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DLI for the Treatment of Hematologic Malignancies

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61 yo WM with CMML dx 11/06, evolved to AML 7/07, nl cytogenetics. Bu/Cy MUD 10 ... October 1979) Graft-versus-leukaemia reactivity induced by alloimmunisation ... – PowerPoint PPT presentation

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Title: DLI for the Treatment of Hematologic Malignancies


1
DLI for the Treatment of Hematologic Malignancies
  • Mark A. Schroeder
  • 9/5/08

2
Objectives
  • Review a case
  • History and DLI rational
  • Review DLI indications
  • Review DLI results for heme malignancies

3
Case
  • 61 yo WM with CMML dx 11/06, evolved to AML 7/07,
    nl cytogenetics
  • Bu/Cy MUD 10/10 PBSC male donor
  • D30 94 donor 6 recipient
  • Late graft failure at D100 (36 donor)
    Hypocellular marrow with no evidence of leukemia
  • Infectious complications
  • Received 3 G-mobilized DLIs with Fludarabine
    conditioning - no response
  • Underwent second MUD with Bu/TBI conditioning and
    died of treatment related mortality

4
DLI rationale
  • Augment graft-versus-tumor effect
  • T-cells mediate GVL and GVHD
  • Van Lochem et al. BMT 199210181
  • Isolated T-cell clones recognizing tumor, host,
    both or neither
  • Tumor determines effector cell phenotype
  • CD4,CD8,NKT etc…

5
DLI rationale
Weiss et al. J Immun 19941532562
6
History of DLI
  • 1960s-70s - mouse models
  • Bortin et al. Nature 281, 490 - 491 (11 October
    1979) Graft-versus-leukaemia reactivity induced
    by alloimmunisation without augmentation of
    graft-versus-host reactivity
  • Weiden et al. NEJM 19813041529
  • cGVHD correlates with anti-leukemic effect and
    improved survival
  • 1987 Slavin et al. ASH abstract
  • First successful clinical application of DLI
  • 2 yo boy with pre-B ALL relapsed 1 month post sib
    allo

7
DLI in the 1990s
Slavin CritRevOnc/Hem. 200346139
8
Indications
  • Treat tumor recurrence
  • Prophylactic strategy to prevent disease relapse
  • Augment T-cell deplete or RIC transplants
  • Treat mixed chimeras
  • Used in nearly all diseases for which Allo HCT is
    performed

9
Heterogeneous literature
  • Retrospective analyses with few prospective
    results
  • Cell collection methods mobilized vs non
  • Timing post chemo, prophylactic, relapse
  • Cell dose
  • Cell sub-type infused

10
Therapeutic DLI
Tomblyn BMT 2008. 1-11 ePub
11
Therapeutic DLI
Tomblyn BMT 2008. 1-11 ePub
12
Therapeutic DLI
Tomblyn BMT 2008. 1-11 ePub
13
Therapeutic DLI
Tomblyn BMT 2008. 1-11 ePub
14
Collins et al.
  • CML responds the best
  • aGVHD 60, cGVHD 60
  • GVHD correlates with response

Collins JCO 9815433
15
Collins et al.
Collins JCO 9815433
16
Therapeutic DLI Summary
  • Majority CML patients (40)
  • No standard cell dose or pre-DLI treatment
  • Pre-DLI chemo was given to 90/495 (18) patients
  • Improved response for CML patients
  • 139/197 (71) responded
  • 73/298 (24) other heme malignancies

17
Therapeutic DLI summary
  • GVHD improved response rates and survival
  • gt 1x107 CD3/Kg increases risk of aGVHD
  • Longer time from transplant to relapse correlates
    with response to DLI

Dazzi Blood 2000962712
18
Therapeutic DLI summary
  • Percent donor chimerism gt50 increases CR and
    GVHD rate1
  • Mixed chimeras increase risk for post-DLI bone
    marrow aplasia2
  • TCD HSCT receiving DLI for relapse have greater
    response3

1. Schattenberg Leuk Lymphoma199932317 2.
Tomblyn BMT 2008. 1-11 ePub 3. Kolb Blood
1995862041
19
DLI for Myeloid Malignancies
20
CML
Tomblyn BMT 2008. 1-11 ePub
21
CML
Tomblyn BMT 2008. 1-11 ePub
22
Simula et al.
Simula et al. Leukemia 200721943
23
Simula et al.
Simula et al. Leukemia 200721943
24
CML conclusions
  • Over 500 patients in large series and 1/2 had
    only molecular or cytogenetic relapse
  • No salvage therapy prior, except hydrea
  • Cell dose varied
  • Higher initial cell dose increases mortality
  • EDR is well tolerated

25
CML conclusions
  • mCR in 405/527 (77)
  • Response is dose dependent
  • OS at 3 yrs 53-95
  • TKIs may augment effects of DLI and is under
    investigation

