Hemopoietic Cell Transplantation Bart Scott, H. Joachim Deeg

Contents

12.1 Introduction . . . 123

12.2 General Considerations for HCT . . . 124

12.3 Transplant Strategies . . . 125

12.3.1 Conventional (ªMyeloablativeº) HCT 125 12.3.1.1 ªLess Advancedº MDS . . . 125

12.3.1.2 ªAdvancedº MDS . . . 127

12.3.2 Reduced-Intensity Conditioning Regimens . . . 128

12.3.3 Autologous HCT . . . 129

12.4 Special Considerations . . . 129

12.4.1 MDS Is a Disease of ªOlderº Patients 129 12.4.2 Childhood MDS . . . 130

12.4.3 Other Parameters . . . 130

12.4.4 Secondary MDS . . . 130

12.4.5 Post-transplant Relapse . . . 131

12.5 Conclusions . . . 131

References . . . 131

12.1 Introduction

Hemopoietic cell transplantation (HCT) provides effec- tive therapy for various malignant and non-malignant disorders. The indications are relatively clear for some diseases, but are less well defined for others, including myelodysplastic syndrome (MDS). Firstly, MDS is pre- dominantly a disease of older patients, and conventional transplant approaches have not been well tolerated in

that age group. Secondly, in many patients, MDS pro- gresses slowly over many years with only little morbid- ity, rendering the decision as to the optimum time for transplantation difficult (Cutler et al. 2004). Thirdly, our understanding of the pathophysiology of MDS has improved, and several therapeutic compounds directed at exploiting biologic features of the disease have shown efficacy, at least transiently, as non-transplant therapy for MDS (Deeg et al. 2004b; List et al. 2003; Molldrem et al. 2002; Raza et al. 2001; Silverman et al. 2002).

Nevertheless, MDS are clonal stem cell disorders, and the only therapeutic modality with proven curative po- tential is HCT. The indications for HCT depend upon dis- ease stage/risk, patient interest, patient age, donor avail- ability, the promise of alternative modalities, and, in the end, the probability of success with a transplant. Details of disease classification are discussed elsewhere in this volume. According to the French-American-British (FAB) classification, MDS includes refractory anemia (RA; <5% marrow blasts), RA with ringed sideroblasts (RARS; >15% marrow ringed sideroblasts), RA with ex- cess blasts (RAEB; 5±20% marrow blasts), RAEB in trans- formation (RAEBt; 21±30% marrow blasts), and chronic myelomonocytic leukemia (CMML) (Bennett et al. 1982).

The World Health Organization (WHO) recently defined MDS subgroups more narrowly in a revised classification including RA, RARS, refractory cytopenia with multili- neage dysplasia (RCMD), del 5q± syndrome, RAEB-1 (5±

10% marrow blasts) and RAEB-2 (11±20% marrow blasts), and unclassifiable MDS. Furthermore, the threshold for the diagnosis of AML was reduced to

>20% myeloblasts, effectively eliminating RAEBt as a di- agnostic category (Vardiman et al. 2002). In addition, CMML was reclassified as a myeloproliferative disorder.

Hemopoietic Cell Transplantation

Bart Scott, H. Joachim Deeg

The incorporation of cytogenetic findings and the number of cytopenias, in addition to the blast count, into a new risk scoring system termed International Prognostic Scoring System (IPSS) provides improved prognostic precision (Greenberg et al. 1997), not only for the natural history of the disease, but also for results with HCT (Deeg et al. 2002; Nevill et al. 1998).

12.2 General Considerations for HCT

Until quite recently very few patients above the age of 55 years were offered HCT from allogeneic donors (autolo- gous ªtransplantsº using the patient's own cells have been performed up to a higher age ceiling). This policy was based on the observation that the severity and fre- quency of transplant-related morbidity and mortality (TRM) increased progressively with age. Those compli- cations were related not only to the intensity of the transplant conditioning regimens, but also to graft-ver- sus-host disease (GvHD), the most frequent complica- tion after allogeneic transplantation. Therefore, since even in the most favorable group of patients overall mortality rates have been in the range of 25±30%, care- ful assessment of the indications for and timing of transplantation is needed.

