Temsirolimus in the treatment of mantle cell lymphoma: frequency and management of adverse effects


Mantle cell lymphoma (MCL) is a rare subtype of non-Hodgkin lymphoma (NHL), comprising 2– 10% of all NHL [1]. It is characterized by CD5 expression and a t(11;14) chromosomal rearrangement, which leads to cyclin D1 gene overexpression [2]. Primarily a disease of the elderly (median age at diagnosis almost 70 years), MCL affects more than twice as many men than women and has an incidence rate in Europe and the United States of approximately 0.5 cases per 100 000 person years [1]. Patients usually present with advanced disease and prognosis is poor [2–4]. Although survival of patients with advanced MCL has almost doubled over the last three decades, a relatively recent study examining data from two European Lymphoma Study Groups revealed overall survival remains poor with median durations of 3– 5 years, and 5-year survival rates of 22–47% [5].

Anthracycline-based chemotherapy with cyclo- phosphamide, doxorubicin, vincristine and predni- solone in combination with rituximab (R-CHOP) is a standard induction regimen [6], but despite good initial response rates, relapse rates are high [2,3]. Dose-intensive induction regimens have helped to prolong survival, but their use is restricted to younger patients and/or those with fewer comorbidities [3]. Improved knowledge of MCL biology has high- lighted the phosphatidylinositol-3 kinase (PI3K)/ Akt/mammalian target of rapamycin (mTOR) path- way as a promising target for the development of new therapeutic agents to treat this disease [3].

Temsirolimus (Torisel; Pfizer, New York, NY, USA) is an ester derivate of rapamycin that forms a complex with FK506-binding protein (FKBP12) and the resulting complex inhibits the phosphoryl- ation of mTOR substrates, hence abrogating the downstream effects of mTOR [7,8]. Based on the results of a pivotal phase III study [9], temsirolimus is indicated in Europe for the treatment of adult patients with relapsed and/or refractory MCL at the recommended dosage of 175 mg once weekly for 3 weeks followed by maintenance therapy of 75 mg once weekly until the onset of disease pro- gression or unacceptable toxicity [10].

The safety profile of temsirolimus is quite differ- ent when treating solid tumours versus haemato- logical malignancies [11,12]. The indicated dosage is higher for MCL than for renal cell carcinoma [13], and MCL patients receiving temsirolimus have already experienced multiple pretreatments with cytotoxic agents and often have bone marrow disease infiltration. Thus, the vast majority of adverse effects encountered in these patients result in pronounced haematological toxicity. Nonethe- less, many symptoms other than haematological toxicities reported in patients with MCL treated with temsirolimus can be attributed to the mTOR inhibitor, even if the accurate relationship with the drug is difficult to assess with certainty.

Therefore, the aim of this review is to examine currently available tolerability data for temsirolimus in the treatment of MCL and
provide guidance on the incidence and management of both haema- tological and nonhaematological adverse events. Four published clinical studies of temsirolimus in this indication [8,9,11,14], as well as papers identified by a search of Medline and EMBASE using the search terms ‘temsirolimus’ and ‘mantle cell lymphoma’, and ad hoc articles are included.


Haematological toxicity (i.e. thrombocytopenia, neutropenia and anaemia) is the most frequent toxicity observed in patients with MCL treated with temsirolimus (Table 1) [8,9,11,14,15], with the incidence of thrombocytopenia being higher than other toxicities. The impact of temsirolimus schedule is more pronounced for thrombocytope- nia, which typically occurs during induction phase, and grade 3– 4 anaemia, which usually occurs later during the treatment period. The profile of haematological toxicity is generally similar for both temsirolimus 75 and 25 mg maintenance doses. Compared with other indications such as advanced renal cell carcinoma [16], the incidence of haema- tological toxicity tends to be higher in patients with MCL, probably because of prior treatment (chemo- therapy and often stem cell transplantation) and/or bone marrow involvement in relapsed/refractory disease. The origin of thrombocytopenia is mainly drug-induced bone marrow toxicity.

