Transplant Outcomes

A prospective registration study to determine feasibility of hematopoietic SCT in adults with acute leukemia: planning, expectations and reality

Abstract

For adults with acute leukemia, it is important to know whether the therapeutic schemes initially planned were actually implemented. The European Group for Blood and Marrow transplantation Acute Leukemia Working Party prospectively followed 695 consecutive patients who were registered at the time of HLA typing. Of 304 patients with an available matched sibling donor (MSD), SCT was planned in 264, chemotherapy in 33 and autografting in 7. For the rest, an unrelated donor (UD) search was initiated in 198. Among these, 117 were transplanted, 114 received chemotherapy and 77 underwent autografting. Probabilities of receiving a planned treatment were 60 and 65% at 1 and 2 years, respectively. Patients scheduled to receive MSD SCT had an 82% probability, whereas those scheduled to undergo UD SCT had a 57% probability, of receiving their transplant at 1 year. The only factor associated with a lower probability of MSD SCT in first remission was delayed HLA typing (HR=0.82; P=0.03). One year after enrollment, 40% of patients did not follow their initial treatment plan. Because OS was 50% only at 3 years and only 57% of the patients without a MSD underwent SCT, this suggests room for improvement in outcomes for adults with acute leukemia.

Introduction

Hematopoietic SCT has improved significantly over the last 30 years.1, 2, 3, 4, 5 Results of numerous randomized studies comparing allo-SCT, auto-SCT and conventional chemotherapy (CC) have been reported.6, 7 General guidelines have been published with frequent updates.8, 9 Yet, for many patients with AML or ALL, the best therapeutic strategy at the time of diagnosis, relapse or remission remains unknown, and, the actual therapeutic scheme that is followed often does not match the pre-planned treatment regimen. Therefore, in addition to uncertainty about optimum therapeutic regimens, the feasibility of implementing existing regimens and the real outcome of patients remain unknown.

To address these uncertainties, the Acute Leukemia Working Party (ALWP) of the European Group for Blood and Marrow Transplantation (EBMT) launched a prospective, non-interventional registry study. All consecutive patients in participating centers were registered at the time of HLA typing. The therapeutic strategy defined by the local treating team was recorded in the EBMT Paris office. We now report long-term results of this study, which accrued 695 consecutive adult patients from November 2003 to December 2006.

Materials and methods

EBMT centers and patients

Thirty-one centers in fourteen countries participated to the study. To participate, centers had to be EBMT members, report all consecutive transplants to EBMT, and agree to the study design. Patients had to sign an informed consent document that permitted sharing of clinical data according to National rules. All consecutive adult patients with acute leukemia and an indication for SCT were registered as prospective candidates for study enrollment at the time of HLA typing. Questionnaires were completed by treatment teams at the time of registration, at 3, 6 and 12 months post registration, and then yearly until 2012. The final analysis was performed in January 2013.

Prospective questionnaires

Initial registration form

The initial registration form was completed at the time of HLA typing. It asked for patient information and disease characteristics. Results of HLA typing for the whole family had to be reported on the form. If the patient had an HLA-identical family donor, the local treatment team was asked if the team had confirmed a plan for HLA-identical SCT from a family member and a projected date for SCT (Question 1: Q1). Otherwise, the treatment team was asked to document a reason for not planning Replace by MSD SCT. If there was no confirmed HLA-identical SCT donor in the patient’s family, the team was asked to indicate whether they planned an alternative donor SCT (Question 2: Q2). If the answer was ‘yes’, the team had to indicate the type of alternative donor that was being pursued and the criteria for identifying the ideal donor: BM or peripheral blood (PB) from an unrelated donor, cord blood (CB), or stem cells from a haplo-identical donor. If the answer was ‘no’, the team had to indicate whether they planned an autologous SCT (ASCT) or conventional chemotherapy (CC) (Question 3: Q3). Figure 1 summarizes the first questionnaire (registration form).

Figure 1
figure1

Initial questionnaire on intention to treat for consecutive patients HLA typed as prospective candidates for a hematopoietic SCT.