As discussed in Chapter 8, patients in IPSS risk groups low or intermediate-1 may have life expectancies in the range of 5±10 years with supportive care only or low-intensity therapy (Greenberg et al. 1997). However,

reassessment in regard to transplantation is indicated in any patient with disease progression. For patients with intermediate-2 or high-risk MDS by IPSS, HCT is con- sidered the treatment of choice if they are younger than 65 years old and have good performance status. In pa- tients more than 65 years of age with adequate perfor- mance status, low-intensity (non-transplant) therapy might be preferable, unless these patients qualify for transplantation following non-myeloablative (NMA)/re- duced intensity conditioning (RIC).

It is of note that the IPSS, while originally derived from data on survival and leukemic transformation in non-transplanted patients, also impacts on survival after HCT. Among 251 patients transplanted at the Fred Hutchinson Cancer Research Center (FHCRC), the 5- year relapse-free survival (RFS) was 60% with low and intermediate-1 risk, 36% for intermediate-2 risk, and 28% for patients with high-risk disease (Appelbaum and Anderson 1998). Similar results have been reported by Neville et al. (1998), who showed 7-year RFS for pa- tients in the good-, intermediate-, and poor-risk cytoge- netic subgroups (as determined by IPSS) to be 51%, 40%

and 6%, respectively. The corresponding figures for ac- tuarial relapse were 19%, 12% and 82%, respectively.

There was no difference for NRM between the three groups.

In addition to single or multi-organ failure, the ma- jor causes of NRM after allogeneic HCT are GvHD and associated complications, in particular, infections. Fig- ure 12.1 illustrates the impact of acute GvHD on RFS among patients with MDS transplanted from unrelated donors (Castro-Malaspina et al. 2002).

Taking into consideration the IPSS information and transplant results, Cutler et al. (2004), in an analysis in- volving patient data from multiple institutions, have suggested that patients in risk groups intermediate-2 and high, who a priori are transplant candidates, will have the best overall life expectancy if they proceed to transplantation without delay. Patients with low to inter- mediate-1 risk disease, on the other hand, may have the longest life expectancy if HCT is delayed, maybe by sev- eral years (Cutler et al. 2004) (Fig. 12.2).

The role of intensive remission-induction and con- solidation chemotherapy before HCT in patients with MDS has remained controversial. De Witte et al.

(2001) reported on 184 patients who received 1 or 2 re- mission-induction courses followed by consolidation (in patients with complete remission [CR]; patients who did not achieve a CR with induction were advised

Fig. 12.1. Impact of acute GvHD on RFS. There were 151 patients

with grades 0±I and 126 with grades II±IV acute GvHD (p=0.01). This

figure is adapted from research originally published in Castro-Ma-

laspina et al. (2002)

to undergo HCT as salvage therapy or receive therapy with high-dose cytosine-arabinoside [Ara-C]). Follow- ing consolidation, patients then proceeded to either al- logeneic or autologous HCT depending on donor avail- ability. Four-year overall survival in the entire cohort was 26%, and RFS was 29% (de Witte et al. 2001). Ya- koub-Agha et al. (2000) have shown that patients who achieve remissions with pre-transplant chemotherapy have a substantially better outcome after HCT than pa- tients who do not achieve a remission. However, pa- tients who are given induction chemotherapy and fail to respond, have a lower probability of a successful post-transplant course than patients who were not treated pre-transplant (Scott et al. 2005). Controlled studies comparing HCT with and without prior che- motherapy are necessary to definitely answer the ques- tion as to the role of induction chemotherapy.

12.3 Transplant Strategies

We will discuss various transplant approaches. As re- sults with transplants from unrelated donors who are matched with recipients on the basis of high-resolution human leukocyte antigen (HLA) typing are approach- ing those with HLA-identical sibling transplants, we will present those data together rather than strictly separat- ing them.

12.3.1 Conventional (ªMyeloablativeª) HCT 12.3.1.1 ªLess Advancedº MDS

The best results with allogeneic HCT are achieved in pa- tients with low myeloblast counts in the marrow, i.e., RA/RARS (or RCMD, RCRS), at the time of transplanta- tion, and patients without high-risk clonal cytogenetic abnormalities (less advanced MDS) (Table 12.1).

