disease-specific treatment of relapse after allogeneic transplantation
TRANSCRIPT
Disease-Specific Treatment of Relapse after Allogeneic Transplantation
Treatment of Relapse
• Cellular Immunotherapy– Withdrawal of immune suppression– DLI ( + chemotherapy)– Second allogeneic SCT
• Non-Cellular therapies– Supportive care– Conventional chemotherapy or radiation– Novel cytotoxic agents– Biological agents– Immunotherapy approaches
Treatment of Relapse
• Cellular therapy– Withdraw IS– Second BMT with same or
different donor– DLI– Activated DLI– Manipulated DLI
• CD8 depleted, CD4 enriched, antigen-specific.
– Dose titrated DLI– NK cells– Modified T cells (CARs)
• Other therapies– Conventional
chemotherapy or radiation– Antibodies
• CD20, CD33, CD30, CTLA-4, etc…
• Bispecific antibodies– Biological therapy
• Lenalidomide, thalidomide, bortezomib, azacytadine, decitabine, mTor inhibitors,others.
• Interferon, IL-2, etc…• Vaccines
– Others
Available data for treatment of relapse
• CML-CP: DLI restores durable CR in 80% of pts with CP relapse.– Dose, schedule, toxicity
well defined.– Role of TKI’s?
• AML, ALL, NHL, HL, CLL, MM, CML-AP/BC– DLI response rate, most
effective approach, and long term outcomes?
– Second SCT ?– Other therapies ?
An embarrassing lack of data
Excuses (good ones)
• Patients are heterogeneous– Age– Impact of prior transplant
• Myeloablative vs RIC
• GVHD prophylaxis (TCD, alemtuzumab, sirolimus, etc…)
– Different grafts• BM vs PBSC
• TCD, other manipulation
• Donor source and availability (sibling/family, URD, UCB, matched or mismatched)– Different risks, timing to intervention, treatment choice, etc…
– Clinical complications and co-morbidities after allogeneic SCT• May not tolerate therapies well
– Active GVHD? Acute or chronic?• Use of immune suppression
Excuses (good ones)
• Disease-related issues are heterogeneous– Timing of relapse: early vs late relapse may be very different
– Histology (particularly in NHL)
– Disease burden and pace of progression• In indolent diseases residual disease may not require intervention
– Influence of prior therapies and likely drug resistance
• Small numbers of patients studied with some diseases.• No central database or sample repository to assess
interventions.• Reticence for clinical trials in this population (sponsors,
cooperative group, FDA, investigators.– Limits access to new compounds
Excuses (good ones)
• Lack of insurance coverage for clinical trials (and in some cases standard DLI or other therapy)
• Bias for:– Treatment selection
• Depends on patient, disease activity, donor availability, prior therapies…
– Patient selection• Age, co-morbidity, past and present transplant-related complications.
– Reporting of outcomes
Many issues are common to treatment of relapse of multiple
diseases
Cell Dose
• Is there a dose:response relationship?– In CML, low dose DLI (1 x 10^7/kg) with dose
escalation may preserve GVL with limited GVHD.• Is this effective for other indolent relapses (NHL, HL, MM,
CLL?)• Not useful for rapidly progressive acute leukemia
• Is there a dose:toxicity relationship?– Minimal threshold for GVHD may vary by donor
source (haplo vs well matched)– Sibling vs unrelated donor
• Often dosed differently but not supported by comparative trials
Role of Chimerism
• Does mixed or changing chimerism signify relapse?
– For CML, mixed chimerism predicts relapse. Role for intervention depends on timing, pace of change, and other factors
– Significance in other diseases less clear– May depend on the cellular compartment evaluated
(T, NK, myeloid)– Role of intervention for chimerism and influence on
outcome not well defined for most diseases.• “Treatment” of mixed chimerism with DLI may prevent relapse in
some cases, but not others.
Role for Second SCT
• Available data is limited and should be reassessed in the “modern” era.
• Conventional vs RIC conditioning? • Influence of disease type and extent of
relapse?• Same vs alternate donor?• Influence of timing of relapse?• Manipulations to enhance GVT activity of
second SCT?
Overcoming Limitations
• NCI Sponsored Workshop on Relapse after Allogeneic SCT! The first step……
• Define critical issues relating to relapse therapy.
• Multicenter and international collaborations to rapidly test and analyze new therapies for relapse.
Disease-Specific Treatment of Relapse after Allogeneic Transplantation
• Fred Falkenburg
• Joseph Antin
• Marcos de Lima
• Eli Estey
• John Levine
• Jacob Rowe
• Alan Wayne
• David Maloney
• Koen van Besien
• Karl Peggs
• David Porter
• Jose Leis
• Nancy Hardy
• Nicolaus Kröger
• Edwin Alyea
CML
AML
ALL
NHL
MM
CLL
HL
Treatment of CML relapse after allogeneic SCT
Fred Falkenburg
Joseph Antin
Treatment of relapsed Chronic Phase CML with DLI after Allogeneic Hematopoietic Stem Cell
Transplantation (SCT)
Complete remissions in 80-90 % of cases
Relatively low doses of DLI required
Time interval between treatment and response
is dose and disease state dependent
Interferon may potentiate onset and effect
Target recognition may determine balance
between GVHD and GVL
Hematopoiesis-associated minor histocompatibility antigens (mHag) and GVL
reactivity
• In HLA-identical transplantation donor T cells recognizing hematopoiesis-specific antigens on recipient cells eliminate normal and malignant hematopoietic cells of recipient origin
•GVL-reactivity
• (Complete) donor chimerism
• Hematopoiesis-specific mHag may be targets for GVL reactivity with limited induction of GVHD
BCR/ABL expression in bone marrow after DLI
0,00001
0,0001
0,001
0,01
0,1
1S
CT
+1
2
SC
T+
28
DL
I+
1.5 +3
+5
+6
+7
+8
+9
+1
0
+1
1
+1
3
+1
5
+1
8
+2
2
+2
6
weeks post treatment
BCR-ABL/PBGD ratio
< * * ** *
* = negative
RZ
*
Kinetics of immune responses after DLI
0
500
1000
1500
2000
2500
SC
T+1
2
SC
T+2
8
DL
I
+1.5 +3 +5 +6 +7 +8 +9
+10
+11
+13
+15
+18
+22
+26
weeks post treatment
CD8+/tetramer+ cells/mL
0,0
1,0
2,0
3,0
4,0
5,0
WBC/mL
CD8+/HA-2+
CD8+/HA-1+
WBC x10E6
RZ
Treatment of relapsed Chronic Phase CML with DLI after Allogeneic Hematopoietic Stem Cell
Transplantation (SCT)
Which antigens need to be targeted to
provoke a GVL response without GVHD
Targeting hematopoiesis restricted
antigens results in specific GVL?
Are over-expressed self antigens targets
of high avidity T cell responses?
