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Keywords:

  • haemophagocytic lymphohistiocytosis;
  • bone marrow transplantation;
  • unrelated donors;
  • active disease;
  • veno-occlusive disease

Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Haemophagocytic lymphohistiocytosis (HLH) is an autosomal recessive disease with histiocytic and lymphocytic infiltrations in multiple organs. Cure seems possible only by allogeneic bone marrow transplantation (BMT), but matched sibling donors (MSD) are restricted and high mortality rates are associated with BMT from unrelated donors (URD). We report on 12 consecutive HLH patients with an improved outcome following URD transplants. Eight patients received BMT from URD, four from MSD. Five patients had signs of active HLH at the time of BMT. The conditioning regimen consisted of 20 mg/kg busulphan, 60 mg/kg VP-16 and 120 mg/kg cyclophosphamide and, in case of URD, 90 mg/kg antithymocyte globulin. The doses of busulphan and VP-16 were reduced during the programme to 16 mg/kg and 30 mg/kg, respectively. Using a fivefold graft-versus-host disease (GVHD) prophylaxis, GVHD was absent or mild in 10, and moderate or severe in two patients undergoing unrelated transplants. One patient with URD experienced graft failure and was retransplanted on day 37. Major toxicities were hepatic veno-occlusive disease in five, capillary leak syndrome in two, pneumonia in three, sepsis in one, severe mucositis in one and seizures in two patients. All patients are alive without HLH after a median follow-up of 24.5 months. One patient has chronic GVHD, another patient has severe retardation. Three patients show slight to moderate development delay. These results indicate that in HLH, BMT from matched unrelated donors should be performed. Incomplete resolution of disease activity need not impede a successful outcome.

Haemophagocytic lymphohistiocytosis (HLH) is a rare autosomal recessive disease, first described by Farquhar & Claireaux (1952), with a suggested defect of immunomodulation leading to uncontrolled release of cytokines and prostaglandins with histiocytic and lymphocytic infiltration in multiple organs. The clinical presentation is recurrent unexplained fever in an infant or young child with hepatosplenomegaly. Pancytopenia, hypertriglyceridaemia and low fibrinogen levels in such children strongly suggest the diagnosis, and infiltrations of lymphocytes and mature macrophages with prominent haemophagocytosis in bone marrow, spleen or lymph nodes confirm this disease ( Janka, 1983). More than half of the patients reveal cerebrospinal fluid (CSF) pleocytosis with mononuclear cells predominating and CSF protein elevation and a substantial number of those present with neurological abnormalities ( Janka, 1983; Hirst et al, 1994 ; Haddad et al, 1997 ). Hypercytokinaemia ( Imashuku & Hibi, 1991; Henter et al, 1991b ) might explain many of the clinical and laboratory findings such as fever, cytopenia, hypertriglyceridaemia and hypofibrinogenaemia ( Henter et al, 1991a ). Hyperprostaglandinaemia ( Brown et al, 1987 ) has been reported, but a particularly important and consistent finding is impaired natural killer (NK) cell activity ( Perez et al, 1984 ; Eife et al, 1989 ). The disease is rapidly fatal in untreated patients. Conventional chemotherapeutic approaches including steroids, vinca alkaloids and especially epipodophyllotoxins together with intrathecal methotrexate, although capable of achieving sustained remission, eventually led to relapse and death in almost all patients ( Ambruso et al, 1980 ; Fischer et al, 1985 ; Henter et  al, 1986 ; Ware et al, 1990 ).

Transient improvement has been shown by exchange transfusion ( Ladisch et al, 1982 ) and long-term remission was accomplished by predominantly T-cell targeted immunosuppression with methylprednisolone, antithymocyte globulins and intrathecal methotrexate followed by maintenance therapy with cyclosporine A ( Stéphan et al, 1991 ), but ultimately all patients have relapsed and died ( Jabado et al, 1997 ). At present, cure seems possible only by bone marrow transplantation (BMT), first reported by Fischer et al (1986 ). Treatment with allogeneic BMT has since been published with good results for matched sibling donors (MSD), but with high mortality for transplants from unrelated donors (URD) ( Bolme et al, 1995 ; Adachi et al, 1997 ; Baker et al, 1997 ) or from HLA non-identical relatives ( Jabado et al, 1997 ). BMT from these alternative donors offers the only chance of curative treatment for most patients, since MSD availability is restricted to 20% or less ( Bolme et al, 1995 ; Schipper et al, 1996 ) due to the young age and the risk of disease developing in the donor. We report here our single-centre experience of BMT in 12 consecutive patients with HLH, eight of whom received transplants from URDs.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Diagnosis of HLH

