Introduction

With the introduction of reduced-intensity and non-myeloablative conditioning, allogeneic haematopoietic cell transplantation (HCT) has become an attractive treatment option for patients who, due to age or comorbidities, are ineligible for myeloablative conditioned transplants (reviewed in Baron and Sandmaier¹ and Baron and Storb²). A number of retrospective reports have been published comparing outcome and complications after HCT following myeloablative and non-myeloablative conditioning.^{3, 4, 5} Although TRM^{3, 4, 5, 6, 7} and the incidence of liver,⁸ kidney⁹ and lung toxicities^{10, 11} were decreased in patients treated with reduced-intensity or non-myeloablative conditioning, they still experienced considerable morbidity and mortality mainly due to GVHD^{12, 13} and infections.^{14, 15} The low toxicity of the regimens permitted grafting in the outpatient setting, with reported frequencies of patients transplanted entirely without hospitalization ranging between 22 and 53% .^{6, 16} Given the overall lower toxicity of the reduced-intensity and non-myeloablative conditioning regimens, a decrease in hospitalization and outpatient clinic visits in the long term was expected. Only a few studies have dealt with this issue. In a study by McSweeney et al.⁶ a median of 8 days of admission was required during the first 60 days post transplant, while Cordonnier et al.¹⁷ reported a median of 56 days during the first year post transplant. In a previous analysis from our institution,¹⁶ 30 patients treated with non-myeloablative conditioning were admitted for a median of 51 days and had a median of 52 visits to the outpatient clinic during the first year. The most common causes of hospitalization and TRM were alloreactivity and infections. Denmark has a population of 5.5 million inhabitants and our centre performs all allogeneic HCT in the country. HCT with non-myeloablative conditioning was initiated at our centre in March 2000. The number of HCT with myeloablative conditioning has been constant at around 45–50 per year, including approximately 15 children, while there has been a yearly increase in HCT with non-myeloablative conditioning. In 2006, we performed 37 transplants with non-myeloablative conditioning. The steep increase in transplants has required an increase in resources and has now resulted in plans for a second transplant centre in the country. The present paper reports disease-specific outcome of the procedure in the first 100 patients as well as complications and hospital requirements.

Methods

Patients and donors

This analysis includes data from the first 100 patients who underwent allogeneic HCT with PBSCs after non-myeloablative conditioning, between March 2000 and February 2006, at the Transplantation Unit, Department of Haematology, Rigshospitalet, Copenhagen, Denmark (Table 1). Patients with haematological malignancies treatable by HCT were eligible for allogeneic HCT after non-myeloablative conditioning if they were considered to have a TRM with conventional HCT>40% . Although most patients were eligible for non-myeloablative HCT in the outpatient setting, 13 were transplanted while hospitalized due to capacity limitations in the outpatient clinic. For the purpose of reporting the true hospitalization and outpatient clinic requirements, for these 13 patients the 14 initial days of peri-transplant hospitalization were counted as outpatient visits. Of the 100 patients in this study, 30 were reported previously¹⁶ and are included with extended follow-up. Donor selection was based on molecular typing for HLA-A, B, C, DRB1 and DQB1. When available, matched related donors, that is HLA-identical siblings, were preferred to matched unrelated, and CMV serostatus was taken into account when possible. Only a single HLA class I or II allele disparity was allowed between the recipient and the donor. Detailed patient and donor characteristics are summarized in Table 1. Related donors were stimulated with filgrastim 16 g/kg per day from day - 4 to day 0. Leukapheresis was performed on day - 1 and/or day 0 and the leukapheresis products were infused on day 0.⁶ Blood stem cells from matched unrelated donors (MUDs) were mobilized and harvested according to the standard procedures of the transplant centre performing the harvest.

Table 1 - Patient and donor characteristics.