Three month, 6 month and 12 month follow-up forms

These forms documented disease status and the therapeutic strategy followed at each time point: results of the donor search, whether the patient received SCT, the type of planned SCT, plans for SCT from an alternative donor, plans for an autograft, or plans for no SCT. If a patient did not receive an allograft as planned at the time of study registration, these forms documented the reasons for deviations from initial treatment plans.

Transplant follow-up forms

Transplanted patients were followed with the EBMT ‘Promise’ software. ‘Promise’ forms record all characteristics of the donor and the graft, the pre-transplant treatment regimen, time to engraftment, complications post transplant, including graft-versus-host disease (GVH), additional treatment after transplant, disease status at the time of follow-up and date and cause of death.

Analyses and statistics

The primary aim of the study was to describe the pre-defined therapeutic schemes, compliance with and feasibility of each transplant modality. Comparisons between different strategies and transplant modalities were performed using χ2-statistics for categorical and the Kruskal–Wallis test for continuous variables. Variables considered were patient age at diagnosis, diagnosis (AML or ALL), cytogenetics, disease status at the time of HLA typing and at transplantation and size of the treatment center. The feasibility of each therapeutic strategy was estimated at 1 and 2 years after HLA typing in all patients and from first remission (CR1) in patients typed at diagnosis and in patients typed in CR1. Probabilities were estimated using cumulative incidence curves, in which death was considered as a competing event. The Gray test was used for univariate comparisons, whereas multivariate analyses were performed using a Fine-Gray sub proportional-hazard model.10 All factors associated with transplant feasibility with a P-value <0.15 were included in the model.

The secondary objectives were to estimate leukemia-free survival (LFS) and OS from the time of HLA typing in all patients and from CR1 in patients typed at diagnosis and in patients typed in CR1. Leukemia-free survival (LFS) was defined as survival without evidence of disease relapse or progression. Probabilities of OS and LFS were calculated using the Kaplan–Meier estimate; the log-rank test was used for univariate comparisons.

All tests were two sided. The type I error rate was fixed at 0.05 for determination of factors associated with time to event outcomes. Statistical analyses were performed with SPSS 19 (SPSS Inc., Chicago, IL, USA) and R 2.13.2 software packages (R, Vienna, Austria).

Results

Patient characteristics

Thirty-one centers in 14 countries participated in the study. A total of 695 adult patients were registered: 372 male and 323 female. The median age at the time of study registration was 42 years (range, 18–75). Diagnoses included 484 (70%) patients with AML, 199 (28%) with ALL and 12 (2%) patients with bi-phenotypic leukemia. At the time of HLA typing and study registration, 64% of patients were initially diagnosed with leukemia, 24% were in first remission (CR1), 7% were refractory to initial therapy, 4% were in relapse and 1% were in subsequent remission (>CR1). The median follow-up for living patients was 67 months (range, 12–110). Seventeen patients were lost to follow-up during the first year and 11 during the second year. These patients were censored at their last follow-up.

Access to EBMT centers and referral patterns

There was a difference in access to EBMT centers and referral patterns between patients who were typed at diagnosis versus at CR1: in the overall population, 89.4% of the patients HLA typed at diagnosis versus 69% of the patients typed in CR1 were diagnosed in the EBMT transplant center (P<0.001).

Primary objective: allocation to pre-defined therapeutic schemes, feasibility and deviation

Figure 2 details the allocation of patients to various planned therapeutic strategies. Of 695 registered patients, 304 had a MSD. But, local treatment teams decided to proceed to SCT at the time of registration in 264 (38% of the overall population) patients. Of the remaining patients with a MSD, 33 were allocated to CC and 7 to ASCT. The up-front reasons for choosing non-allogeneic SCT were diverse: staff decision to wait (14 patients), low-risk AML (11), old age (4), presence of significant co-morbidities or complications (3), or refusal by the donor or patient (8). A MSD was not identified for 391 patients. A search for an alternative donor SCT was initiated in 198 of these patients, while 114 patients were allocated to CC and 77 were allocated to ASCT. Teams identified a mis-matched family donor (MFD) in 85 patients with no MSD, but MFD SCT was formally planned in only 2 patients.

