British journal ofHuemutalogy, 2002. 119. 1187130
`SHORT REPORT
`
`affirm
`
`Response to thalidomide in chemotherapy—resistant mantle
`
`cell lymphoma: a case report
`
`EDWARD A. WILSON.1 SHIALESHJOBANPilTRA.1 ROBERT Jameson.2 ANNE N. PARKER] AND
`1. GRANT MCQUAKERI
`1I—l‘uemutrilogy Department and 2Pathology Department. Glasgow Royal Infirmary. Glasgow, UK
`
`Received 18 December .2001; accepted 27 April 2002
`
`
`
`lymphoma is an aggressive Bvcell
`Summary. Mantle cell
`lymphoma with a poor median survival despite conven-
`tional therapy. Here. we present the case ol‘ a patient with
`multiply relapsed mantle cell
`lymphoma. having failed
`treatment with chemotherapy. steroids and rituximah. He
`was treated with single—agent
`thalidomide al
`a. dose of
`Keywords: mantle cell lymphoma thalidomide.
`
`
`800 mg daily and entered a good partial remission which
`was maintained [or the next 6 months. There is clearly a
`need for further studies of thalidomide in mantle cell lym-
`phoma to confirm this promising initial result.
`
`Mantle cell lymphoma is an aggressive B-ccll lymphoma.
`accounting for approximately 7% of adult lymphomas in
`Europe and America. Response to conventional chemothen
`apy is poorly maintained. with a. median survival of only
`3
`to ‘1 years. Recent trials of newer therapies.
`including
`fludarabine. rituximab and autologous stein cell transplanu
`tatiou. have likewise proved disappointing (Freedman at al.
`1998). Here. we present
`the case of a multiply relapsed
`patient with chemotherapy resistant disease who entered
`a good partial remission following treatment with thalido-
`mide alone.
`
`CASE REPORT
`
`A 68-year-old man presented in December 1997 with stage
`[Va mantle cell
`lymphoma. He opted to delay treatment
`until luly 1998 when he started a 9 month course of pulsed
`oral chlorambucil. This achieved a moderate reduction in
`lymphadenopathy but progression was evident 6 months
`later, in August 1999. with the onset of severe diarrhoea
`and pancytopenia [Hb 5-0 g/dl. white blood cell
`(WBC)
`count
`2-2 X 109/].
`neutrophiis
`1-1X109f].
`platelets
`44 x 109.11].
`Investigations
`revealed extensive marrow
`infiltration. markedly increased lymphadenopathy and
`splenomegaly. and a new hepatic peri-hiiar
`infiltrate.
`He underwent six cycles of CHOP (cyclophosphamide.
`hydroxydaunomycln. oncovin. prednisone) chemotherapy.
`achieving a major reduction in lymphadenopathy and
`normalization of his blood count. This lasted only until
`
`Correspondence: Dr 1, G. McQuaicer. Department of Haematology.
`Maccwcn Building, Glasgow Royal infirmary. Castie Street. Glasgow.
`0‘} USE, UK Email: grant.mequniier@nortliglasgowscotmhs.uk
`
`128
`
`June 2000. with the onset of jaundice from a lymph node
`mass encasiug the bile duct. He was treated with MEDAC
`(mitoeantrone 10 mg/m2 and cytarabine 500 nag/m;L for
`3 d) and suffered a stormy post—chemotherapy course with
`prolonged neutropenic fever. He remained free of jaundice,
`although a computerized tomography (CT) scan the follow—
`ing month showed static disease. He declined further
`chemotherapy and. in August 2000. underwent a 4: week
`course of rituximab 375 trig/m2 per week. His response,
`however. lasted only 4 weeks when he again deteriorated
`with diarrhoea. Jaundlce and pancytopenia [Hb 8'7 g/dl.
`WBC 30-5 >< 109M,
`neutrnphils
`2-4 x 109M.
`platelets
`54 X 10%) with exfoliating lymphoma cells in his periph-
`eral blood. He was started on prcdnisolone 60 mg daily and
`two doses of vinblastine 10 mg were administered over the
`following month. His
`jaundice again cleared but he
`remained
`severely
`pancytopenlc
`(Hi3
`7-8 g/dl. WBC
`4-7 x 109/1. nontrophils os x 109/}. platelets 20 x 109/1)
`and disease progression was evident on a CT scan in
`November 2000. Four days of dcxamethasone 40 mg was
`tried with no response and.
`in December 2000.
`lie was
`started on thalidomide 200 mg. increased to 400 mg after
`2 weeks. A few days later. he was readmitted severely
`unwell with jaundice. pyrexia and melaena. He remained
`profoundly pancytopenio (Hi3 7'1 gidl, WEC 18 x 10“”.
`neutrophils 0'3 X 109/1. platelets 8 x 109/1) and it was
`suspected that he was bleeding from lymphomatous
`involvement of his bowel. Endoscopy showed a moderate
`haemorragic gastritis. and he was managed supportively
`with blood products and antibiotics. His pyrexia and
`melaena settled over the next 2 weeks but his general
`condition remained very poor. The
`thalidomide was
`increased to 800 mg daily and he was transferred to a
`
`© 2002 Blackwell Publishing Ltd
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`Short Report
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`1 29
`
`JEJZSHICN’
`II; Malt
`l933
`(Iii-MAV—lefi'
`
`
`
`Fig l. Abdominal CT scan (A) in July 2000. showing spienomegaly
`and extensive lymphomaious infiltration at lhe poria-hopatls‘. and
`(B) in May 2001.. showing over 50". reduction in disease bulk.
