Mucositis Grade Research Articles

Low-level laser therapy prevents severe oral mucositis in patients submitted to hematopoietic stem cell transplantation: a randomized clinical trial.

The purpose of this study is to evaluate the effectiveness of low-level laser therapy for the prevention of oral mucositis in patients undergoing hematopoietic stem cell transplantation. This is a randomized, parallel, superiority trial including 35 patients divided into the following: laser (n = 17) and sham (n = 18). The variables assessed were oral mucositis (grade 2 of the World Health Organization oral toxicity scale), severe oral mucositis (grade 3 or 4), and pain (according to a visual analogue scale). In the laser group, a InGaAlP laser, wavelength of 650 nm, power 100 mW, energy per point of 2 J, time 20 s by point, extremity fiber optic 0.028 cm(2), and energy density 70 J/cm(2), was used, applied the first day of conditioning until D + 5, while the sham group received simulated laser over the same period. No statistically significant difference was found in the incidence of oral mucositis (p = 0.146). Severe mucositis was found in 40% of the patients (14/35), 3 in the intervention group (17.65%) and 11 in the sham group (61.11%) (p = 0.015). The cumulative probability of survival with respect to the development of severe oral mucositis was >0.6 for the intervention group and 0 for the control group (p = 0.0397). On the day on which pain was considered the worst, patients in the sham group were more likely to classify their pain as severe compared to those in the laser group (p = 0.041). Low-level laser therapy proved effective for the prevention of severe oral mucositis and intense oral pain in patients submitted to hematopoietic stem cell transplantation.

Dietary counselling and nutritional support in oropharyngeal cancer patients treated with radiotherapy: persistent weight loss during 1-year follow-ups.

The need for dietary counselling and nutritional support in oropharyngeal cancer patients is generally accepted. However, evidence for the effectiveness is sparse. The aim of this study was to describe dietary counselling, nutritional support, body weight and toxicity during and after treatment, and investigate the effect of pre-treatment body mass index (BMI) on survival in oropharyngeal cancer patients. A retrospective chart review was made in 276 oropharyngeal cancer patients treated with radiotherapy (RT). End points were dietary consultations, weight loss, toxicity, overall survival and disease-free survival. Almost all oropharyngeal cancer patients received dietary counselling (94%) and nutritional support (99%). Dietary counselling decreased sharply shortly after treatment to 38% at 1 year after treatment. Overall weight loss increased during the first year of follow-up and ranged from 3% at start of RT, until 11% at 1 year after RT. Overall survival was significantly longer for patients with a BMI above average (P=0.01). Acute dysphagia (P=0.001), mucositis (P=0.000) and toxicity grade 3 (P=0.002) were significantly more prevalent in patients who had lost 10% or more of their body weight. This study showed that patients continue to lose body weight during and until 1 year after treatment, despite nutrition support and frequent dietetic consultation. A BMI above average appears to increase survival time. Future studies, preferably randomized trials, are needed to compare standard dietary counselling with more intensive dietary counselling that consists of earlier and/or prolonged treatment.

High-Dose Melphalan Plus Thiotepa as Conditioning Regimen before Second Autologous Stem Cell Transplantation for “De Novo” Multiple Myeloma Patients: A Phase II Study

High-dose melphalan (MEL) is the standard therapy for autologous stem cell transplantation (ASCT) in multiple myeloma (MM), although the optimal conditioning regimen remains yet to be identified. Thiotepa (THIO) appears to be a potentially effective option, with broad-spectrum antitumor efficacy that can be added to myeloablative multiagent regimens for ASCT in hematopoietic tumors. We conducted a phase II trial, adding THIO (275 mg/m2) to high-dose MEL (140 mg/m2) before a second ASCT, in a tandem ASCT strategy, in 64 patients with “de novo” MM. Overall, there was no transplant-related mortality. The incidence of neutropenic fever and mucositis (grades 3 to 4) was 39% and 9%, respectively. Median number of days to neutrophil and platelet engraftment were 11 and 12, respectively. After the second transplantation, the complete response improved to 43.8%. Overall response rate was 86%. After a median follow-up of 18.1 months, 13 patients had progressed and 3 died from MM. Median progression-free survival was not reached, and actuarial 2-year rates of progression-free and overall survival were 71% and 88.9%, respectively. Our results suggest that THIO/MEL is a feasible and safe conditioning regimen for ASCT in MM and should be explored for efficacy in a phase III study.