However, the high incidence of thrombocyto- penia does not translate into clinically significant bleeding in all studies. In the phase III pivotal study, epistaxis, reported by 35 and 24% of patients treated with weekly maintenance temsirolimus at 75 and 25 mg, respectively, was classified as clinically manageable due to it being only mild to moderate in severity (grade 1–2) [9] and one patient developed grade 3 rectal bleeding in the context of medication dosage error (330 mg instead of 175 mg); it is unknown whether this patient presented with gastrointestinal disease involvement. Also, in the phase II study of low-dose, single-agent temsiroli- mus, only one patient required platelet transfusion [11], and in the phase II study of low-dose temsirolimus in combination with rituximab, one patient experienced grade 4 bleeding (not specified) [14]. In this latter study, introduction of rituximab did not seem to translate into increased haemato- logical (or nonhaematological) toxicity.

In clinical studies, haematological toxicity was generally successfully managed by dose reductions or treatment delay, while still maintaining overall median dose intensities of between 60 and 86% [9,11,14]. In the phase III study, temsirolimus was withheld as soon as platelet count fell below 50 000/ml or absolute neutrophil count below 1000/ml, until haematological recovery [9]. The use of granulocyte colony-stimulating factor (G-CSF) or erythropoiesis-stimulating agents was not reported. In daily practice, management of hae- matological toxicities should follow recommen- dations in the temsirolimus package insert, which are based on those published in the phase III study [9,13]. Blood counts should be performed prior to treatment initiation and once a week during therapy. While peripheral thrombocytopenia is uncommon in MCL, blood smear examination could be useful, for example if schizocytes are present. Also, although it is rarely needed, bone marrow examination may be necessary in case of differential diagnosis of thrombocytopenia sec- ondary to bone marrow involvement by lymphoma. Thrombocytopenia is mostly rapidly reversible after drug delay (typically within 1 week). Platelet trans- fusion may be an option if platelet counts fall below 10 000 or 20 000/ml, or if clinically significant bleed- ing is associated with grade 3–4 thrombocytopenia. Thrombopoietin mimetics should not be used in this indication.When anaemia occurs during temsirolimus treatment, appropriate clinical examination and laboratory tests should be performed in order to determine any underlying causes of anaemia outside
temsirolimus-induced toxicity. Drug exposure history and examination for gastrointestinal bleed- ing (involvement of small intestine and/or colon is seen in 50% of patients with MCL), blood smear examination, reticulocyte count, iron stores and creatinine values should be evaluated. Finally, in rare cases, bone marrow examination may be necess- ary. Red blood cell transfusions and erythropoiesis- stimulating agents are both options for anaemia. If used, prescription of erythropoiesis-stimulating agents should follow international guidelines [17]. The threshold for red blood cell transfusion is commonly between 8 and 9 g/dl, depending on comorbidities such as cardiovascular disease, and the threshold for erythropoiesis-stimulating agent initiation is a haemoglobin level approaching or under 10 g/dl. The goal is to achieve haemoglobin levels at or near to 12 g/dl, at which time the dosage of erythropoiesis-stimulating agents should be titrated to maintain that level. There are no available data on the use of iron supplementation, either oral or intravenous, in this indication.
Neutropenia occurring during treatment with temsirolimus is principally secondary to direct bone marrow toxic effect, but other causes of neutropenia (such as viral infection or drug toxicity) should be evaluated. Bone marrow examination could be useful in rare cases. If absolute neutrophil count falls below 1000/ml, treatment should be postponed until recovery. The use of G-CSF has not been validated in this indication, and administration of G-CSF to maintain dose intensity of temsirolimus (i.e. primary prevention) is not recommended because of a lack of studies.


mTOR inhibitors (everolimus, temsirolimus and others) are often responsible for cutaneous and mucosal toxicity; lesions of the oral cavity appear to be specific to this drug class, and other frequently recorded toxicities include delayed wound healing, acne-like lesions, maculopapular rashes, folliculitis, nail disorders, exanthema and pruritus. The physi- opathology of temsirolimus-induced mucosal and cutaneous ulcerations could involve the inhibition of the growth of keratinocytes [18].

