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					   POSSIBLE MECHANISMS OF IMATINIB
             RESISTANCE

 BCR/ABL gene dependent
  – Point mutations at catalytic site of BCR/ABL gene
  – BCR/ABL gene amplification
  – BCR/ABL gene up-regulation
                                                 Formal evidence in
                                                patients still pending
 BCR/ABL gene independent

  – Increase of protein binding
  – Additional genetic events
  – Quiescent Ph+ cells relatively insensitive to imatinib
            CRYSTAL STRUCTURE OF cABL
                     Domains of the catalytic site




Nucleotide-binding
loop                                                 Activation loop


                                                     Catalytic loop
       MOLECULAR MODELING OF TKS’ ACTIVATION



                            The role of the
                              activation loop domain:
cAbl
                            Switching from
                            gate-closed form (inactive)
                            to
                            gate-open form (active)
Irk




Hck
     IMATINIB-cABL INTERACTION:
        Stabilization of cABL inactive form




Activation loop
                       MAP OF ABL MUTATIONS
                            33                32

                                                                   24
                       20



                   9
              6                                 6                       5 4                    6
       3 2                        1       1             1                           1 1   1                  1   1   1

                                                                catalytic            activation
         ATP-binding loop                                       domain                 loop


 M244V
                                 V289A
     L248V                                            M343T                                        H396R/P
                            E255K/V
           G250E                                              M351T         F359V              L387M
                        Y253F/H               T315I                                                     S417Y
                                                                 E355G/D                                     E459K
               Q252R/H                F311L/I         F317L                                   F382L
                                                                                     V379I                       F486S
Last update Feb 04
BCR/ABL MUTATIONS AFFECTING THE
      IMATINIB BINDING SITE
BCR/ABL MUTATIONS AFFECTING THE
    NUCLEOTIDE BINDING LOOP
BCR/ABL MUTATIONS AFFECTING THE
  NUCLEOTIDE ACTIVATION LOOP
PATTERNS OF IMATINIB RESISTANCE
       IN Ph+ LEUKEMIAS
                              CML clone


             Treatment with
                Imatinib



 Primary                           Cytogenetic response
Resistance
                     Reemergence of
                     Ph chromosome




                              Acquired (Secundary) Resistance
         BCR/ABL MUTATIONS IN FRONT-LINE AND
           ACQUIRED RESITANCE TO IMATINIB
 Authors/Year              Cases    N¡     Front-line resistence         Aquired resistence
                                         mutations am plifications   mutations    am plifications

 Gorre, 2001           LMC-CB My+   7       nt            nt            3/6             2/7
                       LLA Ph+/CB   4       nt            nt            3/3             1/4
                          Ly+

 Br anford, 2002         LMC-FC     11      0/6           nt            3/5              nt
                         LMC-FA      9      1/4           nt            3/5              nt
                       LMC-CB My+    4      nt            nt            2/4              nt
                       LMC-CB Ly+    2      nt            nt            2/2              nt
                        LLA-Ph+      2      nt            nt            2/2              nt

 von Bubnoff, 2002     LMC-CB My+   1       0/1           nt            0/1              nt
                       LMC-CB Ly+   1       0/1           nt            1/1              nt
                        LLA-Ph+     6       0/6           nt            6/6              nt

 Hofm ann , 2002         LLA-Ph+    21      3/8           nt           4/12              nt


 Total                              67     4/26           nt           29/47            3/11

Nt: not evaluated in that study
               Hypothesis
front-line resistance = clonal evolution
      Responder                           Non Responder
                        Imatinib
                                                       Imatinib
 Ph           BCR/ABL

                                                          Other
       Proliferation                         BCR/ABL     defects

                                       Proliferation

      The resistant clone is already the main component
               of the Ph-positive cell population
     CML/002/STI571 protocol

    56/200 pts: never achieved a MCgR (28%)


      40/56 pts: residual material available
             for mutational analysis


all 40 patients analyzed in parallel by DHPLC and
                    sequencing
                 CML/002/STI571: RESULTS
        19/40 (45%) patients who had cytogenetic refractoriness
            to Imatinib showed evidence of a point mutation


            11                                            8




                                                      catalytic           activation
            P- loop                                   domain                loop