Persistance of BCR/ABL despite repeated DLI
CML chronic phase, allogeneic SCT from HLA identical brother
Hematological relapse:
DLI 3x10E7 T cells/kg: hematological remission, molecular persistence
Molecular persistence of disease despite escalating doses of DLI:
Localized myeloid blast crise in epidural space: Systemic chemotherapy Radiotherapy + DLI 1.5x10E8 T cells/kg,
Persistance of BCR/ABL despite repeated DLI isolation of CML reactive CTL clones
0 10 20 30 40 500
20
40
60
80
100
0.000001
0.00001
0.0001
0.001
0.01
0.1
1
*
* too low to quantify
** negative
DLI
Chemotherapy
Time (months)
% D
on
or
ch
imer
ism
BC
R-A
BL
Non-maturated immature CD34 CML cells
Maturated CML cells after culture with cytokines: myelocytes, metamyelocytes, monocytes and
granulocytes
Maturated CML cells incubated with T cell clones for 50 hours
HA-1
no T-cells
C6-1
no T-cells
C6-1HA-1
immature CML cells incubated with T cell clones for 50 hours
Conclusions
CD8+ mHag specific CTL recognizing only maturation associated antigens not present on CD34 positive stem or early progenitor cells may result in persistence of disease
Should CML stem cells be targeted?
Cellular immunotherapy and TKI
Are leukemic stem cells residing after imatinib treatment susceptible targets for cellular immunotherapeutic interventions?
Should allo-SCT performed for persistent CML be combined with continuous treatment with tyrosine kinase inhibitors?
• Isolation of CD34+ CML precursor cells from PB or BM by MACS
• Cytokines: GM-CSF, G-CSF, IL-3, SCF, EPO
• CFSE/PKH labeling of the target cell population
• Ab labeling of specific cell populations (FITC, PE & APC)
• Exclusion of death cells using propidium iodide
• Addition and acquisition of a fixed amount of fluorescent beads
Quantitative flow cytometric analysis of phenotype and proliferative status of CML precursor cells
1
03
2
CFSE
CD
34
CFSE
co
un
ts
Specific kill of proliferating CML precursor cells by Imatinib
CFSE
CD
34
6 days
control 100 M imatinib
↑
CFSE6 days pretreated
48 hours CTL exposure (HLA-A2 restricted mHag-specific CD8+ clone; E/T 3/1)
control + mHag spec. CTL
Cross-resistance of Imatinib pre-treated CML precursor cells to cell death induced by cytotoxic T cells
100M Imatinib
CFSE
CD
34
6 days CTL exposure (HLA-A2 restricted mHag-specific CD8+ clone; E/T 3/1)
control + mHag spec. CTL
Quiescent CML precursor cells are resistant to cell death induced by cytotoxic T cells
no pre-treatment
Conclusions
Quiescent leukemic stem cells are protected from the cytotoxic effect of tyrosine kinase inhibitors
This population of quiescent leukemic stem cells shows cross-resistance to cytotoxic T cells involved in the GVL effect after allo-SCT,
The anti-proliferative effect of tyrosine kinase inhibitors on both the leukemic cells and the T cells may potentially hamper the potentially curative immune response after allo-SCT
If cellular immunotherapy is combined with TKI, should treatment be intermittent?
Treatment of relapsed CML after Allogeneic Hematopoietic Stem Cell Transplantation (SCT)
Identification of target cells and/or antigens to be targeted
Separation of DLI into fractions (CD4 T cells)
Targeting minor histocompatiblity antigens or leukemia
associated antigens by adoptive transfer if purified T cells
Vaccination of patient with mHag, APC.
Vaccination of donor with mHag
Interferon may potentiate onset and effect
Are TKI useful, or harmful?
How to treat extramedullary relapses
Treatment of relapsed acute myelogenous leukemia after
allogeneic stem cell transplantation
Marcos de Lima, MDM. D Anderson Cancer Center
John Levine, MDUniversity of Michigan
Elihu Estey, MDFred Hutchinson Cancer Research Center
AML
Probability of relapse: 20% - 60% - definition of relapse is key.
All results reflect (to a great extent) patient selection.
Major co-variates predicting relapse:- disease stage / cytogenetics- preparative regimen intensity
Ringdén et al. J Clin Oncol; 27; 2009: 4570-4577
Trends affecting comparison with historic data:- better prognostication for diploid patients (FLT3, NPM)- treatment of older patients- use of reduced-intensity regimens
Oran et al. Leukemia (2007) 21, 2540–2544.
Eapen et al. BMT 2004;34:721-727
Donor Lymphocyte Infusions
Addition of chemotherapy improves response rate but not long-term disease control.
GVHD in 10-60% of patients
Marrow aplasia in 5-20%.
TRM: 0-50%
Most series : adults, using mostly related donors.
Responses frequently do not translate into long-term survival, due to GVHD, pancytopenia, infections, and disease relapse.
Donor availability and presence of GVHD are major impediments.
Investigator n Outcomes
Collins et al. 46 6/39 (15%) CR
Kolb et al. 19 5/17 (29%) CR
Shiobara et al. 218/21 (38%) Response7% DFS at 2 years
Donor lymphocyte infusion alone
Kolb H. Blood 1995;86:2041-2050 Loren A, Porter DL. Bone Marrow Transplantation (2008) 41, 483–493.Porter DL et al. Blood 2000;95:1214-1221.
Investigator (n) Outcomes
Collins et al. 7
4/7 (57%) DFS
Kolb et al.
8
4/8 (50%) CR 2/4 (50%) DFS at 2 years
Choi et al.
16
10/16 (63%) CR 31% DFS at 2 years
Levine et al. 65
27/57 (47%) CR 19% DFS at 2 years
D L I and chemotherapy
Porter DL. Leukemia 2003;17:1035-1037.Levine J. Bone Marrow Transplant 2008;42:201-205. Choi S. Leukemia 2004;18:1789-1797.
Schmid, C. et al. J Clin Oncol; 25:4938-4945 2007
Donor lymphocyte infusion
EBMT analysis
399 patients with AML in first hematological relapse after HSCT
DLI = n=171 versus no DLI (n = 228)
Median follow-up was 27 and 40 months
Copyright © American Society of Clinical Oncology Schmid, C. et al. J Clin Oncol; 25:4938-4945 2007
Fig 1. Unadjusted survival of patients with first hematological relapse of acute myeloid leukemia after allogeneic hematopoietic stem-cell transplantation (HSCT)
Multivariate analysis
1- age < 37 years (P = .008)
2- longer CR after HSCT (> 5 months; (P < .0001)
3- use of DLI (P = .04).
Risk Factors for Survival Among Patients Receiving DLI for Treatment of Hematological Relapse After HSCT for AML (n = 171)
Variable PRelative
Risk
95% CI
% blast at relapse (BM), > 35%
.006 0.56 0.38 to 0.85
Female v male .02 1.6 1.07 to 2.4
Cytogenetics (favorable v other)
.004 5.6 1.76 to 1.8
remission versus no remission
< .0001
5.8 2.5 to 13.7
Schmid, C. et al. J Clin Oncol; 25:4938-4945 2007
Second transplant
6% of patients with recurrent leukemia receive a 2nd HSCT
Eapen et al. Bone Marrow Transplant 2004;34:721-727
AML 125
ALL 72
CML 82
Age (years)
10 40 (14)
11–20 56 (20)
21–30 64 (23)
>30 119 (43)
Same donor as 1st transplant 238 85%
Follow-up of survivors, median 93 mo.
