California
`
`_ American Society
`I ~ - 1
`of Hematology
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`I 0
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`JOURNAL OF
`
`THE AMERSCAN
`
`SOCSETY OF
`
`HEMATOLOGY
`
`VOLUME 96
`
`. NUMBER 11
`
`OVEMBER16, 2000
`
`ART 2 OF 2 PARTS
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`Forty-second
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`becember 1-5, 2000
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`DR. REDDY’S LABS., INC. EX. 1054 PAGE 1
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`DR. REDDY’S LABS., INC. EX. 1054 PAGE 1
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`286b
`
`4976
`Abstract¹
`CLINICAL EFFICACY OF IRRADIATION IN CLL PATIENTS:
`PREDICTIVE VALUE OF IN VITRO RADIO-INDUCED
`APOPTOSIS. D Decaudin, J. Delic*, J. Dumont", E. Blot*, G. Tertian*,
`B. Dubray*, C. Grandpeix*,
`J.M. Cossets. Department of Hematology,
`Laboratory of Radiopathology;
`Department of Radiotherapy,
`Instltut
`Curie, Paris; Department
`of Hematology, Hopital du Kremlin-Bicetre,
`Le Kremlin-Bzcetre, France.
`irradiation of CLL patients,
`in case of bulky
`formerly indicated as palhative
`treatment
`disease or hypersplenism,
`has been introduced since few years into myeloablative
`regimens.
`ln order to discrimmate patients for whom such treatment could be beneficial, we investigated
`apoptosis of leukemic cells and response to
`the rclationslup
`between in vitro tadio-induced
`low-dose splenic or lymph node radiotherapy.
`Fourteen patients with CLL and receiving
`low-dose irraihation were included m thein vitro study The median time from diagnosis
`to
`(range 5-156) Three patients were Binet Stage B and eleven
`radiotherapy was 60 months
`patients were Bmet stage C The median blood lymphocyte
`count pnor to irradiation was
`126 10'/1 (range 10-268). Irradiation was the first-hne therapy in three cases, the second in
`seven cases, and the third m four cases Ten and five patients
`received splenic and tumor
`respectively, while one of them had received previous
`site irradiation,
`for a
`radiotherapy
`nasal site, followed by splenic irradiation 2 years later. Doses of radiotherapy
`ranged from
`1 to 5 Gy Leukemic cells were analysed immediately
`after collection or 24 hours of culture
`following in vitro irradiation of 0 to 10Gy. Afler Hoechst staining,
`the proportion of apoptotic
`as the percent of cells presenting
`cells was determined
`by fluorescence microscopy
`for a total number of 10'. The tumor
`charactenstics of apoptosis,
`morphological
`response
`rate was 47% with one complete remission and six partial remissions,
`three of which greater
`than 90% Excluding the patient
`receivmg nasal
`irradiation without
`local recurrence,
`the
`mean duration of response was 3 months
`(range 1-4). For the ten patients
`receiving splenic
`the tumor response rate was 40% with a mean percentage of decrease leukemic
`irradiation,
`cells of 50%, 89 and 24% for responding
`(p & 0.05).
`and refractory patients,
`respectively
`The in vitro study showed a proportion of apoptotic leukemic cells ranged between 2 and
`75%. We observed a high correlation
`between tumor
`response
`and in vitro tests (p &
`0.01)(Mann-Whitney U test). After splemc uradiation, we also found a high correlation
`between the percentage decrease of leukenuc cells and m vitro radio-induced
`apoptosis (r =
`0.87, p & 0.01, Spearman correlation test). The positive predictive value (PPV) of the m
`response was 100% at 2 Gy The PPV of the in vitro tests for
`vitro tests for tumor
`response was 75% at 2 Gy and 100% at 5 Gy. In tlus report, we observed a
`hematological
`apoptosis of leukemic cells and clinical and
`lugh correlation between in vitro radio-induced
`that the sensitivity of leukemic
`hematological
`response to radiotherapy. These results suggest
`cells to irradiation
`should be first evaluated in an in vitro assay to spare refractory patients
`from the useless toxicity of TBI
`
`4977
`Abstract¹
`TREATMENT OF WALDENSTROM'S MACROGLOBULINEMIA
`WITH THALIDOMIDE. M,A. Dirnopoulos, N. Viniou*, A. Zomas", V.
`E. Galani*, C. Matsouka*, O. Economou*, N.
`Grhgoraki"',
`P. Panayiotides*. School of Medicine, University of
`Anagnostopoulos",
`Athens, Athens, Greece.
