Mucositis Associated with Stem Cell Transplantation: Current Status and Innovative Approaches to Management

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Bone Marrow Transplantation (2001) 27, Suppl. 2, S3–S11  2001 Nature Publishing Group All rights reserved 0268–3369/01 $15.00 www.nature.com/bmt Mucositis associated with stem cell transplantation: current status and innovative approaches to management

P Stiff

Loyola University Medical Center, Maywood, IL, USA

Summary: measurement has taken center stage in the transplant arena. In the next few years several active agents will likely be Treatment-related morbidity, and in some cases, mor- available to significantly diminish both the frequency and tality, associated with autologous and allogeneic bone severity of mucositis associated with transplantation. To marrow transplantation has decreased in the past dec- assess benefit, however, a clear understanding of the mech- ade largely due to the use of blood stem cells combined anisms by which chemotherapy and radiation cause muco- with hematopoietic growth factors. However, these pro- sitis and an accurate method to grade its severity is cedures remain morbid, with several series docu- required. This review describes what is known about the menting regimen-related injury to the oral mucous incidence and severity of mucositis, as well as its measure- membranes, the worst form of toxicity from a patient ment, pathophysiology, and clinical consequences. perspective. The pathophysiology of transplant-related Additionally, an overview of several investigational agents mucositis is related to two major events: direct mucosal being tested to control mucositis is presented. basal cell injury leading to atrophy and ulcerations, and local infections that can become systemic, the latter of which are exacerbated by the severe neutropenia Prevalence and severity of mucositis in the bone accompanying high-dose chemotherapy. Recent investi- marrow transplantation population gational agents designed to interfere with these two aspects of mucositis have been developed and are show- Various studies have demonstrated that significant oral ing promise in early clinical trials. In particular, kera- mucositis occurs in about 75% of patients undergoing stem tinocyte growth factor (KGF) and interleukin-11 appear cell transplantation.2–5 Regimens including total body active. They increase basal cell proliferation, prevent irradiation (TBI) plus chemotherapy lead to a higher rate of apoptosis due to the preparative regimen, and appear mucositis than chemotherapy alone. Severity varies widely to ameliorate the mucositis seen with high-dose chemo- among chemotherapy agents; high-dose etoposide and mel- therapy regimens. Oral, nonabsorbable anti-infective phalan appear to cause the most severe forms of mucositis.4 agents are also being tested in an attempt to prevent A recent in-depth survey of 38 patients who had completed both local and systemic infections. Devoid of significant their transplants was undertaken to assess the importance side-effects, KGF is now in large phase 2 trials that, if of mucositis to the patient. Forty-two percent felt that positive, will be a significant advance in promoting less mucositis was their most significant transplant-related tox- morbid transplants by reducing pain and the risk of icity, compared to 13% who cited nausea and vomiting.6 secondary infections and thus may reduce supportive Our center (BMT Program, Loyola University Medical care costs. Bone Marrow Transplantation (2001) 27, Center, Maywood, IL, USA) recently performed a retro- Suppl. 