Stomatologic adverse events are one of the most frequent toxicities described in MCL patients treated with temsirolimus (Table 1); however, the frequency of oral lesions can be reduced with a weekly admin- istration schedule. The lesions induced by mTOR inhibitors are more likely ulcerative lesions (or aphthous mucositis; Fig. 1) than a true chemo- therapy-induced mucositis. These painful lesions, as a consequence, reduce oral intake and patients’ quality of life.

In patients with MCL, grade 1– 2 oral lesions were reported in 29– 39% [11,19]. Incidence of grade 3–4 stomatitis was very low, from 4.5 to 6% [9,19]. In most studies, a distinction between oral lesions (i.e. stomatitis, mucositis, oral pain) is not possible. Before starting treatment with temsirolimus, it is essential to have an oral and dental examin- ation. The treatment of stomatitis is based on a bicarbonate-based mouthwash, ideally with the addition of an antifungal or an antiseptic; however, the results achieved with this strategy will be differ- ent from those expected for classical chemotherapy- induced mucositis. Due to the inflammatory aspect of the ulcerative lesions, treatment with anti-inflammatory agents such as prednisone or aspirin can be used. Mouthwash may be helpful for prevention of aphthous lesions. No dose delay or dose reduction of temsirolimus is needed for the management of stomatologic adverse events.

In MCL clinical studies, grade 1– 2 rash was seen in 46– 51% of patients [8,14]. Temsirolimus-related rash was mainly maculopapular in nature. Grade 3 rash only occurred in 2% of patients [9]. The rash is usually transient and disappears without treatment. To our knowledge, there was no toxic epidermal necrolysis attributed to mTOR inhibitors. Grade 1–2 exanthema was reported in 28% of patients [19]. Grade 1– 2 pruritus was observed in 13% of patients, whereas only 4% of patients had pruritus of grade 3– 4 [9,14]. Nail changes are not uncommon, and these have been described in 19% of patients for grade 1– 2 and only 2% of patients for grade 3 [14]. Hand-foot syndrome and alopecia are not associated with temsirolimus treatment [18].

Dermatological adverse events are easily manageable. Prevention is based on twice-daily moisturizing cream and soap, antidandruff shampoo, loose clothing and use of sun protection of at least 30 SPF. Avoidance of direct sunlight, detergents and alcohol-based perfumed lotion is also recommended. Grade 1– 2 rash can be treated with hydrocortisone 1% cream and should not lead to stopping treatment. Grade 3 rash can be treated with low-dose prednisone (10– 25 mg/day for 7– 14 days). In patients experiencing a grade 4 cutaneous adverse event, temsirolimus treatment should be stopped and the patient referred to a dermatologist. Pruritus can also be treated with antihistamines (H1 antagonist: hydroxyzine, diphenhydramine).


Endocrinological adverse events are common with mTOR inhibitors as discussed below.

FIGURE 1. Examples of aphthous mucositis.


All mTOR inhibitors increase cholesterol and triglyceride levels by increasing nonhigh-density lipo- protein (HDL) cholesterol, including low-density lipoprotein (LDL) levels [20], but temsirolimus has not been specifically investigated. The incidence of abnormal lipid levels in the four studies of temsir- olimus in MCL is shown in Table 1. The frequency varied widely between studies and could be partly explained by methodological differences. Grade 3– 4 toxicity (total cholesterol >10.34 mmol/l, triglycerides >5.7 mmol/l) was unusual in these studies [8,9,11,14]. Increased incidence of cardiovascular adverse events related to hypercholesterolaemia or hypertriglyceridaemia (e.g. atherosclerosis, pan- creatitis) was not observed with temsirolimus.

Pathogenesis of mTOR inhibitor dyslipidaemia is unclear, but some information can be drawn from knowledge of the use of these drugs in the context of solid organ transplantation. Increased plasma levels of apolipoprotein B100 (a major component of very low-density lipoprotein and LDL, and a ligand for the LDL receptor) as a consequence of its decreased catabolism, have been demonstrated in sirolimus- treated kidney transplant recipients [21]. Decreased lipoprotein lipase activity and increased free fatty acid levels may be contributing factors. The absence of adverse effects related to hypercholesterolaemia or hypertriglyceridaemia may be explained by evidence indicating that mTOR inhibitors can counteract the negative effects of dyslipidaemia on cardiovascular risk by the direct effect of mTOR inhibition on atheromatous changes in the vascular wall. This protective effect of mTOR inhibitors on atherosclerosis could be mediated by the action of pro-inflammatory cytokines and cell proliferation mechanisms [22].

