Pediatric Hematology and Oncology, 31:285–292, 2014 C Informa Healthcare USA, Inc. Copyright ISSN: 0888-0018 print / 1521-0669 online DOI: 10.3109/08880018.2013.862754
BRIEF REPORT
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Hemophagocytic Lymphohistiocytosis in Infants: A Single Center Experience from India Mohammed Ramzan,1 Satya Prakash Yadav,1,2 Gaurav Kharya,1 Vasant Chinnabhandar,1 Miriam Enteserian,3 J Inge Henter,3 and Anupam Sachdeva1 1
Pediatric Hematology Oncology & Bone Marrow Transplant Unit, Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi, India; 2 Pediatric Hematology Oncology & BMT Unit, Department of Pediatrics, Fortis Memorial Research Institute, Gurgaon, Haryana, India; 3 Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
There is paucity of outcome data for hemophagocytic lymphohistiocytosis (HLH) in infants from India, especially post stem cell transplant (SCT). We report outcome data of eight infants diagnosed with HLH. Mean age was 7.1 months (range 2–11). Mutation analysis was possible in seven patients. One patient had Griscelli syndrome. In three patients, no known mutation could be identified, while in remaining three homozygous mutations in Perforin, Munc and STX11 gene were identified. All were treated as per HLH 2004 protocol. Four died during induction phase. One patient abandoned therapy. Two underwent SCT, while one is awaiting SCT. First patient is alive and disease-free at 22 months postmatched sibling donor SCT. Second underwent unrelated double cord blood transplant, but died 5 months posttransplant due to renal failure. It is feasible to offer SCT for infants with familial HLH in the developing world although barriers like sepsis and disease refractoriness remain. Keywords developing world, familial, HLH, outcome, transplant
INTRODUCTION Hemophagocytic lymphohistiocytosis (HLH) is a prototype of the hemophagocytic syndrome and occurs most often in children. The primary autosomal recessive form, familial HLH (FHLH) is a very rare disease [1] and estimated incidence is around 1 in 50,000 live births in children [2]. In the developing world, delay in diagnosis, sepsis, treatment abandonment, and lack of stem cell transplant facilities are the major hurdles to improving survival in such patients. Delay in diagnosis of HLH is often due to a variety of factors including the rarity of HLH, complexity and specificity of current diagnostic criteria, and vast differential diagnosis of the disease including malignancies (leukemia, lymphoma, and other solid tumors), infections (viral, bacterial, or parasitic), storage disorders, and rheumatoid disorders. Some other rare genetic diseases which develop a true HLH episode during their clinical course are X-linked Received 14 April 2013; accepted 2 November 2013. Address correspondence to Satya P Yadav, Pediatric Hematology Oncology & BMT Unit, Department of Pediatrics, Fortis Memorial Research Institute, Gurgaon, Haryana, India. E-mail: [email protected]
M. Ramzan et al.
lymphoproliferative syndrome (XLP), and Chediak–Higashi and Griscelli (type 2) syndromes, lysinuric protein intolerance, severe combined immunodeficiency, DiGeorge syndrome, and Omen’s syndrome [3]. To diagnose HLH in an infant, in the developing world setting, is challenging due to nonavailability of tests like perforin, degranulation assay, Natural Killer (NK) cell activity, and Interleukin 2 receptor (IL2-R) levels. Serum ferritin remains the most widely available, affordable, and sensitive marker of HLH [4]. Outcome data of familial HLH from a developing country like India are lacking [5–7]. Here, we report the clinical profile and outcome of eight infants diagnosed with HLH.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Thammasat University on 10/04/14 For personal use only.
