Pilot Studies of Thalidomide in Acute Myelogenous
`Leukemia, Myelodysplastic Syndromes, and
`Myeloproliferative Disorders
`Deborah A. Thomas
`
`The management of acute myelold leukemia (AML), high-risk myelodysplastlc syndromes (MDS) , and
`myeloprollferatlve disorders remains challenging because of the lnablllty of even the most effective treatment
`strategies to produce durable complete remissions. Bone marrow transplant (BMT) Is one such modality with
`potentially curative benefit; however, its applicability generally is limited to patients of younger age with
`suitable donors. Therefore, novel agents and alternative therapeutic strategies need to be studied. The role of
`angiogenesls In hematologic malignancies has been elucidated by several Investigators; hence, inhibitors of
`angiogenesls are being studied in these disorders. Thalidomide appears to have both antiangiogenic and
`immunosuppressive properties and has shown promising results in the treatment of refractory or relapsed
`multiple myeloma and plasma cell leukemia. Consequently, pilot studies of thalidomide for the treatment of
`other hematologic disorders, Including refractory/relapsed AML, high-risk MDS, myeloproliferative disorders,
`and myeloflbrosls are underway at M .D. Anderson Cancer Center. Preliminary results Indicate that thalidomide
`has activity and is well tolerated In the treatment of these hematologic disorders, and thus warrants further
`evaluation.
`Semln Hematol 37(suppl 3):26-34.
`
`
`
`D ESPITE RECENT PROGRESS in the
`
`treatment of acute leukemias, only 25% to
`30% of adult patients are cured. 1· 3 Although
`prognosis varies among acute myeloid leukemia
`(AML) subtypes, most patients relapse follow(cid:173)
`ing an initial complete response (CR) and
`ultimately die of resistant disease. Patients with
`AML who experience a particularly short first
`CR and those who fai l co achieve CR after two
`induction attempts are unlikely
`to respond
`to any currently available chemotherapeutic
`agents. Similarly, patients with high-risk
`myelodysplastic syndromes (MDS) likely to
`progress to AML (refractory anemia with
`excess blasts (RAEB} or refractory anemia
`with excess blasts in transformation [RAEB(cid:173)
`T}) have an estimated survival of less than 1
`year. 4 The standard of care for this population
`remains supportive therapy since intensive
`
`From the Department of Lmkemia, University of Texas
`M.D. Anderson Cancer Center, 1-lomton, TX.
`Address 1·eprint requests to Deborah A. Thomas, MD,
`Assistant Pt·ofessor, Department of Leukemia, University of
`Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd,
`Box 67, Houston, TX 77030.
`Copyright © 2000 by \V.B. Saunders Company
`003 7-196310013 701-3005$10. 0010
`
`chemotherapy regimens, such as those used in
`AML, have been reported to produce high
`rates of treatment-related mortality with rare
`· durable remissions. 5 Less intensive chemo(cid:173)
`therapy combination regimens can result in
`remissions with reduced mortality; however,
`achieving true disease eradication remains
`problematic. 4
`Chronic myelogenous leukemia (CML) is
`characterized by the presence of Philade lphia
`chromosome (Ph) in up to 95% of cases with a
`biphasic or triphasic disease course.6 Most pa(cid:173)
`tients present with ch ronic-phase CML and can
`be effectively managed with interferon alfa(cid:173)
`based therapy or allogeneic bone marrow trans(cid:173)
`plantation (BMT).6.7 Patients who fail to re(cid:173)
`spond to interferon and are ineligible for BMT
`have limited treatment options available, al(cid:173)
`though a few agents such as homoharringtonine
`and tyrosine kinase inhibitors show promise.
`Unfortunately, progression to the accelerated
`phase and/or b lastic phase is associated with
`drug resistance and other poor prognostic fea(cid:173)
`tures. 8,9 In the blastic phase, CR (or second
`chronic phase) may be achieved with regimens
`active in acute lymphoblastic leukemia (ALL) or
`AML; however, responses are typically short(cid:173)
`lived, with an expected su.rvival less than 1 year
`
`26
`
`Semincm in Hematology, Vol 37, No 1, Suppl 3 Uanuary), 2000: pp 26-34
`
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`

`

`Thalidmnide in Hematologic DiJorders
`
`27
`
`from the onset of blastic crisis. 10 In addition,
`Ph-negative CML and other myeloproliferacive
`disorders (including idiopathic myelofibrosis
`(MF} with myeloid metaplasia) are associated
`with poor prognoses and limited therapy op(cid:173)
`tions.11•1 2 MF is a poor prognostic factor for
`patients with CML receiving standard chemo(cid:173)
`therapy.