Second transplants – matched related donor – CIBMTR analysis
Eapen et al. Bone Marrow Transplant 2004;34:721-727
Overall mortality
Age at 2nd HSCT (years)
20 96 1.00
>20 183 1.94 (1.42–2.64) <0.0001
Time from 1st HSCT to relapse (months)
>6 213 1.00
6 52 3.47 (2.49–4.83) <0.0001
RIC was associated with more relapses.
Second transplants – matched related donor – CIBMTR analysis
Disease status at second transplant:
Refractory relapse 39%Untested relapse 56%CR 5%
847 patients with AML, MDS, or myeloid blast crisis of CML received transplants between May 1989 and November 2003 at MDACC.
346 patients relapsed (41%).
72 of 346 (21%) underwent a 2nd HSCT from the same or different donor for AML.
Disease burden may identify patients more likely to benefit from secondallogeneic hematopoietic stem cell transplantation to treat relapsed acute myelogenous leukemia
C Hosing et al. BMT (2005) 36, 157–162
no circulating blasts / <= 5% bone marrow blastsvs circulating blasts + >5% bone marrow blasts
Oran et al. Leukemia (2007) 21, 2540–2544.
Oran et al. Leukemia (2007) 21, 2540–2544;
Salvage chemotherapy
Chemotherapy
Response rates are a function of : - chemosensitivity - remission duration - tempo (and disease “bulk”?) of relapse
No evidence that any particular regimen is superior to any other.
FHCRC data (years 1977-1984)
95 patients relapsed - 55 received chemotherapyResponse rates: CR rate with cytarabine (+/- adriamycin): 32% of 34 patients median DFS of 9.7 months.
FHCRC data (years 1995-2004)
N=220
¾ received chemotherapy +/- immunosuppression withdrawal
Time to relapse 2-year survival estimates
100 days 3% 100-200 days 9% > 200 days 19%
Mielcarek M et al. Biol Blood Marrow Transplant 2007;13:1160-1168.Mortimer J et al. J Clin Oncol 1989;7:50-57.
Novel agents
-A variety of ‘targeted’ agents are under investigation – role unclear in this setting.
-sorafenib – FLT3 positive patients Metzelder S et al. Blood 2009;113:6567-6571.
-5-azacitidine. Jabbour et al. Cancer, 2009;115:1899-1905
Lubbert et al. Bone Marrow Transplant 2009
Unanswered questions
Potentially answerable with a large database:
1- Better definition of subgroups more likely to benefit from interventions (versus palliative care only).
2- DLI after alternative donor transplants.
3 – Salvage therapy for children.
Unanswered questions
Potentially answerable with innovative, multicenter clinical trials:
- how to incorporate newer drugs and/or cell therapy approaches AND prove that they work.
Conclusions
Current therapies benefit a small minority of patients.
This is clearly a ‘phase I’ scenario.
Lack of large, multicenter prospective phase I and II studies to define experimental arms in a randomized study.
Lack of large databases dealing specifically with relapse information.
Lack of a broad discussion and consensus that should ideally involve drug companies and the FDA on the need to enroll patients in phase I, II or III clinical trials for the treatment of AML relapsing after allogeneic HSCT.
Key obstacles for development of large, randomized, prospective clinical studies
Proposed initiatives - Creation of a sample repository.
- Development (or improvement of current available databases) of systems for detailed data collection in the relapse setting.
- Multicenter approach!
-Identification of target antigens, modification of DLI, targeting antigens by adoptive transfer, vaccines etc
- NK cells
- Maintenance therapy : azacitidine, decitabine, sorafenib etc
Treatment of ALL that has relapsed Treatment of ALL that has relapsed after allogeneic Transplantationafter allogeneic Transplantation
Alan S Wayne and Jacob M. RoweAlan S Wayne and Jacob M. Rowe
Relapsed ALLRelapsed ALL
Early diagnosis Early diagnosis is probably crucial
Conventional and investigational therapies
likely to be greater if intervention is prior to intervention is prior to
florid relapse florid relapse
INTRODUCTION• Relapsed ALL has a very poor prognosis –
In adults only 7% survive 5 years
• Relapse post allogeneic transplant, almost always incurable
0 1 2 3 4 50
25
50
75
100
PE
RC
EN
T
7%
N= 609
Fielding AK et al, Blood, 2007
Relapsed ALL Post Allogeneic HSCTRelapsed ALL Post Allogeneic HSCT
While cures are rare, While cures are rare, INDUCTION OF INDUCTION OF REMISSIONREMISSION
and / or and / or PROLONGATION OF RESPONSE PROLONGATION OF RESPONSE is an is an
important endpoint important endpoint
ALL: Therapy at Relapse post Allo HSCT
CURATIVE INTENT SUPPORTIVE CARE ONLY
MINORITY THERAPEUTIC INTENT MINORITY
REMISSION NON-MYELOABLATIVE INDUCTION MAINTENANCE
CONSOLIDATION / MAINTENANCE
ALLO SCT
Graft versus Leukemia (GvL) in ALLGraft versus Leukemia (GvL) in ALLFirst clinical description of GvL in humans was in ALL !First clinical description of GvL in humans was in ALL !
Weiden PL et al, NEJM 300: 1068, 1979
0
20
40
60
80
100
0 1 2 3 8
DiseaseFree
Survival(%) Syngeneic
n=46
Years
Allogeneic GVHD 0-I n=117
Allogeneic,GVHD II - IVn=79
Potent GvL in ALL in CR1Potent GvL in ALL in CR1
Ph negative High risk
0 1 2 3 4 5 6 7 8 9 10
0
25
50
75
100
Rel
ap
se %
63%
37%
p = <.00005
n=261
n=204
Years
49%
24%
n=323
n=239
Ph negative Standard risk
0 1 2 3 4 5 6 7 8 9 10
0
25
50
75
100
No donor
Donor
p = <.00005
Years
Goldstone AH, et al, Blood, 2008
Graft versus Leukemia (GvL) in ALL Graft versus Leukemia (GvL) in ALL REDUCED-INTENSITY CONDITIONING FOR HIGH-RISK ALLREDUCED-INTENSITY CONDITIONING FOR HIGH-RISK ALL
CIBMTR STUDY OF ALL IN CR1 OR CR2CIBMTR STUDY OF ALL IN CR1 OR CR2
RIC (n= 92) vs myeloablative (n= 1421)
Median AgeMedian Age, yrs, 45 28 p= < .0001
OSOS @ 3 yrs, % 38 43 p= .39
TRMTRM @ 3 yrs, % 32 33 p= .86
Marks, DI et al, ASH 2009
100
20
00 17550 200 225
60
40
80
25 100 12575 175
Graft versus Leukemia (GvL) in Relapsed ALLGraft versus Leukemia (GvL) in Relapsed ALL• Donor Lymphocyte Infusions (DLI)
Rarely effective in florid relapseRapid proliferative rate of ALL at relapseLow expression T cell co-stimulatory molecules
Porter DL et al, Blood, 2000
CR following matched sibling DLI in ALL only 10-20% in select patients
Possibly better outcome in unrelated DLI , but data based on very small numbers.
