al. Leucine stimulates translation initiation in skeletal muscle of postabsorptive rats via rapamycin-sensitive pathway. J Nutr. 2000;130(10):2413-2419.
- Crozier SJ, Kimball SR, Emmert SW, et al. Oral leucine administration stimulates protein synthesis in rat skeletal muscle. J Nutr. 2005;135(3):376-382.
- Butteiger DN, Hibberd AA, McGraw NJ, et al. Soy protein compared with milk protein in a western diet increase gut microbial diversity and reduces serum lipids in golden Syrian hamsters. J Nutr. 2016;146(4):697-705.
- McAllan L, Skuse P, Cotter PD, et al. Protein quality and the protein to carbohydrate ratio within a high fat diet influences energy balance and the gut microbiota in c57BL/6J mice. PLoS One. 2014;9(2):e88904.