W E I L L . C O R N E L L . E D U

Should All Eligible Patients with Mantle Cell Lymphoma Be

Transplanted?

Answer: No

Peter Martin, M.D.

The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology

Assistant Professor of Medicine

W E I L L . C O R N E L L . E D U

Let’s define “eligible”

5%

6%

89%

Real-World Upfront Management

RadiationNo therapySystemic therapy

N=1066

Abrahamsson A et al. Blood 2014;124:1288-1295

W E I L L . C O R N E L L . E D U

Let’s define “eligible”

5%6%

89%

Proportion of Patients Receiving Systemic Therapy

RadiationNo therapySystemic therapy

Abrahamsson A et al. Blood 2014;124:1288-1295

W E I L L . C O R N E L L . E D U

Let’s define “eligible”

62%

38%

Age of Patients Receiving Systemic Therapy

>65 years<65 years

Abrahamsson A et al. Blood 2014;124:1288-1295

W E I L L . C O R N E L L . E D U

Let’s define “eligible”

36%

64%

Treatment of <65 years

OtherMCL2

Abrahamsson A et al. Blood 2014;124:1288-1295

W E I L L . C O R N E L L . E D U

Let’s define “eligible”

76%

24%

Proportion of Patients Undergoing Autologous Stem Cell Transplantation

Not transplantTransplant

Abrahamsson A et al. Blood 2014;124:1288-1295

W E I L L . C O R N E L L . E D U

Should 24% of All Patients with Mantle Cell Lymphoma Be Transplanted?

Answer: No

Peter Martin, M.D.

The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology

Assistant Professor of Medicine

W E I L L . C O R N E L L . E D U

Overall Survival Is Better in Real-World Patients That Undergo ASCT

Abrahamsson A et al. Blood 2014;124:1288-1295

W E I L L . C O R N E L L . E D U

But Overall Survival Is Even Better in Patients That Don’t Undergo Any Treatment

Abrahamsson A et al. Blood 2014;124:1288-1295

W E I L L . C O R N E L L . E D U

Interpretation: Observational data is not particularly helpful here.

W E I L L . C O R N E L L . E D U

Autologous Stem Cell Transplantation Provides Durable Remissions!!

Damon L E et al. JCO 2009;27:6101-6108

W E I L L . C O R N E L L . E D U

Autologous Stem Cell Transplantation Provides Durable Remissions

Damon L E et al. JCO 2009;27:6101-6108British Journal of Haematology Volume 158, Issue 3, pages 355-362

W E I L L . C O R N E L L . E D U

Autologous Stem Cell Transplantation Provides Durable Remissions

Damon L E et al. JCO 2009;27:6101-6108British Journal of Haematology Volume 158, Issue 3, pages 355-362

Fenske T S et al. JCO 2014;32:273-281

W E I L L . C O R N E L L . E D U

Autologous Stem Cell Transplantation Provides Durable Remissions

Damon L E et al. JCO 2009;27:6101-6108British Journal of Haematology Volume 158, Issue 3, pages 355-362

Fenske T S et al. JCO 2014;32:273-281Dreyling. Blood 2005; 105:2677-2684

W E I L L . C O R N E L L . E D U

Autologous Stem Cell Transplantation Does Not Result in Cure

Damon L E et al. JCO 2009;27:6101-6108British Journal of Haematology Volume 158, Issue 3, pages 355-362

Fenske T S et al. JCO 2014;32:273-281Dreyling. Blood 2005; 105:2677-2684

W E I L L . C O R N E L L . E D U

Autologous Stem Cell Transplantation Is Associated with a

5-10% Mortality Rate

Study Treatment-Related Mortality

Dreyling 8% (Infection)

MCL2 NRM=7.5% @ 7.4 years

MCL3 NRM=6.9% @ 4.4

CALGB 59909 67 of 79 patients received ASCTNRM = 2

CIBMTR 1-year NRM = 3%

Dreyling. Blood 2005; 105:2677-2684British Journal of Haematology Volume 158, Issue 3, pages 355-362

Damon L E et al. JCO 2009;27:6101-6108Fenske T S et al. JCO 2014;32:273-281

W E I L L . C O R N E L L . E D U

Who Does ASCT Benefit?

