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The European Group for Blood and Marrow Transplantation London, January 2011 The European Group for Blood and Marrow Transplantation STEM CELL TRANSPLANTATION.

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Presentation on theme: "The European Group for Blood and Marrow Transplantation London, January 2011 The European Group for Blood and Marrow Transplantation STEM CELL TRANSPLANTATION."— Presentation transcript:

1 The European Group for Blood and Marrow Transplantation London, January 2011 The European Group for Blood and Marrow Transplantation STEM CELL TRANSPLANTATION FOR PATIENTS WITH WALDENSTROM’S MACROGLOBULINEMIA (WM) Dr Charalampia Kyriakou MD, PhD

2 The European Group for Blood and Marrow Transplantation London, January 2011 WALDENSTROM’S MACROGLOBULINEMIA   Rare   Indolent Lymphoma   Median presentation age 63 years-often have ongoing morbidities from other diseases   Smoldering - Asymptomatic WM - NO TREATMENT   Conventional Therapies up to 90% response, short duration and low CR rates   No cure

3 The European Group for Blood and Marrow Transplantation London, January 2011 WALDENSTROM’S MACROGLOBULINEMIA ISSWM Adverse covariates:.Age>65. Hb≤11.5g/dL.Plt≤100x10 9 /L.IgM>70g/L.Β2-M>3mg/L ?LDH ?CRP ?Previous Line therapies RiskScore * No of pts (%) {n=587 Median FU 5.3yrs} 5yrs survival (%) Low ≤1, Age<65 155(27) 87 Intermediate 2 or Age>65 224(38) 68 High>2 208(35) 36 - LDH-Previous Rx Lines Risk- LDH-Previous Rx Lines ** No of pts (%) {n=183 Median FU 10yrs} 8yrs survival(%) Normal LDH Low - Normal LDH 98 55 High LDH Low-Intermediate – High LDH 51 33 Normal LDH High - Normal LDH 29 5 High LDH High - High LDH 4 0 * Morel et al; Blood 113:4163-4170, 2009 ** Dhodapkar et al; Blood 113:793-796,2009

4 The European Group for Blood and Marrow Transplantation London, January 2011 Regimen / ReferenceNo of PtsStudyORR % Chlorambucil / Facon et al,JCO 1993128Retrospective31 Cladribine / Weber et al, Semin Oncol 200346Prospective Phase II45 Fludarabine / Dhodapkar et al, Semin Oncl 2003172Prospective Phase II38 Fludarabine vs CAP / Leblond et al, Blood 200145/45Prospective Phase II30/11 Rituximab / Gertz et al, Clin Ly My 200469Prospective Phase II52 Rituximab / Dimopoulos et al, JCO 200229Prospective Phase II48 Bortezomib / Chen et al,JCO 200727Prospective Phase II52 Bortezomib / Treon et al, Clin Cancer Res 200727Prospective Phase II48 Treatment For Symptomatic WM

5 The European Group for Blood and Marrow Transplantation London, January 2011 AuthorN of ptsScheduleORR % TTF Dimopoulos et al, JCO 200772Dex/Rituximab/Cyclo83% (7%CR,67%PR)At 2yrs 67% Buske et al, Leukemia 200925/25CHOP vs R-CHOP 60%- 3%CRvs 91%-9%CR 1.9vs 5.2 yrs Rummel et al, German Subgroup Indolent Lymphoma StiL 23/17 R-Bendamustine vs R-CHOP 96%vs 94% PFS at 3yrs 82%vs 58% Treon et al, Blood 200943Fludarabine/Rituximab86%-2%CR4.5 yrs Treon et al, Blood 200925 Thalidomide/ Rituximab 70%-4%CR3yrs Treon et al, JCO 2009 24 Bortezomib/Dex/ Rituximab 83%- 22%CR-nCRNR (FU 2yrs) Treon et al, ASH 2009240 Rituximab Maintenance vs Observation 61.3 vs 22.6(m) TREATMENT FOR SYMPTOMATIC WM

