CONSIDERATIONS IN DESIGNING ACUTE GVHD … · ACUTE GVHD PREVENTION TRIALS: Patient Selection, Concomitant Treatments, ... MDS URD BMT: Ad lt ith MDS / ... MDS, SAA 100 Conventional

CONSIDERATIONS IN DESIGNING ACUTE GVHD PREVENTION TRIALS:

Patient Selection, Concomitant Treatments, S l i d A i E d iSelecting and Assessing Endpoints

CENTER FOR INTERNATIONAL BLOODAND MARROW TRANSPLANT RESEARCH

Potential conflicts/disclosures

Research support for BMT CTN trials: R h E i Li d M k ARoche, Easai, Ligand, Merck, Amgen, Supergen, Therakos, Pfizer

Research support for CIBMTR studies:Research support for CIBMTR studies:Otsuka, Amgen, Fujisawa

Analysis of Fujisawa clinical trial data done inAnalysis of Fujisawa clinical trial data done in collaboration with industry investigators; all other analyses conducted with no knowledge or input form industry supporters

ISSUES IN DESIGNING GVHD PREVENTION TRIALS

Heterogeneity of patients Heterogeneity of preparative regimensHeterogeneity of preparative regimensHeterogeneity in GVHD assessment and treatment philosophiestreatment philosophiesMultiple competing risks


Heterogeneity of patientsHeterogeneity of preparative regimensHeterogeneity of preparative regimensHeterogeneity in GVHD assessment and treatment philosophiestreatment philosophiesMultiple competing risks

SURVIVAL AFTER HEMATOPOIETIC STEM CELLSURVIVAL AFTER HEMATOPOIETIC STEM CELL TRANSPLANTS, 1998-2003

80

100

ILIT

Y, %

60

80

HLA-identical sib (N = 14,473)

PRO

BA

B

40Unrelated (N = 5,358)

0

20 Autotransplant (N = 23,857)

YEARS0 1 2 3 4 5

ENT04_2.ppt

GROUPS WITH HIGH / INTERMEDIATE / POOR OUTCOMEPOOR OUTCOME

GOOD INTERMEDIATE POOR

HLA-identical sibling BMT:Early leukemiaAplastic anemiaHemoglobinopathies

HLA-identical sibling BMT:Acute leukemia CR2+CML BP

HLA-identical sibling, URD, auto-transplants for advanced or Hemoglobinopathies

Immune deficiencies

URD BMT:Same, in children /

d lt

CML BPChildren with ALL-relMDS

URD BMT:Ad lt ith MDS /

advanced or , chemotherapy-refractory disease

young adults

AutotransplantsEarly leukemiaLow-grade lymphoma

Adults with MDS / early leuk

Aplastic anemia

AutotransplantsInt-grade lymphoma /

HD in CRNewly diagnosed myeloma

Relapsed / Sens lymphoma

Acute leukemia CR2+

FACTORS CONSISTENTLY ASSOCIATED WITH HCT OUTCOMEWITH HCT OUTCOME

GENERAL DISEASE-SPECIFIC ???

Donor type: auto vs allo; related vs unrelated; HLA-matched vs mismatched

Leukemia: Duration of disease/remission; time to achieve first remission; prior

Multiple myeloma

CLL

Some lymphomasmismatched

Disease: malignant vs non-malignant; solid tumor vs hematologic cancer

remission; prior consolidation (auto); cytogenetics; WBC at diagnosis

Lymphoma: Histology;

Some lymphomas

Solid tumors

Rare diseases

cancer

Disease stage: early vs interrmediate vs late

Age: children vs

Lymphoma: Histology; chemosensitivity; prior therapy

Aplastic anemia: i f di

Age: children vs adolescents vs young adults vs older adults

Performance status: KPS < 90 vs KPS < 90

Duration of disease; prior transfusions

< 90 vs KPS < 90

CMV status: + vs -

Cumulative Incidence of Grades B-D Acute GVHDHLA-identical Sib Transplants for Leukemia and MDS

1000 9 y

pMyeloablative Conditioning, 2003-2007

80

900-9 y10 - 19 y20-29 y30-39 y

50

60

70

%

40- 49 y50- 59 y>60 y

30

40

50

CI,

10

20

00 50 100 150 200 250 300

Days after Transplant

Cumulative Incidence of Grades C-D Acute GVHDHLA-identical Sib Transplants for Leukemia and MDS

