Therapy of steroid-refractory acute GVHD with CD52 antibody ... - Nature

Bone Marrow Transplantation (2011) 46, 143–147 & 2011 Macmillan Publishers Limited All rights reserved 0268-3369/11

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ORIGINAL ARTICLE

Therapy of steroid-refractory acute GVHD with CD52 antibody alemtuzumab is effective N Schub1, A Gu¨nther1, A Schrauder2, A Claviez2, C Ehlert1, M Gramatzki1 and R Repp1 1 Division for Stem Cell Transplantation and Immunotherapy, Second Department of Medicine, Kiel, Germany and 2Department of Paediatrics, University of Kiel, Kiel, Germany

The efficacy and safety of CD52 antibody alemtuzumab to treat severe acute GVHD in 18 consecutive patients refractory to standard high-dose corticosteroid therapy is reported. Patients (age range 13–68 years) had developed acute GVHD grade III and IV with gut and/or liver involvement after stem cell transplantation from family donors (n ¼ 7) or HLA-matched unrelated donors (n ¼ 11), including five donors with one or two HLA mismatches. Initially, in three patients, start doses of alemtuzumab in the range of 70–80 mg were applied and repeated after 3 to 4 weeks. Impressive responses were seen, but virus reactivation and bacterial infections were frequent. In an attempt to reduce this complication, the next nine patients received a reduced starting dose of 20– 33 mg, and the last six patients received 3–13 mg repeated every 2–3 weeks. Seventeen of 18 patients responded to alemtuzumab, six patients are alive with a median followup of 108 weeks. Chronic GVHD was observed frequently. Although pronounced lymphocyte depletion requiring close monitoring for signs of infections seems inevitable for efficacy, alemtuzumab given in moderate doses has a substantial activity not only in intestinal but also in severe acute GVHD of the liver. Bone Marrow Transplantation (2011) 46, 143–147; doi:10.1038/bmt.2010.68; published online 29 March 2010 Keywords: alemtuzumab/Campath-1H; allogeneic stem cell transplantation; acute GVHD; antibody therapy

Introduction In recent years, techniques of allogeneic hematopoietic stem cell transplantation (HSCT) have improved considerably and allowed use of this procedure in older and less fit patients. Severe acute GVHD remains the main obstacle to apply this therapeutic modality, as it is still the leading

Correspondence: Professor M Gramatzki, Division for Stem Cell Transplantation and Immunotherapy, Second Department of Medicine, University of Kiel, Schittenhelmstr. 12, Kiel 24105, Germany. E-mail: [email protected] Received 25 May 2009; revised 4 November 2009; accepted 18 January 2010; published online 29 March 2010

cause of morbidity and non-relapse mortality. High-dose corticosteroids are standard in initial treatment of patients with acute GVHD achieving response rates of 30–70%. No standard therapy exists once a patient has developed acute GVHD refractory to corticosteroids, although a number of agents have been tried with limited success.1 The antibody alemtuzumab (Campath-1H) is a humanized IgG1 monoclonal antibody targeting CD52, which is expressed on T- and B-lymphocytes and on some monocyte-derived dendritic cells. Licensed for the treatment of fludarabine-refractory B-cell CLL,2 alemtuzumab was also used in T-cell tumors3–5 and due to its known immunosuppressive activity in autoimmune diseases6 and for GVHD prevention.7,8 Although alemtuzumab in the treatment of acute and chronic GVHD in small studies and case reports has already shown therapeutic responses,9–13 very recently Schnitzler et al.14 reported 20 patients with severe intestinal acute GVHD treated successfully with alemtuzumab. Here, we show the efficacy of alemtuzumab for intestinal and liver grade III and IV acute GVHD in 18 steroid-refractory patients and support the idea that smaller doses may be preferable.

Patients and methods Patient characteristics Nineteen consecutive allografted patients with acute GVHD grade III and IV, as defined by consensus criteria,15 and refractory to corticosteroids were treated between November 2004 and November 2007 with alemtuzumab. To be evaluable for this retrospective analysis, patients had to have a life expectancy of 41 week. Therefore, one severely ill patient given alemtuzumab in a desperate situation was not included. Eighteen patients were evaluable for response. Median patient age at the time of first alemtuzumab treatment was 47.1 years (range 13.7–68.9 years). Patients had been diagnosed with AML (n ¼ 10), CLL (n ¼ 1), multiple myeloma (n ¼ 2), Hodgkin lymphoma (n ¼ 1), chronic myelomonocytic leukemia (n ¼ 1), aplastic anaemia (n ¼ 1) or myelodysplastic syndrome (n ¼ 2). Allogeneic stem cell transplantation was performed at the Division for Stem Cell Transplantation and Immunotherapy of the University of Kiel except for one patient,