Full table

Treatment

A total of 97 patients were conditioned with fludarabine 30 mg/m² for 3 days and 2 Gy of TBI while 3 patients were conditioned with TBI 2 Gy only. Post transplant immunosuppression consisted of oral CYA 12.5 mg/kg per day from day - 3 and mycophenolate mofetil 30 or 45 mg/kg per day from day 0 in recipients of related or unrelated donor grafts, respectively. In the first 10 patients transplanted with matched related donor grafts, CYA taper was, in the absence of acute GVHD, planned to start on day +35 and CYA to be discontinued on day +56. In the following patients transplanted with matched related donor grafts, CYA taper was planned to start on day +56 and CYA to be discontinued on day +180. In recipients of MUD grafts, CYA taper was planned from day +100 and discontinued on day +180.^{6, 18, 19} Mycophenolate mofetil was discontinued on day +27 in patients transplanted with matched related donors, tapered from day +42 and discontinued on day +98 in recipients of MUD grafts. Acute GVHD, 'late-onset acute GVHD'^{12, 20, 21} and chronic GVHD were graded according to standard criteria.²²

Supportive care

When transplantation was performed as an outpatient procedure the patients were scheduled for daily visits from day - 4 to +14, thrice weekly until day +28, and once weekly until day +91, and then on days +105, +119, +147, +182, +273, +365 for a total of 40 scheduled visits during the first year post transplant. Then, patients were scheduled for outpatient visits twice yearly. Oral sulphamethoxazole/trimethoprim 800/160 mg was administered twice daily from day - 9 to day - 2, and re-administered as 400/80 mg daily when the ANC was above 0.5 10⁹/l for 2 consecutive days. Oral sulphamethoxazole/trimethoprim was continued until day +180. Oral acyclovir (800 mg) was given twice daily from day - 4, and increased to four times daily from day +28 and continued for 180 days after discontinuation of immunosuppression. Oral fluconazole (400 mg) was given daily from day - 1 to day +75. If the ANC fell below 0.5 10⁹/l oral ciprofloxacin (500 mg) twice daily was started. Routine blood samples for CMV surveillance were taken weekly to day +91. RBC and platelet transfusions were given if haemoglobin was <8.0 g per 100 ml and platelet count was <20 10⁹/l, respectively. A tunnelled Hickman 2-lumen i.v. catheter (Bard Access Systems, Salt Lake City, UT, USA) was inserted 2 weeks pre-transplant and removed on day +91 if the patients were in a stable phase.

Chimaerism analysis

The levels of donor granulocyte (CD15⁺) and CD4⁺ and CD8⁺ T-cell chimaerism were determined sequentially post transplant, as previously described.¹⁶

Statistical analyses

Overall survival (OS) and PFS were estimated by the Kaplan–Meier method, and comparisons were made with the log-rank test. OS was measured from the time of transplantation until death from any cause. Patients still alive at the time of analysis were censored at the date of last follow-up. PFS was calculated from the date of transplantation to the date of first relapse or death. Patients who were alive and in remission were censored at date of the last follow-up. Cumulative incidence estimates were calculated for TRM, relapse-related mortality, GVHD and the probability of discontinuation of immunosuppression.²³ Death without relapse, death without GVHD, death while on immunosuppressive therapy, relapse/progression and rejection/re-transplantation were treated as competing events, where appropriate, in these analyses. TRM was defined as death in CR or death related to transplantation where it was not possible to assess disease status before death. Relapse-related mortality was defined as death with relapsed or progressive disease. Patients who experienced primary graft rejection were not eligible for GVHD evaluation. Comparison of cumulative incidences was performed using Gray's k-sample test.²⁴ In our analyses of outpatient clinic visits and days of admission, we have included both mean and median numbers, since the former is most relevant to estimate the average cost and requirements of a transplant facility, while the latter is probably more meaningful as patient information. Median number of outpatient visits and days admitted to the transplantation unit or intensive care unit (ICU) were calculated on the basis of the number of patients at risk during the time period, while means were calculated using the number of patients experiencing the event during the time period. The number of outpatient clinic visits was counted from the day of the transplant. Where applicable, the Mann–Whitney U-test was used. All P-values were two sided, and a value of P0.05 was considered significant.

Results

Engraftment and donor lymphocyte infusion

The median ANC nadir was 0.25 10⁹/l (range 0–0.9 10⁹/l) and the ANC was <0.5 10⁹/l for a median of 12 days (range 0–57). The ANC did not fall below 0.5 10⁹/l in 16 patients. The median thrombocyte nadir was 29 10⁹/l (range 1–125 10⁹/l) and the median time with thrombocytes <20 10⁹/l was 0 days (range 0–43). In 67 patients, the thrombocyte level did not fall below 20 10⁹/l. Two patients experienced primary graft rejection, that is donor chimaerism was never demonstrated, and six experienced secondary graft rejection after initial engraftment. Seven patients were re-transplanted. Nine patients received donor lymphocyte infusion (DLI) due to relapse or progression and six due to low chimaerism (Masmas et al., in preparation).