90

1000-9 y10 - 19 y

Myeloablative Conditioning, 2003-2007

70

80

10 19 y20-29 y30-39 y40- 49 y50- 59 y

50

60

CI,

%

>60 y

20

30

40

0

10

20

0 50 100 150 200 250 300Days after Transplant

Cumulative Incidence of Grades B-D Acute GVHDUnrelated Donor Transplants for Leukemia and MDS

90

1000-9 y10 19 y


70

80

90 10 - 19 y20-29 y30-39 y40- 49 y50- 59 y

50

60

I, %

50 59 y>60 y

30

40

CI

10

20

00 50 100 150 200 250 300


Cumulative Incidence of Grades C-D Acute GVHDUnrelated Donor Transplants for Leukemia and MDS

90

1000-9 y10 - 19 y


70

80

10 19 y20-29 y30-39 y40- 49 y50- 59 y

50

60CI

>60 y

20

30

40

0

10

20

0 50 100 150 200 250 300Days after Transplant

Cumulative Incidence of Grades B-D Acute GVHDHLA-identical Sib Transplants for Leukemia, MDS, SAA

100

Conventional Conditioning, 2003-2007

70

80

90

SAA (n=51)

AML, ALL, CML, MDS (n=2279)

50

60

70

I, %

30

40

C

10

20

00 10 20 30 40 50 60 70 80 90 100


Cumulative Incidence of Grades B-D Acute GVHDUnrelated Donor Transplants for Leukemia, MDS, SAA

Conventional Conditioning 2003-2007

90

100

AML, ALL, CML, MDS (n=4764)

Conventional Conditioning, 2003-2007

60

70

80 SAA (n=64)

40

50

60

CI,

%

20

30

40

0

10

0 10 20 30 40 50 60 70 80 90 1000 10 20 30 40 50 60 70 80 90 100


PROGNOSTIC FACTORS FOR AGVHD in 1 960 adults receiving HLA-identical sib transplants1,960 adults receiving HLA identical sib transplants

Factor RR

Age 40y vs Younger (only for BM grafts) 1.43

PBSC vs BM Graft (only for young patients) 1.44SC s G a t (o y o you g pat e ts) 1.44

White/Black vs Hispanic/Asian 1.54

CML vs Acute Leukemia 1.35

KPS <90 vs 90-100 1.27

CyTBI vs BuCy 1.40

D/R CMV -/- vs not 1 20D/R CMV -/- vs not 1.20

Does This Really Matter?Does This Really Matter?

Ratanatharathorn et al. (Blood, 1998): FK506+MTX vs. CSA+MTX in HLA-FK506 MTX vs. CSA MTX in HLAidentical sibling BM transplants (n=329)Stratified on patient age (<40 vs. >=40) and donor/recipient sex match

Incidence of aGVHD grade II-IVg

CSA+MTX

FK 506+MTXFK-506+MTX

Copyright ©1998 American Society of Hematology. Copyright restrictions may apply.

Ratanatharathorn, V. et al. Blood 1998;92:2303-2314

Overall Survival

CSA+MTX

FK-506+MTX

W i l f FK 506 d i l GVHD i id


Ratanatharathorn, V. et al. Blood 1998;92:2303-2314

Worse survival for FK-506 group despite lower aGVHD incidence

Figure 5.

CSA+MTX (n=48)Advanced Di

FK-506+MTX (n=68)

Disease

Ratanatharathorn V et alRatanatharathorn, V. et al. Blood 1998;92:2303-2314

E lEarly Disease


FUJISAWA TRIAL OF GVHD PROPHYLAXIS

Stage of malignancy 0.02

Tacrolimus CyclosporineCharacteristics N=165 N=164 P Value

g g yAdvanced 41% 29%(not in CR, CLL, Myeloma) 59% 71%

Diagnosis 0.70gMDS 4% 8%ALL 11% 9%AML 27% 27%CML 31% 35%CML 31% 35%NHL 8% 10%Hodgkin Disease 1% 1%Myeloma 9% 5%Myeloma 9% 5%CLL 4% 2%Others 5% 3%

