Preemptive and Maintenance Strategies to Prevent Relapse after

Allogeneic Stem Cell Transplantation

Mohamad MohtyHôpital Saint-Antoine

Université Pierre & Marie CurieParis

Evolution of Allo HSCT Activity in Europe 1990-2009

HSCT

EBMT Activity survey on HSCT in 2009: main indication - allogeneic

Baldomero H et al. BMT 2011 Feb 28. [Epub]

AcuteLeukemia

-3 -2 -1-4-6 -5 +14 +21 +100 >1800

GraftConditioning

Supportive Care and prevention of relapse

GVHD prophylaxis and therapy

Patient(age, gender,

CMV, comorbidities…)

1

2

3 5

6

4

Diseasefeatures

How to improve allo-HSCT outcome?

Reduced Mortality after allo-HSCT over the past decade (FHCRC, Seattle)

Gooley, TA. et al. N Engl J Med 2010

Agenda

1. Relapse

2. Thoughts on the ‘ideal’ agent

3. Focus on myeloid leukemias

4. Discuss maintenance of remission

5. Epigenetic manipulation of GVL / GVHD

Risk Factors for Relapse post Allo-SCT

- Transplant beyond first CR- Disease-related poor risk features (e.g. cytogenetics, FLT3-ITD mutations; del17p etc.)- Secondary disease (e.g. prior chemo/radiotherapy; priorMDS etc.)- Age >60 years and comorbidities- CB transplantation- Reduced intensity and non-myeloablative conditioning- In vitro and in vivo T cell depletion- Gender donor/recipient combinations other than FM- Specific KIR haplotypes

Outcome post Relapse after Allo-SCT

Generally poor long-term survival and limited DLI response

Risk factors influencing outcome

- Patient age

- Remission duration

- Use of DLI

- Favorable disease features

- Presence of comorbidities

- Disease stage at relapse (e.g. lower tumor burden at relapse)

Probability of relapse: 20% - 60%(outcomes frequently reported ‘mixed’ with different type of diseases)

Trends that may confound comparisons with historic data:- new treatments (ie, hypomethylating agents, lenalidomide )- treatment of older patients- use of reduced-intensity conditioning regimens- length of follow-up

Relapse Incidence post Allo-SCT

Current areas of controversy

- Impact of novel therapies- Impact of new molecular classifications- Incidence of relapse after haplo and CBT- Preferred timing in light of availability of haplo and UCB

CML could be considered the gold standard

- Reliable marker of disease persistence or recurrence

- Interventions are effective (DLI, TKIs)

Why prevent relapse ?

1- For obvious reasons !

2- Treatment of relapse post transplant is suboptimal (for most diseases)

3- Treatment of relapse post transplant is likely more expensive than prevention (for most diseases)

(Some) Strategies for Preventing Relapse

1- Improve conditioning regimen

2- Improve graft selection

3- Select patients

4- Pre-emptive treatment of relapse - Minimal residual disease-based (PCR, flow cytometry, donor cell chimerism, etc)- based on pre-transplant high-risk parameters or on dynamic approaches, such as presence of MRD after allo-SCT etc

5- Maintenance of remission

*Donor Chimerism of CD34+ cells from peripheral blood samples was assessed on day 56 following HSCT and every 4–8 weeks thereafter by fluorescence-activated cell sorter

Phase II trial to evaluate the efficacy of azacitidine in thetreatment of MRD and prevention of hematological relapse

in patients with AML/MDS post-HSCT (RELAZA)

Inclusion criteria

• AML or MDS

• <80% of CD34+ donor cells (DC) post-HSCT*

• Still in CR (<5% blasts)

Treatment schedule

• ≤4 cycles of azacitidine(75mg/m2/day; day 1–7 of 28-day cycles)

• An additional four cycles were permitted if patient achieved minor response:

– improved DC but still <80%

– stabilization or further decrease of DC in absence of relapse

Endpoints

• Primary endpoint– major response:

>80% DC after 4 cycles

• Secondary endpoints• major or minor

response at 6 months after last cycle

• relapse rate• tolerability and

safety

MRD-based pre-emptive treatment of AML/MDS patients with azacitidine following HSCT

Platzbecker U, et al. Leukemia 2012;26:381–9

A total of 20 patients experienced a decrease in donor chimerism to<80% post-HSCT and consequently received 4 cycles of azacitidine

MRD-based pre-emptive treatment of AML/MDS patients with azacitidine following HSCT, cont’d

Platzbecker U, et al. Leukemia 2012;26:381–9

(Some) Strategies for Preventing Relapse

1- Improve conditioning regimen

2- Improve graft selection

3- Select patients

4- Pre-emptive treatment of relapse - Minimal residual disease-based (PCR, flow cytometry, donor cell chimerism, etc)- based on pre-transplant high-risk parameters or on dynamic approaches, such as presence of MRD after allo-SCT etc

5- Maintenance of remission

Candidate agents

- FLT3 inhibitors

- Histone deacethylase inhibitors

- Hypomethylating agents

- Lenalidomide and other ImIDs

- Proteasome inhibitors

Candidate agents

- Monoclonal antibodies (lymphoid > myeloid)

- Moxetumomab pasudotox (anti CD22)

- Immunostimulatory mAb:– anti-CTLA-4, anti-PD1, anti-PDL1 (antagonistic)– anti-4-1BB, anti-OX40 (agonistic)

- Cells – educated or not

- Tumor vaccines

- Etc

The “ideal” maintenance agent1- Active against the disease.

2- Not too toxic.

