doi:10.1182/blood-2002-03-0701Prepublished online July 5, 2002;   

 Jesus F San Miguel and Stephen MackinnonAngel Leon, Kwee Yong, Ana Sureda, Ann Hunter, Jordi Sierra, Anthony H Goldstone, David C Linch,Chopra, Javier Garcia-Conde, Don W Milligan, Stephen Schey, Alvaro Urbano-Ispizua, Anne Parker, Jose A Perez-Simon, Panagiotis D Kottaridis, Rodrigo Martino, Charles Craddock, Dolores Caballero, Raj disordersbetween two prospective studies in patients with lymphoproliferative Non-myeloablative transplants with or without CAMPATH-1H: comparison

(1922 articles)Transplantation   � (3779 articles)Clinical Trials and Observations   �

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1

NON-MYELOABLATIVE TRANSPLANTS WITH OR WITHOUT CAMPATH-1H: COMPARISON BETWEEN TWO PROSPECTIVE

STUDIES IN PATIENTS WITH LYMPHOPROLIFERATIVE DISORDERS.

Jose A Pérez-Simón, Panagiotis D Kottaridis, Rodrigo Martino, Charles Craddock, Dolores Caballero, Raj Chopra, Javier García-Conde, Don W Milligan, Stephen Schey, Alvaro Urbano-Ispizua, Anne Parker, Angel Leon, Kwee Yong, Ana Sureda, Ann Hunter, Jordi Sierra, Anthony H Goldstone, David C Linch, Jesus F San Miguel, Stephen Mackinnon.

Spanish and UK Collaborative Groups for non-myeloablative transplantation.

Correspondence to:Dr José A Pérez SimónServicio de HematologíaHospital Universitario de SalamancaPaseo de San Vicente s/n, 37007Spain FAX: 34-923-294624 e-mail: pesimo@usal.es

Acknowledgement:To Jose Manuel García de Cecilia, Statistician of the SEK University (Segovia) for

his support in the statistical analysis.

Key-words: Non-myeloablative transplants, comparative study, CAMPATH-1H

Copyright 2002 American Society of Hematology

Blood First Edition Paper, prepublished online July 5, 2002; DOI 10.1182/blood-2002-03-0701

2

Summary:Although non-myeloablative conditioning regimen transplants (NMT)

induce engraftment of allogeneic stem cells with a low spectrum of toxicity, GVHD

remains a significant cause of morbidity and mortality. In vivo-T cell depletion, using

CAMPATH-1H, has been shown to reduce the incidence of GVHD . However this type of

maneuvers whilst reducing GVHD may have an adverse impact on disease response, since

NMT exhibit their antitumour activity by relying on a graft versus malignancy effect. In

order to explore the efficacy of CAMPATH-1H as compared to methotrexate (MTX) for

GVHD prophylaxis we have compared the results of 129 recipients of a sibling NMT

enrolled in two pospective studies for chronic lymphoproliferative disordersBoth NMT

were based on the same combination of fludarabine and melphalan but the UK regimen

(group A) used Cyclosporine A plus CAMPATH-1H whilst the Spanish regimen (group B)

used Cyclosporine A plus MTX for GVHD prophylaxis.

Patients receiving CAMPATH-1H had a higher incidence of CMV reactivation

(85% vs 24%, p<0.001) and a significantly lower incidence of aGVHD (23.1% vs 45.1% ,

p=0.006) and cGVHD (5% vs 66.7% , p<0.001). Twenty one percent (group A) and 67.5%

(group B) of patients achieved CR or PR 3 months after transplant (p<0.001). Eighteen

patients in group A received donor lymphocyte infusions (DLI) in order to achieve disease

control. At last follow up there was no difference in disease status between the groups with

71% vs 67.5% (p=0.43) of patients reaching CR or PR in groups A and B, respectively. No

significant differences were observed in event free or overall survival between both groups.

In conclusion, CAMPATH-1H significantly reduced GVHD but its use was associated with

a higher incidence of CMV reactivation. Patients receiving CAMPATH-1H often required

DLI in order to achieve similar tumour control but the incidence of GVHD was not

significantly increased after DLI.