Ratanatharathorn V, Blood 1998AOB00_22.ppt

Ratanatharathorn V, Blood 1998

There is considerable heterogeneity in the Group labeled as “Advanced”labeled as Advanced

Acute leukemia, CR1 16%100 day mortality

Acute leukemia, Rel 1 30%Acute Leukemia, CR2 21%CML, CP1 13%C 22%

Range:

Early: 13-30CML, AP 22%MDS 22%MPS 22%NHL / HD PIF 33%

Advanced: 22-40

NHL / HD, PIF 33%NHL / HD, CR1 17%NHL / HD, Rel 1 30%NHL / HD CR2 30%NHL / HD, CR2 30%NHL / HD, Rel 2 33%NHL / HD, Other 40%CLL 35%CLL 35%Multiple Myeloma 40%

Further investigation into whether imbalance gin prognostic factors led to survival difference

Comparison of matched IBMTR controls for advanced disease patients in abovefor advanced disease patients in above trial (n=116 )Matched on diagnosis, pre-tx disease status, age (within 5 years)Controls received CSA+MTX

Horowitz et al, BBMT, 1999)

Acute GVHDGroup Probability P-valueFK-treated trial pts 28% 0.01

FK-matched controls(received CsA)

50%(received CsA)CsA-treated trial pts 58% 0.19

CsA-matched controls(received CsA)

45%

FK-matched controls 50% <0 67FK-matched controls(received CsA)

50% <0.67

CsA-matched controls 45%(received CsA)

Two-Year SurvivalGroup Probability P-valueFK-treated trial pts 27% 0.51

FK-matched controls(received CsA)

24%(received CsA)CsA-treated trial pts 42% 0.66

CsA-matched controls(received CsA)

45%

FK-matched controls 24% <0 01FK-matched controls(received CsA)

24% <0.01

CsA-matched controls 45%(received CsA)



Why Does Conditioning Regimen Matter?Why Does Conditioning Regimen Matter?

Affects GVHD risk and timing (myeloablative vs reduced intensity vs minimal intensity)Affects risk of other competing events (early morbidity and mortality)Variable interaction with treatments to be tested

PROGNOSTIC FACTORS FOR AGVHD in 1 960 adults receiving HLA-identical sib transplants1,960 adults receiving HLA identical sib transplants

Factor RR

Age 40y vs Younger (only for BM grafts) 1.43

PBSC vs BM Graft (only for young patients) 1 44PBSC vs BM Graft (only for young patients) 1.44

White/Black vs Hispanic/Asian 1.54

CML vs Acute Leukemia 1.35

KPS <90 vs 90-100 1.27

CyTBI vs BuCy 1.40

D/R CMV -/- vs not 1 20D/R CMV -/- vs not 1.20


Affects GVHD risk and timing (myeloablative vs reduced intensity vs minimal intensity)Affects risk of other events (early morbidity and mortality)Variable interaction with treatments to be tested

BMT CTN 0402: FK+MTX vs FK+Sirolimus for GVHD Prophylaxis after HLA-id sib PBSCT

Endpoint – GVHD-free survivalMonitoring rules: mucositis and VODg

Stopped for excessive VODRisk found to be predominantly in patients receiving BuCy conditioningRe-opened with restriction to TBI-based

diti iconditioning


Affects GVHD risk and timing (myeloablative vsAffects GVHD risk and timing (myeloablative vs reduced intensity vs minimal intensity)Affects risk of other events (early morbidity and ( y ymortality)Variable interaction with treatments to be testedBUT……….

Results of GVHD prophylaxis tested with a i l i f l dparticular regimen are often extrapolated to

other regimens without further evaluation



Interobserver Variability

Stratification on center helpful to address institutional differences in approach – but not individual differencesppBlinding

DesirableExpensiveDifficult (impossible?) when drug levels must be monitored or when therapies affect levels of other drugsp g

Independent observersExpensiveL i i ll diffi lLogistically difficult

Collection of primary data – allows computation of grade by predetermined algorithm, external reviewy p g

Treatment before reaching primary endpointTreatment before reaching primary endpoint

BMT CTN 0302: Treatment for Grades B-D AGVHDRequired enrollment within 24 hours of startingRequired enrollment within 24 hours of starting corticosteroids MANY patients ineligible because of corticosteroid therapy for Grade A AGVHD, including stage 1 skin only