GVHD

Of 98 patients eligible for GVHD analysis, 66 developed grade II–IV acute GVHD, of which 23 had grade III–IV acute GVHD. The cumulative incidences of grades II–IV and III–IV acute GVHD were 67 and 24% , respectively (Figure 1a). Chronic GVHD occurred in 47 patients, of whom 34 developed extensive chronic GVHD. The cumulative incidence for the development of extensive chronic GVHD was 49% (Figure 1b). There were no significant differences in acute or chronic GVHD between recipients of related or unrelated grafts. The cumulative incidence of discontinuation of systemic immunosuppressive therapy was 37% at 5 years, and serves as a surrogate marker for successful GVHD prophylaxis and treatment (Figure 1c).

Figure 1.

Cumulative incidences of patients (N=98) with acute GVHD grades II–IV, III–IV (a) and extensive chronic GVHD (b). Probability of discontinuation of systemic immunosuppression (N=100) (c).

Full figure and legend (39K)

Relapse and survival

The median follow-up of all 100 patients enrolled in this study was 534 days (range 38–2324) and the 4-year OS, PFS and relapse-related mortality was 59, 50 and 25% , respectively (Figure 2). The OS and PFS according to diagnosis and stage are shown in Figure 3. Patients with a favourable outcome encompassed CLL, non-Hodgkin's lymphoma (NHL), myelodysplastic syndrome (MDS) with <5% blasts and AML. These patients had a 3-year PFS between 61 and 71% . Patients with a less favourable outcome encompassed Hodgkin's disease (HD), multiple myeloma (MM) and MDS 5% blasts (Figure 3) at anytime during their disease course. These patients had a significantly lower 3-year PFS between 19 and 38% (P=0.001).

Figure 2.

Overall survival (OS), PFS, relapse-related mortality (RRM) and TRM of all patients (N=100).

Full figure and legend (17K)

Figure 3.

Overall survival (OS) and PFS after haematopoietic cell transplantation (HCT) following non-myeloablative conditioning, according to disease-specific groups. The AML patients were divided into a group in first CR and into a group in >1 CR. All patients with AML or myelodysplastic syndrome (MDS) had <5% blasts at the time of transplantation. Patients with MDS were divided into a group who never experienced blast 5% and into a group who at sometime during the course of their disease had 5% blasts but were reduced to <5% BM blasts by chemotherapy.

Full figure and legend (52K)

Treatment-related mortality

A total of 14 patients died from treatment-related causes, with a TRM of 17% at 3 years (Figure 2). Six patients died from GVHD-associated complications, while four patients died from infectious causes (Legionella pneumonia, Pseudomonas aeruginosa septicaemia, suspected fungal central nervous system infection and pneumonia). Two patients died of acute respiratory distress syndrome, one patient died of treatment-related MDS and one due to complications related to a secondary larynx cancer. There was no significant difference in TRM between patients transplanted with MUD or sibling donors.

Hospitalization

During the follow-up period the median and mean numbers of outpatient visits per patient were 50 (range 0–202) and 56 (95% confidence interval (CI) 50–62) (Table 2). During the first year post transplant patients experienced a median of 43 (range 0–77) and a mean of 41 (95% CI 38–45) outpatient visits, which were 17% more than the 35 post transplant visits scheduled, thus making the mean number of outpatient visits during the first year account for 73% of the mean number of outpatient visits during the follow-up period (Table 2). In the following years post transplant, the requirements for outpatient visits gradually decreased from a median and mean of 13 (range 0–43, 95% CI 10–15) during the second year to a median and a mean of 5 during the seventh year (Table 2). During the follow-up period all 100 patients were admitted at least once, with a mean hospitalization of 69 days (95% CI 56–82) and a median of 47 days (1–319) (Table 2). Total 2 out of 100 patients did not require admission during the first year, while 98 were admitted and hospitalized for a median of 43 days (1–319), thus making the mean number of days hospitalized during the first year account for 77% of the mean number of days hospitalized during the follow-up period (Table 2). In the subsequent years post transplant the mean and median number of admissions was reduced (Table 2). In patients surviving more than 1 year post transplant, there were no significant differences in mean and median days of hospitalization between disease-specific groups. Sixteen patients were admitted to the ICU, for a total 514 days, with the mean of the first year post transplant accounting for 80% of the mean days in the ICU during the follow-up period (Table 2). Eight patients died while in the ICU, and eight were discharged alive, of whom six were still alive at last follow-up. Patients were only admitted to the ICU during the first 3 years post transplant. Eighty-eight per cent of deaths in the ICU were due to circulatory collapse or respiratory distress related to infectious causes, while 8 and 6% were related to cardiogenic shock and engraftment syndrome, respectively.

