The OBR Blog

December 12, 2018 - 03:12 pm comments0 Comments

SAN DIEGO—Too often, strategies known to be effective within the realm of supportive and palliative cancer care remain on the back burner. This often-observed fact was reinforced at a recently convened ASCO-sponsored symposium, where results from several studies revealed that guidelines are being ignored or overlooked to the detriment of optimal care.

Prophylaxis for chemotherapy-induced vomiting is one of two examples that illustrate the point. Many patients with cancer do not receive what has been proven to improve quality of life, according to data presented at the Palliative Care and Supportive Care Oncology Symposium by Eric J. Roeland, MD, a hospice and palliative care physician at Massachusetts General Hospital, Boston.

The data were pulled from an electronic medical database with records from 40 institutions. New starts of highly emetogenic chemotherapy (HEC) were matched with new starts of antiemetic prophylaxis. Current guidelines for control of emesis from ASCO, ESMO, and the NCCN in patients initiating HEC call for triple-drug prophylaxis with an NK1 receptor inhibitor, such as aprepitant; a 5-HT3 receptor inhibitor, such as ondansetron; and dexamethasone.

Of the three regimens currently classified as HEC that were evaluated, physicians were found to be more than 90% adherent to guideline-directed triple-drug antiemetic prophylaxis in 56% of patients initiating a course of cyclophosphamide plus anthracycline; 32% in patients initiating a course of cisplatin; and 2% in patients initiating carboplatin, Dr. Roeland reported.

The low adherence rate for carboplatin can be discounted because this drug only received a HEC designation in 2017, which came after the study period, but cisplatin had a listing as a HEC requiring triple-drug prophylaxis during the time of the study, and it is notorious for its emetogenic propensity. Published studies suggest up to 90% of patients receiving cisplatin in a dose of 50 mg/m2develop nausea and vomiting within 24 hours if prophylaxis is not provided. The results from Dr. Roeland’s study database suggest that up to 68% of these patients are exposed to toxicity that could be modified.

Triple therapy “is an achievable target,” he said, citing the low but still substantial proportion of physicians who did reach 90% adherence. Of physicians who failed to achieve this level of adherence, many did not come close. The distribution of adherence among below 90% adherence was “scattered across lower levels down to zero.”

“Opportunities still exist for most physicians to improve individual adherence of evidence-based guideline-recommended antiemetic prophylaxis,” he said.

As the risk of emesis from HEC-designated drugs in guidelines is known, “upfront triple prophylaxis” should be standard, according to Dr. Roeland.

His data provide another reminder that clinicians often overlook proven and guideline-recommended strategies beyond standard anti-cancer regimens with the potential to make their patients’ lives better. A similar statement could be made about palliative care based on data presented at the same meeting.

Palliative care strategies

Neither of two studies that evaluated palliative care strategies was focused on the proportion of patients who go untreated, but both implied that this therapy is not being offered routinely. The reason is that each had control groups who were not treated even though ASCO has already released clinical practice guidelines for the routine integration of palliative care (Ferrel BR et al. J Clin Oncol 2017;35:96-112).

Not surprisingly, given the background, both studies associated palliative care with benefit. On the basis of the results, both sets of authors recommended routine palliative care despite existing evidence-based guidelines that make the same recommendation.

One of the two studies was a multicenter randomized trial. In this trial, 302 patients with unresectable lung (40%), gastrointestinal (27%), prostatic (18%) or other solid tumors were randomized to palliative care, which included psychosocial support and physical exercise guided by a specialized team, or usual care without palliative strategies.

Patients customized their care by identifying aspects of quality of life for which they needed help. These were evaluated with a validated tool called EORTC-QLC-C30. Change from baseline in the same domains with EORTC-QLC-C30 was the primary study outcome. The absolute 3.0-point difference favoring palliative care reached significance (P=0.047). When assessed with a sensitivity analysis, the 3.3-point difference favoring palliative care was even more robust (P=0.005).

The conclusion, delivered by Lise Nottelmann, MD, Palliative Team, Department of Oncology, Vejle Hospital, Vejle, Denmark, was that palliative care “integrated into the standard oncology treatment” offers meaningful benefit to patients.