`lhe best c hance
`Allogeneic DMT offers
`for cure of AML, high-risk MDS, CML, and
`other myeloproliferative disorders. Unfortu(cid:173)
`nately, most patients with these malignancies
`are not candidates for BMT because of advanced
`age or ocher patient-specific characteristics
`(such as poor perfor mance status).7 Evaluation
`of new drugs with novel mechanisms of anci(cid:173)
`neoplasric action is ongoing in an effort to
`improve outcomes in hematologic disorders
`associated with a poor prognosis or no standard
`of care. Interest in agents that inhibit angio(cid:173)
`genesis in the bone marrow stroma has recently
`intensified.
`
`Antiangiogenesis in Hem atologic
`Disorders
`
`Rationale
`The rationale for studying antiangiogenesis in
`hematologic disorders is based on the initial
`concept chat neovascular izacion (or angiogene(cid:173)
`sis) is required for the growth of solid cu(cid:173)
`mors. 13· 14 The role of angiogenesis has since
`been established for such malignancies. Unril
`recently, it was uncertain if the growth and
`proliferation of circulating leukemic cells were
`angiogenesis dependenr. 15 Perez-Atayde ec al
`recently reported that children with ALL have
`increased bone marrow scroma vascularity and
`high urinary levels of basic fibroblast growth
`factor (bFGF; a marker of neovascularization) at
`diagnosis compared with a control group (chil(cid:173)
`dren with solid tumors or lymphomas without
`marrow involvement).1 5 The median pretreat(cid:173)
`ment m icrovessel density (MVD) and the MVD
`of "hot spots" (single field with highest MVD)
`were significantly higher (P < .000 1) in ALL
`marrows compared with controls. Furthermore,
`three-dimensional
`recon(cid:173)
`a compurer-aided
`struction model of marrow vascularity showed
`complex branching of microvessels in ALL
`
`marrows; such complex branching was not
`observed in the control group. Urinary bFGF
`levels were high in ALL patients before induc(cid:173)
`tion chemotherapy, variable during induction,
`and slightly lower when CR was achieved.
`Several studies have shown that angiogenesis
`accompanies plasma cell growth of monoclonal
`gammopathies, the progression of B-cell non(cid:173)
`Hodgkin's lyn1phornas, and chc ac:Livacion of
`multiple myeloma (MM). 16 •20 R ecently, evalu(cid:173)
`ation of MVD in 36 patients with newly
`diag nosed MM identified a correlation between
`MVD and degree of marrow plasmacytosis
`and cytogenetic abnormalities. 21 P atients with
`lower mean MVDs experienced longer dura(cid:173)
`tions of event-free and overall survival follow(cid:173)
`ing total therapy (remission induction followed
`by tandem a urotransplants and interferon main(cid:173)
`tenance) compared with patients with a mean
`MVD of at least six vessels per field. Overall,
`these findings suggest that leukemia and other
`hematologic disorders are angiogenesis-depen(cid:173)
`dent and may be effectively treated with agents
`that inhibit angiogenesis in the microenviron(cid:173)
`ment.
`
`Anti tumor Effects of Thalidomide
`During the late 1950s and early 1960s, thalido(cid:173)
`mide was used as a sedative-hypnotic (increases
`rapid eye movement [REM] and stage 3-4
`sleep22
`) and an antiemetic during pregnancy,
`until its teratogenic effects were recognized. An
`increased
`incidence of limb malformations
`suggested inhibition of neovascularization in
`the developing fetal limb bud. Subsequently,
`D'Amato et al demonstrated direct inhibition
`of bFGF-scimulated angiogenesis in a rabbit
`cornea micropocket assay following oral admin(cid:173)
`istration of thalidomide. 2 3 This characterization
`of thalidomide's mechanism of teracogenicity
`suggested that the drug may have therapeutic
`potential in pathologic angiogenesis.