METHODS All infants with confirmed diagnosis of HLH as per revised HLH 2004 guidelines [3] (Table 1) were included in this retrospective study from a single center from January 2010 to December 2012. These cases were managed with dexamethasone, cyclosporine, and etoposide (VP-16) based chemotherapy as per HLH 2004 protocol [3]. Acute manifestations were managed symptomatically. In view of clinical suspicion of familial HLH, the DNA samples of the patients and their parents were sent to Sweden for further genetic analysis, after parental consent. Treatment response was assessed using clinical criteria (fever, splenomegaly, jaundice, pallor, and bleeding) and laboratory parameters (complete blood counts, serum triglyceride, ferritin, and fibrinogen levels). Infants with familial HLH underwent stem cell transplant as per institutional protocol and outcome was noted. RESULTS Eight infants were referred to our center with history of prolonged fever and hepatosplenomegaly (six males and two females). Mean age of presentation was 7.1 months (range 2–11). It took average of 20 days between onset of symptoms and diagnosis of HLH. One infant had family history of two siblings dying with similar illness, and two had history of consanguinity in the parents. Five infants had recurrent respiratory tract infection; one had gastrointestinal tract involvement and one had liver abscess. Bleeding was evident in two at the time of presentation. Two had failure to thrive. Lymphadenopathy and skin involvement were not present in any infant. In view TABLE 1 Revised Diagnostic Guidelines for HLH3 The diagnosis HLH can be established if one of either 1 or 2 below is fulfilled (1) A molecular diagnosis consistent with HLH (2) Diagnostic criteria for HLH fulfilled (five out of the eight criteria below) (A) Initial diagnostic criteria (to be evaluated in all patients with HLH) • Fever • Splenomegaly • Cytopenias (affecting two of three lineages in the peripheral blood): Hemoglobin < 90 g/l (in infants < 4 weeks: hemoglobin C inherited from the mother). One had a homozygous stop mutation (c.528 529delinsAA; p.Cys176X) in PRF1 (his parents were heterozygous carriers for this mutation). Another had homozygous mutation in STX11 causative of FHL4. This mutation was a novel mutation, not described earlier with an aminoacid change from leucine to proline, p.Leu58Pro. (mother and the father had that mutation in a heterozygous form) EBV and cytomegalovirus are known triggering factors for HLH. Three patients had associated cytomegalovirus infection. All were treated as per HLH 2004 protocol [3]. Four patients died during induction phase due to their preexisting morbidities (gram negative sepsis and hemorrhage) or primary refractory disease in three. Two patients underwent allogeneic stem cell transplant (SCT) of whom one died. One patient abandoned therapy and one is still under treatment and due for his stem cell transplant. Transplant in Familial HLH Case 1: A 2-year-old male child was referred from Pakistan for unrelated stem cell transplantation (SCT) following the diagnosis of familial hemophagocytic lymphohistiocytosis (FHLH). He was symptomatic since the age of 2 months. He had no siblings and there was no history of consanguinity in the parents. He was diagnosed with HLH and received therapy as per HLH 2004 protocol in his home country. His genetic study showed homozygous mutation in STX11 gene. He underwent unrelated double cord blood transplant (CBT) at our center and was conditioned with campath (1 mg/kg from day −8 to day −4), fludarabine (150 mg/m2 from day −7 to −3), and melphalan (140 mg/m2 on day −2). Double CBT performed with one 5/6 and other 4/6 HLA matched units (details in Table 3). In India, we faced graft failure in first few unrelated cord transplants due to poor viability of cells in the single cord unit. So, to overcome this and to ensure quick engraftment, we opted for double cord transplant, which is not a norm or standard of care in the West. Cyclosporine and methyl prednisolone were used for GVHD prophylaxis. His neutrophils and platelets were engrafted on day +21 and day +31, respectively. FISH for XX/XY, on day +25, showed no XX suggestive of engraftment of 5/6 matched Cord A that was from a male. However, molecular chimerism studies could not be done. On day +40, routine CMV PCR showed reactivation with 9000 copies while on valganciclovir prophylaxis. By day +50, he developed diarrhea without any blood or mucus. He was started on intravenous ganciclovir. He responded well to this treatment. Steroids were tapered. On day +70, he had represented with low-grade fever and diarrhea. His sepsis workup and CMV were repeated all of which were negative. Endocsopic biopsy was suggestive of gut GVHD. Oral C Informa Healthcare USA, Inc. Copyright
2/M
7/M
11/F 9/F
6/M
10/M
4/M
4/M
1
2
3 4
5
6
7
8
Spleen
+
+
+ +
+
+
+
+
Fever
+
+
+ +
+
+
+
+
+
+
+
+
+ +
+
+
Cytopenia
1.3
1.2
2.0
1.0
2.0 2.6
2.9
1.0
Fib.
