HSCT of Greater Benefit to Children with Confirmed Familial HLH, Trial Finds

HSCT of Greater Benefit to Children with Confirmed Familial HLH, Trial Finds
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Overall five-year survival following hematopoietic stem cell transplant is higher among children with a confirmed diagnosis of familial hemophagocytic lymphohistiocytosis (HLH) than those lacking a confirmed diagnosis, a large clinical trial reported.

These results support the need for a thorough patient selection with pretransplant analyses, including confirmation of familial HLH, to avoid unnecessary risks, the researchers wrote.

Results were described in the study “Stem cell transplantation for children with hemophagocytic lymphohistiocytosis: results from the HLH-2004 study” published in the journal Blood Advances.

HLH is characterized by an overactive immune system. The condition is called primary HLH when is caused by genetic mutations. Familial HLH (FHL), the most common type of primary HLH, occurs when mutations affect one of four genes — PRF1, UNC13D, STX11, and STXBP2 — known to play a role in the controlling immune system activity.

Treatment for HLH aims to dampen the overactive immune system. Currently, hematopoietic stem cells transplant (HSCT) — cells that can form all types of blood cells in the body — remain the only effective cure for primary HLH and certain forms of secondary HLH.

HSCT is used to re-establish a healthy immune system, with the patient first undergoing chemotherapy to deplete the diseased blood cells followed by the transplant.

This treatment approach, which has led to a significant increase in patient’s survival, results from a series of collaborative international studies, including the HLH-94 study launched by the Histiocyte Society in 1994.

The HLH-94 protocol established that, before the transplant, patients undergo treatment for eight weeks with the chemotherapy agent etoposide and the corticosteroid dexamethasone, plus cyclosporin A (after week eight) for those with FHL or with persistent disease.

Patients with progressive neurological symptoms or abnormalities in the cerebrospinal fluid (CSF, the fluid surrounding the brain and spinal cord) are given the anti-inflammatory medication methotrexate injected directly into the spinal canal (intrathecal administration).

Following the HLH-94 study, the Histiocyte Society launched the international HLH-2004 study (NCT00426101) to further refine the initial treatment protocol.

Specifically, in the HLH-2004 study, cyclosporin A is administered from day one, and steroids are added to the intrathecal administration of methotrexate.

Researchers now reported the outcomes of 187 children in the HLH-2004 study. Of them, 134 had a confirmed FLH diagnosis; familial HLH status was not verified for the remaining 53.

Half of these children (91, corresponding to 49%) had their transplant before they were 1 year old, and 21 (11%) received the transplant by age of 6 or older. (Transplants in this study took place between Jan. 1, 2004, and Dec. 31, 2012.)

Overall, the median time to transplant was 148 days, and in 86% of the cases a transplant was performed within one year of the study’s start.

Among the 134 with confirmed FHL, the median time the transplant was 129 days. This time was significantly longer for children without verified FLH, given the transplant after a median of 190 days.

Seventy percent of children with confirmed FHL had their transplant within six months of the study’s start, in contrast to 47% of children without verified FLH.

Children without verified FLH were significantly older compared to those with confirmed FLH at the start of the treatment (median age of 441 vs. 103 days, or about 15 months old vs. 3.4 months), and at the time of the transplant (651 vs. 309 days, or about 21.7 months vs. 10.3 months).

While 58% of children with FLH (total of 78) had their transplant before reaching 1 year of age, this occurred in 25% (13 children) of those without verified FLH.

By Dec. 31, 2017 (data cut-off), a total of 120 children (64%) were alive. The overall survival after five years of the HSCT was 66%, and event-free survival (EFS) was 60%.

Five-year overall survival was significantly higher among children with confirmed FLH (71%) compared to those without verified FLH (52%). EFS was also higher in FLH children compared to those without it, 62% vs. 52%, but this difference was not statistically significant.

Girls with verified FLH had a significantly higher overall survival (75%) compared to girls without verified FLH (44%);  no significant differences were found for boys (61% vs. 66%).

Researchers noted that neither EFS nor overall survival were significantly influenced by the type of transplant donor — a matched unrelated donor, a matched-related donor, an umbilical cord blood donor, or others.

Of 150 children with information on day 100 post-transplant, 137 had a successful transplant procedure. Of these, 100 successful cases were among children with verified FHL (out of 107), and 37 among children with unverified FHL (out of 43).

Acute graft-versus-host disease (GVHD), moderate to severe, was reported in 31 children by 100 days post-transplant, and 21 had chronic GVHD lasting from one to five years after the transplant. Of note, GVHD occurs when immune cells from the donor are transplanted together with the stem cells, and view the recipient’s body as foreign and react against it.

Children achieving a complete response to HSCT — defined as blood levels of ferritin below 500 microgram/L — showed a higher five-year overall survival (81%) than those with a partial response (59%).

Twenty children, 18 with confirmed FHL, underwent a second HSCT. Ten of them were still alive after a minimum of three years of follow-up. Two children, both alive at the last follow-up, needed a third transplant.

In total, out of the initial 187 children, 67 died after the transplant — 43 with confirmed FHL and 24 without verified FHL. The majority (87%) died during the first year, 54% within 100 days, six between the second and third year, and three after five years post-transplant.

More than half (36 children, 54%) died due to transplant-related mortality, and 18 (27%) due to HLH relapse. Children without verified HLH were more likely to die from an HLH relapse than those with verified HLH.

Based on the results, the researchers concluded that “post-HSCT survival in FHL remains suboptimal,” as the five-year overall survival of 66% “reported here was not better than the 64% reported in HLH-94,” they wrote.

Nonetheless, the team is “optimistic that post-HSCT survival in FHL can be improved.”

Given that patients whose FHL is not officially diagnosed seem to do worse than those with verified FHL, “a thorough patient selection with pretransplant analyses, including confirmation of FHL, is recommended,” the team wrote.

Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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Patrícia holds her PhD in Medical Microbiology and Infectious Diseases from the Leiden University Medical Center in Leiden, The Netherlands. She has studied Applied Biology at Universidade do Minho and was a postdoctoral research fellow at Instituto de Medicina Molecular in Lisbon, Portugal. Her work has been focused on molecular genetic traits of infectious agents such as viruses and parasites.
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Patricia holds her Ph.D. in Cell Biology from University Nova de Lisboa, and has served as an author on several research projects and fellowships, as well as major grant applications for European Agencies. She also served as a PhD student research assistant in the Laboratory of Doctor David A. Fidock, Department of Microbiology & Immunology, Columbia University, New York.
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