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Acta Haematol 2005;114(suppl 1):2732

DOI: 10.1159/000087042

Future Directions in Haematology:

Beyond Multiple Myeloma

H. Grant Prenticea Stephano Sacchib Nigel Russellc

aPharmion Corporation, Boulder, Co., USA and Windsor, UK; bDip. di Oncologia ed Ematologia,

Facolt di Medicina, Universit di Modena e Reggio Emilia, Reggio Emilia, Italy; cMolecular Medical Sciences,

Division of Haematology, Nottingham University Medical School, Nottingham, UK

cause of thalidomides ability to activate natural killer

cells and cytotoxic T-lymphocytes. Partial responses to

thalidomide treatment have been recorded in patients

with lymphoma. In a phase II study to assess the activity

of thalidomide in patients with Waldenstrms macro-

globulinaemia, a partial response was seen in 25% of

patients who received a starting dose of 200 mg, which

was escalated in 200 mg increments every 14 days as

tolerated to a maximum of 600 mg. Although further

study is required, thalidomide shows promise in the

treatment of a number of haematological malignancies,

many of which currently have limited treatment options

and poor prognosis.

Copyright 2005 S. Karger AG, Basel

Although a large amount of the literature, and muchdiscussion, has concentrated on the use of thalidomide inmultiple myeloma, there is also growing evidence for itsusefulness in the management of other haematological

malignancies. Here we review some of the most recentlypublished data.

Myelodysplastic Syndromes

Thalidomide is one of a small number of drugs beingexplored as a novel treatment in the myelodysplastic syn-dromes (MDS). A publication in Bloodin 2001 included

Key Words

Haematology Myelodysplastic syndromes

Myelofibrosis Primary amyloidosis Waldenstrms

macroglobulinaemia Mantle cell lymphoma

Abstract

Thalidomide acts on the microenvironment of myelo-

dysplastic syndromes (MDS) by influencing cytokine

networks, and growing evidence supports thalidomides

usefulness in the management of haematological malig-

nancies, such as MDS. The European Collaboration

Group on Myelofibrosis with Myeloid Metaplasia re-

viewed patients who received at least four weeks tha-

lidomide treatment, in doses ranging from 50 mg/day to

400 mg/day. The results showed that 30% of patients had

increases in haemoglobin, and, of these, almost 40% be-

came transfusion independent. Platelets were increased

in a significant proportion of patients, and approximate-

ly 40% of patients had a reduction in their spleen size.

Data on thalidomide and acute myeloblastic leukaemia(AML) are conflicting: a recently published study indi-

cated that thalidomide does not have a role in the man-

agement of acute myeloblastic leukaemia (AML), while

other studies suggest some patients may respond be-

H. Grant PrenticePharmion Ltd, Riverside House, Riverside WalkWindsor SL4 1NA (UK)Tel. +44 (0) 1753 240600E-Mail [email protected]

2005 S. Karger AG, Basel00015792/05/11450027$22.00/0

Accessible online at:www.karger.com/aha

This article was prepared from a presentation given at a European

Expert Meeting on Multiple Myeloma.
http://dx.doi.org/10.1159%2F000087042http://dx.doi.org/10.1159%2F000087042


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Prentice/Sacchi/RussellActa Haematol 2005;114(suppl 1):273228

83 patients treated with thalidomide, with dose escala-tion to 400 mg/day, as tolerated [1]. The patients had tocomplete 12 weeks of therapy before evaluation, and out-come was analysed on an intention-to-treat basis. Thirty-two patients did not reach 12 weeks and were included inthe analysis as non-responders; 16 (19%) had a haemato-

logical response. Those that did respond tended to be pa-tients with lower risk MDS, such as refractory anaemia(RA) (9 patients), or with ringed sideroblasts (RARS) (5patients), although 2 patients with excess blasts (RAEB)also responded.

A smaller cohort of 31 patients from this trial was stud-ied more intensively [2]. Ten of these patients were ery-throid responders, 6 of whom discontinued blood trans-fusion, with a median time to response of 10 weeks. Thepatients who responded more often started with higherplatelet counts and lower numbers of blasts in the bonemarrow. In addition, those that responded had a higher

microvascular density (MVD) in the bone marrow, high-er transforming growth factor-beta and higher tumour ne-crosis factor-alpha. Of interest, the haemoglobin level wasinversely correlated with the level of vascular endothelialgrowth factor (VEGF) [2].

