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on behalf of the Sub-Committee

Disease-Specific Methods and Strategies for Monitoring Relapse Following Allogeneic Stem Cell Transplantation Pediatric Acute Lymphoblastic Leukemia. on behalf of the Sub-Committee. Peter Bader, Wendy Stock, Andre Willasch, Alan Wayne. Surveillance of Remission. Two principle approaches:

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on behalf of the Sub-Committee

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  1. Disease-Specific Methods and Strategies for Monitoring Relapse Following Allogeneic Stem Cell TransplantationPediatric Acute Lymphoblastic Leukemia on behalf of the Sub-Committee Peter Bader, Wendy Stock, Andre Willasch, Alan Wayne

  2. Surveillance of Remission • Two principle approaches: • Chimerism • Characterization of post transplant hematopoiesis • MRD • Direct detection of the underlying malignancy

  3. Hematopoietic Chimerismin Children with ALL Bader et al., J Clin Oncol 33: 1696 (2004)

  4. Studies on Chimerismand Intervention

  5. Conclusions I • Immunotherapy (WD of immunosuppression, DLI) is principally effective as pre-emptive treatment • Chimerism can be used as surrogate marker for identifying patients at risk for impending relapse • However: • Not in all patients! Additional role for • MRD?

  6. Retrospective Studies - MRD prior to SCTLiterature

  7. Prospective Study: MRD Prior SCT ALL REZ BFM Group: CR2 EFS CIR EFS CI Bader et al.: JCO 2009 MRD < 10-4: n = 46; cens.= 29; pEFS = .60  .08 CI (relapse) = .13  .06 ≥ 10-4: n = 45; cens.= 14; pEFS = .27  .07 CI (relapse) = .57  .08 p = .0004 p < .001

  8. Conclusions II • MRD prior to stem cell transplantation has a profound impact on post transplant outcome! • What adds MRD post transplant?

  9. Retrospective Studies -MRD Post SCTLiterature

  10. Prospective StudyBFM Group

  11. MRD - Highest Level post SCTAll Patients pEFS pRFS MRD < 10E-6 MRD < 10E-6 MRD <10E-4 - 10E-6 MRD <10E-4 - 10E-6 MRD ≥ 10E-4 MRD ≥ 10E-4 < 10-6: n = 46; cens.= 26; pEFS = .55  .08 n = 46; cens.= 37; pRFS = .77  .07 ≥ 10-6- <10-4n = 25; cens.= 12; pEFS = .48  .10 n = 25; cens.= 17; pRFS = .62  .11 ≥ 10-4: n = 21; cens.= 03; pEFS = .09  .06n = 21; cens.= 03; pRFS = .11  .07 P=0.002P=0.000

  12. Conclusions III andSummary • MRD assessment in BM post transplant is predictive for relapse • Serial BM investigations are warranted. • Current working recommendations of the BFM: days 30, 60, 100, 200, 300, 365, at 18 months and 24 months. • Summary: • Patients with mixed chimerism have a high risk for relapse • Patients, who become/remain MRD positive >10-4, have a very high risk to develop relapse • Additional treatment in these patients is warranted

  13. MRD in adults with ALL • Shown to be useful predictor of DFS in many studies (non-transplant) • Independent prognostic feature • Mostly using PCR techniques – IgH/TCR, fusion genes • “Informative” assay available in 60-90% of patients • Early CR time-points predictive of outcome: from 4-22 weeks following initiation of treatment • Fewer studies evaluating role of MRD in setting of alloSCT

  14. AlloSCT improves outcome of MRDpos in CR1 but much room for improvement SCT or H/C-auto vchemo SCT or H/C (n = 36) rest (n = 18) Bassan, R. et al. Blood 2009;113:4153-4162

  15. MRD following alloSCT in Adults with ALL

  16. Achievement of Molecular Remission Prior to AlloSCT is Important in Ph+ ALL Dombret et al: Blood 100:2002 MRD status prior to transplant predicts DFS

  17. Combination of ChemoRx + Imatinib Produces Molecular Remissions

  18. Is Transplant in CR1 Still Treatment of Choice for Ph+ ALL? Transplanted patients No transplant Yanada, M. et al. J Clin Oncol; 24:460-466 2006

  19. Imatinib Treatment of Molecular Relapse with Following Allo-SCT for Ph+ ALL Wassmann, B. et al. Blood 2005;106:458-463

  20. Summary • MRD detection both prior to and following alloSCT for adults with ALL is associated with poor DFS • Clinical interventions based on MRD measurements suggest utility but data are very limited: • Allocation to alloSCT in CR1 • Post-transplant intervention to prevent relapse • Targeted therapy (e.g. imatinib) following transplant • Challenge: implementation of standardized MRD assays that can be done in “real-time” • IgH/TCR qPCR assays are laborious • Data on flow cytometric measurements of MRD in adults with ALL are lacking

  21. Disease-Specific Methods and Strategies for Monitoring Relapse Following Allogeneic Stem Cell Transplantation Chronic Lymphocytic Leukemia Sebastian Böttcher, Issa Khouri, Peter Dreger

