Disease-Specific Treatment of Relapse after Allogeneic Transplantation

Treatment of Relapse

Cellular ImmunotherapyWithdrawal of immune suppressionDLI ( + chemotherapy)Second allogeneic SCTNon-Cellular therapiesSupportive careConventional chemotherapy or radiationNovel cytotoxic agentsBiological agentsImmunotherapy approaches

Treatment of RelapseCellular therapyWithdraw ISSecond BMT with same or different donorDLIActivated DLIManipulated DLICD8 depleted, CD4 enriched, antigen-specific.Dose titrated DLINK cellsModified T cells (CARs)Other therapiesConventional chemotherapy or radiationAntibodiesCD20, CD33, CD30, CTLA-4, etcBispecific antibodiesBiological therapyLenalidomide, thalidomide, bortezomib, azacytadine, decitabine, mTor inhibitors,others.Interferon, IL-2, etcVaccinesOthers

Available data for treatment of relapseCML-CP: DLI restores durable CR in 80% of pts with CP relapse.Dose, schedule, toxicity well defined.Role of TKIs?AML, ALL, NHL, HL, CLL, MM, CML-AP/BCDLI response rate, most effective approach, and long term outcomes?Second SCT ?Other therapies ?

An embarrassing lack of data

Excuses (good ones)

Patients are heterogeneousAgeImpact of prior transplant Myeloablative vs RICGVHD prophylaxis (TCD, alemtuzumab, sirolimus, etc)Different graftsBM vs PBSCTCD, other manipulationDonor source and availability (sibling/family, URD, UCB, matched or mismatched)Different risks, timing to intervention, treatment choice, etcClinical complications and co-morbidities after allogeneic SCTMay not tolerate therapies wellActive GVHD? Acute or chronic?Use of immune suppression

Excuses (good ones)

Disease-related issues are heterogeneousTiming of relapse: early vs late relapse may be very differentHistology (particularly in NHL)Disease burden and pace of progressionIn indolent diseases residual disease may not require interventionInfluence of prior therapies and likely drug resistanceSmall 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 selectionDepends on patient, disease activity, donor availability, prior therapiesPatient selectionAge, 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 leukemiaIs there a dose:toxicity relationship?Minimal threshold for GVHD may vary by donor source (haplo vs well matched)Sibling vs unrelated donorOften 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 factorsSignificance in other diseases less clearMay 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 stepDefine 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 TransplantationFred FalkenburgJoseph AntinMarcos de LimaEli EsteyJohn LevineJacob RoweAlan WayneDavid MaloneyKoen van BesienKarl PeggsDavid PorterJose LeisNancy HardyNicolaus KrgerEdwin Alyea

CMLAMLALLNHLMMCLLHL

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 casesRelatively low doses of DLI requiredTime interval between treatment and response is dose and disease state dependentInterferon may potentiate onset and effectTarget recognition may determine balance between GVHD and GVL

Hematopoiesis-associated minor histocompatibility antigens (mHag) and GVL reactivityIn HLA-identical transplantation donor T cells recognizing hematopoiesis-specific antigens on recipient cells eliminate normal and malignant hematopoietic cells of recipient originGVL-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 DLI0,000010,00010,0010,010,11SCT+12 SCT+28DLI+1.5+3+5+6+7+8+9+10+11+13+15+18+22+26weeks post treatment

Kinetics of immune responses after DLIRZ

HA-2,-1, A2-HY tetramers DL (3)

Blad2

Blad3


2.614.976615688214.9766156882SCT+12

3.715.113174061415.11317406147.5565870307

4.316.06295907668.0314795383DLI

3.48.174093264224.52227979278.1740932642

451.182477899534.12165193334.121651933

2.91175.558166150582.0156860105109

3.42508.7071945285195.4836774957+6

1.21719.56161510221264.964866282159

0.7200.9371146732150.7028360049+8

1.1167.2984397998182.5073888725+9

1.7130.3675129752223.487165100393.1196521251

2.351.0524213679272.279580629168.0698951573

2.4109.6664688427255.8884272997+13

3.397.1655939146267.205383265172.8741954359

3.525.6160214813128.080107406638.424032222

2.784.6076957696105.759619712+22

2.9109.355989352327.3389973381136.6949866903

WBC x10E6/ml

CD8+/HA-2+ /ml

CD8+/HA-1+ /ml

CD8+/HY-A2+ /ml

weeks post treatment

CD8+/tetramer+ cells

WBC

data f-up roozeboom

datum8/27/9810/8/984/27/997/30/9912/14/9912/23/991/6/001/20/001/27/002/3/002/10/002/17/002/24/003/2/003/16/003/30/004/20/005/18/006/15/00

