CLINICAL OBSERVATIONS, INTERVENTIONS, AND THERAPEUTIC TRIALS
`
`Thalidomide produces transfusion independence in long-standing refractory
`anemias of patients with myelodysplastic syndromes
`Azra Raza, Peter Meyer, Diya Dutt, Francesca Zorat, Laurie Lisak, Fabiana Nascimben, Morne du Randt, Christopher Kaspar,
`Cathryn Goldberg, Jerome Loew, Saleem Dar, Sefer Gezer, Parameswaran Venugopal, and Jerome Zeldis
`
`Thalidomide was administered to 83 pa-
`tients with myelodysplastic syndrome
`(MDS), starting at 100 mg by mouth daily
`and increasing to 400 mg as tolerated. Thirty-
`two patients stopped therapy before 12
`weeks (minimum period for response evalu-
`ation), and 51 completed 12 weeks of
`therapy.
`International Working Group re-
`sponse criteria for MDS were used to evalu-
`ate responses. Intent-to-treat (ITT) analysis
`classified all off-study patients as nonre-
`sponders. Off-study patients belonged to a
`higher risk category (P5 .002) and had a
`Introduction
`
`higher percentage of blasts in their pre-
`therapy bone marrow than patients who
`completed 12 weeks of therapy (P5 .003).
`No cytogenetic or complete responses were
`seen, but 16 patients showed hematologic
`improvement, with 10 previously transfu-
`sion-dependent patients becoming transfu-
`sion independent. Responders had lower
`pretherapy blasts (P5 .016), a lower dura-
`tion of pretherapy platelet transfusions
`(P5 .013), and higher pretherapy platelets
`(P5 .003). Among responders, 9 had refrac-
`tory anemia (RA); 5 had RA with ringed
`
`sideroblasts; and 2 had RA with excess
`blasts. By ITT analysis, 19% of patients (16
`of 83) responded, and when only evaluable
`patients were analyzed, 31% (16 of 51) re-
`sponded. It was concluded that thalidomide,
`as a single agent, is effective in improving
`cytopenias of some MDS patients, espe-
`cially those who present without excess
`blasts. (Blood. 2001;98:958-965)
`
`© 2001 by The American Society of Hematology
`
`Myelodysplastic syndromes (MDSs) have few therapeutic options that
`are even palliative, and none that are curative,1 especially if the affected
`patients are not suitable candidates for hematopoietic stem cell transplan-
`tation.2-4 Despite intense interest in growth factors,5-12 differentiating
`agents,13-15 and cytotoxic drugs,16-19 supportive care continues to be the
`standard therapy for the majority of patients. The clinical and biological
`heterogeneity of MDS suggests the possibility of multiple therapeutic
`targets, especially in light of the recent novel insights into the pathogen-
`esis of cytopenias. It appears that large numbers of hematopoietic cells
`are not only rapidly proliferating in the bone marrow, but also
`simultaneously undergoing programmed cell death.20-28 Furthermore,
`apoptosis in the hematopoietic cells is mediated by cytokines, such as
`tumor necrosis factor alpha (TNF-a), transforming growth factor beta,
`interleukin 1 beta (IL-1b), and IL-6.29-33 Attempts to suppress this
`excessive cytokine-mediated apoptosis in MDS with cytoprotective34
`and/or anticytokine therapies35-37 have resulted in substantial improve-
`ments in the cytopenias of some MDS patients.
`The bone marrows of MDS patients also demonstrate markedly
`increased neo-angiogenesis and higher-than-normal levels of vascular
`endothelial growth factor.38,39 Finally, in addition to the frequent
`involvement of B-cells in the MDS process itself,40 a more intrinsic
`immune defect may also exist in these patients.41 T-cell lymphopenia,
`especially that affecting the CD41 cells, has been described,42 and
`suppression of T-cell function by means of antithymocyte globulin
`(ATG) and cyclosporin is associated with improvement in the cytope-
`
`nias.43,44 Thalidomide was considered a potentially useful drug for MDS
`patients. It is an immune-modulatory agent with anticytokine activi-
`ties45-51 and has antiangiogenic effects.52-54 Thalidomide has meaningful
`activity in multiple myeloma,55 even though the precise mechanism of
`its action remains unclear. On the basis of this rationale, a pilot study was
`conducted to test the efficacy of thalidomide in improving the ineffec-
`tive hematopoiesis seen in patients with myelodysplastic syndromes.
`The results of this pilot study are encouraging enough to warrant larger
`prospective trials in the future.
