Key words : Acute leukemia, Dental caries, Febrile neutropenia, Graft-versus-host disease, Mucositis

Introduction

Hematopoietic stem cell transplant (HSCT) is presently widely used to cure patients with benign and malignant diseases.¹ However, HSCT is complex, and serious transplant-related complications may develop. Infections, graft-versus-host disease (GVHD), and mortality after transplant may be caused by patient-related factors.^1,2 In the standard workflow, patients are evaluated by various specialists in terms of transplant eligibility. For example, patients are routinely evaluated by dental departments in terms of oral foci of infections (OFIs),³ which are treated with antimicrobial drugs or via interventional tooth and gingival procedures before transplant.^4-6 However, if tooth extraction is required, this may prolong the pretransplant period and is associated with a risk of relapse of diseases such as leukemia and lymphoma.^7,8 Good nutrition during intensive chemotherapy is important in terms of transplant toleration and the ability to deal with complications. The OFI-related treatments may affect nutrition both during and after transplant.^3,4 This creates a dilemma for dentists and transplant doctors:4 are such patients eligible for transplant?

Ablative and nonmyeloablative conditioning regimens used in autologous HSCT and allogeneic HSCT contain cytostatic drugs with or without radiation or monoclonal antibodies, such as anti-T-lymphocyte globulin (ALG), affect phagocytic functions and cellular immunity of patients.⁹ In addition, posttransplant cyclophosphamide has been widely used to create immune tolerance between donor cells and recipients, more frequently in HLA-incompatible related- or unrelated transplants.¹⁰ Limited studies are available on the relationship between dental and oral health problems and the course of HSCT. Studies investigating this relationship according to transplant protocols are insufficient. Patient eligibility criteria in terms of OFI detected before transplant have not been adequately defined. Here, we investigated the relationship between pretransplant OFI status and posttransplant compli-cations and early mortality in patients undergoing autologous and allogeneic HSCT, thus receiving ablative or nonmyeloablative transplant protocols.

Materials and Methods

Study design and patients
This single-center retrospective study was conducted between January 2012 and January 2022. Our study included 502 consecutive adult stem cell transplant recipients (mean age 54 y; range, 16-75 y) who underwent autologous HSCT and 428 consecutive adult stem cell transplant recipients (mean age 42 y; range, 16-72 y) who underwent allogeneic HSCT using bone marrow and/or peripheral blood stem cells from HLA-matched or HLA-mismatched (related or unrelated) donors. We evaluated the associations between OFIs detected before transplant and the posttransplant infectious complications, GVHD, and early mortality. According to our standard operating procedures (SOPs) (a quality management system), after giving written consent for transplant, all patients are evaluated for transplant suitability by consultants in relevant departments (for example, patients are routinely evaluated in the dental department using SOP KIT-KY-018). All patients undergo thorough dental examinations by an experienced dentist pre-HSCT. Panoramic dental radiography is taken of all recipients. All dental records, radiographic scans, and associated reports are reevaluated by 3 specialists in dental medicine, with a particular focus on OFI. Patients with acute OFIs receive appropriate antimicrobial drugs before transplant. Depending on the urgency of the clinical situation, tooth extraction or reconstruction can be postponed until after transplant by the attending transplant physician.

Transplant protocols and supportive therapy were administered according to the relevant SOPs in each patient who underwent an autologous or allogeneic HSCT (KIT KU-002). Febrile neutropenia (FEN) episodes, bacteremia, other bacterial infection, invasive fungal infections, and mucositis, according to the Common Terminology Criteria for Adverse Events version 4.0, were recorded as infectious complications. Clinical data included patient age, sex, smoking habit, diabetes, the Sorror comorbidity score, European Group of Blood and Marrow Transplantation (EBMT) score, type of underlying disease, the need for a second transplant, patients needing heavy treatments, and stem cell mobilization protocols.

The autologous HSCT study groups included carmustine-etoposide-cytarabine melphalan (BEAM), mitoxantrone-melphalan (MITO/Mel), and melphalan 200 mg/m² (Mel200) groups. The allogeneic transplant groups included busulfan-fludarabine-ALG (BuFuALG), busulfan-fludarabine-cyclophosphami-de (BuFu/Cy), fludarabine-cyclophosphamide-ALG (FuCyALG), busulfan-fludarabine-ALG-cyclophosp-hamide (BuFuCyALG/Cy), total body irradiation-cyclophosphamide (TBI/Cy), and “other” groups. All conditioning regimens were of myeloablative dose intensity, with the exception of FuCyALG.