Introduction:

Non-myeloablative transplants (NMT) are currently being evaluated in patients with

hematological malignancies considered poor candidates for conventional allogeneic

transplantation due to advanced age or other concurrent medical conditions. The rationale

3

for NMT relies on previous observations that adoptive transfer of allo-reactive donor

lymphocytes may eradicate refractory or recurrent disease.1-5 Therefore, in an effort to

reduce the toxicity associated with high dose chemotherapy,6-11 several groups have

designed less toxic regimens that might exhibit their antitumor effect relying on a graft

versus malignancy effect rather than on myeloablative chemotherapy.12-16 Although these

regimens have been shown to permit engraftment of allogeneic haemopoietic stem cells

with a low spectrum of toxicity, GVHD remains a significant cause of increased morbidity

and mortality.4-16, 17-20 The ideal approach for GVHD prophylaxis remains uncertain and

several agents have been introduced to reduce incidence and severity. The UK

Collaborative group has incorporated CAMPATH-1H as part of a fludarabine-based

protocol and a low incidence of GVHD has been reported in both related and unrelated

donor transplants.21 However, this type of intervention to reduce the incidence and severity

of GVHD may have an adverse impact on disease response, since several studies have

suggested a positive correlation between GVHD and GVL effect,6, 15, 16, 19, 22-25 both in

myeloid and also in lymphoid malignancies18,20,25,26 and higher relapse rates have been

reported after syngeneic or T-cell depleted transplants.27,28 Thus the ideal approach is to

establish the optimum balance between the risk/benefit of decreasing GVHD versus an

increase in the risk of relapse.

In order to explore the efficacy of CAMPATH-1H in comparison to methotrexate

(MTX) (both in combination with cyclosporine) for GVHD prophylaxis and its impact on

the outcome of patients transplanted for lymphoproliferative disorders, we have

retrospectively compared the results of two prospective studies carried out in the United

Kingdom21 and Spain.29 Both NMT schedules were based on the same combination of

fludarabine and melphalan but the UK regimen (group A) used cyclosporine A plus

CAMPATH-1H whilst the Spanish regimen (group B) used cyclosporine A plus MTX.

Patients included in this study underwent transplantation from February 1998 to January

2001 (group A) and from February 1999 to May 2001 (group B).

PATIENTS AND METHODS:

4

Patient characteristics:

We have analyzed 129 patients with chronic lymphoproliferative disorders who were

included in both registries and underwent a peripheral blood stem cell transplant from HLA

matched siblings. Both studies included patients considered candidates to receive a

transplant from a related donor but who had a high risk of transplant related mortality

(TRM) due to advanced age (≥45 years old, n=77) or other concurrent medical condition

(relapse after a previous autologous transplantation, n=30; severe organ disfunction, active

fungal infection or heavily pretreated patients; n=22).. Patients gave written informed

consent for inclusion in the protocols, which were approved by all local ethical review

boards as well as the Spanish (protocol 99-0151) and the UK (study number 974/0127)

Drug Agencies.

No significant differences were observed between the two groups in median age,

diagnosis or previous transplant. Disease status at transplant was categorized as low risk

(patients in CR1 and CR2), high risk (patients with refractory or progressive disease and

>1st partial response) and intermediate risk (the rest of cases, ie. >2nd CR); no differences

were observed in terms of disease status. In contrast, there was a sex mismatch in 56% of

the CAMPATH-1H group (A) compared to 35% in MTX group (B) (p=0.031). In addition,

in 37% of cases in group A both donor and recipient were CMV negative compared to only

9% in group B (p=0.009). Other patient characteristics are specified in Table 1.

