Pediatr Transplantation 2014: 18: E124–E129

© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd

Pediatric Transplantation DOI: 10.1111/petr.12244

Haploidentical parental hematopoietic stem cell transplantation in pediatric refractory Langerhans cell histiocytosis Jun Y, Quan QM, Bin W, Hua ZG, Li Z, Rui Z, Guang JC, Hao MH, Long DY, Jing Y, Xuan Z. Haploidentical parental hematopoietic stem cell transplantation in pediatric refractory Langerhans cell histiocytosis. Abstract: Children with MS-LCH that fail to respond to conventional chemotherapy have poor outcomes. HSCT represents a potential salvage approach. It has been applied in over 50 cases in recent years. HSCT can achieve greater disease control than chemotherapy, but it carries a high risk of transplant-related mortality; thus, the haploidentical parental HSCT is used infrequently in pediatric refractory LCH. We report the first successful haploidentical parental HSCT, with no T-cell depletion, in two girls, aged 26 months and five months, with refractory MS-LCH. The mothers were donors with 5/6 and 4/6 HLA matches, respectively. The conditioning regimen included busulfan + cyclophosphamide + etoposide + antithymocyteglobulin  fludarabine; the GVHD prophylaxis was based on cyclosporine + methotrexate  mycophenolate-mofetil  zenapax. In both cases, the stem cells were sourced from peripheral blood and BM, which included CD34+ cells (13.17 9 106/kg and 40.23 9 106/kg, respectively). These patients survived and showed no signs of disease activity in 54- and 44-month post-HSCT follow-ups. Our results indicated that, for patients that fail chemotherapy delivered early in the disease, but do not show organ dysfunction progression, it may be possible to achieve successful haploidentical parental HSCT with a strong myeloablative regimen.

LCH is a rare disorder, which manifests in a wide variety of clinical presentations and courses, ranging from a solitary bone or skin lesion, called a “single-system disease”, to a disseminated, multiple-organ involvement, called a “multisystem disease” (1–3). Although advancements in conventional chemotherapy have resulted in cures for most patients, chemotherapy has continued to fail in patients with MS-LCH. This is due to the involvement of “high-risk organs,” like the hematopoietic system, liver, Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BM, bone marrow; DI, diabetes insipidus; GVHD, graft-versus-host disease; HLA, human leukocyte antigen; HSCT, hematopoietic stem cell transplantation; LCH, Langerhans cell histiocytosis; MSLCH, multisystem LCH; MUD, matched unrelated donor; PBSC, peripheral blood stem cell; PTA, prothrombin activity; RIC, reduced-intensity conditioning regimen; SCT, stem cell transplantation; TBIL, total bilirubin.


Yang Jun, Qin Mao Quan, Wang Bin, Zhu Guang Hua, Zhang Li, Zhang Rui, Jia Chen Guang, Ma Hong Hao, Duan Yan Long, Yang Jing and Zhou Xuan Department of Hematology and Oncology, National Key Discipline of Pediatrics (Capital Medical University), Ministry of Education, Beijing Children’s Hospital, Capital Medical University, Beijing, China

Key words: refractory – Langerhans cell histiocytosis – haploidentical – stem cell transplantation – pediatric Zhou Xuan, MD, Department of Hematology and Oncology, Beijing Children’s Hospital, Capital Medical University, Beijing, China Tel.: +86 010 59617614 Fax: +86 010 59615864 E-mail: [email protected] Accepted for publication 29 January 2014

spleen, or lungs. Patients with MS-LCH have a poor prognosis, with a survival rate of only 10– 59% (4–7). In 1987, HSCT was introduced as a salvage treatment for refractory or recurrent LCH in young adults (8). Over 50 pediatric cases have received allogeneic HSCTs, and over 35 cases identified from the literature survived (1–3, 8–23). However, HSCT from a haploidentical parental donor has been performed infrequently in pediatric patients, due to the nearly 100% failure rate (3, 13, 15, 23). In this article, we describe two pediatric patients with MS-LCH that received haploidentical parental HSCTs, and this treatment cured the original diseases. Patients and methods Case 1 A two-yr-old girl was diagnosed with LCH, based on standard criteria, when she was 15 months old. She received chemotherapy at 23 months old. The disease had involved