`T halidomide also inhibits tumor necrosis
`faccor-a (TNF-a) production by stimulated
`monocytes. 24 Clinical efficacy in a wide variety
`of inflammatory conditions and graft-versus(cid:173)
`host disease (GVHD) after allogeneic BMT and
`renal t ransplantation suggests that thalidomide
`possesses
`immunosuppressive properties. 25.29
`Interestingly, a reduced risk of leukemia relapse
`
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`

`

`28
`
`Deborah A. Thomas
`
`has been observed in patients who respond to
`thalidomide for GVHD. 27 Thalidomide metab(cid:173)
`olites have demonstrated cytotoxic effects on
`leukemic cells through induction of morpho(cid:173)
`logic d ifferentiat ion in vitro.30
`The similarities between chemotherapeutic
`agents and thalidomide in terms of ceratogenic(cid:173)
`ity prompted clinical investigation of thalido(cid:173)
`mide's potential as an antineoplastic agent. An
`early study of thalidomide in various advanced
`malignancies showed a lack of objective re(cid:173)
`sponses31; however, preliminary data of more
`recent studies of thalidomide in the treatment
`of cancer are encouraging. For example, in a
`phase I trial of thalidomide for AIDS-related
`Kaposi's sarcoma (n = 12), rwo patients achieved
`partial responses (PRs) and seven had stable
`disease (SD ).32 In another phase I study, thalid(cid:173)
`omide (100 mg) was administered to 48 pa(cid:173)
`tients with advanced ovarian, renal, breast, or
`skin cancer; 10 patienrs had SD (median dura(cid:173)
`tion, 12 weeks; range, 8 to 25 weeks).33 Fur(cid:173)
`t hermore, an association was noted between SD
`and stable/falling serum and urinary vascular
`endothelial growth facror (VEGF), whereas dis(cid:173)
`ease progression was associated with rising
`VEGF levels. 'H Lastly, thalidomide has demon-
`. scrated significant act ivity as single-agent ther(cid:173)
`apy for high-risk refractory MM and as a
`component of combination chemotherapy for
`p lasma cell leukemia and fulminanr MM.3 4 .35
`
`Thalidomide in AML,. MDS,. and
`M yeloproliferative Disorders
`Pilot studies are being conducted at M.D.
`Anderson Cancer Center to assess the efficacy
`and tolerability of thalidomide in refractory/
`relapsed AML, high-risk MDS, CML, and other
`myeloproliferative disorders. Additional out(cid:173)
`come measures include the effects of thalido(cid:173)
`mide on bone marrow MVD and serum levels of
`VEGF and bFGF (data not shown).
`
`Eligibility
`Refractory or relapsed AML patients were eli(cid:173)
`gible if the duration of their first CR was less
`t han 12 months. High-risk MDS patients
`(those with RAEB or RAEB-T) were eligible
`after failure of frontl ine therapy (usually com-
`
`bination chemotherapy such as topotecan/cytar(cid:173)
`abine 4). CML pat ients in any phase of disease
`were eligible; however, patients with chronic(cid:173)
`phase were required to have failed interferon(cid:173)
`based therapy and be ineligible or unwilling ro
`undergo allogeneic BMT. Those patients with
`Ph-negative CML and other myeloproliferative
`disorders (with or without myelofibrosis) were
`eligible regardless of disease stat us or previous
`therapy.
`All patients were required co be 2:: 12 years of
`age and have adequate hepatic and renal func(cid:173)
`t ion (serum bilirubin and creatinine ::5 2.5 mg/
`dL) and a Zubrod performance status <3.
`Signed informed consent was required, includ(cid:173)
`ing agreement of female patients to use safe
`contraceptive methods during the study period
`and for at least 4 months after their last
`thalidomide dose. Patients who were pregnant
`or lactating were excluded. Those who had a
`h istory of seizures, neurotoxicity, serious infec(cid:173)
`tions not controlled by antibiotics, or act ive
`CNS d isease were also ineligible. Concurrent
`treatment with cytotoxic chemotherapy, bio(cid:173)
`logic therapy, or radiation was not permitted,
`with the exceptions of hydroxyurea, anagrelide,
`and granulocyte colony-stimulating factor (G(cid:173)
`CSF). G -CSF was indicated if the granulocyte
`count was <0.5 X 109/L due to thalidomide or
`as required for supportive care in the evenr of a
`life-threatening infection.