`Thahdomide
`is an active agent
`in patients with refractory multiple myeloma. Based on
`these data we performed a phase 11 study m order to evaluate the activity of thalidomide
`in
`Waldenstrom's macroglobuhnemia
`(WM) Thalidomide was administered
`on a dose-
`escalating schedule of 200 mg daily p o x 14 days with dose escalation by 200 mg every
`two weeks to a maximum dose of 600 mg. Twenty patients were treated with a median age
`of 74 years
`(range 48 to 85 years) Hemoglobin was & 10.0 gr/dl
`in 5 patients,
`serum
`lgM was &3.0 gr m 9 patients
`monoclonal
`and lymphadenopathy
`and splenomegaly were
`in 7 and 10 patients
`present
`respectively. Ten patients were previously
`untreated,
`1 was
`relapsing off treatment,
`5 were pnmary
`refractory and 4 were treated dunng refractory
`(25%) achieved at least 50% reduction of serum monoclonal
`relapse. Five patients
`IgM and
`at least 50% reduction of tumor at all involved sites. At least 25% reduction of IgM was
`responders witlun 4 weeks of thahdomide
`noted in all eventual
`ueatment. Responses occuned
`in 3 of 10 previoulsy
`untreated patients and in 2 of 10 preheated patients. One responding
`patient with artial fibrillation died of an embolic cerebral accident 4 months after achieving
`a response and the other responding
`remain without progression for 2+ months
`patients
`to
`12 + months Some degree of toxicity was observed m almost all patients. Grade 2 or 3
`toxicities included constipation m 6 patients,
`somnolence in 3 patients,
`tremor in 2 patients
`in 2 patients This explained the inability
`to reach the targeted dose of
`and neuropathy
`thalidomide 600 mg p.o QD in all but 4 patients,
`the median darly dose of this agent was
`200 mg We conclude that
`activity in WM. A relatively
`thalidonude
`has moderate
`low
`median dady dose could be adinuustered
`to this elderly patient population.
`
`4978
`Abstract¹
`THALIDOMIDE AND DEXAMETHASONE COMBINATION FOR
`MULTIPLE MYLEOMA REFRACTORY TO DEXAMETHASONE-
`BASED REGIMENS. M.A. Dimopoulos, K. Zervas*, E. Galani", V.
`Grigoraki", E. Vervessou*, E. Samantas"', C. Kiamouris", D. Ghka*, C.
`Papadimitrhou*, N. Anagnostopoulos*.
`School of Medicine, University of
`Athens, Athens, Greece.
`Recent data suggest
`30% of patients
`is active in approximately
`thahdomide
`that
`(pts)
`with refractory multiple myeloma. Between 7/99 and 7/00 we treated 38 pts with refractory
`200 mg PO q h s, increased to 400 mg after two weeks (in
`myeloma with thalidomide
`absence of severe side effects), and mtennhttent
`dexamethasone 40 mg p o. x 4 days on days
`1-4, 9-12, 17-20 followed by monthly
`(days 1-4). Pts median age was 67
`dexamethasone
`
`MYELOMA/CLL - THERAPY, EXCLUDING TRANSPLANTATION
`(49 to 79 years)
`years
`Immediately
`has consisted of lugh-dose
`prior
`therapy
`pals
`(21 pts) or VAD (17pts). Twelve pts had previously
`dexamethasone
`received an autoiogpI
`stem cell transplant Fo~een pts were considered as prlinary
`refractory slid 24 pts were
`treated dunng reftactory relapse. Serum b2-microglobulin & 3 0 mg/dl was present
`in 66',
`of pts and elevated serum LDH hn 26% Among the 33 patients evaluable
`for iesponse s
`far, 17 (52%) have achieved a partial
`response defined by reductions & 50% of sera&
`monoclonal protein and/or by &75% of unne monoclonal piotein The time to response wss
`short (median: 1.5months,
`range 0.5 to 3 months). Side effects included constipauon (75%)
`(54%), tremor
`somnolence
`(25%), dry slunhash
`(18%), headache
`morning
`(14%) asd
`(7%).Our results indicate activity of the combmation of tha)hdonuhte
`peripheral neuropathy
`with dexamethasone
`in pts with multiple myeloma
`refractory to dexamethasone-based
`regimens. Pts accrual and follow up is ongoing in order.
`to dcfme the activity of thjs
`and to assess the duration of response
`combination in pts'subsets
`
`4979
`Abstract¹
`THE ROLE OF BISPHOSPHONATES IN MULTIPLE MYELOMA.
`META-ANALYSIS OF PUBLISHED RANDOMIZED TRIALS. II
`Djulbegovic,'. Wheatley",'. Lacevic",'. Bos,'
`Ross*," IJ
`Goldschmidt,'. Glasmacher.'Blood and Bone Marrow Transplantation
`H. Lee Moffitt Cancer Center, Univ. of South Florida, Tampa, FL, USA
`'Clinical Trials Unit, Univ. of Birmingham,
`'Dpt, pf
`United Kingdom;
`Internal Medicine, Univ. Hospital, Maastricht, The Netlzerlands;
`Dpt. pf
`Haematology, Northampton General Hospital, United Kingdom;
`'Dpt, pf
`Internal Medicine V, Univ. of Heidelberg, Germany;
`'Dpt. of Intern/hi
`Medicine I, Univ. of Bonn, Germany.
