Histiocytic Disorders Allogeneic bone marrow transplantation ... - Nature

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Histiocytic Disorders Allogeneic bone marrow transplantation for children with histiocytic disorders: use of TBI and omission of etoposide in the conditioning regimen GA Hale1,4, LC Bowman1,4,5, JP Woodard1,4, JM Cunningham1,2,4, E Benaim1,4, EM Horwitz1,2,4, HE Heslop1,4,6, RA Krance1,4,6, W Leung1,4, PD Shearer1,3,4 and R Handgretinger1,4 1 The Division of Stem Cell Transplantation, Department of Hematology-Oncology, Memphis, TN, USA; 2Division of Experimental Hematology, Department of Hematology-Oncology, Memphis, TN, USA; 3International Outreach Program St Jude Children’s Research Hospital, Memphis, TN, USA; and 4Department of Pediatrics, Memphis College of Medicine, University of Tennessee, Memphis, TN, USA

Summary: The histiocytoses are rare disorders of antigen-processing phagocytic or antigen-presenting cells. Allogeneic bone marrow transplantation (BMT) can be curative of these disorders. We report a series of five children with Langerhans cell histiocytosis (n ¼ 2) or hemophagocytic lymphohistiocytosis (n ¼ 3), who received allogeneic BMT with a total body irradiation (TBI)-containing regimen (TBI, cytarabine, and cyclophosphamide) at our institution between 1995 and 2000. One of these patients received busulfan, cyclophosphamide, and etoposide for the first of two BMTs. All grafts except one (a matched sibling-donor graft) were T-cell-depleted grafts from unrelated donors. All received cyclosporine graft-versushost disease (GvHD) prophylaxis; the recipient of the matched sibling graft also received methotrexate. Three patients engrafted at a median of 24 days after transplantation. The patient who did not receive TBI experienced primary graft failure and recurrent disease. After the TBI-containing conditioning regimen was given, a second transplant engrafted on day +17. One patient with concurrent myelodysplastic syndrome died of toxicity on day +33 without evidence of engraftment. No acute or chronic GvHD was observed. Four patients survive disease-free, a median of 63 months after transplantation, all with Lansky performance scores of 100. We conclude that a conditioning regimen containing TBI but not etoposide is effective in allogeneic BMT for children with histiocytic diseases. Bone Marrow Transplantation (2003) 31, 981–986. doi:10.1038/sj.bmt.1704056

Keywords: allogeneic bone marrow transplantation; total body irradiation; langerhans cell histiocytosis; hemophagocytic lymphohistiocytosis

Histiocytic disorders comprise a wide variety of diseases that result from the abnormal proliferation and accumulation of dendritic cells and macrophages.1–4 The three main categories of histiocytic disorders are (1) dendritic-cell disorders (eg, Langerhans cell histiocytosis, LCH), (2) macrophage disorders (eg, hemophagocytic lymphohistiocytosis, HLH), and (3) the malignant disorders of mononuclear phagocytes (eg, acute monocytic leukemia).1 Allogeneic bone marrow transplantation (BMT) can be curative for patients with recurrent or refractory histiocytic disorders. Although localized LCH is usually cured by chemotherapy, multisystem LCH can be resistant.5,6 Several reports describe the long-term survival of patients with recurrent or refractory LCH after allogeneic BMT.7–12 HLH, unlike LCH, is rarely curable by chemotherapy alone, and allogeneic BMT has increased the probability of survival for patients with HLH.13,14 Owing to the young age of patients with these disorders, most reported BMT preparatory regimens have excluded total body irradiation (TBI). Most of these regimens have included etoposide, which is active against histiocytic disease. Here we describe our institution’s experience with a conditioning regimen for allogeneic BMT in children with histiocytic disorders that includes TBI and does not include etoposide.