We applied the five diagnostic criteria used by the Histiocyte Society for the diagnosis of HLH ( Henter et al, 1991a ), i.e. (1) fever geqslant R: gt-or-equal, slanted7 d, with peaks geqslant R: gt-or-equal, slanted38.5°C; (2) splenomegaly geqslant R: gt-or-equal, slanted3 cm below the costal margin; (3) cytopenia affecting two or more of three lineages with haemoglobin <9.0 g/dl, platelets <100 × 109/l and neutrophils <1.0 × 109/l; (4) hypertriglyceridaemia geqslant R: gt-or-equal, slanted2.0 mmol/l or hypofibrinogenaemia leqslant R: less-than-or-eq, slant1.5 g/l, and (5) haemophagocytosis in bone marrow or spleen or lymph node without evidence of malignancy.

CNS disease

Central nervous system (CNS) disease was evaluated by clinical examination and CSF analysis for pleocytosis and protein content in all patients. If CSF analysis revealed abnormalities, neuroradiological studies were performed. CSF pleocytosis and elevated protein were classified as CNS disease.

Familial HLH

The diagnosis of familial HLH was made when there was an affected sibling or close relative, and diagnosis of presumptive familial HLH was made in the absence of positive family history, but presence of parental consanguinity.

Natural killer (NK) cell activity

NK cell activity was assayed as previously described ( Schneider et al, 1984 ). Briefly, non-adherent peripheral blood cells were tested against 51Cr-labelled K562 target cells. Radioactivity released into the supernatant was quantified after 4 and 16 h of incubation.

Patients

Between August 1992 and February 1998, 12 patients with HLH were transplanted at Hamburg University after informed consent had been given by the children's parents in all cases. All patients were receiving transplants for the first time.

Pretreatment

All patients, except for the first three (unique patient number (UPN) 116, 121 and 226) were treated according to the treatment protocol designed by the Hemophagocytic Lymphohistiocytosis Study Group of the Histiocyte Society (HLH-94). Briefly, it consists of an 8-week induction phase with dexamethasone and VP-16, including methotrexate (MTX) intrathecally in case of CNS disease, followed by maintenance therapy with weekly alternating pulses of VP-16 and dexamethasone plus daily CSA.

Disease status at BMT

Active HLH at the time of BMT was defined as the presence of all three parameters of the following within 2 weeks prior to BMT: unexplained fever geqslant R: gt-or-equal, slanted38.5°C for at least 2 d, splenomegaly geqslant R: gt-or-equal, slanted4 cm and one of the following: cytopenia affecting at least one lineage (haemoglobin leqslant R: less-than-or-eq, slant9.0 g/dl, neutrophils leqslant R: less-than-or-eq, slant1.0 × 109/l, thrombocytes leqslant R: less-than-or-eq, slant100 × 109/l) or hypofibrinogenaemia leqslant R: less-than-or-eq, slant1.5 g/l or CSF pleocytosis with protein elevation. Hypertriglyceridaemia was not included, because morning blood samples in small infants are often not fasting blood samples.

Conditioning regimen

In the first four patients the conditioning regimen consisted of oral busulphan, 20 mg/kg total dose, given at a dose of 5 mg/kg/d on days −8, −7, −6 and −5; VP-16, 60 mg/kg total dose, given on day −4 as a 6 h i.v. infusion; and cyclosphosphamide, 120 mg/kg total dose, given at a dose of 60 mg/kg/d on days −3 and −2 as a 1 h i.v. infusion. Dose reductions were performed in the following eight patients: In patients UPN 305, 338, 342, 343, 373, 412 and 467 busulphan was given at a total dose of 16 mg/kg, and in patient UPN 383 who showed elevated busulphan serum levels, only 14 mg/kg was given. VP-16 dosage was reduced twice: Three patients (UPN 305, 338 and 342) received 45 mg/kg, and five patients (UPN 343, 373, 383, 412 and 467) received 30 mg/kg total dose. Phenytoin was administered before and parallel to busulphan as anticonvulsive prophylaxis, dexamethasone was given on days −4 and −3 for prevention of VP-16 induced anaphylactic-like symptoms and sodium-2-mercaptoethane sulphonate was given on days −3 and −2 for prophylaxis of haemorrhagic cystitis.