The European Group for Blood and Marrow Trans- plantation (EBMT) reported on 131 patients, most con- ditioned with total body irradiation (TBI)-based regi- mens (70%) and transplanted from HLA-identical sib- lings. Five-year RFS was 52%, and relapse incidence 13% for patients with RA/RARS (Runde et al. 1998).

Among 510 patients with MDS transplanted from unre- lated donors (National Marrow Donor Program) those conditioned with busulfan (BU) plus cyclophosphamide (CY) [BUCY] fared better than patients prepared with other, generally TBI-containing regimens (Castro-Mala- spina et al. 2002). RFS and relapse rate in patients with RA were 40% and 5%, respectively (Castro-Malaspina et al. 2002). BUCY regimens have been used by several transplant teams (Nevill et al. 1998; O'Donnell et al.

1995); some have added cytosine arabinoside (Rata- natharathorn et al. 1993). Despite encouraging results, however, NRM due to infections, GvHD, and single or multi-organ toxicity was in the range of 30±54% (Cas- tro-Malaspina et al. 2002; Nevill et al. 1998; Runde et al. 1998).

The team at the FHCRC recently reported results achieved with a BUCY regimen in which the busulfan

a 12.3 ´ Transplant Strategies 125

Fig. 12.2. Impact of IPSS risk category on likely benefit from HCT.

While based on several assumptions, the data suggest that patients in risk groups intermediate-2 (int-2) and high, if candidates for HCT, should be transplanted without delay. Patients in the lower risk groups may benefit from delaying transplantation until there is evidence for disease acceleration. This figure was originally pub- lished in Cutler et al. (2004)

Table 12.1. Transplant outcome in patients with MDS conditioned with a regimen of ªtargetedº busulfan and cyclophosphamide (Deeg et al. 2002)

MDS risk group Transplant outcome (proportion)

l

RFS Relapse NRM

All patients (n=109) 0.57 0.13 0.31 IPSS

Low 0.80 0.00 0.20

Intermediate-1 0.64 0.06 0.30

Intermediate-2 0.40 0.29 0.31

High 0.29 0.42 0.29

RFS relapse-free survival, NRM non-relapse mortality

a

At 3 years after transplantation

(BU) dose was adjusted to maintain steady state plasma levels of 800±900 ng/ml (targeted BUCY) (Deeg et al.

2002) (Fig. 12.3). The 3-year probability of RFS was 68% among 69 patients with RA/RARS transplanted from HLA-identical sibling donors, and 70% with unre- lated donors. NRM among all patients combined was 12% at 100 days, and 31% at 3 years; relapse occurred in 5% of patients. Outcome tended to be superior in pa- tients transplanted with granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood progenitor cells (PBPC) rather than marrow.

A large retrospective survey of the EBMT group compared results with marrow and G-CSF-mobilized PBPC for allogeneic HCT from HLA-identical siblings (TBI- or chemotherapy-based conditioning regimens).

Similar to the FHCRC data, the incidence of treatment failure in all MDS subgroups was lower with PBPC than with marrow (Guardiola et al. 2002) (Fig. 12.4). Only pa- tients with RA and high-risk cytogenetics did not derive a net benefit from the use of PBPC. The incidences of acute GvHD were comparable, while chronic GvHD was more frequent with PBPC. Nevertheless, these stud- ies showed excellent overall results with allogeneic HCT in less advanced MDS with up to 70% RFS. They sug- gest, furthermore, that the lack of a suitably matched re- lated donor should not be cause to abandon plans for transplantation, and a search for an unrelated donor should be pursued.

Fig. 12.3. Impact of pre-transplant IPSS risk on relapse (A) and RFS (B) after allogeneic HCT. int-1 intermediate-1; int-2 intermediate-2.

This figure is adapted from research originally published in Deeg et al. (2002)

Fig. 12.4. Relapse-free (A, C) and CC

overall survival (B, D) after HCT for

MDS. All patients received transplants

from HLA-identical siblings, using

either bone marrow (Ðб) or pe-

ripheral blood (...) as a source of

stem cells. Panels A and B include

patients in all IPSS groups, panels C

and D only intermediate-2 and high-

risk patients. This figure is adapted

from research originally published in

Guardiola et al. (2002)