More work needs to be done in this area, especially inlight of the preliminary data regarding thalidomide ana-logues such as Revlimid(CC-5013) [3]. Such data wouldindicate that this family of compounds may have an im-portant role in patients with low-risk MDS, especiallythose with the 5q minus syndrome. A subgroup of MDSpatients that have a substantial probability of response toimmunosuppressive type treatments has now been iden-tified [4]. The human leukocyte antigen correlation ofthese has also been established. We should, in future, beable to dissect out patients within this heterogeneous dis-ease group and direct appropriate therapy. In addition,there may be an indication for the combination of tha-lidomide with the demethylating agents, azacitidine ordecitabine, given that thalidomide particularly acts onthe MDS micro-environment by influencing cytokinenetworks, whereas azacitidine and decitabine act primar-ily on the MDS malignant cells.

Myelofibrosis

A study published in 2004 presented data from 16 pa-tients [5]. These were predominantly older males andwere all transfusion dependent. Some patients had symp-tomatic splenomegaly. Thalidomide was given in a dose-escalating manner, as tolerated, by the individual patient.

Haemoglobin levels increased in 6 of the 16 patients andplatelets increased in 5 out of 7 patients, who were throm-bocytopenic at entry. The spleen size was reduced in 3 of13 patients and LDH, often considered a good marker formyelofibrosis activity, was reduced in 7 of 12 patients,although it increased in 4. The conclusion of this paper

was that thalidomide was useful [5].Other reports have also indicated that thalidomidemay have an effect in myelofibrosis. A publication from2002 reported on 12 patients with progressive disease [6].There was dose escalation of thalidomide from 100 to600 mg. Eleven patients were evaluable at the end of thestudy, with 7 of these showing reduced spleen size. Hae-moglobin levels rose in 3 of 4 anaemic patients, and 2 ofthese became transfusion independent. In responding pa-tients, the microvascular density, VEGF and basic fibro-blast growth factor were all reduced.

A phase II study published in 2003 aimed to give

50 mg thalidomide per day for 6 months [7]. Predniso-lone was also given for 1 month at 0.5 mg/kg and thentapered. The authors noted that those that responded,even when the prednisolone was tailed off, tended tomaintain their response. This approach was well toleratedin 20 of 21 patients who completed at least three monthstherapy and, of these, 62% had a clinical response. Allincreased their haemoglobin, 7 of 10 became transfusionindependent, 6 of 8 with platelets less than 100 ! 109/lincreased their platelet count by more than 50% and thespleen size was reduced by more than 50% in 4 of 21 pa-tients.

A meta-analysis of five separate trials using six param-eters was published in 2002 [8]. In all cases, the dose ofthalidomide was greater than 100 mg. Twenty-nine per-cent of patients in these studies with moderately severeanaemia increased their haemoglobin or discontinuedtransfusion, and 38% of those with thrombocytopenia in-creased their platelets. Forty-one percent had a reductionin spleen size. There was a decrease in the Dupriez sever-ity score in 45% of the patients. Those with major symp-tom severity and with splenomegaly had a 62% responserate, while in 20% of patients there was disease progres-

sion.A review from the European Collaboration Group onMyelofibrosis with Myeloid Metaplasia of patients re-ceiving at least four weeks thalidomide treatment, rang-ing from 50 to 400 mg/day, showed that 30% had increas-es in haemoglobin [9]. Of those, almost 40% becametransfusion independent. Platelets were increased in a sig-nificant proportion of patients, and approximately 40%had a reduction in their spleen size.


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Acta Haematol 2005;114(suppl 1):2732 29

In contrast to these reports, however, is a phase IIstudy published in 2002 [10]. This study escalated tha-lidomide to 800 mg per day in 15 patients, 14 of whomwere evaluable. Five out of these 14 patients discontinuedtreatment within 3 months because of poor tolerance,with 80% of patients complaining of fatigue. This may

have been due to the high doses involved (tolerance hasbeen seen to be an issue at higher doses), but the conclu-sion of the authors was that thalidomide is not useful inmyelofibrosis.