2, S3–S11. spective survey of the toxicities of bone marrow transplan- Keywords: high-dose chemotherapy; mucositis; stem tation (BMT) in 41 patients who underwent either allog- cell transplantation eneic (11) or autologous (30) transplantation. Of the 41 patients, 21 received high-dose chemotherapy alone and 20 received chemotherapy and radiation as their preparative regimen. Twenty-five underwent transplant more than 1 Oral mucositis is undoubtedly one of the most debilitating year prior to the survey, and 11 less than 6 months prior toxicities of hematopoietic stem cell transplantation. Until to the survey. As shown in Figure 1, mucositis was felt to recently, the only successful way to manage this common be the most debilitating toxicity by 50% of all the patients, complication was to provide good oral hygiene and copious by 30% of patients receiving high-dose chemotherapy 1–5 amounts of narcotic analgesics. However, with the recent alone, and by 65% of patients receiving TBI-based investigation of several experimental agents that may not regimens. only diminish the severity of mucositis but also decrease Utilizing a 1–10 severity scale (Figure 2), patients who its frequency, an emphasis on pathophysiology and accurate listed mucositis as their most toxic side-effect rated it on average as a 9. No patient listed it at less than 7. Addition- Correspondence: Dr P Stiff, Professor of Medicine and Pathology, Direc- ally, 84% reported their mucositis as more severe than tor, BMT Program, Loyola University Medical Center, 2160 South First expected and 65% reported either no symptom control or Avenue, Maywood, Illinois 60153, USA 50% improvement at best with palliative symptom control. Mucositis management P Stiff S4 caused by the ablative regimen and local infections that develop on the damaged mucosal surface, which are exacerbated by neutropenia.7–9 This combination of factors (Figure 3) leads to the approximate 30% incidence of bacteremia associated with infections (most often streptococcal organisms) of disrupted mucous membranes.10–14 Overall, clinical evidence of injury begins 2–4 days following com- pletion of the preparative regimen, develops over the next week, and then slowly begins to heal.7–9 In actuality, injury begins with the initiation of the preparative regimen, which damages the actively dividing cells at the basal cell layer. This in turn causes decreased cell renewal, decreased cell differentiation, and increased apoptosis. Subsequently, generalized atrophy and ulceration occur, especially in areas Figure 1 Loyola BMT toxicity survey: patient-reported perception of the prone to trauma from the teeth such as the inner lips and most severe toxicity associated with bone marrow transplantation. NV = buccal area. Based on in vitro studies, Sonis et al8 have nausea and vomiting. postulated that local release of cytokines such as interleukin 1 and TNF-␣ occurs early in the course of the high-dose chemotherapy, which promotes increased vascularity of the basal cell layer and may initiate the series of events listed above. The second phase of mucosal injury begins at the point of mucosal ulceration, at which time aerobic and anaerobic bacteria develop in and exacerbate lesions. Neutropenia complicates these local infections. From 25% to 75% of bacteremias seen post-transplant may have disrupted oral mucus membranes as the portal of infection.10–14 This phase is likely complicated by the use of broad-spectrum anti- biotics, which can lead to local and eventually systemic gram-negative, viral, and fungal infections. With routine use of acyclovir for herpes simplex viral (HSV) infections