In the general population, lowering LDL chole- sterol levels reduces the risk of cardiovascular disease. Higher HDL cholesterol levels are also associated with decreased cardiovascular risk, but there is still no approved drug for modulation of HDL level. Evidence of the cardiovascular impact of hypertriglyceridaemia is less marked, possibly neutral and still debated. Alternatively, major hypertriglyceridaemia is included in the causation of acute pancreatitis. When dyslipidaemia occurs, an associated cause should be explored, such as drug-induced dyslipidaemia, other diseases (i.e. hypothyroidism, renal diseases, diabetes) or exces- sive alcohol intake. Familial history of dyslipidae- mia should also be explored, and a qualitative and quantitative evaluation of diet should be conducted. As the consequences of mTOR inhibitor- induced dyslipidaemia on cardiovascular morbidity and overall mortality are unknown and, regardless, patients requiring therapy with temsirolimus for relapsed MCL have a reduced life expectancy, management of dyslipidaemia should be appropri- ate and not become another ‘medical burden’ for patients. Diet can be modified, without excess; a high-fat diet and high rapid-acting carbohydrate intake should be avoided.

The threshold for therapeutic intervention and target lipid levels are not known. Precisely, it is unknown whether association with other cardiovas- cular risk factors should be taken into account to decide treatment. In patients without a medical history of dyslipidaemia or lipid-lowering drugs, it is recommended that serum lipid levels (LDL cholesterol, HDL cholesterol and triglycerides) should be measured before treatment and every 2 months during treatment. If therapeutic inter- vention is needed, statins (such as pravastatin) are the first choice, except in the case of isolated hypertriglyceridaemia, when fibrates are used. Safety of statin therapy should be monitored clin- ically (muscle pain) and biologically (creatine phos- phokinase levels). A reasonable treatment objective could be a LDL cholesterol level less than 1.6 g/l.

In patients already receiving statins when initiating temsirolimus, there is no evidence to justify statin dose modification. Serum lipid levels should be measured before treatment, at day 15, day 30 and then every 1 or 2 months during treatment. If LDL cholesterol levels increase, statin dosage should be increased, according to safety parameters. The treatment objective depends on previously deter- mined objectives and on cardiovascular risk level.


The incidence of hyperglycaemia during temsiroli- mus treatment of MCL is shown in Table 1. All-grade hyperglycaemia is common during treatment and grade 3–4 hyperglycaemia (glycaemia >13.9 mmol/l or 2.5 g/l) was reported in 4– 11% of patients; how- ever, information on preexisting diabetes in these patients is lacking. Overall, the incidence of hyper- glycaemia does not appear to be dose-related.In all patients, potential causes of hypergly- caemia should be investigated, such as pancreatic disease, haemochromatosis or other sources of drug-induced hyperglycaemia (e.g. glucocorticoids, pentamidine, etc). Again, as the relationship between mTOR inhibitor-induced hyperglycaemia and diabetes microvascular and macrovascular complications, and overall mortality is uncertain, and given the reduced life expectancy of this patient population, management should aim to avoid clinical emergencies, such as hypoglycaemia and hyperosmolar states, without requiring strict con- trol of hyperglycaemia for the majority of patients. Lifestyle changes are important for the improve- ment of glycaemic control, with moderate intensity exercise encouraged. A specific diet should be recommended (less saturated fat, and higher intake of fibre, legumes and foods with a high glycaemic index) without strict control on calorie intake. In patients with preexisting diabetes, a complete evaluation of glycaemic control, and complications of diabetes, is required before initiating temsiroli- mus; patients should continue to see a diabeto- logist. Intensive lowering of glycated haemoglobin (HbA1c) is no longer recommended for all patients. Thus, the objective of glycaemic control should be to maintain HbA1c between 6.5 and 8%. Plasma glucose level (fasting plasma glucose in patients without preexisting diabetes) and HbA1c should be measured prior to commencing temsirolimus, and at day 15, day 30 and every 1–2 months during treatment. If glycaemia and/or HbA1c increases, treatment should be modified by a diabetologist. Standard treatment is with metformin, starting at a dosage of 500 mg twice daily in patients without preexisting diabetes. Metformin is contraindicated in patients with renal insufficiency. Other oral agents are available and, in some cases, insulin will be required.


