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- Patients and methods
Competitive inhibition of interleukin 2-dependent lymphocytes by daclizumab demonstrates some beneficial effects in the treatment of graft-versus-host disease (GVHD). Sixteen patients with steroid refractory GVHD received daclizumab (1 mg/kg BW) on d 1, 2 (−5), 7, 14 and 21. Twelve patients suffered from grade III–IV acute GVHD and four patients from extensive chronic GVHD. Responses were observed in nine patients (six acute, three chronic GVHD). Fourteen out of 16 patients acquired infections during daclizumab treatment and three deaths were infection related. Daclizumab demonstrates limited activity and is associated with an increased incidence of infectious complications.
Graft-versus-host disease (GVHD) is a major concern in haematopoietic stem cell transplantation, and the major risk factor of transplant-associated morbidity and mortality. The incidence reported for acute GVHD (aGVHD) grade II–IV after transplantation from human leucocyte antigen (HLA)-matched marrow unrelated donor (MUD) is 78% and the incidence of grade III–IV is 36%, in spite of immunosuppressive drugs such as cyclosporine A (CsA), prednisolone and methotrexate (MTX) used for prevention of GVHD (Storb et al, 1990; Nademanee et al, 1995). While steroid dose escalation is the cornerstone of treatment strategies for severe GVHD, the prognosis becomes worse if GVHD does not respond to dosages ≥ 2 mg/kg methylprednisolone. An innovative strategy in GVHD therapy seems to be the administration of a humanized anti-interleukin 2 receptor alpha chain antibody (Anasetti et al, 1994; Blaise et al, 1995). Przepiorka et al (2000) recently reported response rates of 29% and 47%, respectively, using two different time schedules of antibody administration.
Patients and methods
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- Patients and methods
To date, 16 patients have been enrolled on this on-going prospective study. All patients received a GVHD prophylaxis consisting of CsA (according plasma levels) and prednisolone [0·5 mg/kg body weight (BW) d 7–13, 1 mg/kg BW d 14–24, afterwards tapered].
Chronic GVHD (cGVHD) was first treated with CsA, prednisolone dose escalation and the addition of mycophenolate mofetil (2 × 1 g/d). Patients not responding received methylprednisolone.
Patients were eligible if they suffered from severe aGVHD or cGVHD after allogeneic bone marrow or peripheral blood stem cell transplantation unresponsive to methylprednisolone ≥2 mg/kg BW given for ≥ 3 d.
Patients (1–5, 15, 16) received daclizumab in a dosage of 1 mg/kg BW on d 1–5 and once every week thereafter until d 28. Patients 6–14 received 1 mg/kg BW on d 1 and 2, followed by one application per week thereafter for a period of 28 d. Other immunosuppressive drugs remained unchanged during the first week of treatment; afterwards, steroids were tapered. Response was monitored clinically every day, and patients not responding to daclizumab on d 28 of treatment were considered non-responders. Response to treatment was defined as complete response (CR) if stage 0 in all involved organs was achieved and as partial response (PR) if a reduction by at least one stage in at least one organ system was achieved, without worsening in other organ systems (Przepiorka et al, 2000). Diagnosis as well as response in all patients with gut-GVHD was confirmed by colonoscopy and histological techniques.
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Patients' characteristics are depicted in Table I. All patients with the exception of two received peripheral blood stem cells from HLA-identical related (n = 6) or unrelated (n = 10) donors. Eleven patients received a fully matched graft whereas five patients were mismatched (Table I). The conditioning regimen consisted of busulphan (16 mg/kg BW) and cyclophosphamide (120 mg/kg BW) in 11 patients, fractionated total body irradiation (fTBI; 13·5 Gy) and cyclophosphamide (120 mg/kg BW) in three patients, busulphan, cyclophosphamide and thiotepa (5 mg/kg BW) in one patient, and of total body irradiation (4 Gy) and fludarabine (30 mg/m2 on 5 consecutive days) in one patient.