Characterization of the patient with chemotherapy-induced oral mucositis / Caracterização do paciente com mucosite oral induzida por quimioterapia / Caracterización de la paciente con mucositis oral inducida por quimioterapia

Objectives: To characterize cancer patients with oral mucositis treated at a private health facility. Methodology: An exploratory study with descriptive quantitative approach developed in 87 patients in a private practice oncology in Teresina, PI, from August 2011 to January 2012. Results: Findings indicated the prevalence of oral mucositis in males and in the age groups 40-59 years and more than 60. The most common cancer diagnoses were gastrointestinal tract and breast cancer, the treatments focused on chemoradiation, determining predominantly grades I and II of oral mucositis. Overall, mucositis had low discontinuation of cancer treatment and nursing procedures were mainly observed when patients had mucositis grade I. Conclusion: Patients are mostly female, age 40-59 years, with an education 11 or more years. Have an income 2-4 minimum wages and the most frequent types of cancers were the gastrointestinal tract and breast cancer, respectively. Descriptors: Stomatitis. Oncology. Chemotherapy. Nursing

Sodium Bicarbonate Containing Mouthwash for Preventing Radiotherapy-Induced Oral Mucositis in Patients With Locally Advanced Head and Neck Cancer

Background: In spite of all complications and disabilities due to advanced head and neck malignancies, treatment of oral mucositis following radiotherapy is mainly supportive and oral hygiene is the mainstay of treatment. In this context, mouthwash containing sodium bicarbonate can have a major role in the treatment of this complication. Objectives: The present trial assessed the value of this type of mouthwash for preventing oral mucositis following radiotherapy in patients suffered locally advanced head and neck squamous cell carcinoma. Patients and Methods: Twenty nine patients suffered locally advanced squamous cell carcinoma were consecutively entered into the study. All patients had stage III to IV head and neck malignancies. The patients were randomly assigned to receiving bicarbonate mouthwash (20 ml every 6 hours per day from the beginning to the end of the treatment) (n = 18) or placebo (n = 11). The mouthwash assessed was containing 1 vial of sodium bicarbonate, 500 ml of normal saline, and diphenhydramine 25 mg/kg). Results: A significant difference was revealed in the mucositis scoring between the intervention and placebo group so that mucositis grade III or more was observed in 7 patients in intervention group (38.9%) and in 9 patients in control group (81.8%) that the observed discrepant was significant (p = 0.024). The first evidences of oral mucositis in intervention group was found in forth weeks of treatment (sessions of 16 to 17 of treatment schedule), while the appearance of mucositis in placebo group was occurred in the middle of the third week (sessions of 13 to 14 of treatment). Conclusions: Oral care by mouthwash containing sodium bicarbonate for head and neck cancer patients undergoing radiotherapy is an effective interventional option to prevent oral mucositis.

A new prognostic model for chemotherapy-induced febrile neutropenia.

The objective of this study was to develop and validate a new prognostic model for febrile neutropenia (FN). This study comprised 1001 episodes of FN: 718 for the derivation set and 283 for the validation set. Multivariate logistic regression analysis was performed with unfavorable outcome as the primary endpoint and bacteremia as the secondary endpoint. In the derivation set, risk factors for adverse outcomes comprised age ≥ 60 years (2 points), procalcitonin ≥ 0.5 ng/mL (5 points), ECOG performance score ≥ 2 (2 points), oral mucositis grade ≥ 3 (3 points), systolic blood pressure <90 mmHg (3 points), and respiratory rate ≥ 24 breaths/min (3 points). The model stratified patients into three severity classes, with adverse event rates of 6.0 % in class I (score ≤ 2), 27.3 % in class II (score 3-8), and 67.9 % in class III (score ≥ 9). Bacteremia was present in 1.1, 11.5, and 29.8 % of patients in class I, II, and III, respectively. The outcomes of the validation set were similar in each risk class. When the derivation and validation sets were integrated, unfavorable outcomes occurred in 5.9 % of the low-risk group classified by the new prognostic model and in 12.2 % classified by the Multinational Association for Supportive Care in Cancer (MASCC) risk index. With the new prognostic model, we can classify patients with FN into three classes of increasing adverse outcomes and bacteremia. Early discharge would be possible for class I patients, short-term observation could safely manage class II patients, and inpatient admission is warranted for class III patients.

Smoking during radiotherapy for head and neck cancer and acute mucosal reaction

AimWe compared the incidence of RTOG/EORTC grade III and higher acute mucositis in patients with head and neck cancer who continued to smoke during radiotherapy with those who quit smoking. BackgroundThere are conflicting data on the relationship between smoking during radiotherapy and the severity of acute mucosal reaction. More studies dealing with this issue are needed. Materials and methodsAmong 136 patients receiving curative radio(chemo)therapy, 37 (27%) declared that they had not quit smoking during radiotherapy. The intensity of mucositis was scored daily by a nurse and weekly by a physician using the RTOG/EORTC scale. The main end-point of the study was the highest observed RTOG/EORTC grade of mucositis. ResultsPatients who smoked during radiotherapy (smokers) were younger than their counterparts who quit smoking (non-smokers), p=0.06. There were no other differences in the baseline characteristics between smokers and non-smokers. Grade III/IV acute mucositis was observed in 43.5% of all patients. The percentage of patients with grade III/IV acute mucositis was similar in smokers and non-smokers (46% vs. 42%, p=0.71). Nine patients (smokers [13.5%]; non-smokers [4%], p=0.05) required prolonged hospitalization to heal mucositis. ConclusionsIn the whole group, smoking during radiotherapy was not related to acute mucosal toxicity evaluated as the rate of the highest observed grade of mucositis.