Drug-related pneumonitis is a class-effect toxicity of mTOR inhibitors, but the pathophysiology of this toxicity in patients with cancer remains unclear [23–25]. Most of the data available concern temsirolimus and everolimus, mainly in patients with advanced renal cell carcinoma [23–26]. The presence of radiographically diagnosed pulmonary toxicity seems to be slightly more frequent with everolimus than for temsirolimus (39– 46% for everolimus and 29% for temsirolimus) [23–26]. However, this high incidence is mainly based on retrospective radiographic reviews; it was reported in less than 15% of patients by investigators during the same trials, suggesting that, in most of the cases, clinical and radiological findings were judged to be not relevant by investigators [26].

The incidence of pulmonary adverse events in patients with MCL is shown in Table 1. No drug- related pneumonitis was reported with the two dose schedules of temsirolimus investigated in the randomized phase III registration trial, but 2% of the 54 patients treated at the lower dose schedule reported grade 3 dry cough, suggesting that some mild interstitial pneumonitis may have occurred [9]. Ansell et al. [14] reported a pneumonitis incidence of 15% in 71 patients wherein temsirolimus was combined with rituximab (with 8% considered grade 3). This incidence seems to be higher than what was observed when temsirolimus was given alone; grade 3 pneumonitis was seen in only one out of 35 patients in the study of Witzig et al. [8] and in none of the 29 patients treated with low-dose tem- sirolimus alone in the study of Ansell et al. [11], although in this study, 11% of patients had grade 3 dyspnoea. Despite the low incidence of clinically relevant lung toxicity, but the relatively frequent radiological abnormalities documented, patients receiving temsirolimus should be cautiously moni- tored with radiographic or scanographic evaluation during treatment, especially if there are underlying pulmonary diseases.

As mentioned previously, less than half of the patients had symptoms: dyspnoea and dry cough are the most common and fever seems to be infrequent. Radiologically, two different patterns were observed: ground glass opacities and lung parenchymal con- solidation. The time to onset seems to be short, with most of the cases diagnosed within 16 weeks, but late occurrence is also observed (see Maroto et al. [26] for review).

Treatment is usually adapted to severity: grade 1 (asymptomatic radiographic findings) with no dose interruption, grade 2 with dose delay and reduction and grade 3 with treatment discontinuation, accord- ing to National Cancer Institute Common Termi- nology Criteria for Adverse Events version 3.0 [27]. The pulmonary abnormalities observed were acute and inflammatory, without occurrence of long-term scarring and fibrosis [23,26]. However, in patients treated for longer periods of time, the potential evolution to fibrotic processes is not clearly known. Steroids and antibiotics are usually given to symp- tomatic patients with prior adapted investigations (pulmonary function testing with diffusing capacity of the lung for carbon monoxide measure, endo- scopy and bronchoalveolar lavage, especially if fever is present). Regression of pulmonary abnormalities is usually observed when temsirolimus is stopped,with or without associated antibiotics and steroids [23,26].


Except for diarrhoea, that is regularly reported in clinical studies assessing safety and tolerability, gastrointestinal complications are rarely described with temsirolimus, and their frequency is difficult to establish accurately. Among gastrointestinal toxic- ities that have been observed, the most commonly reported are diarrhoea, nausea and vomiting, abdominal pain, and in some cases hepatic or pan- creatic complications. Apart from the impact on the general status of patients, leading to fatigue and weight loss, these symptoms may have a negative effect on their adherence to treatment and outcome. So, it is essential that these symptoms are taken into account and adequately managed in order to avoid the necessary dose reduction or treatment discontinuation.


