SCT, stem cell transplant; allo, allograft; FIC, full -intensity conditioning; RIC, reduced-intensity conditioning; MUD, matched unrelated donor; Sib, sibling; M, male; F, female; B, blood; BM, bone marrow; Spl, spleen; Liv, liver; LN, lymph nodes; Pleu, pleural effusion; Asc, ascites; Chylo, chylothorax; Peri, periorbital oedema; CNS, central nervous system; DCF, pentostatin; CHOP, Cyclophosphamide, Doxorubicin, Vincristine, Prednisolone; Vapec-B, vincristine, doxorubicin, prednisolone, etoposide, cyclophosphamide and bleomycin; Sx, splenectomy; Chl, chlorambucil; R, rituximab; CR, complete response; PR, partial response; NR, no response (including stable disease); BEAC, BCNU, etoposide, cytarabine and cyclophosphamide; BEAM, BCNU, etoposide, cytarabine, and melphalan; Cyclo, cyclophosphamide; TBI, total body irradiation; Mel, melphalan; Etop, Etoposide; FDR, fludarabine; Alem, Alemtuzumab; Dexa, dexamethasone; DFS, disease-free survival; OS, overall survival.
Stem cell transplantation after alemtuzumab in T-cell prolymphocytic leukaemia results in longer survival than after alemtuzumab alone: a multicentre retrospective study
Article first published online: 1 MAR 2010
© 2010 Blackwell Publishing Ltd
British Journal of Haematology
Volume 149, Issue 6, pages 907–910, June 2010
How to Cite
Krishnan, B., Else, M., Tjonnfjord, G. E., Cazin, B., Carney, D., Carter, J., Ketterer, N., Catovsky, D., Ethell, M., Matutes, E. and Dearden, C. E. (2010), Stem cell transplantation after alemtuzumab in T-cell prolymphocytic leukaemia results in longer survival than after alemtuzumab alone: a multicentre retrospective study. British Journal of Haematology, 149: 907–910. doi: 10.1111/j.1365-2141.2010.08134.x
- Issue published online: 20 MAY 2010
- Article first published online: 1 MAR 2010
- T-cell prolymphocytic leukaemia;
- stem cell transplantation;
T-cell prolymphocytic leukaemia (T-PLL) is a rare malignancy with an aggressive course and limited treatment options (Robak & Robak, 2007; Dungarwalla et al, 2008). The median survival in historical series is <1 year (Matutes et al, 1991). Only a minority of patients achieve a transient response to purine analogues (Mercieca et al, 1994). Used in two published series, the anti-CD52 monoclonal antibody alemtuzumab (Campath-1H) resulted in overall response rates between 51 and 76%, and complete responses (CR) between 39·5 and 60% (Dearden et al, 2001; Keating et al, 2002). Median survival remained short (7·5–9 months), but was 15–16 months in patients achieving CR. With approval from the research ethics and clinical research committees of the Royal Marsden NHS Trust, we investigated whether stem cell transplantation (SCT) after alemtuzumab can prolong survival in T-PLL.
Data were reviewed retrospectively from 28 patients in the UK (n = 16), Norway, France, Australia, New Zealand, Spain and Switzerland, treated between 1996 and 2008 with either autologous (n = 15) or allogeneic (n = 13) SCT after alemtuzumab. All centres followed the same protocol (Dearden et al, 2001) and all protocol-treated patients who underwent SCT were included in this study. Patient characteristics and treatment history are shown in Table I. Three non-responders to alemtuzumab achieved a good partial response (PR) after conditioning treatment, prior to SCT (Patients 15, 21 and 25, Table I).
|Patient||Type of SCT||Sex||Age (years)||Site of disease||Immuno- phenotype||Prior therapy||Best response to prior therapy||Response to alemtuzumab||Conditioning regimen||Response after SCT||Relapse||DFS from SCT (months)||Vital status||OS from alemtuzumab (months)|
|6||Autograft||F||53||B/BM||CD4+/CD8+||Vapec-B, Sx, DCF||PR||CR/CR||Mel/TBI||CR||Yes||9||Died||55|
|16||Allo RIC MUD||M||51||B/BM/Skin||CD4−/CD8+||DCF||NR||PR*||FDR/Mel/Alem||CR||No||110||Alive||120|
|17||Allo FIC MUD||F||53||B/LN||CD4+/CD8+||NONE||CR||Cyclo/TBI||CR||No||37||Alive||48|
|18||Allo FIC MUD||M||56||B/BM/Spl||CD4+/CD8−||NONE||CR||Cyclo/TBI||CR||No||43||Alive||48|
|19||Allo FIC Sib||M||39||B/BM||CD4−/CD8+||DCF, Sx||NR||CR||Cyclo/TBI||CR||Yes||31||Died||37|
|20||Allo FIC MUD||F||41||B/BM/Spl/LN||CD4+/CD8+||NONE||CR*||Cyclo/TBI||CR||No||28||Alive||33|
|21||Allo RIC Sib||M||51||B/BM/Sp/Liv/LN||CD4−/CD8+||DCF||NR||NR*||FDR/Mel/Alem||CR||Yes||24||Died||33|
|22||Allo FIC MUD||M||51||B/BM/Spl/LN/Chylo||CD4+/CD8−||CHOP+R||NR||CR/PR||Cyclo/TBI||CR||No||21||Died||32|
|23||Allo RIC MUD||F||61||B/BM/LN/Skin/Peri||CD4+/CD8−||NONE||CR||FDR/Mel/Alem||CR||No||25||Alive||29|
|24||Allo RIC Sib||M||60||B/Spl/LN/Skin||CD4+/CD8−||NONE||CR*||FDR/Cyclo/Alem||CR||Yes||5||Died||18|
|25||Allo FIC MUD||M||50||B/BM/Spl/Liv/LN||CD4−/CD8+||NONE||NR*||Dexa-BEAM/TBI||CR||No||11||Died||18|
|26||Allo FIC Sib||M||56||B/BM/Spl||CD4−/CD8+||NONE||CR||Cyclo/TBI||CR||Yes||9||Died||14|
|27||Allo FIC Sib||M||40||B/BM/LN||CD4−/CD8+||NONE||CR||Cyclo/TBI||CR||No||2||Died||7|
|28||Allo FIC Sib||M||57||B/BM/Spl||CD4+/CD8+||DCF||PR||CR*||Cyclo/TBI||NE||NE||1||Died||3|
Clinical outcomes were compared against 23 patients with T-PLL who did not undergo SCT, retrospectively selected to include only those who achieved CR and survived >6 months after alemtuzumab treatment. Treated between 1992 and 2008, nine received alemtuzumab as first-line therapy and 14 received prior therapy: pentostatin alone (n = 7), other single agents (n = 4), or 2–3 prior therapies (n = 3).