Data on patients with and without pretransplant OFI and data on patients with complete treatment for OFI were obtained from forms created to evaluate transplant patients. The forms met the Joint Accreditation Committee: International Society for Cellular Therapy and European Blood and Marrow Transplantation (JACIE) criteria for the Nucleus electronic data management system (PRANA version 9.3.39; Monad Software). All data were verified by an independent data audit of quality management group.

Inclusion criteria
Patients who fulfilled all of the following criteria were included: age ≥17 years and treatment with autologous or allogeneic HSCT for benign or malignant hematological diseases, including marrow failure syndromes, sickle cell disease, Hodgkin or non-Hodgkin lymphomas, multiple myeloma, and acute or chronic leukemias. Patients who underwent second transplant procedures were included.

Exclusion criteria
The following patients were excluded: those programmed for discharge, those who were transplanted at other centers, those with concurrent systemic inflammatory disease or organ failure, those with severe infections within 1 month before commencement of the conditioning regimen, and those under 16 years of age.

Ethical approval
Local ethics committee approval was obtained prior to study start (approval no. KA22-61). Written and verbal informed consent was obtained from all patients.

Definitions
Acute oral infections were defined as fistulae with purulent drainage, symptomatic periapical granulomas, symptomatic deep caries, fresh extraction sockets, and acute periodontal abscesses with purulent drainage. Chronic OFIs included apical periodontitis, caries profunda with the potential for pulp exposure, furcation involvement, infection-related root remnants, partially erupted wisdom teeth with pericoronitis, ongoing endodontic treatment, and cysts. Periodontitis was defined as radiological attachment loss (distance between the cementoenamel junction and the alveolar bone crest >3 mm).6 Mucositis was defined as damage to or inflammation of the inside of the mouth, mucosa, or palate as defined by an otolaryngologist or a transplant physician and/or a newly developed OFI diagnosed after transplant by a specialist in dental medicine. A FEN episode was defined as fever >38 °C at least once or >37.5 °C at least twice during the neutropenic period. The term “other bacterial infection” refers to regional infections other than bacteremia (including cellulitis, pneumonia, and urinary tract infection).

Heavily pretreated patients were those who had received combination chemotherapy or chemoim-munotherapy before transplant. Neutrophil engraft-ment was defined on the first day of 3 consecutive days on which the absolute neutrophil count was 500 cells/mm³ (0.5 × 10⁹/L) or greater. Patients received acyclovir herpes prophylaxis, fluconazole antifungal prophylaxis, ofloxacin bacterial prophylaxis, and sulfamethoxazole Pneumocystis jirovecii prophylaxis in accordance with the SOPs (BMT-TU 002).

Acute GVHD (aGVHD) was evaluated using standard criteria and recorded up to 6 months after transplant.^11,12 A diagnosis of chronic GVHD (cGVHD) was based on both clinical and histological criteria when examining the skin and other affected sites, as previously described, and was recorded up to 2 years after transplant.^13,14 We defined OFI-associated bacterial infection as the development of a dental abscess and cellulitis or growth of streptococci or anaerobic agents in cultures performed within 100 days after cellular product infusion. Mortality within 100 days in such patients was defined as OFI-related mortality.

Study endpoints
The primary endpoints were 100-day infections (bacterial or fungal infections, bacteremia, FEN, and mucositis), aGVHD or cGVHD, and 100-day mortality. The secondary endpoints were the risks of 100-day infection, aGVHD, cGVHD, and 100-day mortality by BEAM or MITO/Mel status (the reference groups) in the autologous groups and by FuBuALG status in the allogeneic transplant groups.

Statistical analyses
Interobserver reliability in terms of OFI diagnosis was evaluated. For cases with chance agreement, we estimated the Fleiss kappa (κ) for pretransplant OFI (8 categories). We interpreted agreement as “slight” for κ = 0.00 to 0.20, “fair” for κ = 0.21 to 0.40, “moderate” for κ = 0.41 to 0.60, “substantial” for κ = 0.61 to 0.80, and “almost perfect” for κ?> 0.80.¹⁵

We used the Fisher exact test to compare baseline categorical variables and the Pearson chi-square test to compare between the estimates of proportions. We used Cox univariate regression analyses to derive risk estimates (odds ratios [OR] with 95% confidence intervals [CIs]) for 100-day infection, aGVHD at 6 months, cGVHD at 2 years, and 100-day OFI-related mortality. The BEAM protocol, which is frequently preferred by centers performing autologous transplants, and the BuFuALG protocol, for allogeneic transplants, served as the reference protocols during risk analyses. Univariate logistic regression analysis was used to calculate mortality risks. P < .05 was considered significant. All statistical analyses were performed using SPSS software version 17.0.

