This consensus applies to healthcare institutions at all levels for treating rare hematologic diseases. The target patient population includes individuals with rare hematologic diseases listed in the first Chinese list of rare diseases. The target healthcare professionals include physicians, pharmacists, nurses, other healthcare workers, and policymakers involved in managing rare diseases.

A nominal group technique was used to discuss a specific topic (off-label drug use in treating rare hematologic diseases) in an online conference format organized by an experienced facilitator and attended by 26 relevant experts. The consensus development process and reporting adhered to the World Health Organization Handbook for Guideline Development (2^nd edition) (Word Health Organization, 2014), the Statement of Reporting Items for Practice Guidelines in Healthcare (RIGHT) (Chen Y et al., 2017), and the specification of evidence-based pharmaceutical evaluation methods for off-label drug use (T/GDPA 1-2021, 2021, Guangdong Pharmaceutical Association) (The specification of evidence-base pharmaceutical evaluation method for off-label drug use, 2021). Conflicts of interest and disclosures were managed according to the Recommendations for the Conduct, Reporting, Editing, and Publication of Scholarly Work in Medical Journals of the International Committee of Medical Journal Editors.

The group members comprised experts from the following disciplines: hematologic medicine, clinical pharmacy, and pharmaceutical administration. The composition and positions of the panel members are shown in Supplementary Table S1.

The “Consensus” includes drugs commonly used off-label in treating rare hematologic diseases, presented in a tabular format for clarity and organized by therapeutic properties and application fields. The inclusion criteria for these drugs are based on the “2023 Guangdong Pharmaceutical Association Off-Label Drug Use Directory” (Guangdong Pharmaceutical Association, 2023), with adjustments for the unique aspects of rare disease medications: (1) included in package inserts from the United States, Europe, or Japan; (2) listed in the “Chinese Pharmacopoeia Clinical Medication Instructions” or “Clinical Diagnosis and Treatment Guidelines” (published by the Chinese Medical Association and People’s Medical Publishing House); (3) included in leading international and Chinese guidelines or consensus documents; (4) rated by Micromedex^® with an efficacy rating and recommendation level IIb or evidence level C or above; and (5) supported by published randomized controlled trial studies in first-quartile (Q1) SCI journals of the relevant field.

When Micromedex^® lacks evaluations for certain off-label drugs commonly used in rare diseases, the consensus adopts the Thomson Micromedex^® classification system standards to assess the efficacy, recommendation, and evidence levels of the included drugs, as described by the expert drafting group. Details of this classification system are provided in Supplementary Table S1.

After analyzing and summarizing the retrieved data, expert opinions were gathered through meetings and online consultations to supplement the evidence. Finally, the writing team prepared an evidence report, which was reviewed by the consensus conference.

The writing team developed recommendations based on the best available evidence. When direct supportive evidence was insufficient, expert clinical experience was collected online to supplement recommendations. After discussions of expert evidence, the team formulated an initial draft of the expert consensus. The guideline members provided feedback on recommendations and the expert consensus statement, ultimately establishing linguistic consensus.

The “Consensus” is structured in a tabular format to enhance clarity and conciseness. Each entry in the consensus table includes the following elements: “Generic Name,” specifying the drug’s official generic designation; “Dosage Form,” detailing the dosage form such as tablet or injection form; “Off-Label Type,” describing how the drug is used beyond its approved indications; “Off-Label Content,” providing specific details on the conditions or symptoms treated off-label; “Specific Usage,” outlining the dosage and administration details for off-label use; “Evidence and References,” including citations that support off-label use; and “Evidence Level,” indicating the grade or level of evidence supporting the drug’s efficacy and safety for off-label use.