12.3.1.2 ªAdvancedº MDS

The incidence of post-transplant relapse increases with the proportion of marrow blasts present at the time of transplantation (advanced MDS [RAEB/RAEBt]) and with increasing IPSS scores, reflecting primarily the im- pact of high-risk karyotypes in addition to the propor- tion of myeloblasts (Castro-Malaspina et al. 2002; Deeg et al. 2002; Nevill et al. 1998; Sierra et al. 2002). Relapse rates in the range of 15±80% have been reported (Appel- baum et al. 1990; Castro-Malaspina et al. 2002; Deeg et al. 2002; Runde et al. 1998). Studies in the 1980s using CY and TBI containing regimens reported 30±40%

RFS (Appelbaum et al. 1990). To determine if more in- tensive conditioning would improve results, 31 patients with RAEB, RAEBt, or CMML to be transplanted from related or unrelated donors at the FHCRC were prepared with a BUCY plus TBI regimen (Anderson et al. 1996).

Compared with historical controls conditioned with CY- TBI, relapse rates were lower (28% vs. 54%), but NRM was markedly increased (68% vs. 36%), and RFS at 3 years was not improved (23% vs. 30%).

The EBMT study already cited also included 63 pa- tients with RAEB/RAEBt, and 18 patients with acute myeloid leukemia transformed from MDS (tAML).

The 5-year RFS was 34%, 19%, and 26% for patients with RAEB, RAEBt, and tAML, respectively (Runde et al.

1998). Most of the patients (70%) were prepared with TBI-containing conditioning regimens. Relapse oc- curred in 28 patients (at 1±33 months); RFS at 5 years was 34% for RAEB, 19% for RAEBt, and 26% for tAML.

Younger age and shorter disease duration were asso- ciated with better outcome. Another EBMT trial in- cluded 105 patients (69 conditioned with TBI) who re- ceived HLA-matched unrelated donor transplants. RFS was 27%, 8%, and 27% for RAEB, RAEBt and tAML pa- tients, respectively (Arnold et al. 1998). A recent report from the International Bone Marrow Transplant Regis- try (IBMTR) on 452 patients transplanted from HLA- identical siblings (44% conditioned with TBI regimens) between 1989 and 1997 showed a RFS of 40% at 3 years (Sierra et al. 2002). Corresponding figures for relapse incidence and NRM were 23% and 37%, respectively.

The proportion of marrow blasts at transplantation was the strongest predictor for relapse and RFS, and younger age correlated with higher probability of sur- vival.

CY is not stem cell toxic but contributes to non-he- mopoietic toxicity. Thus, in another trial, 60 patients

with RAEB, RAEBt, CMML, or tAML (20 related, 40 un- related donors) were conditioned with BU plus TBI, aimed at reducing the relapse rate, and did not receive CY (Jurado et al. 2002). The Kaplan-Meier estimate of survival at 3 years was 26%, while the relapse incidence of 25% was comparable to that observed previously with a regimen combining BUTBI with CY (BUCYTBI) (An- derson et al. 1996). Overall NRM was 38% at 100 days.

Particularly disappointing were results with unrelated donors. The data showed that CY was not required to achieve engraftment of donor cells, and suggested that high-dose TBI may not be the optimum modality for conditioning. Similar to the results in patients with less advanced MDS, the use of PBPC resulted in a lower in- cidence of treatment failure than the use of marrow in all patient groups with advanced MDS (Guardiola et al. 2002).

Other trials have evaluated toxicity and efficacy of conditioning regimens that combine (targeted) BU with fludarabine (Flu) rather than CY (Bornhåuser et al.

2003). The transplant team in Calgary used a regimen of intravenous (i.v.) Flu, given over 5 days, and i.v.

BU, 3.2 mg/kg, given once a day over 3 h on 4 consecu- tive days, combined with rabbit ATG (Thymoglobulin [THY]), 4.5 mg/kg, plus methotrexate (MTX) and cy- closporine (CSP). The study enrolled 70 patients with various diagnoses, including MDS, and patients were given marrow or PBPC from related or unrelated do- nors. There were two cases of graft failure (from unre- lated donors), and the incidence of acute GvHD was 8%, and chronic GvHD 36%. The day 100 mortality was 2%

with related, and 8% with unrelated donors. Projected RFS at 2 years was 74% for low-risk, and 65% for high-risk disease (Russell et al. 2002). A recently con- cluded FHCRC trial of targeted BUCY in patients with high-risk MDS also incorporated THY in a dose escala- tion design (Deeg et al. 2004a). While the rates of GvHD were higher than in the Calgary study, they were lower than in concurrent trials not using THY. A trial in 96 patients at the M.D. Anderson Cancer Center in Hous- ton including 22 patients with MDS also used a FluBU regimen (without THY) (de Lima et al. 2004). While re- sults for patients with MDS are difficult to separate out, the incidence of acute GvHD (grades II±IV) was 15% for related and 68% for unrelated transplant recipients.