W E I L L . C O R N E L L . E D U

Hoster E et al. JCO 2014;32:1338-1346

European MCL Younger: MIPI Predicts Outcome Post-Transplant

W E I L L . C O R N E L L . E D U

MCL2: MIPI Predicts Outcome Post-Transplant

British Journal of HaematologyVolume 158, Issue 3, pages 355-362, 29 MAY 2012

W E I L L . C O R N E L L . E D U

Response to Induction Pre-Transplant Predicts Outcome Post-Transplant

Kolstad A et al. Blood 2014;123:2953-2959

W E I L L . C O R N E L L . E D U

MCL3: Pre-Transplant PET Predicts Outcome Post-ASCT

Kolstad A et al. Blood 2014;123:2953-2959

W E I L L . C O R N E L L . E D U

Clinical Lymphoma Myeloma and Leukemia, Volume 14, Issue 2, 2014, 114 - 121

U Minn: Pre-Transplant PET Predicts Outcome Post-ASCT

W E I L L . C O R N E L L . E D U

European MCL Younger Trial: Pre-Transplant MRD Status Predicts Outcome Post-ASCT

Williams M E Hematology 2013;2013:568-574

W E I L L . C O R N E L L . E D U

MCL3: Pre-Transplant MRD Status Predicts Outcome Post-ASCT

Kolstad A et al. Blood 2014;123:2953-2959

W E I L L . C O R N E L L . E D U

Liu H et al. Haematologica 2012;97:579-585

CALGB59909: Pre-Transplant MRD Status Predicts Outcome Post-ASCT

W E I L L . C O R N E L L . E D U

Should 12% of All Patients with Low-Risk, PET-Negative, MRD-Negative

Mantle Cell Lymphoma Be Transplanted?

Answer: No

Peter Martin, M.D.

The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology

Assistant Professor of Medicine

W E I L L . C O R N E L L . E D U

How Does ASCT Prolong Survival?

• Eliminate sub-clones before they accumulate new mutations that confer resistance to subsequent treatment

W E I L L . C O R N E L L . E D U

C h e m o t h e r a p y w o r k s b y i n d u c i n g d s D N A d a m a g e

W E I L L . C O R N E L L . E D U

Frequent Somatic Mutations in The DNA Damage Response Pathway

Beà S et al. PNAS 2013;110:18250-18255

W E I L L . C O R N E L L . E D U

Nordic MCL2/3: TP53 add prognostic information to MIPI

British Journal of HaematologyVolume 166, Issue 1, pages 98-108, 29 MAR 2014 DOI: 10.1111/bjh.12854

W E I L L . C O R N E L L . E D U

Complex karyotype in mantle cel l lymphoma is a prognostic factor

Genes, Chromosomes and CancerVolume 53, Issue 1, pages 106-116, 29 OCT 2013 DOI: 10.1002/gcc.22123

W E I L L . C O R N E L L . E D U

Interpretation:~50% of MCL cases may be chemoresistant at diagnosis

W E I L L . C O R N E L L . E D U

Should X% of All Patients with Low-Risk, PET-Negative, MRD-Negative,

TP53W T , ATMW T Mantle Cell Lymphoma Be Transplanted?

Answer: No

Peter Martin, M.D.

The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology

Assistant Professor of Medicine

W E I L L . C O R N E L L . E D U

Can Chemotherapy Make Cancer Worse?

Levine et al. Nature Medicine 2014;20(4)

W E I L L . C O R N E L L . E D U

Chemotherapy Increases Clonal Heterogeneity in CLL

Landau, D.A. et al. Cell 152, 714–726 (2013).

W E I L L . C O R N E L L . E D U

L Ding et al. Nature 000, 1-5 (2012)

Clonal Evolution in AML

W E I L L . C O R N E L L . E D U

Should X% of All Patients with Low-Risk, PET-Negative, MRD-Negative,

TP53W T , ATMW T Mantle Cell Lymphoma Be Transplanted?

Answer: NoPeter Martin, M.D.

The Charles, Lillian and Betty Neuwirth Clinical Scholar in Oncology

Assistant Professor of Medicine

W E I L L . C O R N E L L . E D U

Conclusions• The minority of patients with MCL are eligible to receive

aggressive transplant.– Is this question even relevant to real-world practice?

• Conventional chemotherapy does not cure MCL, regardless of the dose. But it dose induce real toxicity.– Do the ends justify the means?

• Aggressive approaches appear to be most active in patients with the best prognosis.– There is a clear selection bias in data.

W E I L L . C O R N E L L . E D U

Conclusions• MCL is inherently chemoresistant

– More chemotherapy doesn’t make it better

• Chemotherapy can induce clonal heterogeneity– May be worse in the long run

• Aggressive therapies should be undertaken in the context of a clinical trial.

• Honest and open discussions with patients should guide management decisions.