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Amyloidosis: Choices In the use of Conventional & High Dose Therapy

Scottsdale, Arizona. Rochester, Minnesota. Jacksonville, Florida. Amyloidosis: Choices In the use of Conventional & High Dose Therapy. Stem cell transplant for AL. Why does stem cell transplant work ? Is it better treatment or Do we just select the best patients to offer transplant ?. 100.

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Amyloidosis: Choices In the use of Conventional & High Dose Therapy

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  1. Scottsdale, Arizona Rochester, Minnesota Jacksonville, Florida Amyloidosis: Choices In the use of Conventional & High Dose Therapy

  2. Stem cell transplant for AL Why does stem cell transplant work ? Is it better treatment or Do we just select the best patients to offer transplant ?

  3. 100 90 80 70 60 Percent alive 50 40 PBSCT Cases (N=63)Controls (N=63) 30 20 P < 0.001 10 0 Years follow-up 0 1 2 3 4 PBSCT for AL Case Control: OS from Diagnosis Dispenzieri, et al, Blood, 2004. 103(10): p. 3960-3

  4. Transplantation Organ response Organ responses take timeMedian 5-6 mo Day 100, hematologic CR Complete organ response Year 0 1 2 3 4

  5. Averaged change in proteinuria after stem cell transplantation. Differences in proteinuria became and remained significant after 3 months.

  6. Response to SCT

  7. Treatment-related mortality in PBSCT (any death occurring before day 100 post transplant) • Cox multivariate analysis: • Number of organs involved • Serum creatinine • Gertz BMT 2004

  8. Experience Matters: CIMBTR results by year of transplantation

  9. Prognostic Factors for SCT for AL • Number of organs clinically involved • Cardiac chemistries • Troponins • BNP • FLC assay • Absolute level • Response to Tx • Serum albumin and alkaline phosphatase

  10. High dose 83 12% 22% 13% 37% 72% Total Lo dose 42 19% 21% 2% 24% 48% Grand Total 125 14% 22% 10% 33% 64% AL Amyloid Responses after PBSCT Gertz et al BMT, 2004 Conditioning N Death <d+100 Heme only Organ only Both Any

  11. 1 .8 .6 P=0.05 %, Surviving .4 High Intensity .2 Intermediate Intensity 0 0 10 20 30 40 50 60 70 80 Months Amyloid Transplant Survival Dose Intensity Gertz et al BMT, 2004

  12. Myeloma causes of Death relate to Tumor Mass In AL death is driven by organ Failure/dysfunction If the M protein falls does this translate to improved survival ? How much of a reduction is sufficient to impact outcomes ? Should M protein be used as a trial endpoint? Does Tumor Mass Reduction Matter: Why does transplant work ?

  13. AL TRANSPLANT POPULATION • Median 24-hour urine protein loss was 3.4 g/day • One-, 2-, and 3-organ involvement occurred in 48%, 38%, and 14% of patients, respectively • D+100 mortality 11% • CR IF- S&U & NL FLC ratio • PR 50% S&U M component & involved FLC

  14. AL TRANSPLANT POPULATION • 69% of patients had renal involvement, 51% had cardiac involvement, 11% had peripheral nerve involvement, and 16% had hepatic involvement. • Echocardiographic analysis showed a median septal thickness of 12 mm and a median ejection fraction of 65%. • Median % of bone marrow plasma cells was 7, range from 1 - 78

  15. Overall Survival of 282 Transplanted Amyloid Patients Stratified by Hematologic Response CR (n=93) PR (n=108) Surviving NR (n=81) Months CP1245979-1

  16. INTERPRETING AL RESPONSE/SURVIVAL • Skew in the data since with an 11 % mortality rate a substantial number of patients become inevaluable for response • Landmark analysis at 6 months to exclude early deaths from advanced organ failure gives a better assessment of responses impact on outcome