Haploidentical HSCT in refractory LCH the skin, bone, gastrointestinal tract, and lymph nodes. She also had developed DI with pituitary gland involvement; she had been prescribed desmopressin for urine volume control. Before transplantation, the desmopressin dosage was increased from 5.5 to 8.3 lg/kg/day. The disease had involved several high-risk organs, including the lung, liver, spleen, and hematopoietic system. She was treated with 12 wk of chemotherapy, according to the treatment protocol described in the Third International Study for LCH-III for Group I. ( NCT00488605). During the six wk of tapering the prednisone dose, the patient developed a rash relapse (confirmed by skin biopsy), but she responded to chemotherapy with a regain of organ function. Nevertheless, the rash relapsed many times at regular intervals during the chemotherapy. Thus, the disease appeared to be refractory to conventional treatment. In 2009, at 26 months old, she received a haploidentical parental HSCT. The conditioning regimen included busulfan (3.5 mg/kg/day, po, days 9 to 6), cyclophosphamide (50 mg/kg/day, days 5 to 2), etoposide (500 mg/m2, days 4 to 2), and rabbit -anti-thymocyte-globulin (2.5– 3.5 mg/kg/day, days 6 to 2); the GVHD prophylaxis was based on cyclosporine (2.5 mg/kg from day 1), methotrexate (15 mg/m2, IV, day +1 and 10 mg/m2 days +3, +5, +8, +11), and zenapa (1 mg/kg/day, days 0, +4, +8, +15, +22). On day 0, she received an infusion of PBSCs and BM (plasma-depleted, but no T-cell depletion) from the mother, who displayed 5/6 matches (the A loci was mismatched) in HLA. The infusion contained 23.86 9 108/kg nucleated cells and 13.17 9 106/kg CD34+ cells. For GVHD prophylaxis, on day 0, donor mesenchymal cells (1.18 9 106/kg) were administered. Engraftment was achieved on day +11. Full donor chimerism was detected on day +14. The rash appeared on day +11, and diarrhea appeared on day +25, but it was not initially severe. Unfortunately, the patient developed septic shock on day +26. Although the infection was controlled with meropenem, the diarrhea progressed. Stage 4 GVHD developed in the gut (1500–3000 mL/day of diarrhea and bloody stool), and it was confirmed with a rectal biopsy. The diarrhea improved after another two doses of zenapax (2 mg/kg/wk), methylprednisone (2 mg/kg/day), and tacrolimus (0.1 mg/kg/day). The tacrolimus did not always achieve the target level of 5–15 ng/mL; therefore, the dose was increased to 0.5 mg/kg/day. Tacrolimus was combined with variconazol, but the level of tacrolimus remained below 4 ng/mL. Finally, we had to discontinue the tacroli-

Fig. 1. MRI(TIWI) of pituitary gland before and post-SCT. (a) T1-weighted images before SCT showing loss of normal posterior pituitary bright signal. (b) T1-weighted images at 17 months post-transplant, showing restoration of posterior pituitary bright signal.


mus due to psychiatric symptoms, worsening liver enzyme values, and bilirubin with coagulation on day +39. Acute liver failure was confirmed on day +41 (AST 1005.0 IU/L, ALT 726.0 IU/L, PTA 19.3%, and TBIL rose from 53 to 90 lM in two days). GVHD was classified as Grade IV (gastrointestinal [4], skin [2], liver [2]) with an extreme reduction in clinical performance. The severe condition of the patient precluded a liver biopsy. We suspected that liver failure had been caused by a combination of drug toxicity and GVHD; the drug toxicity may have been the main cause, because we used high-dose FK506 throughout. We discontinued the drugs known to be highly hepatotoxic (like voriconazole). Then, we administered the anti-fungal, micafungin, methylprednisone, another three doses of zenapax (2 mg/kg/wk), cyclosporine, and another three infusions of donor mesenchymal cells (1.27, 1.5, and 2 9 106/kg on days +33, +39, and +52, respectively) for treating acute GVHD. We also administered plasma with the prothrombin complex for treating dysfunctional coagulation. At the same time, to repair liver function, we administered ademetionine, hepatocyte growth-promoting factors, and glutathione. The liver enzyme values, bilirubin, and coagulation function finally recovered to acceptable levels on day +108. Cyclosporine was tapered at 17 months and stopped at 25 months post-transplantation, with no symptoms of GVHD. The patient received multiple follow-up examinations at six, 17, and 39 months post-transplantation. The examinations included imaging and laboratory assessments. At all follow-ups, the patient displayed good nutritional status. The patient achieved full donor chimerism and her blood type was the same as that of the donor on follow-up. The serum IgG, IgM, IgA, CD4, CD8, and NK returned to normal levels. No new lesions appeared in CT scans. Images of bones showed that most bones had undergone repair. The liver, spleen, and lung appeared normal on CT scans and ultrasound images, and the functions of these high-risk organs had returned to normal. Interestingly, the patient displayed controlled DI after transplantation; she discontinued the desmopressin after recovering from diarrhea, and she never required it again. The urine volume had decreased to below 3000 mL/m2, and urine osmolarity increased from 100 to 110 mosm/L before transplantation to 420– 450 mosm/L at the subsequent post-transplantation follow-up. The “bright spot” detected on the MRI in the neurohypophysis partially reappeared and cerebellar atrophy improved (Fig. 1). At the 54-month post-transplantation follow-up, there were no signs of disease activity.