In a second study, which enrolled 118 lung cancer patients and 62 caregivers, evaluated a palliative care protocol for the outpatient community-based setting. The author of this study, Huong Q. Nguyen, PhD, RN, Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena, acknowledged that palliative care has been shown to be beneficial previously. However, “most trials have been conducted in specialized centers with limited translation into the real-world setting.”

This study was conducted in two phases. After a first phase of usual care over 14 months, nurse-led palliative care was initiated and evaluated over 23 months. Again, care was customized by concerns defined as most important by enrolled patients. Change from baseline in quality of life was evaluated in both patients and caregivers with multiple tools, including FACT-L and FACIT-SP12.

In patients, “significant immediate improvements observed in physical, emotional, and functional well being at one month [on palliative care] were sustained at three months when compared to usual care (P=0.01),” reported Dr. Nguyen. In caregivers, improvements in physical (P=0.04) and spiritual (P=0.03) domains were also documented relative to usual care.

The findings demonstrate that palliative care “can be successfully adapted to the community setting,” Dr. Nguyen concluded.

On the basis of their results, both authors advocated the integration of palliative care into standard management of patients with late stage cancer, but they only reinforce current guidelines. The fact that the studies were considered necessary underscores an unstated premise that acceptance of palliative care remains incomplete. Like antiemetic prophylaxis for emetogenic drugs, the question is not whether palliative care can improve quality of life, the question is why the opportunity for benefit is so often overlooked.

By Ted Bosworth

As the ASH Annual Meeting concludes, the late-breaking abstracts are always of great interest. We take a brief look at one non-malignant hematology presentation that has implications for oncology, as well as three malignant hematology presentations on advances in targeted therapies for CLL and multiple myeloma.

Rivaroxaban Thromboprophylaxis in High-Risk Ambulatory Cancer Patients Receiving Systemic Therapy: Results of a Randomized Clinical Trial (CASSINI) (LBA-1)—short summary of this one

Patients with cancer have a higher risk for venous thromboembolism (VTE), which can lead to death, morbidity, hospitalization, and delay in cancer treatment.

Alok A. Khorana, Department of Hematology and Medical Oncology, Cleveland Clinic, Cleveland, OH, reported results of the CASSINI trial (NCT02555878), a double-blind, randomized, placebo-controlled, parallel-group, multicenter study in adult ambulatory patients with various cancers initiating a new systemic regimen and at increased risk for VTE, defined as Khorana score ≥ 2 for a risk-adapted approach to prophylaxis.

Patients were randomly assigned to rivaroxaban, a direct oral anticoagulant (n=420), or to placebo (n=421) for 6 months. An important aspect of the trial was the use of ultrasonography of the lower extremity at baseline to identify pre-existing clots, which occurred in 4.5% of screened patients who were therefore not enrolled.

There was no significant difference between groups in the primary efficacy outcome of cumulative thromboembolic events; 38.7% of events occurred in patients who had discontinued treatment. For patients who remained on treatment, rivaroxaban significantly reduced events (2.62%) versus placebo (6.41%; P=.007), and significantly reduced a composite of the primary endpoint and all-cause mortality (P=.003).

There were no significant differences in safety outcomes between the groups for bleeding. A risk-benefit analysis showed that the number needed to treat (NNT) was 26 for patients who remained on treatment. The number needed to harm (NNH) was 101 for major bleeding and 135 for clinically relevant non-major bleeding for patients on treatment.

Dr. Khorana concluded that baseline screening for VTE could be considered for patients starting systemic cancer therapy. The findings of this study, along with a similar study that has just concluded, should inform future recommendations for thromboprophylaxis for higher-risk ambulatory patients with cancer.

Phase 3 Randomized Study of Daratumumab Plus Lenalidomide and Dexamethasone (D-Rd) Versus Lenalidomide and Dexamethasone (Rd) in Patients with Newly Diagnosed Multiple Myeloma (NDMM) Ineligible for Transplant (MAIA) (LBA-2)

Thierry Facon, Service des Maladies du Sang, Hôpital Claude Huriez, Lille, France, presented the pre-specified interim analysis of the MAIA study, a phase 3 trial evaluating daratumumab plus lenalidomide and low dose dexamethasone (D-Rd) versus Rd in patients with transplant-ineligible, newly diagnosed multiple myeloma. Daratumumab is a human, CD38-targeted, IgG1κ monoclonal antibody.