Figure 2 Loyola BMT toxicity survey: patient-rated severity of mucositis (1–10 scale).

In contrast, those citing nausea and vomiting as the worst toxicity reported their symptoms controlled on average greater than 50% of the time. Most importantly, of those reporting mucositis as the worst toxicity, 65% still had residual oral symptoms at the time of the survey, including symptomatic xerostomia in nearly 50% and a higher rate of cavities compared to pretransplant in 21%. The conclusions from these surveys indicate that mucositis, while transient in the post-BMT period (lasting on average 7–10 days), is considered by patients to be their worst and most severe toxicity. Despite our best efforts at good hygiene and narcotic use – at our center, mucositis is treated with oral rinses and topical anesthetics, as well as systemic narcotics – our patients are still experiencing sig- niﬁcant mucositis-associated morbidity. More importantly, as will be discussed, several recent reports demonstrate that severe mucositis is not only associated with a decrease in quality of life, but may be associated with increased mortality, extended hospitalization, and increased costs.

Pathophysiology

There appear to be two major events that lead to the symptoms of mucositis in the BMT population: direct injury Figure 3 Pathophysiology of mucositis.

Bone Marrow Transplantation Mucositis management P Stiff S5 and topical or systemic anticandidal therapies, HSV and Table 2 OMAS mucositis scale Candidal infections are now uncommon. Uncontrolled local infections (often due to poor hygiene predisposing to Location Ulceration/ Erythemab pseudomembrane formation) and deep ulcerations are fac- Pseudomembranea tors that can delay wound healing and also lead to increased pain. However, they are largely prevented by good oral Upper lip 0, 1, 2, 3 0, 1, 2 Lower lip 0, 1, 2, 3 0, 1, 2 hygiene including salt solutions and nonalcohol Right cheek 0, 1, 2, 3 0, 1, 2 mouthwashes.1,4,7,9 Left cheek 0, 1, 2, 3 0, 1, 2 Basal cell regeneration normally begins 9–14 days after Right vertical/lateral tongue 0, 1, 2, 3 0, 1, 2 injury, and thus mucositis begins to resolve at about the Left vertical/lateral tongue 0, 1, 2, 3 0, 1, 2 2 Floor of mouth 0, 1, 2, 3 0, 1, 2 time of neutrophil reconstitution following transplant. Epi- Soft palate 0, 1, 2, 3 0, 1, 2 thelial cell regeneration is also associated with the return Hard palate 0, 1, 2, 3 0, 1, 2 of a normal oral bacterial ﬂora. However, chronic injury including persistent xerostomia and increased dental cavi- a0 = none; 1 = Ͻ1cm2;2= 1–3 cm2;3= Ͼ3cm2. ties is not uncommon despite repair of the acute injury.2,15 b0 = none; 1 = not severe; 2 = severe. OMAS = Oral Mucositis Assessment Scale. Reproduced with permission from Sonis ST et al., Cancer 1999; 85: 2103–2113. Mucositis assessment scales

With the development of potentially effective therapies to Table 3 WCCNR stomatitis staging system prevent or decrease the severity of mucositis, it is critical to have an accurate description of the anatomic changes of Stage Lesions Color Bleeding mucositis, as well as methods to measure its severity.16–18 While the World Health Organization (WHO) toxicity grad- 0 None Pink None 19 1 1–4 Slightly red N/A ing scale (Table 1) is widely used, it has long been felt 2 Ͼ4 Moderately red Upon eating and to be too subjective to accurately represent the anatomic oral hygiene and pathophysiologic changes that occur during mucositis. 