`
`Dosage and Administration
`Thalidomide (50-mg gelatin capsules) was ad(cid:173)
`ministered orally at an initial daily dose of 200
`mg at bedtime. The daily dose was escalated by
`200 mg each week if toxicity was < grade 0 to
`l (according to t he National Cancer Institute
`criteria) ro a maximum daily dose of 800 mg. If
`grade 2 toxicity occurred, the current dose was
`maintained until roxicity decreased to < grade
`1. Grade 2 toxicity persisting longer than 2
`weeks resulted in a dose reduction by 1 dose
`level. If grade 3 to 4 toxicity was observed,
`thalidomide was held until it was less than
`grade 3 and was resumed at a lower dose level.
`
`Evaluations
`The baseline assessment (performed within 2
`weeks of treatment initiation) included a corn-
`
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`

`

`Thalidomide in Hematologic Disorders
`
`29
`
`prehensive history and physical examination,
`hematologic profile, sequential multiple analy(cid:173)
`sis-12 (SMA-12), bone marrow aspirate and
`biopsy (to assess MVD) with cytogenetics , uri(cid:173)
`nalysis, electrocardiogram, and chest x-ray.
`Each patient was required to have a hemato(cid:173)
`logic profi le, SMA-12, history, and physical
`examination (including neurolog ic) every week
`uncil reaching a stable n1aximum dose; die
`interval between assessments was then leng th(cid:173)
`ened to every 2 co 4 weeks. V EGF and bFGF
`levels were obcained at baseline and a t specified
`time intervals (depending on diagnosis) during
`thalidomide therapy. Bone marrow aspirare and
`biopsy were to be repeated at the end of therapy
`to determine response or at any time during
`therapy if disease progression was suspected.
`
`Response Criteria
`Patients who received at least 2 weeks of
`thalidomide therapy were considered evaluable
`for
`response. For patients with h ig h-risk
`MDS or other acute leukemias (AML, RAEB,
`RAEB-T, chronic myelomonocytic leukemia in
`transformation [CMML-T}, or CML in blastic
`phase), CR was defined as <5% blasts in a
`normocellular or hypercellular marrow with
`granulocyte count > l. 5 X 109 IL and platelet
`count >100 X 109/L for at least 4 weeks.
`Complete resolution of excramedullary disease
`was required for CR.
`PR was defined as a reduction of the marrow
`leukemia infiltrate (MLI = marrow blast per(cid:173)
`cent times cellularity) co less than 20% with
`correction of the absolute neutrophil and plate(cid:173)
`let counts (without G-CSF or transfusion sup(cid:173)
`port) as defined for C R. H ematologic improve(cid:173)
`ment was defined as achievement of any one of
`the criteria required for CR where this feature
`was abnormal prior to therapy (for example,
`normalization of marrow blasts to <5%, in(cid:173)
`crease in the absolute neurrophil count to
`>1.5 X 109 /L, increase in the p latelet count to
`>100 X 109/L) in the AML, MDS, and CML in
`blastic phase categories. Hematologic improve(cid:173)
`ment in the MPD/MF categories also included
`the following: (1) >50% reduction in hepato(cid:173)
`megaly and/or splenomegaly, (2) ;::::50% reduc(cid:173)
`tion in packed red blood cell transfusion re(cid:173)
`quirements, and/or (3) ;:::: 50% improvement in
`
`t he neucrophil and/or platelet count. Response
`outcome was defined as resistant disease if the
`patient survived the treatment but disease per(cid:173)
`sisted and/or the patient failed to achieve count
`recovery or other hematologic improvement
`(such as reduction in transfusion requirements
`or splenomegaly) within a reasonable time pe(cid:173)
`riod. Progressive disease (PD) was defined as
`im:reasiug MLI ur pt:ripheral l>lascs, i111 .. rcasing
`transfusion requirements, progressive organo(cid:173)
`megaly, or other such features pertinent to the
`underlying diagnosis. All patients who had
`received at least one dose of thalidomide were
`considered evaluable for toxicity according to
`the National Cancer Institute criteria .
`
`Results
`
`Demographics
`from
`Twenty-eight patients were enrolled
`September 1998 to February 1999 (Table 1).
`The median age of the patient population was
`65 years (range, 24 to 85 years); 5 7% were
`male, and 25% had performance status >2 .