6 The European Group for Blood and Marrow Transplantation London, January 2011 Anagnostopoulos et al Biol Blood Marrow Transplant. Aug;2006 Tournilhac et al Semin Oncol. Apr;2003 P. Dreger, N. Schmitz Biol Blood Marrow Transplant. May;2007 David Maloney; IWMW;Venice, Italy,2010 STEM CELL TRANSPLANTATION FOR WM PATIENTS

7 The European Group for Blood and Marrow Transplantation London, January 2011 Deliver high - lethal dose chemo-radio therapy to destroy tumour cellsDeliver high - lethal dose chemo-radio therapy to destroy tumour cells Provide a source of haemopoietic stem cells to salvage the ablated marrowProvide a source of haemopoietic stem cells to salvage the ablated marrow Establish organ graft tolerance to prevent rejection of donor cellsEstablish organ graft tolerance to prevent rejection of donor cells Provide immune effector cells to mediate graft-vs-tumour activityProvide immune effector cells to mediate graft-vs-tumour activity Haematopoietic Stem Cell Transplantation Objectives E.D. Thomas et al, N. Engl. J. Med. 257, 491-496 (1957) Intravenous Infusion of Bone Marrow in Patients Receiving Radiation and Chemotherapy

8 The European Group for Blood and Marrow Transplantation London, January 2011 Autologous/Allogeneic Stem Cell Transplantation Cells either obtained from G-CSF/+ Chemotherapy (for ASCT) mobilised peripheral blood stem cells or bone marrow harvestCells either obtained from G-CSF/+ Chemotherapy (for ASCT) mobilised peripheral blood stem cells or bone marrow harvest Requires HLA-matched donorRequires HLA-matched donor –Matched sibling (25% chance of matching any sibling) –Umbilical cord blood cells –Mismatched donors –Matched unrelated donor Search International donor registriesSearch International donor registries

9 The European Group for Blood and Marrow Transplantation London, January 2011 Regimen Intensity for Allogeneic Stem Cell Transplantation Immunosuppressive Myelosuppression Myelosuppression Flu / TBI 2Gy Flu / Cy Flu / Mel / Campath Flu / Bu / ATG BEAMCampath FLAG / Ida TBI 2Gy Cy / TBI By/TBIMelp/VP16/TBICyclo/VP16/BCNU Reduced Intensity Conventional Myeloblative

10 The European Group for Blood and Marrow Transplantation London, January 2011 The Perfect Transplant Regimen Low toxicity and TRM Low incidence of GVHD High level of tumour control Good immune reconstitution Disease responds to DLI

11 The European Group for Blood and Marrow Transplantation London, January 2011 Sources of Stem Cell Transplantation Autologous Autologous Donor availableDonor available No GVHDNo GVHD No ImmunosuppressionNo Immunosuppression Less toxicity Higher relapse rates Allogeneic Stem cells free of WMStem cells free of WM Undamaged stem cellsUndamaged stem cells Immune mediated graft-vs-tumour effectImmune mediated graft-vs-tumour effect Replaces damaged host haemopoiesisReplaces damaged host haemopoiesis DLI may provide augmented anti-WM activityDLI may provide augmented anti-WM activity May be curativeMay be curative More toxicity, GVHD More toxicity, GVHD Lower Relapse rates Lower Relapse rates

12 The European Group for Blood and Marrow Transplantation London, January 2011 Questions ??? Can Stem Cell Transplantation be used as a curative approach to WM? WHO ?Indication ?Indication ?Risk-benefit ?Risk-benefit ?Recipient Performance Status, Specific HCT comorbidity index, risk score for mortality ?Recipient Performance Status, Specific HCT comorbidity index, risk score for mortalityWHEN ?Not too early not too late ? “frontline” ?Age ?Age ?Response target? Cure ? Significance of disease status pre-post on the overall management ?Response target? Cure ? Significance of disease status pre-post on the overall management ?Long term risks ?Long term risks TYPE ?Conditioning ?Auto ?Allo ?MAC ?RIC?Intensity?SIB?MUD ?GVHD prophylaxis ?purging ?GVHD prophylaxis ?purging

13 The European Group for Blood and Marrow Transplantation London, January 2011 ALLOGENEIC STEM CELL TRANSPLANTATION FOR HIGH RISK WM PATIENTS (n=25, MAC:12, RIC:13) Garnier et al, Haematologica 2010 Median FU: 64 (11-149) months, Heavily pre-treated, 44% chemorefractory Dx 67% 67% 25%

