Lenalidomide‐induced tumour flare reaction in mantle cell lymphoma (2010)

Tumour flare reaction (TFR) following lenalidomide is characterised clinically by painful enlargement of lymph nodes and/or spleen, low-grade fever and skin rash. Despite being relatively common in chronic lymphocytic leukaemia (CLL) (affecting 30–58% of patients) (Chanan-Khan et al, 2006; Ferrajoli et al, 2008), TFR has never been reported in association with mantle cell lymphoma (MCL) (Habermann et al, 2009; Reeder et al, 2009). Here, we report our experience of TFR developing in three of 25 patients with relapsed MCL treated with lenalidomide within a phase II trial. Patient 1 presented at relapse with marked splenomegaly (20 cm) and lymphocytosis (white cell count (WCC) 258·1 × 109/l, 93% lymphocytes), and commenced lenalidomide 25 mg/d. On day 6, he developed acute left hypochondrial pain with a rapidly rising leucocytosis (WCC 357·4 × 109/l, 96% lymphocytes) which eventually peaked at 498·0 × 109/l on day 11 (Fig 1). Repeat imaging confirmed a diffuse increase in splenic size (24 cm) with no evidence of infarction or haemorrhage. He continued on full-dose lenalidomide with a gradual fall in WCC to 370·4 × 109/l, but subsequently developed grade 4 thrombocytopenia necessitating cessation of lenalidomide on day 15. His splenic pain improved although he remained dependent on regular analgesics. On day 28, he was admitted to hospital with dehydration secondary to vomiting and commenced a second cycle of lenalidomide 15 mg/d. The following day, he had an acute cerebral infarct complicated with aspiration pneumonia and died 3 d later. White cell count (WCC), lymphocyte count and platelet count of Patient 1 in relation to lenalidomide treatment (Len) and symptoms. CVE, cerebrovascular event. Patient 2 presented at relapse with multiple subcutaneous nodules on imaging, only one of which was clinically palpable over the right flank. She commenced lenalidomide 25 mg/d but, on day 4, developed several new subcutaneous nodules over her face and right scapula which slowly regressed in size and disappeared over the following week. Her right flank lesion completely resolved after one cycle of lenalidomide and she remains on treatment twelve months later having achieved an excellent partial remission. Patient 3 presented at relapse with nasopharyngeal and tonsillar involvement, and commenced lenalidomide 25 mg/d. On day 8, he developed an itchy erythematous rash predominantly over his face with lesser involvement of his trunk and limbs. He also complained of tenderness in his submandibular and upper cervical regions although had no obvious lymphadenopathy palpable. His rash and tenderness gradually resolved over the following week with no specific treatment, and he continues to receive full-dose lenalidomide. There are no reports of TFR in association with multiple myeloma or myelodysplasia. Moreover, until very recently, its occurrence was believed to be unique to CLL with overall incidences of 58% (Chanan-Khan et al, 2006) and 30% (Ferrajoli et al, 2008) reported following lenalidomide starting doses of 25 mg/d and 10 mg/d respectively. Most cases develop within the first 24 h, resolve within 14 d, and are adequately managed with analgesics ± steroids (Chanan-Khan et al, 2006). Prophylactic steroids appear to reduce the severity but not the overall incidence of TFR (Chanan-Khan et al, 2006), and are not considered necessary if a starting dose of 10 mg/d is used with gradual dose escalation (Ferrajoli et al, 2008). Despite an initial suggestion that the occurrence of TFR may correlate with lenalidomide efficacy in CLL (Chanan-Khan et al, 2008), this has not been consistently proven and its exact relationship to disease response therefore remains uncertain (Ferrajoli et al, 2008). It has now become evident that lenalidomide-induced TFR is not specific to CLL and can occur in other haematological malignancies. TFR has recently been reported in three patients with relapsed/refractory Hodgkins disease, all of whom were managed with analgesics/steroids and subsequently went on to attain disease control with ongoing lenalidomide (Corazzelli et al, 2010). Interestingly, the timing of these TFRs was somewhat delayed (onset between days 26 and 33 of therapy) compared to CLL but the duration of symptoms was similar (7–10 d). We now report the first three cases of lenalidomide-induced TFR in association with MCL, all of which presented within 8 d of starting treatment. In two patients the reactions were mild, short-lived and required no specific therapy whereas one patient had a more severe and prolonged reaction which required hospital admission for specific pain control measures. Despite this, the TFR did appear to be resolving without additional intervention until the clinical course was complicated by a fatal cerebrovascular event. The exact pathophysiology of TFR remains unclear although it is likely that some form of immunomodulatory mechanism is responsible. Preliminary in vitro data has shown that lenalidomide significantly upregulates the surface expression of B cell activation markers (predominantly CD40 and CD86) on primary CLL cells thereby potentially increasing their immunogenicity to autologous T cells. Furthermore, this upregulation can be antagonised by dexamethasone (an agent commonly used to prevent or treat TFR symptoms) and appears to at least partially correlate with the development of TFR in vivo (Andritsos et al, 2008). In patients with Hodgkins disease treated with lenalidomide, serum levels of B cell activating cytokines (specifically IL-6, IL-7, APRIL and BAFF/BLyS) and polyclonal free light chains have both been observed to increase in parallel with the clinical features of TFR before returning to normal limits as the reaction subsides (Corazzelli et al, 2010). Hence, systemic B cell activation (of both normal and malignant lymphocytes) would appear to play a role in the aetiology of TFR although the potential involvement of other immune effector cells in its pathophysiology has not yet been excluded. In conclusion, TFR can occur in patients with MCL during the initial stages of lenalidomide treatment as has been described in other haematological malignancies. The symptoms and signs can easily be mistaken for disease progression and clinicians therefore need to be aware of this specific complication. The low incidence of TFR in MCL (3/25, 12%) in conjunction with its typically mild and self-limiting course does not necessitate a lower starting dose than the currently recommended 25 mg/d nor the routine use of prophylactic steroids. Furthermore, none of our three patients required steroids during their acute reaction although the decision as to whether this measure is warranted in future cases clearly needs to be made on an individual patient basis.