M244V                      298                M343T
   L248V                                                                           H396R/P
                        E255K/V
         G250E                                    M351T           F359V         L387M
                      Y253F/H         T315I                                             S417Y
                                                       E355G/D                               E459K
           Q252R/H              F311L/I       F317L                            F382L
                                                                          V379I                 F486S
DETECTION OF ABL MUTATIONS MAY BE
      CLINICALLY IMPORTANT


 The presence of some specific mutations may
  offer prognostic information

 Different mutants show different degrees of
  resistance to Imatinib
    MUTATED vs. NON-MUTATED
                Progression to AP/BC        Dead

Mutated                  11/19              7/19
Non-mutated              2/22               0/22

 Time to progression                   Overall Survival
         P-LOOP vs. NO P-LOOP
                  Progr. to AP/BC         Dead

P-loop                   9/11             6/11
No P-loop                 2/8              1/8

 Time to progression                Overall Survival
PROGNOSTIC SIGNIFICANCE
  OF P-LOOP MUTATIONS


             Figure 2. Kaplan-Meier survival
             curves for patients with mutations.
             There was a significant difference in
             the survival rate of patients in AP and
             late-CP with P-loop and non–P-loop
             mutations. With one exception, patients
             with P-loop mutations died.




                   (Brandford et al, Blood 2003)
FACTORS WHO AFFECT PROBABILITY OF
   BCR/ABL MUTATION DETECTION




                       (Brandford et al, Blood 2003)
       CML CONCLUSIONS
 Cytogenetic and Molecular response are
  relevant surrogate marker for CML
  monitoring



 Resistance to STI571 is a complex
  phenomenon and search for point mutation
  is crucial for CML patient management.
            SPECIFIC GENOTYPES OF ALL
                Childhood ALL                                                    Adult ALL
                                                                    TEL/AML1-    Hyperdiplody         Hypodiploidy
                    Hypodiploidy      Others                          t(12;21)       7%                   2%
                        1%             22%                               2%                                          Others
 Hyperdiplody                                                  MYC-t(8;14)                                            23%
     24%
                                               BCR/ABL-           4%
                                                t(9;22)
                                                             E2A/PBX1-
                                                  3%           t(1;19)
                                                                 3%
                                                MLL
                                          rearrangements     HOX-10q24
                                                8%              8%
                                                             TAL1-1p32
                                           HOX11L2-5q35        12%
TEL/AML1-
 t(12;21)                                      3%
                                                             LYL1-19p13
   22%                                          LYL11-9p13      3%
                                                   2%
                                                                HOX11L2-5q35               MLL              BCR/ABL-
      MYC-t(8;14)                            TAL1-1p32              1%
         2%          E2A/PBX1-                                                       rearrangements          t(9;22)
                       t(1;19)     HOX-10q24    7%                                         10%                 25%
                         5%           1%



                                                 T-Cell ALL
     Outcome of Adult Ph+ ALL with
Authors
           Conventional CHT %DFS
         Ye Pt %C Remission OS                              %OS
                ar   s   R    duration    median,    (y)     (y)
                             median, mo    mo
Bloomfield et   19 29 46         7          11        -       -
al              89
Secker-         19   23 64       -          8         -       -
Walker et al    91
Gotz et al      19   25 76       9          13        -     6(3)
                92
Westbrook et    19   12 71       10         11        -       -
al              92
Larson et al    19   25 70       7           -      11(3)   16(3)
                95
GFCH            19   12 59       -          5         -     5(3)
      Adult Ph+ ALL: MRC UK
         ALL12/ECOG E2993
•
              Study Outcomes
    1389 patients with ALL
•   267 (19%) Ph+ ALL
    – CR 76%
    – 5-yr OS 23%
    – 5-yr EFS 18%


                        5-yr OS
     Ph+ ALL              (%)
     MFD                   37   OR = 0.84
     No related            27   P = 0.4
     donor
     MFD SCT              42    OR = 1.19 2003;102:80a - Abs 268
                                 Goldstone et al. Blood.
IMATINIB IN THE TREATMENT OF
    Monotherapy
               Ph+ ALL
        - Salvage treatment
        - Maintenance therapy after
    chemotherapy in newly
    diagnosed patients
        - ―First line‖ induction for newly
    diagnosed patients
        - MRD treatment after SCT

