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Allograft and preemptive immuneintervention in CLL
(NRM) and relapse/progression were calculated using the Fine and Gray approach, considering death as competing risks. In order to evaluate the impact on outcomes of MRDneg achieve- ment, we performed time dependent analyses considering MRDneg occurrence as a time-dependent event. Outcome data were estimated by the Mantel-Byar method and graphically illustrated by Simon-Makuch plots25,26 (Online Supplementary Appendix).
Results
Patients’ characteristics, donor type and protocol adherence
Between September 2012 and February 2015, 43 patients fulfilling the 2006 EBMT consensus criteria were recruited in 16 French centers; due to donor comorbidities, one patient included was not eventually transplanted. The pres- ent analysis includes the remaining 42 patients (32 male and 10 female). Patients’ characteristics are depicted in the Table 1. Before HSCT, patients had received a median of two
lines of treatment (range, 1-5); the last one being alem- tuzumab for 17 patients, immunochemotherapy for 21 and BCR inhibitors for four. Details of previous lines of treat- ment per patients are reported in the Online Supplementary Table S1. Eight patients were in CR/CRi (including six with blood MRDneg status) and 34 in PR pre-transplantation. Donors were HLA-identical siblings (n=16) or HLA- matched (10/10) unrelated donors (n=26).
The trial profile of the immune-intervention applied in this study and the representative protocol adherence is shown in the Online Supplementary Appendix (Online Supplementary Figure 1B). One patient died before D30. Among the 41 remaining patients, seven were not treated strictly according to study protocol: four patients had an unplanned early CsA withdrawal for primary (n=1) or sec- ondary (n=1) graft failure or mixed chimerism (n=2). One of these last two patients relapsed at 13 months, whereas the second, who later received DLI, was still in mixed chimerism without relapse at 18 months. For two patients, CsA was tapered early, despite MRDneg status, due to renal failure in one patient. Finally CsA was reduced at D120 instead of D90 for one patient with D90 MRDpos status.
Post-transplantation response and outcomes
Engraftment occurred in 40 of the 42 transplanted patients while two presented graft failure. In the latter patients, both in PR at transplantation, the last line were alemtuzumab plus dexamatasone, interrupted 49 days before transplant in one patient and ibrutinib interrupted 9 days before transplant in the other. Assessment of the response according to the iwCLL criteria between 3 and 6 months found CR/CRi and PR for 13 (31%) and 26 (62%) patients, respectively. Response was not evaluated for three patients because of early death (n=1) or graft rejection (n=2). Response was classified as partial when there was lymph node >15 mm persistence (n=6), spleen enlargement (n=4), both (n=3) or incomplete evaluation (n=13) (Online Supplementary Table S2).
Seventeen patients developed grade 1 (n=8), 2 (n=6) and 3 (n=3) aGvHD. Limited and extensive cGvHD occurred in 15 and nine of the 39 patients who engrafted and were still alive at D100, translating into a cumulative incidence at 2 years of cGvHD of 61% (95% Confidence Interval [CI]: 54- 68), including limited and extensive cGvHD in 38% (95% CI: 23-53) and in 23% (95% CI: 10%-36%) patients respec- tively. Two cases of primary cGvHD were diagnosed fol- lowing planned immune-intervention: one was a limited cGVHD after DLI administration for early progression at D35 and one was an extensive cGvHD after cessation of CsA due to D90 MRD positivity.
Seven of the 42 patients died. Causes of death were extensive cGvHD (n=2), pulmonary aspergillosis plus Pneumocystis jiroveci pneumonia associated with limited cGvHD (n=1) and early cytomegalovirus infection (n=1) in a patient who received alemtuzumab in the last weeks prior to transplantation. The three remaining deaths were related to disease progression with Richter transformation. Moreover three patients presented severe complications, namely two polyradiculopathy and one Epstein–Barr virus- induced lymphoproliferative disease.
With a median follow-up of survivors of 36 months (range, 19-53) the 3-year OS, PFS, and NRM were 86.9% (95% CI: 70.8-94.4), 62.9% (95% CI: 45.8-75.9) and 9.5% (95% CI: 3.7-23.4) respectively. Ten patients had progres- sion occurring after a median of 12 months (range, 1-34).
Table 1. Patients’ characteristics
Sex Female
Male
Median age at transplant: y (range)
Median time between diagnostic and HSCT: y (range)
Indication for HSCT: n
del(17)p and/or TP53 mutation, 1st line
del(17)p and/or TP53 mutation, in relapse
Purine analogs refractoriness without TP53 abnormality Early relapse (<2 y) after fludarabine based combination or autologous transplant without TP53 abnormality
Median prior treatment lines: n (range)
Last line before HSCT: n
Alemtuzumab (+/- Dexamethasone) Bendamustine based combination (B, BR, BOMP) R-DHAC
Ibrutinib
Idelalisib + rituximab
Rituximab
Median time between last line and HSCT: d (range)
Prior exposure to alemtuzumab: n
Median interval between alemtuzumab (last line) and HSCT: d (range)
HSCT done ≤ 60 days post alemtuzumab: n
Disease status at transplantation: n CR/CRi
PR
Lymph node > 15 mm* Lymph node ≤ 15 mm
Blood MRD at transplantation Median MRD level: % (range) Negative MRD: n
Donor type (HLA 10/10): n HLA Matched sibling HLA Matched unrelated
Patients (n=42)
10 32
58.6 (40.6 - 68.6) 4.5 (0.2 - 14.7)
11 16 3
12
2 (1-5)
17 14 6 3 1 1
63 (7-179)
20
85 (37-179)
6
8 34 25 17
0.78 (<10-4 - 70)
6 16
26
HSCT: hematopoietic stem cell transplantation; B: bendamustine; BR: bendamustine, rituximab; BOMP: bendamustine, ofatumumab, méthylprednisolone; R-DHAC: rituximab, carboplatin, cytarabine,dexamethasone;CR:complete remission;PR:partial remission;MRD:minimal resid- ual disease. n: number, d: days, m: months, y: years. * No patient with lymph node >50 mm.
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