Abstract P6-11-04: OOTR-N007: A phase II neoadjuvant study of letrozole plus palbociclib in postmenopausal patients with ER positive, HER2 negative breast cancer

Abstract Background : CDK4-associated kinase activity is required to maintain breast tumorigenesis. Virtually all ER-positive cell lines harbour loss of p16ink4a. Low expression of CDK inhibitors p21 and p27 and high expression level of cyclin E and D1 have all been associated with resistance to anti-estrogen therapy. In preclinical models, Rb deficiency is associated with resistance to antiestrogen therapy. Palbociclib (PD 0332991, Pfizer Inc.) is an oral, potent, highly selective reversible inhibitor of CDK4/6 that prevents cellular DNA synthesis by prohibiting progression from G1 into the S phase. Palbociclib in combination with letrozole has shown promising activity in metastatic setting. Methods : In an open-label, multi-center, single arm pilot study efficacy and safety of neo-adjuvant palbociclib 100 mg QD for 3 weeks plus letrozole 2.5 mg QD in 4 week cycles for 4 months was studied. Postmenopausal patients of mostly Chinese ancestry, with histologically confirmed ER+, HER2- invasive breast cancer and tumor greater than 2 cm were registered. Patients with T3N1, T4 or any N2, N3 were excluded. Aim : The primary endpoint is Objective Response Rate (ORR). The secondary end-point include Pathologic Response Rate (PRR), Disease-Free Survival (DFS), safety. Exploratory analysis of gene and protein expression in tumors and serial whole blood is planned. Results : As of June 2014, 11 patients were recruited. 9 patients completed treatment and 2 are still on study. Of the 9 patients that completed study at time of this abstract, 1 patient had a complete pathological response (pCR) and 7 had a partial response (ORR of 89%). Baseline Ki67 levels were low (median 18%), consistent with luminal type A disease. On average, patients underwent surgery 24 days after completion of the study. Ki67 was measured at baseline, cycle 1 day 15, and at the time of surgery. Median Ki67 at time of surgery was 10%. There were no significant changes in Ki67 that could be related to treatment outcome based on this preliminary data analysis in surgical samples only. In the first 8 patients, whom all started at a dose of 125mg palbociclib, 4 patients developed grade 3/4 neutropenia in the absence of fever. Neutropenia was well manageable with G-CSF and/or dose modification. Protocol amendment allowed starting dose of 100 mg with dose titration to 125mg after the first cycle. 3 patients started at 100mg and grade 4 neutropenia without fever occurred in 1 subject. Another common side effect was low grade mucositis (n=5). Conclusion : Based on these initial results, the addition of palbociclib to neo-adjuvant letrozole appears to be safe and effective. Historically, ORR in this patient population with letrozole alone is below 55%. The addition of palbociclib increased the preliminary ORR to 89%. One patient had a pCR, uncommon for patients on neo-adjuvant endocrine therapy. Complete safety and efficacy data will be included for at least 11 patients, including initial biomarker results. The study continues enrolment up to 45 patients. Citation Format: Louis WC Chow, Chi-Kei Lam, Wings TY Loo. OOTR-N007: A phase II neoadjuvant study of letrozole plus palbociclib in postmenopausal patients with ER positive, HER2 negative breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-11-04.

Hangeshashinto Improves the Completion Rate of Chemoradiotherapy and the Nutritional Status in Patients with Head and Neck Cancer

Purpose: Severe oral and pharyngeal mucositis is one of the most critical toxicities known to lead to the discontinuation of chemoradiotherapy (CRT) for head and neck cancer (HNC). Hangeshashinto (TJ-14) is a Kampo medicine that relieves chemotherapy-induced oral mucositis. We investigated the effect of TJ-14 on mucositis, nutritional status, and the completion rate of CRT. Methods: The study group comprised patients with advanced HNC who were treated with concomitant weekly cisplatin and 70 Gy of radiotherapy. The primary endpoint was the completion rate of chemotherapy, and the secondary endpoints were the grade of mucositis and the nutritional status. Results: A total of 57 patients were included in this study. The completion rate of CRT among patients who were treated with TJ-14 was 91.4%. There was a significant difference in the completion rate of CRT between the groups treated with and without TJ-14 (p = 0.0452). The reduction in body weight was significantly improved from 10.89 to 5.89% with TJ-14 administration (p = 0.003), and the reduction in serum albumin was also significantly decreased from 17.37 to 8.73%. (p = 0.024). Conclusion: This therapy allowed a high completion rate of CRT as well as significant benefits in terms of nutritional status. We plan to carry out a further large-scale study of TJ-14.

P13 Can the epidermal growth factor receptor inhibitor cetuximab make a difference in locally advanced head and neck cancers outcomes?