– What we do is different from what we say we doPrevention trials that have Grade B-D or IV-IV AGVHD as anPrevention trials that have Grade B D or IV IV AGVHD as an endpoint may be compromised by treatments initiated for lesser degrees of GVHD

0402: Primary endpoint includes Grade II IV AGVHD or0402: Primary endpoint includes Grade II-IV AGVHD or treatment for Grade I GVHDStratification by center



TIMELINE OF TRANSPLANTTIMELINE OF TRANSPLANTComplications: Secondary tumors

Acute and/or chronic GvHDViral infectionsCMV VZV PCPp

PBSC/BM harvests in

Secondary tumors, cataracts, endocrine

changes, QoL

CMV, VZV, PCP, IPBacterial

infectionsHSV mucositis

VOD

MarrowBlood & Marrow Changes:

ABMT

BM/SCre-

infusion

Marrow function

Immune function

eg: DHAP and GF and PBSC

Collect & freezegcsf

BMT Process:

Growth

Red cell transfusionsPlatelet transfusions

Donor search or obtain autologous stem cells

Chemo XRT

Supportive Therapy:

TIME LINE -12

-4

-2

0 1 2 6 60th

AntibioticsNutrition

Antiemetics

factors

DMM00_A2.ppt

12 4 2 monthsMarrow

failureDisease

remissionDisease

recurrence

Continuous complete remission

(cure)

High-dose myeloablativ

e therapy

Primary diagnosis

and treatment

Relapse and

salvage therapy

Disease State:

HOW DO COMPETING RISKS AFFECT ABILITY TO DO CLINICAL TRIALS IN HCT?DO CLINICAL TRIALS IN HCT?

Complicates the primary endpointComplicates the primary endpointHow do you treat patients who die before they have a chance to get the primary endpoint?have a chance to get the primary endpoint?May make final result unclear

Impairs ability to attribute toxicities to interventionImpairs ability to attribute toxicities to interventionMay lead to reporting many adverse events

May be increased by intervention even if GVHDMay be increased by intervention even if GVHD is decreased leading to overall adverse result

Impact of Competing Risks of Choice of EndpointImpact of Competing Risks of Choice of Endpoint

Acute GVHD – may be decreased at theAcute GVHD – may be decreased at the cost of increasing other toxicities

Need to ensure that the therapy doesNeed to ensure that the therapy does “no harm”, ie., unacceptable increases in adverse events, infections, non-, ,relapse mortality, recurrent malignancy

Survival – impacted by many things other than GVHD – unlikely to be able to show a benefit

Simulation Study using Multistate Models: What if AGVHD was decreased with NO impact on the rate of p

relapse or other causes of TRM?1459 patients with acute leukemia in CR1

Relapse TRM Survival

Real 17% 20% 65%

No AGVHD 18% 11% 72%

50% ↓ in AGVHD

17% 16% 69%

BMT CTN 0402: Composite Endpoint

Primary ObjectiveTo compare the rates of 114-day Grades II-IV acute

GVHD f i l b t t dGVHD-free survival between study arms

Rationale: Considers potential effects on both acuteRationale: Considers potential effects on both acute GVHD and TRM in primary endpoint

80% power to detect an increase in GVHD-free survival 114 days from randomization from 60 75%75%Sample size n = 312 patients

Summary

Transplant outcomes are influenced by many patient, disease and treatment factors – these must be considered for their

t ti l f di f l ti f GVHD ipotential confounding of evaluation of GVHD regimensThere is considerable variability in GVHD assessment and treatment approaches – blinding, stratification on center are importantGVHD is an important barrier to successful BMT outcome but not the only onethe only one

Improved survival requires better therapies to prevent GVHD AND to prevent and treat other transplant-related complications and disease recurrencecomplications and disease recurrenceA good GVHD prevention strategy must decrease GVHD without excessively increasing other causes of morbidity and mortality BUT cannot be expected to substantially improve survival by itself

Documents

CONSIDERATIONS IN DESIGNING ACUTE GVHD … · ACUTE GVHD PREVENTION TRIALS: Patient Selection, Concomitant Treatments, ... MDS URD BMT: Ad lt ith MDS / ... MDS, SAA 100 Conventional