3 Coalescing Very red Spontaneous Indeed, the symptoms that this scale measures may not be due to mucositis at all, but to local infection, hemorrhage, WCCNR = Western Consortium for Cancer Nursing Research. or the presence of an underlying malignancy. The WHO Reproduced with permission from the WCCNR, Can Oncol Nurs J 1998; 8 scale can be assigned without even examining the patient, : 160–165. and thus can potentially reflect ideologies other than clinical mucositis. However, it may be the most accurate meas- bines both subjective and objective measures and might ure of the clinical consequences of mucositis (ie pain and suffice as a single scale to measure mucositis. the requirement of parenteral medication and nutrition). There is no question that these newer scales more accu- The lack of specificity in the WHO scale has led to scales rately represent the anatomic severity of mucositis com- that ‘measure’ mucositis objectively such as the modified pared to the WHO scale, and thus can lead to an improve- Oral Mucositis Assessment Scale (OMAS; Table 2)20 and ment in the management of mucositis patients. the Western Consortium for Cancer Nursing Research (WCCNR) scale (Table 3),21,22 as well as scales that use a combination of both anatomic and subjective measures Clinical consequences of mucositis such as the Oral Assessment Guide (OAG; Table 4).23 The advantages and disadvantages of more complicated scales In addition to pain and decreased quality of life, recent are obvious. The OMAS scale is the most technically chal- studies have begun to more accurately measure the specific lenging as it measures lesion size and erythema at nine dif- medical complications and consequences of mucositis. ferent sites in the oral cavity. Obviously, this scale is very Rapoport et al24 sought to identify predictors of mucositis difficult to use in patients with severe pain who are unable following stem cell transplantation. They utilized the OAG to open their mouths for a sufficient oral examination, a as their measure of mucositis severity and made the peak very common phenomenon in the BMT setting. The OMAS score for mucositis (MUCPEAK) of the OAG one of their and WCCNR scales are strictly observational tools; the study endpoints. They found that a diagnosis of leukemia, revised WCCNR is the less cumbersome of the two, parti- the use of TBI in the preparative regimen, and allogeneic cularly for patients with severe mucositis. The OAG com- BMT were all significantly associated with mucositis. Sev- ere mucositis (ie MUCPEAK score of у18) was correlated with an increased incidence of bacteremia and mortality. Table 1 World Health Organization Mucositis Scale In their study, 60% of those with a score у18 developed bacteremia compared with 30% of those with lower MUC- Grade 0: None PEAK scores (P = 0.001). In addition, patients with scores Grade 1: Soreness/erythema у Grade 2: Erythema, ulcers, but able to eat solids 18 had a mortality rate of 24% compared to a 4% mor- Grade 3: Ulcers, requires liquid diet tality rate for those with lower scores (P = 0.001). A multi- Grade 4: Oral alimentation not possible variate analysis of the independent risk factors could not be performed in this study because many of the variables