Diarrhoea is the most frequent and most common adverse effect related to temsirolimus treatment (Table 1). Frequencies of all-grade diarrhoea ranging between 32 and 44% have been reported in phase II and III studies, but incidences of grade 3– 4 diar- rhoea are very low (3– 11%) [8,9,11,14]. The exact mechanism is still unclear and probably due to a variety of factors, such as an imbalance in the diges- tive flora, changes in prostaglandin synthesis by the mucosa or modifications of electrolytic and water exchange through the mucosa. Consequences can be severe, leading in some cases to dehydration and/ or renal insufficiency, particularly in old and fragile patients. Prophylactic measures consist of dietary advice, such as avoiding meats or foods that could increase diarrhoea (e.g. spicy foods, certain fruits, etc). In the case of symptomatic diarrhoea that could interfere with daily activities and treat- ment compliance, treatment with loperamide or racecadotril should be initiated.

Nausea and vomiting

Nausea and vomiting are less common (Table 1), although it is difficult to accurately assess the role of temsirolimus in the occurrence of nausea or vomit- ing, as patients have usually already received many chemotherapy regimens and are likely to present with these symptoms before any treatment has begun. The four clinical studies of temsirolimus conducted in patients with MCL report the occur- rence of nausea with an incidence of up to 49% [8,9,11,14]. However, most incidences were grade 1 or 2 in severity. The incidence of vomiting is very rare, with grade 3 vomiting reported by only one patient (4%) in a phase II trial of the North Central Cancer Treatment Group (NCCTG) investigating low-dose single-agent temsirolimus in relapsed MCL [11].

Nevertheless, these symptoms could represent a major adverse effect that could challenge treatment efficacy and adherence. Management of nausea/ vomiting should take into account the psycho- logical personality of each patient. Similar dietary advice as that given for diarrhoea is suggested and, when necessary, an appropriate treatment should be proposed, taking into account that in some cases oral administration may not be possible. Medication given usually includes antiemetic agents such as metoclopramide, domperidone, chlorpromazine or ondansetron. In most cases, treatment with temsirolimus is not impacted and is able to be maintained at the same dosage.

Abdominal pain

Abdominal pain is sometimes the result of diarrhoea or nausea/vomiting. In some cases, it could also be related to a lymphoma mass in the abdomen. Thus, it is a frequent adverse effect reported by patients. In the phase III study reported by Hess et al. [9], the incidence of abdominal pain in the two temsiroli- mus treatment groups (175/75 and 175/25 mg) was as high as 42% compared with an incidence of 15% with the investigator’s choice of treatment. However, this adverse event has not been reported in the remaining clinical studies [11,14] except for one case of grade 3 abdominal pain reported in another phase II NCCTG study in which single- agent temsirolimus 250 mg per week was investigated [8].

However, abdominal pain can also be the con- sequence of temsirolimus therapy, with pancreatitis the cause of the symptoms in the vast majority of cases. Thus, it is important to monitor pancreatic enzymes (lipase) and to perform a computed tomo- graphy scan to ascertain the correct diagnosis. In some very rare cases, bowel perforation has been described [28], but it is likely that it was due to an intestinal lymphoma mass rather than being a direct toxicity of temsirolimus.

Because of the role of temsirolimus in increasing serum lipid levels, some hepatic complications can occur in predisposed patients with underlying liver disease. In most cases, symptoms comprise elevated bilirubinaemia or enzymes (aspartate amino- transferase, alanine aminotransferase, amylase or lipase) without any clinical significance and do not necessitate treatment interruption. However, some patients will require close monitoring, with dose reduction and/or treatment interruption until resolution of the disorder.