Jun et al. Table 1. Literature review: outcome of children with refractory LCH who underwent allogeneic HSCTs

Reference Hatakeyama et al. (1) Conter (2) Kudo et al. (pt 13) (3)

Median age at SCT (months) 9 3 yr 8




Cause of death

UCB MSD (CB) sibling UCB (9)


Alive, NAD Alive, NAD Alive, NAD

– – – –

MSD Haplo (2) (2x)* Greinix et al. (9) Stoll et al. (10) Frost and Wiersma (12) Conter et al. (11) Broadbent and Ladisch (pt10) (13)

25 18 yr 16 27 20



Haplo (2x)

Ayas et al. (14) Egeler et al. (pt2) (15)

Unknown Unknown

MSD Haplo

Suminoe et al. (16) Nagarajan et al. (17)

17 21


Hale et al. (pt2) (18)



21 20

MUD5/6 MSD (4)

Akkari et al. (pt5) (19)

Ingram et al. (20) Kesik et al. (21) Kinugawa et al. (pt4) (22)

15 4 yr 55

MUD (1) MSD MSD MSD (2) Sibling 4/6 (1) Syngeneic twin (1)



Alive, NAD (7)

Dead (2)

LCH-related (2) progressive disease

Alive, NAD Dead (2)

LCH-related (2) progressive disease

Alive, NAD Alive with hypogon Alive, NAD Alive, NAD Dead (2) Dead (2) Alive, NAD (1) Alive, with LCH (1) Dead (1) Alive, NAD (1) Dead (1)

LCH-related (1) progressive disease

Dead (1)

Alive, NAD Alive, NAD

– Transplant-related (2) respiratory failure adenoviral infection – –


Transplant-related multi-organ failure

Alive, NAD Dead (2)


Alive, NAD Alive, NAD (1) Dead (1) Dead (1) Alive, NAD (1) Dead Alive, NAD Alive, NAD Dead Dead Alive, NAD


Alive, NAD

BU/VP16 (1) U/CY/VP16 (1) BU/CY (2)

– – – – Transplant-related (6) VOD (2) respiratory failure (2) septicemia (1) capillary leakage (1)

Transplant-related (2) Toxicity multi-organ failure LCH-related (1) progressive disease – – Transplant-related (2) septicemia

Haploidentical HSCT in refractory LCH Table 1. Continued


Median age at SCT (months)




Cause of death

Steiner (pt9) (23)


MUD (3)


Alive, NAD (2)

LCH-related (1) pulmonary insufficiency (LCH disease and CMV infection)

MSD (3)

Haplo (3) (2x)†


Dead (1) Alive, NAD (3)

Transplant-related Klebsiella sepsis


Alive with full autologous recovery

Alive, NAD

pt, patient; CB, cord blood; TBI, total body irradiation; FlU, fludarabine; MEL, melphalan; Cy, cyclophosphamide; VP16, etoposide phosphate; Bu, busulfan; ATG, antithymocyte globulin; ALG, antilymphocyte; Ara-C, arabinosylcytosine; CAMP, Campath-1 h; TT, thiotepa; UCB, unrelated cord blood; MSD, matched sibling donor; Haplo, haploidentical; NAD, no activity disease; VOD, veno-occlusive disease; CMV, cytomegalovirus; TLI, total lymph node irradiation; 2x, received the second transplantation. *Used the same donor’s PB for the second transplantation, after late rejection of the first HSCT from a haploidentical father. † All patients that received a haploidentical HSCT had the second HSCT due to an early or late rejection; two patients repeated the haploidentical HSCT, and one patient received the MUD HSCT.