`used in the management of multiple myelohna
`(Bs) are mcreasingly
`Bisphosphonates
`(MM). AIM; To synthesize
`about benefits and harms of Bs in Mih(
`aviulable knowledge
`(MA) of available published
`we performed meta-analysis
`evidence METHODS: We
`identified 10 randomized,
`placebo controlled trials (RCTs), of which 9 tnals setved as a
`basis for this analysis
`(Bs. etidronate 2 trials, clodronate 4, pamidronate 2, ibandronate
`1),
`trial was excluded from the analysis. A total of 1058 patients
`A small cross-over
`treated
`with Bs and 1017patients with placebo were included in analysis Heterogeneity
`among the
`thus allowmg poolmg pf .
`for the major outcomes considered in analysis,
`was imnimal
`data in this MA. RESULTS: The published evidence demonstrated
`a beneficial effect ofBs,
`on prevention of pathological
`fractures. On average for every 8 patients
`vertebral
`treated:,
`with Bs one patient will avoid a vertebral
`fracture dunng median foflow-up of 22 5 months
`4 to 24 months, OR=0.53, 95%CI 0.39-0.72,P=0.00005). There was no significant
`effect of Bs on non-vertebral
`fractures (OR=0.99, 95%CI 0.69-1.40,p=0.9).There was also,'
`beneficial effect of Bs on bone pain with absolute risk reduction of 14% (95%CI ranges
`from 8%-19%),indicating that on average for every 7 patients
`treated with Bs one patierit
`will not experience pain. We found no significant effect of Bs on hypercalcemia
`(OR=0.84,
`95%CI:0.6-1.16,P=0.3].Administration of Bs was associated with non-significant mcrease,
`of gastro-intestinal
`side (GI) effects (OR=1.28, 95%CI 0.95-1 74, P=0.11).We found np
`significant effect of Bs on overall mortality in MM (OR=0.97, 95%CI 0.86-1.09) Results
`not change when subgroup analysis according to type of Bs was performed The major
`limitatton of our study is that it has not mcluded unpublished
`data or mdividual-patient
`data.
`CONCLUSIONS: Based on our review of available evidence, Bs reduce the probability of
`vertebral
`and bone pain associated with MM. Further evidence is
`fractures
`needed to determine whether
`some Bs are more effective than others and whether Bs have,
`an effect on mortahty.
`
`'rials
`
`'range
`
`'id
`
`"
`
`.'athological
`
`Enschede,'arameswaran
`
`'
`
`.
`
`'oxicity
`
`4980
`Abstract¹
`A PHASE II STUDY OF FLUDARABINE (F) AND MITOXANTRONE .
`(N) IN THE TREATMENT OF PREVIOUSLY UNTREATED B-CELL
`CHRONIC LYMPHOCYTIC LEUKEMIA. Sari H.
`L. Guevarra",'eresa M. O'rien",':
`Venugopal,'gnes
`Stephanie A. Gregory.'Section
`of Hematology, Rush-Presbyterian-St.
`Luke's Medical Center, Chicago,
`IL, USA.
`Fludarabine
`alone is an effective initial mduction
`for CLL patients, with
`therapy
`disease, resulnng in an overall response of 78% (Keathng, Blood 1998).
`progressive/advanced
`Mitoxantrone
`has well documented
`activity m lymphoid malignancies
`and may even act
`such as F The regimen of F, N and
`synergistically with other chemotherapeutic
`agents
`dexamethasone
`is effective for indolent NHL but immunosuppressive
`to the pomt of requiring
`infectious prophylaxis
`/CO 1966).In this study, we assessed the efficacy and
`(McLaughhn,
`of FN as initial
`for CLL patients with stage 11(progressive), 111
`induction treatment
`or IV disease. The median age was 58 (range 47-80) and M F ratio of 2 1 Three patients
`(22%) had stage IH, and 4 pan ents (45%) had stage IV: ',
`had stage 11 disease, 2 patients
`disease patients were treated with the regimen of F 25 mg/mz
`IV on days 1-3 and N 12 nhg/,
`
`m'n day 1 The cycles were repeated every 28 days for a maximum of 6 cycles Stag)ng ':
`
`'33%)
`
`with CT scans and bone marrow studies were performed before and after treatment CR wss
`defined as disappearance of all disease and bone mar/w lymphocytes &30% PR was
`achieved if patients had a &50% reduction in measurable disease. A total of 11 patients we«
`studied. Of the 9 evaluable patients, 4 (44%) achieved CR and 5 (56%) PR with 100% OR
`A total of 4 patients
`(3 CRs and 1 PR) progressed at 7, 10, 20 and 36 months; a median Pf
`months. One patient progressed at 5 months but had received only 2 cycles of treatnient
`A total of 4 patients
`(1 CR and 3 PRs) rehnahn without progression at 8, 9, 25 and 27 months
`The panent at 25 months had stable disease and underwent
`at
`stem cell transplant
`penpheral
`tolerated and the adverse events were comparable «
`20 months. The regimen was well
`those from F alone. There were 3 hospitalizations
`for neutropemc
`fevers and most patients
`had grade 3-4 neutropenia. No antibiotic prophylaxis was required Although
`this was s
`the combination of FN is more efficacious (100% OR)
`phase 11 study,
`it shows
`that
`but not more toxic than F alone in the upfront
`for CLL patients The median thin
`treatment
`
`'5
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`'mall
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