Allogeneic stem cell transplantation of adult chronic myelomonocytic leukaemia. A report on behalf of the Chronic Leukaemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT)

Authors


PD Dr Nicolaus Kröger, Bone Marrow Transplantation, University Hospital Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany. E-mail: nkroeger@uke.uni-hamburg.de

Abstract

Summary. We report the results of 50 allogeneic transplantations from related (n = 43) or unrelated (n = 7) donors, performed for chronic myelomonocytic leukaemia (CMML) in 43 European centres. The median age at transplant was 44 years (range 19–61). Eighteen patients had excess blasts ranging from 5% to 30% at the time of transplantation. Two graft failures were observed (4%). Neutrophil (> 0·5 × 109/l) and platelet engraftment (> 50 × 109/l) was reached after a median of 17 d (range 11–38) and 27 d (range 11–48) respectively. Acute graft-versus-host disease (GvHD grade II–IV was seen in 35% of patients, while 20% developed severe-acute GvHD grade III/IV. Twenty-six patients (52%) died of treatment-related causes. After a median follow-up of 40 months (range 11–110), the 5-year-estimated overall survival was 21% (95% CI: 15–27%) and the 5-year-estimated disease-free survival (DFS) was 18% (95% CI: 13–23%). Earlier transplantation in the course of disease, male donor, use of unmanipulated grafts, allogeneic transplantation and occurrence of acute GvHD favoured better DFS, but did not reach statistical significance. The 5-year estimated probability of relapse was 49%. The data showed a trend for a lower relapse probability of acute GvHD grade II–IV (24% vs 54%; P = 0·07), and for a higher relapse rate in patients with T cell-depleted grafts (62% vs 45%), suggesting a ‘graft-versus-CMML effect’.

Chronic myelomonocytic leukaemia (CMML) is a rare haematological neoplastic disease, characterized by increased numbers of monocytic cells in the bone marrow and peripheral blood. Because of its dysplastic features, CMML was classified as a subtype of myelodysplastic syndromes (MDS) by the French–American–British (FAB) group (Bennet et al, 1994). It is the least frequent form of MDS (< 10%). Blood and marrow may be similar to refractory anaemia with excess of blasts (RAEB) except for significant monocytosis. However, CMML shares features of both myelodysplastic and myeloproliferative disorders (MPS). According to the FAB proposal, CMML-MDS is diagnosed by a white blood count (WBC) < 13 × 109/l, whereas CMML-MPS is characterized by a WBC > 13 × 109/l. The distinction between CMML-MDS and CMML-MPS does not provide prognostic information about the clinical course of disease (Germing et al, 1998). Other investigators have suggested that evolution fromCMML-MDS to CMML-MPS was a frequent event and CMML-MDS could be considered as an early stage of CMML-MPS in most cases (Voglova et al, 2001). As a result, the World Health Organization (WHO) recently classified CMML as a MPS (Harris et al, 1999). The initial control of leucocytosis using conventional chemotherapy is obtained in the majority of patients with CMML, but complete and sustained responses are rare (Beran et al, 1996; Cambier et al, 1996; Wattel et al, 1996). The median survival is 24 months and complex chromosomal changes, mainly involving chromosomes 5, 7, 8, 12, 16 and 21, usually predict a high rate of transformation to acute leukaemia (Ribera et al, 1987; Greenberg et al, 1997). As conventional approaches have no curative potential, high-dose chemotherapy followed by stem cell transplantation is an attractive alternative especially in younger patients. This report from the European Group for Blood and Marrow Transplantation (EBMT) Registry analyses the outcome of 50 adult patients who received an allogeneic stem cell transplantation from either a related or an unrelated donor for CMML.