donorpat

SCT+12SCT+28DLI+1.5+3+5+6+7+8+9+10+11+13+15+18+22+26

Hbmmol/l7.76.76.67.77.17.36.76.455.66.565.95.8777.77

Trombox10E9/l6761681572943032702314014082942125210181163162156135

WBCx10E67.28.72.63.74.33.44.02.93.41.20.71.11.72.32.43.33.52.72.9

% lymfo%30322822101214192850975755382925262936

abs lymfox10E3/ml216027847288144304085605519526006796279358746968259107831044

% CD3+CD8+%23.099.4316.688.1616.0216.2423.0936.8526.0231.412016.4814.215.619.4725.1612.5824.0123.61

% CD45+CD14-%93.9165.0781.0887.985.7781.0675.7974.2776.0395.3581.167.9471.2980.1274.1485.4589.3888.8890.16

abs # CD3+CD8+x10E3/ml531403150768082171273326198167152186170183243128212273

% HA-2+%000.010.020.020.010.030.430.770.870.120.110.070.030.060.040.020.040.04

CD8+/HA-2+0015151685111762509172020116713051110972685109

% HA-1+%000.010.020.010.030.020.030.060.640.090.120.120.160.140.110.10.050.01

CD8+/HA-1+0015158253482195126515118322327225626712810627

% HY-A2+%0.010.010.010.010.020.040.030.050.040.030.030.05

CD8+/HY-A2+534088341095993687338137

chimerisme MNC

patient47080twm95

chimerisme Leuco

patient95

BCR/ABL VB8.00E-049.90E-013.40E-01negnegnegnd

BCR/ABL BM1.20E-037.90E-022.30E-01dub posdub posnegneg

morfologieCML+hypoplasieCML--ntb

CML--


2.614.976615688214.9766156882SCT+12

3.715.113174061415.11317406147.5565870307

4.316.06295907668.0314795383DLI

3.48.174093264224.52227979278.1740932642

451.182477899534.12165193334.121651933

2.91175.558166150582.0156860105109

3.42508.7071945285195.4836774957+6

1.21719.56161510221264.964866282159

0.7200.9371146732150.7028360049+8

1.1167.2984397998182.5073888725+9

1.7130.3675129752223.487165100393.1196521251

2.351.0524213679272.279580629168.0698951573

2.4109.6664688427255.8884272997+13

3.397.1655939146267.205383265172.8741954359

3.525.6160214813128.080107406638.424032222

2.784.6076957696105.759619712+22

2.9109.355989352327.3389973381136.6949866903

WBC x10E6

CD8+/HA-2+

CD8+/HA-1+

CD8+/HY-A2+


CD8+/tetramer+ cells

WBC

Blad2

Blad3


2.614.976615688214.9766156882

3.715.113174061415.1131740614

4.316.06295907668.0314795383

3.48.174093264224.5222797927

451.182477899534.121651933

2.91175.558166150582.0156860105

3.42508.7071945285195.4836774957

1.21719.56161510221264.9648662821

0.7200.9371146732150.7028360049

1.1167.2984397998182.5073888725

1.7130.3675129752223.4871651003

2.351.0524213679272.2795806291

2.4109.6664688427255.8884272997

3.397.1655939146267.2053832651

3.525.6160214813128.0801074066

2.784.6076957696105.759619712

2.9109.355989352327.3389973381

WBC x10E6

CD8+/HA-2+

CD8+/HA-1+


CD8+/tetramer+ cells/mL

WBC/mL

bcrabl PBGD ratio rozeboom

-3.096110013-2.919618754

-3.1116106997-1.5199135645

-0.0043648054-1.0233729087

+1.5+1.5

+3+3

-0.468521083-0.408272164

+6+6

+7+7

+8+8

-5.5-5.4

+10+10

+11+11

-5.5-5.4

+15+15

-5.5-5.4

-5.5-5.4

-5.5-5.4

BCR/ABL PB

BCR/ABL BM

weeks after DLI

bcr-abl/PBGD ratio

data f-up roozeboom

datum8/27/9810/8/984/27/997/30/9912/14/9912/23/991/6/001/20/001/27/002/3/002/10/002/17/002/24/003/2/003/16/003/30/004/20/005/18/006/15/00