Case 2 A three-month-old girl presented with a rash and ear secretions that had started when she was 40 days old. A biopsy of the lymph nodes confirmed a diagnosis of LCH. The involved regions included the skin, bone, lymph nodes, and ears. Several high-risk organs were also involved, including the lung, liver, and spleen. She was treated with six wk of chemotherapy, according to the treatment protocol described in LCH-III for Group I. A new lesion appeared in the lung and the liver was enlarged indicating that the lung and liver did not respond to conventional treatment, thus, the disease was refractory. She received a haploidentical parental HSCT at five months of age (January 2010). The conditioning regimen included fludarabine (30 mg/m2/day, days 13 to 10), busulfan (1.1 mg/kg/day, IV, days 9 to 6), cyclophosphamide (50 mg/kg/day, days 5 to 2), etoposide (500 mg/m2, days 4 to 2), and rabbit-antithymocyte-globulin (2.5–3.5 mg/kg/day, days 6 to 2). She also received GVHD prophylaxis, based on cyclosporine (2.5 mg/kg from day 1), methotrexate (15 mg/m2, IV, day +1 and 10 mg/m2, days +3, +6), and mycophenolatemofetil (0.25 g/day from day 0). She received PBSC + BM with no T-cell depletion from the mother, who displayed 4/6 HLA matches (the A and B loci were mismatched). The infusion contained 40.23 9 106/kg CD34+ cells. She also received donor mesenchymal cells (1.85 9 106/kg) on day 0 for GVHD prophylaxis. Engraftment was achieved on day +8 and a rash appeared on the same day. Stage 2 GVHD of the skin developed, and it was confirmed by skin biopsy. This condition improved with corticosteroid treatment. Tacrolimus was administered instead of cyclosporine to treat the new rash on day +33, and efficacy was confirmed.

Cyclosporine was administered instead of tacrolimus at six months, and then it was tapered off at 12 months posttransplantation, due to no GVHD symptoms. However, mild chronic GVHD of the oral mucosa developed at 14 months, and cyclosporine was re-administered. Finally, cyclosporine was tapered off again at 23 months and stopped at 32 months post-transplantation. At the followup, no symptoms were detected to indicate severe GVHD or complications. At the three-, five-, eight-, and 28-month post-transplantation follow-ups, the patient underwent the typical examinations. She displayed full donor chimerism, and she showed good nutritional status. Images of bones showed repair in most parts. Normal hearing was recovered, and the appearance and function of the liver and spleen also returned to normal. However, the NK level remained low at 28 months post-transplantation. There were no signs of disease activity or GVHD in the follow-up at 44 months.


Currently, most patients with multisystem histiocytosis have a good prognosis, due to improvements in chemotherapy regimens; the survival rate is 94–79%. Nevertheless, non-responding patients have a poor outcome, with 10–59% survival (4–7). No optimal salvage strategy has been validated for patients that fail to respond to combination chemotherapy (24). Since 1987, refractory LCH has been salvaged with allogeneic transplantation (8). Those reports described 56 E127