`
`hospice for terminal care. His clinical condition. however.
`progressively improved over the next 2 months and he was
`discharged home in February 2001. His liver function tests
`normalized and there was a dramatic improvement in his
`peripheral blood count (as 128 g/di. wec 3'4. x 109/1.
`neutrophils 2-1>< 109/1, platelets 119 x 109/1). Over
`the
`next 4 months, he remained in a good general condition
`apart from the development of a spontaneous deep vein
`thrombosis and leg ulcers. Disease reassessment showed
`over 50% reduction in lymphadenOpathy on a CT scan
`(Fig 1) and a generally hypoceliular bone marrow trephine
`with a marked reduction in the lymphoid infiltrate (Fig 2).
`in July 2001. he again became pancytopenic (Hi) 9-0 gfdl.
`wec 0-8 x 10% neutrophils
`0.25 x 109/1,
`platelets
`95 x 109/1) and rapidly succumbed to a fatal septicaemia
`from a urinary tract infection. Unfortunately. owing to the
`speed of his final deterioration. it was not possible to further
`investigate the cause of his pancytopenia or the state of his
`disease at that time.
`
`DISCUSSION
`
`This case demonstrates many typical features of mantle cell
`lymphoma. The majority of patients are male and present in
`
`Pig 2. Bum: marrow irephine stained for CDZO (A) in AugustZOOO.
`showing extensive paratrabeclzlar infiltration by lymphoma. and
`[13) in May 2001. showing a hypooeiluiar marrow but with signi-
`[icaniiy less lymphocytic infiltrate.
`
`the seventh decade oflife with stage IV disease. After 3 years
`of treatment. his lymphoma was resistant to both chemo-
`therapy and steroids and had progressed following treatment
`with rituximab. He had developed bone marrow failure.
`severe gastrointestinal bleeding and jaundice. and was
`entering the terminal phase of his illness. Two months
`following the introduction of thalidomide. he demonstrated a
`dramatic response that was sustained for a further 6 months.
`Alter many years in disrepute for its teratogenicity and
`neurotoxicity. there has been a recent revival of interest in
`thalidomide For its antitumour effects. This has been most
`extensively studied in myeloma where a 30% response rate
`has been documented in refractory and relapsed disease
`(Singhal 3: rd. 1999'. Alexanian 8: Weber. 2000: Munshi
`et (ll. 2000). Ongoing studios are investigating its effective
`mess in early mycloma as well as in other haematological
`and solid malignancies (Alexanian et al. 2000]. It has been
`used with some success in low-grade lymphoplasmacytold
`lymphoma (Dimopoulos et til, 2001), however. 'its use in
`mantle Cell lymphoma has not previously been reported.
`Thalidomide was initialiy used in myeloma for its activity
`against angiogenesis. which has recently been implicated in
`the development of haematological malignancies. Neovas—
`polarization of the bone marrow Occurs in both myeioma
`
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`Short Report
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`(Alexanian at al. 2000) and lymphoma (Ribatti et all. 1996:
`Salven ct ul. 1997). and has been correlated with more
`aggressive disease. In addition to its anti-angiogenic action.
`thalidomide exerts a number of anti-inflammatory and
`immunomodulatory effects on both tumour cells and the
`surrounding microenvlronrncnt. This includes inhibition of
`tumour necrosis
`factor
`(1
`(TNFoL) production (Stirling.
`2000). which is elevated in some lymphoma patients and
`associated with a poorer prognosis (Sailes at al. 1996).
`Despite our knowledge of these diverse biological actions.
`the precise mechanism of thalidomide’s antitumour effect
`remains undetermined.
`Thalidomide is not a cytotoxic agent and may. therefore.
`be well
`tolerated by patients with bone marrow failure.
`NeutrOpenia has occurred in up to 25% of human immu-
`nodeficiency virus (HIV) patients on thaiidomide but this
`has rarely occurred in myeloma patients (Clark at al. 2001).
`Of concern is the possible association between thalidomide
`and venous thromboembolism. ri‘hls has been observed in
`patients receiving combined thalidomide and chemotherapy
`but not in those receiving thalidomide alone (Zangari et al.
`2001). Results of other studies are needed to confirm this
`association and to more accurately quantify the risk. Other
`known adverse effects include sedation, rash. peripheral
`oedema. dyspnoea. hypotension. peripheral neuropathy and
`constipation (Clark at al, 2001).
`This case demonstrates the effect of thalidomide against
`multiply relapsed mantle cell
`lymphoma. following treat-
`ment with chemotherapy.
`steroids and rituximab. The
`result is similar in that obtained in myelorna. with less
`than 2 months to onset of action and a median remission of
`7 months (Alexanian 8; Weber. 2000: Munshi et al. 2000).
`There is clearly a need for further studies of thalidomide in
`mantle cell lymphoma.
`
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`© 2002 BiacitWell Publishing Ltd. British looms] of Haematology 119: 128—130
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