Figure 2
figure2

Flowchart of the planned therapeutic strategies for study patients (intention to treat).

Table 1 indicates patient and disease characteristics by the scheduled treatment. Patients scheduled for ASCT were older (P=0.03). A significantly greater number of patients with ALL (P=0.001), poor-risk AML (P<0.001) and active disease (P<0.001) were allocated to receive allogeneic UD/cord blood SCT. Figure 2 shows the reasons for protocol deviation. Among the 264 patients allocated to MSD SCT, 49 were not allografted, primarily because they relapsed or died (34 patients) before SCT. Autologous SCT was planned in 84 patients but not performed in 31, essentially for the same reasons as mentioned above. Out of the 147 patients for whom chemotherapy was planned at registration, 34 actually received SCT.

Table 1 Distribution of patients and disease characteristics by intention to treat

Out of 198 patients for whom an alternative donor was sought, 81 did not proceed to SCT, the main reasons being disease progression in 38 and lack of a suitable donor in 22. The search for an alternative donor was restricted to volunteer donors in the case of 123 patients and extended to CB banks for 75 patients. An alternative donor was found for 139 (70%) patients: UD for 121 patients, CB for 15, and UD and CB in the case of 3 patients. The time from initial search to donor identification was 46 days (range, 12–224) for UDs and 36 days (range, 12–165) for CB. Figure 3 shows reasons for non compliance in patients who were scheduled by intention to treat for a MSD and reached CR1.

Figure 3
figure3

Flowchart of patients achieving CR1 and planned (intent to treat) for a matched sibling donor transplant.

Overall, the probabilities of a patient receiving a leukemia treatment that was decided upon at the time of study registration were 60±2% and 65±2% at 1 and 2 years, respectively. For patients initially scheduled to receive an allo-SCT, the probabilities of actually receiving SCT at 12 and 24 months were 82±2% and 83±3% with a MSD SCT and 57±4% and 61±4% with an alternative donor SCT (Figure 4). For patients transplanted in CR1, the median time to reach SCT after achieving CR1 was 97 (range, 22–352) days for MSD SCT, 107 (range, 47–345) days for UD SCT with PB, 138 (range, 85–333) days for UD SCT with BM and 135 (range, 72–316) days for ASCT.

Figure 4
figure4

Probability of receiving the type of transplant initially planned in patients who actually were transplanted. MSD=matched sibling donors; UD=unrelated donors.

Factors associated with feasibility of allogeneic transplantation

In order to study the factors associated with feasibility of an allogeneic transplantation in CR1, we selected patients for whom an allotransplantation was planned, HLA typed at diagnosis and who achieved first remission (n=234; 121 in the MSD group and 113 in the UD group) and patients HLA typed in CR1 (n=118; 85 in the MDS group and 33 in the UD group). In this population, the probabilities of receiving an allograft in CR1, 1 year after CR1, were 77±3% for MSD SCTs and 52±4% for UD transplants. For patients scheduled to receive a MSD SCT, the time when HLA typing was done had a significant impact on the feasibility of the transplantation in CR1: 84±3% for patients typed at diagnosis versus 67±5% for those typed at time of CR1 (P=0.003). The other factor associated with a higher probability of transplantation in CR1 was a poor cytogenetic group: 82±4% versus 74±4% (P=0.02) (Table 2). By multivariate analysis, adjusting for diagnosis, cytogenetics, center size, age and interval from diagnosis to CR1, the only factor associated with a lower probability of transplantation in CR1 was HLA typing delayed to CR1, as compared with HLA typing at diagnosis (HR=0.82 (CI: 0.69–0.98), P=0.014). For patients scheduled to receive a UD transplant, none of the factors studied was significantly associated with the feasibility of the transplant in CR1 (Table 2).