Table I. Patients' characteristics.
| No.|| Gender|| Age|| Diagnosis||Disease stage at transplant|| Donor||HLA match Grad|| Conditioning||Infectious complication|| Outcome|
|1||M||55||CML||1 cP||Unrelated||Identical||Bu Cy||HSV, CMV, sepsis||Alive, +459|
|2||F||45||CML||1 CP||Related||Identical||Bu Cy||CMV, sepsis||Alive, +458|
|3||M||32||Phi+ALL||1 CR||Unrelated||Identical||TBI Cy||CMV, toxoplasmosis||Death, +63|
|4||F||56||AML||2 CR||Related||Identical||Bu Cy||Sepsis||Death*, +200|
|5||F||34||CML||1 cP||Unrelated||Identical||Bu Cy||CMV, sepsis||Death, +116|
|6||M||54||CML||1 cP||Unrelated||Cw, DRB1||Bu Cy||Sepsis||Death, +79|
|7||M||33||AML||2 CR||Unrelated||Identical||Bu Cy TT||CMV, sepsis||Death, +74|
|8||M||52||CML||2 cP||Unrelated||DRB1, DRB3, DQ||Bu Cy||CMV, sepsis||Death, +91|
|9||M||44||MDS||SD||Related||Identical†||Bu Cy||Sepsis, ARDS||Death, +190|
|10||F||28||AML||2 CR||Unrelated||Identical||Bu Cy||Sepsis||Death, +59|
|11||M||47||ALL||2 CR||Related||B, C||TBI Cy||CMV, sepsis||Death, +37|
|12||M||52||AML||6. CR||Unrelated||DRB1, DQ||TBI Flu‡||None||Death, +6|
|13||F||61||AML||2 CR||Related||Identical||Bu Cy||Sepsis||Death, +400*|
|14||F||48||MDS||1 CR||Related||Identical||Bu Cy||None||Alive, +634|
|15||M||21||CML||1 cP||Unrelated||Identical†||Bu Cy||CMV, sepsis, aspergillosis||Death, +300|
|16||M||23||ALL||Second relapse||Unrelated||B||TBI Cy||CMV||Alive, +391|
Underlying disease was a chronic myeloid leukaemia (n = 6; all in first or second chronic phase), acute myeloid leukaemia (n = 5; all in CR), acute lymphoblastic leukaemia (n = 3; two in CR, one in relapse), and myelodysplastic syndrome in two patients (one in CR, one in stable disease). Patients developed aGVHD symptoms (patients 1–12) 19–50 d post transplantation (median 30 d), and cGVHD symptoms (patients 13–16) were observed 100–220 d (median 169 d) post transplantation. Twelve out of 16 patients were at risk of developing cytomegalovirus (CMV) reactivation, and nine of these demonstrated CMV reactivation during daclizumab as determined by CMV polymerase chain reaction (PCR) or a positive pp65. Four of these patients suffered from CMV colitis. Daclizumab treatment was initiated after a median period of 5 d (range 3–13 d) after the first signs of aGVHD had occurred. In patients with cGVHD, daclizumab was initiated 23 d (median) after the first signs of cGVHD had occurred (range 14–45 d). Three of four patients with cGVHD responded to daclizumab (one CR, two PR) whereas the patient with progressive acute to chronic GVHD did not respond. Out of the 12 patients with aGVHD, one demonstrated a CR, seven a PR and four were non-responsive (Table II). Five patients with aGVHD died (d 5–27) after treatment initiation. Four of them as a result of refractory GVHD in combination with CMV infection or sepsis (patients 6, 10 and 11), and one as a result of cerebral toxoplasmosis (patient 3). The other five patients of the aGVHD group died as a result of leukaemia relapse (patient 4) or unresponsive GVHD (patients 5, 7, 8, 9). Two of the aGVHD patients are still alive 458 and 459 d post daclizumab treatment. Of the cGVHD group two patients died as a result of GVHD and two patients are still alive on d 391 and 634 respectively.
Table II. Response to treatment according to organs involved.
| ||Overall GVHD||Skin GVHD||Gut GVHD||Liver GVHD|
|No.||Before||On d 28*||Before||On d 28*||Before||On d 28*||Before||On d 28*|
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In comparison to the data published by Przepiorka et al (2000), we investigated patients with aGVHD as well as cGVHD. When comparing patients with aGVHD, we included only patients with aGVHD grade III–IV unresponsive to high-dose methylprednisolone. Nine of our 12 patients with aGVHD suffered from severe gut GVHD (confirmed by histological investigation) and, in four patients, only skin GVHD was the reason for daclizumab treatment. Out of the patients with gut or liver aGVHD, only two patients responded to daclizumab. These observations are similar to the data published by Przepiorka et al (2000), which reported a CR in 37% of patients with gut GVHD, and 17% of patients with liver GVHD. Furthermore, in this study only 16 out of 43 patients suffered from severe GVHD grade III–IV. Therefore, the efficacy of daclizumab in the treatment of severe gut as well as severe liver GVHD seems to be limited.
