Phase 3 Data Support Leaving the “Neutrodiet” Behind After Stem Cell Transplant

Federico Stella, MD

A nonrestrictive diet did not increase the rate of infection, deaths, poor nutritional outcomes, or acute graft-vs-host disease (GVHD) in patients experiencing neutropenia following stem cell transplant, according to findings from a phase 3 trial which were presented at the American Society of Hematology Annual Meeting & Exposition. Investigators noted that these findings mean a restrictive diet is an unnecessary burden for a patient’s quality of life.¹

There were no differences between the 2 arms in terms of infections. The number of grade 2 or worse infections that were reported with the protective diet (n = 117) was 72 (65%) which was comparable to the 69 (62%) that were reported with the nonrestrictive diet (n = 113; RR, 1.0; 95% CI, 0.81.3; P = .80). The rates of severe infection (defined as grade 3 or higher), fever of undetermined origin, sepsis, and pneumonia, were determined to be balanced by investigators.

Microbiological isolation results showed that, in both arms, the bacteria most frequently isolated at blood and stool culture were enterobacteriaceae and C. difficile. Prophylactic fluroquinolones lowered the bloodstream infection rate (RR, 0.2; 95% CI, 0.001-0.600; P = .002) but was not found to prevent severe infections (RR, 1.1; 95% CI, 0.8-1.4; P = .07).1

In the nonrestrictive diet arm, more patients maintained body weight at 1 month post ASCT than those in the protective diet arm (mean change, –2.7kg vs –3.7 kg; P = .04). There were no differences between the 2 arms in terms of use and number of days of parenteral nutrition and serum albumin and body mass index variation.

Moreover, 35% of patients in the nonrestrictive group stated that “diet prescriptions don’t negatively impact my alimentation.” Only 16% of patients in the protective diet group agreed with the same statement (RR, 0.5; 95% CI, 0.3-0.8; P = .006), indicating that the nonrestrictive diet correlated to higher patient satisfaction.

Lastly, the incidence of grade 3 or higher acute GVHD was comparable between the 2 arms. In the protective diet arm, 20% of patients experienced this toxicity, compared with 9.5% of patients in the nonrestrictive diet arm (RR, 2.1; 95% CI, 0.5-9.1; P = .40).1

One death was reported in the nonrestrictive diet arm.

“The rate of infection, death, nutritional outcomes and acute GVHD incidence was not different between patients receiving a protective diet versus a nonrestrictive diet during neutropenia,” Federico Stella, MD, University of Milan, said in a presentation of the findings. “The results of this randomized study demonstrated the use of a restrictive diet is an unnecessary burden for our patient’s quality of life.”

Following stem cell transplant, infections represent a major cause of morbidity and mortality. Because of infection centers 93% of blood marrow transplant centers implement a restrictive diet. While some health care professionals have argued that non restrictive diets should have been standard practice since 2008,² according to Stella, evidence-based results surrounding the restrictive diet’s efficacy are lacking.^1,3,4

This study was designed to assess the infection risk in patients receiving a nonrestrictive diet compared with a protective diet following autologous or allogeneic stem cell transplantation.¹

The trial included patients who were either undergoing allogeneic-stem cell transplant (both myeloablative and reduced-intensity) or autologous-stem cell transplant (myeloablative), and who were receiving high-dose chemotherapy and experiencing a period of neutropenia of 7 days or greater. Exclusion criteria included an active infection before neutropenia, being unable to consume food orally, receiving the stem cell for a non-onco-hematological disease, needing to undergo a second allogeneic-stem cell transplant or requiring a transplant with a umbilical cord blood or aploidentical donor. ¹

A total of 247 patients were enrolled and randomly assigned 1:1 to receive either a protective (n = 117) or nonrestrictive diet (n = 113). The protective diet included foods cooked at 80 °C or hotter, and or thick peel fruit. Yogurt, honey, cold cuts, sausages, raw fish and meat, and raw vegetables and fruits were all forbidden. ¹

In comparison, the nonrestrictive diet only prohibited raw fish and meat. All other food were allowed so long as they abided by hospital hygiene standards^.1

The trials primary end point was to demonstrate the absence of significant differences in grade 2 or worse infections and death during the neutropenia period across the 2 study arms. Secondary end points included the incidence of gastrointestinal infections and fevers of undetermined origins, overall survival at 30 days and cumulative incidence of acute GVHD, and the nutritional status of patients, defined as the change in body weight and length of hospital stay.

According to Stella, the patient demographics were balanced in sex, age, disease type, type of transplantation, previous lines of therapy, disease status at enrollment, and antimicrobial prophylaxis. Approximately half (43%) of patients overall were female and the median age of study participant was 56 years (range, 22-72). Lymphoma was the most common malignancy among patients (47%), with multiple myeloma following (40%), acute myeloid leukemia (4%), and other disease (9%) thereafter.

Overall, 175 patients (79%) received autologous stem cell transplant, including 88 in the protective and 87 in the nonrestrictive cohorts; 41 patients received allogeneic (18%), including 20 and 21 in the protective had non-restrictive cohorts, respectively.

In the protective diet, 5 patients were lost to follow-up and 1 patient withdrew. In the nonrestrictive diet arm, 1 patient was lost to follow-up, and 1 withdrew consent. A total of 111 patients remain in trial follow-up in both arms.

References

1. Stella F, Marasco V, Levati G, et al. Non-restrictive diet does not increase infections in patients with neutropenia after stem cell transplantation: final analysis of the NEUTRODIET a multicenter, randomized trialBlood. 2022;140(suppl 1):417-419. doi:10.1182/blood-2022-158662
2. Gardner A, Mattiuzzi G, Faderl S, et al. Randomized comparison of cooked and noncooked diets in patients undergoing remission induction therapy for acute myeloid leukemia. J Clin Oncol. 2008;26(35):5684-5688. doi:10.1200/JCO.2008.16.4681
3. Peric Z, Botti S, Stringer J, et al. Variability of nutritional practices in peritransplant period after allogeneic hematopoietic stem cell transplantation: a survey by the Complications and Quality of Life Working Party of the EBMT. Bone Marrow Transplant. 2018;53(8):1030-1037. doi:10.1038/s41409-018-0137-1
4. Trifilio S, Helenowski I, Giel M, et al. Questioning the role of a neutropenic diet following hematopoetic stem cell transplantation. Biol Blood Marrow Transplant. 2012;18(9):1385-1390. doi:10.1016/j.bbmt.2012.02.015