Background This is an update of a randomized study comparing the use of cetuximab versus platinum based chemotherapy with concurrent hyperfractionated radiation therapy (HRT) in locally advanced non metastatic head and neck carcinoma. Acute and late toxicity as well as progression free survival (PFS) were set as primary end points, while overall survival (OS) was set as secondary end point. Methods Between December 2009 and August 2013, 37 patients were randomly assigned to HRT consisting of 120 cGy twice daily, to a total of 69.6–75.6 Gys in 58–63 fractions over 6 weeks, plus either platinum-based chemotherapy (Arm A: 22 patients) or weekly cetuximab (Arm B: 15 patients). The overall radiation dose was the same for the two groups. The median follow up time of the whole group was 19.3 months (IQR: 6.1–37.1 ms). Results The mean Overall treatment time was 62 days in both arms ( p = 0.93). Skin toxicity (Grade > 3) was experienced in 36.4% of patients in arm A and 40% in arm B ( p = 0.82). Mucositis (Grade > 3) was 54.5% in arm A and 60% in arm B ( p = 0.74). Hematologic toxicity of (Grade > 3) occurred in 18.2% and 13.3% of the cases respectively ( p = 0.9). The mean percent of weight loss was (9.2%, SD = 5.8) in group A, and (13 %, SD = 6) in group B respectively ( p = 0.06). Complete response was observed in 16 patients (72.7%) and 8 patient (53.3%) of arm A and B respectively p = 0.23. Partial response was achieved in 2 (9.1%) patients in arm A and in 6 (40%) in arm B. The 1-year PFS for the whole group, arm A, and arm B were 67.6%, 63.9% and 75% respectively ( p = 0.37).The 2-year O.S was 88.9% and 90% for arm A and B respectively. Conclusions When HRT is used, both platinum-based and cetuximab concomitant regimens seem to have equivalent PFS and OS. Moreover, the toxicity profile for both regimens is largely similar although a trend for less haematological but more skin and mucosa toxicities were noticed in the cetuximab arm.

Effects of honey on oral mucositis in patients with head and neck cancer: A meta-analysis.

The objective of this study was to perform a meta-analysis of the efficacy of honey in the management of oral mucositis during radiotherapy in patients with head and neck cancer. Meta-analysis using MEDLINE, Scopus, and the Cochrane Library as data sources. Two authors independently searched the databases for relevant studies from inception to June 2014. Included in the meta-analysis were randomized controlled studies published in English comparing the oral administration of honey (honey group) with placebo or no treatment (control group) in patients with head and neck cancer who were undergoing radiotherapy or chemoradiotherapy. Excluded studies failed to report quantifiable outcome measures regarding oral mucositis. Outcomes of interest included the degree and incidence of mucositis, incidence of microbial colonization, and weight loss. Nine studies comprising 476 patients were included in the meta-analysis. The incidence of moderate to severe mucositis and the mean mucositis grade during the first 3 weeks of therapy were significantly lower in the honey group than the control group. Additionally, the onset of mucositis was significantly later in the honey group than the control. Although there were no significant differences in the incidences of microbial colonization and pain experienced between the two groups, the incidence of weight loss was significantly lower in the honey group than control group. Oral administration of honey after radiotherapy could prevent moderate to severe mucositis and associated weight loss. However, because our results were based on an analysis of a small number of trials, further trials are required to confirm these results. NA.

Prediction of serious complications in patients with seemingly stable febrile neutropenia: validation of the Clinical Index of Stable Febrile Neutropenia in a prospective cohort of patients from the FINITE study.

To validate a prognostic score predicting major complications in patients with solid tumors and seemingly stable episodes of febrile neutropenia (FN). The definition of clinical stability implies the absence of organ dysfunction, abnormalities in vital signs, and major infections. We developed the Clinical Index of Stable Febrile Neutropenia (CISNE), with six explanatory variables associated with serious complications: Eastern Cooperative Oncology Group performance status ≥ 2 (2 points), chronic obstructive pulmonary disease (1 point), chronic cardiovascular disease (1 point), mucositis of grade ≥ 2 (National Cancer Institute Common Toxicity Criteria; 1 point), monocytes < 200 per μL (1 point), and stress-induced hyperglycemia (2 points). We integrated these factors into a score ranging from 0 to 8, which classifies patients into three prognostic classes: low (0 points), intermediate (1 to 2 points), and high risk (≥ 3 points). We present a multicenter validation of CISNE. We prospectively recruited 1,133 patients with seemingly stable FN from 25 hospitals. Complication rates in the training and validation subsets, respectively, were 1.1% and 1.1% in low-, 6.1% and 6.2% in intermediate-, and 32.5% and 36% in high-risk patients; mortality rates within each class were 0% in low-, 1.6% and 0% in intermediate-, and 4.3% and 3.1% in high-risk patients. Areas under the receiver operating characteristic curves in the validation subset were 0.652 (95% CI, 0.598 to 0.703) for Talcott, 0.721 (95% CI, 0.669 to 0.768) for Multinational Association for Supportive Care in Cancer (MASCC), and 0.868 (95% CI, 0.827 to 0.903) for CISNE (P = .002 for comparison between CISNE and MASCC). CISNE is a valid model for accurately classifying patients with cancer with seemingly stable FN episodes.

Efficacy of percutaneous endoscopic gastrostomy on unplanned treatment interruption and nutritional status in patients undergoing chemoradiotherapy for advanced head and neck cancer.