Patients were randomly assigned to D-Rd (n=368) or Rd (369); treatment continued until disease progression. Median age was 73 years, and notably, 44% of patients were age ≥75 years. The primary endpoint was progression-free survival (PFS).

At a median follow-up of 28 months there was a 44% reduction in risk of progression or death in the D-Rd group (71% at 30 months vs 56% for placebo; HR 0.56; 95% CI 0.43-0.73; P<.0001). Median PFS in the Rd group was 31.9 months and not reached in the D-Rd group. This benefit was seen across most sub-groups analyzed.

The overall response rate was 93% for D-Rd versus 81% for Rd (P<.0001); complete response rates and at least very good partial response rates were higher for D-Rd than for Rd. The minimal residual disease (MRD)-negative rate was significantly higher for D-Rd (24%) than for Rd (7%; P<.0001). Patients who were MRD negative had longer PFS. There is no difference between groups in overall survival (OS) at this follow-up time.

The safety profile was consistent with that seen for these combinations in other studies. Because of the inclusion of lenalidomide, the incidence of secondary primary malignancies (SPM) was determined; it was 3% for D-Rd and 4% for Rd; hematologic SPM occurred in 0.5% of each arm.

Dr. Facon concluded that the results of this study support D-Rd as a new standard of care for patients with transplant-ineligible newly diagnosed multiple myeloma.

A Randomized Phase III Study of Ibrutinib (PCI-32765)-Based Therapy Vs. Standard Fludarabine, Cyclophosphamide, and Rituximab (FCR) Chemoimmunotherapy in Untreated Younger Patients with Chronic Lymphocytic Leukemia (CLL): A Trial of the ECOG-ACRIN Cancer Research Group (E1912) (LBA-4)

The E1912 (NCT02048813) trial showed that ibrutinib plus rituximab (IR) improves PFS and OS compared with fludarabine, cyclophosphamide, and rituximab (FCR) in younger patients with previously untreated CLL. FCR has been the most active chemo-immunotherapy to date for CLL and has not been compared with ibrutinib as an initial treatment for younger patient with CLL.

Patients age ≤70 years (median age 58 years) with CLL were randomly assigned 2:1 to IR (n=354) or to 6 cycles of FCR (n=175). Patients in the IR group received 1 cycle ibrutinib, 6 cycles IR, then ibrutinib until disease progression.

At a median follow-up of about 3 years, PFS was significantly longer in the IR group (HR 0.35; 95% CI 0.22-0.5; P≤.00001), as was OS (HR 0.17; 95% CI .05-0.54; P≤.0003). Neutropenia, anemia, thrombocytopenia, and neutropenic fever occurred significantly less often with IR than FCR; atrial fibrillation and hypertension occurred significantly more often with IR than FCR. There were no significant difference in infection, bleeding, or diarrhea.

Presenter Tait D. Shanafelt, MD, Stanford University, Stanford, CA, concluded that these results establish IR as the most effective first-line therapy in patients age ≤70 years with CLL.

Acquisition of the Recurrent Gly101Val Mutation in BCL2 Confers Resistance to Venetoclax in Patients with Progressive Chronic Lymphocytic Leukemia (LBA-7)

Venetoclax, a selective BCL2 inhibitor induces deep and durable responses in CLL. However, most patients treated with venetoclax will eventually experience disease progression, and the mechanisms of resistance to venetoclax in patients are largely unknown.

This study looked at 67 patients with relapsed CLL; 21 had CLL-type progressions; of these, 15 had samples suitable for genomic analysis. A new mutation that was not present in pre-treatment samples, BCL2 Gly101Val, was detected in four patients using targeted amplicon sequencing. This is the first acquired BCL2 mutation described in patients with CLL treated with venetoclax. BCL2 Gly101Val occurs in the BH3-binding groove and has not been detected in other B-cell malignancies. BCL2 Gly101Val reduces the binding of venetoclax to BCL2 as much as 180-fold.

Piers Blombery, MBBS, University of Melbourne, Melbourne, Australia, said that they have detected BCL2 Gly101Val in patient samples months to years before relapse, and the mutation has subsequently been detected in three additional patients in the original group of 15 studied.