    Combination treatment with:
        - Chemotherapy in newly diagnosed
    patients
   Imatinib Monotherapy:
Relapsed/Refractory Ph+ ALL
          Imatinib Monotherapy in Relapsed/
                  Refractory Ph+ ALL

    Response to Treatment (Imatinib 400 or 600 mg/d)

                           Ph+ ALL          CML LyBC
                            n = 48            n=8
Hematologic response       29 (60%)            4 (50%)
 CR                        9 (19%)             4 (50%)
 CR–marrow                 5 (10%)                  0
 PR                        15 (31%)                 0

Failure                    12 (25%)            4 (50%)

Not evaluable               7 (15%)                 0

                                      Ottmann OG, et al. Blood. 2002;100:1965-1971.
                                      Imatinib Monotherapy in Relapsed/
                                              Refractory Ph+ ALL
                                                              Time to Progression

                                    100
% of Patients Without Progression


                                     90
                                     80

                                     70
                                     60

                                     50

                                     40

                                     30

                                     20
                                                                                     Ph+ ALL (n = 48)
                                     10
                                              = Censored observations
                                      0
                                          0   1     2     3      4      5   6    7      8      9     10      11     12
                                                              Months Since Start of Treatment

                                                                                       Ottmann OG, et al. Blood. 2002;100:1965-1971.
    Imatinib Monotherapy in Relapsed/
            Refractory Ph+ ALL
     Nonhematologic Drug-Related Adverse Events

                         All enrolled patients (n
                                   = 56)
                         All Grades Grade 3/4
Nausea                    43 (77%)          1 (2%)
Vomiting                  35 (63%)                0
Lower limb edema          16 (29%)          1 (2%)
Periorbital edema         15 (27%)          1 (2%)
Abdominal pain            14 (25%)                0
Muscular cramps            8 (14%)                0
                                     Ottmann OG, et al. Blood. 2002;100:1965-1971.
Skin rash                  6 (11%)          1 (2%)
         Imatinib Monotherapy in Relapsed/
                 Refractory Ph+ ALL
     Hematologic Toxicity and Laboratory Abnormalities


                               All enrolled patients (n = 56)
                               Grade 3           Grade 4
Anemia                         17 (30%)                4 (7%)
Thrombocytopenia               12 (21%)              15 (27%)
Leukocytopenia                 15 (27%)              23 (41%)
Increased ALP                   1 (2%)                     0
Increased ALT                   2 (4%)                     0
Increased bilirubin             2 (4%)                     0


                                          Ottmann OG, et al. Blood. 2002;100:1965-1971.
 Imatinib Monotherapy in Relapsed/
Refractory Ph+ ALL (studies 109/114)
              Relapse After Allogeneic SCT


                                      Patients (n = 20)
    Hematological
                                              15 (75%)
    Response
      CR                                        11 (55%)
      CR - marrow                               4 (20%)
      PR                                               -
    Failure                                     5 (25%)
                        Ottmann OG, et al. Blood. 2001;98:589a-590a.
                        Ottmann OG, et al. Ann Hematol. 2002;81(suppl 2):S36-S37
                        Ottmann OG, Wassmann B. Best Pract Res Clin Hematol. 2003;15:757-769
                        Wassmann B, et al. Blood. 2004;103:1495-1498.
 Imatinib Monotherapy in Relapsed/
          Relapse After Allogeneic SCT
Refractory Ph+ ALL (studies 109/114)
Relapses after Ima-induced
CR (no.)                   11/15
Time to progression after  4 (2–7)
Ima-induced CR             months
Ongoing CR
                          4/15
 Patients (no.)
                          11 (6–23)
 Duration
                          months
                                                  SCT
                            10
                     10,000000


                                                                                                     Imatinib 600mg/d
                             1
                      1,000000
                                                                                   Relapse
  P190/ Gus copies




                           0.1
                      0,100000



                          0.01
                      0,010000



                      0,001000
                         0.001                                                                             CHT
                                                                                                          Vincristine + Prednisone
                        0.0001
                      0,000100
                                                                                                          Imatinib

