iwCLL 2017 | Allogeneic transplantation using HLA-compatible donors is effective in younger high-risk CLL patients - an EBMT registry study

On 15^th May 2017, during iwCLL, the second half of the “Additional Therapies for the Relapsed/Refractory CLL Patient” session was jointly chaired by Guillermo Dighiero (Unité d'Immunohématologie et d'Immmunopathologie, Institut Pasteur) and Federico Caligaris-Cappio (Università Vita-Salute San Raffaele).

During this session, Michael van Gelder from Maastricht University Medical Center, The Netherlands, gave a presentation titled “Allogeneic hematopoietic stem cell transplantation using HLA-compatible donors in younger high cytogenetic risk CLL patients results in very high long-term Progression-Free Survival and Low Non-Relapse Mortality and may therefore favorably compete with the sequential use of kinase- and BCL2 inhibitors – a report From the CMWP of EBMT.”

Current preferred treatment option for R/R CLL include:

• Kinase inhibitors: ibrutinib, idelalisib+rituximab
• BCL2 inhibitors: venetoclax

These achieve very high responses; however, relapses remain especially in high-risk CLL:

• Del(17p), TP53 mutation or del(11q) (median PFS with ibrutinib is 26 months)
• Up to 33% progress with Richter’s transformation

High-risk CLL patients generally respond to kinase and BCL2 inhibitors, either immediately or after failure on ≥1 kinase and/or BCL2 inhibitors. Short PFS has been reported after sequential use of kinase and/or BCL2 inhibitors.

Allogeneic Hematopoietic Stem Cell Transplant (alloHCT) can result in very long PFS, independent of cytogenetics. But, Non-Relapse Mortality (NRM) is a downside; it depends on age, performance, remission status at time of alloHCT, HLA match and donor-patient relation, sex-mismatch, etc.

EBMT registry data of transplanted CLL patients was analyzed and focused on younger (<50 years old) high-risk CLL patients and aimed to identify factors that predict low 2-year NRM and high 8-year PFS. It also aimed to study the impact of del(17p)/del(11q) on PFS. Median follow-up was 90.4 months.

Patient and disease characteristics

Risk factor

Numbers

Age (years)

 

<45 years

80 (41%)

45–50 years

117 (59%)

Median

46 years

Prior Chemosensitivity

 

Purine-analogue refractory

67 (40%)

Relapse after chemo-immunotherapy

32 (19%)

Cytogenetics

 

Del(17p)

23 (17%)

Del(11q) and no del(17p)

48 (35%)

Median number of prior lines of therapy (range)

3 (0–10)

Previous autologous HCT

24 (12%)

Responsiveness at time of alloHCT

114 (62%)

Karnofsky (n=179)

 

90–100

152 (84%)

≤80

29 (16%)

Transplant characteristics

Risk factor

Numbers

Conditioning (n=194)

 

Non-myeloablative (2Gy TBI-based)

58 (30%)

Reduced intensity

89 (46%)

Myeloablative

47 (24%)

Donor type

 

Matched related

83 (42%)

Match unrelated

97 (49%)

Partially mismatched unrelated

17 (9%)

Patient-donor sex match (n=193)

 

Female donor for male patient

39 (20%)

CMV IgG in patient (n=180)

 

Positive

69 (38%)

2-year NRM risk factor – multivariate analysis

Risk factor

HR (95% CI)

p-value

Age (in decades)

0.8 (0.4–1.6)

0.55

Cytogenetics

 

 

No del(17p) or del(11q)

1

 

Del(17p) and/or del(11q)

1.3 (0.6–2.9)

0.51

Donor type

 

 

HLA-identical sibling

1

 

Matched unrelated

2.5 (1.1–5.4)

0.03

Partially matched unrelated

4.0 (1.4–11.6)

0.01

Sex match

 

 

All other combination

1

 

Female donor for male patient

1.5 (0.7–3.3)

0.27

8-year PFS risk factor – multivariate analysis; patient characteristics

Risk factor

HR (95% CI)

p-value

Donor type

 

 

HLA-identical sibling

1

 

Matched unrelated

1.2 (0.8–1.8)

0.41

Partially matched unrelated

2.8 (1.5–5.2)

<0.01

Sex match

 

 

All other combination

1

 

Female donor for male patient

1.2 (0.7–1.9)

0.50

Using the Cox models for 2- and 8-year PFS:

Defining good and poor transplantation risk patients

Good risk patients

Poor risk patients

46 years old

Del(17p) and/or del(11q)

No prior autoHCT

Remission at the time of alloHCT

No remission at the time of alloHCT

HLA-matched sibling

 

No sex mismatch

Unrelated female donor

In conclusion, low-NRM risk factors can be identified (good transplant risk). Good transplant risk young CLL patients have a fairly good outcome: very low NRM and 8-year PFS of more than 50%.