Patients and methods Patients

Correspondence: Dr G Hale, Department of Hematology-Oncology, St Jude Children’s Research Hospital, 332 N. Lauderdale, Memphis, TN 38105-2794, USA 5 Current address: Emory University, Stem Cell Transplantation, 1405 Clifton Road, NE, Atlanta, GA 30322, USA 6 Current address: Baylor College of Medicine, 6621 Fannin St MC3-3320, Houston, TX 77030, USA Received 17 September 2002; accepted 15 January 2003

We reviewed the records of all 171 children who underwent allogeneic BMT between October 1995 and May 2000 at St Jude Children’s Research Hospital, and identified five patients with high-risk histiocytic disorders, defined as HLH or refractory LCH. All patients had recurrent or persistent disease that had failed primary chemotherapy and immunosuppressive therapy that included etoposide, steroids, and/or cyclosporine. The characteristics of these

BMT conditioning regimens for histiocytosis GA Hale et al

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cases are shown in Table 1. Two patients had refractory LCH and three had HLH. One patient had both refractory LCH and myelodysplastic syndrome (MDS). The diagnosis of LCH was based on standard criteria and was confirmed by tissue biopsy.15–17 The diagnosis of HLH was based on the criteria specified by the Histiocyte Society.18 Two of the patients with HLH had a family history of the disorder. During this time, a total of 21 patients (including the five who underwent transplantation) were treated at our institution for histiocytic disorders. Those with HLH and all LCH patients with recurrent, refractory or persistent disease were referred for transplant. Table 2 shows selected characteristics of the patients, donors, and transplants.

Conditioning regimen The TBI-containing conditioning regimen, graft manipulation, and GvHD prophylaxis were those used for patients undergoing allogeneic BMT at our institution for hematologic malignancies. One patient’s donor was an human leukocyte antigen (HLA)-identical sibling, and four patients had matched (at five or six HLA loci) unrelated donors. For their first BMT, all patients except one (n ¼ 4) had a conditioning regimen of TBI, cytarabine (six doses of 3 g/m2/dose), and cyclophosphamide (two doses of 45 mg/ kg/dose), 45 mg/kg of mesna (45 mg/kg divided into five doses) was administered before and 3, 6, 9, and 12 h after each dose of cyclophosphamide.19 TBI was given in eight fractions; the total dose was 12 Gy for recipients of matched sibling-donor transplants and 14 Gy for recipients of unrelated-donor transplants. Recipients of unrelateddonor transplants also received antithymocyte globulin (ATG) as part of the conditioning regimen to enhance immunosuppression. One patient (patient 2) received a non-TBI-containing preparative regimen for the first BMT; the regimen comprised busulfan (16 doses of 1 mg/kg/dose), cyclophosphamide (four doses of 50 mg/kg/dose), etoposide (three doses of 500 mg/m2/dose), and equine ATG (three doses of 30 mg/kg/dose).20 After primary graft failure and autologous reconstitution of hematopoiesis, this patient underwent the TBI-based regimen described above and received a second unrelated-donor graft.

days before transplantation, all recipients began receiving cyclosporine at dosages adjusted to yield a whole-blood concentration of 200–350 ng/ml by fluorescence polarization immunoassay. The patient whose donor was a matched sibling received a short course of methotrexate for additional GvHD prophylaxis.

Supportive care Supportive care measures were provided as previously described.21 Patients without significant GvHD who received T-cell depleted grafts were eligible to receive donor-derived cytotoxic-T-cells specific for Epstein–Barr virus as prophylaxis against Epstein–Barr virus lymphoproliferative disease. Prior to 1997, the first infusion was given at day +60 followed by a second infusion 30 days later. After 1997, patients received a single infusion on day +60.22

Engraftment Engraftment was considered to have occurred on the first of three consecutive days on which the absolute neutrophil count (ANC) was 40.5 109/l and hematopoiesis was documented to be of donor origin by chimerism assay.

Follow-up After discharge, all patients were examined at least monthly for the first year after transplant and then at least annually in our Transplant clinic. Neuropsychology testing was performed in the Department of Behavorial Medicine using age-appropriate tools as previously described.23

Toxicity Regimen-related toxicity scored by using the National Cancer Institute (NCI) Common Toxicity Criteria. Acute GvHD, chronic GvHD, VOD, and autoimmune hemolytic anemia (AIHA) were diagnosed according to standard criteria.24–26

Results

GvHD prophylaxis

Patient characteristics

Grafts from unrelated donors were depleted of approximately 1.5 logs of T lymphocytes by use of monoclonal antibodies to CD6 and CD8 plus rabbit complement.19 At 2

