Allogeneic Hematopoetic Stem cell transplant

A key role to play in management of high risk CLL

Why does allogeneic HSCT have an important place in CLL therapy? • Strong graft vs leukemia effect

– Immune anti-CLL impact• It can overcome adverse prognosis• It can restore normal immune function• It is the only curative therapy for CLL• Cure possible even with:

– Transformation, post HSCT progression• Patients can have normal quality of life

– Much improved from that experienced with active CLL

Graft vs Leukemia

Graft vs leukemia effect

• Higher chance of CR / OS with gvhd• Auto HSCT has no impact in CLL• CLL response to:

– Withdrawal of immune suppression– Onset of gvhd– Donor lymphocyte infusion

Toze, BMT Nov 2005

• TCD Allo SCT• DLI• Real time q PCR of CLL

specific IgH rearrangement

Gribben, Blood Aug 05

Valkova, Hematol Oncol 2010

Valkova, Hematol Oncol 2010

Survival post adverse prognosis

403020100

Overall survival from date of diagnosis (y)

1.0

0.8

0.6

0.4

0.2

0.0

Cum

Sur

viva

lTreatment, n=585

No treatment,n=411

P < 0.001

Huang, Toze 2014

2520151050

Time from 1st to 2nd treatment (y)

1.0

0.8

0.6

0.4

0.2

0.0

One

Min

us C

um S

urvi

val

Median 1.9 (range 0.1 - 21.5)

• 2012– First line – 89/246 (36%)– Second line – 48/246 (20%)– Third line – 42/246 (17%)– Fourth line – 28/246 (11%)– Fifth line – 18/246 (7%)– Sixth line – 10/246 (4%)– Seventh line – 5/246 (2%)– Eighth line – 2/246 (0.8%)– Subsequent lines (Ninth) – 4 (2)/246 (1.6%, 0.8%)

44% 3rd line or higher…..

Multiple therapies given over a patient’s lifetime

Survival of CLL Patients by Line of Therapy

1441209672482400

20

40

60

80

100

Time (Months)

Overall survival (%

)

Total Died Subgroup609 129 Initial Dx327 167 1st Rx794 548 1st fludarabine salvage233 158 fludarabine refractory

Fludarabine failed

Alkylating agents failed

MDACC data, M Keating.

Prognosis – FISH and other

Poor prognosis• Short duration of response to therapy• Inadequate response to therapy• High-risk markers

– FISH• 17p,11q, clonal evolution

– B symptoms– Bulky disease– Advanced stage– CD38 +– IgVH unmutated status– High B2 microglobulin

17p deletion …..

• Dreger et al; Blood, 7 October 2010

FISH FISH

Donor Donor

Dreger et al; Blood, 7 October 2010

Allo HSCT can cure CLL!!!

Swic, Toze 2014

Swic, Toze 2014

Building better transplants

• Improved safety• Risk lower if well prepared• Choice of regimen intensity

– Non-myeloablative– Reduced intensity– Full intensity

Improved survival with less intense conditioning

Swic, Toze 2014

Excellent survival with reduced intensity and post SCT CR

Swic, Toze 2014

Comorbidity

Improved survival with low comorbidity index

Does SCT improve survival?

Lines of evidence

• Donor / no donor comparison– Herth / Dreger, Heidelberg

• Decision analysis– Kharfan-Dabaja, Beirut

• Population based comparison– Swic / Toze, Vancouver

2 yr OS 88% SCTVs 38% no SCTMortality halved by SCT

“It is intriguing that the survival of the donor group was at no time inferior to that of the no-donor group, implying that the superior disease control provided by allografting is never counteracted by the NRM risk associated with alloSCT.”

“This notion is further substantiated by the fact that mortality due to CLL progression before intended transplant was higher than transplant-related mortality in this high-risk selection.”

Dreger, 2014

CLL is the enemy –not the allo SCT

Decision analysis

BC Population-based data:OS of patients treated with SCT vs non-SCT tx

403020100

Overall Survival (y)

1.0

0.8

0.6

0.4

0.2

0.0

Cum

Sur

viva

l

SCT, n=103

Treated, no SCT,n=494

P = 0.033

Swic, Toze 2014

Conclusion…..

• SCT wins when compared to non-transplant therapy

Quality of life• CLL

– “CLL has a profound impact on QoL at all disease stages” Shanafelt

– QoL best in PFS state– Worst with advanced disease, progression

• Allo HSCT is a PFS state that reverses advanced CLL

• Allo HSCT– Gvhd impacts QoL but absence of malignancy

NB

• SCT restores immune function• Clinical experience – Excellent QoL for

most post SCT• Novel agents - promising• Potential concerns remain

Will novel agents be a panacea for all patients?

• No – Some will develop resistance

• Stilgenbauer data– Long term impact of drugs

• Effect on CLL – escape from response• Other long term effects

Patient Characteristics with Acquired SNVs

Stilgenbauer, S. IWCLL 2013.

Study  Age,years Gender # of Prior

Treatments Cytogenetics IbrutinibTreatment 

Durationon

Ibrutinib 

Best Response  Mutation 

PCYC‐04753 59 Female 5 17p‐, +12 560 mg qd 621 days  PR  C481S BTK 

PCYC‐1102 75 Male 2 17p‐, complexkaryotype 420 mg qd 673 days  PR  R665W PLCg2 

PCYC‐1108 59 Female 3 11q‐ BR x 6 cycles420 mg qd 388 days  CR  C481S BTK 

PCYC‐1109 51 Male 2 complex karyotype

Ofatumumab x24 weeks 420 mg qd

674 days  CR  C481S BTK 

PCYC‐1102  69 Male 9 17p‐, complex karyotype 840 mg qd 868 days  PR  C481S BTK 

Single Nucleotide Variations (SNVs) Acquired at Time of Ibrutinib Resistance

Stilgenbauer, S. IWCLL 2013.

Patient ID Gene Position

Before Treatment

After Treatment

DNA and RNA Nucleotide Change

Amino Acid Change

Mutant Allele Frequency (DNA)

Mutant Transcript Frequency (RNA)

B00‐00G BTK chrX:100611165 Not present T1441A C481S 63% 85%

CEO‐AOE BTK chrX:100611164 Not present G1442C C481S 32% 93%

BAG‐AAB PLCγ2 chr16:81946260 Not present C1993T R665W 65% 47%

B00‐C0F BTK chrX:100611164 Not present G1442C C481S ND ND

BAG‐A0B BTK chrX:100611164 Not present G1442C C481S ND ND

Deep sequencing of sequential specimens obtained at baseline and at relapse after durable remission 

Dreger, 2013

High-risk patients

• Inadequate response to standard therapy– Short response duration– Need for retreatment with short treatment-free

interval• High risk of death from infection, CLL• Risk of transformation• Risk of aquistion of high-risk FISH, CE

What can allo HSCT do in CLL?

1. Cure 50-60% of patients2. Produce CR in >70% of patients3. Eliminate high-risk FISH abnormalities4. Restore normal immune function including

normal immunoglobulin levels5. Result in ability for patients with progressive

disease post-transplant to respond to therapy (? Immune ‘reset’)

6. Allow patients to live a normal life free of CLL

CLL is the enemy –not the allo SCT