The Histiocytosis Association of Canada is pleased to launch a new series titled “Ask a Histio Expert” where we speak with leading Canadian experts in various areas of histiocytosis and ask them questions about the latest in treatments and research updates. This week HAC spoke with Dr. Ahmed Naqvi, a hematologist/oncologist at Sick Kids Hospital in Toronto.
Dr Naqvi is a co-director of the Histiocytoses program at Sick Kids and is an active member of the Histiocyte Society (HS). HAC asked Dr. Naqvi to share his expertise in hemophagocytic lymphohistiocytosis (HLH), and we sincerely thank him for sharing his insights and time on this important topic, as well as his ongoing dedication to help families impacted by this group of disorders.
Have question for a histio expert? Contact us by visiting histiocytosis.ca/contact-us.
HAC: How has our understanding of HLH changed in the last 5 years?
Dr. Naqvi: The major focus has been to try and find newer, less toxic, and effective agents to use in patients with HLH in an attempt to acquire a good control of the disease prior to stem cell transplant.
While the commonly used “HLH-1994 protocol” is often very harsh and associated with various toxicities, new modalities like biologic agents, target chemicals known as cytokines. These cytokines are responsible for all the symptoms and organ damage seen in patients with HLH. Initial trials using some of these biologics have shown reasonably good results. In 2018, FDA approved one of the biologics known as emapalumab for the treatment of patients with primary HLH and those with refractory, recurrent, or progressive disease. A study for the same agent has just finished enrolment of newly diagnosed patients in addition to those with recurrent or refractory disease. The same agent is being tried for children with HLH secondary to rheumatologic disorders (also known as MAS). This therapy is undergoing review in Canada, and is not yet approved for use by Health Canada.
There have also been changes in the pre-transplant preparative regimens, known as conditioning. The regimens used in past were very intense, and resulted in a lot of side effects and toxicity. The current regimens are reduced in intensity and toxicity, leading to better survival outcomes.
HAC: Is it safe for people with HLH to get the COVID vaccine?
Dr. Naqvi: Yes, it is generally safe for people with HLH to get the vaccine. However those on active treatment, including ones who have received a stem cell transplant, should consult their physician to schedule it at an appropriate time. Be sure to speak with your doctor if you have any questions about the vaccine and how it relates to your condition.
HAC: Is there a clear difference between primary and secondary HLH and how they are treated?
Dr. Naqvi: Primary HLH is an inherited condition, mostly seen in early childhood and caused by various defects in some genes (i.e. mutations) and, therefore, is called familial HLH. Secondary HLH is seen in the presence of an underlying disorder, which could be an infection, malignancy, or an autoimmune stimulus.
Most of the time, at presentation, it is difficult to clearly differentiate between primary and secondary HLH. However certain features like age at presentation, consanguinity of parents, family history, and any associated disease can help in differentiation. There are certain laboratory features that can also help in differentiating the two but a final diagnosis of primary HLH can only be made after finding changes (mutations) in one of the known disease-causing genes.
The curative treatment for almost all cases of primary HLH is stem cell transplant. Secondary HLH in majority of the cases gets better when the underlying condition is treated. However some cases of secondary HLH require steroids for a short period of time. It is very rare that a case of secondary HLH is treated with intense primary HLH-like therapy.
The Histiocytosis Association of Canada is pleased to launch a new series titled “Ask a Histio Expert” where we speak with leading Canadian experts in various areas of histiocytosis and ask them questions about the latest in treatments and research updates.
Recently, HAC spoke with Dr. Oussama Abla, MD, Director of the Paediatric Histiocytosis Program, Division of Haematology/Oncology, at Sick Kids Hospital in Toronto. Dr. Abla is the current Chair of the International Rare Histiocytic Disorders Registry with the Histiocyte Society and is also the Canadian Coordinator of the LCH-IV International Trial with the Histiocyte Society. He graciously shared his expertise with us on LCH.
HAC sincerely thanks Dr. Abla for generously donating his time, and for his ongoing support and dedication for helping Canadians with LCH and other histiocytic disorders.
Have question for an expert? Contact us by visiting histiocytosis.ca/contact-us.
HAC: How has our understanding of LCH changed in the last few years?
Dr. Abla: Langerhans cell histiocytosis (LCH) was previously considered an inflammatory disease caused by a disrupted immune system. Currently, however, LCH is recognized as an inflammatory neoplastic disease, or a benign cancer, especially after the discovery of genomic mutations in the MAPK pathway in most cases.
The MPAK pathway is responsible for regulating cell differentiation and production, and it consists of many genomic steps including ARAF, BRAF, MAP2k1 and ERK genes. An activating mutation of any of these genes, particularly the BRAF-V600gene (present in 60% of LCH patients) can lead to the development of LCH in both children and adults.
These discoveries have led to the development of new targeted therapies including BRAF inhibitors, like dabrafenib and vemurafenib, and MEK inhibitors like cobimetinib and trametinib. These drugs are now being frequently used for patients with LCH who are resistant to first-line chemotherapy or those with relapsed disease (i.e. disease that has come back). These therapies have proven to be very effective in high-risk patients and much more tolerable than chemotherapy.
In addition, patients with LCH involving the brain who have neurodegeneration (CNS-ND) and whose prognosis used to be poor, tend to respond very rapidly to BARF and MEK inhibitors with an amazing improvement of their quality of life.
Future clinical trials in LCH will very likely include the combination of BRAF or MEK inhibitors with or without mild chemotherapy as front-line therapy for high-risk LCH patients. The timing of these trials and the optimal duration of these drugs are yet to be determined.
HAC: Is it safe for people with LCH to get the covid19 vaccine?
Dr. Abla: Yes. It is generally safe for patients with LCH to get the COVID-19 vaccine. We have given the vaccine to many children (aged 12 and older) with LCH who are off therapy, on chemotherapy, or on targeted inhibitor therapies and none of them has had any adverse reaction to mention. As always, we encourage you to speak with your doctor and care team beforehand, and to discuss any questions you may have.
HAC: How would someone go about participating in, or supporting, clinical trial initiatives in Canada?
Dr. Abla: In Canada, the LCH-IV global clinical trial for the treatment for Langerhans Cell Histiocytosis is currently open. It began in November 2019 (with Montreal Children’s Hospital opening the first Canadian site) and has since expanded to nine Canadian childhood cancer programs in Quebec, Ontario, British Columbia and Nova Scotia. The trial provided access to the latest treatment approaches for children with LCH in these provinces and is coordinated in part by the Histiocyte Society.
Canadian children with LCH may be eligible to participate at the LCH-IV Clinical treatment trial which is now open in most of the C17 centers (C17 is the national childhood cancer and blood diseases consortium representing all pediatric cancer programs across Canada).
In order to participate at this trial, parents can contact their closest pediatric tertiary oncology center, or connect with a trial coordinator by emailing us at firstname.lastname@example.org.
Individuals who are willing to support clinical trials initiatives in Canada can contact the Histiocytosis Association of Canada (HAC) by visiting their website histiocytosis.ca or email email@example.com directly.
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