Five patients underwent allogeneic BMT for histiocytic disorders at our institution during the study period (Table 1). Their median age at BMT was 7 months (range,

Table 1

Patient characteristics

Patient

Diagnosis

Sites of disease at diagnosis

Disease status at BMT

1 2 2a 3 4 5

LCH, MDS HLH HLH HLH LCH HLH

Liver, spleen Liver, spleen, bone marrow Liver, spleen, bone marrow Skin, liver, spleen, bone marrow Skin, middle ear, liver, spleen, bone marrow Liver, spleen, bone marrow

Refractory disease CR1 CR2 CR1 Refractory disease Relapse 1

a

Age at BMT (months)

Second transplant. LCH=Langerhans cell histiocytosis; MDS=myelodysplastic syndrome; HLH=hemophagocytic lymphohistiocytosis; CR=complete remission.

Bone Marrow Transplantation

3 5 13 7 21 15

Time since transplantation. 100% host cells by chimerism analysis. Second transplant. M=male; F=female; Neg=negative; Pos=positive; RRT=regimen-related toxicity; CY=cyclophosphamide; Ara-C=cytarabine; TBI=total body irradiation; BU=busulfan; VP16=etoposide; VOD=venoocclusive disease; AIHA=autoimmune hemolytic anemia; HUS=hemolytic uremic syndrome. c

b

No 0 +26 Neg/Neg O/A+ 6 Unrelated M/M 5

TBI,CY, Ara-C

0 +18 Neg/Pos A+/O+ 5 TBI,CY, Ara-C M/M 4

a

Alive, 28 months No

Alive, 54 months

VOD, adenovirus enteritis, AIHA AIHA No

No

HUS Torulopsis sepsis No No +17 +26 Neg/Neg Neg/Neg F/M F/M 2c 3

TBI,CY, Ara-C TBI,CY, Ara-C

Unrelated HLA-identical sibling Unrelated

6 6

O+/A+ O+/O+

0 +23b F/F 2

BU,CY,VP16

Unrelated

6

O+/A+

Neg/Neg

0 0

No

5 months Alive, re-transplanted post-BMT No Alive, 74 months No Alive, 72 months

Died day +33, relapse No

Respiratory failure, Trichosporon sepsis, Aspergillus infection None No 0 N/A Neg/Neg O+/A 6 TBI, CY, Ara-C Unrelated M/F 1

Conditioning Patient Sex, patient/ regimen donor

Table 2

Transplant procedure

Type of donor

CMV status, Days post-BMT Antigens Blood Acute GvHD Chronic Grade 3–4 matched type, patient/ patient/donor ANC X0.5 109/l (grade) GvHD RRT donor

Relapse post-BMT

Outcome, durationa


3–21 months). No patient had documented central nervous system (CNS) disease. Prior to BMT, all patients had been treated with chemotherapy, and none had received radiation therapy. All three HLH patients entered complete remission (CR) with initial chemotherapy. One of these patients received a transplant during first remission, one with second remission, and one with active disease. Two patients with refractory LCH never entered remission; both underwent BMT with active disease. The two patients with refractory LCH never entered remission; both underwent BMT with active disease. Recipients of unrelated-donor grafts received a median of 1.64 108 nucleated cells/kg (range, 0.7–2.0 108/kg), a median of 3.1 106 CD34+ cells/kg (range, 1.8–6.0 106/kg), and a median of 0.9 106 CD3+ cells/kg (range, 0.5–1.2 106/kg). The recipient of an unmanipulated matched sibling graft received 6 109 nucleated cells/kg. One patient with HLH underwent a second unrelated-donor transplant during second remission, after primary graft failure and disease recurrence.

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Engraftment Of the four patients who received a TBI-containing conditioning regimen for initial BMT, three engrafted at a median of 24 days (range, 18–26 days) after BMT. The fourth patient (patient 1), who had concurrent MDS, died 33 days after BMT without evidence of engraftment. The only patient who received a chemotherapy-based conditioning regimen (patient 2) experienced primary graft failure with autologous reconstitution, reaching an ANC of 0.5 109/l on day 23 after BMT. This patient engrafted on day 17 after receiving the conditioning regimen that included TBI but not etoposide, and infusion of a second allograft.