Hemophilia, a rare X-linked recessive hereditary bleeding disorder, is categorized into Hemophilia A and Hemophilia B. Hemophilia A results from a deficiency of clotting factor VIII. At the same time, Hemophilia B is due to a deficiency of clotting factor IX, each due to mutations in their respective genes. The prevalence of hemophilia in China is approximately 2.73–3.09 per 100,000 (Xue and Yang, 2022). Primary treatment approaches include plasma-derived or recombinant clotting factor replacement, non-factor replacement, and gene therapy. However, there are no approved indications in the drug package inserts for immune tolerance therapy for Factor VIII inhibitors or the hemostatic treatment of low-titer Factor VIII inhibitors (Xue F, et al., 2023). Supplementary Table S2 presents the expert consensus on off-label drug use in the treatment of hemophilia.

Castleman’s disease (CD), or giant lymph node hyperplasia or angiofollicular lymph node hyperplasia, is a relatively rare lymphoproliferative disorder. The generally accepted pathogenic mechanisms of CD mainly involve cytokine interleukin-6 (IL-6), human herpesvirus 8 (HHV-8), and human immunodeficiency virus (HIV) infection. The incidence rate is approximately 0.2 per 10,000, although no data is available on the incidence of CD in China (Zhang L, et al. 2023). According to current guidelines and consensus, targeting IL-6 is the preferred first-line treatment for newly diagnosed idiopathic multicentric Castleman’s disease (iMCD). However, IL-6 targeted therapy is not universally effective, achieving an efficacy rate of only 34% in randomized controlled trials (RCTs). Siltuximab, the only IL-6-targeted drug approved in China for iMCD, is costly and increases the economic burden on patients. Additionally, drug-targeting pathways beyond IL-6 have yet to receive approval in China. Table 1 presents the expert consensus on off-label drug use to treat Castleman’s disease.

Erdheim-Chester disease (ECD) is a rare form of non-Langerhans cell histiocytosis known as lipid granulomatosis. This disease predominantly affects middle-aged and older individuals, with no marked gender differences in incidence rates. ECD can involve the skeletal system and multiple organs, most frequently affecting the diaphyseal and metaphyseal regions of the long bones, particularly in the lower extremities. Approximately 1,000 cases of ECD have been reported globally, yet comprehensive epidemiological data is lacking in China (Merai H, et al., 2020). There are no RCTs investigating treatments for ECD. Glucocorticoids and immunosuppressants have shown effectiveness in some cases. Additionally, BRAF inhibitors are applicable to patients with BRAF mutations, and other kinase inhibitors have also demonstrated efficacy in patients without such mutations. Interferon-alpha is commonly used to treat this condition, and recent studies highlight the potential of TNF-alpha antagonists, IL-6 antagonists, and IL-1 antagonists (Haroche J, et al., 2020). However, these therapeutic agents have not received approval for these specific indications. Table 2 presents the expert consensus on the off-label use of these drugs to treat ECD.

Fanconi anemia is a rare genetic blood disorder that predominantly manifests in childhood, with an incidence rate of approximately 1 in 136,000 (Che R, et al., 2018). Androgens have been found to improve blood cell counts in approximately 50% of affected patients. However, androgen treatments currently available in China lack approval for this specific therapeutic indication. Table 3 presents the expert consensus on the off-label use of androgen medications for Fanconi anemia.

Langerhans cell histiocytosis (LCH) is a group of histiocyte proliferative disorders characterized by an unknown etiology. It is traditionally categorized into three clinical types: Letterer-Siwe disease (L-S disease), Hand-Schüller-Christian disease (H-S-C disease), and eosinophilic granuloma (EGB), each marked by the pathological proliferation of Langerhans cells. The incidence rate among children is approximately 3–5 per million, whereas in adults, it is less than 1 to 2 cases per million (Baumgartner I, et al., 1997). There are no widely accepted treatment recommendations for adult patients. Recent advances in chemotherapy have significantly improved the prognosis of this disease. However, these chemotherapeutic agents have not received approval for the indication of LCH in China (Dai and Cao, 2023). Table 4 presents the expert consensus on the off-label use of drugs for LCH.