3- Not myelotoxic (or with tolerable myelotoxicity).

4- Can be given early after transplant.

5- Influence donor cells favorably.

6- Increase immunogenicity of malignant cells.

- Relapsed AML / MDS after allogeneic HSCT:

- Doses of 16 – 40 mg/m2 for 5 days in 28-30-day cycles induced complete remission and reversion to full donor chimerism in 20-25% of patients treated (n=19)

Jabbour et al. Cancer. 2009 Feb 20;115(9):1899-1905

Low dose azacitidine to treat relapsed AML / MDS after allogeneic transplant

Classic idea : Allogeneic stem cell transplant context (with BuCy): - decitabine 400 mg / m2, 600 mg / m2 and 800 mg / m2

de Lima. Cancer. 2003 Mar 1;97(5):1242-7.

Phase 1 study of low-dose prolonged exposure schedules of decitabine in hematopoietic malignancies.

5-20 mg/m2 5 days/week x 2 weeks 15 mg/m2 best - 30 times < MTD

Issa JP et al. Blood. 2004 Mar 1;103(5):1635-40.

Hypomethylating Agent dose

Duration of exposure - longer may be better.

Dose – is low better, same or worse ??

Ideal maintenance agent

1- Active against the disease.2- Not too toxic.3- Not myelotoxic (or with tolerable myelotoxicity).4- Can be given early after transplant.5- Influence donor cells favorably.6- Increase immunogenicity of malignant cells.

Trial design

1- Dose may not be the same as in other scenarios!2- Phase III trial mandatory given multiples biases,

confounding variables etc

Median age = 60 ( range, 24 – 67 )

Median comorbidity score : 3 (range, 0-8)

Chemotherapy regimens prior to HSCT (median = 2)

AML from MDS : 73% MDS : 5% AML : 22%

Median bone marrow blasts at transplant : 10% (0-86%)

CR at HSCT : 20%

Protocol 2005-0417

Patient characteristics

Cancer 2010.

Protocol 2005-0417

- Azacitidine was well tolerated

- Approximately 60% of the patients (heavily pre-treated, refractory etc) were able to receive at least one cycle

- At least 4 cycles at 32 mg/m2 could be delivered.

- Randomized protocol 2008-0503 is ongoing :

32 mg/m2 daily X 5 days, every 30 days, for 1 year, versus no maintenance.

5-Azacitidine +/- DLI post transplant

Ideal maintenance agent

1- Active against the disease.

2- Not too toxic.

3- Not myelotoxic (or with tolerable myelotoxicity).

4- Can be given early after transplant.

5- Influence donor cells favorably.

6- Increase immunogenicity of malignant cells.

Hypomethylating Agents – Potential Effects

• Increased expression of tumor-associated antigens ie CTA (Roman-Gomez, 2007) Tatjana Stankovic et al. Goodyear et al.

• Increased expression of KIR ligands on hematopoietic cells (Liu, 2009)

• Recovery of reduced expression of HLA class I, II and III antigens on tumor cells (Campoli & Ferrone, 2008) (Pinto et al – 1984)

• Increased expression of known Minor antigens (Hambach, 2009)• Affect microRNA function - inhibition of oncogenes

• Increased FoxP3 expression and Treg generation (Polansky, 2008) (Choi et al. 2010) (Sanchez-Abarca et al. 2010) John DiPersio et al. Goodyear et al. Blood 2011.

↑ GVL

? GVL Tolerance

Without affecting relapse ?

Goodyear et al Blood 2012• 27 patients (median age 59)• Median follow up 7 months (3-21)• 11 sib, 16 VUD• CR1=18, CR2=7, relapse 2

• Control cohort: FMC 50 no AZA

- Induction of an increase in circulating T-regs in the early post transplant period

- Induction of a memory T cell-mediated response in the bone marrow to putative tumour antigens

- 15/18 pts (80%) who had 6 cycles of treatment had detectable CD8+ T cell responses to tumour specific peptides

Biological rationale for treating patients with azacitidine post-HSCT

1. Jabbour E, et al. Cancer 2009;1115:1899–905; 2. Weiden PL, et al. N Engl J Med 1979;300:1068–733. Ringden O, et al. Br J Haematol 2009;147:614–33; 4. Edinger M, et al. Nat Med 2003;9:1144–50

5. Floess S, et al. PLoS Biol 2007;5:e38

It has been hypothesised that azacitidine post-HSCT could promote the graft–versus-leukaemia (GVL) effect and reduce graft–versus-host disease (GVHD)1

It has been hypothesised that azacitidine post-HSCT could promote the graft–versus-leukaemia (GVL) effect and reduce graft–versus-host disease (GVHD)1

GVHD GVL

Donor T-cells

Donor T-cells

Host healthy

cells

Host cancer cells

Tregcells4

Immune response

Immune response

Associated with increased risk of GVHD2

Associated with lower relapse rates post-HSCT3

Regulated by FOXP3 which is inactivated by

hypermethylation5

Could azacitidine hypomethylateFOXP3, elevate Treg cells and

promote the GVL effect?

Low dose AZA decreases the incidence of cGVHD

Conclusions- Maintenance therapy can likely contribute to the success

of allo-SCT and disease cure

- Epigenetic modifiers (e.g. hypomethylating agents) may modulate GVL and GVHD after allo-SCT

- Other MAbs and immunomodulatory drugs may prove useful

- Disease resistance to be watched carefully

- The post transplant scenario, once the realm of GVHD trials, may provide an ideal arena to improve disease control now that new therapies (cellular and otherwise) are available.