`
`Patients, materials, and methods
`
`All patients, after signing an informed consent form approved by the
`Institutional Review Board of Rush-Presbyterian–St Luke’s Medical Cen-
`ter, Chicago, IL, participated in the study, MDS 98-21, titled “A pilot study
`of thalidomide (thalidomide) in patients with myelodysplastic syndromes.”
`Every patient had a pretherapy bone marrow aspirate and biopsy examina-
`tion performed at the Rush Cancer Institute (RCI). All samples were
`reviewed at the central facility by a hematopathologist at RCI/Rush-
`Presbyterian–St Luke’s Medical Center to confirm the diagnosis of MDS.
`Each patient started by taking 100 mg thalidomide by mouth at bedtime and
`increased the dose as tolerated to 400 mg by mouth at bedtime over the next
`several weeks. The drug was provided free of charge for the patients by
`Celgene (Warren, NJ). In the present study, no premenopausal woman of
`childbearing age was included. Newly diagnosed, as well as previously
`
`From the Rush Cancer Institute, Rush-Presbyterian–St Luke’s Medical Center,
`Chicago, IL, and the Celgene Corporation, Warren, NJ.
`
`financial interest in the Celgene Corporation, and A.R. is a member of the
`Speakers Bureau for the Celgene Corporation.
`
`Submitted March 17, 2000; accepted April 11, 2001.
`
`Supported by a National Cancer Institute grant (PO1 CA75606), The Roy Ringo
`Grant for Research in MDS, and a grant from The Woman’s Board TIME
`Center.
`
`J.Z. is an employee of the Celgene Corporation, which supplied thalidomide
`free of charge to the patients in this study. A.R. and P.V. have declared a
`
`Reprints: Azra Raza, Professor of Medicine, Director, Pre-Leukemia and
`Leukemia Program, Rush-Presbyterian–St Luke’s Medical Center, 2242 West
`Harrison St, Suite 108, Chicago, IL 60612-3515; e-mail: araza@rush.edu.
`
`The publication costs of this article were defrayed in part by page charge
`payment. Therefore, and solely to indicate this fact, this article is hereby
`marked ‘‘advertisement’’ in accordance with 18 U.S.C. section 1734.
`
`© 2001 by The American Society of Hematology
`
`958
`
`BLOOD, 15 AUGUST 2001 z VOLUME 98, NUMBER 4
`
`DR. REDDY’S LABS., INC. EX. 1023 PAGE 1
`
`

`

`BLOOD, 15 AUGUST 2001 z VOLUME 98, NUMBER 4
`
`THALIDOMIDE CAUSES TRANSFUSION INDEPENDENCE IN MDS
`
`959
`
`diagnosed, patients were eligible as were patients with both primary de
`novo and secondary MDS cases. Patients belonging to all subtypes of MDS
`as per the French-American-British (FAB) classification56 and to all risk
`categories according to the International Prognostic Scoring System
`(IPSS)57 were eligible. Patients were required not to have received any
`therapy for MDS for at least 4 weeks prior to starting thalidomide except for
`supportive care with transfusions. No other treatment for the primary
`disease such as growth factors could be administered to study patients while
`they were on thalidomide. Pyridoxine at 100 mg by mouth daily was
`prescribed for every patient as prophylaxis against peripheral neuropathy.
`Weekly complete blood counts (CBCs) with differentials were obtained,
`and upon completion of 12 weeks of therapy, the patients returned to RCI
`for a response evaluation, at which time all the pretherapy studies were
`repeated. In case of any evidence of a partial or complete response or stable
`disease as judged by the principal investigator, thalidomide was continued
`at the maximum tolerated dose for up to 1 year. Therapy was stopped in
`nonresponding patients at this time and they were taken off the study.
`The clinical end point of the study was to determine the efficacy of
`thalidomide in those patients who were able to complete at least 12 weeks
`of therapy at the maximally tolerated dose.
`
`Response criteria
`
`Response criteria outlined in the report of an International Working Group
`(IWG) to standardize response criteria for MDS58 were applied by an
`independent team (Global Therapeutic Development, Seattle, WA) to assess
`responses. Minor modifications had to be made to these criteria because this
`analysis was retrospective. The subsections below on “Pretherapy assess-
`ments” and “Assessments during therapy” describe modified criteria.
`Complete remission (CR). Bone marrow evaluation: CR is defined as
`repeat bone marrow evaluation showing fewer than 5% myeloblasts with
`normal maturation of all cell lines and no evidence for dysplasia. When
`erythroid precursors constitute fewer than 50% of bone marrow nucleated
`cells, the percentage of blasts is based on all nucleated cells; when there are
`50% or more erythroid cells, the percentage of blasts should be based on the
`nonerythroid cells.