Donors

Four patients received bone marrow from MSD, one of whom revealed reduced NK-cell activity on three occasions (5-year-old brother of UPN 338). Eight patients received marrow from URD, two of whom were mismatched at one HLA-B locus. The donor marrow was concentrated in vitro by a Ficoll-Hypaque gradient. T cells were not depleted. The bone marrow was infused on day 0 approximately 26 h after the last dose of cyclophosphamide.

Graft-versus-host disease (GVHD) prophylaxis

Post-transplant immunosuppression included CSA and MTX ( Storb et al, 1986 ). CSA was administered at a dose of 3 mg/kg by continuous infusion from day −1 until oral nutrition was re-established. Subsequently, CSA was given orally at a dose of 12.5 mg/kg until day 50. Afterwards, CSA reduction was scheduled as follows: until day 85, 10 mg/kg, until day 100, 8 mg/kg and thereafter until day 180, 4 mg/kg. Patients received MTX at a dose of 15 mg/m2 i.v. on day 1, and at 10 mg/m2 on days 3, 6 and 11. Day 11 MTX was not administered to the last six patients in order to further reduce mucosal and hepatic toxicity. In URD transplants we used a fivefold GVHD-prevention with CSA, MTX, rabbit antithymocyte globulin (ATG), IgM-enriched immunoglobulins and metronidazole. ATG (Fresenius, Bad Homburg, Germany) was given at a total dose of 90 mg/kg divided into doses of 30 mg/kg/d as 12 h i.v. infusion on days −3, −2 and −1. 30 min prior to each administration of ATG, 2 mg/kg methylprednisolone and 1 mg of clemastinhydrogenfumarate was administered intravenously. All patients with URD, except the first two (UPN 121 and 226) received additional IgM-rich immunoglobulin infusions (Pentaglobin®, 350 mg/kg/4 h i.v. on days 1, 3, 7, 14, 21 and 28) and metronidazole (22 mg/kg/d p.o. or i.v. from day −8 until discharge).

Staging for GVHD

Seattle criteria were used for the staging and grading of acute GVHD (aGVHD) ( Glucksberg et al, 1974 ) and chronic GVHD (cGVHD) ( Shulman et al, 1980 ).

Regimen-related toxicity

For the diagnosis of hepatic veno-occlusive disease (HVOD), Seattle criteria ( McDonald et al, 1993 ) were modified because the patients were of very low weight and six showed hepatomegaly prior to conditioning therapy. HVOD was clinically defined as the presence of all three of the following: bilirubin geqslant R: gt-or-equal, slanted34.2 μmol/l before day 20, weight gain geqslant R: gt-or-equal, slanted5% over baseline and increase in liver size geqslant R: gt-or-equal, slanted3 cm over baseline under the costal margin. Mucositis was graded according to Bearman et al (1988 ) and the number of days that morphine was needed was taken from the clinical records. Capillary leak syndrome (CLS) was defined as the presence of all three of the following: generalized oedema, weight gain geqslant R: gt-or-equal, slanted10% over baseline and pleural effusions or ascites.

Engraftment and analysis of mixed chimaerism

The day of engraftment was defined as the first day with an absolute neutrophil count (ANC) >0.5 × 109/l. Haemopoietic chimaerism was documented by the determination of donor-type DNA by PCR amplification of six different polymorphic loci as previously described ( Stockschläder et al, 1995 ).

Supportive care

Patients were kept in reverse isolation from day −1 and received granulocyte colony-stimulating factor (G-CSF) at a daily dose of 10 μg/kg as continuous infusion from day 1 until engraftment. Prophylactic ciprofloxacillin and fluconazole were given daily from day −9 and daily acyclovir prophylaxis was administered from day 1. Pneumocystis carinii prophylaxis with cotrimoxazole was given on 3 consecutive days a week and immunoglobulins were substituted until day 120.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Patient characteristics prior to BMT including the diagnostic criteria for HLH described above are listed in 1 Table I. The diagnostic criteria for HLH, as suggested by the Histiocyte Society, were completely fulfilled by only 7/12 patients. Haemophagocytosis was missing in four patients, cytopenia affecting two lineages was missing in one, and hypertriglyceridaemia and hypofibrinogenaemia were missing in another patient. In these patients the diagnosis was made on the basis of a positive family history, the presence of CNS disease, and the absent NK-cell activity (see 1 Table I). Five patients met the diagnosis of familial HLH, another two patients were diagnosed with presumptive familial HLH. The median age at diagnosis was 7.5 months (range 2–27). All patients had recurrent unexplained fever, splenomegaly and hepatomegaly as well as absent or reduced NK cell activity.