Pancreatic complications are less common [29] and are probably related to the interaction of temsirolimus with the insulin pathway, resulting in hyperglycaemia or diabetes in predisposed patients. As discussed previously, in patients with preexisting conditions, blood glucose and HbA1c levels should be closely monitored and, if necessary, dietary modification, insulin or oral glycaemic therapy indicated. Acute pancreatitis is a rare, but severe, complication of unknown causation (except wherein there is evidence of lithiasis migration). In cases of acute and sudden abdominal pain, it is necessary to monitor lipase and amylase levels, and to perform a computed tomography scan. In case of elevated enzymes without evidence of lith- iasis, temsirolimus treatment should be stopped until resolution of symptoms and normalization of laboratory values, with close monitoring upon resumption of therapy.


Other miscellaneous adverse events reported with temsirolimus are discussed below.


Although common fatigue and asthenia are probably the most difficult symptoms to evaluate in cancer patients, most patients consider fatigue a major secondary effect which impacts their quality of life and consequently compromises treatment adherence and, therefore, efficacy [29]. Among the published data of temsirolimus in MCL, the feeling of fatigue is often reported with an incidence of up to 75% [8,9,11,14], although it is difficult to establish a causal relationship between temsirolimus and this symptom in cancer patients who have already experienced many anticancer therapies.

Mechanisms of fatigue and asthenia are numer- ous and varied, including factors related to patient disposition, the disease and/or treatment. Age has an important impact on fatigue as elderly patients are less resistant and more likely to suffer from asthenia. Pain, weight loss, emotional stress and anxiety also contribute to worsening and accentu- ating feelings of fatigue [30]. Furthermore, cancer patients often have metabolic disturbances such as hypophosphataemia, hypocalcaemia, hypomagne- saemia or thyroid dysfunction, which also
contribute to exaggerating the sensation of fatigue and impact the quality of life [31,32]. The under- lying disease and/or treatment with temsirolimus can induce several adverse effects that could con- tribute to the onset or increased feelings of fatigue. Among these factors, anaemia is a frequent event that occurs in the natural history of the disease and is often amplified with treatment. Anaemia is also due to inflammatory signs related to cytokine deregulation that add to erythropoietin decrease and alteration of haeme metabolism [33,34].

The management of asthenia in patients receiv- ing temsirolimus therapy should take into account not only the causes but also the consequences and symptoms caused by this adverse event. Simple measures such as rest, adapted diet and physical exercises could help patients efficiently. Patients receiving temsirolimus should be monitored for metabolic disorders such as hypophosphataemia or hypocalcaemia and supplemented in case of decrease. Thus, regular thyroid function tests should be performed to detect hypothyroidism and to supplement patients. Additionally, regular blood count tests should be conducted to detect anaemia. Patients can be offered either blood transfusion or treatment with erythropoietin with or without iron administration to correct and/or prevent haemoglobin decreases.


Apart from pulmonary complications, infection related to treatment with temsirolimus occurs in approximately 50% of patients (Table 1) [35]. The incidence of infection was increased in patients with grade 3– 4 neutropenia in the phase III trial [9]. Infection complications can occur even in the absence of neutropenia, but the incidence of grade 3– 4 infections remains relatively low [8,11], and severe or life-threatening infectious complications are rare. Patients should be particularly monitored for herpes reactivation.Patients with grade 3 or 4 neutropenia could receive G-CSFs in order to maintain the absolute neutrophil count around 1000/ml. Prophylactic medication with cotrimoxazole and acyclovir to prevent Pneumocystis infection and herpes recur- rence is also recommended.


Acute hypersensitivity is a severe but fortunately rare complication of temsirolimus therapy. In most cases, patients experience chills, fever and, less often, dyspnoea. These symptoms can occur with the first as well as with subsequent infusions and should be carefully anticipated in patients with a history of allergy. However, as premedication of patients with an H1 antihistamine 30 min before the start of infusion is recommended, the incidence of hypersensitivity reactions has become very low [13,28]. In patients with a history of allergy or grade 1– 2 hypersensitivity reaction during the first infusion of temsirolimus, preventive treatment with corticotherapy should be given. In cases of recurrent allergic reactions despite corticotherapy or following grade 3– 4 hypersensitivity reaction, and regardless of the time of onset, treatment with temsirolimus should be discontinued.