These data suggest excellent tolerability of FluBU regi- mens, and additional trials are warranted.

a 12.3 ´ Transplant Strategies 127

12.3.2 Reduced-Intensity Conditioning Regimens As outlined above, a major drawback of HCT has been the high rate of TRM. The recent development of NMA or RIC transplant regimens (ªmini-transplantsº) has, therefore, met with considerable interest (Carella et al. 2000). The rationale is that a reduction in the in- tensity of cytotoxic conditioning regimens will be asso- ciated with lower toxicity and thereby reduce NRM. The post-transplant administration of immunosuppressive drugs (e.g., CSP plus mycophenolate mofetil or tacroli- mus plus MTX) will facilitate donor cell engraftment and enhance the allogeneic (immunologic) effect of do- nor lymphocytes against the patients' cells (graft-ver- sus-MDS effect) (McSweeney and Storb 1999). In view of the generally high incidence of NRM in older pa- tients, such an approach is particularly attractive for the treatment of patients with MDS. RIC regimens are also of interest for patients with co-morbid medical conditions, and for patients who relapse after a conven- tional transplant, since conventional transplants have generally not been very successful because of severe tox- icity, particularly in adult patients.

Earlier transplant strategies generally developed in the direction of intensification of conditioning regimens to eradicate the underlying disease and prevent relapse.

The use of NMA regimens represents a dramatic depar- ture from that approach, counting heavily on immuno- logic effects of allogeneic donor cells against the pa- tient's disease. The field is developing rapidly (Kroger et al. 2001, 2003; Parker et al. 2002; Sierra et al. 2002;

Storb et al. 2000; Stuart et al. 2003; Taussig et al.

2003). It would be inappropriate, however, to simply contrast NMA with more conventional (ablative) regi- mens. All efforts are directed at achieving the best re- sults with the least toxic regimens. Thus, as already de- scribed above, we are also witnessing progressive mod- ifications of conventional (ablative) regimens. Finally, because of problems with sustained engraftment of do- nor cells and, in parallel, disease progression in the pa- tient, we are observing ªre-intensificationº of NMA reg- imens, in other words, steps toward optimization of conditioning from both directions.

Kroger et al. (2003) have used a regimen of fludara- bine combined with a reduced dose of BU and showed a RFS of 38% at 3 years among 37 patients with MDS or tAML (transplanted from related (n=19) or unrelated HLA-matched (n=18) donors). The cumulative inci- dence of relapse was 32%. De Lima and colleagues

(2004) recently reported the M.D. Anderson experience with two regimens: Flu, 100 mg/m

, plus cytosine arabi- noside, 4 mg/m

, and idarubicin, 36 mg/m

(FAI), com- pared with Flu 100±150 mg/m

, plus melphalan, 140 mg/

m

(FM). There were 26 patients with high-risk MDS in- cluded in this study of 94 patients. The FM regimen was significantly associated with a higher degree of donor cell engraftment, and a lower incidence of relapse (30% vs. 61%; p=0.029) but also a higher incidence of TRM (p ( =0.036). The 3-year survival rates were 30%

and 35% for the FAI and the FM regimens, respectively.

A recent update on NMA regimens by the Seattle consortium included 78 patients with MDS (45 related, 33 unrelated transplants; 46 were IPSS low/intermedi- ate-1, and 32 intermediate-2/high or unknown) (Stuart et al. 2003). These patients were conditioned with Flu (3´30 mg/m

) plus 200 cGy of TBI. Graft failure oc- curred in 6% of patients, and 42% of patients relapsed.

The NRM was 14% at day 100, and 25% at 1 year. Ap- proximately 20% of patients were surviving at 3 years (25% with low-risk, and less than 10% with high-risk disease) (Stuart et al. 2003).