Patients and methods

Patient characteristics.  The study group consisted of 50 patients allografted for de novo chronic myelomonocytic leukaemia. All patients were reported to the European Blood and Marrow Transplantation Registry between December 1988 and January 2000. To avoid overlap with juvenile chronic myelomonocytic leukaemia (JMML), patients younger than 18 years were excluded from this analysis. Insufficient information was available to distinguish between CMML-MDS and CMML-MPS. All patients had denovo CMML, and therapy-related acute leukaemia, and acute leukaemia evolved from CMML was excluded. Eighteen patients had excess blasts ranging from 5% to 30% at the time of transplantation. Transplantation characteristics are listed in Table I. Twenty-nine patients were men and 21 women. The median age was 44 years (range 19–61). The median time from diagnosis to transplant was 9 months (range 1–57). Nineteen patients received chemotherapy before transplantation. Cytogenetic data were available in 29 patients; 18 did not show cytogenetic abnormalities, whereas 11 patients showed cytogenetic abnormalities, mainly involving monosomy 7 (see Table I).

Table I.  CMML patients' characteristics (n = 50).
  1. CsA, cyclosporin A; MTX, methotrexate.

Age (median)44 (range, 19–61)
Recipient sex (male:female)29:21
Donor sex (male:female)27:23
Identical siblingn = 38
Related with mismatchn = 5
Related-matchedn = 1
Unrelated-matchedn = 6
Stem cell source
 Bone marrown = 40
 PBSCn = 9
 Bone marrow + PBSCn = 1
Cytogenetics
 Not availablen = 21
 Normaln = 18
 Abnormaln = 11
Abnormal karyotype (n = 11)
 Monosomy 7, trisomy 2n = 3
 Monosomy 7, monosomy 8n = 2
 Monosomy 7n = 1
 t(15;6), del(15)n = 1
 t(3;4), del(2), del(3)n = 1
 Monosomy 7, inv 3qn = 1
 Trisomy 21, lost Yn = 1
 t(6;10)n = 1
 1;17n = 1
Prior treatment (before transplantation)
 Nonen = 10
 Unknownn = 19
 Chemotherapyn = 19
 Growth factorsn = 1
 Hormonesn = 1
Blast percentage in bone marrow at time of transplantation
 Unknownn = 5
 ≤ 5%n = 28
 6–10%n = 10
 11–20%n = 6
 21–30%n = 1
GvHD prophylaxis
 CsA + MTXn = 17
 CsA + MTX + Prednisonen = 7
 CsAn = 3
 CsA + Prednisonen = 3
 T-cell depletionn = 11
 Unknownn = 12
Conditioning
 TBI-basedn = 26
 Chemotherapy onlyn = 24
Median time from diagnosis to transplantation9 months (range, 1–57)

Transplantation procedures and donor characteristics.  Thirty-eight patients were transplanted with stem cells from a human leucoyte antigen (HLA)-identical sibling, one patient from a matched-related donor, five patients from a mismatched-related donor and six patients were transplanted from an HLA-compatible unrelated donor. Eleven patients received an ex-vivo T cell-depleted graft. Donor sex was female in 23 and male in 27 patients.

Twenty-six patients received a conditioning regimen, including total-body irradiation (TBI), and 24 patients received a chemotherapy-based conditioning regimen. Bone marrow was the stem cell source in 40 patients, peripheral blood stem cells (PBSC) in nine patients, and one patient received PBSC and bone marrow.

Statistical methods.  The probabilities of haematopoietic recovery, graft-versus-host disease (GvHD), transplant-related mortality (TRM), relapse incidence (RI), disease-free survival (DFS) and overall survival (OS) were estimated from the time of transplantation, according to the Kaplan–Meier (KM) product limit method. The univariate groups were compared using the two-tailed log-rank test and assessment of hazard ratio was perform using univariate Cox model analysis. If necessary, P-spline method and penalized Cox model were used to define the most appropriate cut-off value(s) for continuous covariates. In addition to the source of haematopoietic stem cell used for transplantation, the following covariates were analysed in univariate analysis: recipient age at transplantation, time interval between diagnosis and transplantation, recipient gender, marrow blast percentage at transplantation, cytogenetics, donor gender, conditioning regimen (total-body irradiation or not), T-cell depletion and acute GvHD. When groups were compared according to continuous covariates, Mann–Whitney U-test or Kruskal–Wallis one-way anova on ranks test were used for difference in medians. According to the group sizes, chi-square or Fisher's exact tests were used to compare categorical covariates. s plus 2000 professional was used for all statistical analysis.