Alemtuzumab for treatment of steroid-refractory acute GVHD N Schub et al

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who was referred from another transplant centre for further treatment. Seven patients had an HLA-identical sibling donor. All other patients were HLA typed by molecular methods for 10 alleles (HLA-A, -B and -C as well as -DRB1 and -DQB1). Six patients had a 10/10 HLA-matched unrelated donor (MUD) and five had an HLA-mismatched unrelated donor (MMUD) (three patients with one HLA mismatch, two patients with two HLA mismatches). One patient was transplanted with bone marrow; all others received peripheral blood stem cells. Five male patients had female donors. Patient characteristics are summarized in Table 1.

Conditioning therapy Anti-T-cell globulin (ATG) was part of the conditioning therapy in 13 patients (n ¼ 10 related donor, n ¼ 3 unrelated donor). Five patients did not receive ATG conditioning (n ¼ 1 unrelated donor, n ¼ 4 related donor). One of the 18 evaluable patients had been treated with alemtuzumab before allogeneic transplantation. GVHD Standard GVHD prophylaxis consisted of CSA 3 mg/kg/ day starting at day 1 and a short course of MTX on days 1, 3 and 6 after HSCT or CSA and mycophenolate mofetil (MMF) 2 15 mg/kg/day. In one patient with HLA-Amismatched graft (8/10), GVHD prophylaxis was intensified (CSA, MTX, MMF, etanercept, basiliximab). Diagnosis of acute GVHD was primarily based on clinical findings, supported by biopsy whenever indicated. All patients had acute GVHD grade III or IV and received initial treatment with corticosteroids of X2 mg/kg/day for X7 days. Insufficient response to corticosteroids led to the start of alemtuzumab therapy. The median time to onset of

Table 1

acute GVHD was 30 days (range 7–132 days) after allogeneic transplantation. Two patients developed lateonset acute GVHD (d þ 115, d þ 132). Most of the patients had been treated with one or more immunosuppressive drug (tacrolimus, infliximab, basiliximab, rituximab, etanercept, daclizumab) before initiation of alemtuzumab therapy (see Table 2).

Infections Upon initiation of acute GVHD treatment, all patients received anti-infective prophylaxis usually consisting of trimethoprim-sulfamethoxazole, fluconazole and aciclovir. Screening for infections was performed by weekly tests for candida- or aspergillus-antigenemia, for oral HSV or EBV evidence and stool testing for adenovirus. CMV infection was monitored twice weekly by quantitative CMV-PCR and CMV pp65 antigenemia testing. When indicated, pre-emptive treatment with valganciclovir was initiated.

Alemtuzumab application Alemtuzumab was administered intravenously. The first three patients (cohort I) were treated with initial alemtuzumab doses of 73–83 mg, given as escalated doses starting with 3 mg, increasing to 10 mg and finally 30 mg on 4 or 5 subsequent days followed by 10–40 mg on 2 consecutive days every 3–4 weeks. The second group of patients (cohort II, n ¼ 9) received initial doses of 20–33 mg alemtuzumab escalated over 2 or 3 days followed by a single injection of 20 mg every 2–3 weeks. The third group of patients (cohort III, n ¼ 6) received 3–13 mg of alemtuzumab as initial dosage on 1 or 2 days followed by a single injection of 5–10 mg every 2–3 weeks. Alemtuzumab was continued until improvement of GVHD or occurrence of infections.