  22. Overview • Techniques • MRD kinetics • Clinical significance of MRD

  23. Techniques

  24. ASO IGH qPCR and MRD flow in CLL- Comparative analysis in 530 samples - Böttcher, Leukemia, 2009

  25. n = 43 n = 106 IgH-consensus PCR- Sensitivity - Böttcher, Leukemia, 2004

  26. n = 43 n = 106 IgH-consensus PCR- Sensitivity - Böttcher, Leukemia, 2004

  27. Techniques for MRD in CLL

  28. MRD kinetics

  29. MRD patterns after allogeneic SCT I SCT ↓ CSA red. ↓ Ritgen, Leukemia, 2008

  30. MRD patterns after allogeneic SCT II SCT ↓ CSA red. ↓ Ritgen, Leukemia, 2008

  31. MRD patterns after allogeneic SCT III SCT ↓ CSA red. ↓ DLI ↓ Ritgen, Leukemia, 2008

  32. MRD patterns after allogeneic SCT

  33. Prognostic significance

  34. Prognostic significance MRD +12 months after alloSCT MRD –ve (1/27) MRD +ve (5/11) Dreger, ms. in prep.

  35. MRD +ve (8/13) MRD –ve (1/16) Prognostic significance MRD +6 months after alloSCT Farina, Haematologica, 2009

  36. MRD kinetics after RIC alloSCT * and Moreno personal communication 2009

  37. Summary: MRD after alloSCT • Techniques: have to be quantitative & sensitive ( 10-4) • MRD flow • ASO IgH qPCR • Retrospective analyses show that: • delayed, likely GVL-mediated MRD clearance occurs • MRD clearance: • predicts of very low relapse risk • is durable • might serve as surrogate marker for cure • MRD persistence after CsA tapering can be used as trigger for preemptive immun-therapy (DLI) • Treatment aim to be tested prospectively : MRD negativity (< 10-4) 12 months after alloSCT

  38. Perspective: MRD after alloSCT • Test MRD negativity (< 10-4) 12 months after alloSCT prospectively • Treat MRD after alloSCT using • DLI • alternative treatment options (e.g. Rituximab) • Delineate mechanisms of MRD clearance

  39. Relapse Monitoring after Allogeneic Stem Cell Transplantation for Lymphomas Issa Khouri, Julie Vose

  40. Cheson, JCO 2007

  41. “False Positive” PET Scans in Therapy of Lymphomas • 996 PET scans in 706 patients with lymphoma • PET to evaluate recurrence after treatment • 31/134 scans (23.1%) were False Positive • 7 brown fat • 5 thymic hyperplasia • 4 muscle contraction • 4 non-specific inflammation of the colon • 4 pulmonary/mediastinal inflammation • 4 intestinal: gastritis (2), colitis (2) • abscess, lactating breast, H. zoster (1 ea) Castellucci et al. Nuc Med Commun 26: 689-794, 2005.

  42. BM Involvement Present No BM Involvement, GCSF(+) Examples of Bone Marrow Findings on PET in Two Patients with NHL Message: The films look the same!

  43. Survival in NHL Relapsing post AlloUsing CT Criteria Khouri et al. unpublished data

  44. Detection Early relapse in Lymphoma • Quantitative PCR -IgH in b-cell disease -t(11,14) in MCL and t(14,18) in FL -t-cell receptor in t-cell lymphoma • Chimerism

  45. Chimerism Mixed Full Donor P value No. of patients 17 16 CR: PR at NST,% 29 71 63 38 Achieved CR, no. (%) 17 (100) 16 (100) Chronic GVHD, no. (%) 10 (59) 11 (69) No. of relapse, (%) 1 (6) 1 (6) Chimerism at day 90 and Outcomepost NST 0.06 0.5 Khouri, Blood 2008

  46. Donor Lymphocyte Infusion with Rituxan (for b-cell) after Allo Yes 1. Failure of disease response 2. Responding, but failing to achieve CR at 6 months No 1. If stable mixed chimera (SMC) in the absence of measurable disease or disease progression 2. SMC definition: - > 50% donor cells - No significant decrease of >20% on two consecutive analysis

  47. Disease specific Monitoring of Relapse after Allogeneic Hematopoietic Cell Transplantation Multiple Myeloma NCI Workshop 1./2.-11.2009 Nicolaus Kröger

  48. Conventional techniques for Monitoring • Bone marrow aspiration: infiltration often underestimated • Serum/24h urine electrophoresis (agarose gel or capillary zone): lowest detectable level of M-component: 0.2 - 0.6 g/L • Immunofixation (serum/urine): lowest detectable level of M-component: 0.12 - 0.25 g/L • Free light chain assay (κ/λ ratio) : useful in light chain disease and non-secretory, necessary to determine sCR, early response assessment due to short half time (6h)

  49. Imaging monitoring • More than 80% of the pts develop osteolytic bone lesions • The hallmark of myeloma bone disease is an increased osteoclastic bone resorption and an exhausted osteoblast function resulting in a reduced bone formation even in patients in complete remission • Standard: conventional radiology as skeletal survey involving cervical, thoracic and lumbar spine, skull, chest, pelvis, humeri and femora • Disadvantage: low sensitivity, no exact response assessment • CT: high sensitivity, but higher radiation dose • MRI: high sensitivity, no radiation dose, detect extramedul-lary disease • PET-CT: highest sensitivity for extramedullary disease

  50. Flow-cytometry • Flow cytometry has become an easy applicable method to detect residual myeloma cells The European Myeloma Network recommends a minimal panel including • CD19, CD56, CD20, CD117, CD28 and CD27. • Plasma cell gating should be based on CD38 vs. CD138 expression • This method is less sensitive (10-4) than allele-specific oligonucleotides PCR (ASO-PCR) Rawstron 2008

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