440
395
320
194
461 200
674
480
TG
649
22207
600
10922
1000 12600
552
11282
Ferritin
N
D
D
N
D N
N
N
LFT
+
−
−
+
+ +
+
+
HLH (B.M.)
−
−
−
−
Yes −
No
Yes
HSCT
Rab27
N.I
Not done
PERF-1
N.I N.I
MUNC13
STX 11
Mutation
Abandoned therapy
Alive
Alive
Died 6 months posttransplant due to Foscarnet induced renal failure Died at 1.5 months into therapy due to CNS involvement (seizures) Alive 2 years posttransplant Died at 1 month of therapy due to sepsis Alive after 6 months of therapy Abandoned after 1 month of therapy Died at 1 month into therapy due to sepsis Died at 1 month into therapy due to bleeding
Survival outcome
Age—in months, + present, − Absent, TG-Triglyceride in mg/dl, Ferritin in ng/ml, Fib.—Fibrinogen in g/dl, M-male, F-Female, HSCT-Hematopoeitic stem cell transplant, N.I—Not Identified, LTFU—Lost to Follow up, N—Normal, D—Deranged, B.M—Bone Marrow.
Age/Sex
SN
TABLE 2 Clinical and Lab Profile of Infants with HLH
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Outcome of HLH in Infants TABLE 3 Details of Two Infants with HLH Who Underwent Allogeneic Stem Cell Transplant Case 1
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Age at HSCT Sex Family history Mutation Type of transplant Cell dose
Conditioning
Engraftment of neutrophils Engraftment of platelets Complications Outcome
Case 2
2 years Male No STX 11 UCBT Cord A: 5/6 HLA match, sex male, blood group B+, nucleated cell dose was 62.4 × 107 Cord B : 4/6 HLA match, sex female, blood group O+, nucleated cell dose120.44 × 10 7 RIC with Campath (0.2 mg/kg/day from day −8 to −4), Fludarabine (30 mg/m2 /day from day −7 to −4), and Melphalan (140 mg/m2 on day −2) 21
11 months Female Yes Not identified MSD (brother) peripheral 6.9 × 106 /kg body weight of the recipient
31
26
Acute gut and skin GVHD, CMV, PRES Died at 4 months post-CBT due to foscarnet-induced renal failure
Acute gut GVHD, PTLD
RIC Fludarabine (30 mg/m2 /day from day −11 to −7), Melphalan (140 mg/m2 on day −6), and ATG (2.5 mg/kg/day from day −5 to −2) 22
Alive at 22 months post-BMT
FHLH: Famalial Hemophagocytic Lymphohistiocytosis, HSCT: Hematopoeitic Stem Cell Transplant, GVHD: Graft versus Host Disease, PRES: Posterior Reversible Encephalopathy Syndrome, PTLD: Posttransplant Lymphoproliferative Disorder, MSD: Matched Sibling Donor, UCBT: Unrelated Cord Blood Transplant, RIC: Reduced Intensity Conditioning, ATG: Antithymocyte globulin.