The median age of the 15 autograft patients was 58 (range 43–68) years. Eight (53%) were male. At the time of SCT, 11 autograft patients were in their first CR after alemtuzumab, two were in a second CR and two were in a good PR. After autograft, all 15 patients achieved CR. There was one case of early treatment-related mortality (TRM), due to pneumonitis and multi-organ failure (Patient 15). Other toxicity included autoimmune haemolytic anaemia (Patient 10), streptococcal septicaemia and cutaneous herpes (Patient 13) and Escherichia coli with Klebsiella pneumoniae (Patient 2). Five patients remained alive and in CR, at 8, 45, 81, 107 and 115 months after the autograft. Nine patients relapsed, at a median of 15 months (range 5–56 months) and all died, 2–28 months after relapse. The median survival of the autograft patients, measured from the start of alemtuzumab treatment, was 52 months.
The 13 allograft patients were significantly younger than the autograft patients (P = 0·02), with a median age of 51 (range 39–61) years. Ten (77%) were male. At the time of SCT, 9 allograft patients were in their first CR after alemtuzumab and four were in a good PR. One non-assessable patient died 22 days post-SCT (Patient 28); all the others achieved CR. There were two cases of early and two of delayed TRM, including two sibling and two matched unrelated donor (MUD) allografts; all four patients had received full-intensity conditioning. These deaths were due to a fungal infection and subsequent multi-organ failure (Patient 28), refractory gut graft-versus-host disease (GvHD) and pseudomonal sepsis (Patient 27) and Epstein Barr virus (EBV)-associated post-transplant lymphoproliferative disease (PTLD) (Patients 22 and 25), with gastrointestinal and skin GvHD (Patient 25). Two other patients with EBV-positive PTLD relapsed and died of progressive disease (Patients 24 and 26). All the allogeneic SCT patients received ciclosporin and methotrexate as prophylaxis for GvHD. However, four patients developed GvHD, of whom three had full-intensity conditioning. Additional to the two fatalities reported above, Patient 17 had mild skin GvHD and Patient 16 had chronic, mild to moderate GvHD of gut, liver, skin and eyes continuing after 9 years. Other toxicity included haemorrhagic cystitis (Patient 18) and parvoviremia reactivation, with consequent red blood cell aplasia (Patient 20).
Five allograft patients remained alive and in CR at a follow-up from SCT of 25, 28, 37, 43 and 110 months; all had MUD allografts, two with reduced-intensity conditioning. Four patients relapsed and died of progressive disease, all after sibling allografts, two with full-intensity and two reduced-intensity conditioning (Table I). Patient 26 died of progressive disease 3 months after being reported minimal residual disease (MRD)-negative by polymerase chain reaction, probably due to disease harboured in ‘sanctuary’ sites (Dearden et al, 2001). The median survival of the allograft patients was 33 months.
Overall survival was similar in the autograft and allograft groups (P = 0·2, Figure 1A). Univariate analysis showed no significant association between survival and gender, age, extranodal disease, immunophenotype, prior treatment, response to alemtuzumab, whether in CR or PR prior to SCT, or conditioning regimen (data not shown). All 13 relapsed patients died of progressive disease. Five allograft and five autograft patients remained alive and in CR at a median follow-up from SCT of 81 and 37 months respectively. The median survival of all SCT patients was 48 months (Figure 1B).
The 23 non-SCT patients were similar to the SCT group in gender (70% males), disease characteristics, clinical presentation and prior treatment. Their median age was 64 (range 35–81) years, similar to the autograft group but older than the allograft group (P = 0·004) and the SCT patients as a whole (P = 0·007). However, their CR rate after alemtuzumab was higher than that of the SCT group. One non-SCT patient remained in CR 47 months after alemtuzumab treatment. Three further patients remained alive at 15, 19 and 34 months, all recently relapsed. Nineteen patients died from progressive disease. The median survival of the non-SCT patients was 20 months (Figure 1B), which compares favourably with previous reports, as described above. There was no association between age and survival in either group; thus the superior outcome after SCT was not accounted for by the age difference.
The evidence presented here suggests that SCT after alemtuzumab may provide benefit over alemtuzumab alone. Both autografts and allografts are associated with long-term survival in some patients.
Monica Else was funded by the Arbib Foundation. We thank John Swansbury, Benet Nomdedeu, Robin Ireland, Béatrice Mahe, Anil Lakhani, Saad Rassam and all those other doctors who referred patients for this series. No further funding was involved.
Conflict of interest
Claire Dearden received honoraria and research funding from Schering Health Care (UK). The remaining authors declare no conflict of interest.
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