                       0.00001
                      0,000010



                     0.000001
                     0,000001
                           09-set-99    27-mar-00   13-ott-00    01-mag-01   17-nov-01
                                 Sep-99 Mar-00 Jun-00       Oct-00      May-01    Nov-01 05-giu-02
                                                                                         Apr-02      22-dic -02      10-lug-03
                                                                                                                  Dec-02       Aug-04


PB blasts (x109/L) 39,2                    0       1,0          0           0         0      0                        0          0

BM blasts (%)                      95     <5       30          <5           <5        <5     35                      <5         <5

 Donor (XY)                       20/20   20/20   20/20       25/30        19/20     25/26
  mitosis

Ph+ mitosis                       15/15    -      12/20       0/20         0/20      0/20    5/30                    0/20       0/26
     Imatinib Monotherapy in
       Relapsed/Refractory
                      II Studies
Ph+ ALL: Phase allogeneic SCT 109/114
       Salvage before

46 Ph+ ALL patients with relapsed or refractory disease enrolled

   16 patients ineligible for SCT (age, comorbidity, or patient refusal)
   30 patients eligible for SCT

       18 patients treated with imatinib for refractory disease
       12 patients treated with imatinib for relapsed disease

           22 patients transplanted at a median of 67 days
           (range, 34–246 days) after starting imatinib



                                            Wassmann B, et al. Leukemia. 2002;16:2358-2365.
        Imatinib Monotherapy in
                Relapsed/
                 Considerations
           Refractory Ph+ ALL brief,
Imatinib produced pronounced, albeit
 hematologic responses in a majority of
 relapsed/refractory Ph+ ALL patients,
 including those who relapse after allogeneic
 SCT
Imatinib is also effective in enabling ~70% of
 relapsed/refractory Ph+ ALL patients to
 undergo subsequent allogeneic SCT
Imatinib used as salvage treatment shows a
                             Time progression
             1                2                   3                   4             5 N
                         N                                N               N     N      Ph+
 N       N   N                        N   N                       N                N
                     N       N                    N                             N
     N                                    N                   N                   Ph+    Ph+
 N           N           N   N                        N                   N          Ph+
                                  N                               N
      N      N                                N                             Ph+ Ph+       Ph+
                                                                                         Ph+
                     N   N   N            N               N
 N                                                    N         Ph+       Ph+
         N       N                N
                  N N            N        N                Ph+     Ph+
 N            N             N                 Ph+ Ph+
          N                        N                          Ph+
      N               N       N         Ph+         Ph+
  N          N N          N                              Ph+       Ph+
      N N           N             Ph+         Ph+
               N                                              Ph+
    N                        Ph+       Ph1           Ph+          Ph+
 N     N    N     N
               N        Ph+       Ph1        Ph1           Ph+
    N    N         Ph+                            Ph1              Ph+
 N                           Ph1       Ph1             Ph1    Ph+
     N        Ph+                            Ph1
                       Ph+        Ph1                             Ph+
 N       Ph+      Ph+                             Ph1      Ph1
                            Ph+        Ph1                    Ph1
    Ph+      Ph+      Ph+                              Ph1
                                Ph+          Ph1
Ph+     Ph+ Ph+                  Additional genetic defects Ph1
                  Ph+    Ph+   Ph+   Ph+    Ph+ Ph1 Ph1 Ph1Ph+
                                                   Ph+    Ph+
                                                                                     Ph1
     Sensitivity to Imatinib
  GENOMIC INSTABILITY OF Ph+
            CELLs
BCR/ABL protein causes ROS-oxidative
 DNA damage and its unfaithful repair

                  Nowicki et al, Blood 2004 -
 prepub on line



BCR/ABL protein translocates to the
 nucleus and its nuclear activity leads to
 the impairment of DNA damage repair
   BCR/ABL INTRACELLULAR
CONTENT OF ACUTE AND CHRONIC
       Ph+ LEUKEMIAS
                        m-bcr ALL

                        M-bcr ALL

                        M-bcr CML
BCR-ABL / CG NCN




                                         NS             NS              Does the high BCR/ABL
                                                                        content of Ph+ acute
                                             p=0.001     p<0.001        leukemias correlate with
                   n=   24    17   29   24    17   29   24    17   29
                                                                        their genomic instability?
                             ABL         B2M/100             GUS
POSSIBLE MECHANISMS OF
  IMATINIB RESISTANCE
 BCR/ABL gene dependent
  – Point mutations at catalytic site of BCR/ABL gene
  – BCR/ABL gene amplification
  – BCR/ABL gene up-regulation


