Reduced intensity allogeneic haematopoietic cell transplantation for chronic lymphocytic leukaemia: related donor and umbilical cord allografting

Authors


Allogeneic haematopoietic cell transplantation (HCT) for chronic lymphocytic leukaemia (CLL) is increasingly used due to its incurability with conventional treatments, especially in patients with poor risk and multiply relapsed disease (Schetelig et al, 2003; Dreger et al, 2005; Sorror et al, 2005; Delgado et al, 2006). Reduced intensity conditioning (RIC) regimens may permit HCT with acceptable morbidity and mortality for older patients, though many still lack suitable human leucocyte antigen (HLA) matched related donors (MRD). Umbilical cord blood (UCB) has been shown to be an effective graft source for patients with haematological malignancies who need an allogeneic transplant but lack a MRD or unrelated donor (URD) (Majhail et al, 2008; Brunstein et al, 2009), yet only preliminary reports on its use are available for CLL (Rodrigues et al, 2009). We report our initial experience for CLL in patients undergoing RIC HCT from both MRD and UCB donors.

Twenty-six consecutive allogeneic transplants for CLL performed between 2000 and 2009 were analyzed. RIC HCT eligibility included either: age (≥55 years for MRD; >45 years for UCB), Karnofsky performance status ≥60%, organ dysfunction [ejection fraction (EF) ≥35%, carbon dioxide diffusion capacity (DLCO) ≥35%], or recent serious infection. Donors were either HLA-identical MRD (n = 12) or double UCB (n = 14) units matched at 4/6–6/6 HLA loci to recipients and to each other. All patients received cyclophosphamide (50 mg/kg intravenously day −6), fludarabine (40 mg/m2 intravenously daily days −6 to −2) and total body irradiation (200 cGy day −1). Equine anti-thymocyte globulin (ATG) 15 mg/kg IV intravenously every 12 h for six doses days −3 to −1 was given to nine patients not receiving multi-agent chemotherapy within the preceding 3 months. Graft-versus-host disease (GVHD) prophylaxis was ciclosporin (CSA) dosed to trough levels of 200–400 ng/ml (days −3 to +180) plus mycophenolate mofetil (MMF) 1–1·5 g every 12 h (days −3 to +30) in all but one patient. Comorbidity scores (HCT-comorbidity index) were calculated retrospectively (Sorror et al, 2005). Neutrophil recovery was defined as the first of three consecutive days with absolute neutrophil count ≥0·5 × 109/l. Platelet engraftment was defined as the first day of a sustained count >20 × 109/l without transfusion for 7 d.

Fludarabine resistance and poor risk cytogenetics were common (Table I), and all patients were heavily pretreated [median of 5·5 (MRD) and 4 (UCB) different regimens]. There were no significant differences in disease bulk, fludarabine resistance, or cytogenetic risks between patients receiving UCB versus MRD allografts (data not shown). Graft failure occurred in 3 (21%) UCB HCT cases. Two of these patients survive with autologous, non-CLL recovery, one 6 years and one 7 years after HCT. The proportion of patients with acute GVHD, grade III–IV at 100 days was 38% [95% confidence interval (CI) 20–57]. Cumulative non-relapse mortality (NRM) was 19% (95% CI 4–24%) at 100 days (Table II) and did not differ by pre-HCT comorbidity score (data not shown). Overall survival (OS) at 3 years was 51% (95% CI 29–68) while progression-free survival (PFS) at 3 years was 38% (95% CI 19–57). Following HCT, 10 of 12 (83%) MRD patients and 10 of 14 UCB patients (71%) achieved complete remission (P = 0·65). Relapse/progression at 1 year was 15% (95% CI 2–29%) and 25% (95% CI 8–42%) at 3 years.

Table I.   Patient, disease and transplant characteristics.
  1. MRD, matched related donor; UCB, umbilical cord blood; Cy, cyclophosphamide; Flu, fludarabine; TBI, total body irradiation; GVHD, graft versus host disease; CSA, ciclosporin; MMF, mycophenolate mofetil; HCT, haematopoietic cell transplant.

