ofW0
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`British Journal of Haematology, 2002, 119, 128-130
`SHORT REPORT
`
`Response to thalidomide in chemotherapy-resistant mantle
`cell lymphoma: a case report
`
`EDWARD A, WILSON,! SHIALESH JOBANPUTRA,’ ROBERT JACKSON,” ANNE N. Parker! ano
`"Haematology Department and *Pathalagy Department, Glasgow Royal Infirmary, Glasgow, UK
`I. GRANT McQuaxer!
`
`Received 18 December 2001; accepted 27 April 2002
`
`
`
`lymphoma ts an aggressive B-cell
`Summary. Mane cell
`lymphoma with a poor median survival despite conven-
`tional therapy. Here, we present the case of a patient with
`multiply relapsed mantle cell
`fymphoma, having failed
`treatment with chemotherapy, steroids and rituximab. 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
`wes maintained for the next 6 months. There is clearly a
`need for further studies of thalidomide in maotie cell lym-
`phoma to confirm this promising initial result.
`
`Mantle cell lymphoma is an aggressive B-cell lymphoma,
`accounting for approximately 7% of adult lymphomas in
`Europe and America. Response to conventional chemother+
`apy is poorly maintained, with a median survival of only
`3
`to 4 years. Recent trials of oewer therapies,
`including
`fludarabine, riteximab and autologous stem cell transplan-
`tation, have likewise proved disappointing (Freedman et 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 manue cell
`lymphoma, He opted lo delay treatment
`until July 1998 whenhe started a 9 month course of pulsed
`aral 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 10/1,
`neutrophils
`1:1 x 10%/1,
`platelets
`44x 10°/I],
`Investigations
`revealed extensive marrow
`infiltration, markedly increased lymphadenopathy and
`splencmegaly, and a new hepatic peri-hiar
`infiltrate.
`He underwent six cycles of CHOP (cyclophosphamide,
`hydroxsydaunomycin, oncovin. prednisone) chemctherapy,
`achieving a major reduction in lymphadenopathy and
`normalization of his blood count. This lasted only until
`
`Correspondence: Dr 1. G. McQuaker, Department of Haematology,
`Macewen Building, Glasgow Royal Infirmary, Casle Street, Glasgow,
`G4 CSF, UK. E-amail: prant.mequaker@uorthglasgowscotnhs.uk
`
`128
`
`June 2000, with the onset of jaundice from a lymph node
`mass encasing the bile dact. He was treated with MIDAC
`(mitezantrone 10 mg/m? and cytarabine 500 mg/m? for
`3 4} 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 mg/m? per week. His response,
`however, lasted only 4 weeks when he again deteriorated
`with diarrhoea, jaundice and pancytopenia (Hb 8:7 g/dl,
`WBC 305 10°/,
`neutrophils 24x 10°/1
`platelets
`54 x 10°/l) with exfoliating lymphomacells in his periph-
`eral blood, He was started on prednisolone GO mg daily and
`two doses of vinblastine 10 mg were administered over the
`following month. His
`jaundice again cleared but he
`remained
`severely
`pancytopenic
`(Hb
`7:8 g/dl, WBC
`4:7 %10°/1, neutrophils 05 x 1067/1, platelets 20 x 107/)
`and disease progression was evident on a CT scan in
`November 2000. Four days of dexamethasone 40 mg was
`tried with no response and.
`in December 2000, he 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 pancytopenic (Ab 7-1 g/dl, WBC 1-8 x 10/1,
`neutrophils G3 x 10°/L platelets 8 x 10°7/1l) and it was
`suspected that he was bleeding from lymphomatous
`involvement of his bowel. Endoscopy showed u 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
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`© 2002 Blackwell Publishing Ltd
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`eeerewe
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`Fig 1, Abdominal CT scan (A) In July 2000, showing splenomegaly
`and extensive lymphomatous infiltration al {he porta-hepatis, and
`(B) In May 2001, showlng over 50% reduction in disease bulk,
`
`hespice for terminal care. His clinical condition, however,
`progressively improved over the next 2 months and he was
`discharged home tn Pebruary 2001, His liver function tests
`normalized and there was a dramatic improvement in his
`peripheral blood count (Fb 12-8 g/dl, WRC 3-4 « 10°/L,
`neutrophils 2-1 x 10°/l, platelets 119 x 10°/l}), Gver
`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% reductton in lymphadenopathy on a CT scan
`(Fig 1} and a generally hypocellular bone marrow trephine
`with a marked reduction in the lymphoid infiltrate (Fig 2}.