Pro
bab
ility
(%
)
Weeks after complete remission
CMLn=12
ALLn=5
AMLn=10
Disease Free Survival, if CR after unrelated DLI
Suggested Treatment of Relapsed ALL post TransplantSuggested Treatment of Relapsed ALL post Transplant
UNFIT FOR INTENSIVE THERAPY FIT FOR INTENSIVE THERAPY
CONSERVATIVE CARE NO RESPONSE BEST AVAILABLE REGIMEN TO ACHIEVE CR ORNON-MYELOABLATIVE VERY GOOD (STABLE) PR (e.g., TKI) VCR + PREDNISONEMONOCLONAL ANTIBODIES
NO PRIOR GVHD PRIOR GVHD GRADE I
DLI SECOND ALLOGENEIC TRANSPLANT
+/- SECOND ALLOGENEIC TRANSPLANT* Consider clinical trial
* *
Investigational ApproachesInvestigational Approaches
PH-POSITIVE PH-NEGATIVE
NOVEL CHEMOTHERAPY MONOCLONAL ANTIBODIESand TARGETED AGENTS +/- CHEMOTHERAPY
NOVEL TKIs
UNCONJUGATED CONJUGATED
CD 20 GEMTUZUMAB OZOGAMICIN CD 22 (Anti CD33) CD 52 ANTI-CD22 IMMUNOTOXIN (CD 19)
Anti Flt3 (B-lineage) I131 -LABELLED ANTI- CD45
Bi-specificBi-specific DENILEUKIN DIFTITOX
(IL-2)
NELARABINE
CLOFARABINE
LIPOSOMAL VINCRISTINE
GAMMA SECRETASE
INHIBITORS
55 kD recombinant single chain variable fragments (scFv) Anti-CD19 Fv (HD37)Fv (HD37) Anti-CD3 Fv (L2K-07) Gly/Ser linker
Anti-CD19 Bi-Specific T-Cell Engager (BiTE) MEDI-538, MT103, Blinatumomab
Fv: variable fragment; VH: variable heavy-chain; VL: variable light-chain; sc: single chain
BM Pre BM Day 10
Courtesy of Rupert Handgretinger, October 2009
Clearance of marrow blasts
Increase in CD8 T+ cells
CD19 BiTE for Relapse after SCTCD19 BiTE for Relapse after SCTActive against childhood ALLActive against childhood ALL
Clearance of MRD
CD19 BiTE
Future Directions - Cancer Vaccines I Future Directions - Cancer Vaccines I
Attractive conceptually in this patient population due to low toxicity
Efficacy more likely in states of minimal residual disease
More data in AML, but similar rationale may be applicable in ALL
50
00 144 16 18
250
150
350
2 8 106 12
100
300
200
10-3
10-5
10-2
10-4
10
20
30
40
0
Future Directions - Cancer Vaccines Future Directions - Cancer Vaccines I II I
• PEPTIDE VACCINES – SOME DATA IN AML USING WT1 PEPTIDE. MINIMAL TOXICITY
platelets
blasts
Bla
sts,
%
Mailander V, Leukemia, 2004Mailander V, Leukemia, 2004
Months
Pla
tele
ts (
/nl)
VaccinationChemo-therapy
WT
I/PB
GD
Future Directions - Cancer Vaccines Future Directions - Cancer Vaccines IIIIII
PR1, a leukemia-associated antigen, studied for vaccination in AML, PR1, a leukemia-associated antigen, studied for vaccination in AML, with some successwith some success [HESLOP HE, STVENSON FK AND MOLLDDREM JJ, HEMATOLOGY, ASH EDUCATION 2003][HESLOP HE, STVENSON FK AND MOLLDDREM JJ, HEMATOLOGY, ASH EDUCATION 2003]
Dendritic cells and antigen presenting cells utilized to improve the Dendritic cells and antigen presenting cells utilized to improve the immune response to tumor associated antigen in multiple myelomaimmune response to tumor associated antigen in multiple myeloma [AVIGAN D ET AL, ASH 2008 AND 2009][AVIGAN D ET AL, ASH 2008 AND 2009]
Rationale applicable to other malignancies including ALLRationale applicable to other malignancies including ALL
SUHOSKI MM , MOL THER, 2007 SUHOSKI MM , MOL THER, 2007
Disease-Specific Interventions for Relapse of non-Hodgkin Lymphoma After
Allogeneic Transplantation
David Maloney MD, PhD
Koen van Besien, MD
NHL Relapse Following Allogeneic HCT: A Wide Range of Issues to Consider
• Many different histologic subtypes of NHL– indolent to aggressive behavior
• Patients often treated with Allogeneic HCT as “last resort”– after failed high-dose therapy and autologous HCT– with chemotherapy refractory disease
• Transplanted with a variety of conditioning intensities– myeloablative, reduced intensity, nonmyeloablative– T depleted or T replete grafts– HLA matched or mismatched, related, unrelated, cord
blood or haploidentical stem cell sources
Factors that Influence the Outcome of NHL Relapse post Allogeneic HCT
• Histology• Presence or absence of GHVD• T-replete vs T-depleted grafts• Disease status at HCT (chemorefractory vs
sensitive)• Transplant conditioning intensity• Timing of relapse (early vs late)
Approach to the Treatment of NHLRelapse post Allogeneic HCT
• In the absence of GHVD– Withdrawal of immunosuppression (IS)– Donor Lymphocyte Infusions (DLI)
• Monoclonal antibody therapy• Chemotherapy +/- DLI• Radiotherapy +/- DLI• Immune stimulants (IL-2 etc)• Second allogeneic HCT
Specific Therapies: Withdrawal of Immunosuppression
• No prospective trials• Several reported successes
Study Cond for HCT n Histology Chem/XRT CR/PR
Response
van Besien 1997
Ablative 9 DL (4)LBL(2)FL(2)PL (1)
? 3 3 CR2+-22+ mo
Bishop 2008
RIC 13 DL 0 6 3 long CR42+-63+ mo
Specific Therapies: Donor Lymphocyte Infusions (DLI)
• An option in the absence of GVHD• More commonly reported following T-depleted
HCT• Response often correlated with disease
histology and pace of progression• Some risk of subsequent GVHD• A wide range of CD3 cell doses used
Specific Therapies: Donor Lymphocyte Infusions (DLI)
• Usually reported in context of larger transplant trials
Study Cond for HCT
n Histology Chem/XRT
CR/PR Response
Russell 2005 T-dep (15)T-replete (2)
17 DL (5),MCL(4)FL(4),CLL (4)
9 11 PFS 3 y 52%OS 3 y 58%
Bloor 2008 T-dep (16) 17 CLL (3),MCL (3)FL (6),DL (5)
8 13 10 in remission f/u 26 mo