14 The European Group for Blood and Marrow Transplantation London, January 2011 Garnier et al, Haematologica 2010 Allogeneic Stem Cell Transplantation For High Risk WM Patients (n=25)

15 The European Group for Blood and Marrow Transplantation London, January 2011 EBMT Lymphoma Registry WM-SCT Activity 1995-2007 Allo-SCTAuto-SCT SCT activity by year of SCT

16 The European Group for Blood and Marrow Transplantation London, January 2011 Median Follow-up for the surviving pts, years (range): 4.2 (0.5- 14.8) Alive: n= 107 (68%)  No progression: n=78 (49%)  Relapse or progression: n=71(45%) Time to relapse or progression: 15m (1-110) Dead: 51 (32%)  Disease progression: 42 (26%)  Non-disease Progression: 9 (8%) Infection:6, MOF:2, Cardiac:1 Secondary Malignancies Secondary Malignancies: 10 (6.3%) [AML: 1, MDS: 4, Melanoma: 1,Prostate Ca: 1, Small Cell Lung Ca: 1, Other solid tumors: 2] Kyriakou et al, JCO 2010 WM ASCT – RESULTS (n=158)

17 The European Group for Blood and Marrow Transplantation London, January 2011 Post- Autologous Stem Cell Transplantation (ASCT) Outcome by disease status at the time of ASCT (n=158) Disease status at ASCT Total VGPR1>VGPR2 Chemosensitive disease Chemorefractorydisease CR10321034 VGPR201936277 PR0018523 No response (SD/Prog) 4011318 NE00213 NA00303 Total34229111158 Kyriakou et al, JCO 2010

18 The European Group for Blood and Marrow Transplantation London, January 2011 Non Relapse Mortality – Relapse Rate - ASCT 1.0 0.0 0.2 0.4 0.6 0.8 0 12345678 Time after ASCT (years)‏ Cumulative Inidenece NRM Relapse or Progression 52% 4.6% 5.6% 3.8% Kyriakou et al, JCO 2010 0.0 0.1 0.2 0.3 0.4 0.5 0246810 Time after ASCT (years)‏ Cum Inc Sec Malignancy 8.4% Secondary malignancies

19 The European Group for Blood and Marrow Transplantation London, January 2011 0.0 0.2 0.4 0.6 0.8 1.0 Probability of Survival PFS: ALL PTS OS: ALL PTS 0 12345678 Time after ASCT (years)‏ 68.5% 41% 77.6% 61.7% Progression Free And Overall Survival - ASCT Kyriakou et al, JCO 2010

20 The European Group for Blood and Marrow Transplantation London, January 2011 0.0 0.2 0.4 0.6 0.8 1.0 012345678 Time after ASCT (years)‏ PFS Landmark: 6 months - IF (n=33)‏ + IF (n=18)‏ p=0.08 Progression Free And Overall Survival By Immunofixation Kyriakou et al, JCO 2010

21 The European Group for Blood and Marrow Transplantation London, January 2011 Adverse prognostic Factors for Post ASCT Outcome: Multivariate analysis Adverse prognostic factor Relative risk Confidence interval P value Relapse / Progression ≥ 3 prior lines of therapy Refractory disease at ASCT 2.5 3.9 1.5 – 4.1 1.6 – 9.4 0.001 0.003 Progression free survival ≥ 3 prior lines of therapy Refractory disease at ASCT 2.4 4.1 1.5 – 3.9 1.8 – 9.2 0.001 < 0.001 Overall survival Male sex ≥ 3 prior lines of therapy Age at ASCT > 60 years Refractory disease at ASCT 2.0 3.1 1.9 3.1 1.1 – 3.9 1.7 – 5.9 1.0. - 3.8 1.2 – 8.1 0.04 0.001 0.05 0.03 Kyriakou et al, JCO 2010

22 The European Group for Blood and Marrow Transplantation London, January 2011 Progression Free and Overall Survival By disease Status at ASCT