donorpat

SCT+12SCT+28DLI+1.5+3+5+6+7+8+9+10+11+13+15+18+22+26

Hbmmol/l7.76.76.67.77.17.36.76.455.66.565.95.8777.77

Trombox10E9/l6761681572943032702314014082942125210181163162156135

WBCx10E67.28.72.63.74.33.44.02.93.41.20.71.11.72.32.43.33.52.72.9

% lymfo%30322822101214192850975755382925262936

abs lymfox10E3/ml216027847288144304085605519526006796279358746968259107831044

% CD3+CD8+%23.099.4316.688.1616.0216.2423.0936.8526.0231.412016.4814.215.619.4725.1612.5824.0123.61

% CD45+CD14-%93.9165.0781.0887.985.7781.0675.7974.2776.0395.3581.167.9471.2980.1274.1485.4589.3888.8890.16

abs # CD3+CD8+x10E3/ml531403150768082171273326198167152186170183243128212273

% HA-2+%000.010.020.020.010.030.430.770.870.120.110.070.030.060.040.020.040.04

CD8+/HA-2+0015151685111762509172020116713051110972685109

% HA-1+%000.010.020.010.030.020.030.060.640.090.120.120.160.140.110.10.050.01

CD8+/HA-1+0015158253482195126515118322327225626712810627

% HY-A2+%0.010.010.010.010.020.040.030.050.040.030.030.05

CD8+/HY-A2+534088341095993687338137

chimerisme MNC

patient47080twm95

chimerisme Leuco

patient95

BCR/ABL PB0.00080.0007720.990.34negnegnegnd

-3.096110013-3.1116106997-0.0043648054-0.468521083-5.5-5.5-5.5-5.5-5.5

BCR/ABL BM0.00120.02830.0790.23dub posdub posnegneg

-2.919618754-1.5199135645-1.0233729087-0.408272164-5.4-5.4-5.4-5.4-5.4

morfologieCML+hypoplasieCML--ntb

CML--

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 GVHDTargeting 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 DLICML 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

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 hoursHA-1no T-cellsC6-1

no T-cellsC6-1HA-1immature CML cells incubated with T cell clones for 50 hours

ConclusionsCD8+ 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 TKIAre 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?

Quantitative flow cytometric analysis of phenotype and proliferative status of CML precursor cells 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 beads1032CFSECD34CFSEcounts

Specific kill of proliferating CML precursor cells by ImatinibCFSECD346 dayscontrol100 mM imatinib

CFSE6 days pretreated48 hours CTL exposure (HLA-A2 restricted mHag-specific CD8+ clone; E/T 3/1)control+ mHag spec. CTLCross-resistance of Imatinib pre-treated CML precursor cells to cell death induced by cytotoxic T cells100mM Imatinib

CFSECD346 days CTL exposure (HLA-A2 restricted mHag-specific CD8+ clone; E/T 3/1)control+ mHag spec. CTLQuiescent CML precursor cells are resistant to cell death induced by cytotoxic T cellsno pre-treatment

ConclusionsQuiescent 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-SCTIf 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 targetedSeparation 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 mHagInterferon may potentiate onset and effectAre TKI useful, or harmful?How to treat extramedullary relapses

Treatment of relapsed acute myelogenous leukemia after allogeneic stem cell transplantationMarcos 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 Ringdn 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, 25402544. 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.

Donor lymphocyte infusion alone Kolb H. Blood 1995;86:2041-2050 Loren A, Porter DL. Bone Marrow Transplantation (2008) 41, 483493.Porter DL et al. Blood 2000;95:1214-1221.

Investigatorn Outcomes Collins et al. 46

6/39 (15%) CR

Kolb et al. 195/17 (29%) CRShiobara et al. 21

8/21 (38%) Response7% 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.

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

Schmid, C. et al. J Clin Oncol; 25:4938-4945 2007Donor lymphocyte infusionEBMT 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

Schmid, C. et al. J Clin Oncol; 25:4938-4945 2007Fig 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) Schmid, C. et al. J Clin Oncol; 25:4938-4945 2007

VariablePRelative Risk 95% CI

% blast at relapse (BM), > 35%.0060.560.38 to 0.85Female v male.021.61.07 to 2.4Cytogenetics (favorable v other).0045.61.76 to 1.8remission versus no remission< .00015.82.5 to 13.7

Second transplant

6% of patients with recurrent leukemia receive a 2nd HSCT Eapen et al. Bone Marrow Transplant 2004;34:721-727Second transplants matched related donor CIBMTR analysis

AML125ALL 72CML 82

Age (years) 1040 (14)112056 (20)213064 (23)>30119 (43)

Same donor as 1st transplant238 85%

Follow-up of survivors, median93 mo.

Eapen et al. Bone Marrow Transplant 2004;34:721-727RIC was associated with more relapses.Second transplants matched related donor CIBMTR analysis

Overall mortality

Age at 2nd HSCT (years) 20961.00>201831.94 (1.422.64)62131.00 6523.47 (2.494.83)

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 leukemiaC Hosing et al. BMT (2005) 36, 157162no circulating blasts / 5% bone marrow blasts

Oran et al. Leukemia (2007) 21, 25402544.

Oran et al. Leukemia (2007) 21, 25402544;

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

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.


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.

Key obstacles for development of large, randomized, prospective clinical studies

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.