`Peripheral blood evaluation. (Absolute values must last at least 2
`months.) (1) hemoglobin levels greater than 11 g/dL (untransfused patient
`not on erythropoietin); (2) neutrophil levels of 100/mL or higher (for patients not
`on a myeloid growth factor); (3) platelet levels of 100 000/mL or higher (for
`patients not on a thrombopoietic agent); (4) 0% blasts; (5) no dysplasia.
`Partial remission (PR) criteria. (Absolute values must last at least 2
`months.) PR is defined as a patient’s meeting all the CR criteria (if abnormal
`before treatment) except for bone marrow evaluation. The bone marrow
`criteria for PR are either that blasts decrease by at
`least 50% from
`pretreatment levels or that the MDS FAB classification be a less advanced
`category than at pretreatment. Cellularity or morphology is not relevant.
`Other criteria. (1) Stable disease is defined as failure to achieve at least
`a PR, but with no evidence of progression for at least 2 months. (2) Failure
`is defined as death during treatment or as disease progression characterized
`by worsening of cytopenias, increase in the percentage of BM blasts, or
`progression to an MDS FAB subtype more advanced than at pretreatment.
`(3) Disease transformation is defined as transformation to acute myelog-
`enous leukemia (AML), with at least 5% blasts. (4) A cytogenetic response
`requires 20 analyzable metaphases by conventional cytogenetic techniques.
`(5) A major cytogenetic response is defined as no detectable cytogenetic
`abnormality if pre-existing abnormality was present. (6) A minor cytoge-
`netic response is defined as 50% or more reduction in abnormal metaphases.
`Pretherapy assessments. (These incorporate minor modifications from
`the IWG response criteria.) For all patients, the baseline CBC to which
`improvements were compared was standardized with the use of a mean
`value for the 4 weeks prior to the start of therapy.
`Assessments during therapy. (These incorporate minor modifications
`from the IWG response criteria.) Responses were assessed at 12, 16, and 20
`weeks of therapy. Absolute values closest
`to the 12- and 16-week
`assessments were used, and responses had to be sustained for at least the
`subsequent 8 weeks. With regard to packed red blood cell transfusions
`(PRBCs) and transfusion independence, the same 4-week time period prior
`to treatment was used to determine transfusion dependence and to obtain a
`
`baseline monthly requirement. Subsequent transfusions were reviewed at
`12, 16, 20, 24, and 28 weeks. Patients who received a transfusion from day
`0 to week 12 were not considered transfusion independent; however, a
`patient who did not receive any transfusion at week 16 and sustained that
`independence for another 8 weeks was then considered transfusion
`independent. Patients were called late responders if they showed hemato-
`logic improvement (HI) after 20 weeks of therapy.
`Hematologic improvement. All improvements must last at least 8
`weeks. For a designated response (CR, PR, HI), all relevant response
`criteria must be noted on at least 2 successive determinations at least 1 week
`apart after an appropriate period following therapy.
`Erythroid response (HI-E). (1) Major response is defined as an increase in
`hemoglobin (Hb) greater than 2 g/dL for patients with pretreatment Hb below 11
`g/dL, and as transfusion independence for transfusion-dependent patients. (2)
`Minor response is defined as an increase of 1 to 2 g/dL in Hb for patients with
`pretreatment Hb less than 11 g/dL, and as a 50% decrease in PRBC requirements
`for transfusion-dependent patients.
`Platelet response (HI-P). (1) Major response is defined as an absolute
`increase of 30 000/mL or higher for patients with a pretreatment platelet
`count lower than 100 000/mL, and as stabilization of platelet counts and
`platelet transfusion independence for platelet transfusion–dependent pa-
`tients. (2) Minor response is defined as a 50% or greater increase in platelet
`count with a net increase greater than 10 000/mL, but less than 30 000/mL,
`for patients with a pretreatment platelet count less than 100 000/mL.
`Absolute neutrophil response (HI-ANC). (1) Major response is de-
`fined as at least a 100% increase or an absolute increase of 500/mL,
`whichever is greater, for patients with an ANC (absolute neutrophil count)
`lower than 1500/mL before therapy. (2) Minor response is defined as an
`ANC increase of at least 100% but an absolute increase less than 500/mL for
`an ANC that was lower than 1500/mL before therapy.
`
`Cytogenetic studies
`
`Standard karyotypic analysis by means of GTG banding was performed on
`every patient before therapy was started and each time a marrow was
`performed thereafter.