Efficacy of percutaneous endoscopic gastrostomy (PEG) on unplanned treatment interruption and nutritional status was examined in patients undergoing chemoradiotherapy (CRT) for advanced head and neck cancer. We retrospectively reviewed hospital charts of 44 patients with advanced head and neck cancer who were treated with CRT. CRT-induced mucositis of grade 3 or worse and inadequate oral intake of less than one third of their usual intake developed in 33 patients who were recommended PEG placement, but not in 11 patients. Thirteen patients accepted PEG placement and then completed CRT (compliant group). However, among 20 patients who refused both PEG and nasogastoric tube (NGT) placements (non-compliant group), 10 required unplanned interruptions of CRT at a radiation dose around 30-40 Gy (UI-CRT group) while 10 others could complete CRT without interruption (C-CRT group) CRT. Total serum protein levels were significantly decreased after CRT in all patients. It is suggested that therapeutic PEG placement is useful for preventing unplanned interruption of CRT in patients with advanced head and neck cancer. After severe mucositis and inadequate oral intake have developed during CRT, PEG placement should be considered before the radiation therapy dose of 30 Gy.

2-Hour Cryotherapy Effectively Reduces Severe Mucositis Associated with High-Dose Melphalan Followed By Stem Cell Rescue: Results from a Randomized Trial

▪Introduction: Severe mucositis in the autologous transplant setting has been correlated with adverse outcomes; longer febrile neutropenia duration, doubling of infectious risk, 2.7 additional days of total parenteral nutrition, 2.6 additional days of IV narcotics, increased length of stay (LOS), 3.9-fold increase in 100-day mortality, and US$25,405 increase in hospital charges (Sonis, JCO, 2001 19(8)). In a 40 patient randomized trial investigating cryotherapy (6 hours versus none) following high dose melphalan, grade 3/4 mucositis occurred in only 14% of patients using cryotherapy compared to 74% of patients using saline rinses (Lilleby, BMT, 2006 37). Prolonged cryotherapy is a significant hardship for patients and has resulted in nausea, vomiting, headache, toothache, and chills. We performed a randomized study investigating 2 versus 6 hours of cryotherapy in multiple myeloma (MM) patients undergoing autologous stem cell transplant (ASCT) with melphalan conditioning.Hypothesis: We hypothesized that a 2-hour cryotherapy regimen would be non-inferior to 6-hours in severity of mucositis, LOS, and incidence of bacteremia.Methods: We conducted a non-inferiority investigation of 146 sequential MM patients undergoing high dose melphalan with autologous stem cell rescue. Patients were consented and randomized to either 2 (n = 73) or 6 hours (n = 73) of cryotherapy via block randomization based on hemoglobin (less or greater than 11 g/dL), fat free mass (30-50, 50-70, >70 kg), or measured 24hr creatinine clearance (<30, 30-60, >60 mL/min). The cryotherapy process consisted of patients’ melting shaved ice inside their mouth for the designated period of time; flavoring with snow cone syrup was permitted. Inpatient nurse practitioners graded mucositis via WHO criteria. Patients received antifungal (fluconazole) and antiviral (acyclovir or valacyclovir) prophylaxis. Subset analyses investigated the incidence of bacteremia in all patients.Results: Median age was 59 years (range 35 - 72) and 60 (range 38 – 71), and the median measured creatinine clearance was 90.6 mL/min (range 0.2 – 168.7) and 85.4 mL/min (range 21.5 – 196.5) for the 2 hour and 6 hour groups respectively.Length of hospitalization (mean of 15 days) did not differ significantly between the 2 cohorts (p = 0.54). Mucositis was graded daily after melphalan infusion. In the 2-hour cohort, 59% of the patients had mucositis (31 patients with grade 1, 10 with grade 2, and 2 patients with grade 3). In the 6-hour cohort, 64% had mucositis (35 patients with grade 1, 9 with grade 2, and 3 patients with grade 3). These results suggest that 2-hour cryotherapy was not inferior to 6-hour therapy in decreasing mucositis grade. In the entire 146 patient group, approximately 30% developed a positive blood culture after transplant, including 25 (34%) and 20 (27%) in the 6-hour and 2-hour groups respectively. The three most common infectious organisms included gram negatives (n = 12 patients), polymicrobial (n = 7), and non-group A streptococcus (n = 7). In the cohort treated with 2-hour cryotherapy, positive blood cultures did not correlate with grade of mucositis (r = 0.05, p = 0.65).Conclusions: In MM patients undergoing ASCT, 2-hour cryotherapy did not increase mucositis compared to 6-hours. The incidence of blood stream infection was not different between groups. In addition, having an infection did not correlate with grade of mucositis.These results suggest that a 2-hour cryotherapy regimen is not inferior to a 6-hour regimen, and may be considered a standard supportive care measure in patients receiving high dose melphalan. DisclosuresHofmeister:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millenium: Honoraria, Research Funding; ARNO Therapeutics: Research Funding; Onyx: Membership on an entity’s Board of Directors or advisory committees.