prednisolone was restarted at 1.5 mg/kg. By day +117, he had recurrence of loose stools, and his CMV copies had increased to 31,000. With TPN and IV Ganciclovir, he had dramatic reduction in the frequency of diarrhea with reduction in CMV copy number to 1660. Repeat CMV after a week showed 4000 copies, so he was continued with ganciclovir. He had two episodes of sudden onset of convulsions with loss of vision on day +147, which on evaluation was possibly secondary to hypertension with MRI neuroimaging findings, very much suggestive of PRES (posterior reversible encephalopathy syndrome). This patient improved over the next 48 hr without any further seizures, and his vision also fully recovered. Hypertension and seizures were managed accordingly. In the meantime, CMV copies had increased, so possible ganciclovir resistance was suspected and he was started on foscarnet. His condition became stable, and he was shifted back to his home country on the parents’ request. He died 1 week later in his home country, due to foscarnet-induced renal failure. Case 2: An 11-month-old female child who was referred to our center for matched sibling donor stem cell transplant for familial HLH. There was a history of the loss of previous two siblings at the age of 5 and 7 months, with similar illness. She had been treated for 40 weeks as per HLH 2004 Protocol in her home country. The results of genetic tests to diagnose familial HLH, showed no known mutation. She underwent matched sibling donor (MSD) bone marrow transplant at our center. She was given conditioning as mentioned in Table 3. COD cell count of the transfused peripheral blood was 6.9 × 106 /kg body weight of the recipient. Cyclosporine and methotrexate were used for GvHD prophylaxis. Her neutrophils and platelets engrafted on day C Informa Healthcare USA, Inc. Copyright
M. Ramzan et al.
+22 and day +26, respectively. On day +28, she developed diarrhea, gut biopsy confirmed acute GVHD and was managed accordingly. FISH for XX/XY showed 88% donor cells. On day +44, she had throat discomfort and developed enlarged tonsils with white patch 2 days later along with intermittent groaning. EBV copy numbers had increased to 72,000. Finally, diagnosed to have posttransplant lymphoproliferative disorder (PTLD). This responded well to Rituximab 375 mg/m2 per week for four doses. This child is off medication and doing fine at 22 months posttransplant.
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DISCUSSION All our patients had hyperinflammatory syndrome classically described to include the development of fever, splenomegaly, and cytopenias. We had mean serum ferritin levels of 7485 ng/ml (range: 552–22,207) in our patients, although levels over 10,000 mg/l have sensitivity and specificity of 90% and 96%, respectively, for diagnosis of HLH [4]. A recent study from India [5] showed that 36% patients had CNS symptoms at the time of presentation who were finally diagnosed to have HLH. However, none of our patients had CNS disease at the time of presentation. One of our patients had seizure during chemotherapy, possibly due to CNS involvement, who died at home subsequently. Joshi et al. [6] from India, had reported three patients of FHLH (mutation not mentioned). Two of them had low perforin level (0 and .05%). In another case series, [7] three infants were diagnosed to have FHLH on the basis of history of consanguinity and family history, but all died soon after diagnosis. So, diagnosing HLH is the first critical step toward successful therapy, but is challenging in the developing world, due to the rare occurrence, variable presentation, and nonspecific findings of this disorder. Donor search should begin at the time of diagnosis because time to transplant is a key factor in morbidity and mortality from HLH, even though the precise etiology (e.g., genetic defect) has not yet been defined. Generally, SCT is recommended in the case of documented familial HLH, recurrent or progressive disease despite intensive therapy, or CNS involvement [8]. Currently, the only cure for FHLH is allogeneic SCT. Over the past 10 years, several published series have documented the outcomes of patients with FHLH treated with allogeneic SCT after myeloablative conditioning (MAC) regimens, with overall long-term survival ranging from 45% to 65% [9–13]. In 2006, Cooper et al. reported improved survival with reduced-intensity conditioning (RIC), with a survival rate of 75% among a group of 12 patients with FHLH, XLP disease, and Chediak–Higashi syndrome [14]. A follow-up report with additional patients demonstrated survival of 84% with lower transplant-related mortality [15]. However, in 2010, Ohga et al. [13] noted no difference in survival between HLH patients treated at multiple institutions with RIC (n = 11) versus MAC (n = 31). Another study which compared MAC (n = 14) and RIC (n = 26) showed overall estimated 3-year survival of 92% for RIC patients and 43% for MAC patients (P
BRIEF REPORT
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Thammasat University on 10/04/14 For personal use only.