Mobilisation regimens and peripheral blood stem cell collection procedures were

similar in both trials. 21, 29

Conditioning regimen and GVHD prophylaxis:

In both trials the conditioning regimen consisted of fludarabine 30mg/m2

intravenously (IV) for 5 days followed by melphalan 140mg/m2 intravenously in one dose

or divided in two doses: fludarabine 30mg/m2 days –7 to –3 plus melphalan 140mg/m2 on

day –2 in group A and fludarabine 30mg/m2 days –8 to –4 plus melphalan 140mg/m2

divided in two doses on days –3 and –2 in group B. 21,29

5

Acute and chronic GVHD were similarly graded by established criteria in both trials 30,31. In group A GVHD prophylaxis consisted of cyclosporine A (CsA) 3 mg / kg iv

starting on day -1 and switched to an oral dose as soon as the patient could tolerate oral

medications.. The median duration of administration was 4 months for the first 40 patients,

however the observed low incidence of GVHD led physicians to taper the dose by the end

of the second month in the rest of the patients. In patients without evidence of GVHD CsA

was discontinued by the end of the third month. CAMPATH-1H was administered at a dose

of 20 mg / day iv infusion over 8 hours on days -8 to -4.

In group B, CsA was started on day –7. In the absence of grade II or greater acute GVHD,

CsA was tapered 10% weekly starting on day +90 and discontinued by day +150. In both

groups CsA levels were monitored starting on day +1 and were maintained in the

therapeutic range (150-300 ng / mL) until tapering. MTX in group B was given at a dose of

10 mg/m2 IV on days +1,+3 and +6, followed by folinic acid rescue ( 10 mg IV every 6

hours for 4 doses starting 24 hours after each dose of MTX).

Patients with relapsed / progressive disease post-transplant or those not evolving to

100% donor chimerism after discontinuing immunosupression were considered eligible for

DLI in both studies.

An escalated dose regimen starting at 1x106 CD3+ T-cells/kg with dose escalation

at 3 monthly intervals, was used in group A. The median interval from transplant to the first

DLIwas 230 days (182-781). Overall, eighteen patients received DLI in group A. Fifteen

patients received DLI for persistent disease post transplant and 3 for mixed chimerism.In

group B, also an escalated dose regimen at 3 monthly intervals was used, however the

starting dose was 1 x 107 CD3+ T-cells / kg. In this group, 4 patients received DLI due to

persistent disease (n=3) or progression (n=1). The median interval to start DLI after

transplant was +210 days (120-243).Data on chimerism analysis and DLI (manuscript

under preparation) have already been reported.21, 29. Protocols for the prevention and

treatment of transplant complications and supportive care were similar in both groups 21,29.

Finally, patients were monitored for CMV reactivation by weekly CMV

antigenemia (group B) or PCR assay (group A) and pre-emptive therapy with ganciclovir (32,33) was started after one positive antigenemia (group A) or after 2 consecutive positive

PCR assays (group B).

6

Statistical methods:

Comparison of relapse rate and GVHD between groups was performed by using the Chi

square and Fisher’s exact test. Events analyzed were calculated from the time of

transplantation using Kaplan-Meier product-limit estimates. For transplant related mortality

(TRM) patients were censored at last follow-up. Disease free survival (DFS) was calculated

from transplant until disease progression for those patients reaching CR after transplant and

also for those reaching CR after DLI. Patients who suffered TRM and those who were still

alive without progression at the time of reporting were censored at death and last follow-up,

respectively. Event free survival (EFS) was calculated from transplant until disease

progression or death and those patients who did not reach disease response (CR or PR) any

time after transplant were considered events. Overall survival (OS) was calculated from

transplant until death from any cause, and surviving patients were censored at last

follow-up. The incidence and time to onset of chronic GVHD were calculated in patients

followed for at least 90 days.

Results:

Engraftment:

Both regimens induced an early and sustained engraftment.21,28 As shown in Table

2, granulocyte recovery was faster in group A ; the median time for > 500 granulocytes /

mm3 was 12.8 vs 14.7 days (p<0.001) and for > 1,000 granulocytes / mm3 13.7 vs 17.6 days

(p<0.001) for groups A and B, respectively. In contrast, the use of CAMPATH-1H was

associated with a significant delay in platelet recovery: median of 14.4 vs 11.2 days to

reach > 20 x 109 / L platelets (p=0.009) and 21.7 vs 14.1 days to reach > 50 x 109 / L

platelets (p=0.001) in groups A and B, respectively.