Results

Engraftment: haematopoietic recovery

Neutrophil recovery was observed in all but four patients who died by d +4 (n = 1), d +12 (n = 1), and d +16 (n = 2) post transplantation. All patients who received granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPC) achieved neutrophil recovery. Median time to reach an absolute neutrophil count (ANC) above 0·5 × 109/l was 17 d (range: 11–38) for the overall group. The probability of reaching an ANC above 0·5 × 109/l by d +21 post transplantation was 65% for the overall group of patients (95%CI: 44–78%). Neutrophil recovery occurred a median 6 d earlier when PBPC were used (median: 14 d, range: 11–19) rather than bone marrow grafts (median: 20 d, range: 12–38) (P < 0·001). The probability of reaching an ANC above 0·5 × 109/l by d +21 post transplantation was 52% when bone marrow grafts were used (95%CI: 28–69%), vs 100% when PBPC were used (P < 0·001). Twenty-seven patients had platelet recovery (≥ 50 × 109/l), which was reached at a median of 27 d from graft infusion (range: 11–48).

GvHD

Estimates of grade I–IV, grade II–IV and grade III–IV acute GvHD incidences were 59% (95%CI: 41–72%), 35% (95%CI: 19–48%) and 23% (95%CI: 9–35%) respectively. The estimates of grade II–IV acute GvHD incidence were 11% (95%CI: 0–29%), when patients had received T cell-depleted grafts, and 41% (95%CI: 22–56%) when grafts were not manipulated (relative risk: 0·26, 95%CI: 0·03–1·97, P = 0·19). The estimates of grade II–IV acute GvHD incidence were 38% (95%CI: 19–52%) when donors were HLA-matched relatives, and 28% (95%CI: 0–56%) when they were either HLA-mismatched related or HLA-matched unrelated (relative risk: 1·83, 95%CI: 0·41–8·13, P = 0·43). Among the 27 patients who were assessable for chronic GvHD, five developed limited chronic GvHD and two developed extensive chronic GvHD.

TRM

Twenty-six patients died of transplant-related causes, which were mainly related to the occurrence of GvHD (Table II). Estimates of the TRM at 100 d and 1 year post SCT were 35% (95%CI: 20–47%) and 55% (95%CI: 36–68%) respectively. The only covariate associated with an increased 1-year TRM was the percentage of marrow blasts at transplantation [< 5% blast 18% (95%CI: 0–38%) vs ≥ 5% blast 65% (95%CI: 31–82%), relative risk: 4·30 (95%CI: 0·95–19·4), P < 0·06]. Grade II–IV acute GvHD was associated with an estimated increase of 24% of the 1-year TRM, but the difference was not statistically significant [with grade 0–I aGvHD: 49% (95%CI: 23–66%) vs 73% with grade II–IV aGvHD (95%CI: 38–89%), relative risk: 1·79, 95%CI: 0·80–4·01, P = 0·15]. The use of PBPC rather than bone marrow (PBPC: 53% vs bone marrow: 55%, P = 0·44), the type of donor (HLA-matched related: 52% vs other donor types: 64%, P = 0·37), recipient age (as a continuous or categorized covariate), and time interval between diagnosis and SCT (as a continuous or categorized covariate) had no significant impact on the 1-year TRM.

Table II.  Main causes of death.
Cause of deathNumber
Relapse12
GvHD 9
Haemorrhage 4
Interstitial pneumonia 4
Infection/Sepsis 4
Multi-organ failure 2
Graft failure 2
Veno-occlusive disease 1