Acute Myeloblastic Leukaemia

Results of a recently published study indicated thatthalidomide does not have a role in the management ofacute myeloblastic leukaemia (AML), as any of the re-sponses seen in this study were modest and did not reach

significance [11].One study published in 2003, however, indicated that

some patients may respond [12]. This study looked at20 patients with relapsed AML who took between 200and 400 mg of thalidomide per day as a single agent. Fourof 20 patients had at least a partial response, with one ofthose being a complete remission lasting for longer than20 months, at the time of publication.

One interesting observation suggests that immuno-modulatory drugs, such as thalidomide, might have a rolein the management of AML, based on work published in2003 [13]. This study demonstrated that patients who hadspecific leukaemia cell killing of cryo-preserved AML orALL cells (collected at presentation) by lymphocytes,taken during remission, of more than 12% subsequentlymaintained a complete remission. Only one patient re-lapsed (with a new leukaemia). Those that did not showsuch activity had a very rapid relapse and only one ofthese patients remains in remission. The levels of activa-tion in the various lymphocyte subsets were measuredusing CD69 as a marker of activation. It was shown thatthe only cell type to respond by activation was the naturalkiller (NK) cell, which is of increasing interest with regard

to a potential role in the maintenance of remission ofvarious malignancies.Thalidomide is able to activate NK cells and cytotox-

ic T-lymphocytes [14], which may be mediated by inter-leukin-2. It may therefore be of interest to study a main-tenance regimen of thalidomide in patients who havebeen treated for acute leukaemia.

Chronic Lymphocytic Leukaemia

The treatment of chronic lymphocytic leukaemia(CLL) by thalidomide is currently controversial. A pub-lication from Kay and colleagues and the North CentralCancer Treatment Group, presented at ASH in 2003, in-

cluded 28 patients with CLL, mostly males [15]. Patientshad up to three prior treatments or had undergone an al-logeneic bone marrow transplant. They were treated at2001,000 mg as a planned daily dose and 15 were docu-mented to show a flare and an additional five also saidto have probably had a flare. A flare in CLL is manifestby lymph node enlargement, the spleen may increase insize, the lymphocyte numbers increase and the haemoglo-bin and platelet counts might decrease, giving the impres-sion of worsening of the disease. If the dose is reduced,for example to 50 mg/day, and then slowly increased,there will be some responders.

Given this experience, however, with almost all ofthe patients stopping the treatment rapidly, only one

partial response was seen. Twenty patients had stable

disease after this initial flare. The lymphocyte count

decreased between 0.5 and 142! 109/l in responding

patients and median time to progression of disease was

8.5 months. The study was stopped because of the

flares.

A study from Roswell Park, also presented at ASH2003, was a phase I first-line study and included five pa-tients with RAI stage I (the others being more advanced)[16]. Thalidomide treatment was planned for 6 months:the first cohort being treated at 100 mg (6 patients), thenext at 200 mg and the third at 300 mg. They all hadfludarabine starting on day 7 (day 1 being the first day ofthalidomide treatment) for 5 days every 28 days. To date,responses from 6 patients in cohort 1 have been reported,along with 3 in cohort 2. One had a pulmonary embolismat day 3 and came off treatment, but all of the 3 evaluablepatients completed 6 months of treatment and were com-plete responders. Of the entire patient cohort, not all ofwhom have yet reached 6 months to be fully assessed,88% responded, with a mean decrease in the lymphocyte

count of 44%. Half of the patients in this study also hadflares, with lymph node enlargement sometimes accom-panied by a skin rash. Fludarabine given at day 7 doesnot prevent flares, but, nevertheless, this looks to be aninteresting combination, with the authors commentingthat a dose of up to 200 mg/day was well tolerated. Itshould also be noted that, in this case, the response tothalidomide seemed rapid.


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Primary Amyloidosis

Therapy for patients with primary amyloidosis is di-rected at suppressing the underlying plasma cell clone,which, in some patients, can allow gradual regression ofamyloid deposits and improvement in organ function.