Table 1. Table I. Clinical and laboratory findings in patients at diagnosis. Abbreviations: Dx, diagnosis; FH, family history; COS, cosanguinity; TG, triglycerides; b, bone marrow; s, spleen; p, pleural effusion; l, lymph node; nd, not done.Thumbnail image of

Six patients showed CSF pleocytosis and elevated CSF protein at the time of diagnosis. Clinical neurological signs during the time from diagnosis to BMT were cranial nerve palsies (UPN 383 and 412), generalized seizures (UPN 226, 343 and 383), ataxia (UPN 290 and 412), temporary paresis of the right arm (UPN 383), hypotonia (UPN 121, 383 and 412) and opisthotonus (UPN 290 and 343). All six patients with CNS disease received neuroimaging studies, which revealed atrophy (UPN 121, 343 and 383), hyperintense lesions on T2 weighted MRI images (UPN 290 and 412) and areas of demyelination (UPN 121).

The median age at BMT was 18 months (range 7–45) and median time from diagnosis to BMT was 9.5 months (range 4–18). Five patients had splenomegaly geqslant R: gt-or-equal, slanted4 cm, unexplained fever and at least one more sign of HLH (cytopenia, hypofibrinogenaemia or CNS disease) at the time of BMT, considered active disease ( Table II). Patients received a median nucleated cell dosage of 4.1 × 108 cells/kg bodyweight (range 1.3–13.2, Table II). One patient received CD 34+ selected cells ( Table II). Patients engrafted after a median time of 16 d (range 13–43). One patient, who did not show engraftment prior to day 37, received a second transplant on that day and achieved an ANC >0.5 × 109/l on day 43. 10 patients showed no or only mild aGVHD, one patient had grade 2, another grade 3 aGVHD. Five patients were clinically diagnosed as having HVOD, but maximum total bilirubin was only moderately elevated (range 38–108 μmol/l) and hepatic dysfunction resolved completely. Except for patient UPN 116, patients diagnosed as having HVOD received 100 μg prostaglandin E1/d as continuous infusion (Alprostadil, Prostavasin®, Schwarz Pharma, Germany). 11 patients suffered from grade 2, one (UPN 383) from grade 3 mucositis and the median time of morphine needed was 10.5 d (range 7–15). Patient UPN 383 had to be intubated on day 11 due to airway obstruction from mucositis. This patient additionally suffered from HVOD and developed sepsis and CLS with pulmonary oedema and extensive bilateral pleural effusions requiring α- and β-adrenergic support and 24 d of mechanical ventilation.

Table 2. Table II. BMT characteristics and clinical toxicity. Abbreviations: rec., recipient; don., donor; MSD, matched sibling donor; URD, unrelated donor; ANC, absolute neutrophil count; HVOD, hepatic veno-occlusive disease; CLS, capillary leak syndrome.Thumbnail image of

Three patients experienced pneumonia and needed temporary oxygen, two of them required mechanical ventilation for 14 d (UPN 290) and 5  (UPN 343), respectively. The latter patient also had active CNS disease at the time of BMT and continued to have seizures throughout the transplantation period and additionally developed CLS. One patient without CNS disease prior to BMT showed a tonic seizure during the conditioning therapy.

After a median follow-up of 24.5 months (range 8–70) all patients are alive without recurrence of HLH ( 3 Table III). Stable donor haemopoiesis with >95% of donor cells detected by chimaerism analysis has been achieved in 9/11 patients tested. Two patients showed mixed chimaerism at 52 months and 15 months after BMT respectively, both without signs of recurrent disease. NK-cell activity was reconstituted to high levels in three patients and remained weak in seven patients when examined >6 months after BMT ( 3 Table III). Only one patient developed cGVHD, which was extensive and of intestinal localization leading to malabsorption and failure to thrive. Slight psychomotoric retardation was seen in two, moderate in one, and severe in patient UPN 343, who had active CNS disease during BMT.