Patient characteristics

Cohort Patient Age Diagnosis

Gender Donor/stem (donor/patient) cell source

CMV-status Conditioning (donor/patient) protocol

1 1 1 2 2 2 2 2

1 2 3 4 5 6 7 8

19.1 68.9 55.8 37.4 55.7 47.3 48.8 42.3

Hodgkin lymphoma AML AML CMML B-CLL Multiple myeloma AML AML

f/m m/f m/f m/m f/m m/m f/f f/m

MMUD/PBSC MRD/PBSC MUD/PBSC MUD/PBSC MRD/PBSC MUD/PBSC MRD/PBSC MMUD/PBSC

/ /+ +/+ +/+ +/+ +/ +/+ /

2 2 2 2 3 3 3 3 3 3

9 10 11 12 13 14 15 16 17 18

26.1 53.2 66.5 39.3 68.0 64.0 42.4 19.7 13.7 55.0

Aplastic anemia AML AML AML AML MDS Multiple myeloma AML MDS AML

m/m m/m m/m f/m m/m m/m f/m m/m m/f m/m

MMUD/PBSC MRD/PBSC MUD/PBSC MRD/PBSC MUD/PBSC MRD/PBSC MRD/PBSC MMUD/PBSC MMUD/BM MUD/PBSC

/ / +/+ / +/+ +/+ /+ /+ / /

GVHD prophylaxis

Flu/Mel Flu/Bua TBI (12 Gy)/Cy Bu/Cy Flu/Cy Flu/Mel/BCNU Bu/Cy Bu/Cy

ATG/CSA/MTX ATG/CSA/MMFa ATG/CSA/MMF ATG/CSA/MMF CSA/MMF ATG/CSA/MMF CSA/MMF ATG/CSA/MTX/MMF/ Etanercept/Basiliximab Flu/Cy/OKT3/TLI (2 2 Gy) CSA/MTX Flu/Bu ATG/CSA/MMF Flu/BCNU/Mel ATG/CSA/MMF Bu/Cy CSA/MMF Flu/BCNU/Mel ATG/CSA/MMF Flu/Bu ATG/CSA/MMF Flu/BCNU/Mel CSA//MMF Bu/Cy ATG/CSA/MMF Bu/Cy/Mel ATG/CSA/MTX Bu/Cy ATG/CSA/MMF

Abbreviations: BCNU ¼ carmustine; Bu ¼ busulfan; Cy ¼ cyclophosphamide; f ¼ female; Flu ¼ fludarabine; m ¼ male; Mel ¼ melphalan. a After remission-inducing chemotherapy containing Flu/Cytarabin/Idarubicin, stem cells containing donor lymphocytes were given for early relapse. The day of this second donation was counted as day 0. Bone Marrow Transplantation


145 Outcome of alemtuzumab therapy

Table 2

Cohort

Patient

GvHD Therapy a

Acute GvHD c At start of antibody

Startb

Grade

Skin

Gut

GvHD c Week 4

Liver

Grade

Skin

Gut

GvHD Week 8 c Liver

Grade

Skin

IV

3

Gut

Liver

Alemtuzumab Total dose (mg)

4

1

Chronic GvHD

1

1

CSA / MMF / Steroids

17

IV

3

3

4

III

3

3

0

133

-

1

2


15

IV

2

4

4

IV

0

0

4

-d

133

-

1

3

MMF / Steroids / Tacrolimus / Rituximab / Etanercept / Daclizumab

167

IV

3

4

4

IV

1

2

4

-d

153

-

2

4

CSA / MMF / Steroids / Daclizumab

13

IV

3

4

4

IV

0

0

4

IV

0

0

4

153

Extensive (liver)

2

5

CSA / MMF /Infliximab / Steroids

56

IV

3

4

4

IV

0

3

4

III

0

2

3

83

-

2

6


36

III

3

3

2

II

0

1

0

0

0

0

0

91

Limited (gut, sicca), resolved

2

7


35

IV

0

4

0

IV

0

4

0

III

0

3

0

191

-

2

8

Steroids / Daclizumab / Basiliximab

33

IV

1

4

4

III

0

1

3

III

0

0

3

80

-

2

9

Tacrolimus / Steroids

33

III

3

0

3

III

0

0

2

0

0

0

0

169

Extensive (skin, liver)

2

10


10

IV

1

4

3

IV

0

4

0

II

0

1

0

100

Extensive (BOOP)

2

11

CSA / MMF

38

IV

0

4

0

III

0

2

1

III

0

3

0

106

Prolonged acute GvHD, resolved

2

12

CSA / Steroids

32

IV

4

4

2

III

3

3

1

III

3

2

0

143

Extensive (skin / gut / liver)

3

13


31

III

2

3

3

II

0

1

1

0

0

0

0

63

Prolonged acute GvHD

3

14


53

III

3

3

0

I

0

1

0

0

0

0

0

8

Limited (gut, sicca), resolved

3

15


74

III

2

2

0

0

0

0

0

0

0

0

0

16

Extensive (BOOP)

13

-

d

3

16

Steroids / Daclizumab

21

IV

0

4

4

IV

NA

4

4

3

17

MMF / Steroids

11

III

1

3

1

II

0

1

0

II

0

-

1

0

33

-

3

18


8

IV

0

4

3

IV

0

4

0

II

0

2

0

53

-

a

Previous GVHD therapy is underlined when given at alemtuzumab initiation. Start of alemtuzumab infusion (days after first signs of acute GVHD). c Colour indicates change compared with previous evaluation (green denotes improvement; red denotes worsening). d Point of evaluation not reached. b