HLA-Matched Related Donor Hematopoietic Cell Transplantation in Patients with Fanconi Anemia Conditioned with a Combination of Cyclophosphamide and Fludarabine : A Study on Behalf of the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC)

Background.Fanconi anemia (FA) is a rare, phenotypically heterogeneous, inherited disorder clinically characterized by congenital abnormalities, progressive bone marrow failure (BMF) and a predisposition to develop malignancies. Hematopoietic stem cell transplantation (HSCT) is the only curative option for FA patients. However, finding the best conditioning regimen is still challenging for clinicians. To reduce toxicities, we used progressively lower doses of cyclophosphamide (CY) for conditioning through non-irradiation based regimens. A reduced conditioning regimen based on CY 60mg/kg alone was proposed by Bomfim et al (BBMT, 2007). Survival rates were excellent but some patients experienced primary (n=1) or late (n=4) graft failure (11% of the patients). Mucositis was a major problem as 25 patients (60%) presented grade 3 / 4 mucositis. The rate of Chronic graft versus host disease (GvHD) was 29%. We hypothesized that tapering the dose of CY to 40mg/Kg and adding fludarabine (FLU) at 90mg/m2 might improve engraftment, decrease GvHD rates and eventually improve overall toxicity in FA patients transplanted with HLA matched siblings.Method.In 2004, the French reference centre for aplastic anemia and the French Society of Bone Marrow Transplantation and Cell Therapies (SFGM-TC) recommended to use FLU 90mg/m2 (30mg/m2 days -4, -3, -2) and CY 40mg/kg (10mg/kg days -5, -4, -3, -2) for FA patients transplanted from matched family donor. Indication for transplantation was based on hematological complications (transfusions and/or infections). FA patients with morphologic signs of clonal evolution (myelodysplastic syndrome or acute myeloid leukemia) were excluded. All patients in France who received a first Allo-HSCT for FA from a matched related donor between October 2004 and January 2013 using this approach were analyzed (n=20). Clinical data were prospectively collected using ProMISe (Project Manager Internet Server), an internet-based data registry system shared by all SFGM-TC centres. All patients received uromitexan. Ciclosporin A and micophenolate mofetil were used as GVHD prophylaxis. Six patients received an in vivo T cell depletion using antithymocyte globuline because of local policy at their centre. The guidelines were approved by Saint-Louis hospital ethical committee.Results.The median age at transplant was 9 years (range: 6-19). Stem cell source was bone marrow in 16 cases and matched related cord blood in the remaining transplants. None of the patients received peripheral blood stem cells. All patients had severe or moderate BMF (median hemoglobin: 8.9g/dl, median platelets: 31 103/ul, median neutrophils: 0.88 103/ul) at time of transplant. Two patients had chromosomal abnormalities (47,XX,i(1)(q10)[10]/48,idem,+8[3] and 47,XX,+der(1;3)(q10;q10)[14]/46,XX[6]); however, none of them developed overt myelodysplasia/leukemia before transplant. Patients belonged to complementation groups FANC-A (n=17) and FANC-G (n=2). Transplantation was performed within a median of 30 months from FA diagnosis (range: 7-143). A median of 3.8. 108 nucleated marrow cells were infused (range: 0,65-8,97).Within a median follow up of 2 years (range: 0.2-7.4), overall survival was 95% (figure 1). Only one patient with an atypical form of FA associated with severe immunodeficiency prior to transplant died subsequently due to uncontrolled cerebral toxoplasmosis. Engraftment rate was 100% with a median time to neutrophils and platelets recovery of 16.5 (11-28) and 15 (4-29) days, respectively. No grade 3/4 regimen related toxicity was observed and only 1 patient experienced mucositis (grade 2) using this conditioning regimen. Total acute GvHD grade 3 / 4 was only observed in 3 patients (15%) and chronic GvHD was extensive in 2 patients (10%) and limited in 3 patients (15%). Median alive patients karnofsky scored 100% (range 90 – 100%). No secondary malignancy was observed in our cohort so far.Conclusion.The combination of low dose CY (40mg/Kg) plus FLU (90mg/m2) in HLA-matched donor HSCT in patients with FA resulted in an excellent engraftment rate (100%) with no secondary graft failure, low rates of acute and chronic GvHD, low rates of regimen related toxicity, eventually resulting in an excellent overall survival (95% at 2 years). A longer follow-up in this cohort is needed to confirm such excellent results long-term, namely the continued absence of secondary cancer. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Treosulfan-Based Conditioning in Pediatric Hematopoietic Stem Cell Transplantation: A Prospective Study on Pharmacokinetics and Early Clinical Outcomes