Table 2 - Admission and outpatient visits.

Full table

The referring regions of Denmark are charged amounts corresponding to 930, 2125 and 2985 for each outpatient clinic visit, each day of hospitalization in the transplantation ward and the ICU, respectively. These amounts cover all treatment modalities including transfusions, drugs and diagnostic procedures. Based on the mean outpatient clinic visits, admissions to the transplantation ward and ICU, the average transplantation cost was calculated as 162 695 for the first year and 208 050 for the entire observation period.

Causes of hospitalization

For each hospitalization episode, the primary cause of admission was noted and the days were counted. The major causes of admissions were infections and complications due to alloreactivity (Table 3), with 81 and 58 patients, respectively, experiencing one or more hospitalization episode due to one of these causes. The infectious causes most often leading to hospitalization were related to respiratory tract infections (13.4% ), fever of unknown aetiology (10.7% ) and septicaemia (7.0% ) (Table 3). While respiratory tract infections were mainly due to pneumonia of unknown aetiology and septicaemia mainly due to i.v. catheter infections, the group of other infections encompassed a large variety of different, mainly opportunistic pathogens. Twenty-two patients were admitted for 311 days to receive pre-emptive treatment of CMV reactivation (Table 3). The group of other admission causes was a major reason of hospitalization accounting for 14.9% of the total days hospitalized, and covering a large variety of complications due to both the transplantation procedure and comorbidities existing pre-transplant.

Table 3 - Causes of hospitalization.

Full table

Discussion

The rationale for non-myeloablative allogeneic HCT was to introduce a treatment alternative for patients not eligible for myeloablative HCT due to older age or comorbidities. Given the overall lower toxicity of the non-myeloablative conditioning regimens, a decrease in hospitalization requirements was expected. The current study was aimed at evaluating the outcome and hospitalization pattern of the first 100 patients treated with HCT following non-myeloablative conditioning with fludarabine 90 mg/m² and TBI 2 Gy, at Rigshospitalet, Denmark. Haematological toxicity in the present study was, apart from a prolonged period of granulocytopaenia (ANC 0.5 10⁹/l) of 12 days, comparable with previous reports.^{25, 26, 27} In accordance with previously published results,^{12, 28} the cumulative incidences of acute grade II–IV and III–IV GVHD were 67 and 24% approximately 6 months post transplant, while the cumulative incidence of extensive chronic GVHD stabilized at 49% after 3 years. The cumulative incidence of discontinuation of all systemic immunosuppression can be interpreted as the probability of patients surviving the transplant free of progression with or without resolved acute or chronic GVHD. In our study the cumulative incidence of discontinuation of immunosuppression was stable at 37% after approximately 5 years, which is comparable to the findings by Mielcarek et al.¹² and Burroughs et al.²⁸ Meaningful comparisons of outcome parameters across different studies can be problematic due to variations in patient populations and conditioning regimens. The OS, PFS, relapse-related mortality and TRM of all 100 patients in our study were in agreement with a large multi-centre series reported by the Seattle Consortium.²⁹ When observing the PFS according to diagnosis and stage, patients could be segregated into a group with a favourable outcome and a group with a less favourable outcome. The group with favourable outcome encompassed patients with CLL, NHL, MDS with <5% blasts and AML. The outcome for CLL was comparable to several published studies utilizing different conditioning regimens.^{30, 31, 32, 33} Even though the NHL group consisted of several different types of lymphomas, the low-grade lymphomas accounted for almost 60% , explaining an OS and PFS comparable to published studies on low-grade lymphomas.^{34, 35, 36} Patients with AML and MDS are often reported together, with 3-year PFS varying between 13 and 40% .^{37, 38, 39, 40} Most AML patients being in first CR could explain the relatively high PFS in the group of patients with AML in our study. The group with the less favourable outcome encompassed, in agreement with the literature, HD,^{34, 41} MM⁴² and patients with MDS who had had 5% blasts in the BM.³⁸ The clinical impact of the reduced toxicity associated with allogeneic HCT following non-myeloablative conditioning is illustrated by the relatively low cumulative incidence of TRM.^{4, 5} In our study the 3-year cumulative incidence of TRM was 17% , with the most important causes of treatment failure being GVHD and infection, in line with previous reports.^{4, 37, 43}