Table 2 Feasibility of transplantation in CR1 (1-year probability of transplant in CR1)

Secondary objective: outcomes

Outcome per intent to treat

For the 695 patients in this study, the LFS was 39±2% (AML: 39±2%; ALL: 39±2%) and the OS was 50±2% (AML: 51±2%; ALL: 47±3%) 3 years after HLA typing. Within each of the four leukemia treatment groups, LFS 3 years after HLA typing was 46±5% for autologous transplants, 43±3% for MSD SCT, 34±3% for UD SCT and 33±4% for CC (Figure 5). OS 3 years after HLA typing was 56±5% for autologous transplants, 51±3% for MSD SCT, 41±4% for UD SCT and 55±4% for CC (Figure 5). Patients over the age of 50 did significantly worse than younger patients with a LFS of 28±3% versus 44±2% in younger patients and an OS of 39±4% versus 54±2% in younger patients (P<0.001 for LFS and OS). Results for other prognostic factors are summarized in Table 3.

Figure 5
figure5

Leukemia-free survival, by intent to treat, of the four groups of patients (MSD, UD, allo-SCT, CC).

Table 3 Three-year outcome after HLA typing

Outcome per protocols

As a result of changes in strategies, the actual treatment received at the end of the study was CC in 243 patients, ASCT in 76, MSD SCT in 230, UD SCT in 141 (124 volunteers donors and 17 CBs) and haplo-identical SCT in 5. While 21% of patients (n=147) were to receive CC, the real figure was 35% (n=243). LFS and OS 3 years after transplantation were 48±3% and 60±3% for MSD SCTs, 51±6% and 61±6% for autologous SCT and 42±4% and 50±4% for UD SCTs. In patients under 50 years old, the LFS and OS were 63±6% and 70±6% for autologous SCT, 55±4% and 64±4% for MSD SCTs and 43±5% and 50±5% for UD SCTs. In patients over the age of 50, the LFS and OS were 33±6% and 50±6% for MSD SCTs, 41±10% and 48±10% for UD SCTs and 28±9% and 42±10% for autologous SCT.

Discussion

When planning the most effective treatment protocols for patients with acute leukemia, EBMT treatment teams follow EBMT and European Leukemia Net (ELN) guidelines. However, compliance (adherence of the patient and physician to treatment) and treatment feasibility depend on numerous factors, such as patient and physician decisions, disease evolution, and the ability to locate a suitable donor for SCT in a timely manner. This has never been investigated as most studies reported to date by EBMT have been retrospective, have not investigated adherence to treatment protocol guidelines and have not included consecutive patients. The ALWP of EBMT designed this first prospective, non-interventional study in 2002 in an effort to analyze how EBMT teams allocate patients to therapeutic schemes and how often and why deviations occur.

Thirty-one adult leukemia treatment teams in 14 countries participated in this study and registered all their consecutive adult patients with acute leukemia. The study focused on allo-SCT. Therefore, registration took place at the time of HLA typing, as this reflected the team’s decision to include allogeneic transplantation, if feasible, in the patient’s therapeutic personalized decision tree.

This study revealed several important pieces of information. First, in EBMT centers, 64% of patients are HLA typed at initial diagnosis and 24% when they have achieved CR1. This is of interest as some practitioners oppose early HLA typing to save money. They suggest that restricting HLA typing to patients who have achieved CR reduces costs. However, this strategy risks delaying transplant and may jeopardize survival outcomes. For patients with a MSD, HLA typing later, in CR1, was associated with a decrease in transplant feasibility in CR1, which went down from 84 to 67%. In contrast, there was no negative impact of HLA typing and a search for an alternative donor initiated later, in CR1, as the feasibility of transplant did not decrease. The reason for this is unclear. One can, however, speculate on the influence of three contributing interdependent factors as follows. (1) The identification of a matched family donor is more rapid than the identification of a volunteer donor, which requires up to 3 months. Indeed the median duration between HLA typing and transplant was 125 days for a MSD versus 169 days for an UD transplant. Therefore, a decrease in transplant feasibility appears straightforward for MSD but would be less visible for UD transplants. (2) The group of UD transplants contained a significantly higher proportion of poor-risk patients by cytogenetics than the group of MSD transplants (45% versus 32%, P<0.001), which may have accounted for a more stringent application of the initial therapy scheme, hence no or less feasibility decrease. (3) More patients typed in CR1 came from community hospitals and were referred to EBMT centers after achieving CR. These patients may naturally have had more challenges in reaching to SCT centers and transplant procedures, which may have induced a decrease in transplant feasibility, again more visible with MSD. None of these three factors by itself can explain our finding but the three together may have contributed. Our finding that late HLA typing in CR1 rather than early at diagnosis decreases MSD transplant feasibility was not associated with a detectable disadvantage in terms of outcome. Although we feel it is safer to do HLA typing at diagnosis, with the limited information we have presently, we feel it is premature to make this recommendation formal. Anyhow, this finding would not necessarily concern all newly diagnosed acute leukemia patients, but only those under study, that is, those who were referred and typed in EBMT centers.