Cell lines overexpressing BCL2 Gly101Val are resistant to venetoclax and the mutation confers a growth advantage over wild-type cells in the presence of the drug.

Dr. Blombery pointed out that alternative resistance mechanisms can co-exist with BCL2 Gly101Val. These study results could provide a rationale for a limited time course for venetoclax.

As the 2018 American Society of Hematology (ASH) Annual Meeting continues, we focus on two studies that have the potential to be practice-changing for the treatment of older patients with AML and younger patients with favorable-prognosis diffuse large B-cell lymphoma (DLBCL), the development of a personalized risk stratification model for patients with myelodysplastic syndromes (MDS), and the finding that pre-hematopoietic cell transplant (HCT) microbiota injury is associated with poorer overall survival (OS).

Initial Report of the Beat AML Umbrella Study for Previously Untreated AML: Evidence of Feasibility and Early Success in Molecularly Driven Phase 1 and 2 Studies (559)

Results from the Beat AML umbrella study demonstrated that it was feasible to implement a rapid treatment assignment within 7 days or less for 95.8% of elderly patients with AML, reported Amy Burd, PhD, Leukemia and Lymphoma Society.

This precision medicine trial tested the hypothesis that outcomes for patients could be improved by matching them to the increasing number of available targeted therapies. The primary objectives were to determine (1) the feasibility of completing molecular, immunophenotypic, and/or biochemical studies in ≤7 calendar days, (2) the feasibility of assigning patients to sub-studies in the master protocol based on the test results, and (3) the clinical efficacy of novel treatment strategies in each of the sub-studies.

The trial enrolled patients age ≥60 years with previously untreated AML. Treatment was assigned based on the best curative option using molecular profiling results. Median age was 72 years, and 37.9% of patients were age ≥75 years.

So far 365 patients have been enrolled, of whom 285 were assigned treatment; 146 patients received the assigned treatment. Most of the patients who were not treated received other therapies, including standard of care, alternative treatment prior to assignment, or enrollment in an alternative trial after assignment; 7 died during the 7-day period, and 23 opted to enter palliative care.

The trial began with 3 sub-studies, which has since increased to 11 sub-studies, providing more options. Promising efficacy has been seen in several treatment arms, and early death and disease progression prior to treatment assignment is uncommon outside of MLL rearranged AML which progresses rapidly and requires early treatment initiation. Two sub-study updates are being presented at the meeting (abstracts 4053 and 287).

Excellent Outcome of Young Patients (18-60 years) with Favourable-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL) Treated with 4 Cycles CHOP Plus 6 Applications of Rituximab: Results of the 592 Patients of the Flyer Trial of the Dshnhl/GLA (781)

Results of the FLYER trial showed that reducing cycles of CHOP-like chemotherapy from the standard 6 cycles of rituximab (R)-CHOP to 4 cycles of CHOP plus 6 doses of R maintained efficacy and reduced toxicity for younger patients with good prognosis DLBCL.

Viola Poeschel, MD, Department of Hematology, Oncology and Rheumatology, Saarland University Medical School, Homburg/Saar, Germany, presented the results. FLYER enrolled previously untreated patients age 18 to 60 years with stage I/II aggressive B-cell lymphoma, with age-adjusted International Prognostic Index of zero and no bulky disease. Patients were randomly assigned to treatment with 6 cycles or R-CHOP or 4 cycles R-CHOP plus 2 additional cycles of R in 21-day cycles.

The primary endpoint was progression-free survival (PFS). The 36 month PFS was 94% (95% CI 91%-97%) for the 6 x R-CHOP-21 group (n=295), and 96% (95% CI 94%-99%) for the 4 x R-CHOP-21 + 2 x R group (n=293) at a median follow-up of 66 months.

Likewise, the 36-month overall survival (OS) was similar between the treatment groups: 98% (95% CI 96%-99%) in the standard therapy group and 99% (95% CI 98%-100%) in the reduced chemotherapy group at a median follow-up of 67 months.

Fewer hematologic adverse events (AE) were reported in the reduced chemotherapy group, as well as an overall reduction of non-hematologic AEs by approximately one third.