Although a major issue in both health economics and quality of life of patients, only few studies have been published concerning the hospitalization pattern of patients treated with allogeneic HCT following non-myeloablative conditioning.^{16, 17, 44} In the present study, the first year post transplant was by far the most treatment intensive and resource demanding, accounting for 73 and 77% of all outpatient clinic visits and days of hospitalization. Patients had a mean number of 41 outpatient clinic visits, which is 17% more than the scheduled 35 visits, and a mean number of 53 days of hospitalization. Although, in agreement with a previous study from our own institution¹⁶ and a small study comparing the cost between myeloablative and non-myeloablative conditioning prior to HCT,¹⁷ these numbers are approximately twice as high as reported in a recent study by Saito et al.⁴⁴ Regardless of a decrease in outpatient clinic visits and days of admission in the second year, the numbers were not negligible with surviving patients requiring a mean of 13 visits in the outpatient clinic. Furthermore, 37 out of 66 patients surviving more than 1 year required a mean number of 16 days of hospitalization. The following years post transplant the number of outpatient clinic visits and days of hospitalization decreased considerably. The increased number of both outpatient visits and days of hospitalization during the first year in our study as compared to the experience reported by Saito et al.⁴⁴ cannot be explained by relapse-related mortality, TRM or GVHD, which are similar to international reports. An explanation should rather be sought in the inter-institutional differences in facilities, opening hours of outpatient clinics and referral pattern. Owing to the small geographical size of Denmark, and due to Rigshospitalet being the only allogeneic transplantation centre, all patients who have been treated with an allogeneic transplant are followed and treated here for most transplant-related medical problems arising even years post transplant. We therefore believe that our data reflect the true need of these patients. The cost of the transplantation procedure, follow-up and treatment of complications was in the same order of magnitude as published by Saito et al.⁴⁴ Complications due to infections or alloreactivity were the most common causes of admission, with acute GVHD and infections of the respiratory tract accounting for approximately 13–14% of the total days hospitalized. This represents a change from previous experience in our institution¹⁶ where the most common cause of admission was alloreactivity. The change can be explained by the incidence of transplant-related microangiopathy that decreased at our institution after the first 30 patients were transplanted, and that engraftment syndrome only was seen in this original cohort. The causes of hospitalization in Table 3 cannot be related directly to the incidence of different complications, since they only represent the initial cause of admission and not complications that occurred during hospitalization. Sixteen patients required admission to the ICU, with the first year post transplant again accounting for the large majority. Eight out of sixteen of the patients admitted to the ICU were alive and free of progression at the time of follow-up, which is in accordance with data published by Lim et al.⁴⁵ on the survival in the ICU of patients treated with allogeneic HCT. Further emphasizing the point of low toxicity of the non-myeloablative conditioning regimens, all nine patients treated with myeloablative conditioning reported by Lim et al.⁴⁵ died in the ICU.

In conclusion, we found that allogeneic HCT following non-myeloablative conditioning is a valuable treatment option for patients with haematological malignancies without other potentially curative treatment options. Furthermore, we found that despite low TRM the non-myeloablative allogeneic HCT procedure is associated with considerable morbidity, since only approximately one-third of the patients are alive, progression free and without GVHD after 5 years. Treatment-related complications that require admission and outpatient clinic visits occur frequently throughout the first year, and continue during the second year. The information generated could be of value when requirements for ward and outpatient clinic space in a transplant centre are estimated, and when the transplantation procedure and consequences thereof are explained to patients.

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Acknowledgements

We thank the medical, nursing and laboratory staff of the participating departments for their contribution to this study. We also thank Mrs Anne Bjørlig for excellent technical assistance. This study was supported with grants from the Danish Medical Research Council, Novo Nordisk Research Foundation, Benzon Foundation, Danish Cancer Society, Lundbeck Foundation and Rigshospitalet. BK is a Rigshospitalet research fellow.