Results Eighteen evaluable consecutive patients with severe acute GVHD had received intense treatment with steroids and additional immunosuppressive agents but were not responsive. Alemtuzumab therapy started at a median of 33 days (range 8–167 days) after diagnosis of acute GVHD. Patients were usually receiving additional immunosuppressive medication such as CSA or MMF. The immunosuppressive drugs were continued in most of the patients after alemtuzumab was started but could be tapered later. The median total dose of alemtuzumab was 95.5 mg (range 8–191 mg) given within 58 days (median); for details see Table 2. Acute side effects of alemtuzumab administration like fever or systemic inflammatory response syndrome occurred in only six patients. All patients treated with alemtuzumab had grade III or, the majority, grade IV acute GVHD. Involvement of the skin, gut and liver was frequent. All evaluable patients except one responded to alemtuzumab therapy, with five complete responses, one after 4 weeks and four after 8 weeks (Table 2). In nine additional patients, the overall grade of acute GVHD improved. Median stage of skin involvement improved from 2 (range 0–4) at baseline to 0

(range 0–3) and 0 (range 0–3) after 4 and 8 weeks, respectively. Similarly, gut involvement improved from 4 (range 0–4) at baseline to 1.5 (range 0–4) and 1 (range 0–4) after 4 and 8 weeks, whereas liver disease improved from 3 (range 0–4) to 1 (range 0–4) and 0 (range 0–4), respectively. To reduce infectious complications, alemtuzumab dosing was deescalated in two steps. In the first group of patients (n ¼ 3) receiving the highest doses of alemtuzumab eventually all severely ill patients died because of pneumonia, adenovirus sepsis and EBV reactivation resulting in multiorgan failure. Nevertheless, impressive responses were seen due to alemtuzumab therapy, for instance, extraordinary improvement of liver function in patient 1 (Figure 1). The subsequent nine patients received a reduced dose of alemtuzumab, which still led to complete lymphocyte depletion in the peripheral blood. The final group of six patients was started at doses as low as 3–13 mg alemtuzumab and seemed to have sufficient responses. Many infectious complications (Table 3) occurred. All patients suffered from at least one infectious episode during the immunosuppressive therapy with alemtuzumab. Patients showed symptomatic infections with HSV, EBV, adenovirus, polyomavirus, norovirus, rotavirus or parvovirus B19. Opportunistic infections were observed including Bone Marrow Transplantation


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Bilirubin (µmol/L)

*

MMF* CSA Steroids

6 Tacrol.

5

750

Alemtuzumab

4 3

500

2 250 1 0 0

25 50 75 100 Days after stem cell transplantation

Lymphocyte count (cells/nl)

MTX

1000

alemtuzumab treatment. In 3/10 patients, CMV reactivation occurred already during initial GVHD treatment, but after start of alemtuzumab the virus load increased. However, all patients with CMV reactivation could successfully be treated without progression to overt CMV disease. None of the eight CMV-negative (n ¼ 7 donor CMV–, n ¼ 1 donor CMV þ ) patients developed CMV infection. After a median follow-up of 36.5 weeks (range 3.1–164.5 weeks), six patients are alive, 12 patients died, mostly related to infectious complications. The overall survival is

100 Percent survival

pneumonia induced by legionella, candida or aspergillus, cerebral manifestation of toxoplasma gondii and infectionrelated multiorgan failure. However, no EBV-related posttransplantation lymphoproliferative disorders has been observed during alemtuzumab treatment. CMV reactivation was monitored frequently, and all CMV-positive patients (n ¼ 3 donor CMV–, n ¼ 7 donor CMV þ ) developed asymptomatic CMV reactivation during or after

0 125

0

Figure 1

Initial response to alemtuzumab therapy of patient 1 with grade IV acute GVHD showing severe liver involvement: bilirubin levels (broken line) of above 770 mmol/L (45 mg/100 mL) resolved, whereas peripheral blood lymphocyte counts (shaded area) decreased. The length of the vertical lines marked alemtuzumab indicates the dose given ranging from 3 to 30 mg. ‘Tacrol’ indicates tacrolimus used for consolidation.

Table 3

50

0

50

100 Weeks

150

200

Figure 2 Overall survival of all 18 evaluated patients treated with alemtuzumab for steroid-refractory GVHD.