▪IntroductionTreosulfan is an alkylating agent which is increasing applied in regimens prior to allogeneic hematopoietic stem cell transplantation (HSCT) in children. It has strong myeloablative and immunosuppressive activity and, in comparison with busulfan and total body irradiation, a relatively mild toxicity profile. The optimal dose of treosulfan in pediatric patients, remains to be established. To optimize the balance between treosulfan efficacy and toxicity, pharmacokinetic (PK) monitoring may be a valuable tool. With this purpose, we recently developed a PK and limited sampling model (LSM) which allows measurement of treosulfan exposure. We here report the first results of an ongoing prospective study on the relation between the pharmacokinetic profile of treosulfan in pediatric HSCT recipients and clinical outcome.Materials and MethodsChildren (n =26; ≤ 18 years) receiving treosulfan based conditioning prior to their first HSCT in the Leiden University Medical Center, The Netherlands were included. Patients ≥ 1 year of age received treosulfan in a dose of 42 g/m2, divided over 3 days. Two patients aged 1.5 and 7 months received 30 and 36 g/m2, respectively. Treosulfan was combined with fludarabine (30 mg/m2/day, 5 days) in all patients and in n=20 patients thiotepa (8 mg/kg) was added. Serotherapy consisted of anti-thymocyte globuline or alemtuzumab. Blood samples were collected at 1.5, 3.5, 4, 5, 7 and 9 or, when a LSM was applied, at 4-5 and 6-7 hours after the start of a three hour treosulfan infusion. The individual PK profile of each patient was determined by a population PK-model with a one-compartment model. Clearance and volume of distribution were allometrically scaled using body weight, with a fixed scaling exponent of 0.75 and 1.0, respectively.Clinical endpoints of this study were stem cell engraftment, chimerism, GvHD, organ toxicity, relapse and treatment related mortality.ResultsThe median age, clearance, and volume of distribution were 6.5 (0.13-16.8) years, 7.8 L/h (1.2 - 44.7 L/h), and 13.8 L (3.0 - 42.9 L), respectively. Within the n=24 patients receiving 42 g/m2, the mean AUC of treosulfan was 1502 mg*h/L and the inter-patient variability was 14%. The inter-occasion variability was 5.4%, based on the day 1 and day 3 results of 12 patients. Two patients received a lower dose of 30 g/m2 and 36 g/m2, resulting in a day 1 AUC of 1578 mg*h/L and 1349 mg*h/L, respectively. A linear relationship was observed between age and treosulfan exposure (R2 = 24%) and body surface area and treosulfan exposure (R2 = 29%), resulting in a lower exposure in older patients (Figure 1.)In this cohort overall survival is 21/26 (81%). Four patients died prior to engraftment (≤18 days after HSCT), due to infection, toxicity (n = 2) and active malignant disease. Treosulfan exposure in these four patients was similar to the remaining patients of the cohort. Primary engraftment was seen in 95% of the 22 evaluable patients. Of the 21 survivors, 76% are disease free, four patients had a recurrence of initial disease, and one patient had a primary rejection followed by rapid autologous reconstitution. In 46% of the patients mucositis grade 2 or 3 was observed, 23% of the patients had skin toxicity grade 1-2 and 31% had a moderate and transient hepatic toxicity within 28 days after treosulfan administration. Acute GvHD ≥ grade II occurred in 3/26 patients. Severe hepatic toxicity occurred in three patients that received treosulfan as reduced toxicity conditioning because of their pre-existing organ toxicity. No association between treosulfan exposure and primary engraftment, survival and disease status at last follow-up was observed. Furthermore, the higher treosulfan exposure in the younger patients was not correlated with higher toxicity levels.ConclusionOur results demonstrate that PK monitoring provides novel insight in the level and inter-patient variability of treosulfan exposure in pediatric patients. To further improve early and long term clinical outcome in pediatric HSCT recipients individualized, age and possibly disease-specific dosing regimens may in the end be required. To achieve this goal, treosulfan PK monitoring as reported here will be a pivotal instrument to obtain further insight into the correlation between treosulfan dose and clinical outcome parameters. With this aim, we are currently performing a prospective multicenter pediatric study in disease-specific cohorts. [Display omitted] DisclosuresOff Label Use: Treosulfan in conditioning prior to allo-HSCT in pediatric patients.

Causes and Effects of Methotrexate Dose Alterations in Allogeneic Hematopoietic Cell Transplantation

▪AimTo identify the causes and consequences of omission and/or reduction of methotrexate (MTX) doses in graft-versus-host disease (GVHD) prophylaxis used during allogeneic hematopoietic cell transplantation (alloHCT).MethodWe conducted a retrospective medical record review of 125 alloHCTs performed between the years 2011 and 2013 at our hospital where MTX (15, 10, 10, 10 mg/m2 intravenously on day [D] +1, D+3, D+6, D+11 respectively) is used with cyclosporine as GVHD prophylaxis. The association of MTX dose omission with overall survival (OS), non-relapse mortality (NRM) and acute GVHD, measured from a landmark of D+12, was evaluated with univariate and multivariate analysis.Results116 patients (median age 48, range 17-67, 59% male) were eligible for analysis. Commonest indications for alloHCT were acute leukemia (47%) and chronic lymphoproliferative disorders (28%). Conditioning was myeloablative in 54%, donors were siblings in 53%, and grafts were peripheral blood in 87%. 85 patients (73%) received all four full doses of MTX. 22 patients had a dose omission at D+11, and two at both D+6 and D+11. 43 patients were given folinic acid rescue. Documented reasons for MTX alteration were mucositis (n = 22; World Health Organisation mucositis grade 4 in 16 patients, grade 3 in 4 patients and grade 2 in 2 patients), fluid overload (n = 10), liver impairment (n = 8, median bilirubin 83 micromol/L, range 19-204 micromol/L, normal < 21 micromol/L), renal impairment (n = 8, median creatinine 138 micromol/L, range 67-276 micromol/L, normal 45-90 micromol/L) and sepsis (1). MTX omission was associated with poorer OS (48% vs 90%; hazard ratio [HR] for mortality 5.4, 95% CI 2.5-11.7, P < 0.001, Figure 1) and higher NRM (39% vs 5%, HR 10.2, 95% CI 3.4-30.8, P < 0.001, Figure 2) at 12 months post landmark. A pattern of ongoing NRM was observed beyond day 100. Strikingly, those patients who received all four full doses of MTX had NRM of 0% at 100 days post landmark. There was no difference in rates of grade 2-4 (24% vs 22%, P = .950) or grade 3-4 (9% vs 11%, P = .662) acute GVHD, or relapse (20% vs 17%, P = .514), at day 100 post landmark.ConclusionMTX dose reduction has no significant impact on GVHD development, suggesting that MTX omissions or other adjustments of GVHD prophylaxis did not lead to enhanced T cell activation. However, it seems that the need to reduce MTX indicates an increased risk of NRM, likely reflecting ongoing organ dysfunction. Older patients or those with pre-transplant co-morbidities may be better served by strategies that lower the likelihood of organ toxicity, including reduced intensity conditioning and lower initial doses of MTX. [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Mucoadhesive Propolis Gel for Prevention of Radiation-Induced Oral Mucositis