Bone Marrow Transplantation Mucositis management P Stiff S6 Table 4 Oral assessment guide

Category 1 2 3

Voice Normal Deeper or raspy Difﬁculty talking Swallow Normal Some pain Unable Lips Smooth/pink and moist Dry or cracked Ulcerated or bleeding Tongue Pink/moist Coated, shiny ± red Blistered or cracked Saliva Watery Thick Absent Mucous membranes Pink/moist Red, coated without ulcers Ulcers Gingiva Pink, ﬁrm Edematous ± redness Spontaneous or pressure-induced bleeding Teeth/Denture areas Clean, no debris Plaque and localized debris Generalized plaque or debris

Reproduced with permission from the Nebraska Health System, Omaha, Nebraska, USA.

associated with mucositis overlapped (eg acute leukemia link between mucositis, sepsis, and its ultimate compli- and the use of TBI). Thus firm correlation of mucositis and cation, death. mortality cannot be assumed. Nevertheless, for the group Overall, it appears that the various mucositis scales with the highest mortality, those undergoing allogeneic employed in these studies not only accurately measure the transplantation, the correlation of mucositis and mortality objective and subjective features associated with mucositis, was significant. In addition, as total parenteral nutrition but the clinical consequences associated with mucositis as (TPN) use correlated with the presence of bacteremia (P = well. Quality of life, particularly as it relates to pain, 0.0001) and mortality (P = 0.003), it is certainly likely that appears to be accurately measured by the OAG scale, as high MUCPEAK scores were associated with overall was found in the analysis of a novel therapy for mucositis, transplant costs. keratinocyte growth factor (KGF, described later).28 The results of a recent study showed similar clinical cor- relates to severity of mucositis, and strongly suggested a high economic price caused by severe mucositis in the Prevention and therapy of oral mucositis in the BMT BMT population.25 Using the OMAS scale, Horowitz et al25 setting studied 84 patients from eight centers. This diverse group included both autologous (46%) and allogeneic (54%) Oral hygiene, rinses and nutritional supplements transplant patients, and utilized the mean OMAS score for each patient calculated over a 28-day period starting on the Poor dental care pre-BMT is associated with a higher fre- day the preparative regimen began. This mean score was quency of local and possibly systemic infection during analyzed for significant correlations with the incidence of BMT. Therefore, it is important that dental care be optim- infection, number of febrile days, days of TPN, 100-day ized before the patient is subjected to the transplant pro- morbidity, and total hospital charges. They found a signifi- cedure. In general, teeth brushing is usually not rec- cant correlation between the mean OMAS scores and both ommended during periods of mucositis in the BMT setting total days of TPN and total charges. Logistic regression due to the fear of significant oral bleeding and/or the pro- analysis demonstrated that each increase in the OMAS motion of bacteremia from ulcerative lesions. Most centers score of 1.0 was associated with a significant increase in treat patients with oral nonalcohol rinses (eg salt solutions) infections (P = 0.05). Linear regression analysis showed and topical anesthetics (eg dyclonine or xylocaine). A ran- that a 1.0 increase in mean OMAS score was associated domized study in the BMT setting comparing rinses alone with a significant increase in febrile days (P = 0.02), days to aggressive oral care including tooth brushing was of TPN (P Ͼ 0.01), increased days of parenteral narcotic recently reported.29 Sepsis was not higher in the aggressive use (P Ͼ 0.01), and $28554 of additional transplant oral care group, nor were days of fever. Furthermore, differ- charges. Mortality did not correlate with OMAS scores in ences between the groups in the number of patients with this study. moderate to severe mucositis was unremarkable (70/75 in These and additional data from Ruescher et al26 validate the rinses-only group and 64/75 in the intensive therapy the hypothesis that serious infection can result from severe group), confirming a lack of a benefit of aggressive oral mucositis. In that report, streptococcal infections in patients hygiene. with severe ulcerative mucositis were three times higher Glutamine, an essential amino acid, appeared to improve than in patients with mild symptoms. As septic shock can mucosal integrity in preclinical models.30,31 Glutamine-rich develop from streptococcal bacteremia, it is not surprising diets and rinses have been tested as mucositis therapy based that in one of these studies, mortality was higher in patients on these favorable results. In a small, randomized, blinded with the most severe forms of mucositis.27 A direct cause study, oral glutamine 2 g/m2 twice daily during and after and effect cannot be proven, as those with the most severe conventional-dose chemotherapy led to a reduction in oral mucositis were treated with the highest doses of TBI, sug- pain.32 Several randomized, double-blind studies have been gesting that other nonhematopoietic toxicities may have undertaken in the BMT setting. Schloerb et al33 studied 66 contributed to the increased mortality. Nevertheless, BMT patients randomized to either oral glutamine or a gly- because of the association, efforts at decreasing severe cine control at a dose of 10 g three times daily. When TPN mucositis appear appropriate as these studies do suggest a became necessary, those randomized to glutamine received