GVHD and infectious complications:

Patients receiving CAMPATH-1H had a significantly lower incidence of aGVHD

(17.9%) when compared to patients receiving MTX (45.1%) (p=0.001). In addition, in

patients receiving CAMPATH-1H the incidence of grades II-IV and III-IV aGVHD was

significantly lower in comparison to patients receiving MTX: 6.4% vs 43.1% grades II-IV

aGVHD in groups A and B, respectively (p<0.001) and 2.6% vs 13.7% grades III-IV

7

aGVHD in groups A and B, respectively (p=0.015). Interestingly, eighteen patients

received DLI in group A due to relapse / persistence of disease or mixed chimerism and

only 3 of these patients developed GVHD (one grade I, one grade IV and one limited

cGVHD), so that a significantly lower incidence of aGVHD persisted in patients receiving

CAMPATH-1H even after DLI. However, there was no significant difference in terms of

severe aGVHD (grades III and IV) after DLI (p=0.09) (Table 2).

There were also differences in the incidence of chronic GVHD between the

groups.Only two patients receiving CAMPATH-1H developed cGVHD (1 limited, 1

extensive) in contrast to 22 (66.7% of patients at risk) patients receiving MTX (13 cases of

extensive cGVHD) (p<0.001).

Patients were monitored for CMV reactivation by weekly CMV antigenemia (group

B) or PCR assay (group A). Statistically significant differences were observed in the

incidence between both groups. Although a lower percentage of patients in group B were

CMV negative, only 22.7% developed CMV reactivation as compared to 47% in group A

(p=0.018). Even more strikingly, amongst CMV positive patients, 85% had CMV

reactivation in group A vs 24% in group B (p<0.001). Despite the high incidence of

reactivation only one patient died of CMV disease in group A vs none in group B.

Transplant related mortality:

No significant differences were observed in terms of TRM between both groups

although a trend towards a higher mortality rate was observed in group B [10.2% vs 20%

for groups A and B, respectively (p=0.12; log rank: p=0.06, fig 1)].

Overall 25.6% of patients in group A died compared to 29.4% in group B (p=0.6).

33.4% of deaths in group B were related to GVHD compared to 5% in group A. By

contrast, the most frequent cause of death in patients receiving CAMPATH-1H was disease

relapse / progression (60% of deaths vs 20%). Data concerning morbidity and mortality are

specified in table 2.

Disease response:

Disease status was evaluated three months after transplant (table 3). After three

months 21.1% of patients in group A were in CR/PR in contrast to 67.5% in group B

(p<0.001). Interestingly, disease status at transplant significantly influenced response to

8

transplant in patients receiving CAMPATH-1H but not in those receiving MTX. The most

important differences in response were observed in patients categorized as high risk

patients according to disease status pre-transplant with no patient reaching CR or PR in

group A vs 52.9% in group B (p<0.001). In the intermediate risk group of patients 18.8%

reached CR or PR in group A compared to 55.5% in group B (p<0.001). In contrast, no

significant differences were observed in the low risk group, although the number of patients

in this subgroup was too small to reach any conclusion. As previously stated, eighteen

patients received DLI in group A because of relapse / persistence of disease or mixed

chimerism vs four patients in group B. Disease status at last follow-up ( after cyclosporine

A taper and DLI) is summarized in Table 3. Disease status at last follow up was not

significantly different between both groups for the overall series of patients. In addition, no

significant differences were observed according to pre-transplant disease status, since in the

high risk group 53.8% of patients receiving CAMPATH-1H reached CR / PR vs 50% in the

group of patients receiving MTX (p=0.45). Also in the intermediate risk group 55.8% of

patients receiving CAMPATH-1H reached CR / PR as compared to 56.5% of patients

receiving MTX (p=0.76).

On analyzing all patients (Table 4) we found an association between development

of aGVHD and disease response (55.2% of patients developing aGVHD reached CR/PR as

compared to 29.5% for those who did not develop aGVHD, p=0.025) but this association

disappeared after DLI. The same occurred when we analyzed patients developing grades II

to IV aGVHD. In order to evaluate whether these results could be attributed to any of the

GVHD prophylaxis regimens both groups were separately analyzed. No clear relation

between aGVHD and response to transplant or disease status after DLI was observed in

neither group A or B, although this might be related to the lower number of cases included,

when both series were separately analyzed. In addition, 74% of patients developing

cGVHD achieved CR / PR as compared to 29% of patients who did not develop it

(p<0.001). In this case, the impact of DLI could not be evaluated since only two patients in

group A developed cGHVD.