Results

Interobserver agreement in terms of oral foci of infections
The highest interobserver reliabilities (as measured using κ) were those for acute OFI (κ = 0.85; 95% CI, 0.80-0.90), caries profunda (κ = 0.82; 95% CI, 0.75-0.87), persistent apical periodontitis (κ = 0.88; 95% CI, 0.84-0.91), and multiple chronic OFIs (κ = 0.91; 95% CI, 0.87-0.93). Interobserver reliability was substantial for periodontitis (κ = 0.72; 95% CI, 0.64-0.80), gingivitis (κ = 0.73; 95% CI, 0.64-0.80), cysts or periapical lesions (κ = 0.74; 95% CI, 0.66-0.81), and pericoronitis (κ = 0.66; 95% CI, 0.57-0.75).

Clinical features and follow-up
Table 1 shows that, of patients who underwent autologous HSCT, those in the Mel200 group were older than those in the other groups. No patients received transplant when OFI was active. There were no significant between-group differences in sex, smoking habit, diabetes status, the Sorror comorbidity score, or EBMT risk. As expected, most BEAM and MITO/Mel group patients had lymphoma. The Mel200 subgroup included patients with multiple myeloma; most required repeat transplant procedures. Patients who underwent BEAM and MITO/Mel conditioning regimens received more treatment than did Mel200 patients before transplant. For the BEAM and MITO/Mel groups, most stem cell mobilization regimens contained etoposide and granulocyte colony-stimulating factor, but most Mel200 group regimens featured Cy and granulocyte colony-stimulating factor.

Table 1 lists the demographic and clinical features of the matched cohorts in the allogeneic HSCT groups. The mean age was greater in the BuFuALG and BuFu/Cy groups than in the other groups. Patients with myeloblastic leukemia/myelodysplastic syndrome were most frequently prescribed BuFuALG regimens, and patients with acute lymphoblastic leukemia were given TBI/Cy. Patients with sickle cell disease received BuFuCyALG/Cy, and patients with aplastic anemia received FuCyALG. Most second transplants used different protocols. The mobilization regimens and GVHD prophylaxis measures differed between the groups. For patients with sickle cell disease, most of the BuFuCyALG/Cy group received sirolimus and mycophenolate mofetil for GVHD prophylaxis; however, cyclosporine and methotrexate or tacrolimus were used in most of the other groups.

Follow-up and neutrophil engraftment
The median (range) follow-up time for the autologous HSCT groups was 591 days (30-4943 d) for the BEAM group, 982 days (10-5400 d) for the MITO/Mel group, and 1245 days (38-6015 d) for the Mel200 group. The groups were similar in terms of the time to neutrophil engraftment with median (range) of 13 days (8-20 d) for the BEAM, 12 days (9-17 d) for the MITO/Mel, and 11 days (9-15 d) for the Mel200 groups (P > .05).

The median (range) follow-up time for the allogeneic HSCT groups was 939 days (3-5118) days for the BuFuALG group, 527 days (82-2348 d) for the BuFu/Cy group, 798 days (12-8055 d) for the FuCyALG group, 711 days (51-1456 d) for the BuFuCyALG/Cy group, 395 days (4-1134 d) for the TBI/Cy group, and 1436 days (274-3225 d) for “other.” The groups were similar in terms of the time to neutrophil engraftment, with median (range) of 13 days (6-20 d) for the BuFuALG, 14 days (11-20 d) for the BuFu/Cy, 15 days (9-63 d) for the FuCyALG, 11 days (9-16 d) for the BuFuCyALG/Cy, 12 days (8-13 d) for the TBI/Cy, and 12 days (10-21 d) for the “other” groups (P > .05).