`
`Statistical analysis
`
`Distributions of numerical values were described as means and standard
`deviations or as medians and percentiles as appropriate. Comparisons of
`numerical values over time or across groups were made by means of
`Wilcoxon signed rank or paired tests as appropriate. Categorical variables
`were summarized with the use of percentages, and comparisons were
`performed by means of continuity-corrected chi-square tests or Fisher exact
`tests as appropriate. All tests were 2-sided, and P values of less than 5%
`were considered statistically significant. Analyses were performed by
`means of SPSS for Windows (SPSS, Chicago, IL) 10.0 and Splus 2000
`(Insightful, Seattle, WA).
`
`Results
`
`There were 83 patients with a confirmed diagnosis of myelodysplas-
`tic syndromes registered on this protocol. Thirty-two patients
`discontinued the protocol before completing 12 weeks of therapy;
`51 completed 12 weeks. We will present 2 separate sets of analysis:
`(1) an intent-to-treat (ITT) analysis of all 83 patients who either
`completed the 12 weeks on the study (51 patients) or prematurely
`discontinued therapy for various reasons (32 patients) and (2) an
`efficacy-analyzable analysis including only those subjects who
`completed the required minimum of 12 weeks on therapy.
`
`Baseline descriptive values
`
`The median age of the 83 patients was 67 years (Table 1). There were 55
`males and 28 females; 77 had primary de novo MDS, whereas 6 had
`secondary MDS. Thirty-six patients had refractory anemia (RA); 13 had
`
`DR. REDDY’S LABS., INC. EX. 1023 PAGE 2
`
`

`

`960
`
`RAZA et al
`
`BLOOD, 15 AUGUST 2001 z VOLUME 98, NUMBER 4
`
`Table 1. Baseline descriptive values for all subjects in study
`
`Total no. patients enrolled in MDS 98-21
`On study
`Off study
`Median age of patients, y
`Sex
`Male
`Female
`FAB
`RA
`RAEB
`RAEB-t
`RARS
`CMMoL
`MDS duration, d
`Median
`Range
`Transfusion history
`PRBC dependent
`Yes
`No
`Platelet dependent
`Yes
`No
`Primary/secondary MDS
`Primary
`Secondary
`IPSS
`Low
`INT-1
`INT-2
`High
`Biopsy cellularity
`Hyper
`Normal
`Hypo
`Thalidomide dose by duration, wk
`400 mg for at least 8 weeks
`400 mg for less than 8 weeks
`200 mg to 350 mg
`Less than 200 mg
`
`51
`32
`67
`
`55
`28
`
`36
`24
`6
`13
`4
`
`426
`9-3351
`
`63
`20
`
`21
`62
`
`77
`6
`
`21
`37
`12
`13
`
`54
`14
`12
`
`8
`36
`28
`10
`
`MDS, myelodysplastic syndrome; FAB, French-American-British classification;
`RA, refractory anemia; RAEB, RA with excess blasts; RAEB-t, RAEB in transforma-
`tion; RARS, RA with ringed sideroblasts; CMMoL, chronic myelomonocytic leukemia;
`PRBC, packed red blood cell
`transfusion; platelet, platelet
`transfusion;
`IPSS,
`International Prognostic Scoring System; low, low-risk group; INT-1, intermediate-I
`risk group; INT-2, intermediate-II risk group; high, high-risk group.
`
`RA with ringed sideroblasts (RARS); 24 had RA with excess blasts
`(RAEB); 6 had RAEB in transformation (RAEB-t); and 4 had chronic
`myelomonocytic leukemia (CMMoL). These patients were also charac-
`terized into prognostic categories by means of the IPSS.57 Briefly, 21
`patients belonged to low-risk, 37 to intermediate-1 (INT-1), 12 to INT-2,
`and 13 to the high-risk category. Biopsy cellularity was available in 80
`cases; of these, 54 were hypercellular, 14 normocellular, and 12
`hypocellular. The median duration of MDS for the group was 426 days
`(range, 9-3351 days). Sixty-three patients were PRBC dependent, and
`21 were dependent on platelet transfusions at the time treatment started.
`
`whereas only 8 of 51 patients who continued had a high or INT-2
`IPSS score (P 5 .002). Second, off-study patients had a higher
`percentage of blasts in their pretherapy bone marrow (7% versus
`2%, P 5 .003). It appears therefore that patients with more
`advanced disease had decreased tolerance for the side effects of
`thalidomide or were taken off thalidomide owing to disease
`progression as described in the following section.