Finally, results from both registries were analyzed according to the type of the

underlying disease: in multiple myeloma both response to transplant and disease status after

DLI was improved in patients receiving MTX (52.6% of patients in group A reached CR /

PR at last follow up as compared to 68.8% in group B, p=0.029). In MM patients there was

9

no clear relation between aGVHD and disease control, however 50% of those patients who

developed aGVHD reached CR/PR in comparison to 25% for those who did not develop

GVHD (p=0.25).

In Hodgkin´s disease patients, the initial response was better in group B, however disease

status after DLI was similar in both groups (53.3% of patients reached CR / PR in group A

as compared to 50% in group B, p=0.21). Finally, within patients diagnosed with high

grade NHL (n=21), only two were categorized as low risk disease at transplant whilst the

rest were categorized as intermediate (n=9) and high risk (n=10). Response to transplant

was significantly better for patients receiving MTX but, after examining disease status after

DLI no significant differences were observed between the two groups, although we

observed a trend towards a better disease control for patients in group B (26.7% of patients

receiving CAMPATH-1H in CR/PR vs 50% for those receiving MTX). In view of the low

number of patients no other disease categories were analyzed.

Overall survival and disease free survival:

Disease free survival was first calculated identifying only those patients reaching a

complete response after transplant. Median DFS was not reached for patients receiving

CAMPATH-1H and not computed for those receiving MTX since no relapses were

observed among patients reaching CR. No significant differences were found. When we

also considered patients achieving CR after DLI, DFS at 2 years was 76% for patients in

group A vs 100% in group B(p=0.19). When we compared both groups according to pre-

transplant disease status no significant differences were found for any of the risk categories

when we considered disease status after DLI.

Median event free survival (EFS) amongst patients receiving CAMPATH-1H was

438 days vs 267 days for patients receiving MTX. Event free survival at 2 years was 34%

in group A vs 39% in group B, p=0.14 (fig 2). When both groups were examined according

to pre-transplant disease status no significant differences were found for any of the risk

categories when we considered disease status after DLI. When we analyzed only those

patients achieving any response (CR, PR or stable disease), median EFS was not reached

for any of the two groups. For these patients EFS at 2 years was 72% and 76% for groups A

and B respectively, p=0.6 (Fig 3).

10

With regard to overall survival, at the present time the median survival has not been

reached for either of the two groups. No significant differences were observed between

both groups (72% OS at 2 years in group A vs 66% in group B, p=0.22) even when we

considered the different risk categories (Fig 4).

Discussion:

It has been well established that non-myeloablative transplants may offer a reduced

risk of procedure associated mortality,6, 14-16, 21, 29 compared to conventional transplants.8-10

However, despite the considerably lower toxicity, GVHD still remains a major limitation

for this strategy.6, 14-16, 29 In order to explore the impact of CAMPATH-1H on the

prevention of GVHD and the efficacy of NMT, we have performed the first comparative

study between two prospective national studies in patients diagnosed with

lymphoproliferative disorders.

Both conditioning regimens21,29 were based on the same doses of fludarabine and

melphalan, with the only difference being the use of CAMPATH-1H (group A) or MTX

(group B) in addition to CsA to prevent GVHD. Characteristics of patients at transplant

were similar, except for a higher incidence of sex mismatched pairs in the group of patients

receiving CAMPATH-1H and a lower percentage of CMV seronegativity in the group of

patients receiving MTX.

This comparative study has confirmed that CAMPATH-1H significantly reduces the

overall incidence of aGVHD when compared to MTX. In addition, this reduction can be

maintained even after DLI. Since the efficacy of this type of transplant relies primarily on

the graft versus tumor effect,6-10, 24 any attempt to decrease GVHD may be offset by a

higher risk of relapse and the results should be cautiously interpreted. Disease response at

three months was significantly better in the group of patients receiving MTX. In addition,

patients who developed GVHD obtained a better disease response after transplant.

