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
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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

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DLI in the 1990s
Slavin CritRevOnc/Hem. 200346139
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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

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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

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Therapeutic DLI
Tomblyn BMT 2008. 1-11 ePub
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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
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Collins et al.

• CML responds the best
• aGVHD 60, cGVHD 60
• GVHD correlates with response

Collins JCO 9815433
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Collins et al.
Collins JCO 9815433
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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

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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
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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
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DLI for Myeloid Malignancies
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CML
Tomblyn BMT 2008. 1-11 ePub
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CML
Tomblyn BMT 2008. 1-11 ePub
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Simula et al.
Simula et al. Leukemia 200721943
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Simula et al.
Simula et al. Leukemia 200721943
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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

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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

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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
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AML
Schmid et al. JCO 2007254938
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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

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MDS
Responders were high risk MDS with excess blasts
and developed GVHD
Campregher et al. BMT 200740965 Depil et al.
BMT 200433531
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MDS
Campregher et al. BMT 200740965
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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
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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

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DLI for Lymphoid Malignancies
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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
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Multiple Myeloma
Tomblyn BMT 2008. 1-11 ePub
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Multiple Myeloma
Tomblyn BMT 2008. 1-11 ePub
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DLI in MM

• GVHD correlates with response
• CD3 dose gt1x108/kg and CR at time of allo HCT
  predicts response

Lokhorst Blood 20041034362
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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
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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?

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Cytoreductive therapy prior to DLI increases GVHD
Miller et al. Blood 20071102761
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Engineered DLIs

• CD8 depletion
• Ex vivo activated CD3/CD28
• Suicide gene modified T-cells
• CAR modified T-cells

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Conclusion
EBMT 2001 review
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Hodgkins

• 2 reports in HD, n10
• 6 with SD(2) or CR(4)
• 4 with pre-DLI chemo
• 4 with G-CSF mob. product

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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

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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

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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

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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