`
`Drug tolerance and toxicity
`
`Of the 83 patients entered in the study, 32 could not complete the 12
`weeks of therapy. Among these 32, the median duration of therapy
`was 4 weeks (range, 0-8 weeks). One patient never started the drug;
`6 were discontinued for disease progression; 11 discontinued the
`study for other medical problems (fever, bleeding, Sweet syn-
`drome, worsening of renal amyloidosis, spinal chloroma, gum
`hyperplasia, transfusion reaction); and 14 discontinued the treat-
`ment because of side effects from the drug. The most common side
`effects were fatigue (79%), constipation (71%), shortness of breath
`(54%), fluid retention (48%), dizziness (40%), rash (31%), numb-
`ness and tingling in fingers and/or toes (29%), fever and headache
`(27% each), and nausea (25%). Fewer than 5% of patients had
`grade IV toxicity.
`Among the 51 evaluable cases, 34 increased the dose of thalidomide
`as tolerated from 100 mg by mouth at bedtime to 400 mg by mouth at
`bedtime within 4 weeks of starting therapy, but only 8 were able to
`continue at that dose for a full 8 weeks (Table 1). The median duration of
`400 mg therapy for the rest was 14 days (range, 1-42 days). Thus,
`although some of the patients increased the dose levels successfully, the
`higher doses were maintained for only a short period, with the majority
`taking between 150 to 200 mg by mouth at bedtime.
`
`Response evaluation
`
`Of the 83 patients registered in this study, there were no complete
`responders. Sixteen patients showed a hematologic improvement
`as described in Table 2, with 15 responding in the erythroid series
`and 1 showing a minor platelet response. There were no ANC
`responders. Among the 15 showing HI in the erythroid series, 11
`had a major erythroid response and 4 had a minor erythroid
`response. Of the 11 major responders, 6 responded by reducing
`their PRBC transfusion requirements by 100%; 4 showed both a
`decrease in transfusions by 100% and an increase in Hb; and 1
`non–PRBC-dependent patient showed an increase in Hb of more
`than 2 g/dL. One of these patients also showed a minor platelet
`response. Figure 1 shows 5 of the erythroid responders. In addition,
`4 patients also had a minor erythroid response, as shown in Table 2.
`All of these 4 patients showed a 50% reduction in PRBC
`transfusions. The 16th patient had a minor platelet response.
`
`Time to response
`
`Five erythroid responders showed HI within 12 weeks of starting
`thalidomide, 6 within 16 weeks, and 4 at week 20. The platelet
`responder improved his count within 12 weeks of therapy.
`
`Response duration
`
`Comparison of clinical characteristics of patients who stopped
`therapy before 12 weeks versus those who continued for at
`least 12 weeks
`
`There were 2 significant differences between patients who stopped
`therapy before 12 weeks and those who continued. First, 17 of 32
`off-study patients belonged to the high-rish or INT-2 category,
`
`Patient no. 937 died of a reactivated low-grade lymphoma at day
`260. Of the other 15 responding patients, the median duration of
`response was 306 days (range, 90-620 days). Four patients are still
`responding and continuing to take thalidomide. Six patients
`stopped responding and are listed in Table 2. Of the remaining 5
`patients, 3 stopped owing to intolerable side effects, and 2 opted to
`
`DR. REDDY’S LABS., INC. EX. 1023 PAGE 3
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`

`

`BLOOD, 15 AUGUST 2001 z VOLUME 98, NUMBER 4
`
`THALIDOMIDE CAUSES TRANSFUSION INDEPENDENCE IN MDS
`
`961
`
`Table 2. Hematological responses
`
`FAB
`
`BM cellularity
`
`PRBC
`dependent
`
`Responses
`
`Patient
`no.*
`
`Before After
`
`Before After Before After
`
`Reduction
`in PRBC, %
`
`Increase
`in Hb
`
`Platelets
`
`ANC
`
`Response type
`
`Response
`duration,
`d†
`
`Comment