Paroxysmal nocturnal hemoglobinuria (PNH) is a disorder resulting from acquired mutations in the PIG-A gene of hematopoietic stem cells, which leads to increased sensitivity of blood cells to complement. This increased sensitivity causes intravascular hemolysis, thrombosis, and bone marrow failure. The annual global incidence rate of PNH is approximately 1–10 per million (Brodsky RA, 2014). The primary treatment for symptomatic management currently includes complement C5 inhibitors, such as eculizumab. However, there is still off-label use of other medications for the symptomatic treatment of PNH. Table 5 shows the expert consensus on the off-label drug use for PNH.

POEMS syndrome is a multisystem disorder associated with plasma cell disease, characterized clinically by polyneuropathy, organomegaly, endocrinopathy, monoclonal proteinemia, and skin changes. The prevalence rate is estimated to be approximately 0.3 per 100,000 (Soubrier MJ, et al., 1994; Li J, et al., 2011; Kulkarni et al., 2011), and as a group of clinical disorders attributable to plasma cell malignancies. To date, no RCTs have been reported for the treatment of POEMS syndrome, with treatment recommendations derived primarily from case reports. Table 6 presents the expert consensus on the off-label use of drugs to treat POEMS syndrome.

Porphyria includes a group of metabolic disorders resulting from abnormalities in the production and excretion of porphyrins, often influenced by genetic factors. In adults, the most common types are porphyria cutanea tarda, acute intermittent porphyria, and erythropoietic protoporphyria, with incidence rates varying between the different types. There is no epidemiological data available on the prevalence of these disorders in China (Chinese Society of HematologyRed Blood Cell Disease Study Group, 2020). Table 7 presents the expert consensus on the off-label use of drugs to treat porphyria.

Primary light chain amyloidosis is a systemic disease characterized by the deposition of monoclonal immunoglobulin light chains, which possess an antiparallel β-sheet structure in organ tissues, leading to organ dysfunction. The annual incidence rate is estimated to be between 3 and 5 per 1,000,000 people (Kyle RA, et al., 1992), with a higher prevalence observed in males than in females. The clinical manifestations are varied and may include foamy urine, shortness of breath following activity, edema, and discomfort in the liver area. Treatment options include hematopoietic stem cell transplantation, chemotherapy, and supportive care. Chemotherapy regimens commonly use agents such as bortezomib, melphalan, and immunomodulatory drugs (Hematology Oncology Committee of China Anti-Cancer Association, Leukemia & Lymphoma Group Society of Hematology at Chinese Medical Association, 2016). However, these therapeutic drugs have not yet received approval for these specific indications in China. Table 8 presents the expert consensus on the off-label use of drugs for primary light-chain amyloidosis.

Sickle cell anemia is a hereditary hemoglobinopathy characterized by substituting valine for glutamic acid at the sixth position of the β-globin chain, leading to the formation of sickle hemoglobin, which replaces normal hemoglobin. Clinically, it is associated with chronic hemolytic anemia, increased susceptibility to infections, and recurrent pain crises that cause chronic local ischemia and subsequent organ and tissue damage (Payne et al., 2020; Rees DC, et al., 2010). In China, the incidence of sickle cell anemia is relatively low, and specific prevalence data are not yet available. Treatment primarily involves blood transfusions and symptomatic drug therapy. The use of hydroxyurea and L-glutamine is currently off-label. Table 9 presents the expert consensus on the off-label use of drugs for sickle cell anemia.

Wiskott-Aldrich syndrome (WAS) is a rare X-linked recessive genetic disorder characterized by eczema, thrombocytopenia, and immune deficiency, accompanied by an increased risk of autoimmune diseases and malignant tumors. Clinically, WAS is relatively rare, with an estimated annual incidence rate ranging from 1 to 10 in 1,000,000 males and rarer in females (Massaad MJ, et al., 2013; Blundell MP, et al., 2010). Allogeneic hematopoietic stem cell transplantation is the only recognized effective treatment for WAS. Other symptomatic treatments used to manage the condition lack approved indications specifically for WAS. Table 10 presents the expert consensus on the off-label use of drugs for AWS.