Bishop 2008 RIC 5 DL (5) 4 3 3 CR 74+-83+mo
van Besien 1997
ablative 3 DL (2), PL (1) 0
Marks 2002 T-dep 15 FL (15) 8 7 CR 16+-40+ mo
Mandigers 2003
T-dep 7 FL (5), SL (2) 4 6 4 CR 43+-89+ mo
Specific Therapies: Chemotherapy +/- DLI
• Anecdotal reports of chemotherapy +/- DLI generally within clinical trial results– Occasionally successful– Support the concept of ongoing graft-vs-tumor
effects that may be capable of controlling minimal residual disease
– No clear choice of agents– Concern of “ablating” graft appears low, but
needs to be studied
Specific Therapies: Monoclonal Antibody Therapy
• Frequently utilized for B cell NHL– Low hematologic toxicity– May promote antigen priming and graft-vs-tumor
effects• Tumor cell lines exposed to rituximab were more
effective at alloantigen presentation (Selenko 2002)
• Clinical trials from MD Anderson suggest improved outcome following the addition of high-dose rituximab (FL and CLL)
• Reasonable option for most patients
Specific Therapies: Other Immune Modulatory Agents
• Interleukin-2 (Kiss 2003)
– CR in low grade NHL pt (flare GVHD)• Interferon alpha (Kawano 2004)
– CR in DLBCL with IFN + DLI• Thalidomide (Tueger 2006)
– 1 pt with DLBCL and CR
• CTLA-4 blockade with ipilimumab (Bashey 2009)
– 3 pts with HD or MCL had response
Impact of Early vs Late NHL Relapse Post Allogeneic HCT
Progression-Free Survival after relapserelapse < 6 mo after allo (n=12) vs > 6mo after allo (n=11)
0 10 20 30 40 50 60 70 80
Months
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
gres
sion
-Fre
e S
urvi
val
> 6mo relapse < 6mo relapse
P=0.03
Kenkre et al, U Chicago
8/23 durable remissions4 LGL, 1 MCL, 1 HL, 2 DLB6 Chemo, 2 DLI
Specific Interventions: Indolent NHL (FL)
• MD Anderson (Khouri 2008)
– Flu/Cy/Rituximab N=47– All achieved CR, 2 relapses treated with rituximab +/- DLI to CR– OS 85% at 5 years
• Seattle flu(2 Gy TBI) n=46 indolent (Rezvani 2008)
– Relapse rate indolent 14%, 2 treated with IS/rituximab +/- DLI
• UK (alemtuzumab containing) n=41 (Morris 2004)
– Relapse at 3 years 44%– 6/10 responded to DLI leading to 65% current PFS at 3 years
• UK (BEAM-alemtuzumab) n=44 (Ingram 2008)
– Relapse rate of 20%– 4/6 treated with DLI had CR
Specific Interventions: Indolent NHL
• Generally very sensitive to graft-vs-NHL effects with low relapse rate following T replete HCT
• Prototype follicular NHL– Sensitive to IS withdrawal– Monoclonal antibody therapy (rituximab)– DLI
• In the absence of GVHD generally start with above, then consider chemotherapy +/- above
• Long term survival possible post relapse
Specific Interventions: Aggressive NHL
• Seattle flu(2Gy TBI) (Rezvani 2008)
– DLBCL n=32, 41% disease progression• 1 DLI x 3 no effect• 1 IS withdrawal- no effect• 1 second myeloablative HCT died TRM• 1 successful IS withdrawal-rituximab-XRT (alive in CR 54+ mo)• 1 successful second RIC (same donor) (alive CR 34+ mo)• 1 response IS withdrawal/ DLI
• UK flu-mel-alemtuzumab (Thomson 2009)
– DLBCL or transformed (n=48)– 15/48 (33%) relapsed
• 5/12 CR to DLI +/- chemotherapy
Specific Interventions: Aggressive NHL
• French Registry (Sirvent 2009)
– DLBCL n=68
– Relapse at 4 years 41%
– 20/26 relapses died of disease
– 5 in CR after chemo +/- XRT +/- DLI
• Vancouver, BC (Doocey 2005)
– Myeloablative conditioning for DLBCL n=44
– 13 progressed (32%)
– 3 received DLI, all 13 died of disease
• NCI (Bishop 2008)
– N=15 with aggressive NHL with relapse/ persistent disease post HCT
– 6/11 treated with IS withdrawal or DLI responded
– 3 / 4 treated with Chemotherapy/ DLI responded
– 6 remain in long term CR
Specific Interventions: Aggressive NHL
• Generally a kinetic problem post allogeneic HCT• Requires disease control prior to HCT• Early relapse difficult to manage• Limited success with
– IS withdrawal, DLI and antibody therapy• Long term benefit anecdotal
– Aggressive chemotherapy +/- DLI– XRT +/- DLI– Worth considering if disease is sensitive
Specific Interventions: Mantle-cell NHL
• MD Anderson– Myeloablative 1/16 relapsed (Khouri 1999)
– RIC 3/18 relapsed (1/3 responded DLI) (Khouri 2003)
– RIC n=35, (Tam 2009)
• 6 year OS 53%, PFS 46% (3 pts rituximab + DLI)• Seattle (Maris 2004)
– Flu(2Gy TBI), n=33– Relapse rate 9%, none after 6 months
• EBMT n=22 ( Robinson 2002)– Progression at 2 years = 100%, ~50% overall group had T depletion
• UK (Morris, 2004)– Alemtuzumab containing RIC (n=10 mcl)– At 3 years 50% relapse (1/2 responded to DLI)
Specific Interventions: Mantle-cell NHL
• Surprisingly sensitive to allogeneic GVT activity• Late relapses rare following T-replete transplants• Higher relapse rate following T cell depletion
– Requiring DLI or T cell add back
• Similar to indolent NHL for – response to IS withdrawal– DLI– chemotherapy +/- DLI
• Relapsing patients have chance of long-term DFS with RX
Future: Conclusions
• NHL often sensitive to GVT activity• Post transplant modulation is promising
– DLI– Immune modulatory agents
• Achieving a remission may allow re-establishment of GVT effects– Chemotherapy or other +/- DLI
• Ultimately therapy should invoke specific GVT immune responses without GVHD
• Registry studies may be a first step toward prospective studies in specific disease/risk categories.