Hemophagocytic Lymphohistiocytosis in Infants: A Single Center Experience from India Mohammed Ramzan,1 Satya Prakash Yadav,1,2 Gaurav Kharya,1 Vasant Chinnabhandar,1 Miriam Enteserian,3 J Inge Henter,3 and Anupam Sachdeva1 1
Pediatric Hematology Oncology & Bone Marrow Transplant Unit, Department of Pediatrics, Institute of Child Health, Sir Ganga Ram Hospital, Old Rajinder Nagar, New Delhi, India; 2 Pediatric Hematology Oncology & BMT Unit, Department of Pediatrics, Fortis Memorial Research Institute, Gurgaon, Haryana, India; 3 Childhood Cancer Research Unit, Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
There is paucity of outcome data for hemophagocytic lymphohistiocytosis (HLH) in infants from India, especially post stem cell transplant (SCT). We report outcome data of eight infants diagnosed with HLH. Mean age was 7.1 months (range 2–11). Mutation analysis was possible in seven patients. One patient had Griscelli syndrome. In three patients, no known mutation could be identified, while in remaining three homozygous mutations in Perforin, Munc and STX11 gene were identified. All were treated as per HLH 2004 protocol. Four died during induction phase. One patient abandoned therapy. Two underwent SCT, while one is awaiting SCT. First patient is alive and disease-free at 22 months postmatched sibling donor SCT. Second underwent unrelated double cord blood transplant, but died 5 months posttransplant due to renal failure. It is feasible to offer SCT for infants with familial HLH in the developing world although barriers like sepsis and disease refractoriness remain. Keywords developing world, familial, HLH, outcome, transplant
INTRODUCTION Hemophagocytic lymphohistiocytosis (HLH) is a prototype of the hemophagocytic syndrome and occurs most often in children. The primary autosomal recessive form, familial HLH (FHLH) is a very rare disease [1] and estimated incidence is around 1 in 50,000 live births in children [2]. In the developing world, delay in diagnosis, sepsis, treatment abandonment, and lack of stem cell transplant facilities are the major hurdles to improving survival in such patients. Delay in diagnosis of HLH is often due to a variety of factors including the rarity of HLH, complexity and specificity of current diagnostic criteria, and vast differential diagnosis of the disease including malignancies (leukemia, lymphoma, and other solid tumors), infections (viral, bacterial, or parasitic), storage disorders, and rheumatoid disorders. Some other rare genetic diseases which develop a true HLH episode during their clinical course are X-linked Received 14 April 2013; accepted 2 November 2013. Address correspondence to Satya P Yadav, Pediatric Hematology Oncology & BMT Unit, Department of Pediatrics, Fortis Memorial Research Institute, Gurgaon, Haryana, India. E-mail: [email protected]
M. Ramzan et al.
lymphoproliferative syndrome (XLP), and Chediak–Higashi and Griscelli (type 2) syndromes, lysinuric protein intolerance, severe combined immunodeficiency, DiGeorge syndrome, and Omen’s syndrome [3]. To diagnose HLH in an infant, in the developing world setting, is challenging due to nonavailability of tests like perforin, degranulation assay, Natural Killer (NK) cell activity, and Interleukin 2 receptor (IL2-R) levels. Serum ferritin remains the most widely available, affordable, and sensitive marker of HLH [4]. Outcome data of familial HLH from a developing country like India are lacking [5–7]. Here, we report the clinical profile and outcome of eight infants diagnosed with HLH.
Pediatr Hematol Oncol Downloaded from informahealthcare.com by Thammasat University on 10/04/14 For personal use only.