 BCR/ABL gene independent

  – Increase of protein binding
  – Additional genetic events
  – Quiescent Ph+ cells
Imatinib Monotherapy as
 Maintenance treatment

 Newly diagnosed Ph+ ALL pts
(≤60y) after after chemotherapy

 GIMEMA LAL 0201 Protocol
Imatinib Monotherapy as Maintenance
             Treatment
       The GIMEMA 0201-A trial
             Induction Chemotherapy


                     Hem +/- PCR remission


                  Consolidation: HAM schedule


                     Hem +/- PCR remission


                     Ima (400 x 2) for 6 mo.


        Hem CR/ PCR positive        Hem CR / PCR negative


        HLA+             HLA-           Continue Ima


       Allo-SCT      Continue Ima
            The GIMEMA 0201-A trial
                Interim analysis


Patients                                  26
Type of BCR/ABL mRNA
  P190                                   18/26
  P210 (with or without P190)             8/26
Complete hematological remission after   26/26
induction
Q-RT-PCR (only P190 patients) after
consolidation
   <3 logs reduction                      10
                   MRD monitoring in 0201 - A trial

                 10                             GLIVEC


                  1


                 0,1
MRD Level




               0,001


              0,0001


             0,00001


            0,000001
                       0   2   4   6   8   10     12     14     16     18   20   22   24   26   28
                                                              months
                 MRD monitoring in 0201 - A trial
                                           GLIVEC

                                                                             relapse
                                                         relapse
                                                                                   relapse
                 10

                                                                                            DLI
                  1
MRD Level




                 0,1
                                                                                    DLI
                                                 Allo SCT
               0,001


              0,0001


             0,00001


            0,000001
                       0   2   4   6   8    10      12       14    16   18    20       22    24   26   28
                                                               months
                             Relapse probability according to MRD
                               stratification after consolidation
                                     (Ph+ ALL expressing P190)

                                                                 MRD               RC      Relapse
                                                                 reduction
                                                                       >3 logs       7          1
                   100                                                                         1 patient
                                                                     *Abl mutation detected in 10*
                                                                       <3 logs      2
Relapse rate (%)




                    80

                    60

                    40
                                                             p = .03
                    20

                     0

                         0       4      8     12        16      20          24

                                             (months)
      Imatinib Monotherapy as
       Maintenance Treatment
              Considerations


 Imatinib given as single agent is an
 highly effective post-consolidation
 therapy

 In patients with P190BCR/ABL gene
 unsatisfactory molecular response rate
 to conventional CHT is a powerful
 predictor of subsequent resistance
MRD-Triggered Imatinib Post-SCT
MRD-Triggered Imatinib After SCT
Study Design



 Chemo-               CR and
 therapy
               CR SCT                Imatinib
                      MRD+




                           Wassmann B, et al. EHA 2004. Abstract 612.
MRD-Triggered Imatinib After SCT
Patient Features

 Patients                                   27

 Male /female                              14/13

 Age (y)                                48 (16–63)


 Allogeneic/autologous SCT                 24/3
 Graft-vs-host disease at entry             11

 Months from SCT to BCR-ABL detection   3.6 (0.5–18)
 Months from SCT to start of imatinib   4.4 (1–19)


                                             Wassmann B, et al. EHA 2004. Abstract 612.
          MRD-Triggered Imatinib After SCT

Interim Results (Median follow-up of 15.6 months)


                        MRD-      MRD-
                       negative  positive
                                                                   P-value
                      conversio persistenc
                           n         e
Patients               14 (52%)  13 (48%)
Relapse                2 (14%)   12 (92%)
Median                   28.6
                                3 months                           <0.0001
TTP                    months                       Wassmann B, et al. EHA 2004. Abstract 612
   MRD-Triggered Imatinib After SCT

• Molecular response to imatinib therapy in Ph+
  ALL patients with MRD after SCT discriminates
  between those likely to relapse and those likely
  to have sustained molecular remissions