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 after allogeneic TransplantationAlan S Wayne and Jacob M. Rowe

Relapsed ALL Early diagnosis is probably crucial Conventional and investigational therapies likely to be greater if intervention is prior to florid relapse

INTRODUCTIONRelapsed ALL has a very poor prognosis In adults only 7% survive 5 years

Relapse post allogeneic transplant, almost always incurable0123450255075100PERCENT 7% N= 609 Fielding AK et al, Blood, 2007

Relapsed ALL Post Allogeneic HSCT

While cures are rare, INDUCTION OF REMISSION

and / or PROLONGATION OF RESPONSE is an

important endpoint

ALL: Therapy at Relapse post Allo HSCTCURATIVE INTENT SUPPORTIVE CARE ONLYMINORITY THERAPEUTIC INTENT MINORITY REMISSION NON-MYELOABLATIVE INDUCTION MAINTENANCECONSOLIDATION / MAINTENANCE

ALLO SCT

Graft versus Leukemia (GvL) in ALLFirst clinical description of GvL in humans was in ALL !Weiden PL et al, NEJM 300: 1068, 1979DiseaseFreeSurvival(%)Syngeneicn=46YearsAllogeneic GVHD 0-I n=117Allogeneic,GVHD II - IVn=79

Potent GvL in ALL in CR1 Goldstone AH, et al, Blood, 2008

Graft versus Leukemia (GvL) in ALL REDUCED-INTENSITY CONDITIONING FOR HIGH-RISK ALLCIBMTR STUDY OF ALL IN CR1 OR CR2

RIC (n= 92) vs myeloablative (n= 1421)Median Age, yrs,45 28 p= < .0001 OS @ 3 yrs, %38 43 p= .39 TRM @ 3 yrs, %32 33 p= .86Marks, DI et al, ASH 2009

Graft versus Leukemia (GvL) in Relapsed ALLDonor 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, 2000CR 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.Probability (%)Weeks after complete remissionCMLn=12ALLn=5AMLn=10Disease Free Survival, if CR after unrelated DLI

Suggested Treatment of Relapsed ALL post TransplantUNFIT 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 ANTIBODIESNO PRIOR GVHD PRIOR GVHD GRADE I DLI SECOND ALLOGENEIC TRANSPLANT +/- SECOND ALLOGENEIC TRANSPLANT* Consider clinical trial**

Investigational ApproachesPH-POSITIVE PH-NEGATIVE NOVEL CHEMOTHERAPY MONOCLONAL ANTIBODIESand TARGETED AGENTS +/- CHEMOTHERAPY NOVEL TKIsUNCONJUGATED 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-specific DENILEUKIN DIFTITOX (IL-2)NELARABINE CLOFARABINE LIPOSOMAL VINCRISTINEGAMMA SECRETASE INHIBITORS

55 kD recombinant single chain variable fragments (scFv)Anti-CD19 Fv (HD37)Anti-CD3 Fv (L2K-07)Gly/Ser linkerAnti-CD19 Bi-Specific T-Cell Engager (BiTE) MEDI-538, MT103, BlinatumomabFv: variable fragment; VH: variable heavy-chain; VL: variable light-chain; sc: single chain

Courtesy of Rupert Handgretinger, October 2009Clearance of marrow blastsIncrease in CD8 T+ cellsCD19 BiTE for Relapse after SCT Active against childhood ALLClearance of MRDCD19 BiTE

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

Future Directions - Cancer Vaccines I I PEPTIDE VACCINES SOME DATA IN AML USING WT1 PEPTIDE. MINIMAL TOXICITYplateletsblastsBlasts, % Mailander V, Leukemia, 2004

MonthsPlatelets (/nl)VaccinationChemo-therapyWTI/PBGD

Future Directions - Cancer Vaccines III

PR1, a leukemia-associated antigen, studied for vaccination in AML, with some success [HESLOP HE, STVENSON FK AND MOLLDDREM JJ, HEMATOLOGY, ASH EDUCATION 2003] Dendritic cells and antigen presenting cells utilized to improve the immune response to tumor associated antigen in multiple myeloma [AVIGAN D ET AL, ASH 2008 AND 2009] Rationale applicable to other malignancies including ALL

SUHOSKI MM , MOL THER, 2007

Disease-Specific Interventions for Relapse of non-Hodgkin Lymphoma After Allogeneic Transplantation

David Maloney MD, PhDKoen van Besien, MD

NHL Relapse Following Allogeneic HCT: A Wide Range of Issues to ConsiderMany different histologic subtypes of NHLindolent to aggressive behaviorPatients often treated with Allogeneic HCT as last resortafter failed high-dose therapy and autologous HCTwith chemotherapy refractory diseaseTransplanted with a variety of conditioning intensitiesmyeloablative, reduced intensity, nonmyeloablativeT depleted or T replete graftsHLA matched or mismatched, related, unrelated, cord blood or haploidentical stem cell sources