In addition, it is important to mention the high incidence of infectious complications (11 out of 12 patients with aGVHD and three out of four with cGVHD). All of the 11 patients with aGVHD demonstrated septic complications necessitating vasoactive drugs, and nine patients acquired CMV reactivation with clear signs of CMV disease despite pre-emptive therapy. Death was clearly related to infection in three patients with aGVHD (25%). These data are consistent with the results published by Hengster et al (1999), reporting a significantly increased risk of CMV infections in renal allograft recipients after daclizumab (Hengster et al, 1999). Also Anasetti et al (1994) reported on a high rate of infectious complications after anti-TAC application in BMT patients. Sixteen of their 20 patients died as a result of infectious complication or organ failure, possibly infection related [three cases of acute respiratory distress syndrome (ARDS)]. In this study, the antibody was administered in a dose-escalating manner (0·5–1·5 mg/kg BW) once a week, and overall improvement of aGVHD was observed in eight patients. One might argue that infection is the most common cause of death in patients with severe acute and chronic GVHD and, therefore, not related to daclizumab. On the other hand, the high incidence of infectious complications is impressive and suggests at least an additional effect of severe GVHD and daclizumab therapy on the incidence of severe infectious complications (Weisdorf et al, 1990; Anasetti et al, 1994 Hengster et al, 1999). In comparison with high-dose steroids, the incidence of CMV infection seemed to be slightly higher during daclizumab, whereas the transplant related mortality seemed to be similar in both regimens (Van Lint et al, 1998).
In comparison with antithymocyte globulin (ATG) regimens, daclizumab as part of a quadruple induction therapy after orthotopic liver transplantation seems to be safe and effective and associated with fewer steroid-sensitive rejection episodes as well as fewer side-effects (Langrehr et al, 1997). Comparing infusion-associated toxicities after ATG, consisting of chills, pain or nausea, we did not observe similar side-effects after daclizumab infusion. Furthermore, it has been demonstrated that ATG is associated with a deep and long-lasting lymphocyte depletion, even more prolonged than that found after OKT 3 treatment in steroid-resistant rejection of renal allografts (Mariat et al, 1998). But this is not associated with a higher efficacy in the treatment of rejection. Therefore, the risk of complications due to protracted infection, and possibly even secondary malignancies in survivors, is increased after ATG application for the treatment of GVHD (Witherspoon et al, 1994; Mattson et al, 1997).
The application schedules reported to date raise the question of which one is appropriate for such an antibody. Analysing pharmacological data, the terminal elimination half-life is approximately 90 h (Anasetti et al, 1994). Therefore, our schedule, which gives daclizumab on d 1–5 followed by one application per week thereafter, seems to be inappropriate. On the other hand, both long-term survivors with aGVHD received this schedule. Our second schedule is similar to the schedule used by Przepiorka et al (2000), combining a dose-intensive regimen during the first week followed by a weekly maintenance treatment. Using our second regimen, improvement was observed in one patient with aGVHD only. Therefore, pharmacological and dose-finding studies are necessary before starting randomized trials.
Which patients might profit from daclizumab treatment? Comparing our data with the results published by Przepiorka et al (2000) on daclizumab in the treatment of aGVHD suggests that patients with severe-grade III–IV gut, as well as liver, aGVHD might not profit from daclizumab, whereas patients with skin aGVHD and patients with mild grade I–II gut or liver aGVHD seem to be the appropriate group for further investigations. With regard to cGVHD, these data should be interpreted very carefully because, to date, we have only investigated four patients. Our first impression is that daclizumab seems to be effective in cGVHD but further studies are needed to define its role in this setting.
Furthermore, it is important to note that in one of our patients relapse of leukaemia occurred after daclizumab treatment. As demonstrated by Blaise et al (1995), inhibition of interleukin 2 (IL-2) might be associated with an increase in leukaemia recurrence as a result of inhibition of the graft-versus-leukaemia effect.
In conclusion, using our schedule, daclizumab seemed to be of limited benefit in patients with grade III–IV gut or liver aGVHD and was associated with a high risk of infectious complications. Efficacy of daclizumab may be higher in patients with cGVHD and this may be the appropriate group of patients for a controlled study.