Chemotherapy regimens currently utilised include thosewith established activity in myeloma, such as melphalanor VAD. In carefully selected patients, there is evidencefor responses to high-dose melphalan and autologousstem cell transplantation. Thalidomide has establishedactivity in myeloma, and the Mayo Clinic has publisheddata on 12 patients with amyloidosis [17]. In this patientgroup, thalidomide was poorly tolerated and the studywas discontinued.

Much of the experience so far is anecdotal, as few pa-tients have been treated. Thalidomide may be poorly tol-erated in amyloidosis due to the exacerbation of periph-

eral and autonomic neuropathy. There have also beensome unusual side effects reported, including cardiac fail-ure and pulmonary oedema, particularly at high doses ofthalidomide. A study published in 2003 gave thalidomideat a maximum dose of 500 mg/day to patients relapsingafter a high-dose therapy and autologous transplantation.It found responses in 25% of patients, manifest by a re-duction in the urinary BJ protein [18]. They had diffi-culty, however, maintaining those doses in this patientgroup.

The rationale for testing thalidomide in the combina-tion of cyclophosphamide, thalidomide and dexametha-sone, or C-ThaD, is that there has been some activityreported for thalidomide as a single agent and, of course,there is significant activity in myeloma, where there isoften a rapid reduction in paraprotein concentrations.The dose of thalidomide that is being used in this combi-nation in myeloma is low 100200 mg it is well toler-ated in most patients with myeloma and it was felt thatthis dose was more likely to be tolerated in amyloidosisthan the higher doses such as were used in the Mayo Clin-ic study [17]. Another advantage to this regimen is thatit is oral, in contrast to recommendations in the guide-

lines for the UK on amyloidosis, which were publishedin the British Journal of Haematology [19], where thestandard approach has been to use VAD-based treatmentin the absence of significant cardiac dysfunction.

The first patient to be enrolled in the study at Notting-ham was a 62-year-old female with amyloidosis second-ary to stage III A myeloma. She had extensive amyloiddeposits in the bone marrow, organ involvement as dem-onstrated by a SAP scan, abnormal liver function tests,

abnormal coagulation tests and a serum-free light chainconcentration of 1,440 mg/l. The patient was prescribedC-ThaD following initial treatment with oral idarubicinand dexamethasone, during which her liver enlarged andshe lost 10 kg in weight. After five courses of C-ThaD, thehepatomegaly completely resolved, the SAP scans showed

regression of amyloid deposits, liver function and coagu-lation tests all normalised and the patient regained weight.The serum-free light chain levels fell to 159 mg/l, and shesuffered no thalidomide side-effects with that dose sched-ule. She is currently maintained on 100 mg/day thalido-mide and continues in remission. Two further patientshave been recruited to this study to date, with the finalaim being to treat 12 patients. One of these 2 patients hasfailed to respond, the other is undergoing treatment at areduced dose of 50 mg and 100 mg of thalidomide on al-ternate days, on which he is showing signs of response.

It may be that another use of thalidomide would be as

maintenance therapy and that will require a randomisedstudy, perhaps after autologous transplant, where it mightbe better tolerated as about 60% of the patients achievea good response to the high-dose therapy, that will alsolikely be better tolerated in those with a good initial re-sponse to treatment.

Non-Hodgkin Lymphomas

Mantle Cell Lymphoma

Mantle cell lymphoma (MCL) is a B-cell lymphomawith poor median survival, which generally is not curedwith either conventional chemo-immunotherapy or au-tologous stem cell transplantation. Recent reports suggestthat thalidomide has single agent activity in heavily pre-treated relapsed MCL [2023]. Objective responses wereobtained in 4 of the 7 patients treated with doses rangingfrom 100 to 800 mg/day after 3060 days of treatment.The duration of response varied from 6 to greater than 19months. Two patients suffered thalidomide-related sideeffects: one had deep venous thrombosis and one consti-pation, fatigue and paraesthesia. The largest series on ad-

vanced/relapsed MCL included 10 patients with a medianage of 69 years. They were treated with thalidomide at afixed dose of 100 mg/day. Of the 7 evaluable patients, themedian length of therapy was 4 (range 110) months. Twopatients achieved a partial response (PR) and 4 patientsstable disease. Toxicity has been modest, with mild som-nolence and some constipation in the majority of patients[24]. Now the number of patients enrolled is 28, with aresponse rate of approximately 30% [25].