A Personalized Prediction Model to Risk Stratify Patients with Myelodysplastic Syndromes (793)

Current treatment guidelines for MDS are based on risk stratification for progression to AML, and although HCT is potentially curative in high-risk disease, associated toxicities make it inappropriate for low-risk disease. Aziz Nazha, MD, Cleveland Clinic, Cleveland, OH, described the development of a prediction model that uses a machine learning approach to provide a personalized, patient-specific estimate of risk.

Dr. Nazha’s group show that when looking at survival of patients with MDS by Revised International Prognostic Scoring System (IPSS-R) for MDS risk category, outcomes are heterogeneous.

The model was developed using clinical and mutational data from patients with MDS in a combined cohort from the Cleveland Clinic and Munich Leukemia Laboratory (training cohort, n=1471) and validated in a separate cohort (validation cohort, n=831) from the Moffitt Cancer Center. Forty gene mutations commonly occurring in myeloid malignancies were sequenced. Patients undergoing HCT were censored at the time of transplant. An algorithm was used to build the model that randomly selected clinical and molecular variables to determine survival. Variables were ranked from the most to the least important for OS.

A clinic-friendly web application tool has been built from the final model, allowing input of important risk factors to calculate predicted OS for individual patients. Dr. Nazha said that this new model has a better predictability index for OS and leukemia-free survival than the IPSS.

Multicenter Microbiota Analysis Indicates that Pre-HCT Microbiota Injury Is Prevalent across Geography and Predicts Poor Overall Survival (811)

The intestinal microbiota composition is associated with important outcomes after allogeneic (allo) HCT including OS, organ toxicity, relapse, graft-versus-host disease (GvHD), and infection. Most studies have looked at the microbiota after transplantation. Jonathan U. Peled, MD, PhD, Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, described this study looking at the intestinal microbiota composition in 1922 stool samples from patients both before and after allo-HCT in three geographic regions.

Dr. Peled said it was striking that no matter where in the world these patients lived, their intestinal microbiota composition and diversity were comparable at baseline. Higher diversity pre-HCT microbiota is associated with better OS than low diversity (HR 0.69; P=.002), as well as with peri-neutrophil engraftment. After transplant, a decrease in diversity and domination of single species are correlated with poorer outcomes.

Approaches that could manipulate microbiota-host interactions to prevent damage include antibiotics, prebiotics, probiotics, and postbiotics.

 

Lynne Lederman, PhD

By Lynne Lederman, PhD

As the 2018 American Society of Hematology (ASH) Annual Meeting continues, we focus on two studies that have the potential to be practice-changing for the treatment of older patients with AML and younger patients with favorable-prognosis diffuse large B-cell lymphoma (DLBCL), the development of a personalized risk stratification model for patients with myelodysplastic syndromes (MDS), and the finding that pre-hematopoietic cell transplant (HCT) microbiota injury is associated with poorer overall survival (OS).

Initial Report of the Beat AML Umbrella Study for Previously Untreated AML: Evidence of Feasibility and Early Success in Molecularly Driven Phase 1 and 2 Studies (559)

Results from the Beat AML umbrella study demonstrated that it was feasible to implement a rapid treatment assignment within 7 days or less for 95.8% of elderly patients with AML, reported Amy Burd, PhD, Leukemia and Lymphoma Society.

This precision medicine trial tested the hypothesis that outcomes for patients could be improved by matching them to the increasing number of available targeted therapies. The primary objectives were to determine (1) the feasibility of completing molecular, immunophenotypic, and/or biochemical studies in ≤7 calendar days, (2) the feasibility of assigning patients to sub-studies in the master protocol based on the test results, and (3) the clinical efficacy of novel treatment strategies in each of the sub-studies.

The trial enrolled patients age ≥60 years with previously untreated AML. Treatment was assigned based on the best curative option using molecular profiling results. Median age was 72 years, and 37.9% of patients were age ≥75 years.

So far 365 patients have been enrolled, of whom 285 were assigned treatment; 146 patients received the assigned treatment. Most of the patients who were not treated received other therapies, including standard of care, alternative treatment prior to assignment, or enrollment in an alternative trial after assignment; 7 died during the 7-day period, and 23 opted to enter palliative care.

The trial began with 3 sub-studies, which has since increased to 11 sub-studies, providing more options. Promising efficacy has been seen in several treatment arms, and early death and disease progression prior to treatment assignment is uncommon outside of MLL rearranged AML which progresses rapidly and requires early treatment initiation. Two sub-study updates are being presented at the meeting (abstracts 4053 and 287).