Regimen-related toxicity All patients experienced side effects typical of allogeneic BMT. One had post-transplant microangiopathy (hemolytic-uremic syndrome, HUS); and one had moderate hepatic VOD, which resolved without long-term sequelae. No patient had interstitial pneumonitis, acute or chronic GvHD. Patient 1, who had a Lansky performance score of 30 at the time of transplantation, underwent BMT from an unrelated donor for MDS and active HLH, both of which were diagnosed at the same time. His myelodysplastic marrow also had significant fibrosis; however, no histiocytosis was observed in the marrow. His course was complicated by respiratory failure that required ventilatory support, Trichosporon sepsis, and Aspergillus flavus cellulitis and osteomyelitis. On day 31 after transplantation, bone marrow biopsy revealed extensive fibrosis with no evidence of hematopoietic precursors or histiocytic infiltration. Chimerism studies showed no donor hematopoiesis. The patient died of multiple-system failure on day +33. Patient 2 experienced post-transplant HUS after her second unrelated-donor BMT. This complication was characterized by thrombocytopenia and hemolysis requiring blood product transfusion, hypertension requiring drug Bone Marrow Transplantation

MSD=Matched sibling donor; MRD=matched related donor; URD=unrelated donor; MMFM=mismatched family member donor; NR=Not reported; TCD=T-cell depletion of alternative donor grafts; non-TCD=no T-cell depletion.

7% (grade II–IV) 7% 44% (grade III–IV) 9% 43% 6% BuCy VP16, TCD 14 (1URD; 13MMFM) BuCy VP16, non-TCD 23 URD 32 33

All engrafted n=1 grade IV 8% 17% (grade II–IV) BuCy VP16, non-TCD 6 (4 MSD; 2 URD) BuCy VP16, non-TCD 12 (4MRD;8 URD)


20

27 28

20% 57% (grade II–IV) 10%

45% at 3 years for all patients; 44% at 3 years for MUD patients n=1 BOOP All MSD alive 8% 100% at median 2 years

All MMFM recipients died of recurrence. 4/5 MSD alive NR NR

BuCy VP16, TCD 9 (5 MSD; 4 MMFM) for MMFM BuCy VP16, non-TCD 20 (4MSD; 16 URD) 14

11%

Survival CGvHD AgvHD Graft failure No. of patients Reference Description

Table 3

Published series of stem cell transplantation for histiocytic disorders in children

Comments

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Five patients had chronic GvHD; one died of acute GvHD Both MUD recipients died of GvHD or BOOP Five experienced VOD; three required mechanical ventilation; two had seizures. 9/14 alive at a mean 33 months Three required second transplant for graft failure. 51% at 4 years (median 0.8 years) Six died from nonrelapse mortality (three infection,one GvHD, one toxicity, one graft failure); one died from recurrence


therapy, and moderate renal insufficiency. She did not require dialysis or plasmapheresis. Patient 3, who underwent BMT from an HLA-identical unaffected sibling was readmitted to the hospital for Candida glabrata sepsis, requiring vasopressor therapy for hypotension. Patient 4, who underwent BMT from an unrelated donor during active disease, had moderate VOD and adenovirus enteritis. At 12 months after BMT, he had AIHA and required transfusion of packed red blood cells. Steroid therapy elevated his hemoglobin concentration to acceptable values. Steroids were discontinued 19 months after BMT. Patient 5 had active HLH when he underwent BMT from an unrelated donor. At 3 months after transplantation, he had AIHA and required blood product transfusion. His hemoglobin returned to normal with steroid therapy, which was discontinued 7 months post-BMT.

Outcome One patient (patient 1) died of regimen-related toxicity on day +33. Patient 2 had autologous reconstitution of hematopoiesis with disease recurrence after the first BMT. This patient is alive in remission after a second transplant with a TBI-containing regimen. The four surviving patients (median follow-up, 63 months) are free of disease with Lansky performance scores of 100. Of the 16 patients with histiocytic diseases sensitive to standard therapies who did not require transplantation, 14 survived.

Long-term sequelae One patient (patient 2) developed hypothyroidism. No other endocrinopathies were noted. The developmental quotients of all four surviving patients were equivalent to pretransplant baseline values. No second malignancies have occurred.