• Prospective investigation of existing strategies in favorable groups• Radically novel approaches in unfavorable groups (i.e. aggressive
histology/early relapse)
Salvage Options: Hodgkin Lymphoma
Dr Karl PeggsUniversity College London
Dr David PorterUniversity of Pennsylvania Medical Center
“Reduced toxicity” transplantation = increased relapsing population
• Historically NRM prohibitive– Relatively few transplants
performed– Relatively few patients lived
long enough to relapse– Experience in salvaging
relapsing patients limited
• RIC/NST increased allo-HSCT for HL– relapse is the commonest
cause of treatment failure– 44-81% at 2-3 years
Gajewski et al. JCO 1996;14:572
IBMTR
Salvage chemotherapy
• Most series demonstrate relapse risk higher in those with refractory disease at transplant
– Most have received multiple lines of salvage pre-transplant so limited options to explore agents to which patients are naïve
• No published series appear prescriptive re salvage; often the precise regimens used are not described
• Regimens including IVE, ESHAP, mini-BEAM, irradiation, gemcitibine have been used in small numbers, often differing within series
Salvage chemotherapy
• Response rates likely reflect disease-related features e.g. chemosensitivity at transplant, time to relapse, tempo of relapse
• No evidence that any particular regimen isa) likely to affect a cure b) superior to any other
• Anecdotal reports suggest that occasional patients achieve durable responses
• Most relapses occur early - the role of 2nd transplants has not been explored
Novel agents
• Monoclonal antibodies (mAb) are of interest (might augment DLI)
– anti-CD20: CD20+ nodular lymphocyte predominant• relatively few of these cases are transplanted due to the rarity of
NLP HL and high cure rates with conventional approaches
– anti-CD25:– anti-CD30:
• both may be more effective if used as vectors for delivery of radio-conjugates or cytotoxics (monomethyl auristatin E)
• Immunostimulatory mAb:– anti-CTLA-4, anti-PD1, anti-PDL1 (antagonistic)– anti-4-1BB, anti-OX40 (agonistic)
Donor Lymphocyte Infusions
Study n Preceding chemotherapy
CR/PR Response rate
Response rate (DLI only)
Response at latest follow-up: time from last DLI - median (range)
N. American survey (1999)
6 unknown 0/2 29% unknown 2 PR6+ and 18+ months
UK 16 3 8/1 56% 54% 5 CR2223 days (1851-2388)
Spain 11 3 3/3 55% N/A None ongoing
UMN 2 unknown 0/2 100% unknown None ongoing
GITMO 9 0 3 33% 33% unknown
MDACC 14 11 3/3 43% 33% 1 PR264 days
DFCI 13 unknown 2/0 15% unknown unknown
EBMT Registry 41 23 13 32% 44% unknown
EBMT Registry(adolescent)
6 unknown 1/0 17% unknown 1 CR1 year
• Overall response rates in the region 35-55% (30/71 = 42%)• A minority have durable responses (7/24 = 29%)• Durable responses more frequent following T cell depleted HSCT?
• n = 22 progression/relapse (7 post salvage) (17 UCLH, 5 RFH -10 previously reported)
• 10 CR, 5 PR (20 evaluable, RR 75%)
• Response associated with GvHD– 9/10 CR, 4/5 PR– 5 grade III-IV, 4 extensive chronic
• Current status:– 6/10 maintain CR (median 4.8 yrs from DLI)– 3 died in CR (GvHD-related)– 1 progressed (2.3 yrs)– 2/5 PR progressed
• 3 yr OS from relapse 62% and PFS 52%
Peggs et al. ASH 2009;200
Donor Lymphocyte Infusions
Unanswered questions
Largely overlap with those raised for other diseases:
• Nature of the target antigens– EBV antigens?
• Biomarkers of responsiveness: histology, immune profiling
• Role of dose escalation, optimal dosing
• Role of manipulated DLI e.g. CD8-depleted DLI, LMP-specific T cells, ex-vivo activation
• Possible efficacy of genetically re-targeted T cells– CAR or TCR gene therapies e.g. to CD30
Conclusions
• Relapsed HL following allogeneic HSCT is increasingly common
• To date there have been no reports of systematic evaluation of salvage chemotherapy
• There is no published evidence on the use of 2nd transplants
• Increasing experience with DLI confirms graft versus HL, though optimal strategies remain undefined
Proposed Initiatives
• Many of the issues regarding DLI overlap with those in other diseases and could be addressed across disease types.– Dose, schedule, manipulation, timing, MRD, significance of mixed
chimerism
• An international collaborative network would facilitate our ability to address disease-specific issues– Rapid testing of new interventions and early adoption of uniform
treatment strategies.
Treatment of Relapsed CLL after Allogeneic Stem Cell Transplantation
Jose F. Leis, M.D., Ph.D.
Mayo Clinic
&
Nancy M. Hardy, M.D.
NCI Experimental Transplantation and Immunology Branch
Introduction
• Relapse remains a major cause of treatment failure after allogeneic transplantation for CLL
• PFS rates 34-67% and relapse rates 20-48% reported• Risk factors for relapse include bulky disease,
chemotherapy refractory disease at SCT, T-cell depletion, donor selection, marrow involvement at SCT, increased number prior therapies, etc.
• Both early and late relapses occur• R/O donor derived CLL in MRD SCT
– Monoclonal B lymphocytosis in13.5-18% of sibs
Keating, M et al. Leuk Lymphoma 2002; 43:17551762.
Months
Pro
po
rtio
n s
urv
ivin
g
1.0
0.8
0.6
0.4
0.2
00 12 24 36 48 60 72 84 96
(N = 147)
Survival of patients with fludarabine-refractory CLL
Donor Lymphocyte Infusions
Study n Preceding chemotherapy
CR CD3 Dose Notes
Russell 2005 4 None 3 2 x 107/kg DLI-induced aplasia2nd SCT in CR @ 14m
Ritgen 2004 9 None 7 ND CCR > 2 years
Gribben 2005 7 None 6 1 x 107 or 3 x 107/kg 50% gr II-IV aGVHD orextensive cGVHD
Marks 2002 7 None 1 ND 0% CCR
Sorror 2005 8 5 1 1 x 107 to 1.5 x 108/kg 1 PR, no durable response to chemotherapy
Khouri 2004 10 rituximab 7 1 x 107 to 1 x 108/kg 2 PRPlanned rituximab
Sorror 2008 3 “Antibody” ND ND Antibody + DLI
Delgado 2006 14 none 3 1 x 106 to 1 x 108/kg 1 PR, 2 died GVHD
Hoogendoorn 2007
11 none 5 unknown OS 67%, EFS 33% at 2 years
• Overall CR rate is 45% (33/73)• Minority have durable responses
Risk Factors for Failure of DLI“secondary graft-vs.-CLL resistance”
• GCLLSG CLL3X• Used real-time PCR and/or flow-based MRD monitoring• Identified 5 distinct patterns of MRD kinetics• One pattern: GVL response but failed to reach complete
MRD then relapsed despite extensive cGVHD• Possible mechanisms:
– clonal evolution – survival of clonogeneic cells at GVL sactuary sites (LNs)– developed tolerance– presence of tumor stem cell
Ritgen, Leukemia, 2008Ritgen, Leukemia, 2008
Augmenting DLI
• Donor T-cells may not be appropriately activated to induce GVL response
• Ex-vivo co-stimulation donor T-cells with magnetic beads coated with OKT3 & anti-CD28
• Conventional DLI --> escalating aDLI (1 x 106 to 1 x 108/kg in 5 dose levels) 12 days later
• 18 patients: 8 CR (4/7 ALL, 2/4 AML, 1/1 CLL, 1/2 NHL)– CLL patient in CR at 6 years post aDLI– 7 aGVHD (5 grade I-II, 2 with grade III)– 4 cGVHD
Porter, Blood 2006Porter, Blood 2006
Augmenting DLI
• Bi20 (FBTA05), trifunctional, bispecific antibody targeting CD20 (NHL/CLL) and CD3 (T cells) and DLI– Might direct T-cell efficiently to tumor cell
• 6 patients, 3 with p53-mutated CLL, 3 high-grade NHL– CLL patients failed prior DLI, alemtuzumab/rituximab
• All 3 CLL patients showed transient clinical responses– Improved B symptoms, LNs, splenomegaly, clearing
of CLL from blood with increasing doses Bi20• Recurrence of disease within weeks of cessation of Bi20
– Despite 1-4 doses DLI (106 to 108 CD3/kg)
Buhmann, BMT 2009
Chemotherapy Approaches
• Obstacles:– 33-90% reported to be fludarabine-refractory– High-frequency of p53 mutations (up to 50%)– Factors predict for failure to alkylating agents, purine analogues,
and rituximab• Limited data available for salvage chemotherapy
– Usually followed by DLI– Sorror: 5 patients (Flu+rit, CHOP, pentostatin, VCR/pred)- no
durable responses– Delgado: 6 patients (2 CHOP, COP, CMOP=rit/alem,
alemtuz+chl, flu/chl)• 1 patient alive in CR at 40+ months after CHOP and 2 DLI
Agents with activity against fludarabine-refractory, p53 mutated CLL
• Flavopiridol• CDK inhibitor• 45% response rate, 42% in p53 deleted, 72% in 11q deleted• Major toxicity: hyperacute tumor lysis
• Bendamustine• Bifunctional alkylating agent with purine-like structure• Active regardless of p53 or ZAP-70 status• ORR > 50%
• Alemtuzumab• ORR 33%, equivalent for p53 deleted• Cytopenias and infection risk, ? Effect on GVL
Byrd, Blood, 2007; Bergmann, Haematologica, 2005
Agents with activity against fludarabine-refractory, p53 mutated CLL
• High-dose methylprednisolone– 1 gram/m2/day x 5 days + rituximab– ORR 78% including 5/9 p53-deleted with 1 cycle– Infection in 1/3, Effect on GVL?