Frequency of infectious complications
Table 2 shows the effect of pretransplant OFI positivity on posttransplant infectious complications for the autologous HSCT groups. Those with OFIs developed more FEN, bacterial infections, and 100-day infections after transplant than those without OFIs. In the allogeneic HSCT groups, those with OFIs developed more FEN, bacteremia, mucositis, and 100-day infections after transplant than those without OFIs (P < .05). Table 3 shows that, when the autologous HSCT groups were evaluated in terms of pretransplant-detected OFI, there were no significant between-group differences. However, more post-transplant bacterial infections, FEN, and 100-day infections were evident in the groups that received BEAM and MITO/Mel than the group that received Mel200. Most mucositis was noted in the MITO/Mel group.

In the allogeneic HSCT groups, the rates of various OFIs detected before transplant were similar. FEN episodes were least common in the “other” group. The rates of 100-day infection and other post-transplant infectious complications did not differ between the groups (Table 3).

Development of graft-versus-host disease
Positive OFI status before transplant did not affect the development of acute or chronic GVHD after transplant (Table 3). There were no between-group differences in the rates of grade II-IV or grade III-IV aGVHD. The frequencies of limited and extensive cGVHD also did not differ among the allogeneic HSCT groups (Table 3).

Cox regression: univariate risk analyses
Table 4 shows the Cox univariate regression analyses of the infectious risks to 100 days of the matched cohorts of autologous HSCT patients. Compared with that shown in patients who received MITO/Mel, periodontitis and cysts and periapical lesions, associated with the risk of infection to 100 days, were reduced patients who received Mel200 (OR = 0.09; 95% CI, 0.01-0.91 and OR = 0.01; 95% CI, 0.01-10.55, respectively). Table 4 shows that, compared with that shown in the BuFuALG regimen, the risk of 100-day infections associated with OFI did not differ among the other groups.

Mortality
Positive OFI status before transplant did not increase 100-day mortality in any of the groups (Table 2 and Table 3). However, 100-day mortality was affected by factors other than OFI. In the autologous group, univariate logistic regression analyses revealed that smoking and diabetes were associated with 100-day mortality in patients who underwent autologous HSCT (OR = 1.50; 95% CI, 1.01-2.26; P < .05 and OR = 1.72; 95% CI, 1.02-2.91; P < .044). In terms of disease variants, non-Hodgkin lymphoma was associated with 100-day mortality (OR = 1.46; 95% CI, 0.93-2.30; P < .09). In autologous transplant patients, a second transplant and 100-day bacterial infection were associated with 100-day mortality (OR = 2.27; 95% CI, 1.18-4.36; P < .014 and OR = 1.62; 95% CI, 1.02-2.58; P < .040, respectively).

In the allogeneic HSCT groups, the Sorror comorbidity score was associated with 100-day mortality (OR = 2.55; 95% CI, 1.29-5.03; P < .007). In terms of disease type, aplastic anemia increased 100-day mortality (OR = 7.0; 95% CI, 1.98-24.80; P < .003).

Causes of mortality
In terms of the causes of death, 1 patient (0.8%) had a bacterial infection in the BEAM group, 1 patient (0.5%) had a bacterial infection in the BuFuALG group, and 2 patients (4.3%) had fungal infections in the BuFu/Cy group; all were OFI positive.

Discussion

The number of HSCT procedures in centers registered with the EBMT reached 43?581 in 2019, and improve-ments in transplant protocols have facilitated increasing numbers of HLA-mismatched transplants (haploidentical HSCTs) and unrelated donor transplants.¹⁶ To ensure success, it is important to evaluate, among systems in the body, oral and dental health before transplant. Patients with high-risk diseases may have to undergo HSCT without adequate oral treatment before transplant. Some reports have suggested that transplant can be successful even if pretransplant OFIs are present (for example, in emergencies).^4,6,8 However, knowledge on this subject is limited, and the transplant protocols may affect the process. We found that, for patients with aggressive diseases, different transplant types using various conditioning regimens with or without ALG or TBI allow patients with OFI to be urgently transplanted if their care is of high quality.^17-20

The possible reasons why most pretransplant patients show evidence of OFIs include the fact that bone marrow failure, prolonged neutropenia, and/or immunosuppressive treatments may trigger oral problems.²¹ In patients with sickle cell disease, OFIs may be attributable to vaso-occlusive events, chronic hemolytic anemia, depletion of nitric oxide by free hemoglobin, hydroxyurea production, and hygiene-related problems.²² In patients with malignant diseases such as leukemia, disease progression and previous immunochemotherapies facilitate OFI development during treatment.²³ It may be difficult to access the full records of patients with new or exacerbated OFIs. The use of adequate diagnostic tools and accurate data recording facilitate the detection of problems. Here, data on a large number of patients were evaluated by 3 investigators. The interobserver reliability of the various OFI findings before transplant was acceptable. Agreement ranged from substantial to perfect for all findings.