Side effects and infectious situations during alemtuzumab treatment

Cohort Patient Acute CMV Infections Kind of infectious complications side reactivation after effects alemtuzumab HSV stomatitis, candidiasis, adeno virus sepsis, EBV reactivation Pneumonia Pneumonia Pneumonia, sepsis

Follow-up Status at last follow-up (weeks)

1

1

—

No

Yes

12.3

Dead; GVHD and infection

1 1 2

2 3 4

— — —

Yes Yesa Yesa

Yes Yes Yes

3.6 3.1 31.2

Dead, GVHD Dead; GVHD and infection Dead; GVHD and infection (Sepsis after liver transplantation) Dead; GVHD and infection Alive Dead; GVHD and infection Dead; GVHD and infection Dead; GVHD Alive Alive Alive

2 2 2 2 2 2 2 2

5 6 7 8 9 10 11 12

SIRSb — — Fever Fever Fever — —

Yes No Yes No No No Yes No

Yes Yes Yes Yes Yes Yes Yes Yes

3 3 3

13 14 15

— — SIRS

Yes Yesa Yes

Yes Yes Yes

Pneumonia Peritonitis Sepsis, aspergillus pneumonia Disseminated HSV infection, adeno virus sepsis Legionella sepsis Polyoma virus cystitis Cerebral toxoplasmosis, atypical pneumonia Noro virus enteritis, polyoma virus cystitis, parotitis and soft tissue infection Cerebral toxoplasmosis, aspergillus pneumonia Polyoma virus cystitis Parvo virus B19, RSV pneumonia

3

16

SIRS

Yes

Yes

Enterohemorrhagic E. coli sepsis, pneumonia

5.4

3

17

—

No

Yes

67.2

3

18

—

No

Yes

Oral mycosis, adeno virus infection, EBV reactivation Polyoma virus, rota virus, methicillin-resistant staphylococcus aureus, E. coli sepsis

Dead; GVHD and infection Alive Dead; GVHD and infection (Lung GVHD and acute respiratory distress syndrome) Dead, Toxic epidermal necrolysis and GVHD Alive

33.3

Dead, GVHD and infection

9.6 100.4 29.5 10.2 113.2 164.5 117.0 115.2 51.6 91.3 39.6

Infectious complications after alemtuzumab therapy were frequent, intense monitoring for signs of infection and early treatment are obligatory. All CMVpositive patients showed CMV reactivation. a Increasing after start of alemtuzumab infusions. b Systemic inflammatory response syndrome.

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presented in a Kaplan–Meier survival curve in Figure 2. Median follow-up of the patients alive is 108.1 weeks, of the patients that died 21.1 weeks. All patients who succumbed to their disease showed persistent or recurrent acute or chronic GVHD. Three of the four patients aged over 60 years (range 64.0–68.9 years) survived for a long time (range 51.6–117.0 weeks), two of them are still alive. Notably, 13 patients received prophylactic ATG as part of conditioning therapy and 5 of them are alive, in contrast to only 1 patient (related donor) of the 5 patients without ATG prophylaxis. Seven patients developed chronic GVHD, five patients an extensive disease, two in a limited form. Four of them are alive. Two patients showed prolonged acute GVHD without progression to chronic GVHD. Only one patient relapsed with AML and is in continuous complete remission after second transplantation from another donor. One additional patient showed signs of residual multiple myeloma.

Discussion Standard therapy of severe acute GVHD is still limited to high-dose steroids and additional treatment modalities are urgently required for those patients not responding. Here, we present evidence that CD52 antibody alemtuzumab is able to significantly reduce the severity of steroid-refractory grade III and IV intestinal and/or liver acute GVHD, leading to sustained responses in some patients. The initially used higher doses of alemtuzumab, suggested in earlier reports9,10 to be effective for treatment of GVHD, led to remarkable responses. However, the high rate of infections led to death in the first three patients. Therefore, the dose of alemtuzumab was reduced, assuming that a lower dose would be still active due to the limited number of immune cells early after transplantation. Indeed, lower doses of alemtuzumab showed responses in almost all patients, including severe liver involvement. However, intense monitoring over a long period of time for virus reactivation and signs of infections is mandatory. The spectrum of opportunistic infections was remarkable and emphasises the depth of immunosuppression induced by alemtuzumab. The patients reported here were heavily pre-treated with various immunosuppressive drugs before initiation of alemtuzumab therapy. Treatment with low doses at an earlier time point, may even improve outcome with less toxicity as indicated for intestinal acute GVHD by Schnitzler et al.14 In addition, a subcutaneous application will be helpful to reduce infusion-related side effects. The colleagues from Houston have reported effectiveness of subcutaneous alemtuzumab in acute as well as chronic GVHD.11,12 In conclusion, in this difficult to treat patient population, low doses of alemtuzumab applied every 2 weeks may lead to relevant GVHD responses with a more favourable benefit–risk ratio. This schedule should be evaluated in a prospective randomized trial.

Conflict of interest The authors declare no conflict of interest.

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