• Ofatumumab– Humanized anti-CD20 antibody– Impressive activity in relapsed/refractory CLL (ORR 50%)– Effects on acute and chronic GVHD unknown
• Lenalidomide– Immunomodulatory effects: T-cell activation via CD28, NK
cytotoxicity, increased IL-2 expression– 30% RR in 11q or 17p deletion CLL
Bowen, Leuk Lymph, 2007; Coiffier, Blood, 2008: Ferrajoli, Blood, 2008
Conclusions
• There is an absence of evidenced-based therapeutic options for treatment of relapsed CLL after allogeneic transplantation
• Response rates to standard salvage chemotherapy regimens has been disappointing
• Reports on the use of DLI are limited and response rates have been highly variable (0% to 60% CCR) and questions regarding the durability of response raised
• Methods to augment DLI and novel agents active against fludarabine-refractory CLL are promising
Proposed Initiatives
• Development of a national/international consortium to evaluated the optimal use of DLI in treatment of relapsed CLL
• Initiation of multi-center clinical trails to evaluate efficacy of promising novel agents for treatment of relapsed CLL
Nicolaus Kröger, Ted AlyeaNicolaus Kröger, Ted Alyea
Disease specific Treatment of Relapse after Disease specific Treatment of Relapse after Allogeneic Hematopoietic Cell TransplantationAllogeneic Hematopoietic Cell Transplantation
Multiple MyelomaMultiple MyelomaNCI Workshop 1/2-11.2009NCI Workshop 1/2-11.2009
Specific feature of allografting inSpecific feature of allografting inMultiple MyelomaMultiple Myeloma
1.1. Only about 50% will achieve complete Only about 50% will achieve complete remissionremission
2.2. Despite CR, relapse rate is higher than in Despite CR, relapse rate is higher than in other diseases and is about 50% at 5 yearsother diseases and is about 50% at 5 years
3.3. For patients without CR after allografting the For patients without CR after allografting the progression-rate is even higher (>80%)progression-rate is even higher (>80%)
4.4. Extramedullary relapse seems to be Extramedullary relapse seems to be increased after allogeneic SCTincreased after allogeneic SCT
Donor lymphocyte infusion for relapse Donor lymphocyte infusion for relapse
• Studies for relapsed patients:Studies for relapsed patients:ORR: 40-67% and CR: 19-30%ORR: 40-67% and CR: 19-30%
• Acute GvHD II-IV: 52-56% and cGvHD: 26-44%Acute GvHD II-IV: 52-56% and cGvHD: 26-44%
• Strong correlation between response and Strong correlation between response and occurrence of GvHDoccurrence of GvHD
• No clear correlation between CD3 cell dose and No clear correlation between CD3 cell dose and responseresponse
(Lokhorst et al 1997, Verdonck et al 1996, Salama 2000, Ayuk et al., 2004, Tricot 1996, Bertz et al., (Lokhorst et al 1997, Verdonck et al 1996, Salama 2000, Ayuk et al., 2004, Tricot 1996, Bertz et al., 1997)1997)
After standard conditioningAfter standard conditioning
Donor lymphocyte infusion for relapseDonor lymphocyte infusion for relapse
Overall response rate:Overall response rate: 38%: PR: 19% and CR 19%38%: PR: 19% and CR 19%
Acute GvHD II-IV:Acute GvHD II-IV: 38% and c GvHD: 42% 38% and c GvHD: 42% (extensive cGvHD: 10%)(extensive cGvHD: 10%)
Response according GvHD:Response according GvHD:
acute GvHD :acute GvHD : no: 21% ORRno: 21% ORRyes: 67% ORRyes: 67% ORR
chronic GvHD:chronic GvHD: no: 19% ORRno: 19% ORRyes: 63% ORRyes: 63% ORR
van de Donk et al., 2006
After RICAfter RIC
Survival after DLI according resonseSurvival after DLI according resonse
6060 8080 120120
1,01,0
0,80,8
0,60,6
0,40,4
0,20,2
0,00,0
MonthsMonths
10010040402020
Proportion of survivalProportion of survival
CRCR
PRPR
Lokhorst et al., 2004
Novel agents as salvage post allogeneic SCTNovel agents as salvage post allogeneic SCT
RationalesRationalesBortezomib: Bortezomib:
1. 1. highly active against myeloma cells highly active against myeloma cells
2. 2. in animal model: reduced GvHD but retain Graft in animal model: reduced GvHD but retain Graft versus leukemia effect versus leukemia effect (Sun et al., PNAS 2004)(Sun et al., PNAS 2004) and lead to a and lead to a
decreased T-helper 1 response among allreactivedecreased T-helper 1 response among allreactiveT-lymphocytes T-lymphocytes ((Blanco et al., Blood 2006Blanco et al., Blood 2006))
Lenalidomide and ThalidomideLenalidomide and Thalidomide::1.1. Activate T-cells and NK-cells which might augment Activate T-cells and NK-cells which might augment
the graft versus myeloma effect the graft versus myeloma effect (Lioznov et al., BMT 2009)(Lioznov et al., BMT 2009)
2.2. Low dose thalidomide more immunosuppressive Low dose thalidomide more immunosuppressive propertiesproperties
Immunomodulating agentsImmunomodulating agents
Immuno modulating agentsImmuno modulating agents
DoseDose Pat.Pat. PR-CRPR-CR GvHDGvHD ToxTox
Thali-domide
50-600 mg n = 31 29% - 0%n = 5,grade I-II
Neurotoxicity
Lenali-domide
15-25 mg n = 24 58% - 8%n = 3,grade I-II
Myelosuppression (neuro-penia grade 3/4 =25%
Lenali-domide
25 mg n = 16 50%-31%n = 5,(n = 3, grade III/IV)
Myelosuppression,DVT n = 2
Mothy,et al 2005; Lioznov et al 2009; Minnema et al 2008Mothy,et al 2005; Lioznov et al 2009; Minnema et al 2008
Proteasome InhibitorProteasome Inhibitor
Dose Pat. PR - CR GvHD Tox
Borte-zomib
1-1.3 mg/m2
day 1, 4, 8 + 11n = 37 34% - 19% none
Neurotoxicity,grade 1-2: 85%
El-Cheikh, 2008El-Cheikh, 2008
Donor lymphocyte infusion in combination Donor lymphocyte infusion in combination with novel agentswith novel agents