Patients with multiple myeloma who received the upfront Mel200 protocol were older than others. The BEAM and MITO/Mel groups included patients with Hodgkin and non-Hodgkin lymphoma and who had undergone multiple-line immunochemotherapies to treat relapsed refractory disease. Day 100 infections, FEN episodes, bacterial site infections, and bacteremia were more common in the BEAM and MITO/Mel conditioning regimen groups who received autologous HSCT than in the Mel200 group. This may reflect the earlier combination chemotherapy regimens, multiline treatments, and disease characteristics of the former groups. However, it is difficult to explain why FEN episodes and bacteremia were less common in patients with than in those without OFIs. Drugs such as mitoxantrone, melphalan, and etoposide are associated with mucositis and may create a greater risk for a posttransplant FEN episode than does OFI.^24,25 The higher 100-day infection risk in the MITO/Mel group compared with the Mel200 group may reflect the fact that mucositis was more common than periodontitis, cysts, or periapical lesions in the MITO/Mel group.

The allogeneic transplant groups differed in terms of mean age. The TBI/Cy group included the youngest patients. The BuFuCyALG/Cy group included patients with acute leukemia who underwent haploidentical transplant and patients with sickle cell disease who developed tissue damage.²² We found that OFI was associated with 100-day infections, bacteremia, other bacterial infections, and FEN episodes. This is not surprising; the conditioning regimens and severe immunosup-pression used for GVHD prophylaxis in such groups are well-known to be associated with GVHD and infectious complications.¹² With the exception of FEN, the frequencies of infectious complications did not differ among the groups. The antimicrobial prophylaxes (ofloxacin, fluconazole, acyclovir, sulfamethoxazole, and trimethoprim after engraftment) of the various regimens may explain the observations.

Although significant among-group differences were apparent in terms of age, disease, and GVHD prophylaxis, OFI status did not affect the frequencies of grade II-IV or grade III-IV aGVHD. The criteria for GVHD diagnosis and grading continue to be refined; validation studies must continue until the clinical roles played by the conditions are well understood. Until then, the existing definitions of GVHD remain valid.²⁶ Future studies should explore the durations of immunosuppressive treatments and the roles played by prophylactic antimicrobials.

We found that, although 100-day bacterial infections were associated with 100-day mortality in autologous HSCT patients, such mortality was not associated with OFI in any autologous or allogeneic HSCT group. There were no differences in OFI-related 100-day mortality between the groups. Improved management of OFI-related infectious complications might reduce mortality.

The retrospective nature of the work is a limitation of this study. Its strength is that the oral and dental evaluations of the patients before transplant are part of our SOPs; our center was recently awarded JACIE accreditation for the third time. In addition, we always maintain a state-of-the-art medical record system.

We found that OFIs detected before transplant can be ignored in emergencies, and it is safe to proceed to autologous or allogeneic HSCT. There is no need to change the ablative intensities of autologous conditioning protocols or the TBI- or ALG-based ablative allogeneic transplant protocols. However, interventional procedures such as multiple tooth extractions may pose risks, including nutritional issues, septicemia, or endocarditis, in immunosup-pressed patients.^20,21 After autologous or allogeneic HSCT, it is appropriate to follow-up patients with OFIs until immune recovery is evident.

Conclusions

Based on our findings and the available literature, we suggest the following transplant eligibility criteria for patients indicated for autologous HSCT or allogeneic HSCT from HLA-matched (related or unrelated) donors or HLA-mismatched (haploidentical) donors. Eligibility criteria for patients who require autologous or allogeneic HSCT and have pretransplant OFIs^3,27,28 should include the following: (1) risk of disease progression (patients with high-risk acute leukemia or aggressive lymphoma with or without pretransplant residual disease); (2) no history of prolonged neutropenia (less than 14 days) during previous treatments; (3) asymptomatic OFI; and (4) in a postirradiation period. In the following situations, a risk analysis is required before single or multiple tooth extraction and/or long-term oral treatment^3,27,28 (1) immunosuppressive therapy for >3 months before transplant; (2) agammaglobulinemia or hypogam-maglobulinemia; (3) prior severe treatment of refractory disease (>2 rescue regimens); and (4) symptomatic (active) OFI.

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