METHODS All infants with confirmed diagnosis of HLH as per revised HLH 2004 guidelines [3] (Table 1) were included in this retrospective study from a single center from January 2010 to December 2012. These cases were managed with dexamethasone, cyclosporine, and etoposide (VP-16) based chemotherapy as per HLH 2004 protocol [3]. Acute manifestations were managed symptomatically. In view of clinical suspicion of familial HLH, the DNA samples of the patients and their parents were sent to Sweden for further genetic analysis, after parental consent. Treatment response was assessed using clinical criteria (fever, splenomegaly, jaundice, pallor, and bleeding) and laboratory parameters (complete blood counts, serum triglyceride, ferritin, and fibrinogen levels). Infants with familial HLH underwent stem cell transplant as per institutional protocol and outcome was noted. RESULTS Eight infants were referred to our center with history of prolonged fever and hepatosplenomegaly (six males and two females). Mean age of presentation was 7.1 months (range 2–11). It took average of 20 days between onset of symptoms and diagnosis of HLH. One infant had family history of two siblings dying with similar illness, and two had history of consanguinity in the parents. Five infants had recurrent respiratory tract infection; one had gastrointestinal tract involvement and one had liver abscess. Bleeding was evident in two at the time of presentation. Two had failure to thrive. Lymphadenopathy and skin involvement were not present in any infant. In view TABLE 1 Revised Diagnostic Guidelines for HLH3 The diagnosis HLH can be established if one of either 1 or 2 below is fulfilled (1) A molecular diagnosis consistent with HLH (2) Diagnostic criteria for HLH fulfilled (five out of the eight criteria below) (A) Initial diagnostic criteria (to be evaluated in all patients with HLH) • Fever • Splenomegaly • Cytopenias (affecting two of three lineages in the peripheral blood): Hemoglobin < 90 g/l (in infants < 4 weeks: hemoglobin C inherited from the mother). One had a homozygous stop mutation (c.528 529delinsAA; p.Cys176X) in PRF1 (his parents were heterozygous carriers for this mutation). Another had homozygous mutation in STX11 causative of FHL4. This mutation was a novel mutation, not described earlier with an aminoacid change from leucine to proline, p.Leu58Pro. (mother and the father had that mutation in a heterozygous form) EBV and cytomegalovirus are known triggering factors for HLH. Three patients had associated cytomegalovirus infection. All were treated as per HLH 2004 protocol [3]. Four patients died during induction phase due to their preexisting morbidities (gram negative sepsis and hemorrhage) or primary refractory disease in three. Two patients underwent allogeneic stem cell transplant (SCT) of whom one died. One patient abandoned therapy and one is still under treatment and due for his stem cell transplant. Transplant in Familial HLH Case 1: A 2-year-old male child was referred from Pakistan for unrelated stem cell transplantation (SCT) following the diagnosis of familial hemophagocytic lymphohistiocytosis (FHLH). He was symptomatic since the age of 2 months. He had no siblings and there was no history of consanguinity in the parents. He was diagnosed with HLH and received therapy as per HLH 2004 protocol in his home country. His genetic study showed homozygous mutation in STX11 gene. He underwent unrelated double cord blood transplant (CBT) at our center and was conditioned with campath (1 mg/kg from day −8 to day −4), fludarabine (150 mg/m2 from day −7 to −3), and melphalan (140 mg/m2 on day −2). Double CBT performed with one 5/6 and other 4/6 HLA matched units (details in Table 3). In India, we faced graft failure in first few unrelated cord transplants due to poor viability of cells in the single cord unit. So, to overcome this and to ensure quick engraftment, we opted for double cord transplant, which is not a norm or standard of care in the West. Cyclosporine and methyl prednisolone were used for GVHD prophylaxis. His neutrophils and platelets were engrafted on day +21 and day +31, respectively. FISH for XX/XY, on day +25, showed no XX suggestive of engraftment of 5/6 matched Cord A that was from a male. However, molecular chimerism studies could not be done. On day +40, routine CMV PCR showed reactivation with 9000 copies while on valganciclovir prophylaxis. By day +50, he developed diarrhea without any blood or mucus. He was started on intravenous ganciclovir. He responded well to this treatment. Steroids were tapered. On day +70, he had represented with low-grade fever and diarrhea. His sepsis workup and CMV were repeated all of which were negative. Endocsopic biopsy was suggestive of gut GVHD. Oral C Informa Healthcare USA, Inc. Copyright
2/M
7/M
11/F 9/F
6/M
10/M
4/M
4/M
1
2
3 4
5
6
7
8
Spleen
+
+
+ +
+
+
+
+
Fever
+
+
+ +
+
+
+
+
+
+
+
+
+ +
+
+
Cytopenia
1.3
1.2
2.0
1.0
2.0 2.6
2.9
1.0
Fib.