Bone Marrow Transplantation Mucositis management P Stiff S7 i.v. glutamine in their TPN. Those randomized to control wound contraction and healing.45 To date, studies indicate did not. No significant difference was found in hospital a marginal benefit, if any, when evaluated in a ran- stay, TPN days, neutrophil recovery, incidence of positive domized fashion. blood cultures, sepsis, diarrhea, and most importantly, mucositis. In a second study, MacBurney et al34 evaluated Interleukin 11 (IL-11): IL-11, a member of the IL-6 cyto- in a double-blind prospective trial glutamine-supplemented kine family, ameliorates thrombocytopenia following mye- TPN in the transplant setting. In contrast to the first trial, losuppressive chemotherapy.46 Other actions, demonstrated they found an improvement in nitrogen balance, shorter in vitro, suggest its potential value in the modulation of hospital stays, a decrease in positive blood cultures, and mucositis.47,48 IL-11 increases proliferation of the mucosal lower rates of clinical infection in the glutamine-sup- basal cell layer and partially suppresses apoptosis, thus pro- plemented patients. In addition, hospital charges were tecting basal cells from the toxic effects of radiation and found to be nearly $22000 less per patient in the glutamine- chemotherapy. Enhanced survival was seen when it was supplemented group, suggesting that i.v. glutamine when administered pre-radiotherapy in a murine model.47,48 In a given in TPN routinely post transplant can improve out- preclinical model of GVHD, IL-11 prevented the disease comes. In the largest study to date, Anderson et al35 evalu- and led to enhanced survival, presumably by protecting the ated in a randomized, double-blind, placebo-controlled trial basal cell layer of the gastrointestinal tract from the toxic oral glutamine 1 g/m2 four times per day in 193 BMT effects of the preparative regimen and by decreasing patients. In the autologous transplant patients (n = 87), glu- endogenous production of TNF-␣, endotoxin, and IL-2 in tamine was associated with significantly less oral pain by the gastrointestinal tract.49,50 both patient reporting and narcotic use (P = 0.005). There To date, only one trial has been reported exploring was no improvement in these parameters in allogeneic IL-11 in the human BMT setting to reduce mucositis.51 transplant patients. No significant differences were This randomized, placebo-controlled, dose-finding study observed in either group for TPN use, rate of relapse, pro- explored doses of IL-11 from 3 ␮g/kg/day to 50 ␮g/kg/day gression of malignancy, parenteral antibiotic use, graft-ver- along with high-dose chemotherapy using BuMelTT sus-host disease (GVHD), or days of hospitalization. The (busulfan, melphalan, thiotepa). IL-11 was given daily after authors suggested that benefit was not seen in the allogeneic busulfan was completed (ie before melphalan and thiotepa) transplant patients because they were treated with metho- and was continued for a total of 15 days. At doses of 3, trexate for GVHD prophylaxis. 10, and 25 ␮g/kg, there was no difference in the rate of Taken together, these clinical trial data indicate a poten- grade 3 or 4 mucositis (WHO scale) compared to the pla- tial role for parenteral glutamine supplementation in muco- cebo group. However, at the 50 ␮g/kg dose, only one of sitis management. three patients developed severe mucositis, and one did not develop mucositis at all. The authors reported a decreased Hematopoietic growth factors incidence of bacteremia/sepsis in the two highest dose levels (1/7, 14%) as compared to the other groups (12/22, Myeloid growth factors: Myeloid growth factors, given 55%). In addition, the number of days of severe mucositis after standard-dose chemotherapy, appear to partially was reduced in the two highest dose groups. The limitations ameliorate mucositis.36 The rationale for their use is their of these promising data are the small number of patients known proliferative effects on nonhematopoietic tissues. In treated in the 50 ␮g/kg/day group, a dose associated with the initial clinical trial that explored granulocyte colony- an increased incidence of edema and cardiac arrhythmias as stimulating factor (G-CSF) for the prevention of neutro- indicated in myelosuppression studies of IL-11. However, penic fevers and infection, Crawford et al37 noted a drop toxicity concerns might be appropriately addressed by alter- in the overall incidence of mucositis in the G-CSF group ing the IL-11 regimen according to a presumed optimal from 63% to 46% (P = 0.02). A second study by Gabrilove schedule developed in animal models of mucositis (ie et al38 demonstrated a decrease in mucositis from 44% to initiation of IL-11 3 days prior to the preparative regimen). 11% for G-CSF patients receiving an M-VAC regimen Given these promising data, further trials of IL-11 in the (methotrexate, vinblastine, adriamycin, cisplatinum) over prevention of both oral and gastrointestinal mucosal tox- the first two cycles of chemotherapy. Similar results have icity and their consequences are warranted. also been seen for patients treated with conventional chemotherapy and granulocyte–macrophage colony-stimul- Antimicrobial agents ating factor (GM-CSF).39 In the transplant setting, the benefits of myeloid growth It has long been recognized that neutropenic patients not factors have been less impressive. While Nemunaitis et al40 only develop bacteremia from mucositis, but that local noted a reduction in mucositis in patients undergoing a infections can contribute to the misery of this transplant human leukocyte antigen (HLA)-matched sibling allograft complication as well. Controlled trials have been performed with post-transplant GM-CSF treatment, no difference was with a number of agents including hydrogen peroxide and seen in the incidence and severity of mucositis in patients chlorhexidine.1,52,53 In general, these agents have not led to receiving an HLA-matched sibling transplant with high- a significant improvement in mucositis. In fact, hydrogen dose busulfan and cyclophosphamide in the study by Atkin- peroxide may actually have a detrimental effect by son et al.41 Topically administered G-CSF and GM-CSF is developing resistant bacteria and interfering with wound also under investigation.42–44 The rationale for topical use healing by modifying oral pH.52 All of these agents lead to is based on data in animal models that suggest enhanced incomplete antimicrobial killing. While it seems unlikely