Relapse

Fourteen relapses occurred at a median of 4·5 months post transplantation (range: 1–33 months). Twelve of the relapsing patients had died as of the last follow-up evaluation. The 2-year estimated relapse incidence was 42% (95%CI: 21–58%). Treatment of post-transplantation relapses was based on chemotherapy and transfusion, no patient receiving donor lymphocyte infusion. In univariate analyses, none of the following covariates had a significant influence on the relapse incidence: recipient age, marrow blast percentage at the time of transplantation, time interval between diagnosis and transplantation, non-TBI-containing conditioning regimen, and T-cell depletion (Table III). Patients who developed acute GvHD had a lower 2-year relapse incidence [KM estimates: 29% with GvHD (95%CI: 0–50%) vs 51% without GvHD (95%CI: 17–76%), relative risk: 0·34 (95%CI: 0·10–1·17), P = 0·07] (see Fig 1). Furthermore, the difference in terms of treatment failure was significantly increased when considering the occurrence of grade II–IV acute GvHD or not (KM estimates: 51% vs 0%, P < 0·03). Abnormal cytogenetic abnormalities were associated with a higher relapse incidence (KM estimates: 58% with abnormal karyotypes vs 18% with normal karyotypes, P = 0·10).

Table III.  Analysis of factors influencing probabilities of survival, TRM and relapse (univariate analyses).
ParameterOSP-valueDFSP-valueRelapseP-value
Blasts > 5% vs < 5%17% vs 26%n.s.33% vs 12%n.s.48% vs 52%n.s.
Donor female vs male18% vs 25%n.s. 9% vs 31%n.s.64% vs 36%n.s.
BM vs PBSC (allo)22% vs 22%n.s.19% vs 22%n.s.50% vs 61%n.s.
Time from Dx to transplant > 1 year vs < 1 year22% vs 22%n.s.16% vs 21%n.s.48% vs 50%n.s.
TBI vs Non-TBI24% vs 21%n.s.24% vs 14%n.s.38% vs 58%n.s.
BMT before/after 199422% vs 20%n.s.15% vs 21%n.s.62% vs 38%n.s.
Age < 40 vs > 40 years21% vs 21%n.s.21% vs 16%n.s.48% vs 50%n.s.
T-cell depletion vs no T-cell depletion11% vs 29%n.s.11% vs 21%n.s.62% vs 45%n.s.
Identical sibling vs mismatched-related/ matched-unrelated22% vs 18%n.s.18% vs 18%n.s.53% vs 51%n.s.
Cytogenetic normal vs abnormal30% vs 18%n.s.26% vs 18%n.s.18% vs 58%n.s.
GvHD vs no GvHD21% vs 20%n.s.28% vs 11%n.s.29% vs 51%n.s (0·07)
Figure 1.

Probability of relapse according to acute GvHD.

Overall and disease-free survival

The median follow-up time after transplantation was 3·5 years (range: 11 months to 9·3 years) for the surviving patients. Estimates of the 2-year OS and DFS were 21% (95% CI: 15–27%) and 18% (95% CI: 13–23%) respectively (Figs 2 and 3). With nine patients alive among the 39 who received non-T cell-depleted grafts from HLA-matched related donors, the 2-year DFS was 26% (95%CI: 14–46%). Two out of the 11 patients who received grafts from HLA-mismatched related donors (n = 5) or HLA-matched unrelated donors (n = 6) were alive at 2 years post transplantation. Patients who developed acute GvHD had a marginally improved 2-year DFS [KM estimates: 28% (95%CI: 15–52%) vs 11% (95%CI: 3–39%), P = 0·11]. Other covariates which had a marginal impact on the 2-year DFS were: recipient gender (male: 31% vs female: 9%, P = 0·17) and the percentage of marrow blast before transplantation. Patients with 0–10% marrow blasts had a 2-year DFS of 33% (95%CI: 18–60%), compared with 12% if they had more than 10% marrow blasts (95%CI: 2–78%) at the time of transplantation (P = 0·15). Recipient age, time interval between diagnosis and transplantation, year of transplantation, donor/recipient relationship, the use of exvivo T-cell depletion, donor gender and type of graft had no significant impact on the 2-year DFS (Table III).

Figure 2.

Overall survival of CMML.

Figure 3.

Disease-free survival of CMML.