`
`Overall
`Of the 28 enrolled patients, 22 were evaluable
`for response in that they had received at least 2
`
`Table 1.. Specific Diagnoses of 28 Patients Treated
`With Thalidomide
`
`Diagnosis
`
`No. of Patients
`
`Refractory or relapsing AML
`Myelodysplastic syndromes
`RAEB
`RAEB-T
`CMML·T
`Ph-positive CML
`Late chronic phase
`Accelerated phase
`Myeloid blastic phase
`Other myeloproliferative disorders
`Ph-negative CML
`Myeloproliferative disorder with
`myelofibrosis
`Idiopathic myelofibrosis
`Total
`
`10
`9
`6
`2
`1
`4
`2
`1
`1
`5
`3
`
`1
`1
`28
`
`Abbreviations: AML, acute myeloid leukemia; RAEB, refrac(cid:173)
`tory anemia with excess blasts; RAEB-T, refractory anemia
`with excess blasts in transformation; CMML·T, chronic
`myelomonocytic leukemia in transformation; CML, chronic
`myeloid leukemia; Ph, Philadelphia chromosome.
`
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`

`

`30
`
`Deborah A. Th(Jmas
`
`Table 2. Adverse Effects Reported During Treatment
`With Thalidomide
`Adverse Effect
`
`No. (%) of Patients
`
`Fatigue
`Neurotoxicity, reversible
`Sedation, grade 1 or 2
`Confusion, grade 2
`Paresthesias. grade 2
`Orthostasis, grade 2
`Gastrointestinal toxicity
`Emesis, grade 1 or 2
`Constipation, grade 1 or 2
`Rash or skin dryness
`Infection
`Pneumonia
`Cytomegalovirus
`Cellulitis
`Gastroenteritis
`Chronic foot ulcer
`
`1 6 (57)
`12 (43)
`7
`2
`2
`1
`12143)
`2
`10
`9 (32)
`7 (25)
`3
`1
`1
`1
`1
`
`weeks of therapy. Six patients continued th a(cid:173)
`lidomide, with a median treatment duration of
`3 months (range, 1 to 5 month s). Sixty-four
`percent of patients achieved a dose of ac least
`600 mg daily. Reasons for discontinuing tha(cid:173)
`lidomide among evaluable patients included
`failure to respond after 1 mon th of therapy (n =
`7), development of P D (n = 3), toxicity (n = 2;
`fatigue/crying spells, confusion), and death
`(n = 4). O f the six patients w h o were inevalu(cid:173)
`able, three had rapidly P D and three requested
`discontinuation of therapy for one of rhe fol(cid:173)
`lowing reasons: (1) inability to swallow the
`medication, (2) emesis, and (3) severe fatigue .
`The adverse effects reported during t reat(cid:173)
`ment with thalidomide are summarized in
`Table 2 . Adverse effects generally were mild
`to moderate (grade 1 or 2). Overall, fatigue
`was t h e most common adverse effect and was
`dose-limiting. Twenty-one percent of patients
`required a dose reduction due to fatigue or
`sedation . Constipation was manageable with
`the use of laxatives. Most infections obse rved
`occurred in thalidomide nonresponders with
`AML or MOS who had prolonged neut ropenia.
`A chronic foot ulcer in one pat ient was felt to be
`related to concomitan t hydroxyurea.
`Four patients (with AML or high-risk MDS)
`died during the st udy. Probable causes of death
`included arrhythmia (n =
`1), pneL1monia
`resu lting in respiratory arrest (n
`l), and
`pulmonary hemorrhage resulting in sudden
`
`1). The relationships between
`death (n =
`thalidomide therapy and these fatalities were
`not established. I n one pat ient , circumstances
`surrounding the death were unknown.
`
`AML
`Of the 10 patients with AML enrolled, eight
`(80%) achieved prior CR with standard
`first-line chemotherapy (median duration, 10
`months; range, 5 to 24 months). T h e median
`number of prior salvage regim ens received was
`1 (range, 0 t o 5). Four patients received thalid(cid:173)
`omide as their first salvage attempt.
`The median duration of tr eatment on scudy
`was 1 month (range, 12 days to 3 months).