`
`200
`
`Died of lymphoma
`
`Continues in
`remission
`
`Continues in
`remission
`Stopped responding
`Stopped after 1 year
`owing to side
`effects
`Continues in
`remission
`Continues in
`remission
`Stopped responding
`
`4221
`
`4541
`
`227
`306
`
`6201
`
`5271
`
`168
`
`239
`
`937 RA
`
`RA
`
`20
`
`30
`
`1011 RA
`
`RARS
`
`99
`
`70
`
`277 RA
`
`RA
`
`RARS
`963 RA
`400 RARS RARS
`
`460 RARS RARS
`
`1016 RA
`
`RA
`
`340 RARS RA
`
`90
`
`80
`70
`
`50
`
`30
`
`80
`
`N/A
`
`90
`70
`
`50
`
`30
`
`90
`
`Y
`
`Y
`
`Y
`
`Y
`Y
`
`N
`
`Y
`
`Y
`
`N
`
`N
`
`N
`
`N
`Y
`
`N
`
`N
`
`Y
`
`100
`
`Yes
`
`No
`
`No
`
`100
`
`Yes
`
`No
`
`No
`
`No
`
`No
`No
`
`100
`
`100
`50
`
`100
`
`50
`
`No
`
`No
`No
`
`Yes
`
`Yes
`
`No
`
`No
`
`No
`No
`
`No
`
`No
`
`No
`
`HI-E major, 100% PRBC Tx
`reduction at wk 16; minor
`Hb response at wk 16
`HI-E major (PRBC), Tx
`independent at wk 16;
`major (Hb)
`HI-E major, 100% PRBC Tx
`reduction
`HI-E major
`HI-E minor, 50% PRBC Tx
`reduction
`
`No
`
`HI-E major (Hb)
`
`No
`
`HI-E major
`
`No
`
`333 RARS N/A
`
`585 RARS RA
`
`1023 RAEB RAEB
`
`1007 RA
`
`RA
`
`1010 RAEB RAEB
`
`988 RA
`
`RA
`
`50
`
`80
`
`60
`
`20
`
`40
`
`80
`
`N/A
`
`80
`
`70
`
`30
`
`10
`
`70
`
`Y
`
`Y
`
`Y
`
`Y
`
`Y
`
`Y
`
`Y
`
`Y
`
`N
`
`Y
`
`N
`
`N
`
`50
`
`No
`
`100
`
`50
`
`100
`
`100
`
`No
`
`No
`
`No
`
`No
`
`Yes
`
`No
`
`No
`
`Yes
`
`No
`
`No
`
`No
`
`Yes
`
`No
`
`No
`
`No
`
`No
`
`No
`
`No
`
`551 RA
`
`RA
`
`30
`
`N/A
`
`Y
`
`N
`
`100
`
`No
`
`No
`
`No
`
`274 RA
`
`RA
`
`10
`
`30
`
`Y
`
`N
`
`100
`
`No
`
`No
`
`No
`
`HI-E minor, at 16 wks and
`post-50% reduction in
`PRBC Tx
`50% PRBC reduction from
`wk 20 to wk 24 & 28
`H1-P minor
`
`HI-E major (PRBC), Tx
`independent at wk 16
`HI-E minor, 50% PRBC Tx
`reduction at wk 20,
`sustained for 8 wks
`HI-E major (PRBC) major
`(Hb)
`HI-E major, 100% PRBC Tx
`reduction at wk 16, minor
`Plt response at wk 16 (not
`wk 12 owing to plt Tx)
`HI-E major, Tx dependent
`until wk 20, then
`independent through wk
`28
`HI-E major, patient received
`2 U PRBC day 1 of
`treatment, then was Tx
`independent until wk 28
`with 2 U, then
`independent again
`
`Stopped owing to side
`effects
`Stopped owing to side
`effects
`Stopped responding
`
`Stopped owing to side
`effects
`
`90
`
`177
`
`365
`
`381
`
`Stopped responding
`
`359
`
`Stopped responding
`
`188
`
`Stopped responding
`
`365
`
`Stopped after 1 year
`owing to side
`effects
`
`BM indicates bone marrow; Hb, hemoglobin; ANC, absolute neutrophil count; HI-E, hematological improvement in erythroid series; Tx, transfusion; HI-P, hematological
`improvement in platelets; Plt, platelets; for other abbreviations, see Table 1.
`*Unique Rush Cancer Institute patient numbers.
`†Plus sign indicates a continuing response.
`
`stop after 1 year of therapy was completed and they were given the
`option of continuing or stopping.
`
`for both, P 5 .013), and a higher median pretherapy platelet count
`(142 000 versus 57 000/mL, P 5 .003).
`
`Comparison of clinical characteristics in
`responders and nonresponders
`
`A comparison of pretherapy characteristics in responders and nonre-
`sponders among the 51 patients who completed at least 12 weeks of
`therapy showed 3 significant findings (Table 3). Responders had a lower
`median percentage of blasts to begin with (2% versus 3%, respectively,
`P 5 .016), a shorter median duration of platelet transfusions (median 0
`
`Delayed response to thalidomide
`
`Acurious observation, which became apparent in a striking manner, was
`related to the matter of delayed response seen in one of the patients. This
`is described in greater detail below because it may throw some light on
`the possible mechanism by which thalidomide improves the cytopenias
`in MDS patients. This patient is considered a nonresponder by the
`criteria specified in this paper and is not included in Table 2.