Factors that Influence the Outcome of NHL Relapse post Allogeneic HCTHistologyPresence or absence of GHVDT-replete vs T-depleted graftsDisease status at HCT (chemorefractory vs sensitive)Transplant conditioning intensityTiming of relapse (early vs late)

Approach to the Treatment of NHLRelapse post Allogeneic HCTIn the absence of GHVDWithdrawal of immunosuppression (IS)Donor Lymphocyte Infusions (DLI)Monoclonal antibody therapyChemotherapy +/- DLIRadiotherapy +/- DLIImmune stimulants (IL-2 etc)Second allogeneic HCT

Specific Therapies: Withdrawal of ImmunosuppressionNo prospective trialsSeveral reported successes

StudyCond for HCTnHistologyChem/XRTCR/PRResponsevan Besien 1997Ablative9DL (4)LBL(2)FL(2)PL (1)?33 CR2+-22+ moBishop 2008RIC13DL063 long CR42+-63+ mo

Specific Therapies: Donor Lymphocyte Infusions (DLI)An option in the absence of GVHDMore commonly reported following T-depleted HCTResponse often correlated with disease histology and pace of progressionSome risk of subsequent GVHDA wide range of CD3 cell doses used

Specific Therapies: Donor Lymphocyte Infusions (DLI)Usually reported in context of larger transplant trials

StudyCond for HCTnHistologyChem/XRTCR/PRResponseRussell 2005T-dep (15)T-replete (2)17DL (5),MCL(4)FL(4),CLL (4)911PFS 3 y 52%OS 3 y 58%Bloor 2008T-dep (16)17CLL (3),MCL (3)FL (6),DL (5)81310 in remission f/u 26 moBishop 2008RIC5DL (5)433 CR 74+-83+movan Besien 1997ablative3DL (2), PL (1)0Marks 2002T-dep15FL (15)87 CR 16+-40+ moMandigers 2003T-dep7FL (5), SL (2)464 CR 43+-89+ mo

Specific Therapies: Chemotherapy +/- DLIAnecdotal reports of chemotherapy +/- DLI generally within clinical trial resultsOccasionally successfulSupport the concept of ongoing graft-vs-tumor effects that may be capable of controlling minimal residual diseaseNo clear choice of agentsConcern of ablating graft appears low, but needs to be studied

Specific Therapies: Monoclonal Antibody TherapyFrequently utilized for B cell NHLLow hematologic toxicityMay promote antigen priming and graft-vs-tumor effectsTumor 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 AgentsInterleukin-2 (Kiss 2003)CR in low grade NHL pt (flare GVHD)Interferon alpha (Kawano 2004)CR in DLBCL with IFN + DLIThalidomide (Tueger 2006)1 pt with DLBCL and CRCTLA-4 blockade with ipilimumab (Bashey 2009)3 pts with HD or MCL had response

Impact of Early vs Late NHL Relapse Post Allogeneic HCTKenkre et al, U Chicago8/23 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=47All achieved CR, 2 relapses treated with rituximab +/- DLI to CROS 85% at 5 yearsSeattle flu(2 Gy TBI) n=46 indolent (Rezvani 2008)Relapse rate indolent 14%, 2 treated with IS/rituximab +/- DLIUK (alemtuzumab containing) n=41 (Morris 2004)Relapse at 3 years 44%6/10 responded to DLI leading to 65% current PFS at 3 yearsUK (BEAM-alemtuzumab) n=44 (Ingram 2008)Relapse rate of 20%4/6 treated with DLI had CR

Specific Interventions: Indolent NHLGenerally very sensitive to graft-vs-NHL effects with low relapse rate following T replete HCTPrototype follicular NHLSensitive to IS withdrawalMonoclonal antibody therapy (rituximab)DLIIn the absence of GVHD generally start with above, then consider chemotherapy +/- aboveLong term survival possible post relapse

Specific Interventions: Aggressive NHLSeattle flu(2Gy TBI) (Rezvani 2008)DLBCL n=32, 41% disease progression1 DLI x 3 no effect1 IS withdrawal- no effect1 second myeloablative HCT died TRM1 successful IS withdrawal-rituximab-XRT (alive in CR 54+ mo)1 successful second RIC (same donor) (alive CR 34+ mo)1 response IS withdrawal/ DLIUK flu-mel-alemtuzumab (Thomson 2009)DLBCL or transformed (n=48)15/48 (33%) relapsed5/12 CR to DLI +/- chemotherapy