440
395
320
194
461 200
674
480
TG
649
22207
600
10922
1000 12600
552
11282
Ferritin
N
D
D
N
D N
N
N
LFT
+
−
−
+
+ +
+
+
HLH (B.M.)
−
−
−
−
Yes −
No
Yes
HSCT
Rab27
N.I
Not done
PERF-1
N.I N.I
MUNC13
STX 11
Mutation
Abandoned therapy
Alive
Alive
Died 6 months posttransplant due to Foscarnet induced renal failure Died at 1.5 months into therapy due to CNS involvement (seizures) Alive 2 years posttransplant Died at 1 month of therapy due to sepsis Alive after 6 months of therapy Abandoned after 1 month of therapy Died at 1 month into therapy due to sepsis Died at 1 month into therapy due to bleeding
Survival outcome
Age—in months, + present, − Absent, TG-Triglyceride in mg/dl, Ferritin in ng/ml, Fib.—Fibrinogen in g/dl, M-male, F-Female, HSCT-Hematopoeitic stem cell transplant, N.I—Not Identified, LTFU—Lost to Follow up, N—Normal, D—Deranged, B.M—Bone Marrow.
Age/Sex
SN
TABLE 2 Clinical and Lab Profile of Infants with HLH
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Outcome of HLH in Infants TABLE 3 Details of Two Infants with HLH Who Underwent Allogeneic Stem Cell Transplant Case 1
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Age at HSCT Sex Family history Mutation Type of transplant Cell dose
Conditioning
Engraftment of neutrophils Engraftment of platelets Complications Outcome
Case 2
2 years Male No STX 11 UCBT Cord A: 5/6 HLA match, sex male, blood group B+, nucleated cell dose was 62.4 × 107 Cord B : 4/6 HLA match, sex female, blood group O+, nucleated cell dose120.44 × 10 7 RIC with Campath (0.2 mg/kg/day from day −8 to −4), Fludarabine (30 mg/m2 /day from day −7 to −4), and Melphalan (140 mg/m2 on day −2) 21
11 months Female Yes Not identified MSD (brother) peripheral 6.9 × 106 /kg body weight of the recipient
31
26
Acute gut and skin GVHD, CMV, PRES Died at 4 months post-CBT due to foscarnet-induced renal failure
Acute gut GVHD, PTLD
RIC Fludarabine (30 mg/m2 /day from day −11 to −7), Melphalan (140 mg/m2 on day −6), and ATG (2.5 mg/kg/day from day −5 to −2) 22
Alive at 22 months post-BMT
FHLH: Famalial Hemophagocytic Lymphohistiocytosis, HSCT: Hematopoeitic Stem Cell Transplant, GVHD: Graft versus Host Disease, PRES: Posterior Reversible Encephalopathy Syndrome, PTLD: Posttransplant Lymphoproliferative Disorder, MSD: Matched Sibling Donor, UCBT: Unrelated Cord Blood Transplant, RIC: Reduced Intensity Conditioning, ATG: Antithymocyte globulin.
