On 15 thMay 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 Gelderfrom 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.
|
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%) |
|
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%) |
|
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 |
|
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:
|
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%.