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Acta Haematol 2005;114(suppl 1):2732 31

Based on the hypothesis that a treatment strategy tar-geting both lymphoma cell and the microenvironmentcould be active in MCL, relapsed/refractory patients weretreated with thalidomide and rituximab in combination[22]. Concomitant treatment dose/schedules were: ritux-imab 4/weekly infusion at 375 mg/m2 and thalidomide

200 mg/m2

/day during the first 2 weeks, then 400 mg con-tinued as maintenance treatment after completion ofrituximab until disease progression or relapse. Objectiveresponses were achieved in 13 of 16 patients (81%) and1 patient had stable disease (SD). Five patients (31%)achieved a complete response (CR) and 8 (50%) partialresponse. Median progression free survival of the 16 pa-tients was 20.4 months. Fatigue, somnolence and consti-pation were common dose-dependent side effects, and itwas necessary to adapt the maintenance dose on an indi-vidual bases (50200 mg/day). Seven patients sufferedperipheral neuropathy (grades III), 2 patients venous

thrombo-embolism and 1 neutropenia. Despite the lim-ited number of patients, these results suggest that tha-lidomide plus rituximab has marked antilymphoma ac-tivity in relapsed-refractory MCL and an acceptable tox-icity profile.

Other Lymphomas

A phase II study to assess the activity of thalidomideas single agent in patients with Waldenstrms macro-globulinaemia was performed in Greece [26]. Half of thepatients were previously untreated, with a median age of74 years. The starting dose was 200 mg; dose escalationin 200 mg increments every 14 days as tolerated to amaximum of 600 mg was allowed.

A partial response was observed in 25% of patients; inthis group of elderly patients intolerance to thalidomidewas frequent. Thalidomide has been used also for 19 pa-tients with other recurrent/refractory lymphomas [23],including the following histology: diffuse large cell (n =6), follicular small cleaved (n = 4), small lymphocytic(n = 3), mucosa-associated lymphoid tissue (n = 1), man-

tle cell (n = 3) and Hodgkins disease (n = 2). The patients,who had a median age of 62 years and had undergone amedian of five previous treatment regimens, were treatedwith escalating dose (200800 mg/day) until disease pro-gression or prohibitive toxicity. One patient (5%) affectedby recurrent gastric mucosa-associated lymphoid tissuelymphoma after 2 months of treatment achieved CR thatlasted more than 19months. Three patients (16%), twoaffected by diffuse large cell and one by small lympho-

cytic lymphoma, obtained SD that was maintained forlonger than 9 months. Sixteen patients received68 weeksof therapy with a median dose of 400 mg of thalidomide.Treatment was reasonably well tolerated, with the mostcommon thalidomide-related side effects being gradeI/II.

Conclusions

Although further study is needed in each of these con-ditions in order to determine the most appropriate dosingand scheduling regimens and to limit the associated tox-icity, thalidomide shows promise in the treatment of anumber of haematological malignancies, for many ofwhich there are currently limited treatment options anda poor prognosis. It is our view that sufficient informationis available to justify phase III studies in myelofibrosis,

low-grade myelodysplastic syndromes, mantle cell lym-phoma and possibly as maintenance therapy in amyloi-dosis. There is insufficient evidence to date to supportfurther studies in the other lymphomas or acute leukae-mias. Further phaseI/II studies will be of interest inWaldenstrms macroglobulinaemia and perhaps Castle-mans disease.

Increasingly the evidence supports the practice of re-stricting the daily dose of thalidomide to a minimum ef-fective doseto allow the maximum number of patients toreceive treatment for the longest possible time in theserelatively chronic disorders, by restricting the extent oftoxicity. Alternative dosing schedules should be consid-ered, e.g. alternate day and intermittent therapy, aimedat minimising the well-known toxicities. Combinationtherapies will be of interest: such as thalidomide plus ar-senic trioxide in MDS, thalidomide with rituximab andcyclophosphamide in mantle cell lymphoma and thalido-mide with the addition of modest doses of corticosteroidsin myelofibrosis.


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