`Thalidomide daily doses of 800 mg and 600 mg
`were reached by four and two patients, respec(cid:173)
`tively. Of the nine evaluable AML patients, one
`patient achieved hematologic
`improvement,
`three had no response (one with transient re(cid:173)
`duction in MU), three had PD, and two died.
`The following case summarizes the experience
`of the patient with AML who experienced
`hematologic improvement:
`
`A 51 -year-old woman with diploid karyotype
`AML (diagnosed in June 1997) initially achieved
`CR with induction chemotherapy (ifosfamide, cis(cid:173)
`platin, and etoposide) followed by consolidation and
`autologous BMT. She relapsed in February 1998
`after a CR duration of approximately 7 months.
`Combination chemotherapy wich Audarabine, cytar(cid:173)
`abine, and G -CSF produced a second CR of shore
`duration. Subsequently, she received two salvage
`regimens (idarubicin/hydroxyurea, then cyclophos(cid:173)
`phamide/cytarabine/topotecan/G-CSF) that did not
`produce adequate responses.
`In December 1998, she had proliferative disease
`requiring leukapheresis and hydroxyurea. She was
`scarred on thalidomide 200 mg daily, ac which time
`her white blood cell (WBC) count was 18 X 109/L
`with 85% blasts. Bone marrow biopsy revealed 73%
`blasts, 80% cellularicy, and an MLJ of 58. After 2
`weeks of therapy, she developed a left peripheral
`seventh nerve palsy and was confirmed co have CNS
`disease. Incrathecal cycarabine, dexamechasone, and
`radiation therapy were administered. Thalidomide
`was continued at 200 mg daily; it could not be
`escalated because of persistent fatigue and occasional
`emesis requiring pre-dose anciemecics. Hydroxyurea
`was discontinued with a decreasing WBC count.
`Day 29 bone marrow biopsy showed reduced
`blasts (11 %), ceJlularicy (50%), and MLI (5.5).
`
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`

`

`Thalidomide in Hematologic Disorders
`
`3 1
`
`WBC count was recovering from a nadir of 2.2 X
`109/L, with no circulating blasts. CSP analysis
`showed a remarkable differentiation pattern similar
`co chat observed in che peripheral blood (WBC
`count decreased from 66 wirh 7 7% blasts to 1 with
`2% blasts). She recently returned home co Italy and
`concinued caking thalidomide 200 mg daily.
`
`MDS
`Of the nine MDS patients enrolled, six (67 % )
`achieved prior CR with standard first-line che(cid:173)
`motherapy (m edian duration, 3 months; range,
`1 co 14 months). Seven of the nine patients
`(78%) received t h alidomide as their first salvage
`regimen.
`The median duration of treatment on study
`was 45 days (range, 3 days co 3 months). Thalid(cid:173)
`omide daily doses of 800 mg and 600 mg were
`reached by four patients and one patient, respec(cid:173)
`tively. Of the six evaluable MDS patients, one
`achieved CR, three had no response (transient re(cid:173)
`duction in l\1LI observed in one patient), and two
`died. The following case summarizes che experi(cid:173)
`ence of the patient with MDS who achieved CR:
`
`A 60-year-old white man with deletion 5q AML
`(diagnosed in May 1998) achieved an initial CR
`with induction chemotherapy (cyclophosphamide/
`copocecan/cytarabine/G-CSF). He relapsed in No-
`
`vember 1998 after a CR duration of approximately
`3 monchs.
`He was started on thalidomide 200 mg daily, at
`which time his WBC count was 4.2 X 109/L with
`no circulating blasts. Bone marrow biopsy revealed
`11 % biases with 25 % cellularity. The daily thalid(cid:173)
`omide dose was escalated co 600 mg but was
`reduced ro 400 mg following development of grade
`2 fatigue. Day 29 bone marrow biopsy showed
`reduced blasts (4% ) and cellularicy (25 % ).
`Ac day 94, fever and confusion of unknown
`origin were noted; thalidomide was withheld owing
`co possible coxicicy. Lumbar puncture and magnetic
`resonance imaging of che brain were unrevealing.
`Subsequently, he was diagnosed with cyromegalo(cid:173)
`virus anrigenemia and was treated wirh intravenous
`ganciclovir with resolution of confusion and fevec.
`Complaints of constipation prompted chis patient to
`temporarily discontinue thalidomide. CR continued
`after 6 months of follow-up.