The objective of this phase II study was to determine the effectiveness of a mucoadhesive propolis gel in the prevention of radiation-induced oral mucositis. Twenty-four patients who were selected to undergo radiation therapy for oral cancer were included in this open-label trial. They were advised to use a mucoadhesive gel containing propolis 5,0% w/v three times a day starting one day before the course of radiation therapy and concluding after 2 weeks of radiation therapy. A weekly follow-up for evaluation of food intake, pain and grading of mucositis was performed. In order to confirm the absence of Candida-related mucositis in patients who developed mucositis, it was performed exfoliative cytology of buccal mucosa, palate and tongue and the material for Candifast(®) Candida species identification. At the end of the study was made the compliance of patients, quality, appreciation and acceptance of product evaluation. Twenty patients did not develop mucositis, two patients developed grade 1 mucositis and two patients developed grade 2 mucositis. None of the patients discontinued food intake and no pain was observed during the study. Candidosis was not detected in any patient. Mucoadhesive propolis gel could be considered as a potential topical medication for preventing radiation-induced oral mucositis. However, comparative phase III study with larger number of patients should be done for confirmation of the efficacy of the product.

L-glutamine decreases the severity of mucositis induced by chemoradiotherapy in patients with locally advanced head and neck cancer: a double-blind, randomized, placebo-controlled trial.

The incidence of severe mucositis in the oral cavity, pharynx and larynx is high among patients with head and neck cancer (HNC) receiving chemoradiotherapy (CRT), resulting in significant pain and impairment of quality of life. The present study investigated whether L-glutamine (glutamine) decreases the severity of mucositis in the oral cavity, pharynx and larynx induced by CRT. This double-blind, randomized, placebo-controlled trial included 40 untreated patients with squamous cell carcinoma of the nasopharynx, oropharynx, hypopharynx or larynx. Patients received 66 or 70 Gy of total radiation at the rate of 2 Gy/fraction daily and 5 fractions/week. Cisplatin (20 mg/m2) and docetaxel (10 mg/m2) were intravenously co-administered once a week for 6 weeks. Patients were randomized to orally receive either glutamine (group G) or placebo (group P) at a dose of 10 g 3 times a day throughout the CRT course. Mucositis was assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0. The primary end point was mucositis severity. Mucositis developed in all patients. A maximal mucositis grade of G4 was observed in 0 and 25% group G and P patients, respectively, while that of G2 was observed in 10 and 0% group G and P patients, respectively (p=0.023). Glutamine significantly decreased the maximal mucositis grade (group G, 2.9±0.3; group P, 3.3±0.4; p=0.005) and pain score at weeks 4, 5 and 6. Glutamine significantly decreased mucositis severity in the oral cavity, pharynx and larynx induced by CRT in patients with HNC.

Histopathologic grading of oral mucositis.

Oral mucositis is a common adverse effect of cytotoxic chemotherapy and radiation, and it causes debilitating morbidity that may necessitate interruptions in cancer treatment. Animal models of oral mucositis are invaluable tools for testing novel therapeutics, but grading of lesions based on subjective assessments makes conformism between studies difficult. A standardized scoring system that can objectively and reproducibly grade the severity of oral mucositis is critical in comparing and validating efficacies of developing therapeutics. The head region of male Balb/C animals was exposed to collimated radiation delivered as fractions of 8Gy on three consecutive days, or as a single large dose of 22.5Gy. The development of oral toxicity was assessed by histologic analysis of the tongue at various days postradiation. After fractionated radiation, early epithelial atypia of basal cell layer disorganization and nuclear aberrations was evident by day 6. The disease displayed moderate changes of epithelial atrophy and dyskeratosis by day 7.5 with subsequent epithelial breakdown and ulceration by day 9. In contrast, exposure to a single large-dose radiation resulted in bulla formation by day 9 in most animals. An oral mucositis grading system based on histopathologic scoring of tissues is proposed.