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patients with LCH that underwent allogeneic transplantations, and at least one with a syngeneic SCT (Table 1). Among those 56 patients, 35 survived; 33 of the survivors showed no signs of disease activity, one survivor showed full autologous recovery, and one survivor displayed active disease. The other 21 of the 56 patients died after transplantation. Seven died from progressive disease, and 14 died from transplant-related complications, such as respiratory failure, septicemia, etc. Eight patients of the 56 patients accepted haploidentical transplantations, but unfortunately, six of the eight died; one survived with full autologous recovery; and one survived with a second transplantation from a MUD. This study was the first to report successful, haploidentical parental HSCTs, with no T-cell depletion, in pediatric patients with refractory MS-LCH. The choice of using aggressive treatment was substantiated by the patients’ partial responses to chemotherapy regimens based on the LCH-III. Neither of the patients had a well-matched donor at the time that we demonstrated refractory LCH. The patients appeared to possess poor prognostic features, including young age (one displayed symptoms at 40 days of age) and the presence of multi-organ dysfunction. However, we previously had some successful experiences with haploidentical transplantations in other diseases, like leukemia and aplastic anemia. Therefore, we chose to use myeloablative regimens and no T-cell depletion for the haploidentical HSCTs in these patients, despite unfavorable results reported in the literature. We used both PBSC and BM as stem cell sources, because this was our routine practice in China (25–28). Previously, Wang et al. had reported a good outcome in aplastic anemia after treating with a co-transfusion of haploidentical hematopoietic and mesenchymal stromal cells (29, 30). Therefore, we tried this treatment in our patients. Fortunately, the two patients described here achieved good outcomes after haploidentical transplantations, and currently, they have no signs of disease activity or chronic GVHD. Two important reasons for the success with these haploidentical transplantations and the strong myeloablative regimens might be that (1) the patients received transplantations early (6– 12 wk) after chemotherapy failure, and (2) they showed no progression of organ dysfunction after chemotherapy. Case 1 was interesting, because the DI disappeared after transplantation and, in spite of only a 1/3 normal neurohypophysis on the MRI, at 17 months post-transplantation, the pituitary gland appeared to be normal. This was an imporE128

tant discovery, because, in this literature, there is no satisfactory treatment strategy for reversing LCH-associated DI or central nervous system disease (24). We could not explain how the pituitary gland was repaired, but we speculate that the infusion of 49 the typical number of donor mesenchymal cells might have been an effective factor; thus, this approach should be explored further in future research. In conclusion, our results showed that HSCT for refractory LCH represented an important salvage approach. This approach contradicts the currently accepted hypothesis (3, 20, 23) that a RIC is desirable for young children with nonmalignant disease. We showed that a strong myeloablative regimen with a haploidentical parental HSCT might be beneficial for some patients that lack a well-matched donor. For successful transplantation with this approach, two important factors for an effective treatment might be treatment early after a failed chemotherapy, and no progression in organ dysfunction. Conflict of interest

The authors declare no financial interests. References 1. HATAKEYAMA N, HORI T, YAMAMOTO M, et al. Successful treatment of refractory Langerhans cell histiocytosis with pulmonary aspergillosis by reduced-intensity conditioning cord blood transplantation. Pediatr Transplant 2010: 14: E4–E10. 2. CASELLI D, ARICO M, EBMT Paediatric Working Party. The role of BMT in childhood histiocytoses. Bone Marrow Transplant 2008: 41: S8–S13. 3. KUDO K, OHGA S, MORIMOTO A, et al. Improved outcome of refractory Langerhans cell histiocytosis in children with hematopoietic stem cell transplantation in Japan. Bone Marrow Transplant 2010: 45: 901–906. 4. GADNER H, GROIS N, ARICO M, et al. A randomized trial of treatment for multisystem Langerhans’ cell histiocytosis. J Pediatr 2001: 138: 728–734. € 5. GADNER H, GROIS N, POTSCHGER U, et al. Improved outcome in multisystem Langerhans cell histiocytosis is associated with therapy intensification. Blood 2008: 111: 2556–2562. 6. MINKOV M, GROIS N, HEITGER A, et al. Response to initial treatment of multisystem Langerhans cell histiocytosis: An important prognostic indicator. Med Pediatr Oncol 2002: 39: 581–585. 7. A multicentre retrospective survey of Langerhans’ cell histiocytosis: 348 cases observed between 1983 and 1993. The French Langerhans’ Cell Histiocytosis Study Group. Arch Dis Child 1996: 17–24.  8. RINGDEN O, AHSTROM L, LONNQVIST B, BARYD I, SVEDMYR E, GAHRTON G. Allogeneic bone marrow transplantation in a patient with chemotherapy-resistant progressive histiocytosis X. N Engl J Med 1987: 316: 733–735. 9. GREINIX HT, STORB R, SANDERS JE, PETERSEN FB. Marrow transplantation for treatment of multisystem progressive Langerhans cell histiocytosis. Bone Marrow Transplant 1992: 10: 39–44.

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Haploidentical parental hematopoietic stem cell transplantation in pediatric refractory Langerhans cell histiocytosis.

Children with MS-LCH that fail to respond to conventional chemotherapy have poor outcomes. HSCT represents a potential salvage approach. It has been a...
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