`
`Ph-Positive CML
`Four patients with a diagnosis of Ph-positive CML
`were treated with thalidomide; two are evaluable
`for response. Overall, one patient with CML in
`late chronic phase achieved SD and a decrease in
`hydroxyurea requirement at 5 months. The char(cid:173)
`acteristics and outcomes of che four patients with
`CML are summarized in Table 3.
`
`Table 3. Summary of Refractory CML Patients Treated With Thalidomide
`
`Diagnosis Date
`
`Previous Therapy
`
`E><perience With Thalidomide
`
`I nterferon-c:>
`•
`• HHT/cytarabine
`• Pegylated interferon
`• Anagrelide
`• lnterferon-c:>
`• Vincristine/splenic radiation
`• Decitabine
`• Thiotepa
`• Hydroxyurea/anagrelide
`•
`lnterferon-c:>/cytarabine
`• HHT/cytarabine
`• Decitabine
`• Hydroxyurea
`• Cytarabine
`• Splenic radiation
`• Decitabine
`• Liposomal
`daunorubicin/cytarabine
`
`• SD at 3 months
`• Decrease hydroxyurea/anagrelide requi rements
`• Discontinued because of depression/crying spells
`at 4 months
`• SD at 5 months
`• Decreased hydroxyurea requirements
`• No cytogenetic response at 3 months
`
`• PD at day 12
`
`• Decline in performance status at day 12
`• Patient requested to discontinue at that time
`
`Phase
`
`LCP*
`
`10/94
`
`LCP*
`
`3/96
`
`AP
`
`3/94
`
`MBP
`
`10/90
`
`Abbreviations: CML, chronic myelogenous leukemia; LCP, late chronic phase; AP, accelerated phase; MBP. myeloid blastic
`phase; HHT, homoharringtonine; SD, stable disease; PD, progressive disease.
`* Patients evaluable for response.
`
`DR. REDDY’S LABS., INC. EX. 1045 PAGE 6
`
`

`

`32
`
`Deborah A. Thomas
`
`Table 4. Summary of Patients With Refractory Myeloproliferative Disorders Treated With Thalidomide
`
`Patient
`
`Prior Therapy
`
`Thalidomide History
`
`Current Status/ Outcome
`
`Ph(-) CML
`67 yo WF
`
`EPO, G-CSF, splenic
`radiati on
`
`• Escalated to 600 mg/d
`
`45 yo WF
`
`Hydroxyurea, EPO
`
`54 yo WF
`
`None
`
`MPD/MF
`63 yo WM
`
`Hydroxyurea
`
`• Began 10/98
`• Escalated to 800 mg/d
`• Developed grade 2 paresthesias/tremors/
`slow mentation
`• Decreased to 600 mg/d
`
`• Began 10/98
`• Escalated to 800 mg/d
`• Developed grade 2 paresthesias/stocking(cid:173)
`glove neuropathy
`• Held at 600 mg/d x 2 wk
`• Toxicity resolved
`
`• Began 1/99
`• Escalated to 800 mg/d
`• Developed grade 2 rash and constipation
`• Toxicity resolved
`
`MF
`66 yo WM EPO, prednisone
`
`• Began 2/99
`• Escalated 600 mg/d
`• Developed grade 1 constipation and
`fatigue
`
`• Thalidomide discontinued after
`splenic infarction (day 14)
`• Progressive splenomegaly and
`cytopenias
`• Died after 3 months of inpatient
`care
`
`• Splenic infarction (day 13)
`• CT scan (12/98) showed 50%
`decrease in spleen and lesions
`• Day 105 bone marrow showed 30%
`ringed sideroblasts
`• Overall decrease in transfusion
`requirements
`
`• Active therapy x 5 months
`• Spleen reduced 50% (18 cm)*
`• Liver nonpalpable (4 cm)*
`• WBC = 5.5 X 10 9 /L
`(15.1 X 109 /L)*
`
`• Active therapy x 2.5 months
`• Spleen decrease<;:! to 12 cm
`(17 cm) *
`• No change in liver from baseline
`(7 cm)*
`• WBC = 7.7 x 109 /L with 1% blasts
`(11.6 x 109 /L with 2% blasts)*
`
`• Active therapy x 2 months
`• Cyclosporin added for Coombs(cid:173)
`positive anemia
`• No change in spleen (15 cm)* and
`liver (6 cm)*
`• WBC = 4.2 X 109 /L
`(5.2 x 10 9 /L)*
`
`Abbreviations: Ph, Philadelphia chromosome; CML. chronic myeloid leukemia; yo, year old; WF, white female; WM, white
`male; EPO, erythropoietin; G-CSF, granulocyte colony-stimulating factor; CT, computed tomography; WBC, white blood cell;
`MPD/MF, myeloproliferative disorder with myelofibrosis; MF, myelofibrosis.