Ho et al. (2004) reported on 62 patients (24 with HLA-identical siblings and 38 with unrelated donors) conditioned with RIC regimens (FluBU/campath). The day 100 NRM was 0% for siblings and 11% for patients transplanted from unrelated donors. The incidence of relapse ranged from 7 to 80% for IPSS risk groups inter- mediate-1 to high. There were 26 patients who received donor lymphocyte infusions at a median of 273 days after HCT. RFS ranged from 86% for IPSS low-risk pa- tients to 40% among patients with high-risk disease. An increased relapse rate in patients with MDS prepared with RIC was also reported by Martino et al. (2003). It is important to note, of course, that patients prepared with RIC regimens tended to be older and often had co-morbid conditions.

An ªintermediateº intensity regimen was used by Chan et al. (2003). These investigators combined 2 days of photopheresis with pentostatin, 4 mg/m

for 2 consecutive days, and 3´200 cGy of TBI given over 2 days to prepare 18 patients (30±70 [median 54] years old) with MDS for transplantation. Sixteen patients achieved full donor chimerism, and all patients sur- vived beyond day 100. The incidence of acute GvHD was 19%. With a median follow-up of 14 months, the 1 year RFS was 64%.

It appears, therefore, that a standard regimen for al-

logeneic transplants in patients with MDS has yet to be

established. Phase III randomized studies comparing different regimens in well-defined patient populations should be helpful in achieving that goal.

12.3.3 Autologous HCT

Autologous HCT generally does not lead to GvHD and is associated with lower TRM than allogeneic transplants.

It may hold promise in patients in whom a ªpureº pop- ulation of normal hemopoietic stem cells is obtainable.

The EBMT reported results in 79 patients with MDS, showing 2-year RFS of 28% after autologous HCT (de Witte et al. 1997). NRM was 39% in patients more than 40 years of age. These results were restricted, however, to patients who achieved complete remissions after in- duction chemotherapy. Wattel et al. prospectively as- sessed feasibility of autologous HCT (either with bone marrow or PBPC) after conditioning with BUCY in 24 of 39 patients who achieved complete remissions after induction chemotherapy. Among these, 50% were alive 8±55 months after transplantation (Wattel et al. 1999).

De Witte and colleagues (2001) presented data on 184 patients with MDS/tAML who received induction chemotherapy. Among these, 56 had HLA-identical re- lated donors available, and 128 did not. One hundred patients achieved remission and, with or without addi- tional consolidation, 39 were transplanted with allo- geneic and 61 with autologous cells. The rate of contin- uous complete remission was 33% for allogeneic, and 31% for autologous transplants. The 4-year RFS (ex- pressed as proportion of the total cohort) was 25% for allogeneic, and 15% for autologous transplants (de Witte et al. 2001).

The same authors recently reported results in pa- tients with or without HLA-identical sibling donors on an intent to treat basis (Oosterveld et al. 2003). There were 159 patients who received remission induction and consolidation chemotherapy. Sixty-five patients had no donor available, and among these, 33 ultimately received autologous transplants. RFS was 23% for patients with, and 21% for patients without, a donor. Transplants from alternative donors did not significantly alter the survival of the group without a related donor. This intention to treat analysis failed to show a survival advantage for pa- tients with HLA identical sibling donors compared to those without such a donor. The data indicate, however, that outcome with autologous transplantation is superior to that with chemotherapy alone (without a transplant).

12.4 Special Considerations

12.4.1 MDS Is a Disease of ªOlderº Patients The median age of patients at the time of diagnosis of MDS is in the early 70s, an age when aggressive therapy is generally not well tolerated. Transplantation for these patients was, therefore, viewed with great skepticism.

Results show, nevertheless, that many older patients do quite well, and the age ªceilingº for transplantation has been raised progressively.

In an FHCRC trial, 50 patients with MDS, 55±66 years of age, were conditioned with either BU (7 mg/

kg)/CY plus fractionated TBI or targeted BU (prescribed dose 16 mg/kg)/CY (Deeg et al. 2000). Donors were HLA-identical siblings in 34, HLA-non-identical family members in four, identical twins in four, and unrelated volunteers in six patients. The RFS at 3 years was 53%

for RA, 46% for RAEB, and 33% for RAEBt/tAML or CMML (Deeg et al. 2000). When only transplants from HLA-identical siblings were considered, RFS for pa- tients with RA was 67%. Survival in all FAB categories was highest among patients conditioned with targeted BUCY. A recent analysis in a larger cohort of patients confirmed those results and showed no significant im- pact of age up to 66 years on transplant outcome (Deeg et al. 2002).