Discussion

This series is the largest cohort of patients with adult chronic myelomonocytic leukaemia and stem cell transplantation reported to date. The study supports the hypothesis that allogeneic stem cell transplantation may cure at least a minority of patients. Eighteen per cent of adult CMML patients achieved long-lasting haematological remission and may be cured of this otherwise fatal disease. Because CMML is currently classified as a subgroup of the myelodysplastic syndromes, only a few cases of allogeneic stem cell transplantation, mainly as part of MDS registry data, have been reported to date (Anderson et al, 1993; Arnold et al, 1998; Runde et al, 1998; De Witte et al, 2000; Deeg et al, 2000; Zang et al, 2000). Recently, the Seattle group reported an even better DFS of 35% in 21 patients who underwent allogeneic stem cell transplantation with CMML. However, this study also included children (Zang et al, 2000). The European Working Group on Myelodysplastic Syndrome in Childhood reported a 5-year estimated event-free survival of 31% and a relapse rate of 58% after transplantation for childhood CMML (Locatelli et al, 1997). The high rate of treatment failure was also observed in our study with an estimated relapse probability of 49% at 5 years. The median time to relapse was 4·5 months after transplantation. The trend for lower relapse probability (P = 0·07) in patients with acute GvHD grade II–IV and the higher relapse rate in patients with T cell-depleted grafts (73% vs 52%) suggests a graft-versus-CMML effect. In contrast to the relapse-preventing effect, acute GvHD was the major cause of treatment-related mortality in our study. Several approaches have been conducted or are under investigation to separate graft-versus-leukaemia and graft-versus-host disease such as CD34-positive selection and T-cell add back, depletion of CD8+ cell or transduction of a suicide gene into T cells (Tiberghien et al, 1994; Giralt et al, 1995). The possibility of dose-reduced or non-myeloablative conditioning to reduce transplant-related mortality and to achieve at least mixed chimaerism with preservation of a graft-versus-leukaemia effect has been recently described (Giralt et al, 1997; Slavin et al, 1998; McSweeney et al, 2001) and might be a therapeutic option even in older CMML patients. However, to date no published data are available for dose-reduced conditioning followed by allografting in CMML patients. Recently, a small series of advanced MDS patients transplanted with a dose-reduced conditioning showed an estimated 2-year survival of 26% (95% CI:4–52) (Kröger et al, 2001). A lower blast count in bone marrow at the time of transplantation showed a trend for lower relapse rates and better overall survival, but as a result of the relatively low patient number, this difference did not reach statistical significance. However, this would be in accordance with the MDS registry data of the EBMT which showed that patients with RA or sideroblastic anaemia have a 55% disease-free survival compared with a 28% DFS for patients transplanted for RAEB or RAEB in transformation. This is mainly due to a lower relapse rate in patients with less blasts (Runde et al, 1998; De Witte et al, 2000). This fact raises the question whether an induction chemotherapy could reduce the blast count at time of transplantation and may therefore also reduce the relapse rate. Until now, no conclusive data are available in MDS patients as to whether a reduction of blasts prior to transplantation will result in a better outcome. An ongoing EBMT study will address this question. Complex cytogenetic abnormalities or monosomy 7 negatively-influenced outcome with respect to OS (30% vs 18%) and DFS (26% vs 18%) in comparison with patients with a normal karyotype. However, the difference did not reach statistical significance, possibly due to the fact that cytogenetic data in our analysis was available only for 29 patients. The importance of complex cytogenetic abnormalities on outcome has been recently reported in MDS (Runde et al, 2000).

In conclusion, allogeneic stem cell transplantation may cure patients with CMML. Therefore, young patients with suitable HLA-compatible donors should be offered allogeneic stem cell transplantation. In addition, allogeneic transplantation may be considered even for those patients for whom an unrelated donor or a related donor with one mismatch can be identified, as their OS, DFS and relapse outcome was similar compared with patients with a fully-matched related donor. However, as a result of the low number of patients, no definitive conclusion can be drawn. Patients should be transplanted early in their disease course. Improvement of treatment-related toxicity, as well as strategies to reduce relapse rate, are needed to improve results of allogeneic transplantation from related and unrelated donors.