• Early assessment of BCR-ABL transcripts in
  this setting may identify a subset of patients
  requiring treatment in addition to or other than
  imatinib


                                   Wassmann B, et al. EHA 2004. Abstract 612.
Imatinib Monotherapy (600
 mg/d) as Induction in the
          Elderly
              Imatinib-based Treatment of de novo
                         Ph+ ALL (>55 y)
                       Treatment schedule
                                     Cons.I        Cons.II        Reind.                 Cons.III                     Cons.IV          Cons.V
                           28 days




                                                                            (        )                   (        )

     Pre-             d7      4       6             13       17   20            24           28              34         37        41   44        48   52
    Phase
    Day 1-5      R
     BM                    28 days

(   ) optional              Induct
                           Day 7-35
      PS
      I.th.



                                                                                         (    )                          (    )

                      d7      4       6       10             17        21       24           28     32                       38   41             48   52

                                                                  Treatment week (not to scale)

                 Intrathecal MTX 12mg                        I.th. MTX 12mg Ara-C 40mg Dex 4 mg
                                                                                                                                  MRD analysis
                     IDMTX                    VM26 Ara-C                        6-MPMTX* (optional)


                                                                                                                      Wassmann B, et al. Ann Hematol. 2003;82:716-720.
Imatinib-based Treatment of de
               novo
                     (>55
        Ph+ ALL Inductiony)
         Response to

                     Chemotherapy   Imatinib
                        (n = 17)     (n = 15)

Evaluable patients        15             12

 CR                     8 (53%)     11 (92%)
 PR                     1 (7%)       1 (8%)
 NR                     6 (40%)           0
Crossover (no.)           4               -
 CR                        -          3 (75%)


                                    Ottmann OG, et al. EHA 2004 abstract #322
 Imatinib in de novo Ph+ ALL
             (>55 y)
Severe Complications and Mortality

                        Imatinib     Chemotherapy
                         (n = 15)       (n = 17)

 Severe infections         0           8 (47%)
  Pneumonia                            5 (29%)
  Sepsis                               3 (18%)
 Induction death           0           2 (12%)



                                       Ottmann OG, et al. EHA 2004. Abstract 322.
Imatinib monotherapy in de novo Ph+
            ALL (>55 y)
              Considerations

 • Induction imatinib monotherapy produces
   CR rate >90% in elderly patients with Ph+
   ALL
 • Induction imatinib appears to be superior to
   standard chemotherapy induction in this
   population with respect to:
   – CR rates
   – Induction mortality
   – Infectious complications
 • Extended administration of imatinib and
                                 Ottmann OG, et al. EHA 2004. Abstract 322
   Combination Therapy:

Imatinib Plus Hyper-CVAD

 Newly diagnosed Ph-positive
Acute Lymphoblastic Leukemia
Imatinib + Hyper-CVAD: Regimen
   Hyper-CVAD Alternating With MTX +
    Ara-C
     – Imatinib 400 mg days 1–14
     – 8 cycles
     – Risk-adapted IT therapy


   Maintenance x 12 months
     – Imatinib 600 mg daily
     – Vincristine and prednisone monthly
     – Hyper-CVAD + imatinib months 6 and 13


   Allogeneic SCT if Eligible      Thomas DA, et al. Blood. 2004;103:4396-4407
        Imatinib + Hyper-CVAD:
         Response to Therapy
                     Regimen

                    Imatinib+H-CVAD   H-CVAD              VAD
                         (n = 20)     (n = 50)          (n = 31)


Response                 100            94                 61
CR                        —             —                  13
PR                        —             6                  26
Resistant
Courses to CR
 1                        93            70                 84
 2                         7            13                 16
>2                        —             17                 —
Median Days to CR         19            20                 24

                                        Thomas DA, et al. Blood. 2004;103:4396-4407.
                                               Imatinib + Hyper-CVAD:
                                           Remission Duration by Treatment

                                 1.0

                                                                                                   No.       No. Failed
                                                               Hyper-CVAD+ imatinib*               20               2
Remission Duration Probability




                                 0.8
                                                               Hyper-CVAD                          47             33
                                                               VAD                                 19             14
                                 0.6                           *Note: Median time to allogeneic SCT = 3.5 months (n = 10)