Of course, in view of the concern about TRM, it was in this older patient population that NMA/RIC regimens were developed and are being exploited. The average age of patients in those studies has generally been a de- cade or more above that of patients treated with more conventional regimens such as targeted BU/CY. We re- cently analyzed data on 172 patients, more than 40 years of age with MDS/tAML, who were transplanted at the FHCRC. Patients receiving targeted BUCY were 40±65 (median 52) years old, compared with 40±73 (median 62) years for patients conditioned with a regimen of 200 cGy of TBI with or without the addition of Flu. Pa- tients with RA/RARS fared slightly better with BUCY;

however, no difference was observed among patients with more advanced MDS (Scott et al. 2004). The data suggest that various regimens can be used for older pa- tients; however, toxicity is still a problem, and patients should be carefully selected.

a 12.4 ´ Special Considerations 129

12.4.2 Childhood MDS

HCT in children with MDS is discussed in Chapter 7.

12.4.3 Other Parameters

There are additional disease parameters, which are not considered in currently used classification schemes, but may well be relevant for prognosis and treatment out- come. For example, we have shown that the severity of immunophenotypic aberrancies and scatter properties of myeloid and monocytic marrow cells pre-transplant correlates directly with the probability of post-trans- plant relapse, and inversely with RFS (Wells et al.

2003). Therefore, one may want to consider HCT in pa- tients in whom sequential marrow aspirates show wor- sening of flow parameters, even if by established classif- ication schemes the disease is ªstable.º Patients with MDS and associated marrow fibrosis tend to have more rapid disease progression than patients without fibrosis (Maschek et al. 1992). Preliminary transplant data sug- gest, however, that fibrosis does not have a negative im- pact on transplant outcome (B. Scott, unpublished).

Thus, in patients with MDS and associated fibrosis one may want to consider HCT early in the disease course, even if by other criteria, such as IPSS classifica- tion, these patients are considered ªgood riskº. The im- pact of factors such as cellularity or neo-angiogenesis in the marrow remains to be determined.

12.4.4 Secondary MDS

Treatment-related (secondary) MDS occurs after thera- py for various disorders (see Chapter 3). At 10 years after autologous HCT for Hodgkin disease and non- Hodgkin lymphoma incidence figures of 1±20% have been reported (Friedberg et al. 1999; Micallef et al.

2000; Sobecks et al. 1999). The median time from pri- mary disease to secondary MDS ranges from 2±9 years (Friedberg et al. 1999; Micallef et al. 2000). Abnormal, usually high-risk karyotypes (monosomy 7; complex abnormalities) are present in 80±90% of patients (Friedberg et al. 1999; Micallef et al. 2000; Sobecks et al. 1999). Exposure to irradiation and chemotherapy, as given for the patient's original disease, is thought to be the major cause, although a genetic predisposition cannot be excluded. As prior therapy (given for the

original disease) is expected to result in tissue damage, this is likely to predispose the patient to substantial morbidity and mortality with a transplant for secondary MDS.

Among 552 patients who had received autologous HCT for non-Hodgkin lymphoma, Friedberg et al.

(1999) observed 41 who developed MDS at a median of 47 months, for an actuarial incidence of 19.8% at 10 years. Thirteen patients underwent allogeneic HCT, and all died with a median survival of 1.8 months. These results are in agreement with an earlier report by the EBMT group, which showed a 5-year survival of 0% in patients with secondary MDS (de Witte 1999). A French group reported on 70 patients receiving allogeneic HCT (after various conditioning regimens) for therapy-re- lated MDS and AML (Yakoub-Agha et al. 2000). Overall 54 patients died, 19 of relapse, 34 of NRM, and one of relapse of the primary disease. Age greater than 37 years, absence of complete remission at HCT, and inten- sive schedules for conditioning were associated with poor outcome. RFS, relapse incidence, and NRM rates at 2 years were 28%, 42%, and 49%, respectively (Ya- koub-Agha et al. 2000). It is of note, however, that all these patients had been given pre-transplant induction chemotherapy, and patients who achieved remissions had a substantially higher chance of RFS than patients who were not in remission at transplantation.