Bone Marrow Transplantation Mucositis management P Stiff S8 that any anti-infective agent will prevent or delay damage systemic side-effects.59 Given to normal volunteers, KGF to the basal cell layer caused by radiotherapy and chemo- stimulated the proliferation of oral epithelial cells and therapy, a potent anti-infective agent may help alleviate increased the percentage of actively dividing cells as meas- pain, shorten the period of mucositis, decrease the inci- ured by an increase in mitotic figures and Ki 67 positivity. dence of bacteria/sepsis, and thus contribute to a lessening These effects were seen in both murine and human models of morbidity and mortality in this population. after only 2 to 3 days of administration of recombinant One such agent has recently entered clinical trials. IB- human KGF.59–61 KGF stimulates not only proliferation and 367, a naturally occurring antimicrobial agent derived from migration of epithelial basal cells, but also their differen- porcine neutrophil peptides, is active against all microbio- tiation. Effects appear to be maximal on the oral mucous logical organisms found in the oral cavity of patients.54 membranes and the upper digestive tract, primarily stomach After demonstrating benefit in animal models of chemo- and proximal small bowel.61 KGF also has proliferative therapy-induced mucositis, a randomized phase II trial in effects on the epithelial lining cells of the bladder, where the transplant setting was undertaken in 177 patients. The it was shown to ameliorate cyclophosphamide-induced OMAS scale was used to measure mucositis severity. ulcerative hemorrhagic cystitis.62 Patients were randomized up to 1 week pretransplant to In murine models where mice were treated with 5-fluor- receive either IB-367 or placebo. The agent was adminis- ouracil, methotrexate and TBI, or TBI alone, KGF tered in a 3-ml rinse to be used every 3 h while awake. increased survival by 55% or greater.58 In the Patients were instructed to rinse and hold the agent in their chemotherapy/radiation combination model, it significantly mouth for several minutes before expectoration. While prevented weight loss during therapy and accelerated there were dropouts due to the inability to take the agent weight gain during recovery. KGF has also been shown to throughout the entire transplant period, the median time on increase crypt cell survival in the small bowel by 3.5-fold study drug was 17 days, and the major reason for discon- in this model.58 tinuation was hospital discharge. KGF may also have a beneficial effect on GVHD and Overall, the agent reduced OMAS scores by 28% (P = its complications.63 When administered in a murine model 0.06). However, in patients taking the agent for у4 days of GVHD from day −3 to day +7 following allogeneic prior to stem cell infusion, mucositis was reduced by 42% transplant, KGF significantly reduced GVHD mortality and (P = 0.05). A trend toward a decrease in days of severe severity in the gastrointestinal tract by decreasing lipopoly- mucositis and number of febrile days was also seen. There saccharide as well as TNF-␣ levels. However, there was no were no differences in hospital stay between the two adverse effect on antitumor cytotoxic T cell responses. groups. There were also no differences between the groups Thus, in this model of P815 leukemia, GVHD was reduced regarding narcotic use or the ability to eat solid food, per- and leukemia-free survival was enhanced significantly com- haps because of the fact that the preparative regimens pared to controls (42% vs 4% for leukemia-free survival, caused damage to the posterior oropharynx and upper eso- P Ͻ 0.001), demonstrating that KGF can ameliorate acute phagus, as well as the agent’s likely limited distribution in GVHD, but not graft-versus-leukemia effects in this model. the oral cavity. Nevertheless, this type of agent may be Based on these observations, a phase I, placebo-con- valuable as a component to the overall strategy to decrease trolled, dose-escalation trial of KGF was recently perfor- the effects of mucositis, primarily infections. A phase III med in patients with lymphoma who received high-dose study of IB-367 in the BMT setting is underway. chemotherapy utilizing BEAM (BCNU, etoposide, cytosine arabinoside, and melphalan) with an autologous peripheral blood stem cell transplant (Figure 4). The primary endpoint Keratinocyte growth factor (KGF) was the safety of KGF. Secondary endpoints were the bene-