Nevertheless, 18 patients in group A received DLI in order to generate a tumour response

and our analysis has shown that disease status at last follow up did not differ between both

groups. Interestingly, disease response after DLI was not associated with a significant

increase in GVHD since differences in GVHD incidence between both groups remained

even post DLI. In addition, correlation between GVHD and response was not significant

when we considered disease status after DLI. These results are in accordance with previous

11

reports suggesting that the approach of using delayed DLI can induce disease response and

may be associated with less GVHD compared to early infusion34 and also support previous

reports showing that the use of DLI can contribute to overcome the negative effect on GVL

of in vitro T-cell depletion using CAMPATH-1 in myeloid as well as in lymphoid

malignancies35.

This study also confirmed that lymphomas, CLL and multiple myeloma are

susceptible to graft versus tumor effect.18, 20, 25, 26, 36-40 This effect is not equally potent

across tumor subtypes and disorders with low proliferative capacity may respond better

when compared to more aggressive forms of disease. We were also able to demonstrate a

correlation between disease response and severity of GVHD and, not surprisingly, in our

series of myeloma patients, response to transplant was significantly better in group B.

Interestingly, the improved outcome in group B remained even after DLI in group A,

suggesting that an early onset of GVHD might be more beneficial in multiple myeloma.

“Although the use of T-cell depletion combined with cyclosporine may have a

deletereous effect on transplant outcome41, recent reports have unexpectedly shown that

CAMPATH and cyclosporin can reduce the rik of death due to infections 6 months after the

transplant42. Therefore further studies will be needed to explore the mechanism of the

cyclosporin effect and the potential benefit in combination with T-cell depletion”

As previously reported, the use of less intensive regimens may have a beneficial effect on

infections.43 In the immediate post transplant period, the short duration of neutropenia may

result in reduced incidence of bacterial infections. In the present study, CAMPATH-1H

recipients experienced increased incidence of CMV reactivation in comparison to MTX

although only one patient in the former group died due to CMV disease. This difference in

terms of CMV reactivation can not be atributted to the different techniques used in both

trials since several studies have demonstrated that antigenemia and PCR assay have similar

predictive values and show a high linear correlation (44,45). According to this findings, the

CDC have recently recommended that any of both techniques should be selected to

determine the need for pre-emptive treatment (46). On the other hand, we were able to show

that the use of MTX, as expected, was associated with delayed neutrophil engraftment

although unexpectedly platelet engraftment was delayed in patients receiving CAMPATH-

1H although these differences were not clinically important. The delay in platelet

engraftment in group A, might be related to the in vivo T cell depletion induced by

12

CAMPATH-1H, since T lymphocytes may be an important element for platelet

engraftment,47 or in addition, CAMPATH-1H might have direct toxicity on megakaryocytic

progenitors.

Although a major concern about the use of anti-T monoclonal antibodies is the

increased incidence of post-transplant lymphoproliferative disorders (PTLD), in this study,

none of the patients developed PTLD. This is in contrast to previous reports on other anti-T

monoclonal antibodies 48,49 and is probably related to the anti-B cell effect induced by

CAMPATH-1H.

In conclusion, both non-myeloablative regimens offer good results in patients

considered poor candidates to undergo a conventional allogeneic transplantation, but a

different pattern of complications was observed: CAMPATH-1H significantly reduced

GVHD but it was related to a higher incidence of CMV reactivation. These findings have

prompted us to initiate a study to establish an optimum dose of CAMPATH-1H in order to

maintain its efficacy for GVHD prophylaxis without increasing CMV

reactivation.50However, patients receiving CAMPATH-1H required donor lymphocyte

infusion in order to achieve a similar response rate in comparison to those receiving MTX

but the incidence of GVHD did not significantly increase after DLI, thus suggesting the

possibility of separating GVHD from GVL. Finally, better responses were observed early

post transplant in patients with multiple myeloma or with active disease pre transplant

indicating that these patients may benefit from MTX containing regimens. Considering

these results a randomized trial comparing both protocols of GVHD prophylaxis is

warranted.