Specific Interventions: Aggressive NHLFrench Registry (Sirvent 2009)DLBCL n=68Relapse at 4 years 41%20/26 relapses died of disease5 in CR after chemo +/- XRT +/- DLIVancouver, BC (Doocey 2005)Myeloablative conditioning for DLBCL n=4413 progressed (32%)3 received DLI, all 13 died of diseaseNCI (Bishop 2008)N=15 with aggressive NHL with relapse/ persistent disease post HCT6/11 treated with IS withdrawal or DLI responded3 / 4 treated with Chemotherapy/ DLI responded6 remain in long term CR

Specific Interventions: Aggressive NHLGenerally a kinetic problem post allogeneic HCTRequires disease control prior to HCTEarly relapse difficult to manageLimited success withIS withdrawal, DLI and antibody therapyLong term benefit anecdotalAggressive chemotherapy +/- DLIXRT +/- DLIWorth considering if disease is sensitive

Specific Interventions: Mantle-cell NHLMD AndersonMyeloablative 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=33Relapse rate 9%, none after 6 monthsEBMT n=22 ( Robinson 2002)Progression at 2 years = 100%, ~50% overall group had T depletionUK (Morris, 2004)Alemtuzumab containing RIC (n=10 mcl)At 3 years 50% relapse (1/2 responded to DLI)

Specific Interventions: Mantle-cell NHLSurprisingly sensitive to allogeneic GVT activityLate relapses rare following T-replete transplantsHigher relapse rate following T cell depletionRequiring DLI or T cell add back Similar to indolent NHL for response to IS withdrawalDLIchemotherapy +/- DLIRelapsing patients have chance of long-term DFS with RX

Future: ConclusionsNHL often sensitive to GVT activityPost transplant modulation is promisingDLIImmune modulatory agentsAchieving a remission may allow re-establishment of GVT effectsChemotherapy or other +/- DLIUltimately 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 groupsRadically novel approaches in unfavorable groups (i.e. aggressive histology/early relapse)

Salvage Options: Hodgkin Lymphoma

Dr Karl PeggsUniversity College LondonDr David PorterUniversity of Pennsylvania Medical Center

Reduced toxicity transplantation = increased relapsing population

Historically NRM prohibitiveRelatively few transplants performedRelatively few patients lived long enough to relapseExperience in salvaging relapsing patients limitedRIC/NST increased allo-HSCT for HLrelapse is the commonest cause of treatment failure44-81% at 2-3 years


Most series demonstrate relapse risk higher in those with refractory disease at transplantMost have received multiple lines of salvage pre-transplant so limited options to explore agents to which patients are naveNo published series appear prescriptive re salvage; often the precise regimens used are not describedRegimens including IVE, ESHAP, mini-BEAM, irradiation, gemcitibine have been used in small numbers, often differing within series


Response rates likely reflect disease-related features e.g. chemosensitivity at transplant, time to relapse, tempo of relapseNo evidence that any particular regimen islikely to affect a cure superior to any otherAnecdotal reports suggest that occasional patients achieve durable responsesMost 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 predominantrelatively few of these cases are transplanted due to the rarity of NLP HL and high cure rates with conventional approachesanti-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)


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 GvHD9/10 CR, 4/5 PR5 grade III-IV, 4 extensive chronicCurrent 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 progressed3 yr OS from relapse 62% and PFS 52% Peggs et al. ASH 2009;200


Largely overlap with those raised for other diseases:Nature of the target antigensEBV antigens?Biomarkers of responsiveness: histology, immune profilingRole of dose escalation, optimal dosingRole of manipulated DLI e.g. CD8-depleted DLI, LMP-specific T cells, ex-vivo activationPossible efficacy of genetically re-targeted T cellsCAR or TCR gene therapies e.g. to CD30

Conclusions

Relapsed HL following allogeneic HSCT is increasingly commonTo date there have been no reports of systematic evaluation of salvage chemotherapyThere is no published evidence on the use of 2nd transplantsIncreasing 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 chimerismAn international collaborative network would facilitate our ability to address disease-specific issuesRapid 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

IntroductionRelapse remains a major cause of treatment failure after allogeneic transplantation for CLLPFS rates 34-67% and relapse rates 20-48% reportedRisk 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 occurR/O donor derived CLL in MRD SCTMonoclonal B lymphocytosis in13.5-18% of sibs

Survival of patients with fludarabine-refractory CLLKeating, M et al. Leuk Lymphoma 2002; 43:17551762. MonthsProportion surviving1.00.80.60.40.2001224364860728496(N = 147)


Overall CR rate is 45% (33/73) Minority have durable responses

Risk Factors for Failure of DLIsecondary graft-vs.-CLL resistanceGCLLSG CLL3XUsed real-time PCR and/or flow-based MRD monitoringIdentified 5 distinct patterns of MRD kineticsOne pattern: GVL response but failed to reach complete MRD then relapsed despite extensive cGVHDPossible mechanisms: clonal evolution survival of clonogeneic cells at GVL sactuary sites (LNs)developed tolerancepresence of tumor stem cell