Table 3. Table III. Follow-up. Abbreviations: cGVHD, chronic GVHD; NK-cell, natural killer cell; nd, not done.* NK-cell activity was tested against K562 target cells at an effector:target ratio of >20:1; ++: percent lysis was >20% and >50 lytic units; +: percent lysis was between 5% and 20% and >5 lytic units; (+): percent lysis was <5% and <2 lytic units; −: no lysis detectable.† Determination of haemopoietic chimaerism in patient 116 was performed by Hinf I digestion and MS31 hybridization.Thumbnail image of

DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

Our experience of allogeneic BMT in 12 patients with HLH is very encouraging, particularly with respect to unrelated transplants in this disease, since previous studies have reported a high rate of mortality using unrelated donors. The largest series to date with unrelated BMT for HLH has been published by Baker et al (1997 ), who reported an overall survival of 45% at 3 years in 20 patients, 16 with URD and four with MSD. Comparison of the reported data with those of our study is only possible to a limited extent, given the small patient numbers. However, Baker et al (1997 ) encountered a high rate of deaths in patients with evidence of active disease at time of BMT and therefore questioned whether these patients should be offered allogeneic transplantation. Our data suggest that BMT can cure even those patients with three or more signs of disease activity at the time of transplant. However, since definition of active disease is difficult, it seems possible that some of our patients classified as having active disease at BMT had instead stable or residual disease with some remaining abnormalities plus recurrent infection.

The use of G-CSF in our patients resulted in earlier engraftment and the conditioning regimen used may have been less toxic than the regimen used by Baker et al (1997 ), due to the smaller dose of cyclophosphamide. Our programme was started using 20 mg/kg busulphan and 60 mg/kg VP-16, but clinical toxicity required the reduction of both the dose of busulphan and VP-16, which could be done without experiencing graft failure. Sustained remissions of 3–8 years in four patients showing mixed chimaerism following matched related BMT have been reported ( Landman-Parker et al, 1993 ). Two of our patients also showed mixed chimaerism post-BMT without signs of recurrent disease, supporting the hypothesis that donor cells are perhaps capable of controlling T lymphocyte and macrophage activation in HLH ( Landman-Parker et al, 1993 ). These patients indicate that it might not be necessary to completely abrogate host haemopoiesis, which would also favour the use of less toxic conditioning regimens.

Despite the dose reductions of the conditioning regimen and the use of G-CSF, a relatively high rate of regimen-related toxicity and infections was encountered, and three patients had to be supported by mechanical ventilation. The relatively high rate of HVOD in 5/12 patients may be related to pretransplant liver disease from HLH and conditioning with busulphan ( Méresse et al, 1992 ).

Using a fivefold regimen for GVHD prophylaxis in URD transplants, we experienced a very low rate of acute and chronic GVHD. Apart from standard immunomodulation with ATG, CSA and MTX, we included metronidazole, since ineffective anaerobic growth suppression has been identified as a risk factor for aGVHD ( Beelen et al, 1992 ), and IgM-rich immunoglobulins, possibly capable of reducing endotoxinaemia ( Poynton et al, 1992 ) and thereby activation of graft-derived T lymphocytes. This regimen awaits further studies to test its efficacy.

In a recent report on 34 patients with HLH only 7/29 patients with CNS disease were long-term survivors, all of whom had been transplanted with marrow from a related donor soon after remission and all of whom have had only ‘meningitis’, defined as no neurological symptoms except meningism and abnormal CSF ( Haddad et al, 1997 ). Among our six patients with CNS disease, five patients also showed clinical neurological signs other than hypotonia and opisthotonus, and three revealed CNS lesions other than atrophy, which may also result from treatment with steroids. BMT was able to stabilize disease progression in all but one (UPN 343). In addition, reconstitution of NK-cell activity was found in the majority of patients, though in an as yet unexplained variable range of activity.

The use of matched siblings is limited, since HLH may develop in the potential sibling donor and possibly lead to recurrence in the recipient following BMT. Helpful for family donor selection in this respect is the finding that age at onset of disease-related symptoms is usually comparable within a family, but noteworthy exceptions exist with development of disease in a second affected sibling, who was 1–3 years older than the first ( Aricòet al, 1996 ). At present, BMT from URD or from HLA-nonidentical related donors offers the only chance of cure in the vast majority of patients with HLH. Pretreatment according to the Histiocyte Society protocol in most of our patients helped to transiently control disease progression while waiting for donor selection and recruitment. Allogeneic BMT early in the course of the disease will hopefully increase the number of cured patients without neurologic sequelae.

Acknowledgements

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References

The authors thank members of the nursing team and medical staff from both the Bone Marrow Transplant Unit and the Children's Hospital for their excellent patient care. We also thank Dr Paul Moeyes, Amsterdam, for his language advice, and C. & J. Henke, Institut für Blutgruppenforschung, Cologne, for performing Hinf I digestion and MS31 hybridization.

References

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. Acknowledgements
  7. References
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