Excellent Outcome of Young Patients (18-60 years) with Favourable-Prognosis Diffuse Large B-Cell Lymphoma (DLBCL) Treated with 4 Cycles CHOP Plus 6 Applications of Rituximab: Results of the 592 Patients of the Flyer Trial of the Dshnhl/GLA (781)

Results of the FLYER trial showed that reducing cycles of CHOP-like chemotherapy from the standard 6 cycles of rituximab (R)-CHOP to 4 cycles of CHOP plus 6 doses of R maintained efficacy and reduced toxicity for younger patients with good prognosis DLBCL.

Viola Poeschel, MD, Department of Hematology, Oncology and Rheumatology, Saarland University Medical School, Homburg/Saar, Germany, presented the results. FLYER enrolled previously untreated patients age 18 to 60 years with stage I/II aggressive B-cell lymphoma, with age-adjusted International Prognostic Index of zero and no bulky disease. Patients were randomly assigned to treatment with 6 cycles or R-CHOP or 4 cycles R-CHOP plus 2 additional cycles of R in 21-day cycles.

The primary endpoint was progression-free survival (PFS). The 36 month PFS was 94% (95% CI 91%-97%) for the 6 x R-CHOP-21 group (n=295), and 96% (95% CI 94%-99%) for the 4 x R-CHOP-21 + 2 x R group (n=293) at a median follow-up of 66 months.

Likewise, the 36-month overall survival (OS) was similar between the treatment groups: 98% (95% CI 96%-99%) in the standard therapy group and 99% (95% CI 98%-100%) in the reduced chemotherapy group at a median follow-up of 67 months.

Fewer hematologic adverse events (AE) were reported in the reduced chemotherapy group, as well as an overall reduction of non-hematologic AEs by approximately one third.

A Personalized Prediction Model to Risk Stratify Patients with Myelodysplastic Syndromes (793)

Current treatment guidelines for MDS are based on risk stratification for progression to AML, and although HCT is potentially curative in high-risk disease, associated toxicities make it inappropriate for low-risk disease. Aziz Nazha, MD, Cleveland Clinic, Cleveland, OH, described the development of a prediction model that uses a machine learning approach to provide a personalized, patient-specific estimate of risk.

Dr. Nazha’s group show that when looking at survival of patients with MDS by Revised International Prognostic Scoring System (IPSS-R) for MDS risk category, outcomes are heterogeneous.

The model was developed using clinical and mutational data from patients with MDS in a combined cohort from the Cleveland Clinic and Munich Leukemia Laboratory (training cohort, n=1471) and validated in a separate cohort (validation cohort, n=831) from the Moffitt Cancer Center. Forty gene mutations commonly occurring in myeloid malignancies were sequenced. Patients undergoing HCT were censored at the time of transplant. An algorithm was used to build the model that randomly selected clinical and molecular variables to determine survival. Variables were ranked from the most to the least important for OS.

A clinic-friendly web application tool has been built from the final model, allowing input of important risk factors to calculate predicted OS for individual patients. Dr. Nazha said that this new model has a better predictability index for OS and leukemia-free survival than the IPSS.

Multicenter Microbiota Analysis Indicates that Pre-HCT Microbiota Injury Is Prevalent across Geography and Predicts Poor Overall Survival (811)

The intestinal microbiota composition is associated with important outcomes after allogeneic (allo) HCT including OS, organ toxicity, relapse, graft-versus-host disease (GvHD), and infection. Most studies have looked at the microbiota after transplantation. Jonathan U. Peled, MD, PhD, Adult Bone Marrow Transplant Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, described this study looking at the intestinal microbiota composition in 1922 stool samples from patients both before and after allo-HCT in three geographic regions.

Dr. Peled said it was striking that no matter where in the world these patients lived, their intestinal microbiota composition and diversity were comparable at baseline. Higher diversity pre-HCT microbiota is associated with better OS than low diversity (HR 0.69; P=.002), as well as with peri-neutrophil engraftment. After transplant, a decrease in diversity and domination of single species are correlated with poorer outcomes.

Approaches that could manipulate microbiota-host interactions to prevent damage include antibiotics, prebiotics, probiotics, and postbiotics.

 

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