26
AML
  • Only one large analysis focusing on DLI for
    relapsed AML by EBMT
  • 399 AML patients, 171 DLI and 228 no DLI for
    post-transplant relapse
  • Median CD3 107/kg and 74 non-escalated
  • 43 aGVHD
  • 73 received chemo prior to DLI
  • 67 had active AML at DLI
  • 2yr OS 21/-3 with DLI and 9/-2 no DLI

Schmid et al. JCO 2007254938
27
AML
Schmid et al. JCO 2007254938
28
AML predictors of improved survival with DLI
  • Low tumor burden, lt35 blasts
  • Remission at time of DLI
  • Favorable cytogenetics
  • Female
  • Agelt35
  • Relapse gt5months post HSCT

29
MDS
Responders were high risk MDS with excess blasts
and developed GVHD
Campregher et al. BMT 200740965 Depil et al.
BMT 200433531
30
MDS
Campregher et al. BMT 200740965
31
CMML
  • N17
  • 14 MRD, 3 URD
  • 11 pts evolved to AML prior to transplant
  • DLI dose 30-40 x 107 CD3/kg
  • 5 patients underwent DLI
  • 2 with relapsed CMML achieved CR x 15months

Elliott et al. BMT 2006371003
32
AML and MDS conclusions
  • Small sample size
  • Inconsistent pre-DLI treatment
  • Varied DLI cell dose
  • Potential role in high risk MDS
  • Potential role in low risk AML or MRD

33
DLI for Lymphoid Malignancies
34
ALL
  • N44
  • 30 MRD, 4MmRD, 10 MUD
  • Chemo in 28/44
  • CD3 1x106-1x108/kg
  • Non-responders did not respond to second DLI

Collins et al. BMT 200026511
35
Multiple Myeloma
Tomblyn BMT 2008. 1-11 ePub
36
Multiple Myeloma
Tomblyn BMT 2008. 1-11 ePub
37
DLI in MM
  • GVHD correlates with response
  • CD3 dose gt1x108/kg and CR at time of allo HCT
    predicts response

Lokhorst Blood 20041034362
38
NHL
  • DLI works best in low grade lymphomas
  • Unclear if pre-DLI therapy is needed
  • Unclear benefit for bulky disease or rapidly
    progressing

Bloor et al. BBMT 20081450 Russell et al. BMT
200536437
39
Unanswered questions
  • Who?
  • CML, MM, AML/MDS, ALL, lymphomas
  • When?
  • Early after relapse
  • Prophylactic in TCD HSCT
  • After cytoreductive therapy?
  • How much and what?
  • One or multiple doses
  • Composition?

40
Cytoreductive therapy prior to DLI increases GVHD
Miller et al. Blood 20071102761
41
Engineered DLIs
  • CD8 depletion
  • Ex vivo activated CD3/CD28
  • Suicide gene modified T-cells
  • CAR modified T-cells

42
Conclusion
EBMT 2001 review
43
Hodgkins
  • 2 reports in HD, n10
  • 6 with SD(2) or CR(4)
  • 4 with pre-DLI chemo
  • 4 with G-CSF mob. product

44
NHL
  • Russell et al. BMT 200536437
  • N17
  • Disease relapse (10), refractory disease (7)
  • CLL (4), MCL (4), FL (3), DLCL (4), Richters (1)
  • 15 received campath RIC
  • 9 received chemo pre-DLI
  • CD3 2x107 related and 2x106 URD
  • 11/17 achieved CR (FL, CLL, MCL)
  • 3 yr PFS 52
  • 3 yr OS 58
  • 44 aGVHD

45
NHL
  • Bloor et al. BBMT 20081450.
  • N28
  • 24 MRD, 4 URD
  • 26 RIC
  • CLL (6), MCL (3), FL (14), transformed FL (5)
  • Indication PD (17), mixed chim. (11)
  • Pre-DLI treatment 5-rituxan, 2 chemo

46
NHL
  • Bloor et al. BBMT 20081450.
  • Escalating CD3 treatment schema
  • 1x106/kg, 3x106/kg,10x106/kg, 30x106/kg,
    100x106/kg
  • Median 2 (range 1-5) DLIs
  • 13/17 PD pts with CR
  • Median time to response 12 months
  • Est 5 yr PFS 76, OS 88
  • Mixed chimeras 92 donor by 6.7 months
  • GVHD 15 acute and 31 chronic

47
pDLI for MM
  • Alyea et al. Blood 200198934
  • N24. Myeloablative MRD followed by DLI 6-9mos
    post
  • 55 CR, 36 PR, median time to response 6.4mos
  • Peggs et al. BBMT 20039257
  • N20. RIC in vivo TCD HCT (12 MRD, 8URD)
  • DLI at 6 mos then Q3months escalated PRN
  • 2yr PFS 25 and 5/5 patients with GVHD responded
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