`
`DR. REDDY’S LABS., INC. EX. 1023 PAGE 4
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`

`

`962
`
`RAZA et al
`
`BLOOD, 15 AUGUST 2001 z VOLUME 98, NUMBER 4
`
`Figure 1. Hemoglobin and PRBC transfusions in 7 patients. These patients
`became transfusion independent on thalidomide. f, 2 units of PRBC transfused; 1,
`start of thalidomide.
`
`Patient no. 123
`
`This 65-year-old white male was diagnosed with MDS, RA,
`approximately 2 years before starting therapy with thalidomide
`(Figure 2). Cytogenetics revealed a complex karyotype including a
`20q deletion with further evolution in the clone. The patient
`received therapy for his primary MDS with the cytoprotective
`agent amifostine and a combination of pentoxifylline, ciprofloxa-
`
`Table 3. Clinical characteristics of responders and nonresponders
`
`Characteristics
`
`NR (n 5 35)
`
`R (n 5 16)
`
`Median levels
`
`Age, y
`MDS duration, d
`BM biopsy cellularity, %
`BM blasts, %
`PRBC duration, d
`Platelet transfusion
`duration, d
`Maximum thalidomide
`dose, mg/d
`Duration of maximum
`dose, d
`Hemoglobin, g/dL
`ANC, per mL
`Platelets, per mL
`Initial IPSS scores
`
`67
`670
`70
`3
`91
`
`0
`
`400
`
`14
`8.9
`1350
`57 000
`INT-1
`
`69
`321
`55
`2
`132
`
`0
`
`400
`
`12
`8.7
`1050
`142 000
`INT-1
`
`P
`
`.428
`.951
`.152
`.016*
`.79
`
`.013*
`
`.902
`
`.532
`.59
`.136
`.003*
`.468
`
`Figure 2. Delayed response. Peripheral blood indices in an MDS patient (no. 123)
`with RA showing a delayed response to therapy with thalidomide. 1, duration of
`thalidomide therapy (indicated between 2 arrows); f, 2 units of PRBC transfused.
`
`cin, and dexamethasone for 3 months as per protocol MDS 96-0236
`with no response, and with the TNF-soluble receptor Enbrel
`(Immunex, Seattle, WA)37 for 3 months, again with no appreciable
`hematopoietic response but with clearing of rather painful aphthous
`ulcers in his mouth. After a hiatus of several months during which
`he received only supportive care with frequent PRBC transfusions,
`he began taking thalidomide at 100 mg by mouth at bedtime on July
`1, 1999. His pretherapy CBC revealed a hemoglobin of 7.1 g/dL, an
`ANC of 200/mL, and platelets of 84 000/mL. He could not tolerate
`a dose of thalidomide greater than 200 mg by mouth at bedtime. At
`the end of 12 weeks, he was evaluated for response and was found
`to have no evidence of improvement in any of the cytopenias. The
`post-treatment CBC revealed a hemoglobin of 8.1 g/dL, an ANC of
`90/mL, and a platelet count of 38 000/mL. The platelets and ANC
`were found to be in a continuous decline. He was taken off the
`thalidomide on September 29, 1999, and entered a 3-month
`washout period before being considered for further experimental
`therapy. He continued to require red cell transfusions, the last one
`being on November 12, 1999. On December 1, 1999, his hemoglo-
`bin was 8.7 g/dL, his ANC was less than 200/mL, and his platelets
`had fallen to 18 000/mL. On December 16, 1999, his hemoglobin
`was still 8.4 g/dL, but he had not required a PRBC transfusion in
`over a month; his ANC was below 200/mL; and his platelets were
`18 000/mL. Interestingly, from the next week on, a steady improve-
`ment was noted in all 3 cell lines. The patient did not require
`another transfusion for approximately 9 months.
`
`Cytogenetic responses
`
`Cytogenetic results were available in 15 of 16 responders; 7 had a
`normal karyotype, 1 had 2Y, 1 had 81, 1 had del(20q), 1 had t(2;8), 1
`had der(7), and 3 had del(5q). No cytogenetic responses were observed.
`
`Discussion
`
`NR indicates nonresponders; R, responders; for other abbreviations, see Tables
`1 and 2.