Discussion Most published studies have used etoposide-based conditioning regimens omitting TBI so that the late effects of TBI can be avoided, while using the active agent etoposide.14,20,27–33 Results from larger published series are summarized in Table 3. However, our center reports favorable outcomes in a small number of patients using a TBI-containing conditioning regimen that omits etoposide. Allogeneic BMT is known to be curative for patients with HLH. The reported 5-year survival after transplantation (primarily from matched sibling donors) approaches 66%, a rate superior to that of nontransplant therapies.13 However, the results of BMT for patients with active disease and for recipients of alternative-donor grafts have been discouraging, with significant morbidity and mortality because of toxicity, GvHD, and graft failure.12,14,27–29 Some reports associate graft failure with autologous reconstitution,12,30 and disease recurrence was observed in the single patient with autologous reconstitution in our


series. However, other reports do not confirm this observation.12,31 Graft manipulation methodologies can also alter the rate and type of post-transplant complications. Recipients of non-T-cell depleted grafts tend to have lower rates of graft failure, countered by higher rates of acute and chronic GvHD when compared to recipients of T-cell-depleted grafts.14,20,27–33 In the largest series of HLH patients receiving non-T-cell-depleted grafts,20 GvHD was a significant cause of morbidity and mortality. In our series, patients did not experience GvHD or graft failure, and the regimen-related toxicity was similar to that previously reported for patients undergoing allogeneic BMT. The higher rate of engraftment in our series compared to other reports of patients receiving T-celldepleted grafts is likely because of the less profound T-cell depletion obtained, using our methodology and the immunosuppressive effects of TBI. Interestingly, two patients had AIHA after receiving unrelated-donor grafts. Like patients reported in other series, they had nonmalignant disorders, received grafts depleted of T lymphocytes, and had a late onset of AIHA.34,35 However, neither of these patients had GvHD, and neither was receiving immunosuppressive therapy when the anemia developed. In toto, these observations suggest that TBI provides adequate immunosuppression for establishing hematopoiesis for recipients of T-cell-depleted grafts, while not increasing toxicity. The lower rates of GvHD observed in our series were not associated with high rates of relapse, consistent with our published experience in children with hematologic malignancies.19 This observation may be due, in part, to the fact that etoposide is usually included in the initial therapy, and may be less effective in refractory or recurrent disease. In addition, the lower number of patients experiencing graft failure may allow the establishment of donor lymphopoiesis, theoretically allowing an immunologic reaction analogous to a graft-versus-tumor effect. Although poor outcomes are widely reported for patients who have active HLH at the time of BMT, our report confirms that some patients may be cured.36,37 One case report described a patient with refractory HLH who received a non-T-celldepleted graft after a TBI-containing conditioning regimen.36 Engraftment occurred 6 months post-transplant, and the patient remained alive 18 months later. Similarly, one of our two patients with refractory LCH is a long-term survivor 44 months after unrelateddonor BMT, demonstrating that refractory LCH can also be cured after T-cell-depleted allogeneic BMT. Our patient who died was an infant with active MDS, who had disseminated LCH that was unresponsive to therapy, and who was in poor physical condition at BMT. This outcome is consistent with those reported for four patients with MDS and LCH: all had multisystem organ dysfunction and all, including one who had undergone BMT, died after rapid deterioration.38 In this report, we demonstrate that a TBI-containing conditioning regimen, which omits etoposide, is a therapeutic option for patients with histiocytic disorders who are candidates for BMT. In our experience, a conditioning regimen that included TBI but not etoposide was highly

efficacious, resulting in durable engraftment, no GvHD, acceptable toxicity, and eradication of LCH and HLH. This regimen also effectively induced engraftment in a patient who had graft failure after a chemotherapy-based regimen. Although follow-up is short, no second malignancies or cognitive decline have been observed in our young patient population. In the future, nonmyeloablative regimens and newer methods of T-cell depletion may improve outcome by further decreasing toxicity and GvHD.39–43

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Acknowledgements We express our appreciation to Frances Curran and Nancy right for data management; Margaret Aymond, Patricia Johnson, and Cynthia Walker for data collection; and Sara Williams for the manuscript preparation This work was supported in part by NIH Cancer Center Support Grant P 30CA 21765 and by the American Lebanese Syrian Associated Charities (ALSAC).

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