`in July 2001, he again became pancytopenic (Hb 9-6 g/dl,
`WBC 08x 10°,
`neutrophils
`0-25 x 10°/1,
`platelets
`95 x 107A) and rapidly succumbed to a fatal septicaemla
`from a urinary tract infection. Unfortunalely, 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 ai that time.
`
`DISCUSSION
`
`This case demonstrates many typical features of mantle cell
`lymphoma, The majority of patlents are male and present in
`
`129
`
`Short Report
`
`a
`
`
`Fig 2. Bone marrow trephine stained for CD20 (A) in August 2000,
`showing extensive paratrabecular Infiltration by lymphoma, and
`(3) in May 2001, showing a hypocellular marrow but with signi-
`licantly less lymphocylic infiltrate,
`
`the seventh decadeof life with stage IV disease. After 3 years
`of treatment, his lymphoma was resistant to both chemo-
`therapy and stercids and had progressed following treatment
`with rituximab. He had developed bone marrow failure,
`severe gastro-intestinal bleeding and jaundice. and was
`entering the terminal phase of his illness, Two months
`following the introduction of thalldumide, he demonstrated a
`dramatic response that was sustained for a further 6 months,
`After many years in disrepute for its teratogenicity and
`neurotosicity, there has been a recent revival ofinterest 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 et al, 1999; Alexanian & Weber, 2000: Munshi
`et al, 2000}, Ongoing studies ure investigating its offective-
`ness in early mycloma as well as tn other haematological
`andsolid malignancies (Alexanian et al, 2000). It has been
`used with some success in low-grade lymphoplasmacytuid
`lymphoma (Dimopoules et al, 2001), however, ‘ils use in
`mantle cel lymphoma has not previously been reported.
`Thalidomide was initially used in myeloma torits activity
`against angiogenesis, which has recently been implicated in
`the development of haematological malignancies. Neovas-~
`cularization of the bone marrow occurs in both myeloma
`
`© 2002 Blackwell Publishing Ltd, British journal af Haematology 119; 128-130
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`Short Report
`130
`{Alexanian et al, 2000) and lymphoma (Ribatti et al, 1996:
`Salven et al, 1997), and has been correlated with more
`aggressive disease, In addition to its anti-angiogenic action,
`thalidomide exerts a oumber of antl-inflammatory and
`immunomodulatory effects on both tumour cells and the
`surrounding microenvironment, This includes inhibition of
`tumour necrosis
`factor a (TNFa) production (Strling,
`2000), which is elevated in some lymphomapatients and
`associated with a poorer prognosis (Salles et al, 1996),
`Despite our knowledge of these diverse biological actions,
`the prectse mechanism of thalidomide'’s antttumour effect
`remains undetermined.
`Thalidomide Is not a cytotoxic agent and may, therefvre,
`be well
`tolerated by patients with bone marrow failure,
`Neutropenia has occurred tn up to 25% of human immu-
`nodeficiency virus (HIV) patients on thalidomide but this
`has rarely occurred in myeloma patients (Clark et al, 2001}.
`Of concern is the possible associalion between thalidomide
`and venous thromboembolism. This has been observed in
`patients receiving combined thalidomide and chemotherapy
`but net im those receiving thalidomide alone (Vangari et ai,
`2001). Results of other studies are needed to confirm this
`association and to more accurately quantify the risk, Other
`known adverse cffccts include sedation, rash, peripheral
`oedema, dyspnoea, hypotension, peripheral neuropathy and
`constipation (Clark et ai, 2001).
`This case demonstrates the effect of thalidomide against
`multiply relapsed manile cell
`lymphoma, following treat-
`menl with chemotherapy.
`steroids and rituximab. The
`result is similar ta that obtained in myeloma, with less
`than 2 months to onset of action and a median remission of
`7 months (Alexanian & Weber, 20GQ: Munshiet al, 2000}.
`There is clearly a need for further studies of thalidomide in
`mantle cell lymphoma,
`
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`© 2002 Blackwell Publishing Ltd, British Journal of Haematology 119: 128-130
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