23 The European Group for Blood and Marrow Transplantation London, January 2011 EBMT Lymphoma Registry: Allo-SCT-WM: 2000-2007 (n=86; MAC:37, RIC:49 pts) Allo-SCT: Conditioning by year of SCT 32% Chemo-refractory disease, 47% High and 19% Intermediate risk Dx, 10% poor performance status

24 The European Group for Blood and Marrow Transplantation London, January 2011 Characteristics Patient No Median Follow up for surviving pts – range: 50 (7-142) months Alive Median time to response:6 months (range:2-50) Median time to response: 6 months (range:2-50) Disease Response CRVGPRPRSD/PD NE(early deaths) Dead NRM Disease relapse/progression Disease relapse/progression 5615331761530237 WM Allo-SCT - Results Kyriakou et al; JCO 2010

25 The European Group for Blood and Marrow Transplantation London, January 2011 Characteristics Patient No Relapse / Progression Median time to relapse: Median time to relapse: 9 months (2-89) Donor Lymphocyte Infusion Persistent disease/Relapse Mixed chimerism Bone marrow failure Median time from SCT to DLI: Median time from SCT to DLI: 9 months (1-90) Response to DLI for Disease Response to DLI for Disease (n=14) – OR: 80% CR PR No response NE 192114617421 WM Allo-SCT - Results – Donor Lymphocyte Infusion Kyriakou et al; JCO 2010

26 The European Group for Blood and Marrow Transplantation London, January 2011 Outcome Whole series (n = 86) MAC (n = 37) RIC (n = 49) p value Acute GVHD 100-days CI of aGVHD Chronic GVHD Absent Limited Extensive 18-mo CI of cGVHD (95% confidence interval) 45% 45% (35 - 56) 41(48%) 9(11%) 19(22%) 41% (31% - 55%) 61% 61% (47 - 79) 15(41%) 6(16%) 45% 45% (30 - 69) 33% 33% (22 - 49) 26(53%) 3(6%) 13(27%) 36% (24 - 64)0.001n.s. Results Post Allo-SCT - GVHD Kyriakou et al; JCO 2010

27 The European Group for Blood and Marrow Transplantation London, January 2011 0.0 0.2 0.4 0.6 0.8 1.0 0123456 Years after Allo-SCT RELAPSE OR PROGRESSION cGVHD (n=21) No cGVHD (n=31) 6 mo p=0.03 Impact Of Chronic - GVHD On Relapse Rate And Progression Free Survival Kyriakou et al; JCO 2010

28 The European Group for Blood and Marrow Transplantation London, January 2011 0.0 0.2 0.4 0.6 0.8 1.0 Years after Allo-SCT NRM RIC (n=49) MAC (n=37) 012345678 p: n.s. 0.0 0.2 0.4 0.6 0.8 1.0 Years after Allo-SCT NRM 012345678 Whole series (n=86) 23% 27% WM Allo-SCT Non - Relapse Mortality (n=86) Kyriakou et al; JCO 2010

29 The European Group for Blood and Marrow Transplantation London, January 2011 WM Allo-SCT Relapse / Progression (n=86) Kyriakou et al; JCO 2010

30 The European Group for Blood and Marrow Transplantation London, January 2011 0.0 0.2 0.4 0.6 0.8 1.0 012345678 Years after Allo-SCT Whole series (n=86) 72% 66% 64% OVERALL SURVIVAL WM Allo-SCT Overall and Progression Free Survival Kyriakou et al; JCO 2010 0.0 0.2 0.4 0.6 0.8 1.0 012345678 Years after Allo-SCT PROGRESSION FREE SURVIVAL Whole series (n=86) 61% 52%

31 The European Group for Blood and Marrow Transplantation London, January 2011 10 years experience on Stem Cell Transplantation in patients with Waldenstrom Macroglobulinemia EBMT Update Stem cell Transplantation (ASCT vs RIC vs MAC) EBMT Database reported between Jan 2000- Jan 2010 First SCT procedure ASCT n=424 Allo SCTn=226 –RICn=139 –MACn=81

32 The European Group for Blood and Marrow Transplantation London, January 2011 NRM: ASCT - RIC - MAC - Allo-SCT ASCT RIC-Allo-SCT MAC-Allo-SCT NRM (%) 12 mo 36 mo 60 mo ASCT478 RIC Allo-SCT 192223 MAC Allo-SCT 263236