`* Represents the baseline value.
`
`Other Myeloproliferative Disorders
`Five patients w ith myeloproliferative disorders
`ocher than Ph-positive CMl w ere created with
`thalidomide and we re evaluable for response;
`three patients remained on active
`t herapy.
`Three patients achieved hematologic improve(cid:173)
`ment, one had SD, and one developed PD. The
`characteristics and outcomes of the five patients
`with myeloproliferative disorders are summa(cid:173)
`rized in Table 4.
`
`Summary
`
`Although our experience with thalidomid e in
`hematologic disorders has been relatively
`limited, the outcomes t h us far are promis(cid:173)
`ing. The preliminary resul t s observed in
`Ph- negative CML, myelofibrosis, and other my(cid:173)
`eloproliferative disorders are the most encour(cid:173)
`aging. T he hemacologic improvements indicate
`activity similar to what would be expect ed with
`
`DR. REDDY’S LABS., INC. EX. 1045 PAGE 7
`
`

`

`Thalidomide in Hematologic Diswders
`
`33
`
`Uposoma.I Oeunorublcin
`+ Topotecan
`
`Thalktorride
`
`No Thalidomide
`
`Figure 1 . Ongoing phase II randomized trial for poor-risk
`karyotype RAES, RAEB-T, and AML.
`
`interferon alfa. These early findings support
`further study of thalidomide as a single agent
`(with a favorable oral route of administration)
`or in combination with other anciangiogenic
`(interferon alfa or SU-5416) or ch e m o therapeu(cid:173)
`tic agents. Such strategies appear possible since
`thalidomide was well tole rated, with the m a(cid:173)
`jority of patients successfully dose escalated
`according to the protocol design. The most
`commonly reported and dose-limiting adverse
`effects w ere fat igue and sedation. D ose reduc(cid:173)
`t ion (or maintaining the same dose without
`escalation) genera lly resulted in either resolu(cid:173)
`tion of t he side effect or improved tolerance.
`Fur ther investigation is warranted in early
`stage myelodysplastic s yndromes such as re(cid:173)
`fractory anemia o r refractory anemia w ith
`ringed sideroblasts based on the observations
`of increased eryt hropoiesis a nd decreased
`transfusion requirements in some p atients
`w ith MF. I n addition, with the activit y of
`single-agent thalidomide reported in refrac(cid:173)
`t ory MM,3 5 treatment of r efractory lympho(cid:173)
`proliferat ive disorders such as A LL, chronic
`lymphocytic leukemia, and other B-cell ma(cid:173)
`lignancies is warranted . A randomized phase
`II
`trial with firs t - line anrhracycline-based
`combinat ion c hemotherapy with or without
`t h alidomide
`in poor-karyotype AML
`is
`p lanned based on (1) prelim inary reports of
`enhanced resp onses with combination chemo(cid:173)
`therapy and t halidomide in MM and plasma
`cell leukemias,34 and (2) preliminary evi(cid:173)
`dence of anti -leukemia activity 27
`30 (Fig 1).
`•
`Assessm ents of marrow MVD and serum
`
`levels of VEGP, bFG P, angiogenin, and
`TNP- a will be perfor m ed.
`In conclusion, thalidomide appears to be
`well tolerated with evidence of activity in
`hematologic disorders. Continued study is war(cid:173)
`ranted with additional laboratory correlates to
`further elucidate t halidomide's mechanism(s) of
`action and to determine t he optimal therapeutic
`strategy.
`
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`kemia: A comprehensive review w ith emphasis on
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`2 . Estey EH, Kancarjian H, Keating MJ: T herapy for
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`and P ractice. New York, NY, Churchill Livingstone,
`1994, pp 1014-1028
`3. Thomas DA, Kantarjian H, Smith TL, et al: Primary
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