Ritgen, Leukemia, 2008

Augmenting DLIDonor T-cells may not be appropriately activated to induce GVL responseEx-vivo co-stimulation donor T-cells with magnetic beads coated with OKT3 & anti-CD28Conventional DLI --> escalating aDLI (1 x 106 to 1 x 108/kg in 5 dose levels) 12 days later18 patients: 8 CR (4/7 ALL, 2/4 AML, 1/1 CLL, 1/2 NHL)CLL patient in CR at 6 years post aDLI7 aGVHD (5 grade I-II, 2 with grade III)4 cGVHDPorter, Blood 2006

Augmenting DLIBi20 (FBTA05), trifunctional, bispecific antibody targeting CD20 (NHL/CLL) and CD3 (T cells) and DLIMight direct T-cell efficiently to tumor cell6 patients, 3 with p53-mutated CLL, 3 high-grade NHLCLL patients failed prior DLI, alemtuzumab/rituximabAll 3 CLL patients showed transient clinical responsesImproved B symptoms, LNs, splenomegaly, clearing of CLL from blood with increasing doses Bi20Recurrence of disease within weeks of cessation of Bi20Despite 1-4 doses DLI (106 to 108 CD3/kg)

Buhmann, BMT 2009

Chemotherapy ApproachesObstacles:33-90% reported to be fludarabine-refractoryHigh-frequency of p53 mutations (up to 50%)Factors predict for failure to alkylating agents, purine analogues, and rituximabLimited data available for salvage chemotherapyUsually followed by DLISorror: 5 patients (Flu+rit, CHOP, pentostatin, VCR/pred)- no durable responsesDelgado: 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 CLLFlavopiridolCDK inhibitor45% response rate, 42% in p53 deleted, 72% in 11q deletedMajor toxicity: hyperacute tumor lysisBendamustineBifunctional alkylating agent with purine-like structureActive regardless of p53 or ZAP-70 statusORR > 50%AlemtuzumabORR 33%, equivalent for p53 deletedCytopenias and infection risk, ? Effect on GVLByrd, Blood, 2007; Bergmann, Haematologica, 2005

Agents with activity against fludarabine-refractory, p53 mutated CLLHigh-dose methylprednisolone1 gram/m2/day x 5 days + rituximabORR 78% including 5/9 p53-deleted with 1 cycleInfection in 1/3, Effect on GVL?OfatumumabHumanized anti-CD20 antibodyImpressive activity in relapsed/refractory CLL (ORR 50%)Effects on acute and chronic GVHD unknownLenalidomideImmunomodulatory effects: T-cell activation via CD28, NK cytotoxicity, increased IL-2 expression30% 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 disappointingReports 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 raisedMethods 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 CLLInitiation of multi-center clinical trails to evaluate efficacy of promising novel agents for treatment of relapsed CLL

Nicolaus Krger, Ted AlyeaDisease specific Treatment of Relapse after Allogeneic Hematopoietic Cell Transplantation Multiple MyelomaNCI Workshop 1/2-11.2009

Specific feature of allografting in Multiple MyelomaOnly about 50% will achieve complete remissionDespite CR, relapse rate is higher than in other diseases and is about 50% at 5 yearsFor patients without CR after allografting the progression-rate is even higher (>80%)Extramedullary relapse seems to be increased after allogeneic SCT

Donor lymphocyte infusion for relapse Studies for relapsed patients: ORR: 40-67% and CR: 19-30%Acute GvHD II-IV: 52-56% and cGvHD: 26-44%Strong correlation between response and occurrence of GvHDNo clear correlation between CD3 cell dose and response (Lokhorst et al 1997, Verdonck et al 1996, Salama 2000, Ayuk et al., 2004, Tricot 1996, Bertz et al., 1997)After standard conditioning

Donor lymphocyte infusion for relapseOverall response rate:38%: PR: 19% and CR 19%Acute GvHD II-IV:38% and c GvHD: 42% (extensive cGvHD: 10%)Response according GvHD:acute GvHD :no: 21% ORR yes: 67% ORRchronic GvHD:no: 19% ORR yes: 63% ORRvan de Donk et al., 2006After RIC

Survival after DLI according resonse60801201,00,80,60,40,20,0Months1004020Proportion of survivalCRPRLokhorst et al., 2004

Novel agents as salvage post allogeneic SCTRationalesBortezomib: 1. highly active against myeloma cells 2. in animal model: reduced GvHD but retain Graft versus leukemia effect (Sun et al., PNAS 2004) and lead to a decreased T-helper 1 response among allreactive T-lymphocytes (Blanco et al., Blood 2006) Lenalidomide and Thalidomide:Activate T-cells and NK-cells which might augment the graft versus myeloma effect (Lioznov et al., BMT 2009)Low dose thalidomide more immunosuppressive properties