Second, when all strategies were considered, the initial patient treatment allocation was fulfilled in 60% of the cases at 1 year from study entry. For patients initially scheduled to receive an allogeneic transplant, the probability of having this transplant completed by 12 months of study entry was 82% with a MSD and 57% with an UD. For patients with a MSD, the main reason for not receiving the transplant was the absence of remission, relapse or death. In the absence of a MSD, the search for an alternative donor was initiated in only 51% of the patients. One likely reason for this smaller than expected proportion is that a search for CB, in addition to a search for a volunteer donor, was performed for only 75 patients. Moreover, although a haplo-identical donor was indicated as available in 85 patients, only two such transplants were planned. This reflects the usual transplant team practice for the period of this study, and it is likely that the feasibility of UD transplants has increased recently with new transplant modalities developed for CB11, 12 and haplo-mismatch transplants.13, 14

The primary objective of this study was to evaluate the allocation of patients to pre-defined therapies in EBMT centers and to assess feasibility and deviations from initial treatment assignments. Nonetheless, the outcome of patients was of interest. Interestingly, the LFS at 3 years for the 695 patients was 39% and the OS was 50%. Not surprisingly, patients typed at diagnosis or in CR1 had a better LFS and OS than those typed later. Patients allocated to autografts did well, probably attesting to the pertinence of the patient allocation to different therapeutic strategies by the local teams. In so doing, the teams took into account the characteristics of patients and the disease, including all known prognostic factors and co-morbidities, while following the international EBMT and LEN guidelines. As patients differed in terms of prognostic factors, we were not able to make a comparison among the various therapeutic approaches.

The fact that up to 30% of patients scheduled to receive an allograft and up to 50% of those scheduled for an autograft did not achieve SCT has been reported previously by many randomized studies comparing allogeneic transplants, autologous transplants and CC.6, 15, 16, 17 That is why outcome is usually reported not only by intention to treat but also per protocol. The information provided by randomized, prospective studies is of considerable value, but of a different nature. These studies usually test one or two investigational arms versus a reference arm and contain highly selected patients who fulfill stringent inclusion and exclusion criteria. The present study reports on the everyday treatment policy in consecutive patients. It is reassuring to see that there is homogeneity in decision making, leading to an OS of 50% at 3 years. Moreover, this outcome could be improved considerably, as it differs from reports from selected series where LFS has been reported up to 60% at 3 years. At the same time, while 80% of the patients with a MSD actually received their SCT, patients without MSD, candidates for an UD transplant, reached transplantation only in 57% cases, leaving room for improvement.

This prospective, non-interventional study has strengths and weaknesses. Its strength is that, to our knowledge, it is the first of its kind in the hematopoietic SCT field, and it takes advantage of a long follow-up time. The weakness is that therapeutic strategies and transplant modalities have already improved so that the field has evolved. The years to come will tell us whether this gap in transplant feasibility and outcome will be filled all over Europe18 by the constant increase of donor registries and CB banks12 and by the use of reduced-intensity conditioning and haplo-mismatch transplantation.13, 14, 19

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Correspondence to N-C Gorin.

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Labopin, M., Gorin, N., Polge, E. et al. A prospective registration study to determine feasibility of hematopoietic SCT in adults with acute leukemia: planning, expectations and reality. Bone Marrow Transplant 49, 376–381 (2014). https://doi.org/10.1038/bmt.2013.178

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Keywords

  • acute leukemia
  • stem cell transplantation
  • prospective registration study

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