`*Significant at .05 level.
`
`We report upon the success of thalidomide in alleviating the
`cytopenias of some patients with MDS. By the most conservative
`
`DR. REDDY’S LABS., INC. EX. 1023 PAGE 5
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`

`

`BLOOD, 15 AUGUST 2001 z VOLUME 98, NUMBER 4
`
`THALIDOMIDE CAUSES TRANSFUSION INDEPENDENCE IN MDS
`
`963
`
`estimation, assuming that all patients who went off the study before
`being evaluable for a response were in fact nonresponders, the
`response rate is approximately 19% (16 of 83). In an analysis of
`only those patients who finished 12 weeks of therapy, approxi-
`mately 31% (16 of 51) of evaluable individuals responded, with 15
`of 16 showing an erythroid response; some of the responses were
`quite striking. Ten transfusion-dependent patients acquired transfu-
`sion independence. The current study using thalidomide is the
`latest in a series of clinical trials conducted over the last 6 years
`using anticytokine and cytoprotective agents34-37 aimed at improv-
`ing the ineffective hematopoiesis of MDS. An advantage of using
`thalidomide is that in addition to neutralizing the effects of some
`proinflammatory, proapoptotic cytokines,47-51 this drug is also a
`known modulator of the immune system45,46 as well as an
`antiangiogenic agent.52-54
`This pilot study was designed to test the efficacy of thalidomide
`in producing complete or partial remissions in either low- or
`high-risk patients with MDS. The response criteria specified in the
`protocol were similar to those that we and others have used in
`previous trials.34-37 As the study was reaching completion, how-
`ever, the report of an IWG to standardize response criteria for
`myelodysplastic syndromes was published,58 and it was considered
`more appropriate to use the standardized criteria to assess response.
`Given the complexity of the disease and the sensitivity of the
`proposed criteria, an independent team of investigators was asked
`to apply the IWG criteria for response evaluation. In this way, both
`investigator bias and confusion about precisely what is meant by a
`response were eliminated. One potentially confusing aspect of
`these recommendations is that the IWG did not specify the method
`for determining baseline values of ANCs, Hb counts, and platelet
`counts against which response is to be measured. For example,
`given the frequently fluctuating nature of cytopenias in MDS
`patients, and the fact that patients being considered for therapy are
`most likely to be transfusion dependent, these values can vary
`widely from week to week. It is therefore important to decide
`whether an average of several values or one pretherapy absolute
`CBC result will be used as the baseline. The same applies to the
`number of pretherapy transfusions. Finally,
`the IWG did not
`specify how the CBC values during therapy are to be handled for
`response evaluation. For example, an assessment can be made
`every 3 months or every 6 months, but should the average CBC
`results be used for each cycle? The IWG itself anticipated that
`future modifications would be made to its standardized criteria as
`independent investigators began to apply these recommendations
`to assess the results of their clinical trials. Therefore, modifications
`to the criteria were made related to the calculation of pretherapy
`baseline CBC values and values during therapy; these modifica-
`tions are described in detail in “Patients, materials, and methods.”
`We present the results of this analysis, showing that thalidomide is
`capable of producing major hematologic improvements in a subset
`of MDS patients, especially those with low-risk disease.
`Eighty-three patients were registered on the protocol, but only
`51 completed at least 12 weeks of therapy. Of these 51 patients, 34
`were able to increase the thalidomide dose to 400 mg within a
`month, but only 8 stayed at this dose for the remainder of their
`treatment duration. The rest could tolerate this dose for a median of
`2 weeks before decreasing back to the 100 to 200 mg range. A
`dose-response effect was not appreciated, and it can be concluded
`that maintaining the maximally tolerated dose for a longer period of
`up to 6 months is more important than pushing for a higher dose for
`a shorter duration. The most common dose-limiting side effects
`were related to fatigue (79%) and constipation (71%), followed by
`
`shortness of breath (54%) and fluid retention, as manifested
`frequently by ankle edema (54%). More than 50% of the patients
`had grades 1 and 2 toxicity, and fewer than 5% had grade 4
`shortness of breath and fluid retention. Of the 32 patients who were
`taken off the study, 6 had shown unequivocal signs of transforma-
`tion to AML; 11 discontinued the drug owing to worsening medical
`problems, some of which could also be due to disease progression;
`and 14 could not tolerate the side effects. Patients who discontinued
`therapy belonged to a higher risk MDS category than those who
`continued for at least 12 weeks as shown by both their IPSS scores
`(P 5 .002) as well as their initial bone