We analyzed results in 111 consecutive patients with secondary MDS transplanted at the FHCRC between 1971 and 1998 from either related or unrelated donors using the same conditioning regimens as employed con- currently for patients with de novo MDS (Witherspoon et al. 2001). The primary diagnoses included Hodgkin disease, non-Hodgkin lymphoma, carcinoma of the breast, aplastic anemia, multiple myeloma, polycythe- mia vera, and other malignancies or immunologic dis- orders. The 5-year RFS was 8% for patients prepared with TBI regimens, 19% for those given fixed-dose BUCY, and 30% for those prepared with targeted BUCY.

The 5-year relapse rates were 40% for tAML, 40% for

RAEBt, 26% for RAEB, and 0% for RA and RARS

(Witherspoon et al. 2001). Thus, as with de novo

MDS, disease stage was the most important risk factor

for outcome, and the conditioning regimen had a major

impact. Ballen et al. (1997) reported RFS of 14%, and

NRM of 50% at 3 years for 18 patients with secondary

MDS treated with HCT from matched related or unre-

lated donors after preparation with various condition-

ing regimens.

Thus, results obtained with allogeneic HCT for treatment-related MDS are currently not satisfactory, although transplantation may be the only viable option for many of these patients. Efforts must be directed firstly at the prevention of secondary MDS, and sec- ondly at improved tolerability of transplant condition- ing. Some preliminary studies with induction chemo- therapy followed by RIC regimens have yielded encour- aging results.

12.4.5 Post-transplant Relapse

Post-transplant relapse remains a problem in patients with a high myeloblast count or ªhigh-riskº cytoge- netics or both. Reports on the efficacy of donor lympho- cyte infusions in patients with MDS are still limited;

however, there is evidence that this approach may be ef- fective (Bader et al. 1999; Bethge et al. 2004; Castagna et al. 1998; Ho et al. 2004; Shiobara et al. 2000). A Japanese series noted complete remissions in five of 11 MDS pa- tients (Shiobara et al. 2000). Similar results have been presented by Ho et al. (2004) and Depil et al. (2004).

We have given donor lymphocytes to seven patients with MDS (five with RAEB and two with RA), and three (all with RAEB) achieved complete remissions. Two pa- tients are alive, disease free, at more than 2 years (M.

Flowers et al., unpublished observations). These obser- vations are of interest, but firm conclusions cannot be drawn at this point. Some patients with relapse have un- dergone successful second transplants (Stuart et al.

2003). Conceivably, RIC transplants are effective in these patients, particularly if carried out before disease evolution.

12.5 Conclusions

HCT offers potentially curative therapy for patients with MDS. Patients with high-risk MDS (intermediate-2 or high by IPSS criteria) who have HLA-identical related or unrelated donors should be transplanted early in their disease course. Patients with less advanced MDS by FAB criteria (<5% marrow blasts) but with high-risk IPSS cytogenetic findings or severe multilineage cytope- nias according to IPSS, and transfusion dependence or severe neutropenia should also be considered for early transplantation. Patients with low-risk cytogenetic fea- tures and without severe cytopenias may do well for ex-

tended periods of time with more conservative manage- ment. HCT can be carried out successfully, even in the seventh decade of life. Overall, regimens without high- dose TBI appear to be better tolerated than TBI contain- ing regimens. The use of PBPC may offer an advantage over marrow cells, although at the price of a higher in- cidence of chronic GvHD. The place of RIC/NMA trans- plants, other than for patients of advanced age (older than 65 years), remains to be determined.

Improved survival with transplants from unrelated volunteer donors, in part, reflects selection of donors on the basis of high resolution (allele-level) HLA typing.

Autologous transplants are an option for patients with- out a suitable donor if a remission can be induced pre- transplant. The role of pre-transplant induction che- motherapy is currently not clear. Future investigations will focus on identification of additional prognostic pa- rameters allowing to predict prognosis as well as on de- termination of the optimal timing of HCT (Benesch et al. 2002; Cutler et al. 2004).

Acknowledgements. This work was supported by PHS Grants CA87948, CA18029, and HL36444.

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