KGF is a 28 kDa heparin-binding member of the fibroblast growth factor family. It binds to its receptor on a variety of epithelial tissues including skin keratinocytes and stratified squamous epithelium, gastrointestinal and oral epithelial cells, hepatocytes, and type II pneumocytes.55–60 It was initially described in 1989 by Rubin et al,55 who discovered it in the conditioning media of a human embryonic lung fibroblast cell line. It was found at that time to be capable of stimulating DNA synthesis in a variety of tissues, most notably resting epidermal keratinocytes by greater than 500-fold over baseline. In both animal and human models, KGF causes epithelial thickening of the nonkeratinocyte layers of the oral mucosa, with similar activity in the digestive tract, localized primarily to the stomach and upper small bowel.57–61 KGF administered to mice and nonhuman primates has Figure 4 BEAM for Hodgkin’s disease and non-Hodgkin’s lymphoma phase I dose escalation. BEAM = BCNU, etoposide, cytosine, arabinoside, been shown to protect a variety of tissues exposed to dam- and melphalan; KGF = keratinocyte growth factor; PBPC = peripheral age (including radiation and chemotherapy damage) and blood progenitor cell; rHuKGF = recombinant human keratinocyte produce oral mucosal proliferation without other significant growth factor.

Bone Marrow Transplantation Mucositis management P Stiff S9 fit of KGF on the development, severity, and duration of exploring the effect of KGF on mucositis, it is apparent oral mucositis as measured by the WHO and OAG scales, that simple measures to assess mucositis such as pain and and clinical sequelae including the amount of narcotic anal- the ability to swallow solids or liquids are not only easier gesics used, length of hospitalization, and quality of life. to use than more elaborate observational scales, but also Patients eligible for a stem cell transplant for Hodgkin’s appear to be equally predictive of the most severe forms and non-Hodgkin’s lymphoma were eligible for the study. of mucositis. However, in assessing the efficacy of new Adequate CD34 yield was a requirement, with a minimum agents, it would appear appropriate to use not only a subjec- dose of 2 × 106 CD34/kg. Patients had to have a normal oral tive scale, but also a more objective scale in which lesions examination pretransplant. They received, in a randomized in the oral cavity are at least visually assessed. Ultimately, fashion, either placebo or active study drug administered it appears likely that the misery of mucositis may soon be as an i.v. bolus either daily for 3 days before BEAM, or significantly improved by one or more of these agents used daily for 3 days before BEAM with an additional 3 days either singly or in combination. This will be a welcome of treatment beginning on the day of stem cell infusion. and long overdue relief to all patients undergoing stem There was a 2/1 randomization of KGF to placebo. cell transplantation. Dosing began at 5 ␮g/kg/day and increased to a high of 80 ␮g/kg/day. Oral reactions, generally mild to moderate in severity and presumably due to the biologic effects of References the drug, were seen during the initial 3 days of treatment. 1 Sonis S, Clark J. Prevention and management of oral mucos- These included flushing, rash, edema, tingling, white itis induced by antineoplastic therapy. Oncology 1991; 5: tongue, and thick feeling of the tongue. The incidence of 11–18. these reactions was 28% in patients at KGF doses above 2 Woo SB, Sonis ST, Monopoli MM et al. A longitudinal study 20 ␮g/kg compared to 2% in the placebo group. Onset of of oral ulcerative mucositis in bone marrow transplant recipi- the reactions was 36 h after the first dose of KGF, and ents. Cancer 1993; 72: 1612–1617. symptoms resolved in 7 to 10 days. The maximally toler- 3 McGuire DB, Altomonte V, Peterson DE et al. 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