Acknowledgments

We thank the participating centres:

• Hôpital Necker, Unité d'Immunologie et d'Hématologie and INSERM U29, Paris/France: n = 2

• Abt. Innere Medizin III, Universität Ulm/Germany: n = 1

• Department of Hematology, BMT, Hôpital St. Louis, Paris Cedex 10/France: n = 1

• Department of Hematology, University Hospital Gasthuisberg, 3000 Leuven/Belgium: n = 1

• Department of Hematology, Huddinge University Hospital/Sweden: n = 1

• Department of Hematology, Hôpital Saint Antoine, Paris Cedex 12/France: n = 1

• Institute of Hematology & Oncology, Department of Hematology, Hospital Clinic, Barcelona/Spain: n = 1

• Medizinische Klinik, Abteilung II, University Hospital, Tübingen/Germany: n = 1

• BMT Unit/Clinical Immunobiology, University Hospital Innsbruck/Austria: n = 2

• Dipartimento di Biotecnologie Cellulari e Ematologia, University ‘La Sapienza’ Rome/Italy: n = 1

• Department of Haematology, Cliniques Universitaires St. Luc Brussels/Belgium: n = 1

• University Medical Center St. Radboud, Department of Hematology, Nijmegen/the Netherlands: n = 3

• University Medical Centre, Department of Haematology, Utrecht/the Netherlands: n = 1

• Hospital Universitario, ‘Marqués de Valdecilla’, Santander/Spain: n = 1

• Daniel den Hoed Cancer Centre (AZR), Rotterdam/the Netherlands: n = 1

• Sve d'Hématologie, Hôpital Henri Mondor, Creteil/France: n = 1

• Department of Bone Marrow Transplantation, University Hospital Essen/Germany: n = 1

• Clinical Hematology Division, Hospital Santa Creu i Sant Pau, Barcelona/Spain: n = 3

• Division d'Hématologie, Hôpital Cantonal Universitaire, Geneva/Switzerland: n = 1

• Division Oncologia Medica e Chemioterapia, Ospedale Fatebenefratelli e Oftalmico, Milano/Italy: n = 2

• University Hospital Innsbruck, Division of Hematology and Oncology, Innsbruck/Austria: n = 1

• Hospital Clinico Universitario, Servicio de Hematologia y Oncologia, Valencia/Spain: n = 1

• Department of Haematology, Birmingham Heartlands Hospital, Birmingham/United Kingdom: n = 1

• Department of Hematology/Oncology, Medical School of Hannover, Hannover/Germany: n = 1

• Klinik für Hämatologie, Onkologie und Klinische Immunologie, Düsseldorf/Germany: n = 2

• Royal Liverpool University Hospital, Department of Haematology, Liverpool L7 8XP/United Kingdom: n = 1

• Medical Klinik III, Klinikum Grosshadern, München/Germany: n = 1

• Department of Medicine, Helsinki University Central Hospital, Helsinki/Finland: n = 2

• Haematology Department/BMT-Unit, The George Papanicolaou General Hospital of Thessaloniki/Greece: n = 1

• Servei d'Hematologia, R. G. Vall d'Hebron, Barcelona/Spain: n = 1

• Klinik für Knochenmarktransplantation und Hämatologie/Onkologie GmbH, Idar-Oberstein/Germany: n = 1

• Service des Maladies du Sang, CHRU, Angers Cedex 01/France: n = 2

• Department of Hematology, University of Liege, Liege/Belgium: n = 1

• Department of Hematology, K. Marcinkowski University of Medical Science, Poznan/Poland: n = 2

• Department of Pediatrics, University of Jena, Jena/Germany: n = 1

• Department of Hematology, University Tor Vergata, St. Eugenio Hospital, Rome/Italy: n = 1

• Department of Hematology, Institut Catala d'Oncologia, Barcelona/Spain: n = 1

• Division of Hematology, ‘Federico II’ Medical School, Napoli/Italy: n = 2

• Department of Internal Medical I, BMT-Unit, University Hospital, University of Saarland, Germany: n = 1

• Charité, Campus Mitte, Medical Klinik – Onkologie/Hämatologie, Berlin/Germany: n = 1

• Medical Klinik I, Universitätsklinikum Dresden, Dresden/Germany: n = 2

• Department of Medicine, Hematology, Oncology, University of Freiburg Freiburg/Germany: (n = 1)

Ancillary