Treatment planTreatment plan
Thalidomide 100 mgThalidomide 100 mg
DLI: 1 x 10DLI: 1 x 1066 CD3+/kg (MUD) CD3+/kg (MUD)or: 5or: 5 x 10 x 1066 CD3+/kg (related) CD3+/kg (related)
No response:No response:escalating Thaescalating Thalidomide (200 lidomide (200 →→ 300 300 →→ 400 mg) 400 mg)And/or: further DLIAnd/or: further DLI
14 days14 days
Kröger et al., Blood 2004Kröger et al., Blood 2004
CR:CR: 66/18/18 33%33%
PR:PR: 4/184/18 22%22%
MR:MR: 2/182/18 12%12%
SD/NC:SD/NC: 5/185/18 28%28%
PD:PD: 1/181/18 5%5%
Low dose thalidomide (100mg) andLow dose thalidomide (100mg) andescalating DLIescalating DLI
Response rateResponse rate
Med. time to response: 108 days (36 – 266)Med. time to response: 108 days (36 – 266)
67% (ORR)67% (ORR)
Thalidomide and DLIThalidomide and DLI
afterafterSCTSCT
No. of patientsNo. of patients 1818 1111 1818
acute GvHD I-IVacute GvHD I-IV 10 (55%)10 (55%) 5 (46%)5 (46%) 2 (11%)2 (11%)
acute GvHD II-IVacute GvHD II-IV 4 (22%)4 (22%) 3 (27%)3 (27%) 00
chr.GvHD limchr.GvHD lim 4 (22%)4 (22%) 4 (36%)4 (36%) 7 (39%)7 (39%)
chr.GvHD extchr.GvHD ext 1 (6%)1 (6%) 00 0 0
afterafterThal/DLIThal/DLI
afterafterDLIDLI
Treatment options for relapse Treatment options for relapse
ORRORR CRCR Overall survivalOverall survival
1.1. Donor lymphocyte Donor lymphocyte infusion (DLI)infusion (DLI) 40 – 67 %40 – 67 % 19 -30 %19 -30 % med. 23-23.6 momed. 23-23.6 mo
2.2.CD8-depleted CD8-depleted donor-lymphocyte donor-lymphocyte infusioninfusion
71 %71 % 43 %43 % 2year: 55%2year: 55%
3.3. ThalidomideThalidomide 29 – 83 %29 – 83 % 0 – 22 %0 – 22 % 3year: 25%3year: 25%
4.4. LenalidomideLenalidomide 66 %66 % 8 – 23 %8 – 23 % med. 19.9momed. 19.9mo
5.5. BortezomibBortezomib 80 – 100 %80 – 100 % 29 – 30 %29 – 30 % 3year: 50%3year: 50%
7.7. ThalidomideThalidomideplus DLIplus DLI 67 %67 % 22 %22 % 2year: 100%2year: 100%
Novel approaches and future researchNovel approaches and future research
1.1. Manipulation to reduce GvHD after DLIManipulation to reduce GvHD after DLI-- CD8 depleted T-cellsCD8 depleted T-cells-- CD4 enriched T-cellsCD4 enriched T-cells-- Depleting alloreactive T-cellsDepleting alloreactive T-cells-- Alloreactive NK-cellsAlloreactive NK-cells-- Tumor specific T-cells (anti-idiotype, Cancer-tests Tumor specific T-cells (anti-idiotype, Cancer-tests
antigen, HAGantigen, HAG-- Antibody mediated cytotoxicity (BCMA)Antibody mediated cytotoxicity (BCMA)-- Donor vaccination (e.g. idiotype)Donor vaccination (e.g. idiotype)
2.2. Enhance cell mediated cytotoxicityEnhance cell mediated cytotoxicity-- DLI in combination with novel agents (thalidomide, DLI in combination with novel agents (thalidomide, Bortezomib, Lenalidomide)Bortezomib, Lenalidomide)
3.3. Investigate novel drug combinationsInvestigate novel drug combinations, e.g. Lenalidomide , e.g. Lenalidomide plus Bortezomib etcplus Bortezomib etc
Proposed Initiatives for the subcommitteeTreatment of Relapse after allo SCT
1. Dose-finding studies for novel agents after allogeneic SCT
(Lenalidomide, bortezomib, hypomethylating agents)
2. Clinical trial investigating early (MRD based) vs late (clinical based)
therapeutic intervention (DLI and/or novel agents) to treat relapse
after allogeneic SCT
3. Investigate novel agents in combination with adoptive
immunotherapy (T-cells or NK-cells) as treatment for relapse
after allogeneic SCT
4. Investigate in a prospective trial the value of a second allogeneic
SCT in those patient who relapsed to a RIC allograft
Future Directions and Proposals
• Better data collection and reporting.
• Sample repository for relapse.
• Identify target cells and/or antigens for GVT induction.
• Define prognostic factors and use to develop and test appropriate strategies– Clinical– Biomarkers for response?
An embarrassing lack of data
Future Directions and Proposals
• Study novel agents– azacitidine, decitabine, lenalidomide, bortezomib, sorafenib, etc..
• Combination drug, antibody and/or cellular therapies.• Vaccination strategies of patient/donor
– mHag, tumor-specific antigens, APCs
• Modification of DLI– Tumor specific DLI through selection, genetic modification, etc.– Activation– Subset selection or depletion
• Readdress role of second SCT, particularly after RIC SCT.
Obstacles
• Lack of comprehensive databases capturing relapse information.– Registry studies helpful “first step”
• Lack of large multicenter prospective trials to define best therapies.– Difficulty setting up national and international
collaborations.
• Difficulty engaging sponsors, payors, regulators, physicians, patients in very high risk, novel therapies.
Moving Forward
• International multicenter network to rapidly and definitively test and disseminate new treatment approaches for relapse.– Begin with the First International Workshop on the
Biology, Prevention and Treatment of Relapse after Allogeneic SCT.
– Maintain interactions and momentum through workshops, meetings, consortium-building
– Develop trials and seek funding.• Consider trial design carefully for maximum and rapid impact• . Multiple small pilots vs randomized phase II or III?
PROUD
GLOOMY
Disease-Specific Treatment of Relapse after Allogeneic Transplantation
• Fred Falkenburg
• Joseph Antin
• Marcos de Lima
• Eli Estey
• John Levine
• Jacob Rowe
• Alan Wayne
• David Maloney
• Koen van Besien
• Karl Peggs
• David Porter
• Jose Leis
• Nancy Hardy
• Nicolaus Kröger
• Edwin Alyea