  17. Landmark Analysis of Amyloidosis Patients that Survived 6 Months Stratified Based onHematologic Response CR (n=86) PR (n=91) Surviving NR (n=36) P=0.001 Months CP1245979-2

  18. Response Translates to Survival • Do patients with echocardiographic evidence of Cardiac AL also benefit from transplant? • Recognizing that patients with cardiac AL are a highly selected group (milder)…

  19. Overall Survival of 151 TransplantedCardiac Amyloid Patients Stratified byHematologic Response CR n=42 n=56 Surviving NR n=53 P<0.001 Months CP1245979-3

  20. Landmark Analysis of Cardiac AmyloidPts that Survived 6 Months Stratified Basedon Hematologic Response n=38 n=39 Surviving n=18 P<0.001 Months CP1245979-4

  21. DETERMINANTS OF RESPONSE • There was a difference in response rate based on conditioning intensity (p<0.01) and age (p=0.046). However, since this was not a prospective study, patients who received higher intensity therapy tended to be younger and have less extensive organ involvement particularly cardiac

  22. What this study does tell us • In Amyloidosis response is an appropriate surrogate for survival • Response is a legitimate endpoint for Clinical Studies of Therapy including cardiac AL • Complete Responders live longer than partial responders • Partial responders live longer than non responders even correcting for early death by landmark

  23. What this study does not tell us • Is Transplant any better than Chemotherapy ± Novel Agents? • What role does patient selection have in determining response? • Should patients who fail to achieve CR receive post transplant consolidation to move them to CR

  24. Autologous SCT Versus Oral M-DEX for AL • 100 patients randomized to Auto SCT with MEL 140 or 200 mg/m2 or oral M-DEX • No difference between the 2 arms for hematologic responses (65 & 64%). • Median survival is 56.9 months M-Dex arm & 48.6 months for the ASCT arm (p=0.2) • TRM 24%(SCT) vs 2% (M-DEX) • In the ASCT arm only 37 pts (74%) received the planned treatment Jaccard , ASH 2005

  25. Introduction Conventional Dose Therapy • Majority of patients not eligible for PBSCT • Age • Organ dysfunction • Outcomes with conventional treatment poor • Treatments for amyloid evolve from myeloma therapy

  26. Mel - Dex • First therapy to show significant improvement over MP • Phase II multicenter trial by Italian Amyloidosis Center in patients not eligible for SCT Melphalan (0.22 mg/kg) Dexamethasone (40 mg) Given po on days 1- 4 q 28 days Palladini, et al., Blood 103(8): 2004.

  27. Mel - Dex • Total of 46 pts. treated • Hematologic Response Rate 67% (33% CR) • Organ response in 48% • 2 treatment-related deaths in first 100 days • Median Survival = 5.1 yrs.

  28. IMiDs for AL Amyloidosis

  29. ConclusionsLenalidomide + Dex for AL • Activity • Heme responses in ~ 60% • Organ responses in ~ 30% • Most common toxicities are hematologic; next is rash & fatigue • Pre-treatment cardiac biomarkers predict for trial retention, PFS & OS

  30. Bortezomib for AL • No prospective trials • UK experience in relapsed AL: • 18 pts. (9 had Dex added) • Median # prior therapies = 3 • Heme response in 14 (77%), CR 3 (16%) • Organ response in 5 (27%) • Est. median survival = 22 mos. Wechalekar, et al., Blood 108: 129a, 2006

  31. Mayo Randomized Trial Randomization SCT with MEL 200 mg/m2 Mel 20 mg/m2 q 6 weeks + dex 40 mg x 4 days every 3 weeks X 10 cycles

  32. Not wanting transplant Mel 200 HSCT Mel-Dex Hematologic Response No Hematologic Response More chemotherapy Observation Observation Newly Diagnosed AL Amyloidosis Low risk 1-2 organs Age < 71 High Risk Severe cardiac, Or not ‘low risk’

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