33 The European Group for Blood and Marrow Transplantation London, January 2011 Clinical Characteristics ASCT (n= 410) Allo-SCT (n=223) Median FU of survivors (months) 12 (3-112) 17 (1-108) Median time to relapse, months (range) 13 (1-76) 6 (1-58) AliveDead Disease relapse/progression Disease relapse/progression GVHD GVHD Infections Infections Other Other Secondary malignancies Secondary malignancies 81 (%) 19 (%) 65.6 (%) N/A 17 (%) 11.1 (%) 6.3 (%) 65.6 (%) 34.4 (%) 29.9 (%) 30 (%) 8.6 (%) 1.5 (%) Response CR CR VGPR VGPR PR PR No response/Progressive Dx No response/Progressive Dx 58 (%) 15 (%) 27 (%) 53.3 (%) 22.4 (%) 24.3 (%) Patient Characteristics

34 The European Group for Blood and Marrow Transplantation London, January 2011 RR: ASCT - RIC – MAC - Allo-SCT ASCT RIC-Allo-SCT MAC-Allo-SCT RR ( % ) 12 mo 36 mo 60 mo ASCT173857 RIC Allo-SCT 222727 MAC Allo-SCT 171922

35 The European Group for Blood and Marrow Transplantation London, January 2011 PFS: ASCT – Allo - SCT ASCT Allo-SCT PFS (%) 12 mo 36 mo 60 mo ASCT78.561.343.6 Allo-SCT56.446.645 p=0.001

36 The European Group for Blood and Marrow Transplantation London, January 2011 PFS: ASCT - RIC - MAC - Allo- SCT ASCT RIC-Allo-SCT MAC-Allo-SCT PFS (%) 12 mo 36 mo 60 mo ASCT78.561.343.6 RIC Allo-SCT 58.348.148.1 MAC Allo-SCT 55.745.942.7

37 The European Group for Blood and Marrow Transplantation London, January 2011 OS: ASCT - Allo- SCT ASCT Allo-SCT OS (%) 12 mo 36 mo 60 mo ASCT89.678.668.7 Allo-SCT76.758.256.4

38 The European Group for Blood and Marrow Transplantation London, January 2011 ASCT RIC-Allo-SCT MAC-Allo-SCT Overall Survival: ASCT - RIC – MAC - Allo- SCT OS (%) 12 mo 36 mo 60 mo ASCT89.678.668.7 RIC Allo-SCT 73.761.458.2 MAC Allo-SCT 65.555.255.2

39 The European Group for Blood and Marrow Transplantation London, January 2011 Treatment answers from Collaborative International Randomised clinical trialsTreatment answers from Collaborative International Randomised clinical trials Patients with high risk WM have poor prognosis with conventional therapyPatients with high risk WM have poor prognosis with conventional therapy HDT and SCT should be considered as a therapeutic option for high risk WM patientsHDT and SCT should be considered as a therapeutic option for high risk WM patients Autologous Stem Cell Transplantation  Low NRM  Prolonged PFS and OS. Significantly superior ASCT outcomes were observed in patients with chemosensitive disease transplanted early following 1st maximum response  Note risk for secondary malignancies but comparable to the published incidence with conventional Rx  Could be considered for selected younger patients with high risk disease Allogeneic –Stem Cell Transplantation  High transplant related toxicity - Compromised Overall and Progression Free Survival  Consider Allo-SCT only for high risk WM younger and fit patients with relapse refractory disease  Acute GVHD incidence significantly higher for MAC leading to higher early NRM compared to RIC patients  Development of cGVHD is associated with significantly lower relapse rate  Disease response following DLI for relapse disease together with the impact of cGVHD suggest Graft versus WM effect Conclusions

40 The European Group for Blood and Marrow Transplantation London, January 2011 TREATMENT GOALS FOR WM PATIENTS Obtain maximum response – improve outcomeObtain maximum response – improve outcome Improve duration of responseImprove duration of response Prevent reduce complications – reduce late effectsPrevent reduce complications – reduce late effects Maintain quality of lifeMaintain quality of life Industry Voluntary sector Professionals Patients / Families


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