prednisolone was restarted at 1.5 mg/kg. By day +117, he had recurrence of loose stools, and his CMV copies had increased to 31,000. With TPN and IV Ganciclovir, he had dramatic reduction in the frequency of diarrhea with reduction in CMV copy number to 1660. Repeat CMV after a week showed 4000 copies, so he was continued with ganciclovir. He had two episodes of sudden onset of convulsions with loss of vision on day +147, which on evaluation was possibly secondary to hypertension with MRI neuroimaging findings, very much suggestive of PRES (posterior reversible encephalopathy syndrome). This patient improved over the next 48 hr without any further seizures, and his vision also fully recovered. Hypertension and seizures were managed accordingly. In the meantime, CMV copies had increased, so possible ganciclovir resistance was suspected and he was started on foscarnet. His condition became stable, and he was shifted back to his home country on the parents’ request. He died 1 week later in his home country, due to foscarnet-induced renal failure. Case 2: An 11-month-old female child who was referred to our center for matched sibling donor stem cell transplant for familial HLH. There was a history of the loss of previous two siblings at the age of 5 and 7 months, with similar illness. She had been treated for 40 weeks as per HLH 2004 Protocol in her home country. The results of genetic tests to diagnose familial HLH, showed no known mutation. She underwent matched sibling donor (MSD) bone marrow transplant at our center. She was given conditioning as mentioned in Table 3. COD cell count of the transfused peripheral blood was 6.9 × 106 /kg body weight of the recipient. Cyclosporine and methotrexate were used for GvHD prophylaxis. Her neutrophils and platelets engrafted on day C Informa Healthcare USA, Inc. Copyright
M. Ramzan et al.
+22 and day +26, respectively. On day +28, she developed diarrhea, gut biopsy confirmed acute GVHD and was managed accordingly. FISH for XX/XY showed 88% donor cells. On day +44, she had throat discomfort and developed enlarged tonsils with white patch 2 days later along with intermittent groaning. EBV copy numbers had increased to 72,000. Finally, diagnosed to have posttransplant lymphoproliferative disorder (PTLD). This responded well to Rituximab 375 mg/m2 per week for four doses. This child is off medication and doing fine at 22 months posttransplant.
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DISCUSSION All our patients had hyperinflammatory syndrome classically described to include the development of fever, splenomegaly, and cytopenias. We had mean serum ferritin levels of 7485 ng/ml (range: 552–22,207) in our patients, although levels over 10,000 mg/l have sensitivity and specificity of 90% and 96%, respectively, for diagnosis of HLH [4]. A recent study from India [5] showed that 36% patients had CNS symptoms at the time of presentation who were finally diagnosed to have HLH. However, none of our patients had CNS disease at the time of presentation. One of our patients had seizure during chemotherapy, possibly due to CNS involvement, who died at home subsequently. Joshi et al. [6] from India, had reported three patients of FHLH (mutation not mentioned). Two of them had low perforin level (0 and .05%). In another case series, [7] three infants were diagnosed to have FHLH on the basis of history of consanguinity and family history, but all died soon after diagnosis. So, diagnosing HLH is the first critical step toward successful therapy, but is challenging in the developing world, due to the rare occurrence, variable presentation, and nonspecific findings of this disorder. Donor search should begin at the time of diagnosis because time to transplant is a key factor in morbidity and mortality from HLH, even though the precise etiology (e.g., genetic defect) has not yet been defined. Generally, SCT is recommended in the case of documented familial HLH, recurrent or progressive disease despite intensive therapy, or CNS involvement [8]. Currently, the only cure for FHLH is allogeneic SCT. Over the past 10 years, several published series have documented the outcomes of patients with FHLH treated with allogeneic SCT after myeloablative conditioning (MAC) regimens, with overall long-term survival ranging from 45% to 65% [9–13]. In 2006, Cooper et al. reported improved survival with reduced-intensity conditioning (RIC), with a survival rate of 75% among a group of 12 patients with FHLH, XLP disease, and Chediak–Higashi syndrome [14]. A follow-up report with additional patients demonstrated survival of 84% with lower transplant-related mortality [15]. However, in 2010, Ohga et al. [13] noted no difference in survival between HLH patients treated at multiple institutions with RIC (n = 11) versus MAC (n = 31). Another study which compared MAC (n = 14) and RIC (n = 26) showed overall estimated 3-year survival of 92% for RIC patients and 43% for MAC patients (P