13

Table 1. Patient and disease` characteristics

Fludarabine/melphalan/CAMPATH-1H

N=78

Fludarabine/melphalanMTXN=51

p

Age (median, SD) 44 (10,7) 47 (11,3) 0.94Previous transplant 35 (45%) 26 (51%) 0.49Sex mismatched 34 (55.7%) 18 (35.3%) 0.031Patient CMV+Patient CMV- donorCMV+Both CMV-

37 (53%)7 (10%)26 (37%)

27 (81.8%)3 (9.1%)3 (9.1%) 0.009

Disease status at transplant categorized(*) Low risk CR1 CR2 Intermediate risk >CR2 1st PR CR1/2 after 3rd line Untreated relapse / SD High risk Ref / Progressive >1st PR

7 (9.1%)61

53 (67.5%)7442

18 (23.4%)153

7 (13.7%)25

27 (52.9%)218

717 (33,3%)

134 0.25

Disease (**) HD CLL MM MCL Low grade NHL High grade NHL T-NHL Other CLPD

158196111227

10716

7444 0.52

Follow up (median, SD) 400 (273) 253 (200) 0.05(*)low risk: CR1, CR2; high risk: refractory, progressive, >1st PR; rest: intermediate risk (SD: stable disease; PR: partial response)(**) MCL: mantle cell lymphoma; Other Chronic lymphoproliferative disorders: Waldenstrom (n=1/1), T-PLL (n=1), low transformed to high grade HNL (n=5/1), Richter (n=0/2)

14

Table 2: Transplant related morbidity and mortality

Fludarabine/melphalan/CAMPATH-1H

(n=78)

Fludarabine/melphalan/MTX(n=51) p

Days to reach >500 granulocytes >1000 granulocytes >20.000 platelets >50.000 platelets

12.88 (2.84)13.7 (3.89)14.49 (6.49)21.73 (14.1)

14.79 (2.14)17.68 (3.09)11.25 (5.34)14.14 (5.38)

<0.001<0.001

0.0090.001

aGVHD No Grade I Grade II-IV Grade III-IV

64 (82.1%)9 (11.5%)5 (6.4%)2 (2.6%)

28 (54.9%)1 (2%)

15 (29.4%)7 (13.7%)

Yes vs no: 0.001

0-1 vs 2-4: <0.001

0-2 vs 3-4: 0.015

Overall aGVHD(pre+postDLI) No Grade I Grade II-IV Grade III-IV

60 (76.9%)10 (12.8%)3 (3.8%)4 (5.1%)

28 (54.9%)1 (2%)

15 (29.4%)7 (13.7%)

Yes vs no: 0.006

0-1 vs 2-4: <0.001

0-2 vs 3-4: 0.092

cGVHD Limited Extensive

11

913 <0.001

CMV reactivation 27 (46.6%) 10 (22.7%) 0.018CMV reactivation CMV+patient or donor CMV-patient and donor

26 (86.7%)0

7 (25%)0

<0.001

TRM 8 (10.3%) 10 (20%) 0,12

15

Table 3. Disease Response and Transplant Outcome

Fludarabine/melphalan/CAMPATH-1H

N=78

Fludarabine/melphalan/MTXN=51

p

Disease response 3 months after transplantResponse

CR PR Stable /prog free Progression

15 (21.1%)0

48 (67.6%)8 (11.3%)

19 (47.5%)8 (20%)

9 (22.5%)4 (10%) <0.001

Disease status at last follow up*Disease status CR PR Stable /prog free Progression

28 (47.4%)14 (23.7%)16 (27.1%)

1 (1.8%)

19 (47.5%)8 (20%)

9 (22.5%)4 (10%) 0.43

(*) Disease status after CsA taper and DLI

Table 4: Response to transplant according to GVHD development

aGVHDYes No

p

Response to transplantCR / PR

Stable / prog16 (55.2%)13 (44.8%)

26 (29.5%)56 (70.5%) 0.025

Dis.status at last follow up*CR / PR

Stable / prog21 (75%)7 (25%)

47 (67.1%)23 (32.9%) 0.61

cGVHDYes No

Response to transplant CR / PR Stable / prog

17 (74%)6 (23%)

23 (29%)57 (71%) 0.016

(*): disease status after CsA taper and DLI

16

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