The incidence of hypersensitivity reactions in clinical studies of temsirolimus in MCL differs from study to study, depending whether patients present rash, dyspnoea, arthralgia, chills or pruritus. Over- all, the incidence of such manifestations ranges between 1 and 26% [8,9,11], reflecting the difficulty in assessing with certainty the role of temsirolimus in the onset of such symptoms.


No extravasation was reported in the clinical studies of temsirolimus in MCL (see Table 1) [8,9,11,14] and to date, no specific guidelines have been published regarding management of extravasation with temsirolimus. Therefore, the following recom- mendations are based on standard practice in cases of extravasation with cytotoxic products and bear in mind that temsirolimus is not a vesicant agent. It is important to recognize the signs of extravasation, such as a stinging sensation or burns at the injection site, redness, pain and swelling, oedema or induration, so that it can be immediately treated. The perfusion should be stopped and as much of the extravasated product as possible aspi- rated. Further management, including flushing with isotonic NaCl, administration of analgesics and/or topical cream(s) and application of a cold compress, is based on generally available protocols [36,37].


Some of the more rare adverse events reported with mTOR inhibitors are discussed below.

Sexual disorders

There are few data assessing the role of mTOR inhibitors in sexual disorders in cancer patients. The most frequent disorders reported are erectile dysfunction and libido disorders in men, whereas women can present with dyspareunia, vaginal dryness and vulvovaginitis [38,39]. Only one case of grade 4 sexual dysfunction has been reported in a phase II study of temsirolimus in combination with rituximab in patients with relapsed/refractory MCL (Table 1); however, no further details were given [14].

Impaired gonadal dysfunction with decreased testosterone production has been described in male transplant patients receiving sirolimus [40,41]. However, as with asthenia, it is difficult to establish the role of targeted therapy with temsirolimus in the pathophysiology of sexual disorders. Patients with anaemia, fatigue, weight loss and physical alteration are likely to present with sexual disorders regardless of organic or hormonal dysfunction.

The prevention and treatment of sexual disorders should take into account the personality and psychological disposition of each patient. In some cases, it could be helpful to refer patients to a specialist in order to eliminate an organic disorder. In male patients, phosphodiesterase inhibitors can be administered under classical watchfulness for the treatment of erectile dysfunc- tion, and hormonal treatment with testosterone- derived molecules can be used to treat impaired gonadal function. In women, local topical treat- ment or lubrication for vaginal dryness can be successfully used in some cases. Finally, it is also important to consider the problem with both the patient and his or her partner in order to have a comprehensive management of the problem. In some cases, particularly if all other measures are ineffective, it may be necessary to stop temsirolimus treatment, especially if the sexual dysfunction inter- feres with the patient’s quality of life.

Foetal malformations

The role of mTOR inhibitors in foetal malformations is not known, but an American registry in pregnant women has reported a higher incidence of foetal aberrations in women treated with sirolimus [42]. No incidences of foetal malformation have been reported in the clinical studies of temsirolimus in MCL (Table 1) [8,9,11,14]. In light of the unknown risk, it is important to emphasize the role of contra- ception during mTOR inhibitor treatment for both patients and their partners. In case of pregnancy, termination should be discussed as an option, otherwise mTOR inhibitor treatment should be stopped and very close monitoring of the pregnancy commenced.

Psychiatric disorders

The PI3K/AKT/mTOR pathway has been recently explored as one of the possible signalling pathways involved in depression as well as schizophrenic disorders [43] and decreased PI3K pathway signal- ling has been demonstrated in patients with depression disorders. Dysregulation of PTEN and PI3K results in insufficient phosphorylation of lipid second messengers that can potentially affect a patient’s mood [44]. Although no grade 3– 4 depression has been reported in prospective clinical trials of temsirolimus in MCL (Table 1), it is important to note that up to 9% of patients reported grade 1– 2 depression and 15% of patients reported grade 1– 2 anxiety in clinical studies of temsirolimus in MCL [45]. Clinicians need to be aware of this fact in order to evaluate the risk : be- nefit ratio of temsirolimus in patients developing such disorders.


Most adverse events reported with temsirolimus in patients with relapsed/refractory MCL are manage- able, often without impacting administration of temsirolimus.