Immunomodulating agentsImmuno modulating agentsMothy,et al 2005; Lioznov et al 2009; Minnema et al 2008

DosePat.PR-CRGvHDToxThali- domide50-600 mgn = 3129% - 0%n = 5, grade I-IINeurotoxicityLenali- domide15-25 mgn = 2458% - 8%n = 3, grade I-IIMyelosuppression (neuro-penia grade 3/4 =25%Lenali- domide25 mgn = 1650%-31%n = 5, (n = 3, grade III/IV)Myelosuppression, DVT n = 2

Proteasome InhibitorEl-Cheikh, 2008

DosePat.PR - CRGvHDToxBorte- zomib1-1.3 mg/m2 day 1, 4, 8 + 11n = 3734% - 19%noneNeurotoxicity, grade 1-2: 85%

Donor lymphocyte infusion in combination with novel agentsTreatment planThalidomide 100 mgDLI: 1 x 106 CD3+/kg (MUD) or: 5 x 106 CD3+/kg (related)No response: escalating Thalidomide (200 300 400 mg) And/or: further DLI14 daysKrger et al., Blood 2004

CR:6/1833%PR:4/1822%MR:2/1812%SD/NC:5/1828%PD:1/185%Low dose thalidomide (100mg) and escalating DLIResponse rateMed. time to response: 108 days (36 266)67% (ORR)

Thalidomide and DLIafter SCTNo. of patients181118acute GvHD I-IV10 (55%)5 (46%)2 (11%)acute GvHD II-IV4 (22%)3 (27%)0chr.GvHD lim4 (22%)4 (36%)7 (39%)chr.GvHD ext1 (6%)0 0after Thal/DLIafterDLI

Treatment options for relapse

ORRCROverall survival1.Donor lymphocyte infusion (DLI)40 67 %19 -30 %med. 23-23.6 mo2.CD8-depleted donor-lymphocyte infusion71 %43 %2year: 55%3.Thalidomide29 83 %0 22 %3year: 25%4.Lenalidomide66 %8 23 %med. 19.9mo5.Bortezomib80 100 %29 30 %3year: 50%7.Thalidomide plus DLI67 %22 %2year: 100%

Novel approaches and future researchManipulation to reduce GvHD after DLI -CD8 depleted T-cells -CD4 enriched T-cells -Depleting alloreactive T-cells -Alloreactive NK-cells -Tumor specific T-cells (anti-idiotype, Cancer-tests antigen, HAG -Antibody mediated cytotoxicity (BCMA) -Donor vaccination (e.g. idiotype)Enhance cell mediated cytotoxicity -DLI in combination with novel agents (thalidomide, Bortezomib, Lenalidomide)Investigate novel drug combinations, e.g. Lenalidomide plus Bortezomib etc

Proposed Initiatives for the subcommitteeTreatment of Relapse after allo SCTDose-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 SCT3. Investigate novel agents in combination with adoptive immunotherapy (T-cells or NK-cells) as treatment for relapse after allogeneic SCT4. Investigate in a prospective trial the value of a second allogeneic SCT in those patient who relapsed to a RIC allograft

Future Directions and ProposalsBetter 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 strategiesClinicalBiomarkers for response?

An embarrassing lack of data

Future Directions and ProposalsStudy novel agentsazacitidine, decitabine, lenalidomide, bortezomib, sorafenib, etc..Combination drug, antibody and/or cellular therapies.Vaccination strategies of patient/donormHag, tumor-specific antigens, APCsModification of DLITumor specific DLI through selection, genetic modification, etc.ActivationSubset selection or depletion Readdress role of second SCT, particularly after RIC SCT.

ObstaclesLack of comprehensive databases capturing relapse information.Registry studies helpful first stepLack 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 ForwardInternational 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-buildingDevelop trials and seek funding.Consider trial design carefully for maximum and rapid impact. Multiple small pilots vs randomized phase II or III?

Disease-Specific Treatment of Relapse after Allogeneic TransplantationFred FalkenburgJoseph AntinMarcos de LimaEli EsteyJohn LevineJacob RoweAlan WayneDavid MaloneyKoen van BesienKarl PeggsDavid PorterJose LeisNancy HardyNicolaus KrgerEdwin Alyea

An embarrassing lack of dataTapering immune suppression and Cytokines : - response rate : anecdotes onlyTreatment should be offered only for those relapsing longer than 1 yr??Authors suggested that standard chemotherapy +/- DLI be used only in patients who relapse 3-6 months after SCT, with other patients being given clinical trials and palliative care absent such trials

2*An embarrassing lack of data

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Disease-Specific Treatment of Relapse after Allogeneic Transplantation