  2. *Anti-thymocyte globulin was included for 9 patients.

  3. †1 UCB recipient received sirolimus instead of CSA.

Patient Characteristics (n = 26)
 Age, median (range), years53 (43–67)
  ≥ 50 years, n (%)20 (77)
 Female:Male4:22
 Years from diagnosis to transplant, median (range)6·2 (2·3–12·1)
Disease characteristics at HCT
 Bulky disease (≥5 cm), n (%)6 (23)
 Fludarabine refractory, n (%)12 (46)
 Cytogenetics, n (%)
  Standard risk13 (50)
  Poor risk (del 11q, del 17p, complex)11 (42)
  Not tested2 (8)
 Prior regimens, median, (range)4·5 (1–9)
 Splenectomy, n (%)7 (27)
Transplant characteristics
 Stem cell source
  MRD12
  UCB14
 Conditioning
  Cy/Flu/TBI*17 (65)
 GVHD prophylaxis 
  CSA/MMF†25 (96)
 HCT – comorbidity index, n (%)
  Low/Intermediate risk (0–1)10 (38)
  High risk (≥2)14 (54)
  Unavailable2 (8)
Median follow-up, years (range)3·1 (0·4–4·9)
Table II.   Transplant outcomes.
 P value
  1. MRD, matched related donor; UCB, umbilical cord blood; Cy, cyclophosphamide; Flu, fludarabine; TBI, total body irradiation; GVHD, graft versus host disease; CSA, ciclosporin; MMF, mycophenolate mofetil; HCT, haematopoietic cell transplant.

Time to neutrophil engraftment; median days (range)11.5 (0–41) 
 MRD11 (0–13)0·01
 UCB16 (6–41)
Time to platelet recovery >20 × 109/l; median days (range)18 (0–66) 
 MRD17 (0–27)<0·01
 UCB51 (34–66)
Acute GVHD, grades II–IV %, (95% CI) at day 10054 (33–74) 
 MRD58 (30–87)0·92
 UCB50 (23–77)
Chronic GVHD % at 1 year, (95% CI)23 (7–41) 
 MRD36 (8–64)0·63
 UCB14 (0–31)
Non-relapse mortality %, (95% CI) at 1 year23 (7–39) 
 MRD8 (0–23)0·34
 UCB36 (11–61)
Survival %, (95% CI) at 3 years51 (29–68) 
 MRD71 (34–90)0·05
 UCB33 (11–58)
Progression-free survival %, (95% CI) at 3 years38 (19–57) 
 MRD52 (20–77)0·08
 UCB26 (7–51)

These data indicate similar, but quicker neutrophil and platelet engraftment using MRD versus UCB grafts (Table II). The incidence of acute GVHD was similar, but there was a non-significant trend toward less chronic GVHD using UCB. NRM and PFS was similar at 3 years using either graft source but a trend towards lower OS was seen in the UCB cohort.

While URD HCT for CLL is accepted based on promising results reported by the Seattle and German groups (Schetelig et al, 2003; Sorror et al, 2008), there remains limited data on UCB for CLL. A recent report described outcomes of patients with lymphoid malignancies undergoing RIC UCB HCT including 14 patients with CLL. One-year PFS and OS rates for CLL patients were 43% and 51%, respectively (Rodrigues et al, 2009), but limited data on GVHD, NRM or later outcomes was available.

As we reported, chronic GVHD is less frequent after UCB HCT, which, accompanied by limited risks of graft failure, infections and acute GVHD, could make it a preferred option (Majhail et al, 2008). Heterogeneity among patients and the small cohort prevent clear identification of factors contributing to lower OS seen in the UCB group. The small numbers also confound determination of the preferred timing for HCT for these heavily pre-treated patients. Earlier HCT may yield improvements in NRM and thereby increase OS compared to risks of ongoing salvage therapies (Keating et al, 2002). Alternative stem cell sources will be needed for the approximately 30–40% of patients without a well-matched related or URD (Brunstein et al, 2007). Our data indicate that allogeneic HCT can result in long-term remissions for heavily-treated CLL patients using either MRD or UCB HCT.

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