Page 199 - 2021_12-Haematologica-web

Letters to the Editor
Allogeneic hematopoietic cell transplantation out- comes in patients with Richter’s transformation
Approximately 2-10% of chronic lymphocytic leukemia (CLL) cases develop into Richter’s transforma- tion (RT), a more aggressive disease typically manifesting as diffuse large B-cell lymphoma (DLBCL).1 Targeted therapies such as ibrutinib are now commonly used to treat CLL but the transformation rate remains compara- ble to the chemoimmunotherapy era.2 Moreover, these targeted therapies are often used to treat RT despite lim- ited efficacy,1,3 and prognosis for these patients is poor.4-6 The treatment of RT therefore remains challenging in the current era of targeted therapy.
Graft-versus-leukemia activity after allogeneic hematopoietic cell transplantation (alloHCT) is evident in patients with CLL where durable remissions can be achieved in all genetically defined high-risk subsets.7,8 Indeed, several small studies have reported benefit from alloHCT in RT.9-11 In order to better understand the ther- apeutic value of alloHCT in the modern era, we report alloHCT outcomes for 28 consecutive patients with RT who received chemoimmunotherapy and/or targeted therapy prior to alloHCT.
The Blood and Marrow Transplant data repository of the Dana-Farber Cancer Institute was queried to identify all patients aged ≥18 years who underwent alloHCT for RT between January 1, 2010 and May 31, 2019. After obtaining Institutional Review Board approval in accor- dance with the Declaration of Helsinki, a retrospective chart review was performed to confirm the diagnosis of CLL and transformation to RT and 28 patients were iden- tified. Clinical characteristics of these patients are sum- marized in the Online Supplementary Table S1. Median age was 61 years (range: 41-73 years) and 24 (85.7%) were male. Twenty-six patients received reduced intensity conditioning (RIC) HCT. The histologic diagnosis at alloHCT was DLBCL (n=27) and Hodgkin lymphoma (n=1). Median time from CLL diagnosis to RT was 4.5 years (range: 0- 24.4 years). Median time from RT to alloHCT was 0.6 years (range: 0.2-3.8 years). Twenty-six patients (92.8%) were in complete remission (CR) or par- tial remission (PR) at the time of alloHCT. Positron emis-
sion tomography (PET) scan was available for 23 patients and seven (30%) of these 23 patients were PET positive. Of note, since RT is a high risk disease, our current prac- tice is to offer alloHCT only to those patients in at least PR. Median number of total therapies for CLL and RT combined prior to alloHCT was three (range: 1-7): one (range: 0-4) for CLL and two (range: 1-7) for RT. Nine patients received targeted therapies (4 for CLL and 5 for RT) in addition to chemoimmunotherapies before alloHCT. No patient received CAR-T cell therapy. All prior and post-transplant therapies are listed in Online Supplementary Table S2.
Time from CLL diagnosis to RT and alloHCT, relapse, post HCT therapy, and duration of overall survival (OS) for the entire cohort are depicted in Figure 1 along with selected clinical features such as age, prior targeted ther- apy, total number of prior therapies, complex karyotype (defined as ≥5 abnormalities),12 HCT comorbidity index, disease status, donor type, bulky disease, high lactate dehydrogenase (LDH) and/or low platelet counts (<100x109/L), and a PET scan result at transplant and occurrence of grade 2-4 acute graft-versus-host disease (GvHD). Strikingly, the cohort is dichotomized into a group of long survivors and a group that experienced early deaths. In the first group (subjects 15-28), all patients remain alive (4-year overall survival [OS] 100%) with median follow-up 4.9 years (range: 2.2-7.7 years). In the second group (subjects 1-14), 11 of 14 died within 1 year (1-year OS 21%). Remarkably, two of three patients aged >70 years survived over 5 years. Subject 27 was 73 years old at the time of alloHCT, relapsed 11 months after alloHCT, and subsequently received post-transplant therapy (CHOP) and donor lymphocyte infusion from his brother. This patient remains alive 7.3 years after alloHCT. Subject 22 was also 73 years old at the time of alloHCT, had del(17p) and developed RT while on ibruti- nib. This subject subsequently responded to R-EPOCH prior to alloHCT and remains alive in remission 5.2 years after alloHCT.
For the entire cohort, eight relapses (7 RT and 1 CLL) and 13 deaths have occurred: five from disease progres- sion, six from infection and two from GvHD. Of the eight non-relapse deaths, six died within 1 year and two with- in 2 years of alloHCT. Median follow-up among sur-
Table 1. Kaplan-Meier estimates for overall and progression-free survival and estimates of cumulative incidences of non-relapse mortality, relapse, acute graft-versus-host disease and chronic graft-versus-host disease in the competing risks framework.
All
(N=28) (95% CI)
53% (33-70) 39% (21-56) 29% (13-47) 32% (16-50) 36% (19-54) 18% (6-34) 52% (30-70) OS
HR (95% CI)
3.94 (1.36-12.4) 0.016
High Risk
(N=9) (95% CI)
11%* (0.6-39)
0%
33%* (5-67)
56% (16-83)
56% (17-82)
37% (6-71)
25% (2.5-60)
PFS
HR (95% CI)
2.05(0.8-5.09) 0.13
Standard Risk
(N=19) (95% CI)
P
Age ≥65 (N=10) (95% CI)
40% (12-67) 10% (0.6-36) 20% (2-50) 70% (25-91)
Age<65
(N=18) (95% CI) P
61% (35-79) 0.16 55% (30-74) 0.006 34% (13-56) 0.58 11% (2-30) 0.007
4-yr OS
4-yr PFS
4-yr NRM
4-yr Relapse
6 mo. Grade 2-4 aGvHD 6 mo. Grade 2-4 aGvHD 2 yr cGvHD
Grade II-IV aGvHD
P
74% (48-88) <0.0001 58% (33-76) <0.0001
21% (6-42) 0.21 21% (6-42) 0.054 21% (6-42) 0.013
11% (1.7-29) 0.12 61% (33-80) 0.43
NRM Relapse sHR (95% CI) sHR (95% CI)
7.36 (1.59-34) 0.53 (0.1-2.81) 0.01 0.45
Log-rank was used for comparisons of overall survival (OS) and progression-free survival (PFS).Gray test was used for comparisons of non-relapse mortality (NRM),relapse and graft-versus-host disease (GvHD).The table presents results of univariable analysis for the effect of grade 2-4 acute GvHD (aGvHD) on outcomes.Cox model was used for OS and PFS and cause-specific Cox model was used for NRM and relapse. Occurrence of grade 2-4 aGvHD was treated as a time dependent variable. HR: hazard ratio; CI: confidence interval; mo: months; yr: years; cGvHD: chronic GvHD. *3-year estimate as the last patient in this cohort was censored at 36.3 months.
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