                                                P<0.001

                                 0.4




                                 0.2




                                 0.0
                                       0   12      24     36              48            60              72              84
                                                               Months

                                                                                              Thomas DA, et al. Blood. 2004;103:4396-4407.
Imatinib + Hyper-CVAD: Toxicity
          (91 Postinduction Courses)
                              Grade 1–2           Grade 3–4
                                 %                      %
Infections                                              25
Peripheral neuropathy            30                      5
Fatigue                          30                     10
Increase in bilirubin            25                     —
Increase in transaminases        25                     —
Increase in creatinine           25                     —
Fluid retention                  25                      5
Stomatitis                       25                     —
Fracture (fibia, vertebral)      —                      10
Deep vein thrombosis             —                      10
Hyponatremia                     —                       5

                                          Thomas DA, et al. Blood. 2004;103:4396-4407.
          Imatinib + Hyper-CVAD
                Considerations

• Administration of imatinib with
  intensive CT to adults with Ph+ ALL
  appears feasible
• Imatinib plus hyper-CVAD appeared to
  improve DFS and OS relative to earlier
  regimens without increasing toxicity
• Imatinib plus hyper-CVAD was
  associated with a higher rate of
                                 Thomas DA, et al. Blood. 2004;103:4396-4407.
    Imatinib Plus IFN-


 Patients with advanced stage
Ph+ ALL not eligible for SCT or
 other aggressive treatments
                   Imatinib + IFN alfa-2a in Ph+ ALL
                         Treatment Schedule


                      CR, MRD+,      CR, MRD+,                    Refractory
                     No prior SCT    Prior SCT                    to imatinib
                        (n = 4)        (n = 1)                      (n = 1)
  Imatinib
400 mg/d (n = 1)      Start IFN-     Start IFN-               Start IFN-
      or            1 MU 3/week    3 MU 3/week              5 MU 7/week
600 mg/d (n = 5)
                                                                            1 week

                     Escalate to                                 Reduce to
                    3 MU 3/week                               3 MU 3/week




                                              Wassmann B, et al. Leukemia. 2003;17:1919-1924.
                 Imatinib + IFN alfa-2a in Ph+ ALL

 Patient Characteristics


                         Status                               Status
Pt.     Age/Se                        Response
 #        x          at treatment                         at the end of
                                     to treatment
                          start                               study
1        64 M        First relapse   CHR, MRD+            CR (+21 mos)
2        60 F        CR1, MRD+       CHR, MRD+            CR (+11 mos)
3        74 M        CR1, MRD+       CHR, MRD+            CR (+21 mos)
4        47 F*       First relapse   CMR, MRD+               Relapse
    *Prior SCT
                        Primary
5         71 F                       CHR, MRD+            CR (+13 mos)
                      refractory             Wassmann B, et al. Leukemia. 2003;17:1919-1924
     Imatinib + IFN alfa-2a in Ph+ ALL

                Considerations



• Low-dose IFN- plus imatinib is a promising
  option for adults with advanced Ph+ ALL
  who are not candidates for aggressive
  approaches, such as allogeneic SCT
• This combination may produce prolonged
  hematologic and molecular remissions in a
  subset of patients
                                 Wassmann B, et al. Leukemia. 2003;17:1919-1924.
 Role of Imatinib in Adult Ph+ ALL
               Summary
• High genetic instability of Ph+ ALL
  patients
• Combination of Imatinib with intensive
  CHT appears feasible
• Encouraging results from treatments
  based on combination of Imatinib with
  CHT
• Optimal strategies for including
CEINGE
University of Naples ―Federico II‖

Diagnostic Onco-Hematology Unit      Italian Cooperative Study Group on CML -
                                                GIMEMA - CML working party
- B. Izzo                            •S. Tura
- C. Quintarelli                     •M. Baccarani
- M. Intrieri                        •G. Martinelli
- B. De Angelis                      •G. Rosti
- B. de Divitiis
- A. Del Giudice                     University of Turin
- F. Musella
                                     Department of Internal Medicine and Hematology
Clinical Hematology Unit
                                     G. Saglio
                                     D. Cilloni
B. Rotoli
                                     G. Rege Cambrin
L. Luciano                           E. Gottardi
C: Selleri
M. Picardi
A. Camera